Process for the production of ascarilose and related compounds

Abstract

The present application relates to an efficient method for the synthesis of ascarylose and its derivatives. The method for producing ascarylose includes the steps of providing 1-O-substituted rhamnose as a starting material, forming a monosulfonate ester at the 3-OH group of the 1-O-substituted rhamnose, and treating the monosulfonate ester with a hydride source to form 1-O-substituted ascarylose. The step of forming the monosulfonate ester can be successfully carried out on 1-O-substituted rhamnose without a hydroxyl protecting group at either the 2-OH or 4-OH position.

Description

[Technical Field]

[0001] Federally supported research or development This invention was made with the support of the U.S. Government under Grant No. 1843116 from the U.S. National Science Foundation. The U.S. Government reserves certain rights in this invention.

[0002] Field of Invention This application relates to the field of chemical synthesis, and more specifically, the present invention provides an efficient method for producing derivatives thereof from ascarilose and rhamnose. [Background technology]

[0003] Background of the Invention Ascalosides are natural products of the nematode *Ascaris*. Numerous structurally diverse ascaloside structures have been identified in nature, and this molecule is believed to function as an evolutionarily conserved chemical language used by *Ascaris* to control many aspects of its evolution. Ascalosides are also recognized by other organisms and have been demonstrated to have some effect in many organisms, including bacteria, fungi, plants, and mammals, including humans. Ascalosides have potential as products for human pharmaceuticals, agrochemicals, and other diverse and valuable applications. Ascalosides are derivatives of the sugar ascarilose (a dideoxy sugar lacking hydroxyl groups at positions 3 and 6). In nature, ascarilose is a relatively rare sugar, and there are currently no commercial sources of bulk ascarilose. Therefore, all reported total synthesis of ascarilose-containing natural products relies on the deoxygenation of more abundant sugar raw materials, such as rhamnose or mannose, to approach the ascarilose structure. While this method is suitable for small-scale studies and research focused on the synthesis of natural products, obtaining large quantities of ascaloside in this manner is impractical because existing synthetic routes for ascarilose require multi-step synthesis processes that rely on expensive reagents and / or chromatography for purification. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Therefore, there is still a demand for efficient and scalable methods for producing ascarilose and its derivatives. [Means for solving the problem]

[0005] Summary of the Invention A composition and method for the efficient production of ascarilose and ascarilose derivatives are provided. The method involves using rhamnose as a starting material and deoxygenating the 3-position of rhamnose without the need to protect the hydroxyl group at the 2- or 4-position. Thus, a method is provided for converting 1-O-substituted rhamnose derivatives to 1-O-substituted ascarilose derivatives without using hydroxyl protecting groups.

[0006] In one aspect of this disclosure, As a raw material, Formula II:

[0007] [ka] [In the formula, Z is a substituent other than hydrogen.] To provide a 1-O-substituted rhamnose having the structure; Forming a monosulfonate ester at the 3-OH group of the aforementioned raw material; and The process includes treating the monosulfonate ester with a hydride source to form a 1-O-substituted ascarilose. The formation of the monosulfonate ester occurs in the 1-O-substituted rhamnose without a hydroxyl protecting group at either the 2-OH or 4-OH position. A method for producing ascarilose is provided.

[0008] When treating monosulfate esters with a hydride source, a strong base may be added. If a strong base is added, it may be added before the hydride source. Examples of strong bases include, but are not limited to, alkali metal hydrides, alkali metal hydrides, alkali metal oxides, alkali metal alkoxides, and alkali metal amides. In some embodiments, this strong base contains sodium or potassium.

[0009] The hydride source is, in some embodiments, a metal hydride. In one embodiment, two or more different metal hydrides may be used. For example, the first metal hydride may be an aluminum hydride or boron hydride reducing agent, which is used in combination with a second metal hydride reducing agent, which is an alkali metal hydride or an alkaline metal hydride. Exemplary first metal hydrides include LiAlH4, LiBH4, and diisobutylaluminum hydride. An exemplary second metal hydride is sodium hydride.

[0010] In certain embodiments, the step of forming the monosulfonate ester includes contacting the raw materials with a sulfonyl halide or sulfonic anhydride in the presence of a Lewis acid catalyst. This Lewis acid catalyst may be a tin compound, such as a dialkyltin compound. An exemplary dialkyltin compound is a dialkyltin dihalide. Other Lewis acid catalysts, such as Lewis acids containing boron or transition metals, may also be used.

[0011] In one embodiment, the step of forming the monosulfonate ester includes contacting the raw materials with a sulfonyl halide or sulfonic anhydride in the presence of a base. This base may be, for example, an amine base.

[0012] In some embodiments, the raw material comprises a 1-O-substituted rhamnose having the structure of formula II.

[0013] [ka]

[0014] In one embodiment, Z is methyl. In another embodiment, Z is optionally substituted C. 2-24 It is an aliphatic group.

[0015] In another embodiment, Z is given by the following formula:

[0016] [ka] [In the formula, R 4 but, Arbitrarily substituted C 1-40 aliphatic group; A optionally substituted C which may be optionally unsaturated at one or more positions. 1-40 Carboxylic acid chain; and A optionally substituted C which may be optionally unsaturated at one or more positions. 1-40 Ester or orthoester derivatives of carboxylic acid chains Selected from the group consisting of [the specified group]. It is a group that has [a certain characteristic]. For example, Z is

[0017] [ka] This is also acceptable, and in the formula, x is an integer between 1 and 30. Specifically, Z is,

[0018] [ka] That's fine.

[0019] The step of treating the monosulfonate ester with a hydride source to form a 1-O-substituted ascarilose may involve the simultaneous reduction of one or more functional groups on Z.

[0020] The resulting 1-O-substituted ascarilose may be isolated after treating the monosulfonate ester with a hydride source. The yield of the 1-O-substituted ascarilose is at least 40% based on the raw materials. In one embodiment, the method of the present disclosure uses at least 1 kg of raw materials.

[0021] In another aspect of this disclosure, for the production of ascarilose, as a raw material, Formula IV:

[0022] [ka] [In the formula, Z is a substituent other than hydrogen, and Q is an optionally substituted aliphatic or aromatic moiety.] To provide a 3-sulfonate ester of 1-O-substituted rhamnose having the structure of the above as a raw material; and The monosulfonate ester is treated with a strong base and a hydride source to form 1-O-substituted ascarilose. A method is provided that includes this.

[0023] This disclosure includes, but is not limited to, the following embodiments:

[0024] Embodiment 1: A method for producing 1-O-substituted ascarilose, As a raw material, Formula II:

[0025] [ka] [In the formula, Z is a substituent other than hydrogen.] To supply 1-O-substituted rhamnose having the structure; Forming a monosulfonate ester at the 3-OH group of the aforementioned raw material; and The process includes treating the monosulfonate ester with a hydride source to form a 1-O-substituted ascarilose. A method for forming the monosulfonate ester in the 1-O-substituted rhamnose without a hydroxyl protecting group at either the 2-OH or 4-OH position.

[0026] Embodiment 2: The method of Embodiment 1, wherein the step of treating the monosulfonate ester with a hydride source further includes the addition of a strong base.

[0027] Embodiment 3: The method of Embodiment 2, wherein the strong base is added before the addition of the hydride source.

[0028] Embodiment 4: Any one of Embodiments 2 to 3, wherein the strong base is selected from the group consisting of alkali metal hydrides, alkali metal hydrides, alkali metal oxides, alkali metal alkoxides, and alkali metal amides.

[0029] Embodiment 5: A method according to any one of Embodiments 2 to 4, wherein the strong base comprises sodium ions or potassium ions.

[0030] Embodiment 6: Any one of Embodiments 1 to 5, wherein the hydride supply source is a metal hydride.

[0031] Embodiment 7: A method according to any one of Embodiments 1 to 6, wherein the step of treating the monosulfonate ester with a hydride source includes contacting the monosulfonate ester with a first metal hydride and a second metal hydride.

[0032] Embodiment 8: The method of Embodiment 7, wherein the first metal hydride comprises aluminum hydride or a boron hydride reducing agent, and the second metal hydride is an alkali metal hydride or an alkali metal hydride.

[0033] Embodiment 9: Any one of Embodiments 7 to 8, wherein the first metal hydride is LiAlH4.

[0034] Embodiment 10: Any one of Embodiments 7 to 8, wherein the first metal hydride is LiBH4.

[0035] Embodiment 11: Any one of Embodiments 7 to 10, wherein the second metal hydride is sodium hydride.

[0036] Embodiment 12: A method according to any one of Embodiments 1 to 11, wherein the formation of the monosulfonate ester comprises contacting the raw material with a sulfonyl halide or sulfonic anhydride in the presence of a Lewis acid catalyst.

[0037] Embodiment 13: The method of Embodiment 12, wherein the Lewis acid catalyst comprises a tin compound.

[0038] Embodiment 14: The method of Embodiment 13, wherein the Lewis acid catalyst comprises a dialkyltin compound.

[0039] Embodiment 15: The method of Embodiment 14, wherein the Lewis acid catalyst comprises a dialkyltin dihalide.

[0040] Embodiment 16: The method of Embodiment 12, wherein the Lewis acid catalyst contains a boron compound.

[0041] Embodiment 17: The method of Embodiment 12, wherein the Lewis acid catalyst contains a transition metal.

[0042] Embodiment 18: A method according to any one of Embodiments 1 to 17, wherein the formation of the monosulfonate ester comprises contacting the raw material with a sulfonyl halide or sulfonic anhydride in the presence of a base.

