Synthesis of halichondrin

Abstract

To provide methods for synthesis of ketones involving a Ni / Zr-mediated coupling reaction.SOLUTION: The Ni / Zr-mediated ketolization reaction can be used in the synthesis of halichondrins and analogs thereof. Therefore, the present invention also provides synthetic methods useful for synthesis of halichondrins and analogs thereof. Also provided herein are compounds (i.e., intermediates) useful in the synthesis of halichondrins and analogs thereof. In particular, the present invention provides methods and compounds useful in the synthesis of compounds of Formula (H3-A).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. (USSN) 62 / 529,333, filed July 6, 2017; and U.S.SN 62 / 529,310, filed July 6, 2017; the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Background of the Invention Halichondrins are polyether natural products originally isolated by Uemura, Hirata, and coworkers from the marine scavenger Halichondria okadai. See, for example, Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.; Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am. Chem. Soc. 1985, 107, 4796; Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701. Several additional members, including halistatins, have been isolated from various marine scavenger species. Natural products in this class exhibit interesting structural diversity, including the oxidation state of carbons in the C8–C14 polycycle and the length of the carbon backbone. Thus, this class of natural products is sub-grouped into the norhalichondrin series (e.g., norhalichondrin A, B, and C), the halichondrin series (e.g., halichondrin A, B, C), and the homohalichondrin series (e.g., homohalichondrin A, B, C) (see Figure 1). All members except halichondrin A have been isolated from natural sources. Due to their fascinating structural architecture and exceptional antitumor activity, halichondrins have attracted considerable attention from the scientific community. Summary of the Invention

[0003] SUMMARY OF THE INVENTION The present invention provides new synthetic methods useful in the synthesis of halichondrin natural products and related molecules. As described herein, a novel nickel / zirconium-mediated coupling reaction has been developed as a key step in the synthesis. In addition to the synthetic methods, the present invention also provides compounds that are useful synthetic intermediates in the synthesis of halichondrin natural products and their analogs.

[0004] For example, in some embodiments, provided herein is compound (1): [ka] Compound (1) The present invention relates to compounds and methods useful in the synthesis of

[0005] In one aspect, the present invention provides methods for preparing ketones using Ni / Zr-mediated coupling reactions, as outlined in Scheme 1 A. These coupling reactions can be applied to the synthesis of halichondrins (e.g., halichondrins A, B, C; homohalichondrins A, B, C; norhalichondrins A, B, C) and their analogs. Scheme 1A [ka]

[0006] The application of the Ni / Zr-mediated coupling reaction provided herein to the preparation of compounds in the halichondrin system (e.g., halichondrin A, B, C, and their analogs) is outlined, for example, in Scheme 2A. This strategy involves coupling a "left-half" building block with a "right-half" building block via a Ni / Zr-mediated ketolization reaction described herein. Scheme 2A [ka]

[0007] The application of the Ni / Zr-mediated coupling reaction provided herein to the preparation of compounds in the homohalichondrin system (e.g., homohalichondrin A, B, C, and their analogs) is outlined, for example, in Scheme 2B. This strategy involves coupling a "left-half" building block with a "right-half" building block via a Ni / Zr-mediated ketolization reaction described herein. Scheme 2B [ka]

[0008] The application of the Ni / Zr-mediated coupling reaction provided herein to the preparation of compounds in the norhalichondrin system (e.g., norhalichondrin A, B, C, and their analogs) is outlined, for example, in Scheme 2C. This strategy involves coupling a "left-half" building block with a "right-half" building block via a Ni / Zr-mediated ketolization reaction described herein. Scheme 2C [ka]

[0009] The application of the Ni / Zr-mediated coupling reactions provided herein to the preparation of additional halichondrin analogs is outlined, for example, in Scheme 2D. This strategy involves coupling a "left-half" building block with a "right-half" building block via a Ni / Zr-mediated ketolization reaction described herein. Scheme 2D [ka]

[0010] In general, the provided methods for the preparation of halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C) and their analogs involve coupling a "left half" fragment with a "right half" fragment. In another aspect, the invention provides methods useful in the preparation of the "right half" and "left half" building blocks.

[0011] In another aspect, the present invention provides compounds that are useful intermediates en route to halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C), and analogs thereof. For example, in one aspect, the present invention provides novel "left half" and "right half" building blocks of halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C), and analogs thereof, and intermediates useful in the preparation of said building blocks.

[0012] In another aspect, the present invention provides methods useful in the preparation of halichondrin analogs, particularly in the preparation of compound 1. The present invention also provides compounds (i.e., synthetic intermediates) useful in the synthesis of compound 1.

[0013] In one aspect, the present invention provides a method for preparing compound (1) that involves replacing a primary hydroxyl group (—OH; indicated by * in Scheme 1) of compound (2) with an amino group (—NH). The replacement may be carried out in one or more steps. For example, the replacement may be carried out by replacing the primary hydroxyl group of compound (2) with a leaving group (e.g., —OR 1 ), followed by displacement of the leaving group with an amine or amine precursor (e.g., an azide). Scheme 1 [ka]

[0014] Current methods for the synthesis of halichondrins can be found, for example, in International PCT Publications WO 2016 / 176560, published November 3, 2016, and WO 2016 / 003975, published January 7, 2016; the entire contents of each of which are incorporated herein by reference.

[0015] Other current methods for the synthesis of halichondrins can be found, for example, in U.S. Pat. No. 9,938,288, issued April 10, 2018; U.S. Provisional Patent Application No. (USSN) 62 / 586,416, filed November 15, 2017; International Application No. PCT / US2018 / 031765, filed May 9, 2018; and U.S. Patent Application Publication No. US 2018 / 0155361, published June 7, 2018; the entire contents of each of which are incorporated herein by reference.

[0016] The details of certain embodiments of the present invention are set forth in the Detailed Description of Certain Embodiments, as set forth below. Other features, objects, and advantages of the present invention will be apparent from the definition, examples, figures, and claims.

[0017] definition The definitions of specific functional groups and chemical terms are described in more detail below.Chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition (inside cover), and specific functional groups are generally defined as described therein.In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989;and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0018] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725(1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0019] Unless so stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium; 19 F 18 Replace with F, or 12 C 13 C or 14Compounds having this structure, except for the replacement with C, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0020] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 is intended to cover alkyls of the formula:

[0021] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0022] The term "alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C 1~10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1~5In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless so specified, each occurrence of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents (e.g., halogens such as F) (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (unsubstituted C 1~6 Alkyl, for example, -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, for example, unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is substituted C 1~12 Alkyl (substituted C 1~6 alkyl, for example, -CF3, Bn).

[0023] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1~2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0024] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (interposed between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and one or more heteroatoms within the parent chain ("heteroC 1~10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~9 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~8 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~7In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~5 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~3 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2 In some embodiments, heteroalkyl refers to saturated groups having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, heteroalkyl refers to saturated groups having two to six carbon atoms and one or two heteroatoms in the parent chain ("heteroC 2~6 Unless so specified, each occurrence of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In some embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0025] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless so specified, each occurrence of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In some embodiments, the alkenyl group is a substituted C 2~10 Alkenyl. In alkenyl groups, the stereochemistry of the C=C double bond is not specified (e.g., -CH=CHCH3, or [ka] may be an (E)- or (Z)-double bond.

[0026] The term "heteroalkenyl" refers to an alkenyl group that further contains at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (interposed between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl"). 2~10 In some embodiments, a heteroalkenyl group refers to a group having 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In some embodiments, a heteroalkenyl group refers to a group having 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~8 In some embodiments, a heteroalkenyl group refers to a group having 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, a heteroalkenyl group refers to a group having 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In some embodiments, a heteroalkenyl group refers to a group having 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, a heteroalkenyl group refers to a group having 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, a heteroalkenyl group refers to a group having 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2~3 alkenyl). In some embodiments, a heteroalkenyl group refers to a group having 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless so specified, each occurrence of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In some embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0027] The term "alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2~4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkynyl groups include pentynyl (C), hexynyl (C), and the like. Additional examples of alkynyl include heptynyl (C), octynyl (C), and the like. Unless so specified, each occurrence of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In some embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0028] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (interposed between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 2~10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC2~6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2~3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless so specified, each occurrence of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In some embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0029] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms and zero heteroatoms in its non-aromatic ring system ("C 3~14 In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. Exemplary C 3~8 The carbocyclyl group may be any of the aforementioned C 3~6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group may be any of the aforementioned C 3~8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (containing, for example, fused, bridged, or spiro ring systems such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), and can be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring is fused to one or more aryl or heteroaryl groups, as defined above (where the point of attachment is on the carbocyclyl ring; in such instances, the number of carbons designates the number of carbons in the carbocyclic ring system throughout). Unless so specified, each occurrence of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 3~14 In some embodiments, the carbocyclyl group is a substituted C 3~14 It is a carbocyclyl.

[0030] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3~14 In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups are the aforementioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups are the aforementioned C 3~6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless so specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~14 In some embodiments, the cycloalkyl group is a substituted C 3~14 It is cycloalkyl.

[0031] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl"). Heterocyclyl groups can be saturated or contain one or more carbon-carbon double or triple bonds. Polycyclic ring systems of heterocyclyls may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring is fused with one or more carbocyclyl groups, as defined above (where the point of attachment is on either the carbocyclyl ring or the heterocyclyl ring), or ring systems in which the heterocyclyl ring is fused with one or more aryl or heteroaryl groups, as defined above (where the point of attachment is on the heterocyclyl ring); in such instances, the number of ring members designates the number of ring members in the heterocyclyl ring system throughout. Unless so specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In some embodiments, the heterocyclyl is a substituted 3- to 14-membered heterocyclyl.

[0032] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-6 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, 5-6 membered heterocyclyls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0033] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diphenylmethyl ... azepinyl, 1,4,5,7-tetrahydropyran o[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0034] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms ("C") provided in the aromatic ring system. 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; for example, anthracyl). "Aryl" also encompasses ring systems in which an aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms designates the number of carbon atoms in the aryl ring system throughout. Unless so specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In some embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0035] The term "heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array), having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Polycyclic ring systems of heteroaryls can include one or more heteroatoms in one or both rings. "Heteroaryl" encompasses ring systems in which a heteroaryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members designates the number of ring members throughout the heteroaryl ring system. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring is fused with one or more aryl groups, as defined above, where the point of attachment is on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in a fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, for example, on the ring bearing a heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0036] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having provided ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having provided ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having provided ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless so specified, each occurrence of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In some embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0037] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0038] The term "unsaturated bond" refers to a double or triple bond.

[0039] The terms "unsaturated" or "partially unsaturated" refer to a moiety that includes at least one double or triple bond.

[0040] The term "saturated" refers to a moiety that contains no double or triple bonds, i.e., only single bonds.

[0041] The addition of the suffix "-ene" to a group indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0042] Groups may be optionally substituted (are optionally substituted) unless expressly provided as such. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted (are optionally substituted). "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" heteroalkyl group, a "substituted" or "unsubstituted" heteroalkenyl group, a "substituted" or "unsubstituted" heteroalkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with a permissible substituent (e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction). Unless so indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to encompass substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that result in the formation of stable compounds. The present invention contemplates any and all such combinations in order to arrive at stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. It is not intended that the present invention be limited in any way by the exemplary substituents described herein.

[0043] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)Raa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(OR cc )2、-P(R cc )3 + X - 、-P(OR cc )3 + X - 、-P(R cc )4、-P(OR cc )4、-OP(R cc )2、-OP(R cc )3 + X - 、-OP(OR cc )2、-OP(OR cc )3 + X - 、-OP(R cc )4、-OP(OR cc )4、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc )、C 1~10 アルキル、C 1~10 ペルハロアルキル、C2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; where X - is the counterion; Alternatively, two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc has been replaced by; R aa Each occurrence of C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R aaThe groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R bbThe groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; where X - is the counterion; R cc Each occurrence of is independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R cc The groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2Ree , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg group or two geminal R dd The substituents may be joined to form =O or =S; where X - is the counterion; R ee Each occurrence of C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ffThe groups are joined to form a 3- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; and R gg Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2(C 1~6 alkyl), -SO2O(C 1~6 alkyl), -OSO2(C 1~6 alkyl), -SO(C 1~6 alkyl), -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6アル Kinir, C. 3~10 Carbocyclyl, C 6~10aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be joined to form =O or =S; where X - is the counter ion.

[0044] In certain embodiments, carbon atom substituents include: halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2(C 1~6 alkyl), -SO2O(C 1~6 alkyl), -OSO2(C 1~6 alkyl), -SO(C 1~6 alkyl), -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R ggThe substituents may be joined to form =O or =S; where X - is the counter ion.

[0045] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0046] The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxy", by extension, refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb )2)2), where X - , R aa , R bb , and R cc is as defined herein.

[0047] The term "amino" refers to the group -NH. The term "substituted amino" by extension refers to a mono-, di-, or tri-substituted amino. In some embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0048] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, and includes -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2, and -NHP(=O)(N(R bb )2)2)2, where R aa , R bb and R cc is as defined herein, and wherein the group —NH(R bb )R bb is not hydrogen.

[0049] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, -N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2, and -NR bb P(=O)(N(R bb )2)2)2, where R aa , R bb , and Rcc is as defined herein, except that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0050] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, -N(R bb )3 and -N(R bb )3 + X - wherein R bb and X - is as defined herein.

[0051] The term "sulfonyl" refers to -SO2N(R bb )2, -SO2R aa , and -SO2OR aa where R aa and R bb is as defined herein.

[0052] The term "sulfinyl" refers to the group -S(=O)R aa where R aa is as defined herein.

[0053] The term "acyl" refers to a group having the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)O(R X1 ), -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , and -C(=NR X1 )N(R X1)2, where R X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted or two R taken together are heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R taken together are X1The groups form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may or may not be further substituted).

[0054] The term "carbonyl" refers to the carbon directly attached to the parent molecule being sp 2 refers to a group that is hybridized and is substituted with an oxygen atom, nitrogen atom, or sulfur atom, such as a ketone (e.g., -C(=O)R aa ), carboxylic acids (e.g., -CO2H), aldehydes (-CHO), esters (e.g., -CO2R aa , -C(=O)SR aa , -C(=S)SR aa ), amides (e.g., -C(=O)N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2), and imines (e.g., -C(=NR bb )R aa , -C(=NR bb ) OR aa ), -C(=NR bb )N(R bb ) 2) wherein Raa and R bb is as defined herein.

[0055] The term "silyl" refers to the group -Si(R aa )3, where R aa is as defined herein.

[0056] The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

[0057] Nitrogen atoms can be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C6~14 aryl, and 5- to 14-membered heteroaryl, or two R attached to the N atom cc The groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group, and wherein R aa , R bb , R cc , and R dd is as defined above.

[0058] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to herein as an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc , and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0059] For example, a nitrogen protecting group such as an amide group (e.g., —C(═O)R aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (Ν'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamic acid amide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0060] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Troc), 2-trimethylcarbamate (Tm ... Tylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-B umeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate , alkyldithiocarbamates, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitribenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonyl Methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxy Cetiacilvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isoborynylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate , 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

[0061] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)R aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide amide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0062] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacylate Clopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)-2-methylpropanol ) amines, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1, 1-Dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In some embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0063] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NRbb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, where X - , R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0064] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl, and the like. methyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl] [Chemical]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloro ethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl bis(4',4''-dimethoxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IP DMS), diethylisopropylsilyl (DEIPS), dimethyl-t-hexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formic acid, benzoyl formate, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, methoxyacetic acid, triphenylmethoxyacetic acid, phenoxyacetic acid, p-Chlorophenoxyacetic acid, 3-phenylpropionic acid, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonic acid, 4-methoxycrotonic acid, benzoic acid, p-phenylbenzoic acid, 2,4,6-trimethylbenzoic acid (mesitoic acid), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoic acid, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoic acid, Included are 2-formylbenzenesulfonic acid, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyric acid, 2-(methylthiomethoxymethyl)benzoic acid, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, chlorodiphenylacetic acid, isobutyric acid, monosuccinoate, (E)-2-methyl-2-butenoic acid, o-(methoxyacyl)benzoic acid, α-naphthoic acid, nitric acid, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, boric acid, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenic acid, sulfuric acid, methanesulfonic acid (mesylate), benzylsulfonic acid, and tosylic acid (Ts). In some embodiments, the oxygen protecting group is silyl. In some embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB, MPM), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0065] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, where R aa , R bb , and R ccis as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. In certain embodiments, the sulfur protecting group is acetamidomethyl, t-butyl, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl.

[0066] A "counterion" or "anionic counterion" is a negatively charged group attached to a positively charged group to maintain electronic neutrality. Anionic counterions can be monovalent (i.e., contain one formal negative charge). Anionic counterions can also be multivalent (i.e., contain more than one formal negative charge), such as divalent or trivalent. Exemplary counterions are halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, etc.), carboxylate ions (e.g., acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4- , BPh4 - , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylic acid, phthalic acid, aspartic acid, glutamic acid, etc.), and carboranes.

[0067] The term "leaving group" is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or group displaceable by a nucleophile. See, e.g., Smith, March, Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonate ester such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate such as 2-nitrobenzenesulfonyloxy. The leaving group may also be a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., —OC(═O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) ORaa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2, and -OP(=O)(NR bb )2, where R aa , R bb , and R cc is as defined herein).

[0068] As used herein, use of the phrase "at least one instance" refers to one, two, three, four, or more instances, but also, by way of example, covers ranges such as one to four, one to three, one to two, two to four, two to three, or three to four instances (inclusive).

[0069] A "non-hydrogen group" refers to any group defined for a specific variable that is not hydrogen.

[0070] The following definitions are of more general terms used throughout this application.

[0071] As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic reaction, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and the like. Examples of the salts include phonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0072] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0073] Stereoisomers that are not mirror images of one another are termed "diastereomers," and those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, when the compound is bonded to four different groups, paired enantiomers are possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R- and S-ordering rules of Cahn and Prelog, or by the way the molecule rotates plane-polarized light and is designated as dextrorotatory or levorotatory (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0074] The term "small molecule" refers to a molecule, naturally occurring or artificially created (e.g., via chemical synthesis), that has a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). A small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is about 1,000 g / mol or less, about 900 g / mol or less, about 800 g / mol or less, about 700 g / mol or less, about 600 g / mol or less, about 500 g / mol or less, about 400 g / mol or less, about 300 g / mol or less, about 200 g / mol or less, or about 100 g / mol or less. In some embodiments, the molecular weight of the small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and up to about 500 g / mol) are also possible. In some embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR)).

[0075] The terms "catalysis," "catalyze," or "catalytic" refer to an increase in the rate of a chemical reaction due to the addition of a substance called a "catalyst." In some embodiments, the amount and properties of the catalyst remain essentially unchanged during the reaction. In some embodiments, the catalyst is regenerated, or the properties of the catalyst are essentially restored after the reaction. A catalyst may participate in multiple chemical transformations. The effectiveness of a catalyst may vary due to the presence of other substances known as inhibitors or poisons (which reduce catalytic activity) or promoters (which increase its activity). A catalyzed reaction has a lower activation energy (rate-limiting free energy of activation) than the corresponding uncatalyzed reaction, resulting in a higher reaction rate at the same temperature. A catalyst may favorably influence the reaction environment, bind to a reagent to polarize bonds, form specific intermediates not typically produced by uncatalyzed reactions, or cause dissociation of a reagent to its reactive form.

[0076] The term "solvent" refers to a substance that dissolves one or more solutes, resulting in a solution. A solvent may serve as a medium for any of the reactions or transformations described herein. A solvent may dissolve one or more reactants or reagents in a reaction mixture. A solvent may facilitate mixing of one or more reagents or reactants in a reaction mixture. A solvent may also serve to increase or decrease the rate of a reaction compared to a reaction in a different solvent. A solvent may be polar or nonpolar, protic or aprotic. Common organic solvents useful in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide, carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide, N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethyl ether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glycol, dimethyl ether, heptane, n-hexane, hexane Examples of suitable solvents include ethanol, hexamethylphosphoramide (HMPA), 2-methoxyethanol, 2-methoxyethyl acetate, methyl alcohol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide (DMSO), nitromethane, 1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine, tetrachloroethylene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane, 2,2,4-trimethylpentane, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, and p-xylene. [Brief explanation of the drawings]

[0077] Brief description of the drawings The accompanying drawings, which form a part of this specification, illustrate several aspects of the invention and, together with the description, serve to explain the principles of the invention.

[0078] [Figure 1] FIG. 1 shows the structures of halichondrins A, B, and C; homohalichondrins A, B, and C; and norhalichondrins A, B, and C.

[0079] [Figure 2A-C] Figure 2A shows an example of Ni / Zr-mediated ketolization. Figure 2B shows an example of Ni-catalyzed ketone coupling. Figure 2C shows a feasibility study of three variations of Ni-mediated one-pot ketone coupling.

[0080] [Figure 3A-B] Figure 3A shows the proposed catalytic circuit for Ni / Zr-mediated ketolization provided herein, and Figure 3B shows an exemplary coupling with a general radical probe.

[0081] [Figure 4] Figure 4 shows the one-pot ketone coupling with α-OR and other functionalized nucleophiles. Reaction conditions: 1-5 (1.0 equiv.), 1-7 (1.2 equiv.), NiBr₂(dtbbpy) (5 mol%).

[0082] [Figure 5A] FIG. 5A shows an example of a Ni / Zr ketolization reaction. [Figure 5B] FIG. 5B shows a further example.

[0083] [Figure 5C-D] Figure 5C shows the results of a nickel ligand screening experiment, and Figure 5D shows a comparison experiment of NiBr2, NiCl2, and NiI2. [Figure 5E]FIG. 5E shows the results of a solvent screening experiment. [Figure 5F-G] Figure 5F shows the results of a co-solvent screening experiment, and Figure 5G shows an additive screening experiment. [Figure 5H-J] Figure 5H shows a screen for zirconium equivalents, Figure 5I shows studies with various electrophiles, and Figure 5J shows a reducing reagent screening experiment. [Figure 5K-L] Figure 5K shows a concentration study, and Figure 5L shows a substrate ratio experiment.

[0084] [Figure 6] FIG. 6 shows potential routes to halichondrins and their analogs.

[0085] [Figure 7] Figure 7 shows the Ni / Zr ketolization provided herein applied to the synthesis of halichondrin analogs. Reagents and conditions: (a) 2-5 (1.0 equiv.), 2-6 (1.3 equiv.), NiBr₂·(dtbbpy) (30 mol%), Cp₂ZrCl₂ (3 equiv.), (t-Bu)₂(Me)Py (4 equiv.), Zn (6 equiv.) in 5:1 DMI-EtOAc (0.1 M C), rt. (b) HF·Py (20 equiv.), THF, followed by TBAF (4 equiv.), pivalic acid (2 equiv.), DMF, rt. (c) PPTS (5 equiv.), CHCl₂, ∼20 °C, 2 hr. Abbreviations: TES = Et3Si-; SPy-2: 2-thiopyridine; DMI: 1,3-dimethyl-2-imidazolidinone; TBAF: tetrabutylammonium fluoride; PPTS: pyridinium p-toluenesulfonate.

