Methods of making ascaroside and related compounds

Abstract

The present invention relates to methods for efficiently preparing ascarosides and related compounds. A method for preparing ascarosides includes providing a 1-O-substituted rhamnose as a starting material; forming a monosulfonate at the 3-OH position of the 1-O-substituted rhamnose; treating the monosulfonate with a hydride source to form a 1-O-substituted ascaroside. The formation of the monosulfonate can be advantageously performed on a 1-O-substituted rhamnose that has no hydroxyl protecting groups at the 2-OH position or the 4-OH position.

Description

[0001] Federally funded research or development

[0002] This invention was completed with the support of the U.S. government, under grant number 1843116 from the National Science Foundation. The U.S. government holds certain rights to this invention. Technical Field

[0003] This invention relates to the field of chemical synthesis, specifically, it provides a method for efficiently preparing ascarylose and its derivatives using rhamnose. Background Technology

[0004] Ascaroside natural products are secondary metabolites produced by nematodes. Numerous diverse ascaroside structures have been discovered in nature; these molecules are considered an evolutionarily conserved chemical language used by nematodes to control many aspects of their development. Ascaroside can also be sensed by other organisms and has been shown to have a range of effects on many organisms, including bacteria, fungi, plants, and mammals (including humans). Ascaroside has the potential to be used as a human pharmaceutical, agrochemical, and other diverse and valuable products. Ascaroside is a derivative of ascaroside sugar, a dideoxyglycoside lacking hydroxyl groups at the 3- and 6-positions. Ascaroside sugar is a relatively scarce sugar in nature, and there are currently no commercially available bulk sources. Therefore, the complete synthesis of all reported ascaroside-containing natural products relies on the deoxygenation of more abundant sugar feedstocks (such as rhamnose or mannose) to obtain the ascaroside sugar structure. While this method is feasible for small-scale studies and research-oriented natural product synthesis, it is impractical for obtaining large quantities of ascaridosin in this manner because existing ascaridosin synthesis routes require multi-step synthetic sequences, rely on expensive reagents, and / or require chromatographic purification. Therefore, efficient and scalable methods for preparing ascaridosin and its derivatives remain needed. Summary of the Invention

[0005] This invention provides compositions and methods for the efficient preparation of rhamnose and its derivatives. The method uses rhamnose as a starting material and includes deoxygenating the 3-position of rhamnose without requiring protection of the 2- or 4-hydroxyl groups. Therefore, a method is provided for converting 1-O-substituted rhamnose derivatives into 1-O-substituted rhamnose derivatives without the use of hydroxyl protection.

[0006] One aspect of the present invention provides a method for preparing ascarid sugar, comprising: providing 1-O-substituted rhamnose having the structure shown in Formula II as a starting material, wherein Z is a non-hydrogen substituent:

[0007]

[0008] A mono-sulfonate ester is formed at the 3-OH position of the raw material; the mono-sulfonate ester is treated with a hydride source to form a 1-O-substituted rhamnose, wherein the mono-sulfonate ester is formed on a 1-O-substituted rhamnose without a hydroxyl protecting group at the 2-OH or 4-OH position.

[0009] When treating the monosulfate with the hydride source, a strong base may be added. When adding a strong base, it may be added before adding the hydride source. Examples of such strong bases include, but are not limited to, alkali metal hydrides, alkaline metal hydrides, alkali metal oxides, alkali metal alkoxides, and alkali metal amides. In some embodiments of the invention, the strong base contains sodium or potassium.

[0010] In some embodiments of the present invention, the hydride source is 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, wherein the second metal hydride reducing agent is an alkali metal hydride or an alkaline earth metal hydride. Typical first metal hydrides include LiAlH4, LiBH4, diisobutyl aluminum hydride, etc. Typical second metal hydrides are sodium hydride.

[0011] In some embodiments of the present invention, the formation process of the monosulfonate ester includes contacting the raw material with a sulfonyl halide or a sulfonic acid anhydride in the presence of a Lewis acid catalyst. The 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 may also be used, such as Lewis acids containing boron or transition metals.

