Synthesis of structural analogues of largazole and related compounds.

Abstract

Various synthetic methods are disclosed for preparing structural analogs of largazole and its derivatives. One structural analog is the amide isostere of largazole. Another structural analog replaces the thiazole ring of largazole with a pyridine or oxazole moiety. Various intermediate compounds obtained in preparing structural analogs of largazole and its derivatives are also disclosed, including macrocyclic analogs with alcohol functionality.

Description

Detailed Description of the Invention

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS]

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 128,273, filed December 21, 2020, which is incorporated by reference in its entirety herein for all purposes.

[0002] [STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT]

[0002] This invention was made with government support under Grant No. 2R42HL136068-02 awarded by the National Institutes of Health through the National Heart, Lung, and Blood Institute. The Government has certain rights in this invention.

[0003] [Background technology]

[0003] Histone deacetylase (HDAC) inhibitors hold great promise for the treatment of many forms of cancer and other conditions (see, e.g., Williams et al., International Publication No. WO 2016 / 144814, incorporated herein by reference in its entirety). Various classes of HDAC inhibitors are known and are generally classified into five categories: hydroxamates, benzamides, short chain fatty acids, trifluoromethyloxadiazoles, and macrocycles. Specific examples of naturally occurring HDAC inhibitors include SAHA, trichostatin A, apicidin, trapoxin, azumamide, FK228, largazole, FR901375, and spiruchostatin. However, considerable research efforts have been focused on preparing structural analogs of these natural products to understand the relationship between inhibitor structure and HDAC inhibition, find more potent inhibitors, and prepare inhibitors with desirable structural properties.

[0004]

[0004] Particular interest has been focused on the macrocycle largazole and its structural analogs, including amide isosteres in which the ester in the peptide ring is replaced with an amide functionality (see, for example, Bowers et al., J.Am.Chem.Soc. 2009, 131, 2900-2905, and Pilon et al., Cancer Chemother Pharmacol. 2015, 75(4):671-682, both of which are incorporated herein by reference in their entirety). Largazole was isolated as a natural product from the marine cyanobacterium Symploca sp., and the total synthesis of largazole has been successfully completed by several research groups (see, for example, Ying et al., J.Am.Chem.Soc. 2008, 130, 8455-59, which are incorporated herein by reference in their entirety). Largazole has several disadvantages in some circumstances, particularly susceptibility to hydrolysis and conformational flexibility due to the ester functionality in the macrocycle. The amide isostere of Largazole addresses these disadvantages by being more stable to hydrolysis and having a more rigid structure, resulting in increased HDAC binding, both of which are a result of replacing the ester functionality of Largazole with an amide group.

[0005]

[0005] There has also been interest in structural analogs of largazole, which include those that retain the ester functionality on the macrocycle but vary other structural sites on the molecule. For example, in one structural analog of largazole, the thiazole ring of largazole can be replaced with a pyridine or oxazole moiety.

[0006]

[0006] The known synthetic routes to the amide isostere of Largazole and other structural analogues suffer from several drawbacks, including low yields, milligram scale production, synthetic complexity, and high cost (see Bowers et al.). Such known routes also involve the synthesis of macrocycles containing reactive thiol groups, such as compounds of formula (III), where R 1is SH), which is highly biologically active, unstable, and difficult to handle. Thus, there is a need for improved methods of preparing structural analogs of largazole and its derivatives, as well as improved synthetic methods of preparing HDAC inhibitors, including compounds prepared by these improved methods. The invention described herein addresses these and other important needs.

[0007] [overview]

[0007] Some advantages of the invention described herein include the use of a synthetic methodology that uses a macrocycle containing an alcohol functionality as shown in formula (I) rather than a macrocycle containing a thiol functionality. The macrocycle containing an alcohol functionality is more stable, biologically inert (see Table 1), and easier to handle (e.g., can be prepared in crystalline form, see XRD in Figure 10) than the equivalent macrocycle containing a thiol functionality. Other advantages of the methods disclosed herein include higher yields, more consistent yields, gram-scale production, easier and simpler synthesis, use of less expensive materials, and less toxicity of intermediate compounds.

[0008] Compounds of formula (I): [ka] Disclosed is a method for preparing a compound represented by the formula (IV), the compound represented by the formula (V), and the compound represented by the formula (VI), wherein the structures and variables are defined elsewhere herein, in one or more reactions.

[0009] Compounds of formula (III): [ka] A method for preparing The method comprises the step of: [ka] with an activating agent, thereby producing a compound of formula (II): [ka] and forming Also disclosed is a method comprising reacting a compound of formula (II) above with a nucleophile, thereby forming a compound of formula (III), wherein the structures, variables, activators, and nucleophiles are described elsewhere herein.

[0010] In some aspects, the compound of formula (I) above is a compound of formula (Ia), (Ib), or (Ic): [ka] It is.

[0011] Furthermore, the compound of formula (III): [ka] Disclosed is a method for preparing a compound of formula (II) comprising reacting the compound of formula (II) with a nucleophile, wherein the structures, variables, activating agents, and nucleophiles are described elsewhere herein.

[0012] Compounds of formula (XXVI): [ka] Also disclosed are: wherein the structures, variables, activators, and nucleophiles are described elsewhere herein.

[0013] In some aspects, the compound of formula (XXVI) above is a compound of formula (Ia), (Ib), or (Ic): [ka] It is. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 depicts chemical reaction schemes, including Schemes 1, 2, and 3, illustrating certain methods and compounds disclosed herein. [Diagram 2] FIG. 1 depicts chemical reaction schemes, including Schemes 4 and 5, illustrating certain methods and compounds disclosed herein. [Diagram 3] FIG. 1 depicts chemical reaction schemes, including Scheme 6, illustrating certain methods and compounds disclosed herein. [Figure 4] FIG. 1 depicts chemical reaction schemes, including Scheme 7, illustrating certain methods and compounds disclosed herein. [Diagram 5] FIG. 1 depicts chemical reaction schemes, including Scheme 8, illustrating certain methods and compounds disclosed herein. [Figure 6] FIG. 1 depicts chemical reaction schemes, including Schemes 9 and 10, illustrating certain methods and compounds disclosed herein. [Figure 7] FIG. 1 depicts chemical reaction schemes, including Schemes 11 and 12, illustrating certain methods and compounds disclosed herein. [Figure 8] FIG. 1 depicts chemical reaction schemes, including Schemes 13, 14, and 15, illustrating certain methods and compounds disclosed herein. [Figure 9] FIG. 1 depicts chemical reaction schemes, including Schemes 16 and 17, illustrating certain methods and compounds disclosed herein. [Figure 10] FIG. 1 is an XRD of compound 10 (i.e., compound of formula (Ia)).

[0015] [Mode for carrying out the invention]

[0024] As used herein, a "suitable protecting group" is a chemical group used to temporarily block or protect a particular functional portion of a molecule, e.g., COOH, O, S, or N, to allow a reaction to occur selectively at another reactive site of the molecule. A suitable protecting group typically reacts with the COOH, O, S, or N functionality in an acceptable yield to provide a protecting group that is stable to the anticipated reaction. A suitable protecting group must typically be selectively removable in an acceptable yield by one or more reagents that do not react with other sites of the molecule unless such reaction is desired. As detailed herein, a variety of suitable protecting groups can be used to protect carboxylic acid, oxygen, sulfur, and nitrogen functionalities, and such protecting groups are referred to herein as "suitable carboxylic acid protecting groups," "suitable alcohol protecting groups," "suitable thiol protecting groups," and "suitable amine protecting groups," respectively. Such suitable protecting groups are well known in the art and include those described in several published sources, such as: (1) Protective Groups in Organic Synthesis, Theodora W. Greene and Peter GMWuts, 2006, published by John Wiley and Sons, and (2) Bioconjugate Techniques, Greg T. Hermanson, 2013, published by Academic Press, both of which are incorporated by reference in their entirety.

[0016]

[0025] "Suitable alcohol protecting groups" are well known in the art and include, for example, tert-butyldimethylsilyl (TBDMS or TBS), tert-butyldiphenylsilyl (TBDPS), or tetrahydropyran (THP).

[0017]

[0026] "Suitable thiol protecting groups" are well known in the art and include, for example, triphenylmethyl (Trt or trityl).

[0018]

[0027] "Suitable amine protecting groups" are well known in the art and include, for example, 9-fluorenylmethoxycarbamate (Fmoc), t-butylcarbamate (Boc), or benzyloxycarbamate (Cbz).

[0019]

[0028] "Suitable carboxylic acid protecting groups" are well known in the art, and include, for example, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkyl substituted at any position with one or more aryl or heteroaryl, or alkylsilyl. In some aspects, the C1-C6 linear or branched alkyl is, for example, methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl, each of which can be substituted at any position with one or more aryl or heteroaryl. In some aspects, the alkylsilyl is, for example, 2-(trimethylsilyl)ethyl.

[0020]

[0029] In some aspects, any carboxylic acid, amine, or thiocarboxylic acid functionality in any compound disclosed herein can be present as, for example, H, an alkali metal (or ion), an alkaline earth metal (or ion), a salt, or any combination thereof.

[0021]

[0030] When the number of carbon atoms of a functional or other group (e.g., an alkyl group) is specified herein, it is intended that the number refers to the exact number of carbon atoms specified or to a range of carbon atoms. For example, if an alkyl is specified to contain 4 to 8 carbon atoms, an alkyl group containing 12 carbon atoms is not suitable, but rather only alkyl groups containing 4, 5, 6, 7, or 8 carbon atoms are suitable. Furthermore, when the number of carbon atoms is specified as a range, it is intended that any subranges falling within the indicated range, or individual numbers of carbon atoms, are expressly contemplated as if each such subrange or individual number of carbon atoms were expressly set forth herein. For example, C1 to C 24 is intended to include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 carbon atoms. Additionally, all subranges that can be made therein are expressly contemplated, including, but not limited to, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-22, 1-24, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-12, 2-14, 2-16, 2-18, 2-20, 2-22, 2-24, , 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 12, 3 to 14, 3 to 18, 3 to 24, 4 to 5, 4 to 8, 4 to 10, 4 to 12, 4 to 16, 4 to 20, 4 to 24, 6 to 8, 6 to 10, 6 to 12, 6 to 16, 6 to 20, 6 to 24, 8 to 10, 8 to 12, 8 to 16, 8 to 20, 8 to 24, 10 to 14, 10 to 20, 10 to 24, 12 to 18, or 12 to 24 carbon atoms.

[0022]

[0031] Any suitable reaction conditions can be used in carrying out the various reaction steps disclosed herein. Such reaction conditions can include solvents, acids, bases, reagents, catalysts, time, temperature, pH, or any combination thereof. In some aspects, certain reaction products can be purified before proceeding to the next step, or certain reaction products can be carried forward crude to the next reaction step. The various reaction conditions and synthetic reactions disclosed herein are exemplary, but any suitable reaction conditions or synthetic reactions can be used, such as those disclosed in Advanced Organic Chemistry-Part B: Reactions and Synthesis, Francis A. Carey and Richard J. Sundberg, 4th Edition, 2001, published by Springer, which is incorporated herein by reference in its entirety.

[0023]

[0032] As shown in Scheme 1 of FIG. 1, a compound of formula (III): [ka] A method for preparing The method comprises the step of: [ka] C1~C 20 with an activating agent selected from a linear or branched alkylsulfonyl halide, a substituted alkylsulfonyl halide, an arylsulfonyl halide, a substituted arylsulfonyl halide, a halophosphite (e.g., a chlorophosphite), or a halogenating agent, thereby producing a compound of formula (II): [ka] and forming The compound of formula (II) is 1with a nucleophile containing a group, thereby forming a compound of formula (III) above. (Wherein, X is O or NH; Ar is thiazolyl, pyridinyl, or oxazolyl; L is C1~C 24 Straight-chain or branched carbon sulfonic acid esters of substituted C1-C 24 a leaving group selected from a linear or branched sulfonate ester, an aryl sulfonate ester, a substituted aryl sulfonate ester, a heteroaryl sulfonate ester, a substituted heteroaryl sulfonate ester, a phosphate ester, or a halogen; R 1 is R 2 C.O.S., R. 3 S or R 4 R 5 N, and R 2 , R 3 , R 4 , and R 5 are independently hydrogen, C1 to C 24 C1-C linear alkyl (e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.), any one of which is substituted with one or more aryl or heteroaryl (e.g., phenyl, pyridinyl, furanyl, pyrrolyl, thiophenyl, etc., or any combination thereof); 24 Straight chain alkyl, C1-C 24 Branched alkyl (e.g., isopropyl, isobutyl, sec-butyl, tert-butyl, etc.), C1-C substituted with one or more aryl or heteroaryl groups at any position 24 Branched alkyl (e.g., isopropyl substituted with phenyl, isobutyl substituted with pyridinyl, etc.), C3-C 24 Cyclic alkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, etc.), C3-C substituted with one or more aryl or heteroaryl groups at any position. 24Cyclic alkyl (e.g., cyclohexyl substituted with phenyl), C1-C 24 Alkenyl, C1-C 24 Alkynyl, aryl (e.g., naphthalenyl, phenyl, pyridinyl, furanyl, pyrrolyl, thiophenyl, etc.), heteroaryl (e.g., pyridinyl, furanyl, pyrrolyl, thiophenyl, etc.), diphenylmethyl, triphenylmethyl, or any substituted form thereof are disclosed herein. In some aspects, R 1 R 2 COS and R 2 is n-heptyl.

[0024]

[0033] The compound of formula (II) is 1 Also disclosed herein is a method of preparing a compound of formula (III) comprising reacting a nucleophile containing a group with a nucleophile containing a group, the variables of the compounds of formula (II) and (III) being as defined elsewhere herein, as shown in Scheme 1 of Figure 1. In other words, in some aspects, the method of preparing the compound of formula (III) starts with a compound of formula (II) rather than a compound of formula (I). However, in other aspects, the method of preparing the compound of formula (III) starts with a compound of formula (I) via a compound of formula (II) as disclosed elsewhere herein.