[0043] Embodiment 19: The method of Embodiment 18, wherein the base contains an amine.

[0044] Embodiment 20: Z in formula II is replaced with C as arbitrary. 2-24 A method using any one of Embodiments 1 to 19, wherein the aliphatic group is used.

[0045] Embodiment 21: The method according to any one of Embodiments 1 to 20, wherein the raw material contains 1-O-methyl rhamnose (that is, Z in Formula II is CH3).

[0046] Embodiment 22: Z in Formula II is a group having the following formula:

[0047] [Chemical formula] [wherein, R 4 is an optionally substituted C 1-40 aliphatic group; an optionally substituted C 1-40 carboxylic acid chain which may be optionally unsaturated at one or more positions; and an ester or orthoester derivative of an optionally substituted C 1-40 carboxylic acid chain which may be optionally unsaturated at one or more positions selected from the group consisting of.] The method according to any one of Embodiments 1 to 20, which is a group having the above.

[0048] Embodiment 23: Z in Formula II is

[0049] [Chemical formula] wherein x is an integer from 1 to 30. The method according to any one of Embodiments 1 to 20.

[0050] Embodiment 24: Z in Formula II is

[0051] [Chemical formula] The method of Embodiment 23, which is as follows.

[0052] Embodiment 25: The step of treating the monosulfonate ester with a hydride source to form a 1-O-substituted ascarylose simultaneously reduces one or more functional groups on Z. The method according to any one of Embodiments 1 to 24.

[0053] Embodiment 26: Any one of Embodiments 1 to 25, further comprising isolating the 1-O-substituted ascarilose.

[0054] Embodiment 27: The method of Embodiment 26, wherein the 1-O-substituted ascarilose is isolated from the raw materials in a yield of at least 40%.

[0055] Embodiment 28: Any one of Embodiments 1 to 27, wherein the method is carried out using at least 1 kg of the raw material.

[0056] Embodiment 29: A method for producing 1-O-substituted ascarilose: As a raw material, Formula IV:

[0057] [ka] [In the formula, Z is a substituent other than hydrogen, and Q is an optionally substituted aliphatic or aromatic moiety.] To provide a 3-sulfonate ester of a 1-O-substituted rhamnose having the structure; and The monosulfonate ester is treated with a strong base and a hydride source to form 1-O-substituted ascarilose. Methods that include...

[0058] Embodiment 30: The method of Embodiment 29, wherein the strong base is added before the hydride source is added.

[0059] Embodiment 31: The method according to either Embodiment 29 or 30, wherein the strong base is selected from the group consisting of alkali metal hydrides, alkali metal hydrides, alkali metal oxides, alkali metal alkoxides, and alkali metal amides.

[0060] Embodiment 32: Any one of Embodiments 29 to 31, wherein the strong base comprises sodium ions or potassium ions.

[0061] Embodiment 33: Any one of Embodiments 29 to 32, wherein the hydride source is a metal hydride.

[0062] Embodiment 34: A method according to any one of Embodiments 29 to 33, wherein treating the monosulfonate ester with a hydride source includes contacting the monosulfonate ester with a first metal hydride and a second metal hydride.

[0063] Embodiment 35: The method of Embodiment 34, wherein the first metal hydride comprises aluminum hydride or a boron hydride reducing agent, and the second metal hydride comprises an alkali metal hydride or an alkali metal hydride.

[0064] Embodiment 36: Any one of Embodiments 34 to 35, wherein the first metal hydride is LiAlH4.

[0065] Embodiment 37: Any one of Embodiments 34 to 35, wherein the first metal hydride is LiBH4.

[0066] Embodiment 38: Any one of Embodiments 34 to 37, wherein the second metal hydride is sodium hydride.

[0067] Embodiment 39: Z in formula IV is optionally replaced with C 2-24 An aliphatic group, one of the methods from Embodiments 29 to 38.

[0068] Embodiment 40: Any one of Embodiments 29 to 39, wherein Z in Formula IV is CH3.

[0069] Embodiment 41: Z in formula IV is the following:

[0070] [ka] [In the formula, R 4 but, Arbitrarily substituted C 1-40 aliphatic group; A optionally substituted C which may be optionally unsaturated at one or more positions. 1-40 Carboxylic acid chain; and A optionally substituted C which may be optionally unsaturated at one or more positions. 1-40 Ester or orthoester derivatives of carboxylic acid chains Selected from the group consisting of [the specified group]. A method of any one of embodiments 29 to 39, wherein the group has the following characteristics.

[0071] Embodiment 42: Z in formula IV is,

[0072] [ka] The formula is one of the embodiments 29 to 39, wherein x is an integer from 1 to 30.

[0073] Embodiment 43: Z in formula IV is

[0074] [ka] The method of embodiment 42.

[0075] Embodiment 44: A method according to any one of Embodiments 29 to 43, wherein the step of treating the monosulfonate ester with a hydride source to form a 1-O-substituted ascarilose simultaneously reduces one or more functional groups on Z.

[0076] Embodiment 45: Any one of Embodiments 29 to 44, further comprising isolating the 1-O-substituted ascarilose.

[0077] Embodiment 46: The method of Embodiment 45, wherein the 1-O-substituted ascarilose is isolated from the raw materials in a yield of at least 40%.

[0078] Embodiment 47: Any one of Embodiments 29 to 46, wherein the method is carried out using at least 1 kg of the raw material.

[0079] Embodiment 48: Any one of Embodiments 29 to 47, characterized in that the yield of the 1-O-substituted ascarilose is greater than 50%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 70%, greater than 85%, or greater than 90%.

[0080] Embodiment 49: Any one of Embodiments 29 to 48, wherein the preceding method results in the production of a ring-contraction rearrangement product with a content of less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%.

[0081] Embodiment 50: Any one of Embodiments 29 to 49, further comprising the step of acylating the hydroxyl groups of the 2-OH and 4-OH of the 1-O-substituted ascarilose by adding an acylating reagent to a mixture of the raw materials treated with the hydride source and the strong base.

[0082] Embodiment 51: The method of Embodiment 50, wherein the acylation reagent is added to the mixture without a quenching step.

[0083] Embodiment 52: The method of Embodiment 50, wherein the acylation reagent is added to the mixture after the quenching step.

[0084] These and other features, aspects and advantages of this disclosure will become apparent from reading the following detailed description together with the accompanying drawings, which are briefly described below. The present invention includes two, three, four or more combinations of the embodiments described above, and any two, three, four or more combinations of the features and elements shown in this disclosure, whether or not such features or elements are expressly combined in the particular embodiments described herein. This disclosure is generally intended to be read as such that any separable features or elements in any of the various aspects and embodiments of the invention of this disclosure are intended to be combined unless the context otherwise expressly indicates. Other aspects and advantages of this disclosure will become apparent below.

[0085] definition To facilitate understanding of this disclosure, certain terms are first defined below. Further definitions of the terms below and other terms are provided throughout the specification.

[0086] In this application, unless otherwise evident from the context, the term "a" may be understood to mean "at least one." In this application, the term "or" may be understood to mean "and / or." In this application, the terms "comprising" and "including" may be understood to encompass the listed components or processes, whether presented by themselves or together with one or more further components or processes. In this application, the term "comprise" and its conjugations, such as "comprising" and "comprises," do not imply the exclusion of other additives, components, integers, or processes.

[0087] Approximately, roughly: Where used herein, the terms “approximately” and “roughly” are used interchangeably. Unless otherwise noted, the terms “approximately” and “roughly” can be understood to allow for a standard deviation, as understood by those skilled in the art. Where ranges are presented herein, the ends are included. Any numerical values ​​used herein, with or without “approximately” and / or “roughly,” are meant to encompass the normal variation understood by those skilled in the art. In some embodiments, the terms “roughly” or “approximately” mean, unless otherwise noted or evident from the context, a range of values ​​that are within the range of 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less, in either direction (greater than or less than) the given reference value (except where such numbers exceed 100% of the possible value).

[0088] Definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this invention, chemical elements are as follows: Handbook of Chemistry and Physics, 75 th The elements are identified according to the CAS version of the periodic table on the inside of the Ed. cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are described below: Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 rdEdition, Cambridge University Press, Cambridge, 1987; all of the contents of each of these are incorporated herein by reference.

[0089] Certain compounds of the present invention may contain one or more chiral centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. Accordingly, the compounds and compositions of the present invention may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of mixtures of stereoisomers. In certain embodiments, the compounds of the present invention are compounds of high optical purity. In certain other embodiments, mixtures of enantiomers or diastereomers are provided.

[0090] Furthermore, certain compounds described herein may have one or more double bonds that can exist as either Z or E isomers, unless otherwise indicated. The present invention further encompasses compounds as independent isomers substantially free of other isomers, or as mixtures of various isomers (e.g., racemic mixtures of enantiomers). In addition to the compounds themselves as described above, the present invention also encompasses compositions comprising one or more compounds.

[0091] As used herein, the term “isomer” includes any and all geometric isomers and stereoisomers. For example, “isomer” includes cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as being within the scope of the present invention. For example, a compound may be provided substantially free of one or more corresponding stereoisomers in some embodiments and may also be referred to as “stereochemically enriched.”