[0086] [Figure 8A-B]Figure 8A shows exemplary right and left halves of halichondrin, homohalichondrin, and norhalichondrin. Figure 8B shows an exemplary synthesis of halichondrin. Reagents and conditions: In all cases, step 1 was a ketone coupling under the conditions specified in Scheme 3; step 2 was TBAF (10 equiv.), pivalic acid (5 equiv.), DMF, rt, 3-8 hr; step 3 was PPTS, CHCl, ∼20 °C, 2-4 hr. Epimerization of C38-epi-halichondrin was achieved using TMSOTf, CHCl, ∼78 °C. For halichondrin-A or -C systems, these steps were followed, respectively, by PPTS, 2,2-dimethylpropane-1,3-diol, i-PrOH, rt, overnight, or Pd(PPh) , dimedone, CHCl, rt, 4-8 hr. In the norhalichondrin series, at the end of the transformation, the methyl ester was hydrolyzed on C53 by treatment with aq. LiOH, THF, rt. The numbers after i and ii indicate the yield of the ketone coupling and the total yield after the ketone coupling, respectively.

[0087] [Figure 9A-B]Figure 9A shows an exemplary synthesis of the C27-C37 building blocks. Reagents and conditions: a.1. LiBH4, Et2O, 0 °C (~100%). 2. TES-Cl, imidazole, CH2Cl2, rt (~100%). 3. Swern oxidation (see, for example, Rodriguez, A.; Nomen, M.; Spur, B.W.; Godfroid, J.J. Tetrahedron Lett. 1999, 40, 5161); b. 1. Cr catalyst (10 mol%) prepared from (S)-4-E, (Me)2Phen-(OMe)2·NiCl2 (2 mol%), LiCl (2 equiv.), Mn (excess), Cp2ZrCl2 (1.1 equiv.), 2,6-lutidine (1 equiv.), MeCN (C 0.4 M), rt, 1 h (93%, 2 steps; dr = 19:1); 2. MPMO(=NH)CCl3, La(OTf)3, toluene, rt, 6 h; 3. p-TsOH (cat.), MeOH-CH2Cl2, rt, 4 h (88%, 2 steps). c.1. K3PO4 (1 equiv.), 18-crown-6 (3 equiv.), toluene (79%). 2. DIBAL, CHCl2, −78° C., 1.5 h (94%). Abbreviations: 18-crown-6 = 1,4,7,10,13,16-hexa-oxacyclooctadecene; DIBAL = diisobutylaluminum hydride; p-TsOH = p-toluenesulfonic acid. Figure 9B shows exemplary sulfonamide ligands and nickel complexes useful in the Ni / Cr coupling reactions provided herein.

[0088] [Figure 10A-B]Figure 10A shows an exemplary synthesis of C20–C37 building blocks. Reagents and conditions: a. 1. Cr catalyst (10 mol%) prepared from (R)-4-F, (Et)2Phen·NiCl2 (2 mol%), LiCl (2 equiv.), Mn (excess), Cp2ZrCl2 (1 equiv.), MeCN (C 0.3 M), rt, 3 h. 2. TBAF (2 equiv.), AcOH (0.6 equiv.), THF, 0 °C → rt (79%, 2 steps). 3. TES-H (10 equiv.), TEOTf (5 equiv.), CHCl2, 0 °C, 3 h (87%). 4. 2,2-Dimethoxypropane (3 equiv.), acetone, 0 °C → rt. b. DIBAL, CHCl2, −78 °C, 1.5 h (89%, 2 steps). Abbreviations: MPM = p-MeOC6H4CH2-; TES = Et3Si-. Figure 10B shows the reductive cyclization: analysis of the stereochemical pathways of the desired and undesired systems.

[0089] [Figure 11]Figure 11 shows an exemplary synthesis of C1-C37 building blocks in the halichondrin B series. Reagents and conditions: a.1. Cr catalyst prepared from (S)-4-G (10 mol%), (Et)Phen·NiCl (2 mol%), LiCl (2 equiv.), Mn (excess), ZrCpCl (2.5 equiv.), 2,6-di-t-butyl-4-methylidine (2.5 equiv.), MeCN (C 0.05 M), rt, 2 h. 2. KCO (10 equiv.), 60 °C, 16 h, then HO (1 / 10 volume of MeOH) was added and 60 °C, 3 h. b. 2-Methyl-6-nitrobenzoic anhydride (6 equiv.), 4-dimethylaminopyridine (12 equiv.), i-PrNEt (6 equiv.), toluene, 70 °C (syringe pump; 73%, 3 min steps). c. 1. p-TsOH, MeOH, rt, 1 h. 2. TfO (1.2 equiv.), 2,6-lutidine (5 equiv.), CHCl, -78 °C, 15 min, followed by addition of TESOTf (1.5 equiv.), -78 °C → 0 °C, then addition of NaI (5 equiv.) in DMF, rt, 2.5 h (94%, multiple min steps). Abbreviations: TES = EtSi; p-TsOH = p-toluenesulfonic acid.

[0090] [Figure 12] FIG. 12 shows the X-ray structure of the C35 / C37-diol of 4-10-B.

[0091] [Figure 13]Figure 13 shows an exemplary synthesis of the C1-C37 building blocks in the halichondrin A system. Reagents and conditions: a.1. Ac2O, py, rt; 2. CSA, CHCl2-MeOH, rt; 3. TBSOTf, 2,6-lutidine, CHCl2, -78 °C, 1 h (92%, 3 steps); 4. DIBAL, CHCl2, -78 °C, 1 h (88%). The synthetic sequence follows the conditions defined in Figure 11, except that (Me)6PhenNiCl2 (2 mol%) was used for the Ni / Cr-mediated coupling. The overall yield from bis-TBS-4-8 to 4-12-A was 40.8%, which compares favorably with the overall yield in the halichondrin B system. Abbreviations: TBS = tBuMe2Si-; CSA = camphorsulfonic acid.

[0092] [Figure 14A-B] Figure 14A shows an exemplary synthesis of the C1-C37 building blocks in the halichondrin C series. Reagents and conditions: a. Following the synthetic sequence under the conditions defined in Figure 11. The overall yield from 4-8 to 4-12-C was 54.2%, which compares favorably with the overall yield in the halichondrin B series. Figure 14B shows the X-ray structure of the product.

[0093] [Figure 15] Figure 15 shows an exemplary synthesis of a stereocontrolled [6,6]-spiroketal. Abbreviations: MPM = p-MeOC6H4CH2-.

[0094] [Figure 16]Figure 16 shows an exemplary synthesis of the left half of a halichondrin analog. Reagents and conditions: a.1. TBSOTf (2.5 equiv.), EtN (5 equiv.), CHCl, 0 °C to rt, 3 h. 2. NHCl aq., EtOAc, THF, 50 °C, 3 h (100%, 2 steps). b.1. DIBAL (1.3 equiv.), CHCl, -78 °C, 40 min. 2. MePPhBr (4 equiv.), t-BuOK (3 equiv.), THF, 0 °C to rt, 1.5 h (96%, 2 steps). 3. 9-BBN (2.5 eq.), THF, rt, 1.5 h, followed by NaBO H0 aq. 4. TEMPO (10 mol%), PhI(OAc)2 (3 equiv.), NaHCO3 (10 equiv.), 4 °C, 15 h (97%, 2 steps). c.5 (1.4 equiv.), t-BuLi (2.6 equiv.), THF, -78 °C, 15 min (90%). d.1. OsO4 (10 mol%), NMMO (2 equiv.), H2O, acetone, rt, 21 h. 2. Pb(OAc)4 (1.2 equiv.), K2CO3 (3 equiv.), CH2Cl2, rt, 1 h (83%, 2 steps). 3. (MeO)2P(=O)CH2CO2Bn (4 equiv.), K3PO4 (3 equiv.), rt, 23 h. e. LiBr (10 equiv.), DBU (5 equiv.), BnOAc (10 equiv.), MeCN, rt, 12 h; 2. DDQ (2 equiv.), CHCl, buffer (pH 7), rt, 40 min (75%, 3 steps); 3. TESCl (2 equiv.), imidazole (4 equiv.), CHCl, rt, 16 h; 4. H (1 atm), Pd / C, EtOAc, rt, 45 min; 5. (PyS) (1.4 equiv.), PPh (1.2 equiv.), CHCl, rt, 17 h (96%, 3 steps).Abbreviations: DIBAL = diisobutylaluminum hydride; 9-BBN = 9-borabicyclononane; TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy; NMMO or NMO = 4-methylmorpholine N-oxide; DBU = 1,8-diazabicyclo[5.4.0]-undec-7-ene; DDQ = 2,3-dichloro-5,6-dicyano-p-benzoquinone.

[0095] [Figure 17]Figure 17 shows an exemplary synthesis of the left-hand building block of halichondrin. Reagents and conditions: a. 10 (1.8 equiv.), n-BuLi (1.75 equiv.), Li(thienylCuCN) (2.0 equiv.), BF3·Et2O (1.6 equiv.), Et2O, -78 °C, 1 h (81%). b. 1. VO(TMHD)2 (5 mol%), tBuOOH (5.5 M in decane, 2 equiv.), toluene, rt, 5 h. 2. TESCl (2.0 equiv.), imidazole (4.0 equiv.), CHCl2, 0 °C, 2 h (85%, 2 steps). ct-BuLi (2.6 equiv.), THF, -78 °C, 0.5 h (85%). d.1. (PhO)2P(=O)OH (5 mol%), toluene (0.05 M), 0 °C–rt, 12 h. 2. TESCl (3.0 equiv.), imidazole (6.0 equiv.), CHCl2, rt, 2 h (85%, 2 steps). e.1. OsO4 (5 mol%), NMMO (2.0 equiv.), acetone / H2O, rt, 12 h. 2. Pb(OAc)4 (1.5 equiv.), KCO3 (10 equiv.), CHCl2, rt, 10 min. 3. (MeO)2P(=O)COOBn (4 equiv.), KPO4 (8 equiv.), toluene, rt, 15 h (82%, 3 steps). 4. (PhO)2P(=O)OH (5 mol%), THF-H2O (4:1, 0.02 M), rt, 24 h. 5. TBSCl (1.5 equiv.), imidazole (3.0 equiv.), CHCl2, rt, 2 h (80%, 2 steps). f. BnOAc (1 equiv.), and LiCl (10 equiv.), DBU (20 equiv.), MeCN (0.05 M), 24 h (86%) with 8% 18. or BnOAc (1 equiv.), LiCl (10 equiv.), DBU (20 equiv.), M (50 mol%), MeCN (0.05 M), 2 h; then BnOAc (1 equiv.), LiCl (10 equiv.), DBU (20 equiv.), MeCN (0.05 M), 24 h (93%). g.1. DDQ (1.6 equiv.), CHCl, phosphate buffer, 0 °C, 0.5 h.2. TESCl (3 equiv.), imidazole (6 equiv.), CHCl, rt, 2 h (90%, 2 steps). 3. Pd / C, H balloon, EtOAc, rt, 1 h. 4. (PyS) (1.4 equiv.), PPh (1.3 equiv.), toluene, rt, 3 h (91%, 2 steps). Abbreviations: TMHD = tris(2,2,6,6-tetramethyl-3,5-heptanedionate).

[0096] [Figure 18]Figure 18 shows an exemplary synthesis of a left-half building block in the homohalichondrin system. Reagents and conditions: a.1. DIBAL (1.3 equiv.), CHCl, -78°C, 15 min. 2. MePPhBr (4 equiv.), t-BuOK (3 equiv.), THF, 0°C to rt, 20 min. 3. TBSOTf (1.3 equiv.), 2,6-lutidine (2 equiv.), CHCl, 0°C to rt, 1 h. 4. HF·py (ca. 8 equiv.), pyridine, MeCN, -10°C to rt, 1.5 h (96%, 4 steps). b.1. TfO (1.2 equiv.), 2,6-lutidine (4 equiv.), CHCl, -78°C, 10 min. 2. NaCN (10 equiv.), DMSO, rt, 1 h. 3. TBSCl (3 equiv.), pyridine (8 equiv.), AgNO3 (3 equiv.), DMF, 0°C to rt, 18 h (87%, 3 steps). c.1. DIBAL (1.1 equiv.), CH2Cl2, hexane, -78°C, 30 min. 2. (CF3CH2O)2P(O)CH2CO2Me (1.5 equiv.), 18-crown-6 (8 equiv.), KHMDS (1.5 equiv.), THF, -78°C, 30 min (84%, 2 steps). 3. DIBAL (4 equiv.), THF, -78°C to 0°C, 30 min (99%). d.1. (+)-DET (20 mol%), Ti(OPr-i)4 (15 mol%), TBHP (1.5 equiv.), MS 4Å, CHCl2, -10 °C, 15 h (86% desired isomer, 11% undesired isomer). 2. TBAF (6 equiv.), MS 4Å, THF (96%). e.1. TBSCl (1.5 equiv.), EtN (4 equiv.), CHCl2, rt, 5 h (99%). 2. TESCl (1.2 equiv.), imidazole (3 equiv.), CHCl2, 0 °C to rt, 15 min. 3. 9-BBN (3 equiv.), THF, 0 °C to rt, 1 h, followed by NaBO3 H2O aq. (94%, 2 steps). 4.TEMPO (20 mol%), PhI(OAc)2 (3 equiv.), CH2Cl2, rt, 36 h (95%).f.1.5 (1.3 equiv.), t-BuLi (2.5 equiv.), THF, -78 °C, 30 min. 2. OsO4 (10 mol%), NMMO (2 equiv.), H2O, acetone, rt, 4 h. 3. Pb(OAc)4 (1.5 equiv.), K2CO3 (10 equiv.), CHCl2, rt, 15 min (68%, 3 steps). 4. (MeO)2P(=O)CH2CO2Bn (5 equiv.), NaH (4 equiv.), THF, 0 °C, 3 h (88%). g.1. LiBr (10 equiv.), DBU (20 equiv.), MeCN, rt, 11 h (70%). h. DDQ (3 equiv.), CHCl, t-BuOH, buffer (pH 7), rt, 15 min (86%). 2. TESCl (1.5 equiv.), imidazole (3 equiv.), CHCl, rt, 4 hr (97%). 3. H (1 atm), Pd / C, AcOEt, rt, 2 hr (89%). 4. (PyS) (1.2 equiv.), PPh (3 equiv.), toluene, rt, 12 hr (97%). Abbreviations: 18-crown-6 = 1,4,7,10,13,16-hexa-oxacyclooctadecene; KHMDS = potassium bis(trimethylsilyl)amide; 9-BBN = 9-borabicyclononane; DET = diethyl tartrate; TBHP = tert-butyl hydroperoxide; MS = molecular sieves; TBAF = tetrabutylammonium fluoride.

[0097] [Figure 19]Figure 19 shows an exemplary synthesis of the left-handed C38-C53 building block in the norhalichondrin system. Reagents and conditions: a.1. TfO (1.2 equiv.), 2,6-lutidine (4 equiv.), CHCl, -78°C, 10 min. 2. NaCN (10 equiv.), DMSO, rt, 1 h (87%, 2 steps). 3. DIBAL (4.5 equiv.), CHCl, -78°C, 30 min. 4. NaBH (5 equiv.), MeOH, rt, 30 min. 5. TBSOTf (3 equiv.), 2,6-lutidine (3.5 equiv.), CHCl, rt, 30 min (90%, 3 steps). 6. 9-BBN (2 equiv.), THF, rt, 2 h, then NaOH, HO, HO, rt, 3 h (91%). 7. TEMPO (0.5 equiv.), PhI(OAc) (5.0 equiv.), CHCN, HO, THF, rt, 12 h (90%). 8. p-TsOH·HO (1.0 equiv.), HO (10 equiv.), CHCl, rt, 24 h. 9. TESOTf (10 equiv.), 2,6-lutidine (12 equiv.), CHCl, rt, 1 h (76%, 2 steps). b. 1.5, t-BuLi (2.2 equiv.), toluene, EtO, −78 °C, 10 min (82%). 2. OsO4 (5 mol%), NMMO (2 equiv.), H2O, acetone, rt, 12 h. 3. Pb(OAc)4 (2 equiv.), K2CO3 (10 equiv.), rt, 30 min (86%, 2 steps). 4. (MeO)2P(=O)CH2CO2Bn (4 equiv.), K3PO4 (3 equiv.), rt, 36 h (93%). c. LiBr (10 equiv.), DBU (5 equiv.), BnOAc (2 equiv.), CH3CN, rt, 12 h (82%). d. 1. TBAF (1.5 equiv.), HOAc (1.0 equiv.), THF, 0 °C, 5 h (81%). 2. Dess-Martin periodinane (2.0 equiv.), NaHCO3 (10 equiv.), CH2Cl2, rt, 30 min. 3. NaClO2 (3 equiv.), NaH2PO4 (4 equiv.), 2-methyl-2-butene, t-BuOH, H2O, rt, 30 min.4. TMSCH2N2 (3.0 equiv.), benzene, MeOH, rt, 5 min (87%, 3 steps). e.1. DDQ (2.0 equiv.), CHCl2, aqueous buffer (pH 7), rt, 1 h. 2. TESOTf (2.0 equiv.), 2,6-lutidine (2.5 equiv.), CHCl2, rt, 30 min (83%, 2 steps). f.1. Pd / C (10 wt%), H2, EtOAc, rt, 3 h. 2. (SPy)2 (1.4 equiv.), PPh3 (1.2 equiv.), toluene, rt, 12 h (88%, 2 steps). Abbreviations: p-TsOH = p-toluenesulfonic acid.

[0098] [Figure 20] Figure 20 shows the X-ray structure for halichondrin C prepared using the methods described herein. Colorless single crystals of halichondrin C were obtained by recrystallization from MeOH:CH2Cl2 = 1:1.

[0099] [Figure 21] FIG. 21 shows an exemplary synthetic scheme for the preparation of exemplary C33-C43 fragments of halichondrins and their analogs.

[0100] [Figure 22] FIG. 22 shows an exemplary synthetic scheme for the preparation of exemplary C27-C37 fragments of halichondrins and their analogs.

[0101] [Figure 23] FIG. 23 shows an exemplary synthetic scheme for the preparation of exemplary C39-C43 fragments of halichondrins and their analogs. DETAILED DESCRIPTION OF THE INVENTION

[0102] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Provided herein are Ni / Zr-mediated coupling reactions useful in the preparation of ketone-containing compounds. Provided herein are Ni / Zr-mediated ketolization reactions particularly useful in the synthesis of halichondrins and their analogs. Accordingly, also provided herein are methods for the preparation of halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C) and their analogs.

[0103] In some embodiments, provided herein is compound (1): [ka] Compound (1) The method is useful in the preparation of compounds of formula (H3-A), including:

[0104] The present invention also provides compounds (i.e., intermediates) useful in the methods provided herein. In certain embodiments, the compounds provided herein are useful as synthetic intermediates en route to halichondrin and their analogs. Furthermore, the present invention provides reagents and catalysts useful in the methods described herein.

[0105] Ni / Zr-mediated ketolization reaction In one aspect, provided herein are nickel / zirconium-mediated ketolization reactions ("Ni / Zr-mediated ketolization reactions") involving the coupling of a thioester and an alkyl halide (e.g., alkyl iodide, alkyl bromide, alkyl chloride, etc.) or an alkyl leaving group (e.g., alkyl sulfonate) (Scheme 1A). The ketolization reaction can be intermolecular or intramolecular (i.e., in Scheme 1A, R A and R B are optionally linked by a linker). In some embodiments, as shown in Scheme 1B, compounds of Formula (A) can be prepared by combining a primary or secondary alkyl halide (X1 = halogen), and the compound represented by formula (B) is an alkyl thioester (R B = optionally substituted alkyl). Scheme 1A [ka] Scheme 1B [ka]

[0106] As depicted in Scheme 1A, provided herein are compounds of formula (C): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, [ka] or a salt thereof in the presence of nickel and zirconium; R A is optionally substituted alkyl; R B is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; Optionally, where R A and R Bare joined together via a linker, wherein the linker is selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted acylene, and combinations thereof; X 1 is a halogen or a leaving group; and R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

[0107] In some embodiments, R A is a small molecule. B is a small molecule. Small molecules encompass complex small molecules such as natural products, pharmaceuticals, and fragments thereof, as well as intermediates thereto.

[0108] As generally defined herein, a "linker" is a group comprising an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted acylene, or any combination thereof.

[0109] In some embodiments, the compound of formula (A) has formula (A-1): [ka] or a salt thereof; the compound represented by formula (B) is a compound represented by formula (B-1): [ka] or a salt thereof; and the compound represented by formula (C) is a compound represented by formula (C-1): [ka] or a salt thereof, wherein: X 1 is a halogen or a leaving group; R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R A1 , R A2 , R B1 , and R B2 each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; optionally, where R A1 and R B1 are linked together via a linker.

[0110] In some embodiments, R A1 is a small molecule. B1 and R B2 is independently a small molecule. Small molecules encompass small molecules such as natural products, pharmaceuticals, and fragments thereof, as well as intermediates thereto.

[0111] The Ni / Zr-mediated ketolization reactions provided herein may be carried out in an intramolecular fashion to produce cyclic ketones as shown in Scheme 1C. Scheme 1C [ka]

[0112] As shown in Scheme 1C, provided herein are compounds of formula (C-2): [ka] or a salt thereof, comprising the steps of: [ka] or a salt thereof in the presence of nickel and zirconium; R A2 and R B2 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; X 1 is a halogen or a leaving group; R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and [ka] represents a linker.

[0113] The Ni / Zr-mediated ketolization reaction provided herein is carried out in the presence of nickel. In some embodiments, the ketolization reaction is carried out in the presence of a nickel complex. Any nickel complex known or available in the art (e.g., nickel salt, nickel complex, nickel catalyst, or nickel pre-catalyst) may be used in the reaction. In some embodiments, the ketolization reaction is carried out in the presence of nickel(II). In some embodiments, the ketolization reaction is carried out in the presence of nickel(0). In some embodiments, the nickel complex is represented by the formula: NiX2·(ligand), where X is a halogen (e.g., Cl, Br, I, or F). In some embodiments, the "ligand" is a bidentate ligand. In some embodiments, the ligand is an optionally substituted bispyridyl ligand. In some embodiments, the nickel complex is NiX2·(tbbpy), where X is a halogen (e.g., Cl, Br, I, or F), and "tbbpy" has the structure: [ka] In some embodiments, the nickel complex is NiBr2·(tbbpy).

[0114] In some embodiments, the nickel complex is used after complexing a nickel source in solution with a "ligand." In some embodiments, the nickel complex has the formula: NiX2·(ligand), where X is a halogen and "ligand" is a bidentate ligand. In some embodiments, the nickel source is NiCl2; "ligand" is 4,4'-di-tert-butyl-2,2'-dipyridyl (tbbpy); and the resulting nickel complex has the formula NiCl2·(tbbpy). In some embodiments, the nickel source is NiBr2; and "ligand" is 4,4'-di-tert-butyl-2,2'-dipyridyl (tbbpy); and the resulting nickel complex has the formula NiBr2·(tbbpy).

[0115] In some embodiments, nickel is present in a catalytic amount. In some embodiments, nickel is present in the reaction mixture at approximately 1-5 mol%, 5-10 mol%, 1-10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 20-40 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70-80 mol%, or 80-90 mol% relative to the compound represented by Formula (A) or (B). In some embodiments, nickel is present at 1-50 mol%. In some embodiments, nickel is present at 1-10 mol%. In some embodiments, nickel is present at approximately 5 mol%. In some embodiments, nickel is present at approximately 30 mol%. In some embodiments, nickel is present in a stoichiometric or excess amount relative to the compound represented by Formula (A) or (B) in the reaction mixture. In some embodiments, approximately one equivalent of nickel is present (i.e., stoichiometric). In other embodiments, more than one equivalent of nickel is present (ie, an excess).

[0116] As described above, the Ni / Zr-mediated ketolization reaction is carried out in the presence of zirconium. In some embodiments, the reaction is carried out in the presence of a zirconium complex. Any zirconium source (e.g., zirconium salt, complex, catalyst, or pre-catalyst) known or available in the art may be used in the reaction. In some embodiments, the zirconium source is a compound represented by the formula (ligand): n ZrX2, where n is the number of ligands (e.g., 0, 1, 2, 3, or 4) and X is a halogen (e.g., Cl, Br, I, or F). In some embodiments, n is 2 and the ligand is cyclopentadienyl. In some embodiments, the zirconium source is Cp2ZrX2. In some embodiments, the zirconium source is Cp2ZrCl2.