[0025]

[0034] In some aspects, L is any suitable leaving group. The term "leaving group" is well known in the art, but simply explained, a leaving group is a molecular fragment whose bond to a base molecule is broken, and the leaving group leaves the molecule along with the electron pair of the broken bond. In a substitution reaction, a nucleophile typically forms a bond at the site of the base molecule where the leaving group was previously located. Suitable leaving groups include, for example, C1-C 24 linear or branched carbon sulfonate esters of the formula:24 linear or branched sulfonate ester, arylsulfonate ester, substituted (e.g., substituted with any group, such as alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, halide, hydroxyl, alkoxyl, etc., or any combination thereof) arylsulfonate ester, heteroarylsulfonate ester, substituted (e.g., substituted with any group, such as alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, halide, hydroxyl, alkoxyl, etc., or any combination thereof) heteroarylsulfonate ester, phosphate ester, or halogen. For example, in some aspects, L is OMs, OTs, OTf, 2,2,2-trifluoroethanesulfonate, n-octanesulfonate, benzenesulfonate, OP(=O)(OMe)2, OP(=O)(OEt)2, OP(=O)(OPh)2, I, Br, Cl, or F.

[0026]

[0035] In some aspects, as shown in Scheme 1 of FIG. 1, a compound of formula (I): [ka] Disclosed herein is a process for preparing a compound of formula (II) above from

[0027]

[0036] In some aspects, the compound of formula (IX): [ka] From the above, the OR of the compound of formula (IX) 6 to prepare a compound of formula (II) by converting R 6 is H or a suitable alcohol protecting group) are disclosed herein.

[0028]

[0037] In some cases, OR 6is converted to the leaving group L, 6 is the appropriate alcohol protecting group, the appropriate alcohol protecting group is deprotected to obtain a compound of formula (IX) 6 is H), and providing a compound of formula (IX) above, 6 is H), C1 to C 20 with an activating agent selected from a linear or branched alkylsulfonyl halide, a substituted alkylsulfonyl halide, an arylsulfonyl halide, a substituted arylsulfonyl halide, a halophosphite (e.g., a chlorophosphite), or a halogenating agent. Suitable specific activating agents are disclosed elsewhere herein.

[0029]

[0038] In some aspects, the compound of formula (IX) is a compound of formula (I): [ka] and the method comprises the step of reacting the compound of formula (I) with an activating agent selected from a C1-C20 linear or branched alkylsulfonyl halide, a substituted alkylsulfonyl halide, an arylsulfonyl halide, a substituted arylsulfonyl halide, a halophosphite (e.g., a chlorophosphite), or a halogenating reagent, thereby forming the compound of formula (II).

[0030]

[0039] In some aspects, the compound of formula (I) or the compound of formula (IX) is a compound of formula (Ia), (Ib), or (Ic): [ka] It is.

[0031]

[0040] In some aspects, Ar is: [ka] It is.

[0032]

[0041] In some aspects, the nucleophile used in the above process is thiooctanoic acid, whereby the compound of formula (III) above is converted to a compound of formula (XXV): [ka] It becomes.

[0033]

[0042] In some aspects, the nucleophile used in the above method is thiooctanoic acid, X is NH, and Ar is: [ka] whereby the compound of formula (III) is converted to a compound of formula (1): [ka] It becomes.

[0034]

[0043] In some aspects, a compound of formula (1, III-a) as shown in Scheme 2 of FIG. [ka] Disclosed herein is a process for preparing a compound of formula (1) above, comprising the step of producing a compound of formula (1) from a compound of formula (Ia) via formula (II-a), wherein L is as defined elsewhere herein.

[0035]

[0044] In some aspects, the nucleophile used in the above method is thiooctanoic acid, X is O, and Ar is: [ka] whereby the compound of formula (III) is converted to a compound of formula (2): [ka] It becomes.

[0036]

[0045] In some aspects, a compound of formula (2, III-b) as shown in Scheme 3 of FIG. [ka] Disclosed herein is a process for preparing a compound of formula (2) above, comprising producing a compound of formula (Ib) via formula (II-b), wherein L is a leaving group as defined elsewhere herein.

[0037]

[0046] In some aspects, the nucleophile used in the above method is thiooctanoic acid, X is O, and Ar is: [ka] whereby the compound of formula (III) is converted to a compound of formula (3): [ka] It becomes.

[0038]

[0047] In some aspects, a compound of formula (3, III-c) as shown in Scheme 4 of FIG. [ka] Disclosed herein is a process for preparing a compound of formula (3) above, comprising the step of producing a compound of formula (3) above from a compound of formula (Ic) via formula (II-c), wherein L is a leaving group as defined elsewhere herein.

[0039]

[0048] In some aspects, the conversion of a compound of formula (I) to a compound of formula (II) with a suitable activating agent and a suitable base in a suitable solvent can be accomplished at a temperature of −78 to 120° C., −50 to 80° C., −20 to 50° C., or −10 to 10° C.

[0040]

[0049] In some aspects, suitable activators include, but are not limited to, C1-C 20 linear or branched alkylsulfonyl halides, substituted alkylsulfonyl halides, arylsulfonyl halides, substituted arylsulfonyl halides, halophosphites (e.g., chlorophosphites), halogenating reagents, mesyl chloride, tosyl chloride, trifluoromethanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, benzenesulfonyl chloride, n-octanesulfonyl chloride, or any combination thereof.

[0041]

[0050] In some aspects, suitable bases include, but are not limited to, organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, collidine, DBU, DABCO, and inorganic bases such as NaHCO3, KHCO3, Na2CO3, K2CO3, Cs2CO3, NaOH, KOH, or any combination thereof.

[0042]

[0051] In some aspects, suitable solvents include, but are not limited to, hydrocarbons, toluene, chlorobenzene, isopropyl acetate, ethyl acetate, methyl acetate, diethyl ether, CPME, MTBE, THF, 2-methyl-THF, dioxane, acetone, methyl ethyl ketone, acetonitrile, DMF, DMAc, DMSO, DCM, water, or any combination thereof.

[0043]

[0052] In some aspects, the conversion of a compound of formula (II) to a compound of formula (III) with a suitable nucleophile in a suitable solvent can be accomplished at a temperature of -20 to 70°C, -10 to 60°C, 0 to 50°C, or 0 to 30°C.

[0044]

[0053] In some aspects, suitable solvents include, but are not limited to, hydrocarbons, toluene, chlorobenzene, isopropyl acetate, ethyl acetate, methyl acetate, diethyl ether, CPME, MTBE, THF, 2-methyl-THF, dioxane, acetone, methyl ethyl ketone, acetonitrile, DMF, DMAc, DMSO, DCM, water, or any combination thereof.

[0045]

[0054] In some aspects, suitable nucleophiles include, but are not limited to, R 2 COS - , R 3 S - , or R 4 R 5 N - R 2 , R 3 , R 4 , R 5 is defined elsewhere herein. In some aspects, the nucleophile is n-CH 15 COS - It is.

[0046]

[0055] In some aspects, disclosed herein is a method for preparing a compound of formula (I), as shown in scheme 5 of FIG. 2. In some aspects, the method comprises the steps of preparing the compound of formula (I) from a compound of formula (IV; β-functionalized ester), a compound of formula (V), and a compound of formula (VI). The compound of formula (I) can be prepared using standard ester- and amide-forming reactions with appropriate protecting groups on the nitrogen and / or oxygen atoms. The order of bond formation between the three components (IV, V, and VI) is usually not important, and therefore any order of bond formation is feasible. In scheme 5 of FIG. 2, R 6 is H or a suitable alcohol protecting group, R 7 , R 9 , and R 11are independently H, an alkali metal ion, an alkaline earth metal ion, or a suitable carboxylic acid protecting group such as, for example, a C1-C6 alkyl group, a substituted C1-C6 alkyl group, 2-trimethylsilylethyl, benzyl, or a substituted benzyl; R 8 , R 10 , and R 12 is independently H or a suitable nitrogen protecting group. Ar is thiazole, pyridine, or oxazole. X is O or NH. In some aspects, either N atom is a quaternary ammonium.

[0047]

[0056] In some aspects, the method comprises reacting a compound of formula (I): [ka] or a compound of the above formula (IX) [ka] with a compound of formula (IV): [ka] , a compound of formula (V): [ka] and a compound of formula (VI): [ka] The method further comprises the step of preparing the compound from one or more reactions comprising: (In the formula, R 6 is H or a suitable alcohol protecting group, R 8 , R 10 , and R 12 are independently H, a suitable amine protecting group, or a chiral group; R 7 , R 9 , and R 11are independently H, an alkali metal ion, an alkaline earth metal ion, or a suitable carboxylic acid protecting group; Optionally, the suitable carboxylic acid protecting group is selected from C1-C6 linear or branched alkyl, C1-C6 linear or branched alkyl substituted at any position with one or more aryl or heteroaryl, or alkylsilyl; Optionally, the C1-C6 linear or branched alkyl or the C1-C6 linear or branched alkyl substituted at any of the above positions with one or more aryl or heteroaryl is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; Optionally, the alkylsilyl is 2-(trimethylsilyl)ethyl; and Optionally, any N atom is a quaternary ammonium).

[0048]

[0057] In some aspects, the compound of formula (I) or the compound of formula (IX) is a compound of formula (Ia), (Ib), or (Ic): [ka] It is.

[0049]

[0058] In some aspects, the compound of formula (I) is Formula (IV, R 8 =H) of the formula (V, R 9 =H) by condensation to form a compound of formula (VII), The above formula (VII, R 10 =H) of formula (VI,R 11 ═H) under amidation conditions to form a compound of formula (VIII); The above formula (VIII, R 7 and R 11 ═H) under amidation conditions to form a macrocycle of formula (IX); The compound of formula (I) is prepared by the method depicted in Scheme 6 of FIG. 3, which comprises reacting a compound of formula (IX) above under deprotection conditions to remove the alcohol protecting group to form a compound of formula (I).

[0050]

[0059] In some aspects, the compound of formula (IV) above is reacted by condensation with the compound of formula (V) above to form a compound of formula (VII): [ka] Forming The compound of formula (VII) above is reacted with the compound of formula (VI) above by amidation to form a compound of formula (VIII): [ka] and The compound of formula (VIII) above reacts by amidation ring closure to form a compound of formula (IX) above, 6 , R 7 , R 10 , and R 12 (wherein n is as defined elsewhere herein). In some aspects, any N atom is a quaternary ammonium.

[0051]

[0060] In some aspects, R 6 is H or a suitable alcohol protecting group, and When the compound of formula (IV) is reacted with the compound of formula (V), R 8 is H and X is N, then N is neutral or positively charged, R 7 is a suitable carboxylic acid protecting group, R 10 is a suitable amine protecting group and R 9 is H, an alkali metal ion, or an alkaline earth metal ion; When the compound of formula (VI) is reacted with the compound of formula (VII), R 7 is a suitable carboxylic acid protecting group, R 10 is H and optionally R10 is attached to the positively charged nitrogen atom, and R 11 is H, an alkali metal ion, or an alkaline earth metal ion, and R 12 is a suitable amine protecting group, and When the compound of formula (VIII) is reacted by amidation ring closure, R 8 is H, an alkali metal ion, or an alkaline earth metal ion, and X is N, the N is neutral or positively charged, and R 12 is H and optionally R 12 is bonded to a positively charged nitrogen atom.

[0052]

[0061] In some aspects, the choice of protecting group is appropriately chosen based on its orthogonality with other protecting groups. The appropriate method for removing a protecting group for a given functional group depends on the nature of the protecting group in the same molecule.

[0053]

[0062] In some aspects, suitable and preferred nitrogen protecting groups are Boc or Fmoc, which can be selectively removed by acidic or basic conditions.

[0054]

[0063] In some aspects, suitable carboxylic acid protecting groups are C1-C6 alkyl groups, substituted C1-C6 alkyl groups, 2-trimethylsilylethyl, benzyl, or substituted benzyl. In some aspects, suitable carboxylic acid protecting groups are methyl, ethyl, or 2-trimethylsilylethyl. Such protecting groups can be selectively removed under basic and acidic conditions.

[0055]

[0064] In some aspects, condensation reagents are used to prepare ester or amide bonds from carboxylic acids and alcohols or amines, hi some aspects, condensation reagents include HATU, EDC, DCC, T3P, HBTU, TATU, TBTU, COMU, HOTU, BOP, PyBOP, and PyBroP.

[0056]

[0065] In some aspects, the compound of formula (Ia) above is prepared as shown in scheme 7 in Figure 4. The protecting groups and reaction conditions are similar to those described elsewhere herein for compounds of similar or similar structure. The protecting groups and reaction conditions shown in scheme 7 are merely illustrative and are not to be construed as limiting in any manner. Compound 7 is reported in references 1-3, which are incorporated herein by reference in their entirety for all purposes.

[0057]

[0066] In some aspects, the compound of formula (Ib) above is prepared as shown in scheme 8 of Figure 5. The protecting groups and reaction conditions are similar to those described elsewhere herein for compounds of similar or similar structure. The protecting groups and reaction conditions shown in scheme 8 are merely illustrative and are not to be construed as limiting in any manner. The preparation of compound 14 is reported in reference 4, which is incorporated herein by reference in its entirety for all purposes.

[0058]

[0067] In some aspects, the compound of formula (Ic) above is prepared as shown in Scheme 9. The protecting groups and reaction conditions are similar to those described elsewhere herein for compounds of similar or similar structure. The protecting groups and reaction conditions shown in Scheme 9 are merely illustrative and are not to be construed as limiting in any manner. The preparation of compound 18 is reported in Reference 5, which is incorporated herein by reference in its entirety for all purposes.

[0059]

[0068] In some aspects, the compound represented by formula (IV-a, R 8 =H) compound, reacting a compound of formula (X) with a chiral auxiliary of formula (XI) via imine formation to form a compound of formula (XII); reacting said compound of formula (XII) with a compound of formula (XIII) via nucleophilic addition to form a compound of formula (XIV); and The NY bond is cleaved to obtain a compound represented by the formula (IV-a, R 8═H), where Y is a chiral group sufficient to effect diastereoselective nucleophilic addition of a compound of formula (XIII) above to a compound of formula (XII) above to form a compound of formula (IV-a) above as a major product, and R 13 is Cl, Br, I, F, an alkali metal, an alkaline earth metal, ZnX, CuX, Cu, or a transition metal, where each X in ZnX or CuX is independently a halide (e.g., F, Cl, Br, or I).