[0092] Where a particular enantiomer is preferred, this may, in some embodiments, be presented substantially free of the opposite enantiomer and may also be referred to as “optically enriched.” “Optically enriched,” as used herein, means that the compound consists of a significantly larger proportion of one enantiomer. In certain embodiments, the compound consists of at least about 90% by weight of the enantiomer. In some embodiments, the compound consists of at least about 95% by weight, 97% by weight, 98% by weight, 99% by weight, 99.5% by weight, 99.7% by weight, 99.8% by weight, or 99.9% by weight of the enantiomer. In some embodiments, the enantimeric excess of the provided compound is at least about 90%, 95%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, or 99.9%. In some embodiments, enantiomers may be isolated from the racemic mixture by any method known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation or crystallization of chiral salts, or they may be prepared by asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0093] The terms "halo" and "halogen" as used herein refer to atoms selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iod, -I).

[0094] The terms “aliphatic” or “aliphatic group,” as used herein, refer to a hydrocarbon moiety that may be linear (i.e., unbranched), branched, or cyclic (condensed, cross-linked, and spiro-condensed polycyclic), and may be fully saturated or contain one or more unsaturated units, but are not aromatic. Unless otherwise specified, an aliphatic group contains 1 to 30 carbon atoms. In certain embodiments, an aliphatic group contains 1 to 12 carbon atoms. In certain embodiments, an aliphatic group contains 1 to 8 carbon atoms. In certain embodiments, an aliphatic group contains 1 to 6 carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 carbon atoms, in some embodiments, an aliphatic group contains 1 to 4 carbon atoms, in other embodiments, an aliphatic group contains 1 to 3 carbon atoms, and in other embodiments, an aliphatic group contains 1 to 2 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched alkyl, alkenyl, and alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0095] The term "heteroaliphatic" or "heteroaliphatic group," as used herein, refers to an aliphatic group in which one or more carbon or hydrogen atoms are replaced by heteroatoms (e.g., oxygen, nitrogen, sulfur, phosphorus, boron, etc.).

[0096] As used herein, the term "unsaturated" means a moiety having one or more double or triple bonds.

[0097] The term "alkyl," as used herein, means a saturated, linear, or branched hydrocarbon group derived from an aliphatic moiety containing 1 to 6 carbon atoms by the removal of one hydrogen atom. Unless otherwise specified, alkyl groups contain 1 to 12 carbon atoms. In certain embodiments, alkyl groups contain 1 to 8 carbon atoms. In certain embodiments, alkyl groups contain 1 to 6 carbon atoms. In some embodiments, alkyl groups contain 1 to 5 carbon atoms, in some embodiments, alkyl groups contain 1 to 4 carbon atoms, in other embodiments, alkyl groups contain 1 to 3 carbon atoms, and in other embodiments, alkyl groups contain 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, sec-pentyl, isopentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, and dodecyl.

[0098] The term "alkenyl," as used herein, means a monovalent group derived from a linear or branched aliphatic moiety having at least one carbon-carbon double bond by the removal of one hydrogen atom. Unless otherwise specified, an alkenyl group contains 2 to 12 carbon atoms. In certain embodiments, an alkenyl group contains 2 to 8 carbon atoms. In certain embodiments, an alkenyl group contains 2 to 6 carbon atoms. In some embodiments, an alkenyl group contains 2 to 5 carbon atoms, in some embodiments, an alkenyl group contains 2 to 4 carbon atoms, in other embodiments, an alkenyl group contains 2 to 3 carbon atoms, and in yet other embodiments, an alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include ethenyl, propenyl, butenyl, and 1-methyl-2-buten-1-yl.

[0099] The term "aryl" is used alone or as part of a larger term, such as "aralkyl," "aralkoxy," or "aryloxyalkyl," and refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, where at least one ring in the system is aromatic, and where each ring in the system contains 3 to 12 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to aromatic ring systems that may have one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, and anthracyl. The term "aryl" also includes, as used herein, groups in which an aromatic ring is fused with one or more further rings, such as benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl.

[0100] Where used herein, the compounds of the present invention may include "optionally substituted" portions. Generally, the term "substituted," whether followed by the term "optionally" or not, means that one or more hydrogens of the designated portion are replaced by preferred substituents. Unless otherwise indicated, an "optionally substituted" group may have preferred substituents at each of its substituted positions, and if one or more positions in any given structure can be replaced by one or more substituents selected from the specified group, these substituents may be the same or different at each position. The substituent combinations envisioned by the present invention preferably result in the formation of stable compounds or chemically feasible compounds. Where used herein, the term "stable" means a compound that does not substantially denature when subjected to conditions for its manufacture, detection, and, in particular embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0101] A suitable monovalent substituent on the replaceable carbon atom of the "optionally substituted" group is a halogen that may be substituted by R°;-(CH2) 0-4R°;-(CH2) 0-4 OR°;-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0-4 Ph;-(CH2) 0-4 O(CH2) 0-1 Ph;R° may be substituted by -CH=CHPh;-NO2;-CN;-N3;-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)N(R°)2;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR-、SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°、-(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C 1-4 (Linear or branched alkylene) ON(R°)2; or -(C 1-4 The linear or branched alkylene is C(O)ON(R°)2, where each R° may be substituted as defined below, and independently of hydrogen, C 1-8 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent R° entities together with their intervening atom(s) to form a 3-12 member saturated, partially unsaturated, or aryl monocyclic or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0102] Suitable monovalent substituents in R° (or a ring formed by two independent R° atoms together with an intervening atom) are, independently, halogens, -(CH2) 0-2 R l ,-(HaroR l ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure l ,-(CH2) 0-2 CH(OR l )2;-O(HaroR l ), -CN, -N3, -(CH2) 0-2 C(O)R l ,-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR l ,-(CH2) 0-4 C(O)N(R°)2;-(CH2) 0-2 SR l ,-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2)0-2 NHR l 、-(CH2) 0-2 NR l 2、-NO2、-SiR l 3、-OSiR l 3、-C(O)SR l 、 -(C 1-4 linear or branched alkylene)C(O)OR l 、 or -SSR l and each R l is unsubstituted or, when "halo" precedes, is substituted only by one or more halogens, and is independently selected from aliphatic, -CH2Ph, -O(CH2) 1-4 Ph, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R° include =O and =S. 0-1 Suitable divalent substituents on the saturated carbon atoms of a "optionally substituted" group include the following: =O, =S, =NNR

[0103] 2, =NNHC(O)R * 、 =NNHC(O)OR * 、 =NNHS(O)2R * 、 =NR * 、 =NOR * 、 =NOR * 、 -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is selected from hydrogen, C 1-6 aliphatic, which may be substituted as defined below, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to an adjacent substitutable carbon of an "optionally substituted" group include the following: -O(CR<000T095>2) 2-3 O-, where R *Each independent entity is hydrogen, C 1-6 Selected from aliphatic atoms, these may be substituted as defined below, or they may be unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0104] R * Suitable substituents on the aliphatic group include halogens and -R l ,-(HaroR l ), -OH, -OR l ,-O(HaroR l ), -CN, -C(O)OH, -C(O)OR l -NH2, -NHR l , -NR l 2, or -NO2, where each R l It is either not substituted, or, if preceded by "halo", substituted by only one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 A 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0105] A suitable substituent on the substituted nitrogen of the "arbitrarily substituted" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † The following can be cited; here, each R † C may be substituted independently with hydrogen as defined below. 1-6An aliphatic, unsubstituted -OPh, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, R † Two independent entities, together with one or more intervening atoms, form an unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0106] R † Suitable substituents on the aliphatic group are, independently, halogens, -R l ,-(HaroR l ), -OH, -OR l ,-O(HaroR l ), -CN, -C(O)OH, -C(O)OR l -NH2, -NHR l , -NR l 2, or -NO2, where each R l It is either not substituted, or, if preceded by "halo", substituted by only one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, or sulfur.

[0107] As used herein, the term “substantially” means a qualitative condition indicating the degree or extent of all or nearly all of the features or characteristics of the subject.

[0108] Brief explanation of the drawing In the drawings, similar reference symbols generally refer to the same part from different viewpoints, and the drawings do not need to be to a fixed scale. Rather, they are generally intended to be emphasized, not limiting, when illustrating the principles of the compositions and methods of this disclosure. For clarity, not all components are indicated in the drawings. Various embodiments are described below with reference to the following drawings. [Brief explanation of the drawing]

[0109] [Figure 1] The 1H NMR spectrum of a representative product obtained by one embodiment of the method disclosed herein is shown. [Modes for carrying out the invention]

[0110] Detailed description of the invention In one embodiment, the present invention provides a method for converting 1-O-substituted rhamnose to 1-O-substituted ascarilose, To provide 1-O-substituted rhamnose as a raw material; Forming a monosulfonate ester at the 3-OH group of the aforementioned raw material; and The method includes treating the monosulfonate ester with a hydride source to form a 1-O-substituted ascarilose. In certain embodiments, the formation of the monosulfonate ester is carried out on a substrate without a hydroxyl protecting group at the 2 or 4 position of the rhamnose starting material. In certain embodiments, such a method includes contacting the starting material with a sulfonating agent (i.e., a sulfonyl halide, sulfonic anhydride, or similar reagent) in the presence of a Lewis acid.

[0111] In certain embodiments, the Lewis acid comprises a tin compound. In certain embodiments, the Lewis acid is of formula R 1 R 2 The compound contains a tin compound having SnX2, where R 1 and R 2 Each is C 1-40 aliphatic, C 1-40Independently selected from the group consisting of heteroaliphatic, optionally substituted aromatic, and optionally substituted heteroaromatic, R 1 and R 2 They may optionally come together to form optionally substituted rings; and each X may be a halogen, and OR 3 Either they are selected independently, or both X come together to form a carbonyl group, and each R 3 C 1-40 Aliphatic;C 1-40 Independently selected from the group consisting of acyls and optionally substituted aromatics, or two -ORs 3 If a group exists, R 3 The groups come together to form arbitrarily substituted rings.