[0012] In some embodiments of the present invention, the formation process of the monosulfonate ester includes contacting the raw material with a sulfonyl halide or sulfonic anhydride in the presence of a base. The base may be, for example, an amine base.

[0013] In some embodiments of the present invention, the raw material comprises 1-O-substituted rhamnose having the structure shown in Formula II:

[0014]

[0015] In some embodiments of the invention, Z is methyl. In some other embodiments of the invention, Z is optionally substituted C. 2-24 Aliphatic groups.

[0016] In some other embodiments of the present invention, Z is a group represented by the following formula:

[0017]

[0018] Among them, R 4 Choose from the following groups: C that can be optionally substituted 1-40 Aliphatic groups; optionally substituted C 1-40 The carboxylic acid chain, wherein C 1-40 The carboxylic acid chain may optionally be unsaturated at one or more positions; and the C may optionally be substituted. 1-40 esters or orthoesters of the carboxylic acid chain, wherein C 1-40 The ester or orthoester derivative of the carboxylic acid chain may optionally be unsaturated at one or more positions.

[0019] For example, Z can be Where x is an integer from 1 to 30. Specifically, Z can be...

[0020] When the monosulfonate is treated with the hydride source to form the 1-O-substituted ascaridose, one or more functional groups on Z can be reduced simultaneously.

[0021] After treating the monosulfonate with the hydride source, the product 1-O-substituted ascaridose can be isolated. Based on the raw material, the yield of the 1-O-substituted ascaridose is at least 40%. In some embodiments of the invention, the method uses at least 1 kg of the raw material.

[0022] Another aspect of the present invention provides a method for preparing ascarid sugar, comprising: providing a 3-sulfonate ester of a 1-O-substituted rhamnose having the structure shown in Formula IV as a starting material, wherein Z is a non-hydrogen substituent and Q is an optionally substituted aliphatic or aromatic group.

[0023] The monosulfonate was then treated with a strong base and a hydride source to form 1-O-substituted ascaridose.

[0024] This invention includes, but is not limited to, the following embodiments:

[0025] Implementation Method 1: A method for preparing 1-O-substituted rhamnose, comprising: providing 1-O-substituted rhamnose having the structure shown in Formula II as a raw material, wherein Z is a non-hydrogen substituent:

[0026]

[0027] A monosulfonate is formed at the 3-OH position of the raw material; the monosulfonate is treated with a hydride source to form a 1-O-substituted rhamnose, wherein the monosulfonate is formed on a 1-O-substituted rhamnose without a hydroxyl protecting group at the 2-OH or 4-OH position.

[0028] Implementation Method 2: The method according to Implementation Method 1, wherein treating the monosulfonate with a hydride source further includes adding a strong base.

[0029] Implementation Method 3: The method described in Implementation Method 2, wherein the strong base is added before the hydride source is added.

[0030] Implementation Method 4: The method according to any one of Implementation Methods 2-3, wherein the strong base is selected from at least one of alkali metal hydrides, alkaline earth metal hydrides, alkali metal oxides, alkali metal alkoxides and alkali metal amides.

[0031] Implementation Method 5: The method according to any one of Implementation Methods 2-4, wherein the strong base contains sodium ions or potassium ions.

[0032] Implementation method 6: The method according to any one of implementation methods 1-5, wherein the hydride source is a metal hydride.

[0033] Embodiment 7: The method according to any one of Embodiments 1-6, wherein treating the monosulfonate with a hydride source comprises: contacting the monosulfonate with a first metal hydride and a second metal hydride.

[0034] Implementation Method 8: The method according to Implementation Method 7, wherein the first metal hydride includes aluminum hydride or boron hydride reducing agent, and the second metal hydride is an alkali metal hydride or an alkaline earth metal hydride.

[0035] Implementation Method 9: The method according to any one of Implementation Methods 7-8, wherein the first metal hydride is LiAlH4.

[0036] Implementation Method 10: The method according to any one of Implementation Methods 7-8, wherein the first metal hydride is LiBH4.