[0060]

[0069] In some aspects, X is NH and the process comprises: via imine formation to form a compound of formula (X): [ka] with a chiral auxiliary of formula (XI): Y-NH2(XI) to produce a compound of formula (XII): [ka] forming a The compound of formula (XII) can be converted to a compound of formula (XIII) via nucleophilic addition: [ka] to obtain a compound of formula (IV) (wherein X is NH and R 8 is a chiral group Y): [ka] and forming The NY bond is cleaved to give a compound of formula (IV), 8 is H, and when X is N, N is neutral or positively charged, to produce the compound of formula (IV). (wherein Y is a compound represented by the formula (XIII) above, which is capable of reacting with a compound represented by the formula (XII) above to produce a compound represented by the formula (IV) above as a main product. 8 is a chiral group Y), R 6 is a suitable alcohol protecting group, R 7 is a suitable carboxylic acid protecting group, Optionally, the carboxylic acid protecting group is selected from C1-C6 linear or branched alkyl, C1-C6 linear or branched alkyl substituted at any position with one or more aryl or heteroaryl, or alkylsilyl; Optionally, the C1-C6 linear or branched alkyl or the C1-C6 linear or branched alkyl substituted at any of the positions with one or more aryl or heteroaryl is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; and Optionally, the alkylsilyl is 2-(trimethylsilyl)ethyl; and R 13 is H, a halide, or a metal including Li, Na, K, ZnBr, ZnCl, CuCl, CuBr, CuI, Cu, or any combination thereof.

[0061]

[0070] In some aspects, the chiral auxiliary of formula (XI) above is [ka] (wherein R 14 is C1-6 linear and branched alkyl or aromatic or heteroaromatic. In some aspects, R 9is tert-butyl, p-tolyl, an alkyl, an aromatic group, or a substituted version of any of them. In some aspects, the compound of formula (XI) above is (R)-tert-butanesulfinamide.

[0062]

[0071] In some aspects, the compound of formula (XIII) is a bromoacetate that is converted to the corresponding Reformatsky intermediate in the presence of Zn metal, with or without a Cu(I) halide, which reacts with an imine (XII) to form a compound of formula (XIV).

[0063]

[0072] In some aspects, a suitable solvent for a Reformatsky-type reaction is THF, 2-methylTHF, or a combination thereof.

[0064]

[0073] In some aspects, suitable temperatures for reformatski include -20 to 50°C, -15 to 30°C, or 0 to 5°C.

[0065]

[0074] In some aspects, the cleavage of the NY bond can be carried out under acidic conditions such as HCl. Suitable solvents for the cleavage of the NY bond are 1,4-dioxane, diethyl ether, THF, MTBE, or combinations thereof.

[0066]

[0075] In some aspects, suitable temperatures for cleavage of the NY bond include -10 to 50°C, -5 to 40°C, or 0 to 30°C.

[0067]

[0076] In some aspects, the synthetic method shown in Scheme 10 of FIG. 6 can be carried out to prepare an OR 6 This is applied to the synthesis of S-Trt protected compound 24 by replacing with S-Trt. The preparation of compound 1 from compound 24 is reported in reference 1, and the preparation of compound 22 is reported in reference 6, both of which are incorporated herein by reference in their entirety.

[0068]

[0077] In some embodiments, the compound of formula (IV-a) is reacting a compound of formula (X) with an Evans chiral auxiliary 25 by an Evans-type diastereoselective aldol reaction to form a compound of formula (XV) as the major product, reacting the compound of formula (XV) with a compound of formula (XVI) to form a compound of formula (XVII), reacting the compound of formula (XVII) under Mitsunobu reaction conditions to form a compound of formula (XVIII), reducing the N-O bond of the compound of formula (XVIII) to form a compound of formula (XIX), protecting the resulting free nitrogen of the compound of formula (XIX) with a nitrogen protecting group to form a compound of formula (XX), opening the β-lactam of formula (XX) to form a compound of formula (IV-a), removing the protecting group of the compound of formula (IV-a) to form a compound of formula (IV-a, R 8 =H), which is prepared by the method shown in Scheme 12 of Figure 7 (wherein R 6 , R 7 , and R 8 are defined in other parts of this specification, and R 15 is C1-C6 alkyl or benzyl). Formula (XVI) can be a free base or a salt thereof.

[0069]

[0078] In some embodiments, by substituting OR 6 with S-Trt to change the synthetic route of Scheme 12 of Figure 7, a synthetic route shown in Scheme 13 of Figure 8 is disclosed for preparing the corresponding S-Trt derivative (IV-a’, R 8 =H) from compound (X’). The preparation of compound 1 from formula (IV-a’, R 8 =H) is reported in Reference 1.

[0070]

[0079] In some embodiments, the compound of formula (X) is protecting the hydroxyl group of but-3-yn-1-ol with a suitable protecting group to form a compound of formula (XXI); reacting the compound of formula (XXI) with a strong base, such as n-BuLi, LDA, LiHMDS, NaHMDS, KHMDS, EtMgX, MeMgX, iPrMgX to generate the corresponding anion, which is then trapped with formaldehyde, paraformaldehyde, or trioxane to form the compound of formula (XXII); reducing the compound of formula (XXII) with DIBAL to form a compound of formula (XXIII); and The compound of formula (XXIII) may be prepared by a process comprising the step of oxidizing a compound of formula (XXIII) to form a compound of formula (X), as shown in Scheme 14 of FIG.

[0071]

[0080] In some aspects, the compound of formula (IV-b) is reacting the compound of formula (X) with Evans chiral auxiliary 26 via an Evans-type diastereoselective aldol reaction to form a compound of formula (XXIV) as the major product; and The compound of formula (XXIV) is reacted with an alcohol (R 7 The compound is prepared in Scheme 15 of FIG. 8 by a process which comprises reacting with (III)-(OH) to form a compound of formula (IV-b).

[0072]

[0081] In some aspects, X is O and the process comprises: via aldol addition to a compound of formula (X): [ka] with a chiral auxiliary of formula (XXVIII), 1 is a chiral group sufficient to effect diastereoselective aldol addition: [ka] to produce a compound of formula (XXVIX): [ka] and forming The method includes the step of preparing a compound of formula (IV) by esterification of a compound of formula (XXVIX) to prepare a compound of formula (IV) where X is O. In some aspects, Z 1 The chirality of the group controls the stereochemistry of the reaction by forming a particular diastereomer as the major product in the aldol addition. At least two products can be produced in such an aldol addition, but one diastereomeric product is formed in a higher yield than the other possible diastereomeric products. In some aspects, the compound of formula (XXVIII) above is any known compound capable of producing such a diastereoselective aldol addition, such as an Evans-type oxazolidinone chiral auxiliary, an Evans-type oxazolidinethione chiral auxiliary, an Evans-type thiazolidinethione chiral auxiliary, or a Crimmins-type thiazolidinethione chiral auxiliary.

[0073]

[0082] In some aspects, compound 4 is prepared as disclosed elsewhere herein for compounds of similar or similar structure, as shown in Scheme 16 of Figure 9. The selection of reagents and protecting groups is illustrative and not intended to be limiting in any way.

[0074]

[0083] In some aspects, the synthetic method shown in Scheme 10 of FIG. 6 can be carried out by reacting R 6 This is applied to the synthesis of TBDPS-protected compound 4 by replacing with TBDPS. The preparation of compound 10 from compound 4 is described elsewhere herein for compounds of similar or similar structure.

[0075]

[0084] In some aspects, compound 11 is prepared as disclosed elsewhere herein for compounds of similar or similar structure, as shown in Scheme 17 of Figure 9. The selection of reagents and protecting groups is illustrative and not intended to be limiting in any way.

[0076]

[0085] In some aspects, the compound of formula (XXVI): [ka] (Wherein, X is O or NH, Ar is thiazolyl, pyridinyl, or oxazolyl; R 16 OH, OR 6 or L, R 6 is a suitable alcohol protecting group, and L is C1~C 24 Straight-chain or branched carbon sulfonic acid esters of substituted C1-C 24 is a leaving group selected from a linear or branched sulfonate ester, an aryl sulfonate ester, a substituted aryl sulfonate ester, a heteroaryl sulfonate ester, a substituted heteroaryl sulfonate ester, a phosphate ester, or a halogen.

[0077]

[0086] In some aspects, the compound of formula (XXVI) is a compound of formula (Ia), (Ib), or (Ic): [ka] It is.

[0078]

[0087] In some aspects, R 16 is OH. In some aspects, R 16 is L. In some cases, R 16 OR 6 It is.

[0079]

[0088] In some aspects, X is O and Ar is pyridinyl. In some aspects, X is NH and Ar is pyridinyl. In some aspects, X is O and Ar is oxazolyl. In some aspects, X is NH and Ar is oxazolyl. In some aspects, X is NH and Ar is thiazolyl. In some aspects, X is O and Ar is thiazolyl.

[0080]

[0089] In some aspects, the compound of formula (XXVII): [ka] (Wherein, X is O or NH, Ar is thiazolyl, pyridinyl, or oxazolyl; R 17 is R 2 C.O.S., R. 3 S or R 4 R 5 N, and R 2 , R 3 , R 4 , and R 5 are independently hydrogen, C1 to C 24 C1-C linear alkyl (e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.), any one of which is substituted with one or more aryl or heteroaryl (e.g., phenyl, pyridinyl, furanyl, pyrrolyl, thiophenyl, etc., or any combination thereof); 24 Straight chain alkyl, C1-C 24 Branched alkyl (e.g., isopropyl, isobutyl, sec-butyl, tert-butyl, etc.), C1-C substituted with one or more aryl or heteroaryl groups at any position 24 Branched alkyl (e.g., isopropyl substituted with phenyl, isobutyl substituted with pyridinyl, etc.), C3-C 24Cyclic alkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, etc.), C3-C substituted with one or more aryl or heteroaryl groups at any position. 24 Cyclic alkyl (e.g., cyclohexyl substituted with phenyl), C1-C 24 Alkenyl, C1-C 24 In some aspects, the compound of formula (XXVII) above is R 17 R 2 R if COS 2 Exclude compounds where R is an unsubstituted C7 linear alkyl (i.e., R 17 R 2 R if COS 2 is not an unsubstituted C7 linear alkyl.

[0081]

[0090] Various aspects are contemplated herein, some of which are described in the following paragraphs. It is expressly contemplated that any aspect or portion thereof may be combined to form a single aspect.

[0082]

[0091] Aspect 1: Compounds of formula (I): [ka] A method for preparing The method comprises, in one or more reactions, reacting a compound of formula (IV): [ka] , a compound of formula (V): [ka] and a compound of formula (VI): [ka] The method comprises reacting (Wherein, X is O or NH, Ar is thiazolyl, pyridinyl, or oxazolyl; R 6 is H or a suitable alcohol protecting group, R 8 , R 10 , and R 12 are independently H, a suitable amine protecting group, or a chiral group; R 7 , R 9 , and R 11 are independently H, an alkali metal ion, an alkaline earth metal ion, or a suitable carboxylic acid protecting group; Optionally, the suitable carboxylic acid protecting group is selected from C1-C6 linear or branched alkyl, C1-C6 linear or branched alkyl substituted at any position with one or more aryl or heteroaryl, or alkylsilyl; Optionally, the C1-C6 linear or branched alkyl or the C1-C6 linear or branched alkyl substituted at any of the positions with one or more aryl or heteroaryl is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; and Optionally, the alkylsilyl is 2-(trimethylsilyl)ethyl.

[0083]

[0092] Aspect 2: Compounds of formula (III): [ka] A method for preparing The method comprises the step of: [ka] C1~C 20 with an activating agent selected from a linear or branched alkylsulfonyl halide, a substituted alkylsulfonyl halide, an arylsulfonyl halide, a substituted arylsulfonyl halide, a halophosphite (e.g., a chlorophosphite), or a halogenating agent, thereby producing a compound of formula (II): [ka] and forming The compound of formula (II) is 1 with a nucleophile containing a group, thereby forming a compound of formula (III) above. (Wherein, X is O or NH, Ar is thiazolyl, pyridinyl, or oxazolyl; R 1 is R 2 C.O.S., R. 3 S or R 4 R 5 N, R 2 , R 3 , R 4 , and R 5 are independently hydrogen, C1 to C 24 C1-C linear alkyl substituted with one or more aryl or heteroaryl groups at any position 24 Straight chain alkyl, C1-C 24 C1-C branched alkyl, any one of which is substituted with one or more aryl or heteroaryl. 24 Branched alkyl, C3-C 24 cyclic alkyl, C3-C substituted with one or more aryl or heteroaryl groups at any position; 24 Cyclic alkyl, C1-C 24 Alkenyl, C1-C 24or a substituted form of any of them; and L is C1~C 24 Straight-chain or branched carbon sulfonic acid esters of substituted C1-C 24 wherein the leaving group is selected from a linear or branched sulfonate ester of the formula (I), an aryl sulfonate ester, a substituted aryl sulfonate ester, a heteroaryl sulfonate ester, a substituted heteroaryl sulfonate ester, a phosphate ester, or a halogen.

[0084]

[0093] Aspect 3: Compounds of formula (III): [ka] A method for preparing The method comprises the step of: [ka] R 1 with a nucleophile comprising a group (Wherein, X is O or NH, Ar is thiazolyl, pyridinyl, or oxazolyl; R 1 is R 2 C.O.S., R. 3 S or R 4 R 5 N, R 2 , R 3 , R 4 , and R 5 are independently hydrogen, C1 to C 24 C1-C linear alkyl substituted with one or more aryl or heteroaryl groups at any position 24 Straight chain alkyl, C1-C 24 C1-C branched alkyl, any one of which is substituted with one or more aryl or heteroaryl. 24 Branched alkyl, C3-C24 cyclic alkyl, C3-C substituted with one or more aryl or heteroaryl groups at any position; 24 Cyclic alkyl, C1-C 24 Alkenyl, C1-C 24 or a substituted form of any of them; and L is C1~C 24 Straight-chain or branched carbon sulfonic acid esters of substituted C1-C 24 wherein the leaving group is selected from a linear or branched sulfonate ester of the formula (I), an aryl sulfonate ester, a substituted aryl sulfonate ester, a heteroaryl sulfonate ester, a substituted heteroaryl sulfonate ester, a phosphate ester, or a halogen.

[0085]

[0094] Aspect 4: Reacting a compound of formula (II) above with a compound of formula (IX): [ka] From the above, the OR of the compound of formula (IX) 6 wherein R 6 is H or a suitable alcohol protecting group, or the method of any one of aspects 1-3.