[0112] In a particular embodiment, R 1 and R 2 However, each is independent of C 1-20 aliphatic, C 2-12 aliphatic, C 2-8 aliphatic, C 1-6 Aliphatic, or C 1-4 It is aliphatic. In certain embodiments, R 1 and R 2 They are the same. In a particular embodiment, R 1 and R 2 These include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, n-octyl, and C 9-24 Selected independently from linear alkyl groups. In certain embodiments, R 1 =R 2 =n-butyl. In certain embodiments, R 1 =R 2 =n-octyl.

[0113] In certain embodiments, each X is a halogen atom. In certain embodiments, each X is chlorine. In certain embodiments, each X is an alkoxide. In certain embodiments, such an alkoxide is C 1-8It is a linear alkoxide. In certain embodiments, each X is independently selected from the group consisting of methoxide, ethoxide, n-propoxide, i-propoxide, n-butoxide, and i-butoxide. In certain embodiments, each X is an acyl group, and in certain embodiments, such an acyl group is C 1-16 The acyl group is either linear or branched. In certain embodiments, each X is independently selected from the group consisting of acetate, propionate, butanoate, ethylhexanoate, octanoate, or long-chain fatty acid acyl groups.

[0114] In certain embodiments, the Lewis acid comprises a dialkyltin dihalide. In certain embodiments, the Lewis acid is R 1 R 2 The formula contains SnCl2, and in the formula, R 1 and R 2 In the genera and subgenera, they are as defined above. In certain embodiments, the Lewis acid is (R 1 ) Contains 2SnCl2 (i.e., R 1 =R 2 ). In a particular embodiment, the Lewis acid is (R 1 ) Contains 2SnCl2, in the formula, R 1 is an alkyl group. In certain embodiments, the Lewis acid comprises dibutyltin dichloride.

[0115] In certain embodiments, the Lewis acid comprises a boron compound. Suitable boron compounds include, but are not limited to, boron halides, such as BF3 and its complexes, alkylboron compounds, boronates and similar boric acid derivatives, aminoboranes, boron complexes of amino alcohols and other nitrogen-boron complexes, and any combination thereof.

[0116] In certain embodiments, the Lewis acid is used in catalytic amounts (i.e., less than 1 molar equivalent relative to the rhamnose raw material). In certain embodiments, the Lewis acid is present with respect to 1-O-substituted rhamnose in molar ratios of less than 1:2, less than 1:5, less than 1:10, less than 1:20, less than 1:50, less than 1:100, less than 1:200, less than 1:500, or less than 1:1000. In certain embodiments, the Lewis acid is present with respect to 1-O-substituted rhamnose in a ratio between about 1:10 and about 1:200. In certain embodiments, the Lewis acid is present with respect to 1-O-substituted rhamnose in a ratio between about 1:50 and about 1:100, between about 1:100 and 1:400, or between about 1:200 and 1:500. In certain embodiments, the Lewis acid is present with respect to 1-O-substituted rhamnose in a ratio of about 1:100. In certain embodiments, the Lewis acid is present in a ratio of approximately 1:200 relative to 1-O-substituted rhamnose.

[0117] In certain embodiments, the sulfonation of 1-O-substituted rhamnose involves treatment with a base. In certain embodiments, this base is an organic base such as a nitrogen-containing heterocyclic or trialkylamine. In certain embodiments, this base is an inorganic base such as a metal hydroxide, carbonate, or hydride. In certain embodiments, this base includes an amine. In certain embodiments, this base includes a Hünig base (diisopropylethylamine). In certain embodiments, this base includes triethylamine. In certain embodiments, this base includes an alkali metal salt. In certain embodiments, this base includes an alkali metal hydroxide or alkali metal carbonate. In certain embodiments, this base includes sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, lithium hydroxide, lithium carbonate, or a combination of two or more of these.

[0118] The uniqueness of the sulfonate ester formed at the 3-position is not particularly limited. In certain embodiments, this sulfonate ester includes p-toluenesulfonate. In certain embodiments, this sulfonate ester includes methylsulfonate. In certain embodiments, this sulfonate ester includes trifluoromethylsulfonate. In addition to these, this sulfonate ester may include any of a number of other sulfonate esters known in the art and frequently used to activate alcohols for nucleophilic substitution. The selection of which sulfonate ester to use is within the scope of the art, and it is straightforward for a person skilled in the art to test various sulfonate esters according to the methods herein and select the sulfonate ester that provides the best results and / or lowest cost.

[0119] Rhamnose (methyloxane-2,3,4,5-tetrol) is a sugar whose structure is shown below as formula I. "1-O-substituted rhamnose" means rhamnose having a substituent other than H at the position of the hydrogen on the OH group at position 1 (i.e., at the position of H in "1-OH" of formula I). ​​Rhamnose (and the corresponding 1-O-substituted rhamnose) may be provided in its L-form or its D-form. In certain embodiments, the methods provided herein relate to the L-form (naturally occurring form) of rhamnose (and 1-O-substituted rhamnose).

[0120] [ka]

[0121] The 1-O-substituted rhamnose is shown below as formula II, where Z represents the "1-OH substituent".

[0122] [ka]

[0123] The present invention does not impose any particular restrictions on the uniqueness of the substituent ("Z") that replaces hydrogen at the 1-OH position of the rhamnose starting material. Preferably, this substituent does not contain any functional groups or features that interfere with the reagents and reaction conditions used in the deoxygenation process of the present invention. In certain embodiments, the 1-OH substituent (i.e., "Z") is a hydroxyl protecting group. Suitable hydroxyl protecting groups are well known in the art and include, for example, those described in the reference book *Protecting Groups in Organic Synthesis*, Peter GMWuts, editor, ISBN: 9781118057483 (which is incorporated herein by reference in its entirety). In certain embodiments, when ascarilose is converted to a final product having a further 1-O-substitution, it may be desirable and efficient to use a rhamnose starting material having a substituent at the 1-OH position that is identical to the desired substituent of the target ascarilose (or its enantiomer or isomer), or a rhamnose starting material that is a convenient synthetic precursor for the desired substituent. In certain embodiments, the substituent is a side chain of a naturally occurring ascaloside. In a particular embodiment, this substituent has the following structure:

[0124] [ka] In the formula, R 4 is an arbitrarily substituted C 1-40 It is an aliphatic group. In certain embodiments, R 4 C may be unsaturated at one or more positions. 1-40 A carboxylic acid chain, or an ester or orthoester derivative of such a carboxylic acid. In certain embodiments, R 4 C 1-40 It is an alpha-olefin. In certain embodiments, the substituent has the following structure:

[0125] [ka] In the formula, R 4In certain embodiments, the substituent is defined above and is found in the genera and subgenera of this specification, and has the following structure: C 1-40 It is a carboxylic acid chain:

[0126] [ka] In the formula, n is an integer between 1 and 40; and R y This includes -H, metal cations, carboxyl protecting groups, and optionally substituted C. 1-20 Selected from the group consisting of aliphatic groups and optionally substituted aromatic groups, or biomolecular residues such as glycosides, amino acids, peptides, and nucleos blood It is C or a derivative thereof. In certain embodiments, this substituent has the following structure: 1-40 It is an ester or orthoester derivative of a carboxylic acid chain:

[0127] [ka] In the formula, n is an integer between 1 and 40; and R 10 is an arbitrarily substituted C 1-20 The substituent is selected from the group consisting of aliphatic groups and optionally substituted aromatic groups. In certain embodiments, this substituent is a C having the following structure. 1-40 It is an ester or orthoester derivative of a carboxylic acid chain:

[0128] [ka] In the formula, n' is an integer between 1 and 38; and R 10 is an arbitrarily substituted C 1-20 The substituent is selected from the group consisting of aliphatic groups and optionally substituted aromatic groups. In a particular embodiment, this substituent has the following structure:

[0129] [ka] In the formula, x is an integer between 1 and 30.

[0130] In other embodiments of the present invention, it may be desirable to use a rhamnose starting material having a Z substituent at the 1-OH position, which may be removed to function as a protecting group and provide unsubstituted ascarilose or to allow substitution with another substituent at the 1-OH position (e.g., with the side chain of a natural product or derivative containing ascaloside or similar ascarilose). Suitable protecting groups can be found in Protecting Groups in Organic Synthesis, Peter GMWuts, editor, ISBN: 9781118057483. In certain embodiments, the 1-OH substituent is an alkyl group. In certain embodiments, the 1-OH substituent is a methyl group.

[0131] The method disclosed herein may be initiated by a direct reaction of 1-O-substituted rhamnose, or it may include a first step of converting rhamnose to 1-O-substituted rhamnose. Methods of converting OH to OZ to provide 1-O-substituted rhamnose depend on the Z substituent and are known in the art.

[0132] Ascarilose can be illustrated according to the following formula III.

[0133] [ka]

[0134] As described above, in some embodiments, the method of the present disclosure provides a 1-O-substituted ascarilose according to the following formula V. In some embodiments, the method further includes reacting the 1-O-substituted ascarilose (for example, by removing Z when Z is a protecting group (e.g., to produce ascarilose), and optionally by providing a modified ascarilose by imparting further functionality to the ascarilose at the 1-OH position).