[0117] In some embodiments, zirconium is present in a catalytic amount. In some embodiments, zirconium is present in the reaction mixture at 1-5 mol%, 5-10 mol%, 1-10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70-80 mol%, or 80-90 mol% relative to the compound represented by Formula (A) or (B). In some embodiments, zirconium is present in the reaction mixture in a stoichiometric or excess amount relative to the compound represented by Formula (A) or (B). In some embodiments, approximately one equivalent of zirconium is present (i.e., stoichiometric). In other embodiments, more than one equivalent of zirconium is present (i.e., excess). In some embodiments, approximately 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 equivalents of zirconium are present. In some embodiments, approximately 3 equivalents of zirconium are present.

[0118] In some embodiments, the Ni / Zr-mediated ketolization reaction provided herein is carried out in the presence of one or more additional reagents or catalysts, such as a reducing metal. In some embodiments, the reducing metal is zinc. In some embodiments, the reducing metal is magnesium. In some embodiments, zinc metal is used (i.e., zinc(0)). In some embodiments, metallic magnesium is used (i.e., magnesium(0)). In some embodiments, the reaction is carried out in the presence of zinc powder, zinc foil, zinc beads, or any other form of zinc metal. In some embodiments, a zinc salt such as zinc acetate, zinc sulfate, zinc chloride, zinc bromide, zinc iodide, zinc fluoride, zinc sulfide, or zinc phosphate is employed. The zinc may be present in a catalytic amount, a stoichiometric amount, or an excess amount. In some embodiments, the zinc is present in excess (i.e., greater than 1 equivalent) relative to the compound represented by Formula (A) or Formula (B). In some embodiments, between 1 and 10 equivalents of zinc are used. In some embodiments, approximately 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, or 10 equivalents of zinc are present, hi some embodiments, approximately 6 equivalents of zinc are used.

[0119] In some embodiments, the ketolization reaction is carried out in the presence of one or more reagents that serve to activate the zinc metal in the reaction (e.g., by cleaning the surface of zinc oxide). In some embodiments, the reaction is carried out in the presence of a trialkylsilyl halide (e.g., triethylsilyl chloride (TESCl)). This reagent may be present in a catalytic amount, a stoichiometric amount, or an excess amount. In some embodiments, approximately 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, or 10 equivalents of this reagent are present. In some embodiments, approximately 1.5 equivalents of this reagent are present.

[0120] In certain embodiments, the Ni / Zr-mediated ketolization is carried out in the presence of one or more additional reagents (ie, in addition to nickel, zirconium, and zinc).

[0121] In some embodiments, the Ni / Zr-mediated ketolization reaction is carried out in the presence of a base or proton scavenger. In some embodiments, the base is a pyridine base. In some embodiments, the base is 2,6-di-tert-butylpyridine. In some embodiments, the base is 2,6-lutidine. In some embodiments, the base is 2,6-di-tert-butyl-4-methylpyridine. In some embodiments, the base is used in a stoichiometric amount or in an excess amount. In some embodiments, approximately 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, or 10 equivalents of base or proton scavenger are present. In some embodiments, approximately 4 equivalents of base or proton scavenger are employed.

[0122] In some embodiments, the Ni / Zr-mediated ketolization described herein is carried out in a solvent. Any solvent may be used, and the scope of the method is not limited to any particular solvent or mixture of solvents. The solvent may be polar or non-polar, protic or aprotic, or a combination of solvents (e.g., a co-solvent). Examples of useful organic solvents are provided herein. In some embodiments, the ketolization reaction is carried out in 1,3-dimethyl-2-imidazolidinone (DMI). In some embodiments, the ketolization reaction is carried out in a 1,3-dimethyl-2-imidazolidinone (DMI) / tetrahydrofuran (THF) mixture. In some embodiments, the ketolization reaction is carried out in a 1,3-dimethyl-2-imidazolidinone (DMI) / ethyl acetate (EtOAc) mixture.

[0123] The Ni / Zr-mediated ketolization reaction described herein may be carried out in a solvent at any concentration. The concentration refers to the molar concentration (mol / L) of the coupling partner (e.g., a compound represented by Formula (A) or (B)) in the solvent. In some embodiments, the concentration is about 0.1 M. In some embodiments, the concentration is approximately 0.5 M. In some embodiments, the concentration is approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 M. In some embodiments, the concentration is greater than 1 M. In some embodiments, the concentration is less than 0.1 M.

[0124] The Ni / Zr-mediated ketolization reaction described herein can be carried out at any temperature. In some embodiments, the reaction is carried out at about room temperature (i.e., between 18°C ​​and 24°C). In some embodiments, the reaction is carried out below room temperature (e.g., between 0°C and room temperature). In some embodiments, the reaction is carried out at a temperature above room temperature (e.g., between room temperature and 100°C). In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100°C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50°C.

[0125] In some embodiments, the Ni / Zr-mediated ketolization reaction is carried out in the presence of a nickel complex, a zirconium complex, and a reducing metal. In some embodiments, the nickel complex is NiBr(dtbbpy). In some embodiments, the zirconium complex is CpZrCl. In some embodiments, the reducing metal is zinc. In some embodiments, the reaction is carried out in the presence of NiBr(dtbbpy), CpZrCl, and zinc metal. In some embodiments, the reaction is carried out in a polar solvent such as DMI (1,3-dimethyl-2-imidazolidinone). In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100° C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50° C. For example, in some embodiments, the coupling is carried out under the following conditions: 5 mol% NiBr(dtbbpy), 1.0 equivalent CpZrCl, and excess zinc metal in DMI at room temperature.

[0126] In some embodiments, the reaction is carried out in the presence of NiBr(dtbbpy), CpZrCl, zinc metal, and a base or proton scavenger. In some embodiments, the reaction is carried out in the presence of NiBr(dtbbpy), CpZrCl, zinc metal, and (t-Bu)(Me)Py. In some embodiments, the reaction is carried out in a mixture of DMI and EtOAc (ethyl acetate). In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100° C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50° C. For example, in some embodiments, the coupling is carried out under the following conditions: 30 mol% NiBr(dtbbpy), 3.0 equivalents CpZrCl, 6.0 equivalents zinc metal, and 4.0 equivalents (t-Bu)(Me)Py in DMI-EtOAc at room temperature.

[0127] Synthesis of halichondrin and analogues. The Ni / Zr-mediated ketolization reactions provided herein can be applied to the synthesis of halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C) and their analogs. In certain embodiments, the methods are useful in the synthesis of compounds represented by formula (H3-A), such as compound (1). In certain embodiments, the methods include the steps of (1) coupling a "left-half" building block with a "right-half" building block via the Ni / Zr-mediated ketolization reactions provided herein; followed by (2) cyclizing the resulting coupled product (e.g., acid-mediated cyclization); optionally, any synthetic transformations necessary to arrive at the desired product.

[0128] Synthesis of halichondrin The Ni / Zr-mediated ketolization reaction provided herein can be applied to the preparation of halichondrins (e.g., halichondrins A, B, and C) and their analogs. For example, as shown in Scheme 2A, coupling of the left half of formula (L-2-14) with the right half of formula (R-2-I) via Ni / Zr-mediated ketolization produces a ketone of formula (H-2-II), which upon cyclization provides a compound of formula (H-2-I), which is a halichondrin or analog thereof, or an intermediate thereto. Scheme 2A [ka]

[0129] Provided herein are compounds of formula (H-2-I): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P1 , R P2 , R P3 , R P4 , and R P5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0130] In some embodiments, the step of cyclizing the compound represented by Formula (H-2-II) or a salt thereof is carried out in the presence of an acid. The acid may be a Lewis acid or a Bronsted acid. In some embodiments, the acid is a Bronsted acid. In some embodiments, the acid is a sulfonic acid. In some embodiments, the acid is a salt of a sulfonic acid. In some embodiments, the acid is a pyridinium salt. In some embodiments, the acid is pyridinium p-toluenesulfonate (PPTS). In some embodiments, the acid is present in a catalytic amount. In some embodiments, the acid is present in a stoichiometric amount (e.g., about 1 equivalent) or in an excess amount (e.g., more than 1 equivalent). In some embodiments, the acid is present in an excess amount (e.g., about 5 equivalents).

[0131] In some embodiments, the cyclizing step is carried out in the presence of PPTS. In some embodiments, the step is carried out in a solvent such as CH2Cl2. In some embodiments, the reaction is carried out at a temperature ranging from about 0°C to about 50°C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 20°C. For example, in some embodiments, the cyclizing step is carried out under the following conditions: 5 equivalents of PPTS in CH2Cl2 at about 20°C (e.g., for 2 hours).

[0132] In some embodiments, R P1 , R P2 , and R P3 is a silyl protecting group, and R P4 and R P5 is hydrogen. In some embodiments, R P1 and R P2 is TBS, R P3 is TES and R P4 and R P5 is hydrogen.

[0133] In some embodiments, the compound of formula (H-2-II) has the formula (H-2-IIA): [ka] or a salt thereof.

[0134] Provided herein are compounds of formula (H-2-II): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof, [ka] or a salt thereof, wherein R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; X 1 is a halogen or a leaving group; R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P1 , R P2 , R P3 , R P4 , and R P5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Yais hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0135] In some embodiments, the coupling step to provide a compound represented by Formula (H-2-II) is a Ni / Zr-mediated ketolization as provided herein. Any reagent or condition provided herein for Ni / Zr-mediated ketolization may be used in the coupling. In some embodiments, the Ni / Zr-mediated ketolization reaction is carried out in the presence of a nickel complex, a zirconium complex, and a reducing metal. The reaction may also be carried out in the presence of one or more additional reagents, such as a base or a proton scavenger. In some embodiments, the nickel complex is NiBr(dtbbpy). In some embodiments, the zirconium complex is CpZrCl. In some embodiments, the reducing metal is zinc. In some embodiments, the additional base or proton scavenger is (t-Bu)(Me)Py. In some embodiments, the reaction is carried out in the presence of NiBr(dtbbpy), CpZrCl, and zinc metal. In some embodiments, the reaction is carried out in the presence of NiBr(dtbbpy), CpZrCl, and zinc metal. In some embodiments, the reaction is carried out in the presence of NiBr2(dtbbpy), Cp2ZrCl2, zinc metal, and (t-Bu)2(Me)Py. In some embodiments, the reaction is carried out in a polar solvent such as DMI (1,3-dimethyl-2-imidazolidinone). In some embodiments, the reaction is carried out in a mixture of DMI and EtOAc (ethyl acetate). In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100° C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50° C. In some embodiments, the reaction is carried out at about room temperature.

[0136] For example, in one embodiment, the coupling is carried out under the following conditions: 30 mol% NiBr(dtbbpy), 3.0 equivalents CpZrCl, 6.0 equivalents zinc metal, and 4.0 equivalents (t-Bu)(Me)Py in DMI-EtOAc at room temperature.

[0137] In some embodiments, R P1 , R P2 , R P3 , R P4 and R P5 is a silyl protecting group. In some embodiments, R P1 and R P2 is TBS; and R P3 , R P4 , and R P5 is TES.

[0138] In some embodiments, the method for preparing a compound of Formula (H-2-II) further comprises one or more steps of deprotecting one or more oxygen atoms of the compound of Formula (H-2-II) (e.g., to produce a compound of Formula (H-2-IIA) or a salt thereof). In some embodiments, the resulting compound or a salt thereof can then be used in a cyclization step to produce a compound of Formula (H-2-I) or a salt thereof. In some embodiments, the deprotecting step is carried out in the presence of a fluoride source (e.g., when one or more oxygen atoms are protected with a silyl group).

[0139] Examples of fluoride sources useful in the present invention include, but are not limited to, metal fluorides (e.g., sodium fluoride, potassium fluoride, cesium fluoride, silver fluoride) and tetraalkylammonium fluorides (e.g., tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride). In some embodiments, the fluoride source is a tetraalkylammonium fluoride. In some embodiments, the fluoride source is tetrabutylammonium fluoride (TBAF). In some embodiments, hydrogen fluoride (HF) is used. In some embodiments, HF·pyridine is used as the HF source. Other examples of protecting groups useful in the present invention and reagents useful in protection / deprotection reactions can be found in the art, for example, in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0140] Once a compound of formula (H-2-I), or a salt thereof, is obtained, the method may include one or more additional steps (e.g., deprotection, protection, substitution, addition, elimination) to produce the desired compound (e.g., halichondrin A, B, C, or an analog thereof).

[0141] Synthesis of homohalichondrins The Ni / Zr-mediated ketolization reaction provided herein can be applied to the preparation of homohalichondrins (e.g., homohalichondrins A, B, and C) and their analogs. For example, as shown in Scheme 2B, coupling of the left half of formula (L-2-16) with the right half of formula (R-2-I) via Ni / Zr-mediated ketolization produces a ketone of formula (HH-2-II), which upon cyclization provides a compound of formula (HH-2-I), which is a homohalichondrin natural product or an analog thereof, or an intermediate thereto. Scheme 2B [ka]

[0142] Provided herein are compounds of formula (HH-2-I): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P1 , R P3 , R P4 , and R P5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where RXa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0143] In some embodiments, the step of cyclizing the compound represented by Formula (HH-2-II) or a salt thereof is carried out in the presence of an acid. The acid may be a Lewis acid or a Bronsted acid. In some embodiments, the acid is a Bronsted acid. In some embodiments, the acid is a sulfonic acid. In some embodiments, the acid is a salt of a sulfonic acid. In some embodiments, the acid is a pyridinium salt. In some embodiments, the acid is pyridinium p-toluenesulfonate (PPTS). In some embodiments, the acid is present in a catalytic amount. In some embodiments, the acid is present in a stoichiometric amount (e.g., about 1 equivalent) or in an excess amount (e.g., more than 1 equivalent). In some embodiments, the acid is present in an excess amount (e.g., about 5 equivalents).

[0144] In some embodiments, the cyclizing step is carried out in the presence of PPTS. In some embodiments, the step is carried out in a solvent such as CH2Cl2. In some embodiments, the reaction is carried out at a temperature ranging from about 0°C to about 50°C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 20°C. For example, in some embodiments, the cyclizing step is carried out under the following conditions: 5 equivalents of PPTS in CH2Cl2 at about 20°C (e.g., for 2 hours).

[0145] In some embodiments, R P1 and R P2 is a silyl protecting group; and R P4 and RP5 is hydrogen. In some embodiments, R P1 is TBS;R P2 is TES; and R P4 and R P5 is hydrogen.

[0146] In some embodiments, the compound of formula (HH-2-II) has formula (HH-2-IIA): [ka] or a salt thereof.

[0147] Provided herein is a compound of formula (HH-2-II): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, [ka] or a salt thereof, wherein R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; X 1 is a halogen or a leaving group; R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P1 , R P3 , R P4 , and R P5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0148] In some embodiments, the coupling step to provide a compound represented by Formula (HH-2-II) is Ni / Zr-mediated ketolization as provided herein. Any reagents or conditions provided herein for Ni / Zr-mediated ketolization may be used in the coupling. In some embodiments, the Ni / Zr-mediated ketolization reaction is carried out in the presence of a nickel complex, a zirconium complex, and a reducing metal. The reaction may also be carried out in the presence of one or more additional reagents, such as a base or a proton scavenger. In some embodiments, the nickel complex is NiBr(dtbbpy). In some embodiments, the zirconium complex is CpZrCl. In some embodiments, the reducing metal is zinc. In some embodiments, the additional base or proton scavenger is (t-Bu)(Me)Py. In some embodiments, the reaction is carried out in the presence of NiBr(dtbbpy), CpZrCl, and zinc metal. In some embodiments, the reaction is carried out in the presence of NiBr(dtbbpy), CpZrCl, and zinc metal. In some embodiments, the reaction is carried out in the presence of NiBr2(dtbbpy), Cp2ZrCl2, zinc metal, and (t-Bu)2(Me)Py. In some embodiments, the reaction is carried out in a polar solvent such as DMI (1,3-dimethyl-2-imidazolidinone). In some embodiments, the reaction is carried out in a mixture of DMI and EtOAc (ethyl acetate). In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100° C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50° C. In some embodiments, the reaction is carried out at about room temperature.

[0149] For example, in one embodiment, the coupling is carried out under the following conditions: 30 mol% NiBr(dtbbpy), 3.0 equivalents CpZrCl, 6.0 equivalents zinc metal, and 4.0 equivalents (t-Bu)(Me)Py in DMI-EtOAc at room temperature.

[0150] In some embodiments, R P1 , R P2 , RP3 , R P4 and R P5 is a silyl protecting group. In some embodiments, R P1 and R P2 is TBS; and R P3 , R P4 , and R P5 is TES.

[0151] In some embodiments, the method for preparing a compound of formula (HH-2-II) further comprises one or more steps of deprotecting one or more oxygen atoms of the compound of formula (HH-2-II) (e.g., to produce a compound of formula (HH-2-IIA) or a salt thereof). In some embodiments, the resulting compound or a salt thereof is then cyclized to produce a compound of formula (HH-2-I) or a salt thereof. In some embodiments, the deprotecting step is carried out in the presence of a fluoride source (e.g., when one or more oxygen atoms are protected with a silyl group). Examples of fluoride sources are provided herein.

[0152] Once a compound of formula (HH-2-I) or a salt thereof is obtained, one or more additional steps (e.g., deprotection, protection, substitution, addition, elimination) may be performed to produce a desired compound (e.g., homohalichondrin A, B, C, or an analog thereof, or an intermediate thereto).

[0153] Synthesis of norhalichondrin The Ni / Zr-mediated ketolization reaction provided herein can be applied to the preparation of norhalichondrins (e.g., norhalichondrins A, B, and C) and their analogs. For example, as shown in Scheme 2C, coupling of the left half of formula (L-2-15) with the right half of formula (R-2-I) via Ni / Zr-mediated ketolization produces a ketone of formula (NH-2-II), which undergoes cyclization to provide a compound of formula (NH-2-I), which is an intermediate to norhalichondrins or their analogs. Scheme 2C [ka]

[0154] Provided herein are compounds of formula (NH-2-I): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P3 , R P4 , and R P5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R 7is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0155] In some embodiments, the step of cyclizing the compound represented by formula (NH-2-II) or a salt thereof is carried out in the presence of an acid. The acid may be a Lewis acid or a Bronsted acid. In some embodiments, the acid is a Bronsted acid. In some embodiments, the acid is a sulfonic acid. In some embodiments, the acid is a salt of a sulfonic acid. In some embodiments, the acid is a pyridinium salt. In some embodiments, the acid is pyridinium p-toluenesulfonate (PPTS). In some embodiments, the acid is present in a catalytic amount. In some embodiments, the acid is present in a stoichiometric amount (e.g., about 1 equivalent) or in an excess amount (e.g., more than 1 equivalent). In some embodiments, the acid is present in an excess amount (e.g., about 5 equivalents).

[0156] In some embodiments, the cyclizing step is carried out in the presence of PPTS. In some embodiments, the step is carried out in a solvent such as CH2Cl2. In some embodiments, the reaction is carried out at a temperature ranging from about 0°C to about 50°C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 20°C. For example, in some embodiments, the cyclizing step is carried out under the following conditions: in CH2Cl2 at about 20°C (e.g., for 2 hours) and 5 equivalents of PPTS.

[0157] In some embodiments, R P3 is a silyl protecting group; R 7 is optionally substituted alkyl; and R P4 and R P5 is hydrogen. In some embodiments, R P3 is TES;R 7 is methyl; and R P4 and R P5 is hydrogen.

[0158] In some embodiments, the compound of formula (NH-2-II) has the formula (NH-2-IIA): [ka] or a salt thereof.

[0159] Provided herein are compounds of formula (NH-2-II): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof, [ka] or a salt thereof, wherein R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; X 1 is a halogen or a leaving group; R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P3 , R P4 , and R P5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R 7 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0160] In some embodiments, the coupling step to provide a compound represented by Formula (NH-2-II) is a Ni / Zr-mediated ketolization as provided herein. Any reagent or condition provided herein for Ni / Zr-mediated ketolization may be used in the coupling. In some embodiments, the Ni / Zr-mediated ketolization reaction is carried out in the presence of a nickel complex, a zirconium complex, and a reducing metal. The reaction may also be carried out in the presence of one or more additional reagents, such as a base or a proton scavenger. In some embodiments, the nickel complex is NiBr(dtbbpy). In some embodiments, the zirconium complex is CpZrCl. In some embodiments, the reducing metal is zinc. In some embodiments, the additional base or proton scavenger is (t-Bu)(Me)Py. In some embodiments, the reaction is carried out in the presence of NiBr(dtbbpy), CpZrCl, and zinc metal. In some embodiments, the reaction is carried out in the presence of NiBr(dtbbpy), CpZrCl, and zinc metal. In some embodiments, the reaction is carried out in the presence of NiBr2(dtbbpy), Cp2ZrCl2, zinc metal, and (t-Bu)2(Me)Py. In some embodiments, the reaction is carried out in a polar solvent such as DMI (1,3-dimethyl-2-imidazolidinone). In some embodiments, the reaction is carried out in a mixture of DMI and EtOAc (ethyl acetate). In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100° C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50° C. In some embodiments, the reaction is carried out at about room temperature.

[0161] For example, in one embodiment, the coupling is carried out under the following conditions: 30 mol% NiBr(dtbbpy), 3.0 equivalents CpZrCl, 6.0 equivalents zinc metal, and 4.0 equivalents (t-Bu)(Me)Py in DMI-EtOAc at room temperature.

[0162] In some embodiments, R P3 is a silyl protecting group; R 7 is optionally substituted alkyl; and R P4 and R P5 is a silyl protecting group. In some embodiments, R P3 is TES;R 7 is methyl; and R P4 and R P5 is TES.

[0163] In some embodiments, the method for preparing a compound of formula (NH-2-II) further comprises one or more steps of deprotecting one or more oxygen atoms of the compound of formula (NH-2-II) (e.g., to produce a compound of formula (NH-2-IIA) or a salt thereof). In some embodiments, the resulting compound or a salt thereof is then cyclized to produce a compound of formula (NH-2-I) or a salt thereof. In some embodiments, the deprotecting step is carried out in the presence of a fluoride source (e.g., when one or more oxygen atoms are protected with a silyl group). Examples of fluoride sources are provided herein.

[0164] Once a compound of formula (NH-2-I), or a salt thereof, is obtained, the method may include one or more additional steps (e.g., deprotection, protection, substitution, addition, elimination) to produce the desired compound (e.g., homohalichondrin A, B, C, or an analog thereof).

[0165] Synthesis of additional halichondrin analogues Methods for the preparation of additional halichondrin analogs are provided herein. The Ni / Zr-mediated ketolization reaction provided herein can be applied to the preparation of additional halichondrin analogs. For example, as shown in Scheme 2D, coupling the left half of formula (L-2-6) with the right half of formula (R-2-I) via Ni / Zr-mediated ketolization produces a ketone of formula (H3-2-II), which upon cyclization provides a compound of formula (H3-2-I). The compound of formula (H3-2-I) can be subjected to further synthetic transformations to produce the desired compound. Scheme 2D [ka]

[0166] As shown in Scheme 2D, provided herein are compounds of formula (H3-2-I): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P4 , R P5 , and R P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P6 joins together with the intervening atom to form an optionally substituted heterocyclyl; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0167] In some embodiments, the compound of formula (H3-2-II) has formula (H3-2-IIA): [ka] or a salt thereof.