[0086]

[0095] Phase 5: OR 6 to the leaving group L, R 6 is the appropriate alcohol protecting group, the appropriate alcohol protecting group is deprotected to obtain a compound of formula (IX) 6 is H), and The compound of the above formula (IX) (wherein R 6 is H), C1 to C 20Aspect 4, or the method of any one of aspects 1-4, comprising reacting with an activating agent selected from a linear or branched alkylsulfonyl halide, a substituted alkylsulfonyl halide, an arylsulfonyl halide, a substituted arylsulfonyl halide, a halophosphite (e.g., a chlorophosphite), or a halogenating reagent.

[0087]

[0096] Aspect 6: The compound of formula (IX) above is a compound of formula (I): [ka] and The method comprises reacting a compound of formula (I) with a compound represented by formula (I) of C1 to C 20 with an activating agent selected from a linear or branched alkylsulfonyl halide, a substituted alkylsulfonyl halide, an arylsulfonyl halide, a substituted arylsulfonyl halide, a halophosphite (e.g., a chlorophosphite), or a halogenating reagent, thereby forming a compound of formula (II).

[0088]

[0097] Aspect 7: The compound of formula (I) or the compound of formula (IX) above is a compound of formula (Ia), (Ib), or (Ic): [ka] The method of any one of Aspects 1 to 6, wherein

[0089]

[0098] Aspect 8: The method of any one of aspects 1 to 7, wherein L is OMs, OTs, OTf, 2,2,2-trifluoroethanesulfonate, n-octanesulfonate, benzenesulfonate, OP(=O)(OMe)2, OP(=O)(OEt)2, OP(=O)(OPh)2, I, Br, Cl, or F.

[0090]

[0099] Position 9:Ar is: [ka] Aspect 9. The method of any one of aspects 1 to 8, wherein

[0091]

[0100] Aspect 10: The nucleophile is thiooctanoic acid, whereby the compound of formula (III) is converted to a compound of formula (XXV): [ka] 10. The method according to any one of aspects 1 to 9,

[0092]

[0101] Aspect 11: X is NH and Ar is: [ka] whereby the compound of formula (III) is converted to a compound of formula (1): [ka] Aspect 10, or the method of any one of Aspects 1 to 10,

[0093]

[0102] Aspect 12: X is O and Ar is: [ka] whereby the compound of formula (III) is converted to a compound of formula (2): [ka] Aspect 10. The method of any one of Aspects 1 to 11, wherein

[0094]

[0103] Aspect 13: X is O and Ar is: [ka] whereby the compound of formula (III) is converted to a compound of formula (3): [ka] The method of any one of Aspect 10 or Aspects 1 to 12,

[0095]

[0104] Aspect 14: The method comprises the step of: [ka] , a compound of formula (V): [ka] and a compound of formula (VI): [ka] The method further comprises the step of preparing the compound of formula (I) or the compound of formula (IX) from one or more reactions comprising: (In the formula, R 6 is H or a suitable alcohol protecting group, R 8 , R 10 , and R 12 are independently H, a suitable amine protecting group, or a chiral group; R 7 , R 9 , and R 11 are independently H, an alkali metal ion, an alkaline earth metal ion, or a suitable carboxylic acid protecting group; Optionally, the suitable carboxylic acid protecting group is selected from C1-C6 linear or branched alkyl, C1-C6 linear or branched alkyl substituted at any position with one or more aryl or heteroaryl, or alkylsilyl; Optionally, the C1-C6 linear or branched alkyl or the C1-C6 linear or branched alkyl substituted at any of the positions with one or more aryl or heteroaryl is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; and Optionally, the alkylsilyl is 2-(trimethylsilyl)ethyl; any one of aspects 2 or 4-13, or the method of any one of aspects 1-13.

[0096]

[0105] Aspect 15: The compound of formula (IV) above is reacted by condensation with the compound of formula (V) above to form a compound of formula (VII): [ka] Forming The compound of formula (VII) above is reacted with the compound of formula (VI) above by amidation to form a compound of formula (VIII): [ka] and The compound of formula (VIII) above is reacted by amidation ring closure to give the compound of formula (IX) above or the compound of formula (I) above (wherein R 6 is H).

[0097]

[0106] Situation 16:R 6 is H or a suitable alcohol protecting group; When the compound of formula (IV) is reacted with the compound of formula (V), R 8 is H and X is N, then N is neutral or positively charged, R 7 is a suitable carboxylic acid protecting group, R 10 is a suitable amine protecting group and R 9 is H, an alkali metal ion, or an alkaline earth metal ion; When the compound of formula (VI) is reacted with the compound of formula (VII), R 7 is a suitable carboxylic acid protecting group, R 10 is H and optionally R 10 is attached to the positively charged nitrogen atom, and R 11 is H, an alkali metal ion, or an alkaline earth metal ion, and R 12 is a suitable amine protecting group, and When the compound of formula (VIII) is reacted by amidation ring closure, R 8 is H, an alkali metal ion, or an alkaline earth metal ion, and X is N, the N is neutral or positively charged, and R 12 is H and optionally R 12 Aspect 15 or the method of any one of Aspects 1 to 15, wherein is attached to a positively charged nitrogen atom.

[0098]

[0107] Aspect 17: X is NH and the process comprises the steps of: via imine formation to form a compound of formula (X): [ka] with a chiral auxiliary of formula (XI): Y-NH2(XI) to produce a compound of formula (XII): [ka] forming a The compound of formula (XII) can be converted to a compound of formula (XIII) via nucleophilic addition: [ka] to obtain a compound of formula (IV) (wherein X is NH and R 8 is a chiral group Y): [ka] and forming The NY bond is cleaved to give a compound of formula (IV), 8 is H, and when X is N, N is neutral or positively charged, to produce the compound of formula (IV). (wherein Y is a compound represented by the formula (XIII) above, which is capable of reacting with a compound represented by the formula (XII) above to produce a compound represented by the formula (IV) above as a main product. 8 is a chiral group Y), R 6 is a suitable alcohol protecting group, R 7 is a suitable carboxylic acid protecting group, Optionally, the carboxylic acid protecting group is selected from C1-C6 linear or branched alkyl, C1-C6 linear or branched alkyl substituted at any position with one or more aryl or heteroaryl, or alkylsilyl; Optionally, the C1-C6 linear or branched alkyl or the C1-C6 linear or branched alkyl substituted at any of the positions with one or more aryl or heteroaryl is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; and Optionally, the alkylsilyl is 2-(trimethylsilyl)ethyl; and R 13 is H, a halide, or a metal including Li, Na, K, ZnBr, ZnCl, CuCl, CuBr, CuI, Cu, or any combination thereof;

[0099]

[0108] Aspect 18: The chiral auxiliary of formula (XI) above is [ka] (wherein R 14 is tert-butyl, p-tolyl, an alkyl, an aromatic group, or a substituted version of any of them; Aspect 17, or the method of any one of aspects 1 to 17.

[0100]

[0109] Situation 19:R 14 Aspect 18 or the method of any one of aspects 1 to 18, wherein is tert-butyl, whereby the compound of formula (XI) is (R)-tert-butanesulfinamide.

[0101]

[0110] Aspect 20: Compound of formula (XXVI): [ka] (Wherein, X is O or NH, Ar is thiazolyl, pyridinyl, or oxazolyl; R 16 OH, OR 6 or L, R 6 is a suitable alcohol protecting group, and L is C1~C 24 Straight-chain or branched carbon sulfonic acid esters of substituted C1-C 24 wherein the leaving group is selected from a linear or branched sulfonate ester of the formula (I), an aryl sulfonate ester, a substituted aryl sulfonate ester, a heteroaryl sulfonate ester, a substituted heteroaryl sulfonate ester, a phosphate ester, or a halogen.

[0102]

[0111] Aspect 21: The compound of formula (XXVI) above is a compound of formula (Ia), (Ib), or (Ic): [ka] Aspect 20 or the compound of any one of aspects 1 to 20, wherein

[0103]

[0112] Situation 22:R 16 The compound of aspect 20 or any one of aspects 1-21, wherein is OH.

[0104]

[0113] Situation 23:R 16 The compound of aspect 20 or any one of aspects 1 to 22, wherein is L.

[0105]

[0114] Situation 24:R 16 OR 6 A compound according to aspect 20 or any one of aspects 1 to 23, wherein

[0106]

[0115] Aspect 25: X is O, and A compound according to any one of aspects 20 to 24 or any one of aspects 1 to 24, wherein Ar is pyridinyl.

[0107]

[0116] Aspect 26: X is O, and A compound according to any one of aspects 20 to 24 or any one of aspects 1 to 25, wherein Ar is oxazolyl.

[0108]

[0117] Aspect 27: X is NH, and A compound according to any one of aspects 20 to 24 or any one of aspects 1 to 26, wherein Ar is thiazolyl.

[0109] [Example] General methods. Unless otherwise indicated, all materials were obtained from commercial sources and used without purification. All reactions requiring anhydrous conditions were carried out under a positive pressure of argon using flame-dried glassware. Dichloromethane, tetrahydrofuran, methanol, triethylamine, and acetonitrile were degassed with argon and dried by a solvent purification system (JC Meyer, Glass Contour). Flash chromatography was performed on Merck silica gel Kieselgel 60 (230-400 mesh) from EM science using the solvents indicated. 1H NMR spectrum and 13 C NMR spectra were recorded on a Varian 400 MHz spectrometer unless otherwise indicated. Mass spectra were obtained on an Agilent 6224 TOF. Optical rotations were recorded on an Autopol III automatic polarimeter (Rudolph Research, Fairfield, NJ) at 24° C. X-ray diffraction (XRD) was recorded on a Brucker D8 Discover DaVinci.

[0110] [Table 1]

[0111]

[0118] X-ray Diffraction. Figure 10 is the XRD of compound 10 (i.e., the compound of formula (Ia)).

[0112]

[0119] Synthesis of octanethio S-acid. To a solution of thioacetamide (4.38 g, 58.3 mmol) in anhydrous toluene (75 mL) was added octanoyl chloride (10.0 mL, 58.3 mmol). The reaction mixture was stirred at 30 °C for 4 h. The reaction was then cooled to 0 °C, followed by the addition of 10% aqueous NaOH (20 mL). The biphasic mixture was stirred at room temperature for 30 min and acidified to pH 2-3 with aqueous 1 M KHSO4. The acidic solution was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous MgSO4 and evaporated in vacuo. The crude product was filtered through silica to give thiooctanoic acid (7.30 g, 78% yield).

[0113]

[0120] (E)-5-((tert-butyldiphenylsilyl)oxy)pent-2-en-1-ol (34). To a neat mixture of 3-butyn-1-ol (10.0 g, 143 mmol) and imidazole (10.2 g, 171 mmol) was added tert-butyldiphenylchlorosilane (44.5 mL, 150 mmol) dropwise. The reaction mixture was stirred for 3.5 h. The precipitate was filtered and washed with diethyl ether. The combined organic extracts were dried over anhydrous Na2SO4. Evaporation of the solvent in vacuum gave crude (but-3-yn-1-yloxy)(tert-butyl)diphenylsilane, which was used directly without further purification.

[0114]

[0121] To a solution of this crude product in anhydrous THF (600 mL) at -78°C was added a solution of n-butyllithium in hexanes (1.6 M, 98.1 mL, 157 mmol) dropwise. The reaction mixture was stirred at -78°C for 1 h, warmed to room temperature over 2.5 h, and then cooled back to -78°C. To the reaction mixture was added paraformaldehyde (5.57 g, 185 mmol) in one portion, and the resulting suspension was allowed to warm slowly to room temperature and stirred overnight. The mixture was concentrated in vacuo and then partitioned between diethyl ether and water. The phases were separated and the aqueous phase was further extracted with diethyl ether. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude propargyl alcohol, which was used directly without further purification.

[0115]

[0122] To a solution of crude propargyl alcohol in anhydrous diethyl ether (500 mL) at 0° C., Red-Al (70% in toluene) (45.6 mL, 152 mmol) was slowly added and the reaction mixture was stirred for 2 h at 0° C. The reaction mixture was carefully quenched with a wet paste of Na2SO4 until a colorless solid appeared. The aluminum salts were filtered off and the salts were washed repeatedly with hot THF. The combined filtrates were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was then purified by column chromatography on silica gel to give trans-allyl alcohol 34 (29.1 g, 60% yield for three steps) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.73-7.64 (m, 4H), 7.48-7.35 (m, 6H), 5.74-5.62 (m, 2H), 4.07 (d, J= 3.5 Hz, 2H), 3.73 (t, J = 6.6 Hz, 2H), ), 2.32 (q, J = 6.1 Hz, 2H), 1.44 (bs,1H), 1.07 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 135.7, 134.1, 131.1, 129.7, 129.6, 127.7, 63.8, 63.6, 35.7, 27.0,19.3.

[0116]

[0123] (R)-N-((1E,2E)-5-((tert-butyldiphenylsilyl)oxy)pent-2-en-1-ylidene)-2-methylpropane-2-sulfinamide (29). To a solution of DMSO (12.1 mL, 171 mmol) in anhydrous CHCl (200 mL) was added oxalyl chloride (10.8 mL, 128 mmol) over 15 min at −78 °C. After stirring at −78 °C for 30 min, trans-allyl alcohol 4 (29.1 g, 85.5 mmol) in anhydrous CHCl (500 mL) was added dropwise over 30 min and stirred at −78 °C for an additional 2.5 h. Triethylamine (35.7 mL, 256 mmol) was then added dropwise and stirred at −78 °C for an additional hour and allowed to warm slowly to room temperature. After stirring at room temperature for 3 h, the reaction mixture was quenched by the addition of water. The organic phase was separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude aldehyde (27) was immediately used in the next reaction without further purification.

[0117]

[0124] A solution of this crude aldehyde in anhydrous THF (500 mL) was added to Ti(O i(Pr)4 (40.5 mL, 137 mmol) was added at room temperature and stirred for 10 min. To this was added (R)-tert-butanesulfinamide (11.4 g, 94.0 mmol) and the reaction was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaCl. The crude mixture was filtered through Celite and the filter cake was washed with ethyl acetate. The filtrate was then dried over Na2SO4 and concentrated in vacuo and the crude product was purified by column chromatography on silica gel (elution with 15-85% ethyl acetate in hexanes) to give imine 29 (26.2 g, 71%). 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 7.7 Hz, 4H), 7.41 (dq, J =14.0, 6.9 Hz, 6H), 6.60-6.42 (m, 2H), 3.80 (td, J = 6.2, 2.1 Hz, 2H), ), 2.51(q, J = 6.2 Hz, 2H), 1.20 (s, 9H), 1.05 (s, 9H); 13 C NMR (101 MHz,CDCl3) δ 164,1, 148.3, 135.7, 133.7, 130.5,129.9, 127.9, 62.4, 57.3, 36.4, 27.0, 22.6, 19.3; [α] 25 D :-161.6 (c = 1.64, CHCl3).