[0135] [ka]

[0136] The process disclosed herein for forming 1-O-substituted ascarilose by treating rhamnose-derived monosulfonate esters with a hydride source is unexpectedly easy and yielding. The feasibility of this process is particularly surprising, given that prior art has reported that such treatment of monotosylates often results in the rearrangement of sugars to a five-membered ring. For example, Baer et al., in the Canadian Journal of Chemistry (1985, vol.63, p.432, DOI:10.1139 / v85-072), reported that treatment of the same substrate, 2-p-toluenesulfonate ester, results in the rearrangement shown below.

[0137] [ka]

[0138] Similarly, Ito et al. reported that hydride reduction of highly relevant sulfonated sugars yields the corresponding deoxy sugars in low yields due to a preference for ring contraction or OS bond cleavage rather than the desired reductive removal of the tosyloxy group (Chemical and Pharmaceutical Bulletin, 1991, Volume 39, Issue 8, Pages 1983-1989). Likewise, Binkley (J. Org. Chem. 50, 5646 (1985)) reported that hydride treatment of similar substrates having one or more sulfonate esters yields a complex mixture of products containing substantial amounts of ring-contracted products. In contrast, we hereby provide a method that yields unexpectedly high yields of desired 3-deoxy products without extensive rearrangements.

[0139] Thus, in one embodiment, the present invention provides a process for the synthesis of 3-deoxyrhamnose and its derivatives, comprising high-yield reductive cleavage of 3-sulfonate ester derivatives of rhamnose. In a particular embodiment, such a method uses formula IV as a starting material.

[0140] [ka]

[0141] [In the formula, Z is defined as in the genera and subgenera described above and herein, and Q is an optionally substituted aliphatic or aromatic moiety.] To provide a 3-sulfonate ester of a 1-O-substituted rhamnose having the structure; and The monosulfonate ester is treated with a strong base and a hydride source to form 1-O-substituted ascarilose. Includes.

[0142] In certain embodiments, Q includes an optionally substituted aliphatic group. In certain embodiments, Q is methyl, ethyl, C 3-8 Alkyl, -CF3, or C 3-8 Selected from fluoroalkyl groups. In certain embodiments, Q is methyl. In certain embodiments, Q includes an optionally substituted aryl group. In certain embodiments, Q is selected from phenyl, p-tolyl, m-tolyl, o-tolyl, bromophenyl, methoxyphenyl, and nitrophenyl. In certain embodiments, Q is p-tolyl.

[0143] In certain embodiments, a method is provided characterized in that the hydride treatment yields a 3-deoxy product in a yield of more than 50% (based on the initial 3-sulfonate ester of the 1-O-substituted rhamnose raw material). In certain embodiments, the method is characterized in that the hydride treatment yields a 3-deoxy product in a yield of more than 30%, more than 40%, more than 50%, more than 60%, more than 65%, more than 70%, more than 75%, more than 70%, more than 85%, or more than 90%. In certain embodiments, the method is characterized in that the hydride treatment results in the formation of a ring-contraction rearrangement product in a yield of less than 40%. In certain embodiments, the method is characterized in that the hydride treatment results in the formation of a ring-contraction rearrangement product in a yield of less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%.

[0144] In certain embodiments, treating the monosulfonate ester with a hydride source includes contacting the monosulfonate ester with an aluminum hydride compound. In certain embodiments, this hydride source includes LiAlH4. In certain embodiments, this hydride source includes diisobutylaluminum hydride. In certain embodiments, treating the monosulfonate ester with a hydride source includes contacting the monosulfonate ester with a boron hydride compound. In certain embodiments, this hydride source includes NaBH4. In certain embodiments, this hydride source includes LiBH4. In certain embodiments, this hydride source includes alkylboron hydride. In certain embodiments, this hydride source includes lithium triethylborohydride.

[0145] In certain embodiments, treating the monosulfonate ester with a hydride source involves contacting the monosulfonate ester with the hydride source in the presence of a strong base. In certain embodiments, the strong base includes an alkali metal hydride; in certain embodiments, the strong base includes sodium hydride. In certain embodiments, the strong base includes an alkali metal hydride; in certain embodiments, the strong base includes calcium hydride. In certain embodiments, the strong base includes an alkali metal oxide or alkoxide. In certain embodiments, the strong base includes potassium alkoxide. In certain embodiments, the strong base includes sodium alkoxide. In certain embodiments, the strong base includes potassium tert-butoxide. In certain embodiments, the strong base includes sodium tert-butoxide. In certain embodiments, the strong base includes a nitrogen anion. In certain embodiments, the strong base containing a nitrogen anion includes an alkali metal amide (e.g., sodium diisopropylamide or potassium bis(trimethylsilyl)amide).

[0146] In certain embodiments, this strong base contains sodium ions. In certain embodiments, this strong base contains potassium ions. In certain embodiments, this strong base contains rubidium or cesium ions. In certain embodiments, this strong base is not a lithium salt. In certain embodiments, this strong base is not an aluminum salt.

[0147] In certain embodiments, the strong base is added as a solid. In certain embodiments, the strong base is added as a solution in an organic solvent. In certain embodiments, the strong base is added as a suspension.

[0148] In certain embodiments, the method includes treating a monosulfonate ester with a combination of an aluminum hydride compound and a strong base. In certain embodiments, the method includes treating a monosulfonate ester with a combination of an aluminum hydride compound and an alkali metal hydride or alkaline metal hydride. In certain embodiments, the method includes treating a monosulfonate ester with a combination of lithium aluminum hydride and an alkali metal hydride. In certain embodiments, the method includes treating a monosulfonate ester with a combination of lithium aluminum hydride and sodium hydride. In certain embodiments, the method includes treating a monosulfonate ester with a combination of lithium aluminum hydride and an alkaline metal hydride. In certain embodiments, the method includes treating a monosulfonate ester with a combination of lithium aluminum hydride and calcium hydride.

[0149] In certain embodiments, the method includes treating a monosulfonate ester with a combination of an aluminum hydride compound and an alkali metal oxide or alkoxide. In certain embodiments, the method includes treating a monosulfonate ester with a combination of lithium aluminum hydride and an alkali metal hydride. In certain embodiments, the method includes treating a monosulfonate ester with a combination of lithium aluminum hydride and a sodium alkoxide. In certain embodiments, the method includes treating a monosulfonate ester with a combination of lithium aluminum hydride and a potassium alkoxide. In certain embodiments, the method includes treating a monosulfonate ester with a combination of lithium aluminum hydride and a potassium tert-butoxide. In certain embodiments, the method includes treating a monosulfonate ester with a combination of lithium aluminum hydride and a sodium tert-butoxide.

[0150] In certain embodiments, the method includes treating a monosulfonate ester with a boron hydride compound and a strong base. In certain embodiments, the method includes treating a monosulfonate ester with a combination of a boron hydride compound and an alkali metal hydride or alkaline metal hydride. In certain embodiments, the method includes treating a monosulfonate ester with a combination of sodium borohydride or lithium borohydride and an alkali metal hydride. In certain embodiments, the method includes treating a monosulfonate ester with a combination of sodium borohydride or lithium borohydride and sodium hydride. In certain embodiments, the method includes treating a monosulfonate ester with a combination of sodium borohydride or lithium borohydride and an alkaline metal hydride. In certain embodiments, the method includes treating a monosulfonate ester with a combination of sodium borohydride or lithium borohydride and calcium hydride.

[0151] In certain embodiments, the method includes treating a monosulfonate ester with a combination of a boron hydride compound and an alkali metal oxide or alkoxide. In certain embodiments, the method includes treating a monosulfonate ester with a combination of sodium borohydride or lithium borohydride and an alkali metal alkoxide. In certain embodiments, the method includes treating a monosulfonate ester with a combination of sodium borohydride or lithium borohydride and sodium tert-butoxide. In certain embodiments, the method includes treating a monosulfonate ester with a combination of sodium borohydride or lithium borohydride and potassium tert-butoxide.

[0152] There are no specific limitations on the amount of strong base present in the hydride reaction step. In certain embodiments, the strong base is provided in approximately equimolar amounts relative to the monosulfonate ester substrate. In certain embodiments, the strong base is provided in approximately excess molar concentration relative to the monosulfonate ester substrate. In certain embodiments, the strong base is provided in approximately equimolar amounts relative to the hydride reducing agent. In certain embodiments, the strong base is provided in equimolar amounts or higher proportions relative to the free -OH groups present on the monosulfonate ester substrate. In certain embodiments, the base is provided in approximately equimolar amounts relative to the free -OH groups present on the substrate.

[0153] In one embodiment, the present invention provides a method for converting 1-O-methylrhamnose to 1-O-methylascarilose. In a particular embodiment, the method comprises contacting 1-O-methylrhamnose with a sulfonating agent in the presence of a Lewis acid catalyst to selectively sulfonate the 3-OH group of 1-O-methylrhamnose, and then treating the monosulfonate ester with a hydride source to provide 1-O-methylascarilose in a yield of more than 50%. In a particular embodiment, the Lewis acid is a tin compound, such as a dialkyltin dihalide. In a particular embodiment, the Lewis acid is a dialkyltin dichloride, such as dibutyltin dichloride. In a particular embodiment, the sulfonating agent used includes a sulfonyl chloride, such as p-toluenesulfonyl chloride. In a particular embodiment, the hydride source includes an aluminum hydride reducing agent, such as lithium aluminum hydride. In certain embodiments, treating a monosulfonate ester with a hydride reducing agent involves contacting the monosulfonate ester with a strong base, such as an alkali metal hydride, an alkali metal hydride (e.g., NaH or CaH2), or an alkali metal oxide or alkoxide. In certain embodiments, treating a monosulfonate ester with a hydride reducing agent involves first adding at least 1 molar equivalent of a strong base to a monosulfonate ester substrate, and then treating this substrate with at least 1 molar equivalent of a hydride reducing agent. In certain embodiments, treating a monosulfonate ester with a hydride reducing agent involves first adding a strong base to a monosulfonate ester substrate in an amount equal to or greater than the molar equivalent of the free -OH groups present on the substrate, and then treating this mixture with at least 1 molar equivalent of a hydride reducing agent.