[0037] Implementation Method 11: The method according to any one of Implementation Methods 7-10, wherein the second metal hydride is sodium hydride.

[0038] Embodiment 12: The method according to any one of Embodiments 1-11, wherein the formation process of the monosulfonate ester includes: contacting the raw material with a sulfonyl halide or sulfonic anhydride in the presence of a Lewis acid catalyst.

[0039] Embodiment 13: The method according to Embodiment 12, wherein the Lewis acid catalyst comprises a tin compound.

[0040] Embodiment 14: The method according to Embodiment 13, wherein the Lewis acid catalyst comprises a dialkyltin compound.

[0041] Embodiment 15: The method according to Embodiment 14, wherein the Lewis acid catalyst comprises a dialkyltin dihalide.

[0042] Embodiment 16: The method according to Embodiment 12, wherein the Lewis acid catalyst comprises a boron compound.

[0043] Implementation Method 17: The method according to Implementation Method 12, wherein the Lewis acid catalyst comprises a transition metal.

[0044] Embodiment 18: The method according to any one of Embodiments 1-17, wherein the formation process of the monosulfonate ester includes: contacting the raw material with a sulfonyl halide or sulfonic anhydride in the presence of a base.

[0045] Implementation Method 19: The method according to Implementation Method 18, wherein the base includes an amine.

[0046] Implementation Method 20: The method according to any one of Implementation Methods 1-19, wherein in Formula II, Z is an optional substitute for C. 2-24 Aliphatic groups.

[0047] Implementation Method 21: The method according to any one of Implementation Methods 1-20, wherein the raw material comprises 1-O-methylrhamnose (i.e., in Formula II, Z is CH3).

[0048] Implementation Method 22: The method according to any one of Implementation Methods 1-20, wherein in Formula II, Z is a group represented by the following formula:

[0049] Among them, R 4 Choose from the following groups: C that can be optionally substituted 1-40Aliphatic groups; optionally substituted C 1-40 The carboxylic acid chain, wherein C 1-40 The carboxylic acid chain may optionally be unsaturated at one or more positions; and the C may optionally be substituted. 1-40 esters or orthoesters of the carboxylic acid chain, wherein C 1-40 carboxylic acid chain of The ester or orthoester derivative may optionally be unsaturated at one or more positions.

[0050] Implementation Method 23: The method according to any one of Implementation Methods 1-20, wherein, in Formula II, Z is Where x is an integer from 1 to 30.

[0051] Implementation Method 24: The method described in Implementation Method 23, wherein, in Formula II, Z is

[0052] Implementation Method 25: The method according to any one of Implementation Methods 1-24, wherein treating the monosulfonate with the hydride source to form the 1-O-substituted ascaridose can simultaneously reduce one or more functional groups on Z.

[0053] Implementation Method 26: The method according to any one of Implementation Methods 1-25, wherein the method further comprises separating the 1-O-substituted ascarid sugar.

[0054] Implementation Method 27: The method according to Implementation Method 26, wherein, based on the raw material, the 1-O-substituted ascaridose is isolated in a yield of at least 40%.

[0055] Implementation Method 28: The method according to any one of Implementation Methods 1-27, wherein the method uses at least 1 kg of the raw material.

[0056] Implementation Method 29: A method for preparing 1-O-substituted rhamnosine, comprising: providing a 3-sulfonate of 1-O-substituted rhamnosine having the structure shown in Formula IV as a starting material, wherein Z is a non-hydrogen substituent and Q is an optionally substituted aliphatic or aromatic group:

[0057] The monosulfonate was then treated with a strong base and a hydride source to form 1-O-substituted ascaridose.

[0058] Implementation Method 30: The method according to Implementation Method 29, wherein the strong base is added before the hydride source is added.

[0059] Implementation Method 31: The method according to Implementation Method 29 or 30, wherein the strong base is selected from at least one of alkali metal hydrides, alkaline earth metal hydrides, alkali metal oxides, alkali metal alkoxides and alkali metal amides.

[0060] Implementation Method 32: The method according to any one of Implementation Methods 29-31, wherein the strong base contains sodium ions or potassium ions.