[0118]

[0125] Methyl (S,E)-7-((tert-butyldiphenylsilyl)oxy)-3-(((R)-tert-butylsulfinyl)amino)hept-4-enoate (31). An oven-dried flask was charged with Zn powder (34.0 g, 520 mmol) and CuCl (5.20 g, 52.0 mmol). The two solids were mixed under a slow stream of nitrogen while the flask was flame-dried. The flask was cooled to room temperature and anhydrous THF (120 mL) was added, producing a thick slurry. The resulting reaction mixture was heated to reflux and vigorously stirred for 30 min. The heating bath was then removed and methyl bromoacetate (30) (19.7 mL, 208 mmol) in anhydrous THF (40 mL) was added slowly via addition funnel with vigorous stirring until reflux began again. The addition was continued at a rate to maintain a controllable reflux. After the addition was complete, the reaction mixture was stirred for an additional 30 min at room temperature. The mixture was then heated to 50° C. for 30 min. The reaction mixture was cooled to 0° C. To the reaction mixture, a solution of tert-butanesulfinyl imine 29 (23.0 g, 52.0 mmol) in anhydrous THF (120 mL) was added dropwise via addition funnel at 0° C. The reaction mixture was stirred for an additional 18 h at 0° C. The reaction mixture was filtered through a pad of Celite and washed with diethyl ether. The filtrate was washed with saturated aqueous NaHCO3, saturated aqueous NaCl. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (elution with 50% ethyl acetate in hexanes) to give the methyl ester 31 (20.1 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.63–7.70 (m, 4H), 7.44–7.36 (m, 6H), 5.74 (dt, J = 15.1, 6.9 Hz, 1H), 5.42 (ddt, J = 15.4, 7.0, 1.4 Hz, 1H), 4.25 (d, J = 5.7 Hz, 1H), 4.15 (p,J = 6.2, 1H), 3.71–3.65 (m, 5H), 2.69 (dd, J = 15.8, 4.9 Hz, 1H), 2.60 (dd, J = 15.9, 7.1 Hz, 1H), 2.36-2.23 (m, 2H), 1.20 (s, 9H), 1.04 (s, 9H); 13 CNMR (101 MHz, CDCl3) δ 172.0, 135.6, 135.6,131.2, 130.4, 129.7, 127.7, 63.4, 55.6, 54.1, 51.9, 40.9, 36.0, 37.0,00. 22.8,19.3; HRMS (ESI) m / z C 28 H 41 NNaO4SSi [M+Na] + of 538.2423, 538.2421; [α] 25 D : -45.8 (c = 0.80, CHCl3).

[0119]

[0126] Methyl (S,E)-3-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)-7-((tert-butyldiphenylsilyl)oxy)hept-4-enoate (6). To a solution of 31 (5.5 g, 10.7 mmol) in anhydrous dioxane:ether (1:1, 100 mL) was added 1N HCl in Et2O (11 mL, 10.7 mmol). The solution was filtered through a plug of basic alumina and the solution was concentrated in vacuo. In a separate flask, PyBOP (8.32 g, 16.0 mmol) and DIPEA (5.6 mL, 32.0 mmol) were added to a solution of N-Boc-L-valine (5) (2.78 g, 12.8 mmol) in anhydrous CHCl2 (75 mL). The mixture was stirred at room temperature for 5 min and then cooled to 0° C. The HCl salt form of the deprotected amine was dissolved in anhydrous CHCl (25 mL) and the solution was added dropwise to the activated acid at 0° C. under an argon atmosphere. The mixture was allowed to warm to room temperature and stirred for 8 h. The solvent was removed in vacuo and the crude reaction mixture was purified by column chromatography on silica gel (elution with 30% ethyl acetate in hexanes) to give dipeptide 6 (4.1 g, 63% yield for two steps). 1 H NMR (400 MHz, CDCl3) δ 7.71-7.60 (m, 4H), 7.49-7.31 (m, 6H), 6.53 (d, J = 8.4 Hz, 1H),5.73-5.60 (m, 1H), 5.55-5.46 (m, 1H), 5.05 (d, J = 5.4 Hz, 1H), 4.73-4.81 (m,1H), 3.91-3.83 (m, 1H), 3.68-3.62 (m, 2H), 3.64 (s, 3H), 2.59 (d, J = 5.4 Hz,2H), 2.24 - 2.29 (q, J = 6.7, 2H), 2.04-2.14 (m, 1H), 2.16-2.05 (m, 1H), 1.43(s, 9H), 1.03 (s, 9H), 0.93 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), ; 13CNMR (101 MHz, CDCl3) δ 171.9, 170.8, 135.7,134.1, 133.9, 130.1, 129.8, 129.5, 127.8, 63.5, 51.9, 47.6, 38.9, 35.7, 31.2,28.4, 27.0, 19.4, 19.3, 17.7; [α] 25 D :-5.3 (c = 0.7, CHCl3).

[0120]

[0127] Methyl (S,E)-3-((S)-2-((R)-2'-(((tert-butoxycarbonyl)amino)methyl)-4-methyl-4,5-dihydro-[2,4'-bithiazole]-4-carboxamido)-3-methylbutanamido)-7-((tert-butyldiphenylsilyl)oxy)hept-4-enoate (8). Compound 6 (1.93 g, 3.20 mmol) was dissolved in anhydrous CHCl (50 mL) and treated with TFA (7 mL) at 0°C. The resulting solution was allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated in vacuo. The crude TFA salt was then dissolved in toluene, concentrated in vacuo, and dried under high vacuum to remove residual TFA. In a separate flask, PyBOP (2.48 g, 4.76 mmol) and DIPEA (1.66 mL, 9.52 mmol) were added to a solution of 7 (1.36 g, 3.80 mmol) in anhydrous CHCl (30 mL). This was stirred at room temperature for 5 min and then cooled to 0 °C. The crude TFA salt was dissolved in anhydrous CHCl (15 mL) and added dropwise to the solution of activated acid. The reaction mixture was stirred at room temperature for 2 h. The mixture was dried in vacuum and the crude residue was immediately purified by column chromatography on silica gel (elution with 40%-50% ethyl acetate in hexanes) to give 8 (2.2 g, 2.58 mmol, 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.64 (d, J = 8.8 Hz, 4H), 7.46-7.33 (m, 6H), 6.62 (d,J = 8.7 Hz, 1H), 5.73-5.61 (m, 1H), 5.51 (dd, J = 15.5, 6.3 Hz, 1H), 5.29 (s,1H), 4.86-4.74 (m, 1H), 4.63 (d, J = 6.3 Hz, 2H), 4.17 (dd, J = 8.8, 6.3 Hz,1H), 3.76 (d, J = 11.6 Hz, 1H), 3.69-3.61 (m, 3H) 3.65 (s, 3H), 3.33 (d, J =11.6 Hz, 1H), 2.60 (d, J = 5.3 Hz, 2H), 2.26 (q, J = 6.6 Hz, 2H), 2.18-2.07 (m,1H), 1.58 (s, 3H), 1.47 (s, 9H), 1.03 (s, 9H), 0.85 (dd, J = 15.5, 6.8 Hz, 3H),0.81 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 174.8, 171.8, 169.9, 169.8, 163.2, 155.7, 135.6, 134.0, 133.9,130.1, 129.7, 129.5, 127.7, 85.1, 80.5, 63.4, 58.6, 51.8, 47.6, 42.4, 41.6,38.8, 35.7, 30.8, 28.4, 26.9, 24.8, 19.4, 19.3, 17.8; [α] 25 D : -39.5 (c = 1.2, CHCl3).

[0121]

[0128] (12Z,22Z,24R,5S,8S)-8-((E)-4-((tert-butyldiphenylsilyl)oxy)but-1-en-1-yl)-5-isopropyl-24-methyl-24,25-dihydro-4,7,11-triaza-1(4,2),2(2,4)-dithiazolacyclododecaphane-3,6,10-trione (9). To a solution of the methyl ester 8 (2.0 g, 2.40 mmol) in THF:water (50 mL, 2:1) was added LiOH.H2O (0.12 g, 4.6 mmol). The reaction was stirred for 30 min, the reaction mixture was cooled to 0 °C, and acidified to pH ~3-4 by dropwise addition of 1 M aqueous KHSO4. The solution was diluted with water and extracted with CHCl2. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the corresponding acid, which was used directly without further purification. To a solution of the acid in anhydrous CHCl2 (100 mL) at 0° C., TFA (7 mL) was added. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. The crude salt was then dissolved in toluene, concentrated in vacuo, and dried under high vacuum to remove residual TFA. To a solution of HATU (2.70 g, 7.10 mmol), HOBt.H2O (0.650 g, 4.80 mmol) and DIPEA (2.4 mL, 14.2 mmol) in anhydrous CH3CN (1850 mL) at 0° C., a solution of the TFA salt in anhydrous CH3CN (50 mL) was added dropwise over 20 h at 0° C. via syringe pump. After the addition was complete, the resulting mixture was stirred at 0° C. for 8 h and at room temperature for an additional 15 h. The solvent of the reaction mixture was evaporated in vacuum. The resulting residue was dissolved in CH2Cl2 (50 mL), filtered through a pad of Celite and dried over anhydrous MgSO4. The solvent was evaporated in vacuum and the resulting residue was purified on a chromatography column over silica gel (eluted with 3% methanol in CH2Cl2) to give macrocyclic core 9 (1.08 g, 64% yield). 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.64 (d, J = 6.6 Hz, 4H), 7.43–7.34 (m, 6H), 6.50 (d,J = 10.7 Hz, 1H), 6.38 (d, J = 8.9 Hz 1H), 6.19 (d, J = 8.2 Hz 1H), 5.75–5.63(m, 1H), 5.50 (dd, J = 15.5, 5.9 Hz, 1H), 5.24 (dd, J = 17.6, 8.9 Hz, 1H), 4.98(s, 1H), 4.53 (dd, J = 10.7, 3.2). Hz, 1H), 4.24 (dd, J = 17.7, 3.2 Hz, 1H), 3.90(d, J = 11.6 Hz, 1H), 3.70–3.62 (m, 2H), 3.37 (d, J = 11.6 Hz, 1H), 2.72 (dd, J = 15.4, 4.0 Hz, 1H) 2.55–2.20 (m, 2H), 2.27 (q, J = 6.6 Hz, 2H), 1.86 (s, 3H),1.04 (s, 9H), 0.77 (d, J = 6.9 Hz, 3H), 0.36 (d, J = 6.8 Hz, 3H); 13 CNMR (101 MHz, CDCl3) δ 173.8; 63.5,58.3, 48.1, 43.9, 40.9, 40.8, 35.7, 32.1, 27.0, 24.3, 19.6, 19.4, 15.3; HRMS(ESI) m / z C 37 H 47 N5NaO4S2Si[M+Na] + of 740.2736, 740.2736; [α] 25 D :+23.4 (c = 0.29, CHCl3).

[0122]

[0129] (12Z,22Z,24R,5S,8S)-8-((E)-4-hydroxybut-1-en-1-yl)-5-isopropyl-24-methyl-24,25-dihydro-4,7,11-triaza-1(4,2),2(2,4)-dithiazolacyclododecaphane-3,6,10-trione (10). To a solution of compound 9 (1.00 g, 1.40 mmol) in CHCl:methanol (1:1, 60 mL) at 0° C. was added p-toluenesulfonic acid monohydrate (148 mg). The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with solid NaHCO (176 mg), filtered through a pad of Celite, washed with CHCl:methanol (1:1), and then evaporated in vacuo. The crude residue was purified by column chromatography on silica gel (elution with 5% methanol in CH2Cl2) to give compound 10 (0.600 g, 90% yield) as a colorless solid. 1 H NMR (400 MHz, CDCl3:CD3OD= 4:1) δ 7.76 (s, 1H), 7.40-7.34 (m, 1H), 6.51 (d, J =10.8 Hz, 1H), 5.59-5.50 (m, 1H), 5.40 (dd, J = 15.5, 15.7 Hz, 1H), 5.22 (d, J =17.8 Hz, 1H), 4.79-4.74 (m, 1H), 4.50 (d, J = 10.8 Hz, 1H), 4.22 (d, J = 17.8Hz, 1H), 3.87 (d, J = 11.8 Hz, 1H), 3.56-3.49 (m, 2H), 3.30-3.41 (m, 1H),2.92-2.96 (m, 1H), 2.57-2.48 (m, 2H), 2.40-2.32 (m, 1H), 2.20 (q, J = 7.2, 6.8Hz, 2H), 1.85 (s, 3H), 1.40-1.30 (m, 1H), 0.66 (d, J = 6.9 Hz, 3H), 0.18 (d, J= 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3: CD3OD= 4:1) δ 174.0, 170.8, 170.7, 168.5, 167.5, 146.6,131.5, 128.2, 124.5, 84.0, 61.2, 58.3, 49.1, 43.6, 40.7, 40.5, 35.6, 32.3,24.0, 19.4, 15.0; HRMS (ESI) m / z C 21 H 29 N5NaO4S2[M+Na] + Calculated value 502.1559, measured value 502.1568; [α] 25 D :+79.7 (c = 0.4, CH3OH).