[0168] In some embodiments, the method comprises administering to a subject a compound (2): [ka] Compound (2), or a salt thereof, the method comprising: [ka] Compound (C) or a salt thereof.

[0169] In some embodiments, the step of cyclizing the compound represented by Formula (H3-2-II), compound (C), or a salt thereof is carried out in the presence of an acid. The acid may be a Lewis acid or a Bronsted acid. In some embodiments, the acid is a Bronsted acid. In some embodiments, the acid is a sulfonic acid. In some embodiments, the acid is a salt of a sulfonic acid. In some embodiments, the acid is a pyridinium salt. In some embodiments, the acid is pyridinium p-toluenesulfonate (PPTS). In some embodiments, the acid is present in a catalytic amount. In some embodiments, the acid is present in a stoichiometric amount (e.g., about 1 equivalent) or in an excess amount (e.g., more than 1 equivalent). In some embodiments, the acid is present in an excess amount (e.g., about 5 equivalents). In some embodiments, the step is carried out in a solvent. In some embodiments, the reaction is carried out in dichloromethane (DCM). In some embodiments, the reaction is carried out at a temperature ranging from about 0°C to about 50°C. In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about room temperature. In some embodiments, the reaction is carried out at about 20° C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 9-11° C.

[0170] In some embodiments, the cyclizing step is carried out in the presence of PPTS. In some embodiments, the cyclizing step is carried out in the presence of PPTS in DCM. For example, in some embodiments, the cyclizing step is carried out under the following conditions: 5 equivalents of PPTS in DCM at approximately 20°C (e.g., for 2 hours). For example, in some embodiments, the cyclizing step is carried out under the following conditions: 5 equivalents of PPTS in DCM at approximately 9-11°C (e.g., for 3 hours).

[0171] In some embodiments, two R P6 is an oxygen protecting group; and R P4 and R P5 is hydrogen. In some embodiments, two R P6 combines into the following: [ka] and R P4 and R P5 is hydrogen. In some embodiments, two R P6 combines into the following: [ka] and R P4 and R P5 is hydrogen. In certain embodiments, each R P6 , R P4 , and R P5 are each hydrogen. In certain embodiments, one or more free hydroxyl groups of compound (C) are substituted with an oxygen protecting group (e.g., a silyl protecting group).

[0172] As shown in Scheme 2D, provided herein are compounds of formula (H3-2-II): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof, [ka] or a salt thereof, wherein R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; X 1 is a halogen or a leaving group; R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P4 , R P5 , and R P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P6 joins together with the intervening atom to form an optionally substituted heterocyclyl; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where RXa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0173] In some embodiments, the method comprises administering to a subject a compound of formula (EL): [ka] or a salt thereof, [ka] or a salt thereof, to obtain a compound represented by formula (E-1): [ka] or a salt thereof, wherein: R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; X 1 is a halogen or a leaving group; and R P4 , R P5 , and R P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P6 is joined together with the intervening atom to form an optionally substituted heterocyclyl.

[0174] In some embodiments, the step of coupling to provide a compound represented by formula (H3-2-II), (E-1), or a salt thereof is Ni / Zr-mediated ketolization as provided herein. Any reagent or condition provided herein for Ni / Zr-mediated ketolization may be used in the coupling. For an example, see the section above entitled "Ni / Zr-Mediated Ketolization Reaction."

[0175] In some embodiments, the Ni / Zr-mediated ketolization reaction is carried out in the presence of nickel and zirconium complexes. In some embodiments, the Ni / Zr-mediated ketolization reaction is carried out in the presence of a nickel complex, a zirconium complex, and a reduced metal.

[0176] In some embodiments, the nickel is a nickel complex. In some embodiments, the nickel is a nickel(II) or nickel(0) complex. In some embodiments, the nickel complex is represented by the formula: NiX2·(ligand); where X is a halogen and "ligand" is a bidentate ligand. In some embodiments, the nickel complex is used after complexing a nickel source in solution with "ligand." In some embodiments, the nickel source is NiCl2; "ligand" is 4,4'-di-tert-butyl-2,2'-dipyridyl (tbbpy); and the nickel complex is represented by the formula NiCl2·(tbbpy). In some embodiments, the nickel source is NiBr2; and "ligand" is 4,4'-di-tert-butyl-2,2'-dipyridyl (tbbpy); and the nickel complex is represented by the formula NiBr2·(tbbpy).

[0177] In some embodiments, the zirconium complex is CpZrCl. In some embodiments, CpZrCl is present in a stoichiometric amount or in excess (e.g., 1 to 4 equivalents). In some embodiments, the reducing metal is zinc metal. In some embodiments, the reducing metal is manganese metal. In some embodiments, zinc or manganese metal is present in excess. The reaction may also be carried out in the presence of one or more additional reagents, such as a base and / or a proton scavenger. In some embodiments, the reaction is carried out in the presence of (t-Bu)(Me)Py. In some embodiments, the reaction is carried out in the presence of a proton sponge (e.g., 1,8-bis(dimethylamino)naphthalene).

[0178] In some embodiments, the reaction is carried out in the presence of NiBr2(dtbbpy), Cp2ZrCl2, and zinc metal. In some embodiments, the reaction is carried out in the presence of NiBr2(dtbbpy), Cp2ZrCl2, and manganese metal. In some embodiments, the reaction is carried out in the presence of NiBr2(dtbbpy), Cp2ZrCl2, zinc metal, and (t-Bu)2(Me)Py. In some embodiments, the reaction is carried out in the presence of NiBr2(dtbbpy), Cp2ZrCl2, manganese metal, and (t-Bu)2(Me)Py.

[0179] In some embodiments, the reaction is carried out in a polar solvent such as DMI (1,3-dimethyl-2-imidazolidinone). In some embodiments, the reaction is carried out in a mixture of DMI and EtOAc (ethyl acetate). In some embodiments, the reaction is carried out in a mixture of DMI and ethanol. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100°C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50°C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 30°C.

[0180] For example, in one embodiment, the coupling is carried out under the following conditions: 30 mol% NiBr(dtbbpy), 3.0 equivalents CpZrCl, 6.0 equivalents zinc metal, and 4.0 equivalents (t-Bu)(Me)Py in DMI-EtOAc at room temperature.

[0181] In some embodiments, the coupling is carried out in the presence of NiBr(dtbbpy), CpZrCl, and manganese metal in DMI. For example, in some embodiments, the coupling is carried out under the following conditions: approximately 75 mol% NiBr(dtbbpy), 3.5 equivalents of CpZrCl, and 7 equivalents of manganese metal in DMI at approximately 30° C. (e.g., 4 hours).

[0182] In some embodiments, the coupling is carried out by reacting a compound represented by Formula (L-2-6), or a salt thereof, with a compound represented by Formula (R-2-I), or a salt thereof, CpZrCl, and manganese metal in the presence of the compound, followed by adding NiBr(dtbbpy) to the reaction mixture. In some embodiments, the coupling is carried out by reacting a compound represented by Formula (L-2-6), or a salt thereof, with a compound represented by Formula (R-2-I), or a salt thereof, CpZrCl, and manganese metal in DMI in the presence of the compound, followed by adding NiBr(dtbbpy) in a solution of DMI to the reaction mixture.

[0183] In some embodiments, the coupling is carried out by reacting a compound represented by Formula (EL), or a salt thereof, in the presence of a compound represented by Formula (RL), or a salt thereof, CpZrCl, and manganese metal, followed by adding NiBr(dtbbpy) to the reaction mixture. In some embodiments, the coupling is carried out by reacting a compound represented by Formula (EL), or a salt thereof, in DMI, in the presence of a compound represented by Formula (RL), or a salt thereof, CpZrCl, and manganese metal, followed by adding NiBr(dtbbpy) in a solution of DMI to the reaction mixture.

[0184] The coupling reaction to produce a compound represented by Formula (H3-2-II), (E-1), or a salt thereof, can be carried out to produce any amount of product. In some embodiments, the reaction is carried out to produce more than 1 g, 2 g, 5 g, 10 g, 20 g, 30 g, 50 g, 100 g, 200 g, 500 g, or 1 kg of product. In some embodiments, the reaction is carried out to produce less than 1 g of product. In some embodiments, the reaction is carried out to produce between 1 g and 100 g of product (inclusive). In some embodiments, the reaction is carried out to produce approximately 1 g, 2 g, 5 g, 10 g, 20 g, 30 g, 40 g, 50 g, 60 g, 70 g, 80 g, 90 g, or 100 g of product.

[0185] In one embodiment, X 1 is a halogen, and R S is optionally substituted pyridyl. 1 is -I. In some embodiments, R S is 2-pyridyl. 1 is -I; and R S is 2-pyridyl.

[0186] In some embodiments, two R P6 combines into the following: [ka] and R P4 and R P5 is a silyl protecting group. In some embodiments, two R P6 combines into the following: [ka] and R P4 and R P5 is TES.

[0187] In some embodiments, the method for preparing a compound of Formula (H3-2-II) further comprises one or more steps of deprotecting one or more oxygen atoms of the compound of Formula (H3-2-II) (e.g., removing a group R P4 , R P5 , and / or R P6 (e.g., to produce a compound of formula (H3-2-IIA), or a salt thereof). In some embodiments, the resulting compound, or a salt thereof, can then be used in a cyclization step to produce a compound of formula (H3-2-I), or a salt thereof. Similarly, the method for preparing a compound of formula (E-1) can further include one or more steps of deprotecting one or more oxygen atoms of the compound of formula (E-1) (e.g., to remove a group R P4 , R P5, and / or R P6 (e.g., to produce compound (C), or a salt thereof). In some embodiments, the resulting compound, or a salt thereof, can then be used in a cyclization step to produce compound (2).

[0188] In some embodiments, the deprotecting step is carried out in the presence of a fluoride source (e.g., R P4 , R P5 , and / or R P6 is a silyl protecting group). Examples of fluoride sources are provided herein. In some embodiments, the fluoride source is TBAF. In some embodiments, the deprotection step is carried out in the presence of imidazole hydrochloride. In some embodiments, R P4 and R P5 is TES; and the deprotection step (R P4 and R P5 (removing) is carried out in the presence of TBAF and imidazole hydrochloride. P6 combines into the following: [ka] Forming;R P4 and R P5 is TES; and the deprotection step (R P6 , R P4 , and R P5 (removing) is carried out in the presence of TBAF and imidazole hydrochloride. In some embodiments, the reaction is carried out in a solvent such as THF.

[0189] Once a compound represented by formula (H3-2-I), (E-1), or a salt thereof is obtained, the method may include one or more additional steps (e.g., deprotection, protection, substitution, addition, elimination) to produce the desired compound.

[0190] Synthesis of amino analogues of halichondrin. Provided herein are methods for preparing amino analogs of halichondrins, such as compounds of formula (H3-A). For example, as shown below in Scheme 4, compounds of formula (H3-A) can be prepared by converting a compound of formula (H3-OH). The primary hydroxyl group (denoted by * in Scheme 4) can be converted to a compound of formula X. L -R L by treating a compound of formula (H3-A) with a reagent of formula L The group -OR L can then be substituted with an amine or amine precursor. In some embodiments, the method comprises: L The method includes substituting the group with an azide (-N3) (i.e., producing a compound of formula (H3-N3)). The azide moiety can then be reduced to an amine to produce a compound of formula (H3-A). Scheme 4 [ka]

[0191] In some embodiments, the compound represented by formula (H3-A) is compound (1), or a salt thereof. Accordingly, provided herein are methods for preparing compound (1) and salts thereof. For example, as shown below in Scheme 2, compound (1) can be prepared by converting compound (2) to a compound represented by formula (A). In this step, the primary hydroxyl group of compound (2) (indicated by * in Scheme 2) is converted to a compound represented by formula X L -R L Treatment of compound (2) with a reagent represented by the formula L In some embodiments, the leaving group is a sulfonate (i.e., R L is an optionally substituted sulfonyl). L can then be substituted with an amine or amine precursor. In some embodiments, the method comprises: LThe method includes substituting the group with an azide (-N3) (i.e., producing a compound of formula (B)). The azide moiety of compound of formula (B) can then be reduced to an amine to produce compound (1). Scheme 2 [ka]

[0192] As shown in Scheme 4 above, provided herein are compounds of formula (H3-A): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P4 , RP5 , and R P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0193] In certain embodiments, as shown in Scheme 2, the methods provided herein comprise reacting compound (1): [ka] Compound (1), or a salt thereof, the method comprising: [ka] or a salt thereof.

[0194] The step of reducing to form a compound of formula (H3-A), compound (1), or a salt thereof, may be carried out in the presence of any reagent or condition capable of reducing an azide to an amine (e.g., Chem. Rev., 1988, 88(2), pp. 297-368). In some embodiments, the reducing step is carried out in the presence of a phosphine reagent (i.e., Staudinger reaction). In some embodiments, the phosphine is a trialkylphosphine. In some embodiments, the phosphine is a triarylphosphine. In some embodiments, the phosphine reagent is triphenylphosphine (Ph3P). In some embodiments, the phosphine reagent is a polymer-bound phosphine. In some embodiments, the phosphine reagent is a polymer-bound triphenylphosphine. In some embodiments, treatment with the phosphine is followed by treatment with water, e.g., an aqueous work-up.

[0195] In some embodiments, approximately 1 equivalent of phosphine reagent is used. In some embodiments, more than 1 equivalent of phosphine reagent is used. In some embodiments, approximately 1 to 10 equivalents of phosphine reagent are used. In some embodiments, approximately 1 to 5 equivalents of phosphine reagent are used. In some embodiments, approximately 3 equivalents of phosphine are used. In some embodiments, the reaction is carried out in a solvent. In some embodiments, the reaction is carried out in THF. In some embodiments, the reaction is carried out in THF and water. In some embodiments, the reaction is carried out at a temperature ranging from approximately 0°C to approximately 50°C. In some embodiments, the reaction is carried out at a temperature ranging from approximately 0°C to approximately room temperature. In some embodiments, the reaction is carried out at a temperature ranging from approximately room temperature to approximately 50°C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 25°C.

[0196] In some embodiments, the reaction is carried out in the presence of polymer-bound PPh3 in THF and water. In some embodiments, the reaction is carried out under the following conditions: 3 equivalents of polymer-bound PPh3 in THF and water at approximately 25° C. (e.g., for 70 hours).

[0197] In some embodiments, the product is purified and isolated by precipitation. In some embodiments, the product is purified by column chromatography. In some embodiments, the product is isolated and purified using a combination of column chromatography and precipitation.

[0198] In some embodiments, R P6 is hydrogen. In some embodiments, R P6 is an oxygen protecting group. In some embodiments, R P6 is a silyl protecting group. In certain embodiments, one or more free hydroxyl groups of compound (B) and compound (1) are substituted with an oxygen protecting group (e.g., a silyl protecting group).

[0199] Other reagents and conditions may also be used to convert the azide of compound (B) or the compound of formula (H3-N3) to an amine. For example, in some embodiments, the reducing step is carried out in the presence of palladium and hydrogen (e.g., Pd / C and H2). In some embodiments, the reducing step is carried out in the presence of a hydride (i.e., H - ) source is performed.

[0200] As shown in Scheme 4 and provided herein, compounds of formula (H3-N3): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof in the presence of an azide to produce a compound represented by formula (H3-N3), or a salt thereof, wherein: R L is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, or optionally substituted acyl; R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P4 , R P5 , and R P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Yataken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0201] In one embodiment, as shown in Scheme 2, the method comprises reacting a compound of formula (B): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof in the presence of an azide, R L is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, or optionally substituted acyl.

[0202] The reaction to form a compound represented by formula (H3-N3), compound (B), or a salt thereof, is carried out in the presence of an azide. In some embodiments, the azide is an azide salt. In some embodiments, the azide is sodium azide (NaN3) or potassium azide (KN3). In some embodiments, the azide is a tetraalkylammonium azide (i.e., [(alkyl)N]N3). In some embodiments, the azide is tetrabutylammonium azide ([n-BuN]N3). In some embodiments, approximately 1 equivalent of azide is present. In some embodiments, more than 1 equivalent of azide is present. In some embodiments, approximately 1 to 10 equivalents of azide are present. In some embodiments, approximately 5 to 10 equivalents are present. In some embodiments, approximately 8 equivalents of azide are present.

[0203] In some embodiments, the reaction is carried out in a solvent. In some embodiments, the solvent is a polar solvent. In some embodiments, the solvent is a non-polar solvent. In some embodiments, the solvent is toluene. In some embodiments, the reaction is carried out at a temperature above room temperature. In some embodiments, the reaction is carried out at a temperature ranging from room temperature to approximately 150°C. In some embodiments, the reaction is carried out at approximately 100°C.

[0204] In some embodiments, the reaction is carried out in the presence of tetrabutylammonium azide ([n-BuN]N) in toluene. In some embodiments, the reaction is carried out in the presence of tetrabutylammonium azide ([n-BuN]N) in toluene at approximately 100° C. In some embodiments, the reaction is carried out under the following conditions: 8 equivalents of tetrabutylammonium azide ([n-BuN]N) in toluene at approximately 100° C. (e.g., 5 hours).

[0205] In some embodiments, R P6 is hydrogen, and R L is Ts. In some embodiments, R P6 is an oxygen protecting group, and R L is Ts. In some embodiments, R P6 is a silyl protecting group, and R L is Ts. In certain embodiments, one or more free hydroxyl groups of compound (A) and compound (B) are substituted with an oxygen protecting group (eg, a silyl protecting group).

[0206] In some embodiments, the compound of Formula (A) is: [ka] or a salt thereof. "Ts" is a compound of the formula: [ka] It is a tosyl group represented by the formula:

[0207] Also provided herein are compounds of formula (H3-L): [ka] or a salt thereof, the method comprises the step of preparing a compound of formula (H3-OH): [ka] or a salt thereof, L -R L to produce a compound represented by formula (H3-L), or a salt thereof, by reacting in the presence of a reagent represented by formula (H3-L), wherein: R L is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, or optionally substituted acyl; X L is a halogen or a leaving group; R 1 , R 2 , R 3 , and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P4 , R P5 , and R P6are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0208] In some embodiments, the method comprises administering to a subject a compound of formula (A): [ka] or a salt thereof, the method comprising reacting a compound (2): [ka] Compound (2), or a salt thereof, L -R L in the presence of a reagent represented by the formula: X L is a halogen or a leaving group; and R L is optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted phosphoryl, or optionally substituted acyl.

[0209] The reaction to form the compound represented by formula (H3-L), compound (A), or a salt thereof, is carried out by reacting a compound represented by formula X L -R L The entire transformation is carried out in the presence of a reagent of the formula -OR LThe compound is converted into a leaving group represented by the formula (for example, a sulfonyl leaving group).

[0210] In some embodiments, a compound of formula X L -R L is a sulfonating agent. Sulfonating reagents capable of converting a free hydroxyl group into a sulfonate leaving group are known in the art. In some embodiments, a compound represented by formula X L -R L The reagent represented by formula (R L is optionally substituted sulfonyl). In some embodiments, the reagent is a tosyl halide (i.e., X L In some embodiments, the reagent is a sulfonyl chloride (X L is chlorine, and R L is optionally substituted sulfonyl). In some embodiments, the reagent is tosyl chloride (TsCl). In some embodiments, approximately 1 equivalent of the reagent is used. In some embodiments, more than 1 equivalent of the reagent is used. In some embodiments, approximately 3 equivalents of the reagent are used.

[0211] In some embodiments, the reaction is carried out in the presence of one or more additional reagents. In some embodiments, the reaction is carried out in the presence of a base. In some embodiments, the base is a nitrogenous base. In some embodiments, the base is an amine base. In some embodiments, the base is a trialkylamine base. Examples of amine bases include, but are not limited to, triethylamine (TEA) and diisopropylethylamine (DIPEA). In some embodiments, the base is triethylamine (TEA). In some embodiments, the base is a heterocyclic base. Examples of heterocyclic bases include, but are not limited to, pyridine base and imidazole base. In some embodiments, approximately one equivalent of base is used. In some embodiments, more than one equivalent of base is used. In some embodiments, an excess of base (e.g., approximately 6 equivalents) is used.

[0212] In some embodiments, the reaction is carried out in the presence of a Lewis acid. In some embodiments, the Lewis acid is dibutyltin oxide. In some embodiments, the Lewis acid is present in 1 equivalent or less (e.g., 0.5 equivalents).

[0213] In some embodiments, the reaction is carried out in a solvent. In some embodiments, the solvent is dichloromethane (DCM). In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about 50° C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50° C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 25° C.

[0214] In some embodiments, the reaction is carried out in the presence of TsCl, TEA, and a Lewis acid. In some embodiments, the reaction is carried out in the presence of TsCl, TEA, and dibutyltin oxide. In some embodiments, the reaction is carried out in the presence of TsCl, TEA, and dibutyltin oxide in DCM. In some embodiments, the reaction is carried out in the presence of TsCl, TEA, and dibutyltin oxide in DCM at approximately 25° C. In some embodiments, the reaction is carried out under the following conditions: 3 equivalents of TsCl, excess TEA (e.g., approximately 6 equivalents), and less than 1 equivalent (e.g., 0.6 equivalents) of dibutyltin oxide in DCM at approximately 25° C. (e.g., 3 hours).

[0215] In some embodiments, R P6 is hydrogen, and R L is Ts. In some embodiments, R P6 is an oxygen protecting group, and R L is Ts. In some embodiments, R P6 is a silyl protecting group, and R L is Ts. In certain embodiments, one or more free hydroxyl groups of compound (A) and compound (2) are substituted with an oxygen protecting group (e.g., a silyl protecting group).

[0216] Methods for preparing the starting materials (i.e., compounds of formula (H3-OH), compound (2), and salts thereof) are provided herein, by way of example, under the subsection entitled Synthesis of Additional Halichondrin Analogs.

[0217] Preparation of the "right half" building block Also provided herein are methods useful in the preparation of the "right half" building blocks of halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C; and analogs thereof). For example, as described above, compounds of formula (R-2-I) are useful as right half building blocks. As shown below in Scheme 3A, compounds of formula (R-2-I) can be prepared by replacing the substitution (i.e., the group -OR) of compounds of formula (R-4-11B). P7 Base-X 1 The compound of formula (R-4-11B) can be prepared by deprotecting and reprotecting one or more oxygen atoms of the compound of formula (R-4-11A), thereby replacing the group -OR P5 One occurrence of the base -OR P7 As shown in Scheme 3A, compounds of formula (R-4-11) can be prepared by cyclizing compounds of formula (R-4-10). Furthermore, compounds of formula (R-4-10) can be obtained by coupling compounds of formula (R-4-8) with compounds of formula (R-4-9). Scheme 3A [ka]

[0218] As shown in Scheme 3A, provided herein are compounds of formula (R-2-I): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, in the presence of a nucleophilic reagent, thereby forming a group -OR P7 Base-X 1 including substituting into: X 1 is a halogen or a leaving group; R 3 and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P5 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; R P7 is an optionally substituted sulfonyl, an optionally substituted sulfinyl, an optionally substituted phosphoryl, an optionally substituted acyl, or an oxygen protecting group; Optionally, where R P5 and R P7 joins together with the intervening atom to form an optionally substituted heterocyclyl; R X is hydrogen or -OR Xa where R Xais hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0219] In some embodiments, the method comprises administering to a subject a compound of formula (ER): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof in the presence of a nucleophilic reagent, thereby forming a group -OR P7 Base-X 1 including substituting into: X 1 is a halogen or a leaving group; R P5 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R P7 is an optionally substituted sulfonyl, an optionally substituted sulfinyl, an optionally substituted phosphoryl, an optionally substituted acyl, or an oxygen protecting group; Optionally, where R P5 and R P7 is joined together with the intervening atom to form an optionally substituted heterocyclyl.