[0154] In certain embodiments, the method is characterized by the fact that chromatographic purification is not required to obtain a substantially pure product. As used herein, the term “substantially pure” means a product having a purity of about 85% or more, about 88% or more, about 90% or more, about 95% or more, about 98% or more, about 99% or more, or about 99.5% or more. In certain embodiments, the purification of 1-O-methylascarilose is facilitated by substitution of the 2- and 4-hydroxyl groups with substituents that impart hydrophobicity to the product. Such hydrophobic derivatives can be purified, for example, by extraction into a nonpolar organic solvent. Subsequently, in certain embodiments, the method includes a further step of treating the product obtained from the hydride reaction to introduce substituents on the 2- and 4-hydroxyl groups. In certain embodiments, it is convenient if such substituents are cleavable and, if desired, the 2-4-OH compound can be regenerated (e.g., after purification). Such substitutions of 2- and 4-hydroxyl groups may also enable manipulation of 1-O-substituents (e.g., removal and replacement of 1-O-substituents in the 1-O-substituted ascarosides product) or manipulation of 1-O-substituents (e.g., through carbon-carbon bond formation reactions or functionalization of substituents). In certain embodiments, these further steps enable the method to produce valuable ascaroside derivatives, such as ascr#18 or ascr#7, which may have utility in agricultural or human medical applications. (See, for example, von Reuss et al., "Comparative Metabolics Reveals Biogenesis of Ascarosides, a Modular Library of Small-Molecule Signals in C.elegans," J.Am.Chem.Soc. (2012) 134(3), 1817-1824, which is incorporated herein by reference).

[0155] [ka]

[0156] In certain embodiments, the method includes acylation of the 2- and 4-positions of the 1-O-substituted ascarilose product. In certain embodiments, the 2- and 4-positions are substituted with the same acyl group. In certain embodiments, the 2- and 4-positions may be substituted with different acyl groups. In certain embodiments, this acyl group is C 1-5 Optionally substituted acyl, acetate, propionate, butanoate, pyrubate, 2-ethylhexanoate, octanoate, trifluoroacetate, C 5-20 The acyl is selected from the group consisting of optionally substituted acyls, benzoates, and substituted benzoates. In certain embodiments, the 2- and 4-positions are converted to the benzoate ester. In certain embodiments, the 2- and 4-positions are converted to a substituted benzoate ester (e.g., chlorobenzoate, nitrobenzoate, methoxybenzoate, p-tert-butylbenzoate, etc.). In certain embodiments, the method involves acylation of the 2- and 4-positions of the 1-O-substituted ascarilose product in a "one-pot" procedure (e.g., without workup and isolation of the product from the hydride reaction of the sulfonation substrate). In certain embodiments, the acylation reagent (e.g., an acid chloride or acid anhydride) is added to the reaction vessel after the completion of the hydride reaction step. Such additions may include a quenching step (e.g., direct addition to the reaction mixture) or may be performed after the initial quenching step (e.g., addition of a quenching agent, such as water, to consume excess hydride reducing agent and / or neutralize other reactants present in the reaction mixture).

[0157] In certain embodiments, if the method involves substituting the 2- and 4-OH groups of the product 1-O-substituted ascarilose, the 2- and 4-positions are substituted with substituents other than acyl groups. Suitable groups include hydroxyl protecting groups as described in *Protecting Groups in Organic Synthesis*, Peter GMWuts, editor, ISBN: 9781118057483. In certain embodiments, the 2- and 4-positions are converted to ethers. In certain embodiments, the 2- and 4-positions are converted to benzyl ethers or t-butyl ethers. In certain embodiments, the 2- and 4-positions are converted to silyl ethers (e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, etc.). In certain embodiments, the 2- and 4-positions are converted to acetal or ketal derivatives. In certain embodiments, it may be efficient to perform the conversion of the 2- and 4-positions of the 1-O-substituted ascarilose product to a 2-4-monosubstituted or disubstituted ether, silyl ether, acetal, or ketal in a "one-pot" procedure (e.g., without work-up and isolation of the product from the previous reaction). In certain embodiments, a suitable reagent (e.g., alkyl halide, silyl chloride, aldehyde, or ketone) is added to the reaction vessel after the completion of the hydride reaction. Depending on the reactivity of the reagent used, such addition may include a quenching step (e.g., direct addition to the reaction mixture) or may be performed after the initial quenching step (e.g., by consuming an excess amount of hydride reducing agent by adding the quenching reagent and / or by neutralizing other reactive species present in the reaction mixture before the addition of the reagent).

[0158] In certain embodiments, if the method involves substituting the 2- and 4-OH groups of the 1-O-substituted ascarilose product, the method includes isolating the resulting 2-4-substituted 1-O-substituted ascarilose product with a nonpolar solvent. Isolation using a nonpolar solvent can result in substantial purification of the product because many reagent and process-derived by-products are substantially insoluble in the nonpolar solvent and thus remain during extraction. In certain embodiments, the nonpolar solvent used for extraction includes hydrocarbon solvents, such as petroleum ether, pentane, hexane, and heptane. In certain embodiments, the nonpolar solvent used for extraction includes aromatic solvents, such as benzene, toluene, and chlorobenzene. In certain embodiments, the nonpolar solvent may include ethers, such as t-butyldimethyl ether, dioxane, and diphenyl ether. In certain embodiments, the extract obtained contains the product with sufficient purity to allow crystallization of the product from this extract. In certain embodiments, the method includes bringing about crystallization of the product ascarilose derivative by concentration, cooling, or addition of a non-solvent to the extract.

[0159] In certain embodiments, the method is characterized by the amount of raw materials used or the amount of product produced. While the synthesis of ascarilose and its derivatives from rhamnose-based raw materials has been reported in the prior art, there are no reports of such processes being carried out on a large scale. Prior art processes are generally unsuitable for large-scale use due to the cost of the reagents used, the use of difficult reaction conditions (e.g., extremely low temperatures), and / or the need for chromatographic purification of intermediates or final products. In contrast, the method provided herein is suitable for multi-kilogram scale use. Therefore, in certain embodiments, the method is characterized by the supply of raw materials in amounts of at least 100 g, at least 1 kg, at least 5 kg, at least 10 kg, at least 20 kg, or at least 50 kg. In certain embodiments, the method is characterized by the production of a 1-O-substituted ascarilose product in amounts of at least 100 g, at least 1 kg, at least 5 kg, at least 10 kg, at least 20 kg, or at least 50 kg. [Examples]

[0160] The following embodiments illustrate, and are not intended to limit, any particular method of the present invention.

[0161] Example 1: Conversion of L-rhamnose to benzoyl-methyl-ascarilose:

[0162] [ka]

[0163] L-rhamnose H2O (10.0 g, 55 mmol) was dissolved in MeOH (70 mL, 1.7 mol), and H2SO4 (99%, 0.5 mL, 9.4 mmol, 0.2 equivalent) was added. The reaction mixture was then heated under reflux for 5 days (oil bath, 90°C). The reaction mixture was cooled and concentrated to approximately 20 mL, and iPr2EtN (1 mL) was added to quench the residual acid. The reaction mixture was then concentrated until dry, dissolved in MeCN (100 mL), and iPr2EtN (8.4 g, total 70 mmol, 1.3 equivalent) was added, followed by Bu2SnCl2 (836 mg, 2.8 mmol, 0.1 equivalent) and finally pTsCl (11.5 g, 60.2 mmol, 1.1 equivalent). The reaction mixture was stirred at room temperature for 2 hours, then quenched by adding a saturated aqueous solution of NaHCO3 (100 mL), and extracted with phenylethylamine (100 mL x 3). The organic layers were combined, filtered through a 1.5” silica pad, and concentrated. The resulting clear oil was dissolved in THF (100 mL), and NaH (4.4 g, 110 mmol, 2.0 equivalents) was carefully added little by little (in approximately 10 parts), avoiding excessive heat or H2 gas release. The resulting yellow suspension was stirred for 15 minutes, and LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalents) was carefully added in the same manner (in approximately 10 parts), avoiding excessive gas or heat release. Adding another 100 mL of THF caused the suspension to become a thick foam, at which point stirring was stopped. A reflux concentrator was fitted to the flask, and the reaction mixture was heated under reflux for 1 hour (oil bath, 90°C). The reaction mixture was allowed to cool to room temperature, and saturated aqueous Na2SO4 solution was added dropwise until no more bubbles were produced. AcOH was added until the pH of the crude reaction mixture was approximately 7, and then filtered through a 1.5” silica pad. The resulting product was a mixture of a yellow liquid (target product) and a two-layered transparent oil (from NaH) that could be removed with hexane. The target yellow oil was dissolved in pyridine (100 mL), and BzCl (15 mL, 129 mmol, 2.3 equivalents) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 24 hours to warm to room temperature. Saturated aqueous solution of NaHCO3 (200 mL) was added, and the reaction mixture was stirred for 2 hours, evaporated under vacuum, and extracted with hot hexane.The hexane layer was dried over Na2SO4, filtered, and evaporated until dry to obtain benzoyl-methyl-ascarilose (9.1 g, 24.7 mmol, 45% yield) as a clear oil, which was further purified by column chromatography (1:9, toluene:hex). This procedure provides benzoyl-methyl-ascarilose from rhamnose in yields ranging from 38% to 45%. 1 H NMR: CDCl3(600 mHz): δ 8.11 (d, J = 7.1 Hz, 2H), 8.03 (d, J = 7.2 Hz, 2H), 7.61 - 7.54 (m, 2H), 7.50 - 7.41 (m, 4H), 5.22 - 5.20 (m, 2H), 5.20 - 5.15 (m, 1H), 4.74 (s, 1H), 4.07 (dq, J = 9.7, 6.3 Hz, 1H), 3.48 (s, 3H), 2.42 (dt, J = 13.4, 3.7, 3.4 Hz, 1H), 2.20 (ddd, J = 13.5, 11.4, 3.2 Hz, 1H), 1.31 (d, J = 6.3 Hz, 3H).