[0123]

[0130] S-((E)-4-((12Z,22Z,24R,5S,8S)-5-isopropyl-24-methyl-3,6,10-trioxo-24,25-dihydro-4,7,11-triaza-1(4,2),2(2,4)-dithiazolacyclododecaphan-8-yl)but-3-en-1-yl)octanethioate (1). To a solution of 10 (0.400 g, 0.800 mmol) in anhydrous CHCl (10 mL) at 0° C. was added triethylamine (0.240 mL, 1.60 mmol) followed by the dropwise addition of 1-octanesulfonyl chloride (0.240 mL, 1.00 mmol) over 5 min. The reaction mixture was stirred for an additional 15 min. The reaction mixture was then washed successively with ice-cold water, 0.01N aqueous HCl, saturated aqueous Na2CO3, and saturated aqueous NaCl. The organic phase was dried over Na2SO4 and evaporated to give a colorless solid. To a solution of thiooctanoic acid 10 (0.800 g, 2.40 mmol) in anhydrous acetone (2 mL) were added the crude compound and anhydrous K2CO3 (0.240 g, 1.60 mmol) successively. The reaction mixture was stirred at room temperature for 12 h, then diluted with acetone (2 mL), filtered through Celite, washed with 4 mL of acetone, and then concentrated in vacuum. The crude product was purified by column chromatography on silica gel to give 1 (0.310 g, 64% yield) as a colorless solid (eluted with 3% MeOH in CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 6.51 (d, J = 10.9 Hz, 1H), 6.49-6.40 (m, 1H), 6.26 (d, J = 8.2 Hz, 1H), 5.72-5.60 (m, 1H), 5.52 (dd, J = 15.5, 5.7 Hz, 1H), 5.28(d, J = 17.6 Hz, 1H), 5.01-4.92 (m, 1H), 4.54 (dd, J = 3.1, 10.8 Hz, 1H), 4.32(dd, J = 3.4, 17.7 Hz, 1H), 3.89 (d, J = 11.8 Hz, 1H), 3.38 (d, J = 11.6 Hz, 1H), 2.89 (t, J = 7.1 Hz, 2H), 2.74 (dd, J = 15.4, 3.9 Hz, 1H), 2.57-2.48 (m,3H), 2.40-2.32 (m, 2H), 2.16 (q, J = 7.2, 6.8 Hz, 1H), 1.89 (s, 3H), 1.71-1.56(m, 2H), 1.38-1.20 (m, 8H), 0.91-0.80 (m, J = 6.6 Hz, 3H), 0.77 (d, J = 6.9 Hz,3H), 0.35 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 199.7, 173.8, 170.0, 169.7, 168.7, 147.4, 130.8, 129.5, 124.3,84.9, 58.3, 47.9, 44.3, 43.9, 41.0, 40.8, 32.4, 32.1, 31.7, 29.0, 28.9, 28.3,25.8, 24.3, 22.7, 19.6, 15.6, 14.2; HRMS (ESI) m / z C 29 H 43 Calculated value of N5NaO4S3 644.2375 [M+Na] + , measured value 644.2379; [α] 25 D: + 21.2 (c = 0.30, CHCl3), (Literature value [α] 25 D: + 23.2 (c = 0.25, CHCl3)).

[0124]

[0131] Compound 1 was also prepared from compound 10 using a similar method using toluenesulfonyl chloride instead of 1-octanesulfonyl chloride in 50% yield.

[0125]

[0132] Compound 1 was also prepared from compound 10 in a similar manner using methanesulfonyl chloride instead of 1-octanesulfonyl chloride in 61% yield.

[0126]

[0133] (S,E)-1-((R)-4-benzyl-2-thioxothiazolidin-3-yl)-7-((tert-butyldiphenylsilyl)oxy)-3-hydroxyhept-4-en-1-one (32). To a cooled (0° C.) solution of (R)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethenone (26) (7.90 g, 31.5 mmol) in dry CHCl (100 mL) was added dropwise titanium(IV) chloride (34.2 mmol, 3.60 mL) and the solution was stirred for 5 min during which time the reaction mixture turned yellow in color. DIPEA (5.90 mL, 34.2 mmol) was then added to the reaction mixture. The yellow slurry turned dark red and was stirred at 0° C. for 20 min. To this dark red solution, compound 27 (8.90 g, 26.3 mmol) in dry CHCl (10 mL) was added dropwise and the reaction mixture was stirred at 0° C. for 1 h. After completion of the reaction, the reaction was quenched with ammonium chloride solution and then extracted into CHCl. ​​The combined organic phase was dried over anhydrous NaSO and concentrated in vacuum to give a crude residue, which was purified by silica gel column chromatography (eluted with hexane / EtOAc, 8:2) to give 32 (11.0 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.73-7.64 (m, 4H), 7.48-7.29 (m, 11H), 5.85-5.74 (m, 1H), 5.68-5.58(m, 1H), 5.40 (ddd, J = 10.7, 7.0, 4.0 Hz, 1H), 4.73-4.59 (m, 1H), 3.74 (t, J =6.6 Hz, 2H), 3.62 (dd, J = 17.7, 2.9 Hz, 1H), 3.46 - 3.18 (m, 4H), 3.12-2.98(m, 1H), 2.91 (d, J = 11.6 Hz, 1H), 2.40 - 2.28 (m, 2H), 1.08 (s, 9H). 13 CNMR (101 MHz, CDCl3) δ 201.3, 172.4, 136.8,136.1, 133.7, 132.8, 131.4, 129.5, 129.1, 128.6, 128.1, 127.7, 69.3, 67.0,63.3, 45.8, 37.4, 36.2, 34.9, 31.6, 26.8. HRMS (ESI) m / z C 33 H 39 Calculated value of NNaO3S2Si: 612.2038 [M+Na] + , Actual value 612.2024.

[0127]

[0134] 2-(Trimethylsilyl)ethyl (S,E)-7-((tert-butyldiphenylsilyl)oxy)-3-hydroxyhept-4-enoate (11). To a solution of thiazoline-thione 32 (9.30 g, 15.8 mmol) dissolved in 150 mL of CHCl was added 2-trimethylsilylethanol (22.6 mL, 158 mmol) followed by imidazole (1.60 g, 23.6 mmol). The resulting solution was stirred overnight. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (elution with hexane / EtOAc, 8:1) to give compound 11 (7.10 g, 91%) as a clear oil. 1H NMR (400 MHz, CDCl3)7.51-7.30 (m, 10H), 5.66-5.58 (m, 1H) 5.43 (dd, J = 15.3, 7.5 Hz 1H), 4.65-4.51(m, 1H), 4.22-4.10 (m, 3H), 3.64 (t, J = 6.6 Hz, 2H), 2.61 (dd, J = 16.8, 6.1Hz, 1H), 2.47 (dd, J = 16.8, 8.0 Hz, 1H) 2.24-2.36 (m, 2H), 1.06 (s, 9H),0.97-0.92 (m, 2H), 0.03 (s, 9H). 13 C NMR (101 MHz, CDCl3)δ 171.9, 135.7, 133.8, 132.3, 131.8, 129.3, 127.4,69.3, 67.0, 63.3, 46.4, 33.8, 31.5, 26.8, 19.4, -1.3.

[0128]

[0135] 2-(Trimethylsilyl)ethyl (S,E)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-valyl)oxy)-7-((tert-butyldiphenylsilyl)oxy)hept-4-enoate (13). To a solution of compound 11 (7.00 g, 14.0 mmol) in CHCl (150 mL) at room temperature was added N-Fmoc-L-valine (12) (14.2 g, 42.1 mmol), EDCI-HCl (10.8 g, 56.1 mmol), DMAP (0.17 g, 1.40 mmol), and DIPEA (9.80 mL, 56.1 mmol). After stirring for 18 h, the reaction mixture was concentrated in vacuo. The crude residue was purified by flash column chromatography (elution with hexane / EtOAc, 9:1) to give compound 13 (7.34 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.6 Hz, 2H), 7.68 - 7.51 (m, 6H), 7.45-7.26 (m, 10H),5.83 (dt, J = 14.5, 6.9 Hz, 1H), 5.66 (td, J = 7.7, 5.4 Hz, 1H), 5.49 (dd, J =15.5, 7.5 Hz, 1H), 5.28 (d, J = 9.1 Hz, 1H), 4.49-4.05 (m, 4H), 3.65 (t, J =6.6 Hz, 2H), 2.68 (dd, J = 15.8, 8.0 Hz, 1H), 2.54 (dd, J = 15.7, 5.5 Hz, 1H),2.08-2.31 (m, 3H), 1.02 (s, 9H), 0.98-0.84 (m, 5H), 0.80 (d, J = 6.9 Hz, 3H),-0.01 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 170.8, 169.6, 156.1, 143.9, 143.8, 141.2, 135.5, 133.7, 132.6,129.6, 128.2, 127.6, 127.6, 127.0, 125.1, 119.9, 72.0, 66.9, 63.0, 58.7, 47.2,39.7, 35.5, 31.3, 26.8, 19.1, 18.9, 17.2, 14.1, -1.6.

[0129]

[0136] 2-(Trimethylsilyl)ethyl (S,E)-3-((((R)-2-(6-(((tert-butoxycarbonyl)amino)methyl)pyridin-2-yl)-4-methyl-4,5-dihydrothiazole-4-carbonyl)-L-valyl)oxy)-7-((tert-butyldiphenylsilyl)oxy)hept-4-enoate (15). Compound 13 (1.10 g, 1.57 mmol) was dissolved in anhydrous CH3CN (50 mL) and treated with Et2NH (5 mL) at room temperature under argon. The resulting solution was allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated in vacuo. The resulting crude compound was then dissolved in EtOAc, concentrated in vacuo, and dried under high vacuum to remove residual Et2NH. In a separate flask, PyBOP (1.23 g, 2.36 mmol) and DIPEA (0.55 mL, 3.15 mmol) were reacted with the pyridinethiazolen fragment in anhydrous CH2Cl2 (30 mL) at room temperature under argon. 2 To a solution of 14 (0.66 g, 1.89 mmol) was added. This was stirred at room temperature for 5 min and then cooled to 0 °C. The amine was dissolved in anhydrous CHCl (15 mL) and added dropwise to the solution of activated acid at 0 °C under argon. The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the crude residue was immediately purified by column chromatography on silica gel (elution with hexane / EtOAc, 7:3) to give 15 (1.04 g, 71%). 1H NMR (400 MHz, CDCl3) δ 8.64-8.57 (m, 1H), 7.68-7.53 (m, 6H), 7.43-7.30 (m, 6H), 7.13 (d, J= 9.0 Hz, 1H), 5.83 (dt, J = 14.7, 6.8 Hz, 1H), 5.71-5.60 (m, 1H), 5.57-5.44(m, 2H), 4.54-4.40 (m, 3H), 4.21-4.06 (m, 2H), 3.81 (d, J = 11.6 Hz, 1H), 3.64(t, J = 6.7 Hz, 2H), 3.37 (dd, J = 11.5, 1.9 Hz, 1H), 2.75-2.61 (m, 1H), 2.55(dd, J = 15.8, 5.5 Hz, 1H), 2.31-2.06 (m, 3H), 1.55 (s, 3H), 1.44 (s, 9H),1.06-0.87 (m, 11H), 0.81 (d, J = 7.1 Hz, 3H), 0.73 (d, J = 7.1 Hz, 3H), -0.01(d, J = 1.9 Hz, 9H). 13 C NMR (101 MHz, CDCl3) δ 173.9, 170.3, 169.7, 167.0, 149.8, 140.4, 135.5, 133.7, 132.6,129.6, 128.2, 127.6, 120.3, 119.9, HRMS (ESI) m / z C 49 H 71 N4O8SSi2[M+H] + The calculated value is 931.4531, and the measured value is 931.4540.

[0130]

[0137] (14R,7S,10S,Z)-7-((E)-4-((Tert-butyldiphenylsilyl)oxy)but-1-en-1-yl)-10-isopropyl-14-methyl-14,15-dihydro-8-oxa-4,11-diaza-1(2,4)-thiazola-2(2,6)-pyridinacyclododecaphane-5,9,12-trione (16). To a solution of compound 15 (0.10 g, 0.11 mmol) in anhydrous CHCl (10 mL) at 0° C. under argon was added TFA (1 mL). The mixture was stirred at room temperature for 12 h. The solvent was removed in vacuo. The resulting crude salt was then dissolved in toluene, concentrated in vacuo, and dried under high vacuum to remove residual TFA. To a solution of HATU (0.12 g, 0.32 mmol), HOBt.H2O (0.03 g, 0.21 mmol) and DIPEA (0.10 mL, 0.54 mmol) in anhydrous CH3CN / CHCl2 (120 mL, 1:1) at room temperature was added a solution of TFA salt in anhydrous CH3CN / CHCl2 (10 mL, 1:1) dropwise over 10 h at 0 °C via syringe pump. After the addition was complete, the reaction mixture was stirred for 8 h. The solvent of the reaction mixture was evaporated in vacuum. The resulting residue was dissolved in CHCl2 (5 mL), filtered through a pad of Celite and dried over anhydrous MgSO4. The solvent was evaporated in vacuum and the resulting residue was purified by column chromatography on silica gel (elution with 3% CH3OH in CHCl2) and the solution was evaporated to dryness in vacuum to give macrocycle core 16 (15.0 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 5.1 Hz, 1H), 7.80 (s, 1H), 7.64 (dq, J = 6.4, 1.7 Hz,4H), 7.44–7.35 (m, 6H), 6.91 (d, J = 9.1 Hz, 1H), 6.11 (dd, J = 8.4, 4.7 Hz, 1H), 5.93 (dtd, J = 15.1, 6.9, 1.0 Hz, 1H), 5.80–5.68 (m, 1H), 5.66–5.58 (m,1H), 5.09 (dd, J = 17.6, 8.4 Hz, 1H), 4.58 (dd, J = 9.1, 3.6 Hz, 1H), 4.22 (dd,J = 17.6, 4.6 Hz, 1H), 4.06 (d, J = 11.5 Hz, 1H), 3.76-3.66 (m, 2H), 3.38 (d, J = 11.6 Hz, 1H), 3.22–3.15 (m, 2H), 2.81–2.72 (m, 1H), 2.39–2.10 (m, 3H), 1.78(s, 3H), 1.04 (s, 9H), 0.75 (d, J = 6.9 Hz, 3H), 0.65 (d, J = 6.8 Hz, 3H). 13 CNMR (101 MHz, CDCl3+ CD3OD) δ173.9; 124.2, 84.0, 63.4, 58.1, 48.7, 43.6, 35.5, 32.2, 26.8, 24.1,19.4, 19.1, 14.9. HRMS (ESI) m / z C 39 H 48 N4NaO5SSi[M+Na] + of 735.3012, 735.3021.