[0220] As described above, the method for preparing a compound represented by formula (R-2-I), (ER), or a salt thereof, comprises reacting a compound represented by formula (R-4-11B), or a salt thereof, in the presence of a nucleophilic reagent, thereby forming a leaving group -OR P7Base-X 1 In some embodiments, the nucleophile is a halide anion (e.g., Cl). - , Br - , I - , F - In some embodiments, the reaction is carried out in the presence of a halide salt. In some embodiments, the reaction is carried out in the presence of an iodide salt (e.g., NaI, KI), which allows the leaving group -OR P7 is substituted with the group -I. In some embodiments, the iodide salt is sodium iodide (NaI). In some embodiments, the reaction is carried out in the presence of NaI. In some embodiments, the reaction is carried out in a polar solvent (e.g., DMF or DMI). In some embodiments, the reaction is carried out at a temperature ranging from about 0°C to about 50°C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50°C. In some embodiments, the reaction is carried out at about room temperature.

[0221] In some embodiments, the reaction is carried out in the presence of NaI in DMI at about room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 5 equivalents of NaI in DMF at room temperature (e.g., for 2-5 hours). For example, in some embodiments, the reaction is carried out under the following conditions: 5 equivalents of NaI in DMI at room temperature (e.g., for 2-5 hours).

[0222] In some embodiments, the group -OR P7 is a leaving group. In some embodiments, the group -OR P7 is -O-sulfonyl. In some embodiments, the group -OR P7 In some embodiments, the group -OR P7 In some embodiments, the group -OR P7 is -OTf. In some embodiments, the group -OR P7 is -O-acyl. In some embodiments, the group -OR P7 is -O-phosphoryl. In some embodiments, R P5 is a silyl protecting group. In some embodiments, R P5is TES. In some embodiments, -OR P7 is -OTf, and R P5 is TES.

[0223] As shown in Scheme 3A, the compound of formula (R-4-11B) can be prepared by deprotecting and reprotecting one or more oxygen atoms of the compound of formula (R-4-11A), thereby forming the group -OR P5 One of the bases -OR P7 It can be prepared by converting

[0224] For example, in certain embodiments, provided herein are methods for preparing a compound represented by formula (R-4-11B), or a salt thereof, the methods comprising: (a) Formula (R-4-11A): [ka] or a salt thereof to obtain a compound represented by formula (R-4-11C): [ka] or a salt thereof, followed by one or more steps of (b) reprotecting a compound of formula (R-4-11C) or a salt thereof to produce a compound of formula (R-4-11B) or a salt thereof.

[0225] In one embodiment, the method comprises: (a) Formula (ER-2): [ka] or a salt thereof, to obtain a compound represented by the formula: [ka] or a salt thereof; and (b) Reprotecting the product of step (a) to obtain a compound of formula (ER-1): [ka] or a salt thereof, wherein: R P5 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R P7 is an optionally substituted sulfonyl, an optionally substituted sulfinyl, an optionally substituted phosphoryl, an optionally substituted acyl, or an oxygen protecting group; Optionally, where R P5 and R P7 is joined together with the intervening atom to form an optionally substituted heterocyclyl.

[0226] As shown above, the compounds of formula (R-4-11A) and (ER-2) can be deprotected to form the group R P5 may be removed (i.e., step (a)). In some embodiments, R P5 The R group is a silyl protecting group; and step (a) is carried out in the presence of a fluoride source. In some embodiments, the fluoride source is tetrabutylammonium fluoride (TBAF). In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] and step (a) is carried out in the presence of an acid. P5 are bonded together with the intervening atoms to form the formula: [ka] and step (a) is carried out in the presence of an acid. In some embodiments, the acid is p-toluenesulfonic acid (TsOH). In some embodiments, the acid is p-toluenesulfonic acid monohydrate (TsOH·HO). In some embodiments, the acid is present in a catalytic amount.

[0227] In some embodiments, the deprotection step is carried out in DCM and an alcohol (e.g., ROH). In some embodiments, the deprotection is carried out in DCM and MeOH. In some embodiments, the reaction is carried out at a temperature ranging from about 0°C to about 50°C. In some embodiments, the deprotection is carried out at about room temperature. In some embodiments, the deprotection is carried out at about 25°C.

[0228] In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] and deprotection is carried out in the presence of TsOH·HO in DCM and alcohol. In some embodiments, deprotection is carried out under the following conditions: at about 25° C. (e.g., for 4 hours) under the catalyst TsOH·HO (e.g., 0.02 equivalents) in DCM and MeOH.

[0229] In some embodiments, on the compound represented by formula (R-4-11B) or (ER-1), -OR P7 is a sulfonate leaving group, and R P5 is a silyl protecting group; and step (b) is carried out in the presence of a sulfonating reagent and a base (whereby R P7 is introduced as a sulfonyl group), which is then carried out in the presence of a silylating reagent and a base (whereby R P5is introduced as a silyl group). In some embodiments, the sulfonating reagent is a triflating agent. In some embodiments, the sulfonating reagent is TfO. In some embodiments, the silylating reagent is TESOTf. In some embodiments, the base is an amine or a pyridine base. In some embodiments, the base is 2,4,6-collidine.

[0230] In some embodiments, the protecting step is carried out in a solvent. In some embodiments, the solvent is DCM. In some embodiments, the protecting step is carried out at a temperature below room temperature (e.g., from about −78° C. to −40° C.; from about −78° C. to 0° C.; from about −78° C. to room temperature).

[0231] In some embodiments, -OR P7 is -OTf, and R P5 is TES; and step (b) is carried out in the presence of TfO and a base, followed by TESOTf and a base. In some embodiments, the reaction is carried out in the presence of TfO and 2,4,6-collidine in DCM, followed by the addition of TESOTf. In some embodiments, the reaction is carried out under the following conditions: approximately 1.4 equivalents of TfO and 5 equivalents of 2,4,6-collidine in DCM at approximately -78°C, followed by the addition of 1.4 equivalents of TESOTf and warming to approximately -40°C.

[0232] As shown in Scheme 3A and provided herein, compounds of formula (R-4-11A): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof, wherein: R 3 and R5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P5 and R P8 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0233] In some embodiments, the method comprises administering to a subject a compound of formula (ER-3): [ka] or a salt thereof to obtain a compound represented by formula (ER-2): [ka] or a salt thereof, wherein: R P5 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0234] In some embodiments, the step of cyclizing the compound represented by formula (R-4-10), (ER-3), or a salt thereof, is carried out in the presence of an anhydride reagent. In some embodiments, the anhydride reagent is benzoic anhydride. In some embodiments, the reagent is nitrobenzoic anhydride. In some embodiments, the anhydride is 2-methyl-6-nitrobenzoic anhydride (MNBA). The anhydride reagent may be present in a catalytic amount, a stoichiometric amount, or an excess amount. In some embodiments, the anhydride reagent is present in excess (i.e., greater than 1 equivalent) relative to the compound represented by formula (R-4-10) or (ER-3). In some embodiments, the anhydride is present in approximately 3 equivalents.

[0235] In some embodiments, the reaction is carried out by reacting a carboxyl group -COR 8or is carried out in the presence of a nucleophile capable of activating -COH. In some embodiments, the nucleophile is pyridine. In some embodiments, the nucleophile is 4-dimethylaminopyridine (DMAP). In some embodiments, the nucleophile is present in excess (i.e., greater than 1 equivalent) relative to the compound represented by formula (R-4-10) or (ER-3). In some embodiments, the reagent is present in approximately 6 equivalents.

[0236] In some embodiments, the cyclizing step is carried out in the presence of a base. In some embodiments, the base is a nitrogenous base. In some embodiments, the base is an amine base. In some embodiments, the base is a trialkylamine base (e.g., trimethylamine, triethylamine, tributylamine, diisopropylethylamine). In some embodiments, the base is a heteroaryl base (e.g., pyridine base, imidazole base). In some embodiments, the base is diisopropylethylamine (DIPEA). In some embodiments, the base is present in excess (i.e., greater than 1 equivalent) relative to the compound represented by Formula (R-4-10). In some embodiments, the base is present in approximately 6 equivalents.

[0237] In some embodiments, the cyclizing step is carried out in a solvent (e.g., toluene). In some embodiments, the reaction is carried out at a temperature above room temperature. In some embodiments, the deprotection is carried out in DCM and MeOH. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100°C. In some embodiments, the reaction is carried out at about 70°C or 80°C.

[0238] In some embodiments, the cyclizing step is carried out in the presence of an anhydride reagent, a nucleophile, and a base. In some embodiments, the anhydride reagent is 2-methyl-6-nitrobenzoic anhydride. In some embodiments, the nucleophile is DMAP. In some embodiments, the base is a trialkylamine base, such as DIPEA. In some embodiments, the step is carried out in the presence of 2-methyl-6-nitrobenzoic anhydride (MNBA), 4-dimethylaminopyridine (DMAP), and diisopropylethylamine (DIPEA).

[0239] For example, in some embodiments, the cyclizing step is carried out under the following conditions: 6 equivalents MNBA, 12 equivalents DMAP, and 6 equivalents DIPEA in toluene at approximately 70° C. For example, in some embodiments, the cyclizing step is carried out under the following conditions: 3 equivalents MNBA, 6 equivalents DMAP, and 6 equivalents DIPEA in toluene at approximately 80° C. (e.g., for 6 hours). In some embodiments, the reaction involves the slow addition (i.e., dropwise addition) of a compound represented by formula (R-4-10) or (ER-3), or a salt thereof, to the reaction mixture.

[0240] In some embodiments, the compound of formula (R-4-10) has formula (R-4-10A): [ka] or a salt thereof.

[0241] In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] and R 8 is hydrogen. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] and R 8 is hydrogen.

[0242] Also provided herein is a compound of formula (R-4-10): [ka] or a salt thereof, the method comprising the steps of: (a) Formula (R-4-8): [ka] or a salt thereof, with a compound represented by formula (R-4-9): [ka] or a salt thereof, to obtain a compound represented by formula (R-4-10B): [ka] or a salt thereof, (b) cyclizing a compound of formula (R-4-10B), or a salt thereof, to produce a compound of formula (R-4-10), or a salt thereof, wherein: X 3 and X 2 are each independently a halogen or a leaving group; R 3 and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R 6 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 6 The bases, taken together, are: [ka] form; R P5 and R P8 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R X is hydrogen or -OR Xa where R Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Y is hydrogen or -OR Ya where R Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; Optionally, where R Xa and R Ya taken together with these intervening atoms to form an optionally substituted heterocyclyl.

[0243] In one embodiment, the method comprises: (a) Formula (ER-4): [ka] or a salt thereof, [ka] or a salt thereof, to obtain a compound represented by formula (ER-6): [ka] or a salt thereof, followed by (b) Cyclizing a compound represented by formula (ER-6) or a salt thereof to obtain a compound represented by formula (ER-7): [ka] or a salt thereof, wherein: X 3 and X 2 are each independently a halogen or a leaving group; R P5 and R P8 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0244] In certain embodiments, step (a) above (to prepare a compound represented by formula (R-4-10B), (ER-6), or a salt thereof) is a Ni / Cr-mediated reductive coupling reaction; and step (b) above (to prepare a compound represented by formula (R-4-10), (ER-7), or a salt thereof) is an acid-promoted or base-promoted intramolecular furan cyclization. Reagents and conditions for steps (a) and (b) can be found, by way of example, in International PCT Application Publication Nos. WO 2016 / 176560, published November 3, 2016, and WO 2016 / 003975, published January 7, 2016, the entire contents of which are incorporated herein by reference.

[0245] The Ni / Cr-mediated reductive coupling (i.e., step (a)) is carried out in the presence of nickel and chromium. In some embodiments, the nickel is a nickel complex. Examples of nickel complexes include, but are not limited to, those shown in FIG. 9B. In some embodiments, the nickel complex is (Et)Phen·NiCl. In some embodiments, the nickel complex is the following: [ka] In some embodiments, the nickel complex is present in a catalytic amount.

[0246] In some embodiments, the chromium is a chromium complex. In some embodiments, the chromium complex is prepared from a chromium salt and a chiral ligand. In some embodiments, the chromium salt is CrCl2 or CrCl3. In some embodiments, the chiral ligand is a chiral sulfonamide. Examples of chiral ligands include, but are not limited to, those shown in Figure 9B. In some embodiments, the chiral ligand is (S)-4-G. In some embodiments, the chiral sulfonamide ligand is the following: [ka] or a salt thereof. In some embodiments, the chromium complex is present in a catalytic amount.

[0247] The Ni / Cr-mediated reductive coupling may be carried out in the presence of one or more additional reagents. In some embodiments, the coupling is carried out in the presence of a lithium salt (e.g., LiCl or LiBr). In some embodiments, the coupling is carried out in the presence of a reducing metal such as zinc or manganese (e.g., zinc or manganese metal). In some embodiments, the coupling is carried out in the presence of zirconium (e.g., ZrCp2Cl2). In some embodiments, the reducing metal is zinc metal. In some embodiments, the metal is manganese metal. In some embodiments, the coupling is carried out in the presence of a base or a proton scavenger (e.g., 2,6-di-tert-butyl-4-methylpyridine). In some embodiments, the coupling is carried out in the presence of a proton sponge (e.g., 1,8-bis(dimethylamino)naphthalene).

[0248] In some embodiments, the reaction is carried out in a solvent. In some embodiments, the solvent is acetonitrile (MeCN). In some embodiments, the deprotection is carried out in DCM and MeOH. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100°C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50°C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 30°C.

[0249] In some embodiments, the Ni / Cr-mediated reductive coupling is carried out in the presence of a nickel complex, a chromium salt, a sulfonamide ligand, a lithium salt, a zirconium complex, a reducing metal, and a base or proton scavenger. In some embodiments, the coupling step is carried out in the presence of (Et)Phen·NiCl, CrCl, (S)-4-G, LiCl, ZrCpCl, manganese metal, and a base or proton scavenger (e.g., 2,6-di-tert-butyl-4-methylpyridine). For example, in some embodiments, the reaction is carried out under the following conditions: 2 mol% (Et)Phen·NiCl, 10 mol% CrCl, 10 mol% ligand (S)-4-G, 2 equivalents of LiCl, 2.5 equivalents of ZrCpCl, excess manganese metal, and 2.5 equivalents of 2,6-di-tert-butyl-4-methylpyridine in MeCN at room temperature (e.g., for 2 hours).

[0250] In some embodiments, the Ni / Cr-mediated reductive coupling is carried out in the presence of a nickel complex, a chromium salt, a sulfonamide ligand, a zirconium complex, a reducing metal, and a base or proton scavenger. [ka] Nickel complexes, CrCl3, represented by the formula: [ka] In some embodiments, the reaction is carried out in the presence of a sulfonamide ligand of the formula: CpZrCl, manganese metal, and a base or proton scavenger (e.g., 2,6-di-tert-butyl-4-methylpyridine and / or a proton sponge (e.g., 1,8-bis(dimethylamino)naphthalene)). In some embodiments, the reaction is carried out in MeCN. In some embodiments, the reaction is carried out at approximately 30°C. For example, the coupling can be carried out under the following conditions: 3 mol% of a compound of the formula: [ka] Nickel complex, 20 mol% CrCl3, 20 mol% of the formula: [ka] The reaction can be carried out using a sulfonamide ligand represented by the formula (I), 2.6 equivalents of Cp2ZrCl2, 2 equivalents of manganese metal, and 2 equivalents of 2,6-di-tert-butyl-4-methylpyridine, and proton sponge.

[0251] In some embodiments, step (b) (preparing a compound represented by formula (R-4-10), (ER-7), or a salt thereof) is carried out in the presence of a Lewis acid. In some embodiments, the Lewis acid is AgOTf. In some embodiments, the Lewis acid is AgO. In some embodiments, the Lewis acid is SrCO. The Lewis acid may be present in a catalytic amount, a stoichiometric amount, or an excess amount. In other embodiments, step (b) is carried out in the presence of a base. In some embodiments, the base is a carbonate salt. In some embodiments, the base is potassium carbonate (KCO).

[0252] In some embodiments, the reaction is carried out in a solvent. In some embodiments, the solvent is MeOH. In some embodiments, the solvent is MeCN. In some embodiments, the reaction is carried out in MeOH and water. In some embodiments, the reaction is carried out at a temperature above room temperature. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100°C. In some embodiments, the reaction is carried out at 50-60°C. In some embodiments, the reaction is carried out at approximately 60°C. In some embodiments, the reaction is carried out at approximately 55°C.

[0253] In some embodiments, in addition to affecting furan cyclization, the reaction conditions also affect the ester-COR 8 (where R 8 is also sufficient to hydrolyze the product (ER-7) or (R-4-10) which is hydrogen).

[0254] For example, in some embodiments, the reaction is carried out under the following conditions: 10 equivalents of K2CO3 in MeCN at 60° C. (e.g., for 3 hours). In some embodiments, the reaction is carried out in the presence of MeOH and K2CO3 in water at approximately 55° C. As another example, the reaction can be carried out under the following conditions: 10 equivalents of K2CO3 in MeOH and water at approximately 55° C. (e.g., for 23 hours).

[0255] In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is hydrogen; and R 8 is optionally substituted alkyl or hydrogen. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is hydrogen; and R 8 is methyl. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is hydrogen; and R 8 is hydrogen.

[0256] As shown in Scheme 3B, the compound represented by formula (R-4-8) can be prepared by reacting the ester moiety (—COR) of the compound represented by formula (R-4-7). 8Compounds of formula (R-4-7) can be prepared by coupling a compound of formula (R-4-5B) with a compound of formula (R-4-6), followed by the formation of a pyran ring via cyclization of the adduct or the deprotected form of the adduct. Compounds of formula (R-4-5B) can then be prepared by coupling the ester moiety (-COR) of a compound of formula (R-4-5A) with the ester moiety (-COR). 8 The compound of formula (R-4-5A) can be prepared by cyclization of the compound of formula (R-4-4), which can be prepared by coupling the compound of formula (R-4-2) with the olefin of formula (R-4-3). As shown in Scheme 3B, the compound of formula (R-4-2) can be prepared by reducing the lactone of the compound of formula (R-4-1). Scheme 3B [ka]

[0257] As shown in Scheme 3B, provided herein are compounds of formula (R-4-8): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 3 and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R P5 and R P8 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0258] In some embodiments, the method comprises administering to a subject a compound of formula (ER-8): [ka] or a salt thereof, to obtain a compound represented by formula (ER-4): [ka] or a salt thereof, wherein: R P5 and R P8 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0259] The step of reducing the compound represented by formula (R-4-7) or (ER-8) or a salt thereof is carried out by reducing the ester group -CO2R 8to an aldehyde group. In some embodiments, the reducing step is carried out by converting a hydride (i.e., H - The reaction is carried out in the presence of a hydride source. Any hydride source known in the art may be used in this transformation. Examples of hydride sources include, but are not limited to, lithium aluminum hydride (LAH), sodium borohydride (NaBH), lithium borohydride, and diisobutylaluminum hydride (DIBAL). In some embodiments, the hydride source is diisobutylaluminum hydride (DIBAL). In some embodiments, the hydride source is present in a stoichiometric amount or in an excess amount.

[0260] The reducing step may optionally be -CO2R 8 The reaction may include reducing the moiety to an alcohol, followed by oxidation of the resulting alcohol to an aldehyde, to produce a compound of formula (R-4-7), (R-8), or a salt thereof.

[0261] In some embodiments, the reducing step is carried out in the presence of DIBAL. In some embodiments, the reaction is carried out in a solvent. In some embodiments, the solvent is DCM. In some embodiments, the reaction is carried out at a temperature below room temperature. In some embodiments, the reaction is carried out at a temperature ranging from about -78°C to about room temperature. In some embodiments, the reaction is carried out at a temperature ranging from about -78°C to about 0°C. In some embodiments, the reaction is carried out at about -78°C. For example, in some embodiments, the reaction is carried out under the following conditions: DIBAL in DCM at about -78°C. For example, in some embodiments, the reaction is carried out under the following conditions: about 2.3 equivalents of DIBAL in DCM at about -78°C (e.g., for 1 to 2 hours).

[0262] In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is hydrogen; and R 8 is optionally substituted alkyl. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is hydrogen, and R 8 is ethyl. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is hydrogen, and R 8 is methyl.

[0263] As shown in Scheme 3B and provided herein, compounds of formula (R-4-7): [ka] or a salt thereof, the method comprising: Formula (R-4-5B): [ka] or a salt thereof, with a compound represented by formula (R-4-6): [ka] or a salt thereof, to obtain a compound represented by formula (R-4-7A): [ka] or a salt thereof; and (ai) deprotecting and cyclizing a compound of formula (R-4-7A), or a salt thereof, to give a compound of formula (R-4-7), or a salt thereof; R 3 and R 5 are each independently hydrogen, halogen, or optionally substituted alkyl; R 4 Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R 4 The bases, taken together, are: [ka] form; R P5 , R P8 , and R P9 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 groups, together with the intervening atoms, join to form an optionally substituted heterocyclyl ring; and optionally, where two R P9 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0264] In some embodiments, after the step of coupling the compounds represented by formula (R-4-5B) and (R-4-6) (i.e., step (a)), the method further comprises the steps of: (b) Deprotecting the compound represented by formula (R-4-7A) or a salt thereof to obtain a compound represented by formula (R-4-7B): [ka] or a salt thereof; (c) Cyclization to form a compound of formula (R-4-7C): [ka] or a salt thereof; and optionally (d) Reprotecting a compound represented by formula (R-4-7C) or a salt thereof with one or more oxygen atoms to obtain a compound represented by formula (R-4-7B): [ka] or a salt thereof.

[0265] In one embodiment, the method comprises: (a) Equation (ER-9): [ka] or a salt thereof, [ka] or a salt thereof, to obtain a compound represented by formula (ER-11): [ka] or a salt thereof; (b) A compound represented by formula (ER-11) or a salt thereof is reacted with a group R P5 and R P8 and deprotecting the compound under conditions sufficient to remove the compound of formula (ER-12): [ka] or a salt thereof; and (c) Deprotecting and cyclizing the compound represented by formula (ER-12) or a salt thereof to obtain a compound represented by formula (ER-13): [ka] or a salt thereof; (d) Protecting a compound represented by formula (ER-13) or a salt thereof to obtain a compound represented by formula (ER-14): [ka] or a salt thereof; R P5 , R P8 , and R P9 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 groups, together with the intervening atoms, join to form an optionally substituted heterocyclyl ring; and optionally, where two R P9 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0266] In some embodiments, step (a) above (to prepare a compound represented by formula (R-4-7A), (ER-11), or a salt thereof) is a Ni / Cr-mediated reductive coupling reaction; and step (ai) or (c) above (to form a compound represented by formula (R-4-7), (ER-13), or a salt thereof) is a ketal deprotection and acid-promoted intramolecular pyran cyclization. Reagents and conditions for steps (a), (ai), and / or (c) above can be found, for example, in International PCT Publication Nos. WO 2016 / 176560, published November 3, 2016, and WO 2016 / 003975, published January 7, 2016; the entire contents of each of which are incorporated herein by reference.

[0267] The Ni / Cr-mediated reductive coupling (i.e., step (a)) is carried out in the presence of nickel and chromium. In some embodiments, the nickel is a nickel complex. Examples of nickel complexes include, but are not limited to, those shown in FIG. 9B. In some embodiments, the nickel complex is (Et)Phen·NiCl. In some embodiments, the nickel complex is the following: [ka] In some embodiments, the nickel complex is present in a catalytic amount.