[0164] Example 2: Modified conversion of L-rhamnose to benzoyl-methyl-ascarilose:

[0165] [ka]

[0166] L-rhamnose·H2O (10.0 g, 55 mmol) was dissolved in MeOH (70 mL, 1.7 mol), H2SO4 (99%, 0.5 mL, 9.4 mmol, 0.2 equivalent) was added, and the reaction mixture was heated under reflux for 3 days (oil bath, 90°C). The reaction mixture was cooled and concentrated under vacuum. The reaction mixture was dissolved in MeCN (100 mL), and iPr2EtN (8.4 g, total 70 mmol, 1.3 equivalent), then Bu2SnCl2 (836 mg, 2.8 mmol, 0.1 equivalent), and finally pTsCl (11.5 g, 60.2 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at room temperature for 2 hours, quenched by adding saturated aqueous solution of NaHCO3 (100 mL), and extracted with RINKAN (100 mL x 3). The organic layers were combined and concentrated. The obtained oil was dissolved in THF (100 mL), and NaH (4.4 g, 110 mmol, 2.0 equivalents) was added gradually (in approximately 10 parts) while avoiding exothermic reaction or H2 gas release. The resulting yellow suspension was stirred for 15 minutes, and LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalents) was added gradually in the same manner (in approximately 10 parts) while avoiding violent gas or heat release. When another 100 mL of THF was added, the suspension became a thick foam, and stirring was stopped. A reflux concentrator was attached to the flask, and the reaction mixture was heated under reflux for 1 hour (oil bath, 90°C). The reaction mixture was allowed to cool to room temperature, and 30 mL of H2O was added dropwise to the reaction mixture, and then neutralized with 1.0 M HCl until the mixture separated into two clear layers at a pH of approximately 9. This mixture was extracted with HCl (100 mL x 3) and concentrated under vacuum. The resulting product was washed with hexane to remove mineral oil. The crude product was dissolved in pyridine (100 mL), and BzCl (15 mL, 129 mmol, 2.3 equivalents) was added dropwise at room temperature, and the mixture was stirred for 24 hours. Saturated aqueous solution of NaHCO3 (200 mL) was added, and the reaction mixture was stirred for 2 hours, evaporated under vacuum, and extracted with hot hexane.The hexane layer was dried over Na2SO4, filtered, and evaporated to dryness to afford benzoylated-methyl-ascarylose (9.1 g, 24.7 mmol, 45% yield) as a clear oil, which was further purified by column chromatography (1:9, EtOAc:Hex) to give purified benzoylated-methyl-ascarylose from rhamnose in 21% yield.

[0167] Example 3: Example 3 was carried out according to the procedure of Example 1, except that the process was carried out on a large scale using 1 kg of starting L-rhamnose and scaling up all other reagents accordingly.

[0168] Example 4: Example 4 was carried out according to the procedure of Example 1, except that methanesulfonic anhydride was used instead of tosyl chloride and calcium hydride was used instead of sodium hydride.

[0169] Example 5: Example 5 was carried out according to the procedure of Example 1, except that methanesulfonic anhydride was used instead of tosyl chloride and calcium hydride was used instead of sodium hydride.

[0170] Example 6: Example 6 was carried out according to the procedure of Example 1, except that the amount of dibutyltin dichloride was reduced to 1 mol% relative to 1-O-methylrhamnose.

[0171] Example 7: Example 7 was carried out according to the procedure of Example 2, except that iron(III) chloride was used instead of dibutyltin dichloride.

[0172] Example 8: Example 8 was carried out according to the procedure of Example 2, except that excess potassium carbonate was used instead of iPr2EtN.

[0173] Example 9: Deoxygenation of Medium-Chain 1-O-Substituted Rhamnose Derivatives

[0174]

Chem.

[0175] Dissolve compound 5a in MeCN (100 mL), add iPr2EtN (8.4 g, 70 mmol in total, 1.3 equivalents), then add Bu2SnCl2 (836 mg, 2.8 mmol, 0.1 equivalent) and finally pTsCl (11.5 g, 60.2 mmol, 1.1 equivalents). Stir the reaction mixture at room temperature for 2 hours and quench by adding saturated aqueous NaHCO3 (100 mL), then extract with EtOAc (100 mL×3). Combine the organic layers and concentrate. Dissolve the resulting oil in THF (100 mL) and add NaH (4.4 g, 110 mmol, 2.0 equivalents) portionwise (approx. 10 portions). Stir the resulting yellow suspension for 15 minutes and add LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalents) portionwise in the same manner. Add an additional 100 mL of THF, attach a reflux condenser to the flask, and warm the reaction mixture to reflux for 1 hour (oil bath, 90 °C). Cool the reaction mixture to room temperature and add 30 mL of H2O dropwise to the reaction mixture, then neutralize with 1.0 M HCl until the mixture separates into two clear layers. Extract this mixture with EtOAc (100 mL×3) and concentrate under vacuum. Wash the resulting product with hexane to remove mineral oil. Dissolve the crude product in pyridine (100 mL), add BzCl (15 mL, 129 mmol, 2.3 equivalents) dropwise at room temperature, and stir for 24 hours. Add saturated aqueous NaHCO3 (200 mL), stir the reaction mixture for 2 hours, evaporate under vacuum, and extract with hot hexane. Dry the hexane layer over Na2SO4, filter, and evaporate to dryness to obtain compound 5b as an oil, which is further purified by column chromatography (1:9, EtOAc:Hex).

[0176] Example 10: Deoxygenation of Long-Chain 1-O-Substituted Rhamnose Derivatives

[0177] [ka]

[0178] Compound 6a is dissolved in MeCN (100 mL), iPr2EtN (10 g, total 70 mmol, 1.3 equivalents) is added, followed by Bu2SnCl2 (836 mg, 2.8 mmol, 0.1 equivalent), and finally pTsCl (11.5 g, 60.2 mmol, 1.1 equivalent). The reaction mixture is stirred at room temperature for 2 hours, then quenched by adding saturated aqueous solution of NaHCO3 (100 mL), and extracted with SiO2 (100 mL x 3). The organic layers are combined and concentrated. The resulting oil is dissolved in THF (100 mL), and NaH (4.4 g, 110 mmol, 2.0 equivalent) is added little by little (in approximately 10 parts). The resulting yellow suspension is stirred for 15 minutes, and LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalent) is added little by little in the same manner. Add another 100 mL of THF, attach a reflux concentrator to the flask, and heat the reaction mixture to reflux for 1 hour (oil bath, 90°C). Let the reaction mixture cool to room temperature, then add 30 mL of H2O dropwise to the reaction mixture, and neutralize with 1.0 M HCl until the mixture separates into two clear layers. Extract the mixture with RINKAN (100 mL x 3) and concentrate under vacuum to obtain compound 6b as oil.

[0179] Example 11: 1-Methyl-L-rhamnose .Dissolve (10.0 g, 55 mmol) in MeCN (100 mL), add iPr2EtN (8.4 g, total 70 mmol, 1.3 equivalents), then Bu2SnCl2 (84 mg, 0.3 mmol, 0.01 equivalents), and finally add pTsCl (11.5 g, 60.2 mmol, 1.1 equivalents). Stir the reaction mixture at room temperature for 2 hours, then quench by adding saturated aqueous solution of NaHCO3 (100 mL), and extract with SiO2 (100 mL x 3). Combine the organic layers and concentrate. Dissolve the resulting oil in THF (200 mL), and gradually add NaH (4.4 g, 110 mmol, 2.0 equivalents). The resulting yellow suspension is stirred for 60 minutes, and LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalent) is added gradually in the same manner (in approximately 10 parts), avoiding violent gas or heat release. The reaction mixture is heated under reflux for 1 hour (oil bath, 90°C). The reaction mixture is cooled to room temperature, and 50 mL of H2O is added dropwise to the reaction mixture, followed by 50 mL of 4NNaOH. The THF is removed under reduced pressure, and 50 mL of toluene is added. Most of the added toluene is removed by heating under reduced pressure, and a further 100 mL of toluene is added. Benzoyl chloride (200 mmol) and tetrabutylammonium chloride (5 mmol, as a phase transfer catalyst) are added to the resulting two-layer mixture. The two-layer mixture is stirred vigorously for 16 hours, and then allowed to stand. The toluene layer is separated, and the aqueous residue is extracted with further toluene (3 × 50 mL). The combined toluene fraction is dried over Na2SO4, filtered, and evaporated until dry to obtain benzoyl-methyl-ascarilose.