[0131]

[0138] (14R,7S,10S,Z)-7-((E)-4-hydroxybut-1-en-1-yl)-10-isopropyl-14-methyl-14,15-dihydro-8-oxa-4,11-diaza-1(2,4)-thiazola-2(2,6)-pyridinacyclododecaphane-5,9,12-trione (17). To a solution of compound 16 (15.0 mg, 0.02 mmol) in THF (2 mL) at 0° C., 1 M TBAF solution (0.7 ml, 0.07 mmol) was added under argon. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with aqueous NH4Cl and worked up with CHCl (3×2 mL), followed by evaporation in vacuo. The crude residue was purified by column chromatography on silica gel (eluted with 5% CH3OH in CH2Cl2) to give compound 17 (9.0 mg, 90% yield) as a viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 5.0 Hz, 1H), 8.42 (t, J = 6.0 Hz, 1H), 7.88 (s, 1H),7.35-7.29 (m, 1H), 7.12 (d, J = 9.0 Hz, 1H), 6.00 - 5.72 (m, 3H), 4.86 (dd, J =17.3, 6.6 Hz, 1H), 4.53 (dd, J = 9.0, 4.4 Hz, 1H), 4.41 (dd, J = 17.3, 5.5 Hz,1H), 3.98 (d, J = 11.5 Hz, 1H), 3.75-3.50 (m, 2H), 3.06 (dd, J = 15.6, 6.9 Hz,1H), 2.83 (dd, J = 15.6, 4.1 Hz, 1H), 2.49-2.04 (m, 4H), 1.78 (s, 3H), 0.81 (d,J = 6.9 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3+ CD3OD) δ 173.5, 170.6, 169.3, 168.6,159.6, 150.1, 140.1, 131.1, 129.0, 120.9, 117.3, 84.3, 72.5, 60.8, 58.0, 43.9,43.3, 40.0, 35.3, 33.4, 24.6, 18.8, 17.0. HRMS (ESI) m / z C 23 H 30 N4NaO5S[M+Na] + Calculated value: 497.1835, measured value: 497.1828.

[0132]

[0139] S-((E)-4-((14R,7S,10S,Z)-10-isopropyl-14-methyl-5,9,12-trioxo-14,15-dihydro-8-oxa-4,11-diaza-1(2,4)-thiazolan-2(2,6)-pyridinacyclododecaphan-7-yl)but-3-en-1-yl)octanethioate (2). (CAS number: 1800584-53-5) 4 Using the same procedure as in the preparation of compound 1, except that 17 was used instead of 10, compound 2 (7.5 mg, 64% yield) was obtained. 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 5.0 Hz, 1H), 7.81 (s, 1H), 7.39 (dd, J = 5.0, 1.6 Hz,1H), 6.92 (d, J = 9.1 Hz, 1H), 6.21 (dd, J = 8.4, 4.8 Hz, 1H), 5.89 (dt, J =15.4, 6.8 Hz, 1H), 5.81-5.69 (m, 1H), 5.64 (dd, J = 15.5, 6.7 Hz, 1H), 5.12(dd, J = 17.6, 8.4 Hz, 1H), 4.60 (dd, J = 9.1, 3.7 Hz, 1H), 4.29 (dd, J = 17.6,4.7 Hz, 1H), 4.06 (d, J = 11.6 Hz, 1H), 3.39 (d, J = 11.6 Hz, 1H), 3.07-2.73(m, 4H), 2.52 (t, J = 7.6 Hz, 2H), 2.41-2.26 (m, 2H), 2.26-2.07 (m, 1H), 1.82 (s,3H), 1.72-1.54 (m, 2H), 1.40-1.10 (m, 8H), 0.97-0.84 (m, 3H), 0.76 (d, J = 6.9Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 199.3, 173.1, 170.1, 168.5, 168.3, 159.3, 150.8,140.1, 132.7, 128.4, 120.9, 116.9, 84.6, 72.0, 57.9, 44.4, 44.1, 43.6, 40.5,33.7, 32.3, 31.6, 28.9, 27.9, 25.6, 24.9, 22.6, 18.9, 17.1, 14.0. HRMS (ESI)m / z C 3I H 45 N4O5S2[M+H] + Calculated value 617.2826 Measured value 617.2829; [α] 25 D: + 86.9 (c = 0.6, CHCl3), (Literature value [α] 25D: + 94.3 (c = 0.62, CHCl3)).

[0133]

[0140] 2-(Trimethylsilyl)ethyl (S,E)-3-((((R)-2-(2-(((tert-butoxycarbonyl)amino)methyl)oxazol-4-yl)-4-methyl-4,5-dihydrothiazole-4-carbonyl)-L-valyl)oxy)-7-((tert-butyldiphenylsilyl)oxy)hept-4-enoate (19). Using a procedure similar to that used to prepare 15, except using 18 instead of 14 and eluting with 50% ethyl acetate in hexane, compound 19 (0.79 g, 71% yield) was obtained. Yield is for the base fragment (compound 13). 1 H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.68-7.60 (m, 4H), 7.32-7.44 (m, 6H), 7.11 (d, J =9.0 Hz, 1H), 5.84 (dt, J = 14.4, 6.9 Hz, 1H), 5.61-5.69 (m, 1H), 5.56-5.45 (m,1H), 5.19 (bs, 1H), 4.43-4.52 (m, J = 3H), 4.22-4.08 (m, 2H), 3.77 (d, J = 11.5Hz, 1H), 3.66 (t, J = 6.6 Hz, 2H), 3.30 (d, J = 11.5 Hz, 1H), 2.70 (dd, J =15.7, 7.9 Hz, 1H), 2.56 (dd, J = 15.7, 5.6 Hz, 1H), 2.28 (q, J = 6.8 Hz, 2H),2.08-2.18 (m, 1H), 1.57 (s, 3H), 1.46 (s, 9H), 1.06-0.92 (m, 11H), 0.83 (d, J =6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H), 0.03 (s, 9H). 13C NMR (101MHz, CDCl3) δ 174.2, 170.3, 169.6, 161.9,160.7, 139.3, 135.5, 135.5, 133.7, 133.7, 132.4, 129.6, 128.3, 127.6, HRMS (ESI): m / z C 47 H 69 N4O9SSi2(M+H) + Calculated value: 921.4323, Measured value: 921.4329.

[0134]

[0141] (12Z,22Z,24R,5S,8S)-8-((E)-4-((tert-butyldiphenylsilyl)oxy)but-1-en-1-yl)-5-isopropyl-24-methyl-24,25-dihydro-7-oxa-4,11-diaza-1(4,2)-oxazola-2(2,4)-thiazolacyclododecaphane-3,6,10-trione (20). Using a procedure similar to that for the preparation of compound 16, except using 19 instead of 15 and eluting with 5% CHOH in CHCl, compound 20 (19 mg, 25% yield) was obtained. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.65–7.58 (m, 4H), 7.45–7.30 (m, 6H), 7.05 (d, J =8.9 Hz, 1H), 6.15 (dd, J = 9.7, 3.8 Hz, 1H), 5.87 (dt, J = 14.5, 6.9 Hz, 1H), 5.57–5.66 (m, 1H), 5.49 (dd, J = 15.6, 7.2 Hz, 1H), 4.92 (dd, J = 17.6, 9.7 Hz, 1H), 4.50 (dd, J = 8.9, 3.4 Hz, 1H), 4.03–3.90 (m, 2H), 3.67 (t, J = 6.4 Hz, 2H), 3.21 (d, J = 11.4 Hz, 1H), 2.85 (dd, J = 16.6, 10.3 Hz, 1H), 2.61 (dd, J = 16.6, 2.9 Hz, 1H), 2.33–2.19 (m, 2H), 2.00–2.12 (m, 1H), 1.79 (s, 3H), 1.01 (s,9H), 0.65 (d, J = 6.9 Hz, 3H), 0.61 (d, J = 6.9 Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ 173.5, 170.7, 168.7, 163.3, 161.9, 141.2, 135.5, 135.0, 133.8, 133.8, 132.3, 129.6, 128.4, 161.9, 141.2, 127.7,83.8, 72.2, 63.0, 58.1, 50.8, 43.3, 40.3, 37.2, 35.6, 34.2, 26.8, 26.8, 23.8,23.5, 20.2, 19.2, 18.7, 17.2. HRMS (ESI): m / z C 37 H 46 N4NaO6SSi(M+Na) + Offset: 725.2805, Range: 725.2810.

[0135]

[0142] (12Z,22Z,24R,5S,8S)-8-((E)-4-hydroxybut-1-en-1-yl)-5-isopropyl-24-methyl-24,25-dihydro-7-oxa-4,11-diaza-1(4,2)-oxazola-2(2,4)-thiazolacyclododecamphan-3,6,10-trione (21). Using the same procedure as for the preparation of compound 17, except using 20 instead of 16 and eluting with 5% CHOH in CHCl, compound 21 (8.8 mg, 89% yield) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.54-7.46 (m, 1H), 7.06 (d, J = 8.9 Hz, 1H),5.85-5.76 (m, 1H), 5.69-5.54 (m, 2H), 4.82-4.65 (m, 1H), 4.56-4.34 (m, 1H),4.10-3.85 (m, 2H), 3.72-3.46 (m, 2H), 3.24-3.18 (m, 1H), 2.98-2.74 (m, 2H),2.60 (dd, J = 15.8, 3.4 Hz, 1H), 2.25 (q, J = 6.3 Hz, 2H), 2.06-1.91 (m, 1H),1.77 (s, 3H), 0.66 (d, J = 6.3 Hz, 3H), 0.61 (d, J = 6.3 Hz, 3H). 13 CNMR (101 MHz, CDCl3) δ 173.4, 173.4, 170.7,168.7, 163.7, 141.3, 134.6, 131.4, 129.2, 83.3, 72.0, 60.9, 58.5, 42.9, 40.4,37.2, 35.4, 33.8, 23.7, 18.6, 17.3. HRMS (ESI): m / z C 21 H 28 N4NaO6S(M+Na) + Calculated value: 487.1627, Measured value: 487.1623.

[0136]

[0143] S-((E)-4-((12Z,22Z,24R,5S,8S)-5-isopropyl-24-methyl-3,6,10-trioxo-24,25-dihydro-7-oxa-4,11-diaza-1(4,2)-oxazola-2(2,4)-thiazolacyclododecaphan-8-yl)but-3-en-1-yl)octanethioate (3). (CAS number: 1800584-53-5) 4 Using the same procedure as for the preparation of compound 1, except using 21 instead of 10 and eluting with 5% CH3OH in CH2Cl2, compound 3 (6.3 mg, 60% yield) was obtained (eluted with 3% CH3OH in CH2Cl2). 1 H NMR (400 MHz, CDCl3)7.99 (s, 1H), 7.09 (d, J = 9.0 Hz, 1H,), 6.13 (dd, J = 4.2, 8.6 Hz, 1H),5.88-5.78 (m, 1H), 5.68-5.60 (m, 1H), 5.58-5.50 (m, 1H), 4.99 (dd, J = 9.8,17.6 Hz, 1H,), 4.55 (dd, J = 3.5, 10.7 Hz, 1H), 4.10-3.97 (m, 2H), 3.25 (d, J =11.5 Hz, 1H), 2.95-2.83 (m, 3H), 2.69 (dd, J = 2.9, 16.4 Hz, 1H), 2.53 (t, J =7.7 Hz, 2H), 2.32 (q, 2H), 2.17-2.03 (m, 1H), 1.85 (s, 3H), 1.72-1.57 (m, 2H),1.38-1.18 (m, 8H), 0.88 (t, J = 6.6 Hz, 3H), 0.69 (d, J = 6.9 Hz, 3H), 0.65 (d,J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 199.3, 173.4, 170.5, 168.7, 163.2, 161.8, 141.1, 135.0, 132.7,128.4, 83.8, 71.9, 58.1, 44.1, 43.3, 40.3, 37.3, 34.2, 32.2, 31.6, 28.9, 27.9,25.6, 23.8, 22.6, 18.7, 17.2, 14.1; 29 H 43 N4O6S2(M+H) + Calculated value: 607.2624, Measured value: 607.2632. [α] 25 D: + 19.9 (c =0.7, CH2Cl2), (literature value [α] 25 D: + 18 (c = 0.7, CH2Cl2)).

[0137] [References]

[0144] Each of the following references, or any other references disclosed elsewhere in this specification, is incorporated herein by reference in its entirety for all purposes.

[0138] [INCORPORATION-BY-REFERENCE AND VARIATION STATEMENT]

[0145] All references throughout this application, e.g., patent documents, published patent applications, including published or licensed patents or equivalents, and non-patent documents or other source materials, are incorporated herein by reference in their entirety to the extent that each reference is not at least partially inconsistent with the disclosure of this application, as if each reference were individually incorporated by reference (e.g., a partially inconsistent reference is incorporated by reference except for the partially inconsistent portion of that reference).

[0139]

[0146] The terms and expressions used herein are used as descriptive and not limiting, and in the use of such terms and expressions, there is no intention to exclude any equivalents or portions thereof of the features shown and described, but it is understood that various modifications are possible within the scope of the claimed invention. Thus, although the present invention has been specifically disclosed by preferred aspects, exemplary aspects, and optional features, it should be understood that modifications and variations of the concepts disclosed herein can be reclassified by those skilled in the art, and that such modifications and variations are considered to be within the scope of the present invention as defined by the appended claims. The specific aspects provided herein are illustrative of useful aspects of the invention, and it will be apparent to those skilled in the art that the invention can be carried out using many variations of the apparatus, apparatus parts, and method steps described herein. As will be apparent to those skilled in the art, the methods and apparatus useful for the methods of the present invention can include many optional compositions and processing elements and steps.

[0140]

[0147] When a group of substituents is disclosed herein, it is understood that all individual members and all subgroups of the group are individually disclosed, including any isomers, enantiomers, and diastereomers of the members of the group. When a Markush group or other classification is used herein, all individual members of the group and all possible combinations and subcombinations of the group are intended to be individually included in the disclosure. For example, when a compound is described herein such that a specific isomer, enantiomer, or diastereomer of the compound is not specified in the formula or chemical name, the description is intended to include each isomer and enantiomer of the compound described individually or in any combination. Furthermore, unless otherwise specified, all isotopes of the compounds disclosed herein are intended to be encompassed by the disclosure. For example, it is understood that one or more hydrogens of any of the disclosed molecules can be replaced with deuterium or tritium. Isotopes of molecules are typically useful as standards in the testing of the molecule and in chemical and biological studies related to the molecule or its use. Methods for making such isotopes are known in the art. The particular names of the compounds are intended to be exemplary, as it is known that one of skill in the art can give different names to the same compound.