[0268] In some embodiments, the chromium is a chromium complex. In some embodiments, the chromium complex is prepared from a chromium salt and a chiral ligand. In some embodiments, the chromium salt is CrCl2 or CrCl3. In some embodiments, the chiral ligand is a chiral sulfonamide. Examples of chiral ligands include, but are not limited to, those shown in Figure 9B. In some embodiments, the chiral ligand is (S)-4-G. In some embodiments, the sulfonamide ligand is the following: [ka] or a salt thereof. In some embodiments, the chromium complex is present in a catalytic amount.

[0269] The Ni / Cr-mediated reductive coupling may be carried out in the presence of one or more additional reagents. In some embodiments, the coupling is carried out in the presence of a lithium salt (e.g., LiCl). In some embodiments, the coupling is carried out in the presence of a reducing metal such as zinc or manganese (e.g., zinc or manganese metal). In some embodiments, the reducing metal is zinc metal. In some embodiments, the reducing metal is manganese metal. In some embodiments, the coupling is carried out in the presence of zirconium (e.g., ZrCp2Cl2). In some embodiments, the coupling is carried out in the presence of a base or a proton scavenger (e.g., 2,6-di-tert-butyl-4-methylpyridine). In some embodiments, the coupling is carried out in the presence of a proton sponge (e.g., 1,8-bis(dimethylamino)naphthalene).

[0270] In some embodiments, the reaction is carried out in a solvent. In some embodiments, the solvent is MeCN. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100°C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50°C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 40°C.

[0271] In some embodiments, the Ni / Cr-mediated reductive coupling is carried out in the presence of a nickel complex, a chromium salt, a sulfonamide ligand, a lithium salt, a zirconium complex, a reducing metal, and a base or proton scavenger. In some embodiments, the coupling step is carried out in the presence of (Et)Phen·NiCl, CrCl, (S)-4-F, LiCl, manganese metal, and ZrCpCl. For example, in some embodiments, the reaction is carried out under the following conditions: 2 mol% (Et)Phen·NiCl, 10 mol% CrCl, 10 mol% ligand (S)-4-F, 2 equivalents of LiCl, excess manganese metal, and 2.5 equivalents of ZrCpCl in MeCN at room temperature (e.g., for 3 hours).

[0272] In some embodiments, the coupling is performed by coupling a compound of the formula: [ka] The nickel complex, CrCl2, has the formula: [ka] In some embodiments, the reaction is carried out in the presence of a sulfonamide ligand represented by the formula: CpZrCl, manganese metal, and a base or proton scavenger (e.g., 2,6-di-tert-butyl-4-methylpyridine and / or a proton sponge (e.g., 1,8-bis(dimethylamino)naphthalene)). In some embodiments, the reaction is carried out in MeCN at approximately 40° C. For example, in some embodiments, the reaction is carried out under the following conditions: at approximately 40° C. (e.g., for 19 hours) in MeCN at 0.5 mol % or more of a compound of the formula: [ka] Nickel complex, 20 mol% CrCl2, 20 mol% represented by the formula: [ka] The reaction was carried out using a sulfonamide ligand represented by the formula (I), 1.1 equivalents of Cp2ZrCl2, 4 equivalents of manganese metal, and a proton sponge.

[0273] In some embodiments, R P5 and R P8 is a silyl protecting group; and the deprotection in step (b) is carried out in the presence of a fluoride source. In some embodiments, the fluoride source is tetrabutylammonium fluoride (TBAF).

[0274] In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] form a ring represented by two R P9 Tie together the following: [ka] Forming;R P8 is an optionally substituted benzyl or an optionally substituted silyl protecting group; and R 8 is optionally substituted alkyl. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] form a ring represented by two R P9 are joined together, [ka] Forming;R P8 is MPM;R 8 is ethyl. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] form a ring represented by two R P9 are joined together, [ka] Forming;R P8 is TBS; and R 8 is methyl.

[0275] The ketal deprotection and acid-promoted intramolecular pyran cyclization in steps (ai) and (c) (to form a compound of formula (R-4-7), (ER-13), or a salt thereof) involves deprotecting the ketal of the starting material, followed by a cyclization reaction to provide a new six-membered ring of a compound of formula (R-4-7) or (ER-13). The deprotection and cyclization may be performed in the same step or in separate steps, in either order. In certain embodiments, the deprotection and cyclization steps are performed in the presence of an acid (e.g., a Lewis acid or a Bronsted acid). In certain embodiments, the acid is a Lewis acid. In certain embodiments, the deprotection and cyclization steps are performed in the presence of a hydride source.

[0276] In some embodiments, the deprotecting and cyclizing step is carried out in the presence of a trialkylsilyl sulfonate or a trialkylsilyl halide. In some embodiments, the deprotecting and cyclizing step is carried out in the presence of triethylsilyl trifluoromethyl sulfonate (TESOTf). In some embodiments, the deprotecting and cyclizing step is carried out in the presence of trimethylsilyl trifluoromethyl sulfonate (TMSOTf). In some embodiments, TESOTf or TMSOTf is present in a stoichiometric amount or in excess.

[0277] In certain embodiments, the deprotecting and cyclizing steps are carried out in the presence of a trialkylsilane. In certain embodiments, the deprotecting and cyclizing steps are carried out in the presence of triethylsilane (EtSiH). In certain embodiments, EtSiH is present in a stoichiometric amount or in excess.

[0278] In some embodiments, the reaction is carried out in a solvent (e.g., CH2Cl2). In some embodiments, the reaction is carried out at a temperature below room temperature. In some embodiments, the reaction is carried out at approximately 0°C. In some embodiments, the reaction is carried out at a temperature ranging from approximately -78°C to approximately 0°C. In some embodiments, the reaction is carried out at a temperature ranging from approximately -78°C to approximately room temperature.

[0279] In certain embodiments, the deprotecting and cyclizing step is carried out in the presence of a Lewis acid and a hydride source. In certain embodiments, the reaction is carried out in the presence of TESOTf and triethylsilane. In certain embodiments, the reaction is carried out in the presence of TESOTf and triethylsilane in DCM at about 0° C. In certain embodiments, the reaction is carried out in the presence of TMSOTf and triethylsilane. In certain embodiments, the reaction is carried out in the presence of TMSOTf and triethylsilane in DCM at a temperature ranging from about −78° C. to about 0° C. In certain embodiments, the reaction is carried out under the following conditions: 10 equivalents triethylsilane, 5 equivalents TESOTf in DCM at about 0° C. (e.g., for 3 hours). As another example, in certain embodiments, the reaction is carried out under the following conditions: 5 equivalents triethylsilane, 5 equivalents TMSOTf in DCM at a temperature ranging from about −78° C. to about 0° C. (e.g., for 1 hour).

[0280] In some embodiments, the step of reprotecting the compound represented by formula (R-4-7C), (ER-13), or a salt thereof (i.e., step (d)) comprises reacting R P5 In some embodiments, the resulting R P5 The groups are linked together to form the following formula: [ka] In some embodiments, R P5 The group has the formula: [ka] In some embodiments, the reaction is carried out in the presence of a ketal or ketone; and an acid. In some embodiments, the ketal has the formula: [ka] (2,2-dimethoxypropane). In some embodiments, the acid is pyridinium p-toluenesulfonate (PPTS). In some embodiments, the reaction is carried out in the presence of 2,2-dimethoxypropane and PPTS. In some embodiments, the reaction is carried out in a solvent (e.g., THF). In some embodiments, the reaction is carried out in the presence of 2,2-dimethoxypropane in THF and PPTS at approximately 40° C. In some embodiments, the protection is carried out under the following conditions: 4 equivalents of 2,2-dimethoxypropane and 5 mol% PPTS in THF at approximately 40° C. (e.g., 4-5 hours).

[0281] In some embodiments, the compound represented by formula (ER-14), (ER-8), (R-4-7), or (R-4-7B), or a salt thereof, is purified by any combination of silica gel column chromatography, ODS (octadecylsilyl) column chromatography, and recrystallization.

[0282] Also provided herein are compounds of formula (R-4-5B): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 3 is hydrogen, halogen, or optionally substituted alkyl; R P5 and R P8 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0283] In some embodiments, the method comprises administering to a subject a compound of formula (ER-15): [ka] or a salt thereof to obtain a compound represented by formula (ER-9): [ka] or a salt thereof, wherein: R P5 and R P8 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0284] The step of reducing the compound represented by (R-4-5A) or (ER-15) or a salt thereof is carried out by -CO2R 8 In some embodiments, the reducing step converts the moiety to an aldehyde. - The reaction is carried out in the presence of a hydride source. Any hydride source known in the art may be used in this transformation. Examples of hydride sources are provided herein. In some embodiments, the hydride source is diisobutylaluminum hydride (DIBAL). In some embodiments, a stoichiometric or excess amount of DIBAL is used in the reaction.

[0285] The reducing step may optionally be -CO2R 8 The compound may comprise reducing the moiety to an alcohol, followed by oxidation of the resulting alcohol to an aldehyde, to produce a compound of formula (R-4-5B) or (ER-9), or a salt thereof.

[0286] In some embodiments, the reducing step is carried out in the presence of DIBAL. In some embodiments, the reaction is carried out in a solvent (e.g., DCM). In some embodiments, the reaction is carried out at a temperature below room temperature. In some embodiments, the reaction is carried out at approximately -78°C. In some embodiments, the reaction is carried out at a temperature ranging from approximately -70°C to approximately -78°C. In some embodiments, the reaction is carried out at a temperature ranging from approximately -78°C to approximately 0°C. In some embodiments, the reaction is carried out at a temperature ranging from approximately -78°C to approximately room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: -78°C (e.g., for 1 to 2 hours) with DIBAL in DCM. For example, in some embodiments, the reaction is carried out under the following conditions: -70°C to -78°C (e.g., for 1 to 2 hours) with 2.3 equivalents of DIBAL in DCM.

[0287] In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is an optionally substituted benzyl or an optionally substituted silyl protecting group; and R 8 is optionally substituted alkyl. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is the MPM; and R 8 is methyl. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is TBS; and R 8 is methyl.

[0288] Also provided herein is a compound of formula (R-4-5A): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof, wherein: R 3 is hydrogen, halogen, or optionally substituted alkyl; R P5 , R P8 , and R P10 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0289] In some embodiments, the method comprises administering to a subject a compound of formula (ER-16): [ka] or a salt thereof to obtain a compound represented by formula (ER-15): [ka] or a salt thereof, wherein: R P5 and R P8 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0290] In some embodiments, the step of cyclizing the compound represented by formula (R-4-4) or (ER-16), or a salt thereof, is carried out in the presence of a base. Any base may be used in this cyclization reaction. In some embodiments, the base is a phosphate salt. In some embodiments, the base is potassium phosphate (K3PO4). In some embodiments, the base is present in one equivalent or less. In some embodiments, the base is present in an excess amount.

[0291] In some embodiments, the cyclizing step is carried out in the presence of one or more additional reagents, such as a metal chelator. In some embodiments, the reaction is carried out in the presence of a crown ether (e.g., 18-crown-6). In some embodiments, the reaction is carried out in the presence of 18-crown-6. In some embodiments, one equivalent or less of 18-crown-6 is used.

[0292] In some embodiments, the reaction is carried out in the presence of a solvent. In some embodiments, the solvent is toluene and / or MeOAc. In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about 50° C. In some embodiments, the reaction is carried out from 0° C. to room temperature. In some embodiments, the reaction is carried out at about room temperature.

[0293] In some embodiments, the cyclizing step is carried out in the presence of a base and a crown ether. In some embodiments, the reaction is carried out in the presence of KPO and 18-crown-. For example, in some embodiments, the reaction is carried out under the following conditions: 1 equivalent of KPO, 3 equivalents of 18-crown-6 in toluene at room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 0.3 equivalents of KPO, 0.9 equivalents of 18-crown-6 in toluene and MeOAc at approximately 3° C. (e.g., 1-2 hours).

[0294] In some embodiments, the compound of formula (R-4-4) has formula (R-4-4A): [ka] or a salt thereof.

[0295] In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by RP8 is an optionally substituted benzyl or an optionally substituted silyl protecting group; and R 8 is optionally substituted alkyl. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is the MPM; and R 8 is methyl. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is TBS; and R 8 is methyl.

[0296] In some embodiments, the compound represented by formula (R-4-5A) or (ER-15), or a salt thereof, is purified by silica gel column chromatography and / or recrystallization.

[0297] Also provided herein is a compound of formula (R-4-4): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof, with a compound represented by formula (R-4-3): [ka] or a salt thereof, wherein X 4is a halogen or a leaving group; R 3 is hydrogen, halogen, or optionally substituted alkyl; R P5 and R P10 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0298] In some embodiments, coupling a compound represented by formula (R-4-2) and a compound represented by formula (R-4-3) provides a compound represented by formula (R-4-4A): [ka] and a method for preparing a compound represented by formula (R-4-4) or a salt thereof, includes protecting an oxygen atom of a compound represented by formula (R-4-4A) or a salt thereof (e.g., a group R P8 The method further comprises deprotecting the compound to remove the protecting group R P10 may include the step of removing

[0299] In some embodiments, the method comprises administering to a subject a compound of formula (ER-17): [ka] or a salt thereof, with a compound represented by formula (R-4-3): [ka] or a salt thereof, to obtain a compound represented by formula (ER-18): [ka] or a salt thereof, wherein: X 4 is a halogen or a leaving group; R 3 is hydrogen, halogen, or optionally substituted alkyl; R P5 and R P10 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 the groups, together with the intervening atoms, form an optionally substituted heterocyclyl ring; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0300] In some embodiments, the method includes the steps of: (a) protecting the free hydroxyl group of a compound represented by formula (ER-18), or a salt thereof; and (b) deprotecting the resulting compound to provide a group R P10 The method further comprises the step of removing

[0301] In some embodiments, coupling a compound represented by formula (R-4-2) and a compound represented by formula (R-4-3) to produce a compound represented by formula (R-4-4) (or coupling a compound represented by formula (ER-17) and a compound represented by formula (R-4-3) to produce a compound represented by formula (ER-18)) is a Ni / Cr-mediated coupling. The Ni / Cr-mediated reductive coupling is carried out in the presence of nickel and chromium. In some embodiments, the nickel is a nickel complex. Examples of nickel complexes include, but are not limited to, those shown in FIG. 9B. In some embodiments, the nickel complex is (Me)Phen(OMe)NiCl. In some embodiments, the nickel complex is present in a catalytic amount. In some embodiments, the nickel complex is one of the following: [ka] is.

[0302] In some embodiments, the chromium is a chromium complex. In some embodiments, the chromium complex is prepared from a chromium salt and a chiral ligand. In some embodiments, the chromium salt is CrCl3 or CrCl2. In some embodiments, the chiral ligand is a chiral sulfonamide. Examples of chiral ligands include, but are not limited to, those shown in Figure 9B. In some embodiments, the chiral ligand is (R)-4-E. In some embodiments, the chromium complex is present in a catalytic amount. In some embodiments, the sulfonamide ligand is one of the following: [ka] or a salt thereof.

[0303] The Ni / Cr-mediated reductive coupling may be carried out in the presence of one or more additional reagents. In some embodiments, the coupling is carried out in the presence of a lithium salt (e.g., LiCl). In some embodiments, the coupling is carried out in the presence of a reducing metal such as zinc or manganese (e.g., zinc or manganese metal). In some embodiments, the coupling is carried out in the presence of zirconium (e.g., ZrCp2Cl2). In some embodiments, the coupling is carried out in the presence of a base or a proton scavenger (e.g., 2,6-di-tert-butyl-4-methylpyridine or 2,6-lutidine). In some embodiments, the coupling is carried out in the presence of a proton sponge (e.g., 1,8-bis(dimethylamino)naphthalene).

[0304] In some embodiments, the reaction is carried out in a solvent (e.g., MeCN). In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 100°C. In some embodiments, the reaction is carried out at a temperature ranging from about room temperature to about 50°C. In some embodiments, the reaction is carried out at about room temperature. In some embodiments, the reaction is carried out at about 30°C.

[0305] In some embodiments, the Ni / Cr-mediated reductive coupling is carried out in the presence of a nickel complex, a chromium salt, a sulfonamide ligand, a lithium salt, a zirconium complex, a reducing metal, and a base or proton scavenger. In some embodiments, the coupling step is carried out in the presence of (Me)Phen(OMe)NiCl, CrCl, the ligand (S)-4-E, LiCl, manganese metal, 2,6-lutidine, and ZrCpCl. In some embodiments, the reaction is carried out in a solvent (e.g., MeCN). In some embodiments, the reaction is carried out at about room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 2 mol% (Me)Phen(OMe)NiCl, 10 mol% CrCl, 10 mol% the ligand (S)-4-E, 2 equivalents LiCl, 1.1 equivalents CpZrCl, 1 equivalent 2,6-lutidine, and excess manganese in MeCN at room temperature.

[0306] In some embodiments, the coupling is performed by coupling a compound of the formula: [ka] The nickel complex, CrCl2, has the formula: [ka] The reaction is carried out in the presence of a sulfonamide ligand of the formula: CpZrCl, manganese metal, and a base or proton scavenger (e.g., 2,6-lutidine and / or a proton sponge (e.g., 1,8-bis(dimethylamino)naphthalene)). For example, in one embodiment, the reaction is carried out under the following conditions: approximately 30° C. (e.g., for 2-3 hours) at 0.5 mol % of a compound of the formula: [ka] Nickel complex, 20 ml% CrCl2, 20 mol% of the formula: [ka] The reaction was carried out using a sulfonamide ligand represented by the formula (I), 1.1 equivalents of Cp2ZrCl2, 4 equivalents of manganese metal, 2 equivalents of 2,6-lutidine, and a proton sponge.

[0307] In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is an optionally substituted benzyl or optionally substituted silyl protecting group; R 8 is optionally substituted alkyl; and R P10 is a silyl protecting group. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is MPM;R 8 is methyl; and R P10 is TES. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] Form a ring represented by R P8 is TBS;R 8 is methyl; and R P10 is TES.

[0308] Provided herein are compounds of formula (R-4-2): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 3 is hydrogen, halogen, or optionally substituted alkyl; and R P5 and R P10 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 The groups, together with the intervening atoms, are joined to form an optionally substituted heterocyclyl ring.

[0309] In some embodiments, the method for preparing a compound represented by formula (R-4-2), or a salt thereof, includes: Formula (R-4-1): [ka] or a salt thereof, to obtain a compound represented by formula (R-4-1A): [ka] or a salt thereof; By protecting the compound represented by formula (R-4-1) or a salt thereof, a compound represented by formula (R-4-1B): [ka] or a salt thereof; and A step of producing a compound represented by formula (R-4-2) or a salt thereof by oxidizing a compound represented by formula (R-4-1B) or a salt thereof.

[0310] The step of reducing the compound represented by (R-4-2), or a salt thereof, reduces the lactone of the compound. In some embodiments, the reducing step is carried out by reducing the lactone of the compound to a hydride (i.e., H -The oxidation step (i.e., step (c)) is carried out in the presence of a hydride source. Any hydride source known in the art may be used in this conversion. Examples of hydride sources are provided herein. In certain embodiments, the hydride source is lithium borohydride (LiBH). In certain embodiments, the oxidation step (i.e., step (c)) involves Swern oxidation.

[0311] In some embodiments, the reducing step is carried out in the presence of LiBH. In some embodiments, the reaction is carried out in a solvent such as diethyl ether. In some embodiments, the reaction is carried out at approximately 0° C. For example, in some embodiments, the reaction is carried out under the following conditions: LiBH in diethyl ether at 0° C.

[0312] In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] and R P10 is a silyl protecting group. In some embodiments, two R P5 are bonded together with the intervening atoms to form the formula: [ka] and R P10 is TES.

[0313] Also provided herein is an alternative method for preparing a compound of formula (R-4-2), or a salt thereof, comprising the steps of: (a) Formula (R-4-1): [ka] or a salt thereof to obtain a compound represented by formula (R-4-2): [ka] or a salt thereof; (b) Olefination of a compound represented by formula (R-4-2A) or a salt thereof to obtain a compound represented by formula (R-4-2B): [ka] or a salt thereof; (c) Protecting a compound represented by formula (R-4-2B) or a salt thereof to obtain a compound represented by formula (R-4-2C): [ka] or a salt thereof; and (d) Oxidizing a compound represented by formula (R-4-2C) or a salt thereof to obtain a compound represented by formula (R-4-2): [ka] or a salt thereof, wherein: R 3 is hydrogen, halogen, or optionally substituted alkyl; and R P5 and R P10 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 The groups, together with the intervening atoms, are joined to form an optionally substituted heterocyclyl ring.

[0314] In one embodiment, the method comprises: (a) Formula (ER-19): [ka] or a salt thereof to obtain a compound represented by formula (ER-20): [ka] or a salt thereof; (b) Olefining a compound represented by formula (ER-20) or a salt thereof to obtain a compound represented by formula (ER-21): [ka] or a salt thereof; (c) Protecting a compound represented by formula (ER-21) or a salt thereof to obtain a compound represented by formula (ER-22): [ka] or a salt thereof; and (d) Oxidizing a compound represented by formula (ER-22) or a salt thereof to obtain a compound represented by formula (ER-17): [ka] or a salt thereof, wherein: R P5 and R P10 each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R P5 The groups, together with the intervening atoms, are joined to form an optionally substituted heterocyclyl ring.

[0315] In certain embodiments, the step of reducing a compound represented by formula (R-4-1), (ER-19), or a salt thereof (i.e., step (a)) is carried out in the presence of a hydride source. Examples of hydride sources are provided herein. In certain embodiments, the hydride source is lithium borohydride (LiBH). In certain embodiments, the hydride source is diisobutylaluminum hydride (DIBAL). In certain embodiments, the reaction is carried out in a solvent (e.g., toluene). In certain embodiments, the reaction is carried out in the presence of DIBAL in toluene. In certain embodiments, the reaction is carried out at temperatures ranging from about room temperature to about -78°C to about 0°C. In certain embodiments, the reaction is carried out under the following conditions: about 1.3 equivalents of DIBAL in toluene at -78°C to -60°C (e.g., for less than 1 hour).

[0316] In certain embodiments, the step of olefinating a compound represented by formula (R-4-2A), (ER-20), or a salt thereof (i.e., step (b)) is carried out in the presence of an olefinating reagent and a base. In certain embodiments, the olefinating reagent is Ph3PCH3Br. In certain embodiments, the base is an alkoxide. In certain embodiments, the base is t-BuOK. In certain embodiments, the olefinating step is carried out in the presence of Ph3PCH3Br and t-BuOK. In certain embodiments, the reaction is carried out in a solvent (e.g., THF). In certain embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about room temperature. In certain embodiments, the olefinating step is carried out under the following conditions: 4 equivalents of Ph3PCH3Br, 3 equivalents of t-BuOK in THF at 0° C. to 10° C. (e.g., for less than 1 hour).

[0317] In some embodiments, R P10 is a silyl protecting group; and the protecting step (c) is carried out in the presence of a silylating reagent and an amine base. P10is TES; and the silylation reagent is TESOTf. In some embodiments, the amine base is triethylamine (TEA). In some embodiments, the protecting step is carried out in the presence of TESOTf and TEA. In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about room temperature. In some embodiments, the protecting step is carried out in the presence of TESOTf and TEA in THF at 0° C. to 10° C. (e.g., for less than 1 hour).