[0180] The compositions, systems, devices, methods, and processes of this application are intended to encompass modifications and adaptations developed using information from the embodiments described herein. Adaptations or modifications of the methods and processes described herein can be carried out by those skilled in the art.

[0181] It will be understood that the use of headings in this disclosure is presented for the convenience of the reader. The presence and / or placement of headings is not intended to limit the scope of the subject matter described herein. Unless otherwise specified, embodiments described in a section of this application apply both individually and in combination throughout the application to other embodiments.

[0182] Wherever a composition, compound, or product is described as having, including, or comprising certain components, or where a process and method is described as having, including, or comprising certain steps, it is intended that there exist articles, devices, and systems of this application which are essentially composed of or comprise the listed components, and processes and methods of this application which are essentially composed of or comprise the listed processing steps.

[0183] It should be understood that the order of the steps or the order in which specific actions are performed is not important, as long as the described method is operable. Furthermore, two or more steps or actions may be performed simultaneously.

[0184] The present invention provides an efficient method for producing ascarilose and its derivatives from rhamnose. While prior art methods rely on multi-step sequences of hydroxyl group protection and deprotection to enable selective deoxygenation at the 3-position (e.g., Organic Letters 2017 19(11), 2837-2840 DOI:10.1021 / acs.orglett.7b01009), the present invention provides an efficient method for deoxygenating the 3-position of rhamnose without the need to protect the hydroxyl group at the 2- or 4-position. Although other researchers have previously reported the selective functionalization of the 3-OH group of rhamnose, a practical method for deoxygenation at this position in the absence of protection at the 2- or 4-position has not been achieved to date. In detail, prior art (e.g., Baer et al. Canadian J. Chem. 63,432 (1985); Ito et al., Chem. Pharm. Bull. 39(8), 1983-89 (1991); and Binkley, J. Org. Chem. 50,5646 (1985)) demonstrates that such processes tend to result in rearrangement of the sugar skeleton or provide a mixture of products in which the desired 3-deoxy compound is the least abundant component. Therefore, the method of the present invention offers significant advantages over the prior art.

[0185] All publications and patent applications referenced herein represent the level of expertise of those skilled in the art to which the present invention pertains. All publications and patent applications are incorporated herein by reference to the same extent that individual publications or patent applications are incorporated by reference specifically and individually as indicated herein.

[0186] Although the present invention described above is described in some detail for illustrative purposes and for the purpose of clear understanding, it is clear that certain changes and modifications may be made within the scope of the appended claims.

Claims

1. A method for producing 1-O-substituted ascarilose, As a raw material, Formula II: 【Chemistry 1】 [In the formula, Z is a substituent other than hydrogen.] The method involves supplying 1-O-substituted rhamnose having the structure of formula II, wherein the raw material 1-O-substituted rhamnose of formula II is L-rhamnose: 【Chemistry 2】 Having the stereochemistry of; Forming a monosulfonate ester at the 3-OH group of the aforementioned raw material; and The process includes treating the monosulfonate ester with a hydride source to form a 1-O-substituted ascarilose. The hydride source is an aluminum hydride compound or a boron hydride compound. The step of treating the monosulfonate ester with a hydride source includes contacting the monosulfonate ester with the hydride source in the presence of a strong base, A method for forming the monosulfonate ester in the 1-O-substituted rhamnose without hydroxyl protecting groups at either the 2-OH or 4-OH position.

2. The method according to claim 1, wherein the strong base is added before the addition of the hydride source.

3. The method according to claim 1, wherein the strong base is selected from the group consisting of alkali metal hydrides, alkali metal hydrides, alkali metal oxides, alkali metal alkoxides, and alkali metal amides.

4. The method according to claim 3, wherein the strong base comprises sodium ions or potassium ions.

5. The method according to claim 1, wherein the strong base includes an alkali metal hydride.

6. The method according to claim 5, wherein the alkali metal hydride is sodium hydride.

7. The method according to claim 1, wherein the strong base includes an alkaline metal hydride.

8. The method according to claim 7, wherein the alkaline metal hydride is calcium hydride.

9. The method according to claim 1, wherein the strong base contains a nitrogen anion.

10. The method according to any one of claims 1 to 9, wherein the hydride supply source is an aluminum hydride compound.

11. The hydride supply source is LiAlH ４ The method according to claim 10.

12. The method according to any one of claims 1 to 9, wherein the hydride supply source is a boron hydride compound.

13. The hydride supply source is LiBH ４ The method according to claim 12.

14. The method according to any one of claims 1 to 9, wherein the formation of the monosulfonate ester comprises contacting the raw material with a sulfonyl halide or sulfonic anhydride in the presence of a Lewis acid catalyst.

15. The method according to claim 14, wherein the Lewis acid catalyst comprises a tin compound.

16. The method according to claim 15, wherein the Lewis acid catalyst comprises a dialkyltin compound.

17. The method according to claim 16, wherein the Lewis acid catalyst comprises a dialkyltin dihalide.

18. The method according to claim 14, wherein the Lewis acid catalyst comprises a boron compound or a transition metal.

19. The method according to any one of claims 1 to 9, wherein the raw material comprises 1-O-methylrhamnose.

20. The Z in equation II is replaced by C as arbitrarily. ２－２４ The method according to any one of claims 1 to 9, wherein the group is an aliphatic group.

21. The value of Z in equation II is given by the following equation: 【Transformation 3】 [In the formula, R ４ but, Arbitrarily substituted C １－４０ aliphatic group; A optionally substituted C which may be unsaturated at one or more positions. １－４０ Carboxylic acid chains; and A optionally substituted C which may be unsaturated at one or more positions. １－４０ Ester or orthoester derivatives of carboxylic acid chains Selected from the group consisting of [the specified group]. The method according to any one of claims 1 to 9, wherein the group is having the following:

22. In equation II, Z is 【Chemistry 4】 The method according to any one of claims 1 to 9, wherein x is an integer from 1 to 30 in the formula.

23. In equation II, Z is 【Transformation 5】 The method according to claim 22.

24. In equation II, Z is 【Transformation 6】 [In the formula, n is an integer from 1 to 40, and R ｙ is -H, a metal cation, a carboxyl protecting group, an optionally substituted C １－２０ aliphatic group, an optionally substituted aromatic group, or a biomolecule residue.] The method according to any one of claims 1 to 9.

25. The method according to claim 24, wherein R y is a glycoside, an amino acid, a peptide, or a nucleotide.

26. The method according to any one of claims 1 to 9, wherein the step of treating the monosulfonate ester with a hydride source to form a 1-O-substituted ascarilose simultaneously reduces one or more functional groups on Z.

27. The method according to any one of claims 1 to 9, further comprising isolating the 1-O-substituted ascarilose, wherein the 1-O-substituted ascarilose is isolated in at least 40% yield based on the raw materials.

28. The method according to any one of claims 1 to 9, wherein at least 1 kg of the raw material is used.

29. A method for producing 1-O-substituted ascarilose: As a raw material, formula IV: 【Transformation 7】 [In the formula, Z is a substituent other than hydrogen, and Q is an optionally substituted aliphatic or aromatic moiety.] The present invention provides a 3-sulfonate ester of a 1-O-substituted rhamnose derivative having the structure, wherein the 3-sulfonate ester of the 1-O-substituted rhamnose derivative of formula IV of the starting material is L-rhamnose: 【Transformation 8】 Having the stereochemistry of; and The monosulfonate ester is treated with a strong base and a hydride source to form 1-O-substituted ascarilose. Includes, The hydride source is an aluminum hydride compound or a boron hydride compound. The step of treating a monosulfonate ester with a strong base and a hydride source includes contacting the monosulfonate ester with the hydride source in the presence of a strong base. The aforementioned method.

30. The method according to any one of claims 1 to 9 and 29, wherein the yield of the 1-O-substituted ascarilose is greater than 50%.

31. The method according to any one of claims 1 to 9 and 29, wherein the yield of the 1-O-substituted ascarilose is greater than 60%.

32. The method according to any one of claims 1 to 9 and 29, wherein the yield of the 1-O-substituted ascarilose is greater than 90%.

33. The method according to any one of claims 1 to 9 and 29, wherein the method results in the production of a ring contraction rearrangement product of less than 40%.

34. The method according to any one of claims 1 to 9 and 29, wherein the method results in the production of a ring-contraction rearrangement product of less than 5%.

35. The method according to any one of claims 1 to 9 and 29, wherein the monosulfonate ester is selected from p-toluenesulfonate, methylsulfonate, or trifluoromethylsulfonate.

36. The method according to any one of claims 1 to 9 and 29, further comprising the step of acylating the hydroxyl groups of the 2-OH and 4-OH of the 1-O-substituted ascarilose by adding an acylating reagent to a mixture of the raw materials treated with the hydride source and the strong base.

37. The method according to claim 36, wherein the acylation reagent is added to the mixture without a quenching step.

38. The method according to claim 36, wherein the acylation reagent is added to the mixture after the quenching step.

39. ascr#18 or ascr#7 【Chemistry 9】 The method according to any one of claims 1 to 9 and 29 for the production of .

40. ascr#18 or ascr#7 【Chemistry 10】 The method according to claim 11 for the production of [the specified product].

41. ascr#18 or ascr#7 【Chemistry 11】 The method according to claim 13 for the production of [the specified product].

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