[0141]

[0148] Many of the molecules disclosed herein contain one or more ionizable groups from which a proton can be removed (e.g., COOH) or added (e.g., amine), or quaternized (e.g., amine). All possible ionic forms of such molecules and their salts are intended to be included individually in the disclosure of this specification. With respect to salts of the compounds of this specification, those skilled in the art can select from a wide variety of available counterions appropriate for preparing the salt of the present invention for a given application. In certain applications, the selection of a given anion or cation for preparing a salt can result in increased or decreased solubility of the salt.

[0142]

[0149] All combinations or permutations of components described or exemplified herein may be used to practice the present invention unless otherwise stated.

[0143]

[0150] Whenever a range, e.g., a temperature range, a time range, a carbon atom range, or a composition or concentration range, is given herein, all intermediate ranges and subranges, as well as all individual values ​​contained within the given range, are intended to be included in the disclosure. It is intended that any subrange or individual value within a range or subrange included in the description herein can be excluded from the claims.

[0144]

[0151] All patents and publications mentioned in this specification are indicative of the level of skill of those skilled in the art in the field to which this invention pertains. References provided herein are incorporated herein by reference in their entirety, and are intended to indicate the state of the art as of their publication or filing date, and to use this information herein to exclude certain aspects in the prior art, if necessary. For example, when a composition of matter is claimed, it should be understood that available compounds known in the art prior to the applicant's invention, including compounds for which enabling disclosures are provided in the references described herein, are not intended to be included in the composition of matter claimed herein.

[0145]

[0152] As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude further unrecited features or method steps. As used herein, "consisting of" excludes any feature, step, or ingredient not specified in the feature of the claim. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be substituted with either of the other two terms. The invention as adequately described herein may be practiced in the absence of any feature or features, limitation, or limitations not specifically disclosed herein.

[0146]

[0153] Those skilled in the art will understand that starting materials, biological materials, reagents, synthesis methods, purification methods, analytical methods, testing methods, and biological methods other than those specifically exemplified can be used in the practice of the present invention without resorting to undue experimentation. All art-known functional equivalents of any such materials and methods are intended to be included in the present invention. The terms and expressions used are used as descriptive rather than limiting, and there is no intention in the use of such terms and expressions to exclude any equivalents or portions thereof of the features shown and described, but it is understood that various modifications are possible within the scope of the claimed invention. Thus, although the present invention has been specifically disclosed by preferred aspects and optional features, it should be understood that modifications and variations of the concepts disclosed herein can be reclassified by those skilled in the art, and that such modifications and variations are considered to be within the scope of the present invention as defined by the appended claims.

Claims

1. Compound of formula (III): 【Chemistry 1】 A method for preparing The method comprises reacting a compound of formula (I): 【Chemistry 2】 C １ ~C ２０ with an activating agent selected from a linear or branched alkylsulfonyl halide, a substituted alkylsulfonyl halide, an arylsulfonyl halide, a substituted arylsulfonyl halide, a halophosphite, or a halogenating agent, to thereby produce a compound of formula (II): 【Chemistry 3】 forming a The compound of formula (II) is １ with a nucleophile containing a group, thereby forming a compound of formula (III). (Wherein, X is O or NH; Ar is thiazolyl, pyridinyl, or oxazolyl; R １ is R ２ COS, R ３ S or R ４ R ５ N, R ２ , R ３ , R ４ , and R ５ are independently hydrogen, C １ ~C ２４ C, any one of which is substituted with one or more aryl or heteroaryl groups. １ ~C ２４ Straight chain alkyl, C3-C ２４ a branched alkyl group of C3 to C substituted at any position with one or more aryl or heteroaryl groups; ２４ Branched alkyl of C ３ ~C ２４ cyclic alkyl, C substituted at any position with one or more aryl or heteroaryl; ３ ~C ２４ Cyclic alkyl, C2-C ２４ Alkenyl, C2-C ２４ or a substituted form of any of them; and L is C １ ~C ２４ Linear or branched carbon sulfonate esters of the formula １ ~C ２４ wherein the leaving group is selected from a linear or branched sulfonate ester of the formula (I), an aryl sulfonate ester, a substituted aryl sulfonate ester, a heteroaryl sulfonate ester, a substituted heteroaryl sulfonate ester, a phosphate ester, or a halogen.

2. Compounds of formula (I): 【Chemistry 4】 A method for preparing The method comprises, in one or more reactions, reacting a compound of formula (IV): 【Chemistry 5】 , a compound of formula (V): 【Chemistry 6】 and a compound of formula (VI): 【Chemistry 7】 The method includes reacting (Wherein, X is O or NH; Ar is thiazolyl, pyridinyl, or oxazolyl; R ６ is H or a suitable alcohol protecting group, R ８ , R １０ , and R １２ are independently H, a suitable amine protecting group, or a chiral group; R ７ , R ９ , and R １１ are independently H, an alkali metal ion, an alkaline earth metal ion, or a suitable carboxylic acid protecting group; Optionally, the suitable carboxylic acid protecting group is １ ~C ６ C, any one of which is substituted with one or more aryl or heteroaryl groups. １ ~C ６ or alkylsilyl, Optionally, said C １ ~C ６ or a linear or branched alkyl group in which any of the above positions is substituted with one or more aryl or heteroaryl groups. １ ~C ６ wherein the linear or branched alkyl is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; and Optionally, said alkylsilyl is 2-(trimethylsilyl)ethyl.

3. Compound of formula (III): 【Chemistry 8】 A method for preparing The method comprises reacting a compound of formula (II): 【Chemistry 9】 R １ with a nucleophile comprising a group (Wherein, X is O or NH; Ar is thiazolyl, pyridinyl, or oxazolyl; R １ is R ２ COS, R ３ S or R ４ R ５ N, R ２ , R ３ , R ４ , and R ５ are independently hydrogen, C １ ~C ２４ C, any one of which is substituted with one or more aryl or heteroaryl groups. １ ~C ２４ Straight chain alkyl, C3-C ２４ a branched alkyl group of C3 to C substituted at any position with one or more aryl or heteroaryl groups; ２４ Branched alkyl of C ３ ~C ２４ cyclic alkyl, C substituted at any position with one or more aryl or heteroaryl; ３ ~C ２４ Cyclic alkyl, C2-C ２４ Alkenyl, C2-C ２４ or a substituted form of any of them; and L is C １ ~C ２４ Linear or branched carbon sulfonate esters of the formula １ ~C ２４ wherein the leaving group is selected from a linear or branched sulfonate ester of the formula (I), an aryl sulfonate ester, a substituted aryl sulfonate ester, a heteroaryl sulfonate ester, a substituted heteroaryl sulfonate ester, a phosphate ester, or a halogen.

4. The compound of formula (II) is reacted with a compound of formula (IX): 【Chemistry 10】 from the compound of formula (IX), ６ to said leaving group L, ６ is H or a suitable alcohol protecting group.

5. OR ６ to said leaving group L, R ６ is the appropriate alcohol protecting group, deprotecting the appropriate alcohol protecting group to obtain the compound of formula (IX), ６ is H; and The compound of formula (IX) ６ is H), １ ~C ２０ 5. The method of claim 4, comprising reacting with an activating agent selected from a linear or branched alkylsulfonyl halide, a substituted alkylsulfonyl halide, an arylsulfonyl halide, a substituted arylsulfonyl halide, a halophosphite, or a halogenating reagent of the formula:

6. The compound of formula (IX) is a compound of formula (I): 【Chemistry 11】 and The method further comprises reacting the compound of formula (I) with １ ~C ２０ with an activating agent selected from a linear or branched alkylsulfonyl halide, a substituted alkylsulfonyl halide, an arylsulfonyl halide, a substituted arylsulfonyl halide, a halophosphite, or a halogenating reagent, thereby forming the compound of formula (II).

7. The compound of formula (I) or the compound of formula (IX) is a compound of formula (I-a), (I-b), or (I-c): 【Chemistry 12】 The method according to any one of claims 1 to 6, wherein

8. L is OMs, OTs, OTf, 2,2,2-trifluoroethanesulfonate, n-octanesulfonate, benzenesulfonate, OP(=O)(OMe) ２ ,OP(=O)(OEt) ２ ,OP(=O)(OPh) ２ 8. The method of claim 1, wherein the aryl group is selected from the group consisting of I, Br, Cl, and F.

9. Ar is: 【Chemistry 13】 The method according to any one of claims 1 to 8, wherein

10. The nucleophile is thiooctanoic acid, whereby the compound of formula (III) is converted to a compound of formula (XXV): 【Chemistry 14】 The method according to any one of claims 1 to 9,

11. X is NH and Ar is: 【Chemistry 15】 whereby the compound of formula (III) is converted to a compound of formula (1): 【Chemistry 16】 The method of claim 10,

12. X is O and Ar is: 【Chemistry 17】 whereby the compound of formula (III) is converted to a compound of formula (2): 【Chemistry 18】 The method of claim 10,

13. X is O and Ar is: 【Chemistry 19】 whereby the compound of formula (III) is converted to a compound of formula (3): 【Chemistry 20】 The method of claim 10,

14. The method comprises reacting a compound of formula (IV): 【Chemistry 21】 , a compound of formula (V): 【Chemical 22】 and a compound of formula (VI): 【Chemistry 23】 The method further comprises the step of preparing the compound of formula (I) or the compound of formula (IX) from one or more reactions comprising: (In the formula, R ６ is H or a suitable alcohol protecting group, R ８ , R １０ , and R １２ are independently H, a suitable amine protecting group, or a chiral group; R ７ , R ９ , and R １１ are independently H, an alkali metal ion, an alkaline earth metal ion, or a suitable carboxylic acid protecting group; Optionally, the suitable carboxylic acid protecting group is １ ~C ６ C, any one of which is substituted with one or more aryl or heteroaryl groups. １ ~C ６ or alkylsilyl, Optionally, said C １ ~C ６ or a linear or branched alkyl group in which any of the above positions is substituted with one or more aryl or heteroaryl groups. １ ~C ６ wherein the linear or branched alkyl is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; and Optionally, the alkylsilyl is 2-(trimethylsilyl)ethyl.

15. The compound of formula (IV) is reacted with the compound of formula (V) by condensation to form a compound of formula (VII): 【Chemistry 24】 Forming The compound of formula (VII) is reacted with the compound of formula (VI) by amidation to give a compound of formula (VIII): 【Chemistry 25】 and The compound of formula (VIII) reacts by amidation ring closure to give the compound of formula (IX) or the compound of formula (I), ６ The method of claim 2 or claim 14, wherein

16. R ６ is H or a suitable alcohol protecting group; When the compound of formula (IV) is reacted with the compound of formula (V), R ８ is H and X is N, then N is neutral or positively charged, R ７ is a suitable carboxylic acid protecting group, R １０ is a suitable amine protecting group, and R ９ is H, an alkali metal ion, or an alkaline earth metal ion; When the compound of formula (VI) is reacted with the compound of formula (VII), R ７ is a suitable carboxylic acid protecting group, R １０ is H, and optionally R １０ is attached to a positively charged nitrogen atom, and R １１ is H, an alkali metal ion, or an alkaline earth metal ion, and R １２ is a suitable amine protecting group, and When the compound of formula (VIII) is reacted by amidation ring closure, R ６ is H or a suitable alcohol protecting group, R ７ is H, an alkali metal ion, or an alkaline earth metal ion, and R １２ is H, and optionally R １２ The method of claim 15 , wherein is attached to a positively charged nitrogen atom.

17. X is NH and the process comprises: via imine formation to produce a compound of formula (X): 【Chemistry 26】 with a chiral auxiliary of formula (XI): Y-NH ２ (XI) to produce a compound of formula (XII): 【Chemical 27】 forming a The compound of formula (XII) is reacted with a compound of formula (XIII) via nucleophilic addition: 【Chemistry 28】 to obtain a compound of formula (IV) (wherein X is NH and R ８ is a chiral group Y): 【Chemical 29】 forming a Cleavage of the N-Y bond to obtain a compound of formula (IV), ８ is H, and if X is N, then N is neutral or positively charged, to prepare the compound of formula (IV). wherein Y is a compound of formula (XIII) which undergoes a diastereoselective nucleophilic addition to a compound of formula (XII) to give a compound of formula (IV) as a major product, ８ is a chiral group Y; R ６ is a suitable alcohol protecting group, R ７ is a suitable carboxylic acid protecting group, Optionally, the carboxylic acid protecting group is １ ~C ６ C, any one of which is substituted with one or more aryl or heteroaryl groups. １ ~C ６ or alkylsilyl, Optionally, said C １ ~C ６ or a linear or branched alkyl group in which any of the above positions is substituted with one or more aryl or heteroaryl groups. １ ~C ６ wherein the linear or branched alkyl is selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, 2-butyl, tert-butyl, benzyl, or substituted benzyl; and Optionally, the alkylsilyl is 2-(trimethylsilyl)ethyl; and R １３ is H, a halide, or a metal including Li, Na, K, ZnBr, ZnCl, CuCl, CuBr, CuI, Cu, or any combination thereof.

18. The chiral auxiliary of formula (XI) is 【Chemistry 30】 (wherein R １４ is tert-butyl, p-tolyl, an alkyl, an aromatic group, or a substituted version of any of them.

19. R １４ The method of claim 18, wherein is tert-butyl, whereby the compound of formula (XI) is (R)-tert-butanesulfinamide.

20. Compound of formula (XXVI): 【Chemistry 31】 (Wherein, X is O or NH; Ar is thiazolyl, pyridinyl, or oxazolyl; R １６ OH, OR ６ or L; R ６ is a suitable alcohol protecting group, and L is C １ ~C ２４ Linear or branched carbon sulfonate esters of the formula １ ~C ２４ wherein the leaving group is selected from a linear or branched sulfonate ester of the formula (I), an aryl sulfonate ester, a substituted aryl sulfonate ester, a heteroaryl sulfonate ester, a substituted heteroaryl sulfonate ester, a phosphate ester, or a halogen.

21. The compound of formula (XXVI) is a compound of formula (I-a), (I-b), or (I-c): 【Chemistry 32】 21. The compound of claim 20,

22. R １６ The compound of claim 20, wherein is OH.

23. R １６ The compound of claim 20, wherein is L.

24. R １６ OR ６ 21. The compound of claim 20,

25. X is O, and The compound of any one of claims 20 to 24, wherein Ar is pyridinyl.

26. X is O, and The compound of any one of claims 20 to 24, wherein Ar is oxazolyl.

27. X is NH, and The compound of any one of claims 20 to 24, wherein Ar is thiazolyl.

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