[0318] In some embodiments, the step of oxidizing a compound represented by formula (R-4-2C), (ER-22), or a salt thereof is a Johnson-Lemieux oxidative cleavage. For example, in some embodiments, the reaction is carried out in the presence of osmium tetroxide (OsO) or K2OsO4; and N-methylmorpholine N-oxide (NMO). In some embodiments, the reaction is carried out in the presence of sodium periodate (NaIO) or lead acetate Pb(OAc)4. In some embodiments, the reaction is carried out in the presence of osmium tetroxide (OsO) and N-methylmorpholine N-oxide (NMO), followed by sodium periodate (NaIO). In some embodiments, the oxidation step is carried out in the presence of THF, acetone, and / or water. In some embodiments, the reaction is carried out at a temperature ranging from approximately 0° C. to approximately 50° C. For example, in one embodiment, the oxidation step is carried out under the following conditions: 25 equivalents of OsO4 and 3 equivalents of NMO in THF / acetone / water at room temperature (e.g., for 19 hours), followed by the addition of 3 equivalents of NaIO4 at room temperature (e.g., for less than 1 hour).

[0319] Preparation of the left half As described herein, the preparation of halichondrin natural products and their analogs may involve coupling of a "left half" fragment with a "right half" fragment. Methods useful in the preparation of right half building blocks are provided above. In another aspect, the present invention provides "left-hand" building blocks, and methods useful in their preparation.

[0320] Preparation of the left half of halichondrin Provided herein are methods useful for preparing the "left-half" building blocks of halichondrins and their analogs. For example, the left halves of compounds in the halichondrin system (e.g., halichondrin A, B, C, and their analogs) can be prepared as shown in Scheme 4A. For example, a left-half building block of formula (L-2-14) can be prepared by thiolation of a compound of formula (L-5-17), which can be prepared by cyclization of a compound of formula (L-5-16B). To this end, a compound of formula (L-5-16B) can be prepared by cyclization of a compound of formula (L-5-16A), which can be prepared from an intermediate of formula (L-5-15) via oxidation and olefination. As also shown in Scheme 4A, an intermediate of formula (L-5-15) can be prepared by rearrangement of a compound of formula (L-5-14). Compounds of formula (L-5-14) can be prepared by coupling compounds of formula (L-5-12) with compounds of formula (L-5-5). Compounds of formula (L-5-12) can be prepared by epoxidation of compounds of formula (L-5-11), which can be prepared by coupling compounds of formula (L-5-10) with compounds of formula (L-5-9). Scheme 4A [ka]

[0321] As shown in Scheme 4A, provided herein are compounds of formula (L-2-14): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof in the presence of a thiolating agent; R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; R P1 , R P2 , R P3 , and R P4 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0322] As described herein, the step of forming a compound of formula (L-2-14) comprises reacting a compound of formula (L-5-17) in the presence of a thiolation agent. Any thiolation agent known in the art may be used for this purpose. In some embodiments, the thiolation agent is a disulfide. In some embodiments, the thiolation agent is a compound of formula (R S In some embodiments, the thiolation agent is represented by the formula (pyridine-S)2. In some embodiments, the thiolation agent is represented by the formula: [ka] is.

[0323] In some embodiments, the step of thiolating the compound of formula (L-5-17) is carried out in the presence of one or more additional reagents, such as a phosphine reagent (e.g., triphenylphosphine (Ph3P)).

[0324] In some embodiments, the thiolation step is carried out in the presence of a disulfide and a phosphine. In some embodiments, the reaction is carried out in the presence of (Py-S)2 and Ph3P. In some embodiments, the reaction is carried out in a solvent such as CHCl2. In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about 50° C. In some embodiments, the reaction is carried out at room temperature. For example, in some embodiments, the thiolation step is carried out under the following conditions: 1.4 equivalents of (Py-S)2, 1.2 equivalents of Ph3P in CHCl2 at room temperature (e.g., for 10-20 hours).

[0325] In one embodiment, the method for thiolating a compound represented by formula (L-5-17) or a salt thereof comprises the following steps: By deprotecting the compound represented by formula (L-5-17) or a salt thereof, a compound represented by formula (L-5-17B): [ka] or a salt thereof; and The method includes the step of thiolating a compound represented by formula (L-5-17B) or a salt thereof to produce a compound represented by formula (L-2-14) or a salt thereof.

[0326] In some embodiments, R P1 , R P2 , R P3 , and R P4 is a silyl protecting group. In some embodiments, R P1 and R P2 is TBS; and R P3 and R P4is TES.

[0327] Also provided herein are compounds of formula (L-5-17): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; R P1 , R P2 , R P3 , and R P4 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0328] In some embodiments, the step of cyclizing the compound represented by Formula (7-5-16B) is carried out in the presence of a base. In some embodiments, the base is a nitrogenous base. In some embodiments, the base is an amine base or an amide base. In some embodiments, the base is an amidine base or a guanidine base. In some embodiments, the base is an amidine base (e.g., 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)). In some embodiments, the step of cyclizing is carried out in the presence of an acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is a Bronsted acid.

[0329] In some embodiments, the cyclizing step is carried out in the presence of a lithium salt (e.g., LiBr, LiCl). The cyclizing step may be carried out in the presence of one or more additional reagents. In some embodiments, the cyclizing step is carried out in the presence of a cyclizing group such as R 8 In certain embodiments, the cyclizing step is carried out in the presence of —OAc.

[0330] In some embodiments, the cyclizing step is carried out in the presence of a lithium salt and a base. In some embodiments, the cyclizing step is carried out in the presence of LiBr and DBU. In some embodiments, the reaction is carried out in a solvent such as MeCN. In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about 50° C. In some embodiments, the reaction is carried out at room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 10 equivalents of LiBr, 5 equivalents of DBU, and 10 equivalents of BnOAc in MeCN at room temperature (e.g., for 10-20 hours).

[0331] In some embodiments, R P1 , R P2 , and R P3 is a silyl protecting group; and R P4 and R P8 is optionally substituted benzyl. In some embodiments, R P1 and R P2 is TBS;R P3 is TES;R P4 is MPM; and R 8 is benzyl.

[0332] In some embodiments, the compound of formula (L-5-17), or a salt thereof, can be deprotected to remove the group R P4 is eliminated, and equation (L-5-17C): [ka] or a salt thereof; and optionally reprotecting (i.e., removing the group R P4 For example, by switching from a benzyl protecting group (eg, MPM) to a silyl protecting group (eg, trialkylsilyl such as triethylsilyl).

[0333] Provided herein is a compound of formula (L-5-16B): [ka] or a salt thereof, the method comprising: (a) Formula (L-5-15): [ka] or a salt thereof to obtain a compound represented by formula (L-5-15B): [ka] or a salt thereof; and (b) reacting a compound represented by formula (L-5-15B), or a salt thereof, in the presence of an olefin and an olefin metathesis catalyst to produce a compound represented by formula (L-5-16B), wherein: R 1 and R 2 is independently hydrogen, halogen, or optionally substituted alkyl; and R P1 , R P2 , R P3 , R P4 , and R P10 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.

[0334] In some embodiments, the olefin has the formula: [ka] Furthermore, any olefin metathesis catalyst known in the art may be used in the metathesis reaction to provide a compound of formula (L-5-16B).

[0335] In some embodiments, R P1 , R P2 , R P10 , and R P3 is a silyl protecting group; and R P4 is optionally substituted benzyl. In some embodiments, R P1 and R P2 is TBS; and R P3 is TES;R P4 is the MPM; and R P10 is TES.

[0336] Provided herein is a compound of formula (L-5-16B): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof, wherein: R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; R P1 , R P2 , R P3 , R P4 , and R P10 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0337] In some embodiments, the cyclizing step of the compound represented by Formula (L-5-16A) or a salt thereof is carried out in the presence of a base. In some embodiments, the cyclizing step is carried out in the presence of an acid (e.g., a Lewis acid or a Bronsted acid). In some embodiments, the acid is phosphoric acid. In some embodiments, the acid is diphenyl phosphate ((PhO)P(=O)OH). In some embodiments, the acid is present in a catalytic amount, a stoichiometric amount, or an excess amount relative to the compound represented by Formula (L-5-16A). In some embodiments, the acid is present in a catalytic amount (e.g., approximately 5 mol%).

[0338] In some embodiments, the cyclizing step is carried out in the presence of diphenyl phosphate. In some embodiments, the cyclizing step is carried out in a solvent such as THF or a mixture of THF and HO. In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about 50° C. In some embodiments, the reaction is carried out at about room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 5 mol % diphenyl phosphate in THF-HO at room temperature (e.g., for about 24 hours).

[0339] Also provided herein is a compound of formula (L-5-16A): [ka] or a salt thereof, the method comprising: (a) Formula (L-5-15): [ka] or a salt thereof, to obtain a compound represented by formula (L-5-15B) or (L-5-15BB): [ka] or a salt thereof; and (b) A compound represented by formula (L-5-15B) or (L-5-15BB), or a salt thereof, is reacted in the presence of an olefination reagent to obtain a compound represented by formula (L-5-15C): [ka] or a salt thereof, wherein: R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; R P1 , R P2 , R P3 , R P4 , and R P10 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0340] The reaction in step (a) above is an oxidative cleavage; the reaction in step (b) is an olefination reaction. In some embodiments, the oxidative cleavage is carried out via ozonolysis (e.g., in the presence of O). In some embodiments, the cleavage is carried out in the presence of one or more reagents capable of dihydroxylating the double bond (e.g., osmium tetroxide (OsO), N-methylmorpholine N-oxide (NMMO)), followed by a transition metal (e.g., a lead complex such as Pb(OAc)). In some embodiments, the double bond is dihydroxylated by treatment with OsO, NMMO, and water. In some embodiments, the reaction is carried out in the presence of a solvent such as acetone. In some embodiments, the reaction is carried out at a temperature ranging from approximately 0° C. to approximately 50° C. In some embodiments, the reaction is carried out at room temperature. For example, in some embodiments, the double bond is dihydroxylated under the following conditions: 10 mol% OsO, 2 equivalents of NMMO, and water in acetone at room temperature (e.g., for 20-25 hours). The resulting compound is then treated with Pb(OAc) and KCO to produce an aldehyde or hemiacetal. For example, in some embodiments, this step is carried out under the following conditions: 1.2 equivalents of Pb(OAc), 3 equivalents of KCO in CHCl at room temperature (e.g., for approximately 1 hour).

[0341] In some embodiments, the olefination is carried out in the presence of a Wittig reagent or a Horner-Wadsworth-Emmons reagent, represented by the formula: (RO)P(O)CHCOR 8 In some embodiments, the reagent is represented by the formula: (MeO)P(O)CHCOR 8 (e.g., (MeO)2P(O)CH2CO2Bn). In some embodiments, the olefination is carried out in the presence of a base (e.g., a phosphate such as K3PO4).

[0342] In some embodiments, the olefination is carried out using a compound of the formula: (RO)2P(O)CH2CO2R 8 and a base. In some embodiments, the olefination is carried out in the presence of (MeO)P(O)CHCOBn and KPO. In some embodiments, the reaction is carried out in a solvent such as toluene. In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about 50° C. In some embodiments, the reaction is carried out at room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 4 equivalents of (MeO)P(O)CHCOBn, 3 equivalents of KPO in toluene at room temperature (e.g., for about 20-25 hours).

[0343] In some embodiments, R P1 , R P2 , R P3 , and R P10 is a silyl protecting group; and R P4 and R 8 is optionally substituted benzyl. In some embodiments, R P1 and R P2 is TBS;R P3 and R P10 is TES;R P4 is the MPM; and R 8 is benzyl.

[0344] Provided herein are compounds of formula (L-5-15): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof in the presence of an acid or a base, R 1 and R 2is independently hydrogen, halogen, or optionally substituted alkyl; and R P1 , R P2 , R P3 , R P4 , and R P10 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.

[0345] As described above, the method for forming a compound represented by Formula (L-5-15) or a salt thereof involves reacting a compound represented by Formula (L-5-14) or a salt thereof in the presence of an acid or a base. In some embodiments, an acid is used. The acid may be a Lewis acid or a Bronsted acid. In some embodiments, the acid is a Bronsted acid. In some embodiments, the acid is phosphoric acid (e.g., phosphoric acid, diphenyl phosphate). In some embodiments, the acid is diphenyl phosphate ((PhO)2P(=O)OH). In some embodiments, the reaction is carried out in a solvent such as toluene. In some embodiments, the reaction is carried out at a temperature ranging from about 0°C to about 50°C. In some embodiments, the reaction is carried out at about 0°C to room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 5 mol% (PhO)2P(=O)OH in toluene from 0°C to room temperature (e.g., for 10-15 hours).

[0346] In some embodiments, the compound of formula (L-5-15) has formula (L-5-15A): [ka] or a salt thereof, and the method further comprises protecting a compound of formula (L-5-15A) or a salt thereof to produce a compound of formula (L-5-15) (e.g., a compound of formula (L-5-15A) or a salt thereof). P3 Introduce (where the group R P3 is an oxygen protecting group).

[0347] In some embodiments, RP1 , R P2 , and R P10 is a silyl protecting group; and R P4 is optionally substituted benzyl. In some embodiments, R P1 and R P2 is TBS;R P10 is TES; and R P4 is an MPM.

[0348] As shown in Scheme 4A and provided herein, compounds of formula (L-5-14): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof, [ka] or a salt thereof, wherein X 4 is a halogen or a leaving group; R 1 and R 2 is independently hydrogen, halogen, or optionally substituted alkyl; and R P1 , R P2 , R P4 , and R P10 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.

[0349] In some embodiments, coupling a compound of formula (L-5-12) with a compound of formula (L-5-5) can be accomplished by using an organometallic reagent (e.g., X 4In some embodiments, the organometallic reagent is a lithium reagent (e.g., for addition to a compound of formula (L-5-12), converting a compound of formula (L-5-5) to a metal). [ka] (to a compound represented by the formula:). In certain embodiments, the lithium reagent is an organolithium (e.g., n-butyllithium, tert-butyllithium, sec-butyllithium). In certain embodiments, the lithium reagent is LiHMDS or LDA. In certain embodiments, the reaction is carried out in the presence of tert-butyllithium. In certain embodiments, the reaction is carried out in a solvent such as THF. In certain embodiments, the reaction is carried out at a temperature ranging from approximately -78°C to approximately 0°C. In certain embodiments, the reaction is carried out at -78°C to room temperature. For example, in certain embodiments, the reaction is carried out with 2.6 equivalents of tert-butyllithium in THF from -78°C to room temperature (e.g., for less than 1 hour).

[0350] In some embodiments, R P1 , R P2 , and R P10 is a silyl protecting group; and R P4 is optionally substituted benzyl. In some embodiments, R P1 and R P2 is TBS;R P10 is TES; and R P4 is an MPM.

[0351] Also provided herein is a compound of formula (L-5-12): [ka] There is also a method for preparing a compound represented by formula (L-5-11): [ka] or a salt thereof, wherein: R 1 is hydrogen, halogen, or optionally substituted alkyl; and R P1 , R P2 , and R P10 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.

[0352] Any epoxidizing reagent may be used in the epoxidizing step described above. In certain embodiments, the epoxidizing reagent is a peracid (e.g., m-CPBA). In certain embodiments, the epoxidizing reagent is an organometallic reagent. In certain embodiments, the epoxidizing reagent is a titanium reagent (e.g., Ti(Oi-Pr)4). In certain embodiments, the epoxidizing reagent is a vanadium reagent (e.g., VO(TMHD)2). In certain embodiments, the epoxidizing is a Sharpless epoxidation. In certain embodiments, the epoxidizing step is carried out in the presence of one or more additional reagents. In certain embodiments, the epoxidizing is carried out in the presence of a peroxide (e.g., t-BuOOH).

[0353] In some embodiments, the epoxidizing step is carried out in the presence of a vanadium reagent and peroxide. In some embodiments, the reaction is carried out in the presence of VO(TMHD)2 and t-BuOOH. In some embodiments, the reaction is carried out in a solvent such as toluene. In some embodiments, the reaction is carried out at a temperature ranging from about 0°C to about 50°C. In some embodiments, the reaction is carried out at room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 5 mol% VO(TMHD)2 and 2 equivalents of t-BuOOH in toluene at room temperature (e.g., for 1 to 10 hours).

[0354] In some embodiments, R P1 , R P2 , and R P10 is a silyl protecting group; and R P4is optionally substituted benzyl. In some embodiments, R P1 and R P2 is TBS; and R P10 is TES.

[0355] Also provided herein is a compound of formula (L-5-11): [ka] There is also a method for preparing a compound represented by formula (L-5-10): [ka] or a salt thereof, [ka] or a salt thereof, wherein X 4 is a halogen or a leaving group; R 1 is hydrogen, halogen, or optionally substituted alkyl; and R P1 , R P2 , and R P10 is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.

[0356] In some embodiments, coupling a compound of formula (L-5-10) with a compound of formula (L-5-9) can be accomplished by the use of a metal or organometallic reagent (e.g., X 4to a metal). In some embodiments, the reaction is carried out in the presence of copper. In some embodiments, the copper is a copper complex or a copper salt. In specific embodiments, the copper source is Li(thienylCuCN). In some embodiments, the reaction is carried out in the presence of a lithium reagent. In some embodiments, the lithium reagent is an organolithium (e.g., n-butyllithium, tert-butyllithium, sec-butyllithium). In some embodiments, the lithium reagent is LiHMDS or LDA. In some embodiments, the reaction is carried out by converting a compound represented by formula (L-5-10) to a compound represented by formula (L-5-9) with a lithium reagent and a copper reagent (e.g., for addition to a compound represented by formula (L-5-10), a compound represented by formula: [ka] The reaction may also be carried out in the presence of a Lewis acid (e.g., BF3·Et2O).

[0357] In some embodiments, the coupling step is carried out in the presence of a copper source, an organometallic, and a Lewis acid. In some embodiments, the reaction is carried out in the presence of Li(thienylCuCN), n-butyllithium, and BF3·Et2O. In some embodiments, the reaction is carried out in a solvent such as Et2O. In some embodiments, the reaction is carried out at a temperature ranging from about −78° C. to about 0° C. In some embodiments, the reaction is carried out at a temperature ranging from about −78° C. to about room temperature. In some embodiments, the reaction is carried out at approximately −78° C. For example, in some embodiments, the reaction is carried out under the following conditions: 2 equivalents of Li(thienylCuCN), 1.75 equivalents of n-butyllithium, and 1.6 equivalents of BF3·Et2O in Et2O at −78° C. (e.g., for 1 hour).

[0358] In some embodiments, R P1 and R P2 is a silyl protecting group; in some embodiments, R P1 and R P2 is TBS.

[0359] Preparation of the left half of homohalichondrin Also provided herein are "left-hand" building blocks of homohalichondrins (e.g., homohalichondrins A, B, and C) and their analogs, such as a compound of formula (L-2-16). Methods useful for preparing left-hand building blocks of homohalichondrins (e.g., a compound of formula (L-2-16)) are outlined in Scheme 4B. Illustratively, a compound of formula (L-2-16) can be prepared by thiolation of a compound of formula (L-5-26), which can be prepared via cyclization of a compound of formula (L-5-25C). To this end, a compound of formula (L-5-25C) can be prepared by oxidation and olefination of a compound of formula (L-5-25A). As also shown in Scheme 4B, coupling a compound of formula (L-5-24) with a compound of formula (L-5-5) can provide a compound of formula (L-5-25A). Furthermore, compounds of formula (L-5-24) can be prepared by hydroboration, oxidation, and cyclization of compounds of formula (L-5-23A), which can be prepared by epoxidation of the internal olefin of compounds of formula (L-5-22), followed by cyclization. Compounds of formula (L-5-22) can be prepared by reduction of compounds of formula (L-5-21B), which can be prepared by reduction and olefination of nitriles of formula (L-5-21A). The nitriles can be prepared by reduction and olefination of compounds of formula (L-5-3), followed by substitution of compounds of formula (L-5-20) (i.e., the group -OR). P7 to -CN). Scheme 4B [ka]

[0360] As shown in Scheme 4B, provided herein are compounds of formula (L-2-16): [ka] or a salt thereof, the method comprising the step of preparing a compound represented by formula (L-5-26): [ka] or a salt thereof in the presence of a thiolating agent; R S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; R P1 , R P3 , and R P4 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0361] As described herein, the step of forming a compound of formula (L-2-16) comprises reacting a compound of formula (L-5-26) in the presence of a thiolation agent. Any thiolation agent known in the art may be used for this purpose. In some embodiments, the thiolation agent is a disulfide. In some embodiments, the thiolation agent is a compound of formula (R S In some embodiments, the thiolation agent is represented by the formula (pyridine-S)2. In some embodiments, the thiolation agent is represented by the formula: [ka] is.

[0362] In some embodiments, the step of thiolating the compound of formula (L-5-26) is carried out in the presence of one or more additional reagents, such as a phosphine reagent (e.g., triphenylphosphine (Ph3P)).

[0363] In some embodiments, the thiolation step is carried out in the presence of a disulfide and a phosphine. In some embodiments, the reaction is carried out in the presence of (Py-S)2 and Ph3P. In some embodiments, the reaction is carried out in a solvent such as toluene. In some embodiments, the reaction is carried out at a temperature ranging from about 0°C to about 50°C. In some embodiments, the reaction is carried out at room temperature. For example, in some embodiments, the thiolation step is carried out under the following conditions: 1.2 equivalents of (Py-S)2, 3 equivalents of Ph3P in toluene at room temperature (e.g., for 10-20 hours).

[0364] In one embodiment, the method for thiolating a compound represented by formula (L-5-26), or a salt thereof, comprises the steps of: (a) Deprotecting a compound represented by formula (L-5-26) or a salt thereof to obtain a compound represented by formula (L-5-26B): [ka] or a salt thereof; and (b) thiolating a compound represented by formula (L-5-26B) or a salt thereof to produce a compound represented by formula (L-2-6) or a salt thereof. Includes.

[0365] In some embodiments, R P1 , R P3 , and R P4 is a silyl protecting group. In some embodiments, R P1 is TBS; and R P3 and RP4 is TES.

[0366] Also provided herein are compounds of formula (L-5-26): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof, wherein: R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; R P1 , R P3 , and R P4 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0367] In some embodiments, the step of cyclizing the compound represented by Formula (7-5-25C) is carried out in the presence of a base. In some embodiments, the base is a nitrogenous base. In some embodiments, the base is an amidine base, a guanidine base. In some embodiments, the base is an amine base or an amide base. In some embodiments, the base is an amidine base (e.g., 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)). In some embodiments, the step of cyclizing is carried out in the presence of an acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the step of cyclizing is carried out in the presence of a lithium salt (e.g., LiBr, LiCl). The step of cyclizing may be carried out in the presence of one or more additional reagents. In some embodiments, the step of cyclizing is carried out in the presence of a hydroxy group selected from the group consisting of R 8 In certain embodiments, the cyclizing step is carried out in the presence of —OAc.

[0368] In some embodiments, the cyclizing step is carried out in the presence of a lithium salt and a base. In some embodiments, the cyclizing step is carried out in the presence of LiBr and DBU. In some embodiments, the reaction is carried out in a solvent such as MeCN. In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about 50° C. In some embodiments, the reaction is carried out at room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 10 equivalents of LiBr and 20 equivalents of DBU in MeCN at room temperature (e.g., for 10-20 hours).

[0369] In some embodiments, R P1 and R P3 is a silyl protecting group; R P4 is optionally substituted benzyl; and R 8 is optionally substituted benzyl. In some embodiments, R P1 is TBS;R P3 is TES;R P4 is the MPM; and R 8 is benzyl.

[0370] In some embodiments, the compound of formula (L-5-26), or a salt thereof, can be deprotected to form a group R P4 Eliminate equation (L-5-26B): [ka] or a salt thereof; and optionally reprotected (i.e., to remove the group R P4 For example, by switching from a benzyl protecting group (eg, MPM) to a silyl protecting group (eg, trialkylsilyl such as triethylsilyl).

[0371] Also provided herein is a compound of formula (L-5-25C): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof in the presence of an olefin and an olefin metathesis catalyst; R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; R P1 , R P3 , and R P4 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0372] In some embodiments, the olefin has the formula: [ka] Additionally, any olefin metathesis method known in the art may be used in the metathesis reaction to provide a compound of formula (L-5-25C).

[0373] Also provided herein is a compound of formula (L-5-25C): [ka] There is also an alternative method for preparing a compound represented by the formula: (a) Formula (L-5-25A): [ka] or a salt thereof, to obtain a compound represented by formula (L-5-25B) or (L-5-25BB): [ka] or a salt thereof; and (c) reacting a compound of formula (L-5-25B) or (L-5-25BB), or a salt thereof, in the presence of an olefination reagent to produce a compound of formula (L-5-25C), or a salt thereof. Includes.

[0374] The reaction in step (a) above is an oxidative cleavage; the reaction in step (b) is an olefination reaction. In some embodiments, the oxidative cleavage is carried out via ozonolysis (e.g., in the presence of O). In some embodiments, the cleavage is carried out in the presence of a reagent capable of dihydroxylating the double bond (e.g., osmium tetroxide (OsO), N-methylmorpholine N-oxide (NMMO)), followed by a transition metal (e.g., a lead complex such as Pb(OAc)).

[0375] In some embodiments, the double bond is dihydroxylated by treatment with OsO, NMMO, and water. In some embodiments, the reaction is carried out in the presence of a solvent such as acetone. In some embodiments, the reaction is carried out at a temperature ranging from approximately 0° C. to approximately 50° C. In some embodiments, the reaction is carried out at room temperature. For example, in some embodiments, the double bond is dihydroxylated under the following conditions: 10 mol% OsO, 2 equivalents of NMMO, and water in acetone at room temperature (e.g., for 1-5 hours). The resulting compound is then, in some embodiments, treated with Pb(OAc) and KCO to produce an aldehyde or hemiacetal. For example, in some embodiments, this step is carried out under the following conditions: 1.5 equivalents of Pb(OAc), 10 equivalents of KCO in CHCl at room temperature (e.g., for 1 hour).

[0376] In some embodiments, the olefination is carried out in the presence of a Wittig reagent or a Horner-Wadsworth-Emmons reagent. 8 In some embodiments, the reagent is represented by the formula: (MeO)P(O)CHCOR 8 (e.g., (MeO)2P(O)CH2CO2Bn). In some embodiments, the olefination is carried out in the presence of a base (e.g., a phosphate such as K3PO4, or a hydride such as NaH).

[0377] In some embodiments, the olefination is carried out using a compound of the formula: (RO)2P(O)CH2CO2R 8and a base. In some embodiments, the olefination is carried out in the presence of (MeO)P(O)CHCOBn and NaH. In some embodiments, the reaction is carried out in a solvent such as THF. In some embodiments, the reaction is carried out at a temperature ranging from about -78°C to about room temperature. In some embodiments, the reaction is carried out at 0°C. For example, in some embodiments, the reaction is carried out under the following conditions: 5 equivalents of (MeO)P(O)CHCOBn, 4 equivalents of NaH in THF at 0°C (e.g., for about 1 to 5 hours).

[0378] In some embodiments, R P1 and R P3 is a silyl protecting group; R P4 is optionally substituted benzyl; and R 8 is optionally substituted benzyl. In some embodiments, R P1 is TBS;R P3 is TES;R P4 is the MPM; and R 8 is benzyl.

[0379] Also provided herein is a compound of formula (L-5-25A): [ka] or a salt thereof, the method comprising the steps of: [ka] or a salt thereof, [ka] or a salt thereof, wherein X 4 is a halogen or a leaving group; R 1and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; R P1 , R P3 , and R P4 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0380] In some embodiments, coupling a compound of formula (L-5-24) with a compound of formula (L-5-5) can be accomplished by using an organometallic reagent (e.g., X 4 In some embodiments, the organometallic reagent is carried out in the presence of a lithium reagent (e.g., for addition to a compound of formula (L-5-24), converting a compound of formula (L-5-5) to a metal: [ka] In some embodiments, the lithium reagent is an organolithium (e.g., n-butyllithium, tert-butyllithium, sec-butyllithium). In some embodiments, the lithium reagent is LiHMDS or LDA.

[0381] In some embodiments, the reaction is carried out in the presence of tert-butyllithium. In some embodiments, the reaction is carried out in a solvent such as THF. In some embodiments, the reaction is carried out at a temperature ranging from about -78°C to about room temperature. In some embodiments, the reaction is carried out at about -78°C. For example, in some embodiments, the reaction is carried out with 2.5 equivalents of tert-butyllithium in THF at -78°C (e.g., for less than 1 hour).

[0382] In some embodiments, R P1and R P3 is a silyl protecting group; and R P4 is optionally substituted benzyl. In some embodiments, R P1 is TBS;R P3 is TES; and R P4 is an MPM.

[0383] Provided herein is a compound of formula (L-5-24): [ka] or a salt thereof, the method comprising: (a) Formula (L-5-23B): [ka] or a salt thereof to obtain a compound represented by formula (L-5-23C): [ka] or a salt thereof; and (b) cyclizing the compound represented by formula (L-5-23C) or a salt thereof to produce a compound represented by formula (L-5-24) or a salt thereof. comprising: R 1 is hydrogen, halogen, or optionally substituted alkyl; and R P1 , R P3 , and R P10 is each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.

[0384] The step of oxidizing a compound represented by Formula (L-5-23B) is carried out in the presence of an oxidant. In some embodiments, the oxidant is a hypervalent iodine reagent. In some embodiments, the oxidant is a periodinane (e.g., Dess-Martin periodinane). In some embodiments, the oxidant is (diacetoxyiodo)benzene (PhI(OAc)2). In some embodiments, the oxidation is carried out in the presence of one or more additional reagents. In some embodiments, the oxidation is carried out in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). In some embodiments, the oxidation is carried out in the presence of TEMPO and hypervalent iodine. In some embodiments, the oxidation in step (a) and the cyclization in step (b) are carried out in the same step or in subsequent steps. In some embodiments, the cyclization in step (b) is carried out in a separate step and in the presence of an acid (e.g., a Lewis acid or a Bronsted acid) or a base.

[0385] In some embodiments, the oxidizing step is carried out in the presence of PhI(OAc) and TEMPO. In some embodiments, the oxidizing step is carried out in a solvent such as CHCl. ​​In some embodiments, the reaction is carried out at a temperature ranging from about 0° C. to about 50° C. In some embodiments, the oxidizing step is carried out at room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 20 mol% TEMPO, 3 equivalents of PhI(OAc) in CHCl at room temperature (e.g., for 24-48 hours).

[0386] In some embodiments, R P1 and R P3 is a silyl protecting group; and R P10 is hydrogen. In some embodiments, R P1 is TBS;R P3 is TES; and R P10 is hydrogen.

[0387] Provided herein is a compound of formula (L-5-23B): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof; R 1 is hydrogen, halogen, or optionally substituted alkyl; and R P1 , R P3 , and R P10 is each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group.

[0388] In some embodiments, the step of hydrating a compound represented by Formula (L-5-23A) is a hydroboration reaction. Any reagent or condition that effects hydroboration may be used. For example, the reaction may be carried out in the presence of a borane (e.g., BH or 9-BBN), followed by a peroxide (e.g., HO) or a perborate (e.g., sodium perborate (NaBO)). In some embodiments, the reaction is carried out in the presence of 9-BBN. In some embodiments, the reaction involves the addition of NaBO·HO.

[0389] In some embodiments, the hydrating step is carried out in the presence of 9-BBN, followed by NaBO3·H2O. In some embodiments, the reaction is carried out in a solvent such as THF. In some embodiments, the reaction is carried out at 0° C. to room temperature. In some embodiments, the reaction is carried out under the following conditions: 3 equivalents of 9-BBN in THF from 0° C. to room temperature (e.g., over 1 hour), followed by the addition of aqueous NaBO3·H2O.

[0390] In some embodiments, R P1 and R P3 is a silyl protecting group; and R P10 is hydrogen. In some embodiments, R P1 is TBS;R P3 is TES; and R P10 is hydrogen.

[0391] Provided herein is a compound of formula (L-5-23A): [ka] or a salt thereof, the method comprising: (a) Formula (L-5-22): [ka] or a salt thereof, to obtain a compound represented by formula (L-5-22A): [ka] or a salt thereof; and (b) cyclizing the compound represented by formula (L-5-22A) or a salt thereof to produce a compound represented by formula (L-5-23A) or a salt thereof. Includes.

[0392] Any epoxidizing reagent may be used in the epoxidizing step described above. In certain embodiments, the epoxidizing reagent is a peracid (e.g., m-CPBA). In certain embodiments, the epoxidizing reagent is an organometallic reagent. In certain embodiments, the epoxidizing reagent is a titanium reagent (e.g., Ti(Oi-Pr)4). In certain embodiments, the epoxidizing reagent is a vanadium reagent (e.g., VO(TMHD)2). In certain embodiments, the epoxidation is a Sharpless epoxidation. In certain embodiments, the epoxidation is an asymmetric epoxidation (e.g., Sharpless asymmetric epoxidation). In certain embodiments, the epoxidation is carried out in the presence of one or more chiral ligands (e.g., (+)- or (-)-DET, (+)- or (-)-DIPT; where DET = diethyl tartrate and DIPT = diisopropyl tartrate). In certain embodiments, the epoxidizing step is carried out in the presence of one or more additional reagents. In certain embodiments, the epoxidation is carried out in the presence of a peroxide (e.g., t-BuOOH).

[0393] In some embodiments, the epoxidizing step is carried out in the presence of a titanium complex, a tartrate ligand, and a peroxide. In some embodiments, the reaction is carried out in the presence of Ti(Oi-Pr)4, (+)-DET, and t-BuOOH. In some embodiments, the reaction is carried out in the presence of molecular sieves. In some embodiments, the reaction is carried out in the presence of a solvent such as CHCl2. In some embodiments, the reaction is carried out at a temperature ranging from approximately -78°C to about room temperature. In some embodiments, the reaction is carried out at approximately -10°C. For example, in some embodiments, the reaction is carried out under the following conditions: 15 mol% Ti(Oi-Pr)4, 20 mol% (+)-DET, 1.5 equivalents t-BuOOH, and 4 Å molecular sieves in CHCl2 at -10°C (e.g., for 10-20 hours).

[0394] In some embodiments, R P6 and R P10 is a silyl protecting group; and R P1is hydrogen. In some embodiments, R P6 and R P10 is TBS; and R P1 is hydrogen. In some embodiments, R P6 is deprotected prior to the step of cyclizing the compound of formula (L-5-22A).

[0395] In some embodiments, the epoxidation / cyclization is carried out using a compound of formula (L-5-22B): [ka] or a salt thereof, which can then be protected to produce a compound of formula (L-5-23A) or a salt thereof (e.g., a compound having a group R P3 Introduce R P3 is an oxygen protecting group).

[0396] As shown in Scheme 4B, provided herein are compounds of formula (L-5-22): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof; R 1 is hydrogen, halogen, or optionally substituted alkyl; R P1 , R P6 , and R P10 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 8 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.

[0397] The step of reducing the compound represented by (L-5-21B) or a salt thereof is carried out by -CO2R 8 Part -OR P1 In some embodiments, the reducing step converts the hydroxy group to a hydride (i.e., H - The reaction is carried out in the presence of a hydride source. Any hydride source known in the art may be used in this transformation. Examples of hydride sources include, but are not limited to, lithium aluminum hydride, sodium borohydride, lithium borohydride, and diisobutylaluminum hydride. In some embodiments, the hydride source is diisobutylaluminum hydride (DIBAL).

[0398] In some embodiments, the reducing step is carried out in the presence of DIBAL. In some embodiments, the reaction is carried out in a solvent (e.g., THF). In some embodiments, the reaction is carried out at a temperature below room temperature. In some embodiments, the reaction is carried out at a temperature ranging from about -78°C to about room temperature. In some embodiments, the reaction is carried out at approximately -78°C. For example, in some embodiments, the reaction is carried out under the following conditions: 4 equivalents of DIBAL in THF at -78°C (e.g., for 1 hour).

[0399] In some embodiments, R P6 and R P10 is a silyl protecting group; and R 8 is optionally substituted alkyl. In some embodiments, R P6 and R P10 is TBS; and R 8 is methyl.

[0400] In some embodiments, the compound of formula (L-5-22) has formula (L-5-22-C): [ka] or a salt thereof.

[0401] Also provided herein is a compound of formula (L-5-21B): [ka] or a salt thereof, the method comprising: (a) Formula (L-5-21A): [ka] or a salt thereof, to obtain a compound represented by formula (L-5-21C): [ka] or a salt thereof; and (b) reacting a compound represented by formula (L-5-21C) or a salt thereof in the presence of an olefination reagent to produce a compound represented by formula (L-5-21B) or a salt thereof; Includes.

[0402] The step of reducing the compound represented by (L-5-21A), or a salt thereof (i.e., step (a) above) converts the -CN moiety to an aldehyde group (i.e., -CHO). In some embodiments, the reduction step converts the -CN moiety to a hydride (i.e., H -The reaction is carried out in the presence of a hydride source. Any hydride source known in the art may be used in this transformation. Examples of hydride sources include, but are not limited to, lithium aluminum hydride, sodium borohydride, lithium borohydride, and diisobutylaluminum hydride. In certain embodiments, the hydride source is diisobutylaluminum hydride (DIBAL). The reducing step may optionally include reducing the —CN moiety to an alcohol, followed by oxidation of the resulting alcohol to an aldehyde to produce a compound represented by formula (L-5-21C), or a salt thereof.

[0403] In some embodiments, the reducing step is carried out in the presence of DIBAL. In some embodiments, the reaction is carried out in a solvent (e.g., hexane, CHCl). In some embodiments, the reaction is carried out at a temperature below room temperature. In some embodiments, the reaction is carried out at a temperature ranging from about -78°C to about room temperature. In some embodiments, the reaction is carried out at approximately -78°C. For example, in some embodiments, the reaction is carried out under the following conditions: 1.1 equivalents of DIBAL in hexane-CHCl at -78°C (e.g., for 1 hour).

[0404] In some embodiments, the olefination of a compound represented by formula (L-5-21C), or a salt thereof (i.e., step (b) above) is carried out in the presence of a Wittig reagent or a Horner-Wadsworth-Emmons reagent. In some embodiments, the olefination is carried out in the presence of a compound represented by formula: (RO)P(O)CHCOR 8 In some embodiments, the reagent is represented by the formula: (MeO)P(O)CHCOR 8 (For example, (MeO)P(O)CHCOBn). In some embodiments, the reagent has the formula: (CFCHO)P(O)CHCOR 8(For example, (CF3CHO)2P(O)CH2CO2Me). In some embodiments, the olefination is carried out in the presence of a base. In some embodiments, the base is a phosphate, such as K3PO4. In some embodiments, the base is an amide base. In some embodiments, the base is a diisopropylamide base (for example, LDA). In some embodiments, the base is a hexamethyldisilazide base (for example, LiHMDS, NaHMDS, KHMDS). In some embodiments, the olefination is carried out in the presence of one or more additional reagents. In some embodiments, the olefination is carried out in the presence of a crown ether (for example, 18-crown-6).

[0405] In certain embodiments, the olefination is carried out by a method of the formula (RO)2P(O)CH2CO2R 8 and a base. In some embodiments, the reaction is carried out in the presence of (CF3CHO)2P(O)CH2CO2Me and KHMDS. In some embodiments, 18-crown-6 is present. In some embodiments, the reaction is carried out in a solvent (e.g., THF). In some embodiments, the reaction is carried out at a temperature ranging from about -78°C to about room temperature. In some embodiments, the reaction is carried out at -78°C. For example, in some embodiments, the reaction is carried out under the following conditions: 1.5 equivalents (CF3CHO)2P(O)CH2CO2Me, 1.5 equivalents KHMDS, 8 equivalents 18-crown-6 in THF at -78°C (e.g., for 1 hour).

[0406] In some embodiments, R P6 and R P10 is a silyl protecting group; and R 8 is optionally substituted alkyl. In some embodiments, R P6 and R P10 is TBS; and R 8 is methyl.

[0407] Also provided herein is a compound of formula (L-5-21A): [ka] There is also a method for preparing a compound represented by formula (L-5-20): [ka] or a salt thereof in the presence of cyanide; R 1 is hydrogen, halogen, or optionally substituted alkyl; R P6 , R P7 and R P10 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and P7 is a leaving group.

[0408] A method for preparing a compound represented by formula (L-5-21A), or a salt thereof, includes reacting a compound represented by formula (L-5-20), or a salt thereof, in the presence of cyanide. In some embodiments, the cyanide is a cyanide salt (e.g., NaCN, KCN, LiCN). In some embodiments, the cyanide salt is sodium cyanide (NaCN). The reaction may be carried out in the presence of one or more additional reagents (e.g., crown ethers). In some embodiments, the reaction is carried out in the presence of NaCN in a solvent such as DMSO. In some embodiments, the reaction is carried out at a temperature ranging from approximately 0°C to approximately 50°C. In some embodiments, the reaction is carried out at room temperature. For example, in some embodiments, the reaction is carried out under the following conditions: 20 equivalents of NaCN in DMSO at room temperature (e.g., for 1 hour).

[0409] In some embodiments, R P6 and R P10 is a silyl protecting group. In some embodiments, R P6 and R P10 is TBS.

[0410] Preparation of the left half of norhalichondrin Provided herein are methods for preparing the "left-half" building blocks of compounds in the norhalichondrin series (e.g., norhalichondrin A, B, C, and analogs thereof). For example, as shown in Scheme 4C, the left-half building block of formula (L-2-15) can be prepared by converting an ester group (i.e., -COR) of a compound of formula (L-5-32). 8 ) to a thioester moiety (i.e., -C(O)SR S To this end, compounds of formula (L-5-32) can be prepared by oxidation of compounds of formula (L-5-31), which can be prepared by cyclization of compounds of formula (L-5-30). Compounds of formula (L-5-30) can be prepared via oxidative cleavage and olefination of compounds of formula (L-5-28), which can be obtained by coupling compounds of formula (L-5-27) with compounds of formula (L-5-5). Compounds of formula (L-5-27) can be obtained from intermediates of formula (L-5-21A) as described herein. Scheme 4C [ka]

[0411] As shown in Scheme 4C, provided herein are compounds of formula (L-2-15): [ka] or a salt thereof, the method comprising: [ka] or a salt thereof in the presence of a thiolating agent; R Sis optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R 1 and R 2 are independently hydrogen, halogen, or optionally substituted alkyl; R P4 and R P6 each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R 7 and R 8 is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

[0412] As described herein, the step of forming a compound of formula (L-2-15) comprises reacting a compound of formula (L-5-32) in the presence of a thiolation agent. Any thiolation agent known in the art may be used for this purpose. In some embodiments, the thiolation agent is a disulfide. In some embodiments, the thiolation agent is a compound of formula (R S In some embodiments, the thiolation agent is represented by the formula (pyridine-S)2. In some embodiments, the thiolation agent is represented by the formula: [ka] is.

[0413] In some embodiments, the step of thiolating the compound of formula (L-5-32) is carried out in the presence of one or more additional reagents, such as a phosphine reagent (e.g., triphenylphosphine (Ph3P)). ...

Claims

1. Formula (H3-2-I): 【Chemistry 1】 or a salt thereof, During the ceremony: R １ , R ２ , R ３ , and R ５ are each independently hydrogen, halogen, or optionally substituted alkyl; R ４ Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R ４ The bases, together, are: 【Chemistry 2】 Forming; R ６ Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R ６ The bases, taken together, are: 【Transformation 3】 Forming; R Ｐ６ are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R Ｐ６ joins together with the intervening atoms to form an optionally substituted heterocyclyl; R Ｘ is hydrogen or -OR Ｘａ where R Ｘａ is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Ｙ is hydrogen or -OR Ｙａ where R Ｙａ is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; or where R Ｘａ and R Ｙａ joins together with these intervening atoms to form an optionally substituted heterocyclyl The compound or a salt thereof.

2. The compound is 【Chemistry 4】 2. The compound of claim 1, wherein:

3. Formula (H3-2-II): 【Transformation 5】 A compound represented by the formula: During the ceremony: R １ , R ２ , R ３ , and R ５ are each independently hydrogen, halogen, or optionally substituted alkyl; R ４ Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R ４ The bases, taken together, are: 【Transformation 6】 Forming; R ６ Each occurrence of is independently hydrogen, halogen, or optionally substituted alkyl, or two R ６ The bases, together, are: 【Transformation 7】 Forming; R Ｐ４ , R Ｐ５ , and R Ｐ６ are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R Ｐ６ joins together with the intervening atoms to form an optionally substituted heterocyclyl; R Ｘ is hydrogen or -OR Ｘａ where R Ｘａ is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R Ｙ is hydrogen or -OR Ｙａ where R Ｙａ is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; or where R Ｘａ and R Ｙａ are linked together with these intervening atoms to form an optionally substituted heterocyclyl, or a salt thereof.

4. The compound is 【Transformation 8】 4. The compound of claim 3, or a salt thereof, selected from the group consisting of:

5. A compound represented by formula (L-2-6) or a salt thereof: 【Chemistry 9】 R Ｓ is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R １ and R ２ are each independently hydrogen, halogen, or optionally substituted alkyl; R Ｐ４ , and R Ｐ６ are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R Ｐ６ is linked together with the intervening atom to form an optionally substituted heterocyclyl, or a salt thereof.

6. The compound is 【Chemistry 10】 or a salt thereof.

7. Formula (L-5-7B): 【Chemistry 11】 and salts thereof. During the ceremony: R １ and R ２ are independently hydrogen, halogen, or optionally substituted alkyl; R Ｐ４ and R Ｐ６ each occurrence of is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally, where two R Ｐ６ joins together with the intervening atoms to form an optionally substituted heterocyclyl; and R ８ is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group, or a salt thereof.

8. The compound is 【Chemistry 12】 8. The compound of claim 7, or a salt thereof, selected from the group consisting of:

9. The compound is represented by formula (E-1) 【Chemistry 13】 R Ｐ４ , R Ｐ５ , and R Ｐ６ is as defined in claim 3 The compound according to claim 3, which is a compound represented by the formula:

10. The compound has the formula (EL) 【Chemistry 14】 R Ｐ４ , R Ｐ６ , and R ｓ is as defined in claim 5 The compound according to claim 5, which is a compound represented by the formula: or a salt thereof.

11. The compound has the formula 【Chemistry 15】 R Ｐ４ and R Ｐ６ is as defined in claim 5 11. The compound according to claim 5 or 10, which is a compound represented by the formula: or a salt thereof.

12. The compound is represented by formula (EL-1): 【Chemistry 16】 R Ｐ４ , R Ｐ６ and R ８ is as defined in claim 7, The compound according to claim 7, which is a compound represented by the formula: or a salt thereof.

13. Each R Ｐ６ The compound of claims 1, 3, 5, 7, and 9-12, wherein is hydrogen.

14. Two R's Ｐ６ is bonded to the intervening atom 【Chemistry 17】 13. The compound of any one of claims 1, 3, 5, 7, and 9-12, wherein

15. R Ｐ４ 15. The compound of any one of claims 3, 5, 7, and 9-14, wherein is a silyl or benzyl protecting group.

16. R Ｐ４ The compound of any one of claims 3, 5, 7, and 9-14, wherein is TES or MPM.

17. R Ｐ５ 17. The compound of any one of claims 3, 9, and 13-16, wherein is a silyl protecting group.

18. R Ｐ５ The compound of any one of claims 3, 9, and 13-16, wherein is TES.

19. R ８ 17. The compound of any one of claims 7, 12, and 13-16, wherein is hydrogen.

20. R ８ The compound of any one of claims 7, 12, and 13-16, wherein is a benzyl protecting group.

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