[0061] Implementation method 33: The method according to any one of implementation methods 29-32, wherein the hydride source is a metal hydride.

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

[0063] Implementation Method 35: The method according to Implementation Method 34, wherein the first metal hydride includes aluminum hydride or boron hydride reducing agent, and the second metal hydride is an alkali metal hydride or an alkaline earth metal hydride.

[0064] Implementation method 36: The method according to implementation method 34 or 35, wherein the first metal hydride is LiAlH4.

[0065] Implementation method 37: The method according to implementation method 34 or 35, wherein the first metal hydride is LiBH4.

[0066] Implementation method 38: The method according to any one of implementation methods 34-37, wherein the second metal hydride is sodium hydride.

[0067] Implementation Method 39: The method according to any one of Implementation Methods 29-38, wherein in Formula IV, Z is an optional substitute for C. 2-24 Aliphatic groups.

[0068] Implementation method 40: The method according to any one of implementation methods 29-39, wherein in formula IV, Z is CH3.

[0069] Implementation Method 41: The method according to any one of Implementation Methods 29-39, wherein in Formula IV, z is a group represented by the following formula:

[0070] Among them, R 4 Choose from the following groups: C that can be optionally substituted 1-40 Aliphatic groups; optionally substituted C 1-40 The carboxylic acid chain, wherein C 1-40The carboxylic acid chain may optionally be unsaturated at one or more positions; and the C may optionally be substituted. 1-40 esters or orthoesters of the carboxylic acid chain, wherein C 1-40 The ester or orthoester derivative of the carboxylic acid chain may optionally be unsaturated at one or more positions.

[0071] Implementation Method 42: The method according to any one of Implementation Methods 29-39, wherein, in Formula IV, Z is Where x is an integer from 1 to 30.

[0072] Implementation Method 43: The method described in Implementation Method 42, wherein, in Formula IV, Z is

[0073] Implementation Method 44: The method according to any one of Implementation Methods 29-43, wherein treating the monosulfonate with the hydride source to form the 1-O-substituted ascaridose can simultaneously reduce one or more functional groups on Z.

[0074] Implementation method 45: The method according to any one of implementation methods 9-44, the method further comprising separating the 1-O-substituted ascarid sugar.

[0075] Implementation Method 46: The method according to Implementation Method 45, wherein, based on the raw material, the 1-O-substituted ascaridose is isolated in a yield of at least 40%.

[0076] Implementation method 47: The method according to any one of implementation methods 29-46, wherein the method uses at least 1 kg of the raw material.

[0077] Implementation Method 48: The method according to any one of Implementation Methods 29-47, characterized in that the yield of the 1-O-substituted ascaridose 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%.

[0078] Implementation Method 49: The method according to any one of Implementation Methods 29-48, characterized in that the method produces less than 40% of ring contracted rearrangement products, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% of ring contracted rearrangement products.

[0079] Implementation Method 50: The method according to any one of Implementation Methods 29-49 further comprises: acylating the 2-OH and 4-OH in the 1-O-substituted ascaridose by adding an acylating agent to a mixed product obtained by treating the raw material with a hydride source and a strong base.

[0080] Embodiment 51: The method according to Embodiment 50, wherein the acylating agent is added to the mixture without a quenching step.

[0081] Embodiment 52: The method according to Embodiment 50, wherein the acylating agent is added to the mixture after the quenching step.

[0082] These and other features, aspects, and advantages of the invention will become apparent from the following detailed description and the accompanying drawings, which are briefly described below. The invention includes any combination of two, three, four, or more of the embodiments described above, as well as any combination of two, three, four, or more features or elements set forth in the invention, regardless of whether such features or elements are explicitly combined in the detailed description of the specific embodiments of the invention. The invention is intended to be read holistically such that any separable features or elements in the invention, in all its aspects and embodiments, should be considered as combinable unless clearly stated otherwise in the text. Other aspects and advantages of the invention will become apparent from the following description.

[0083] Terminology Definition

[0084] To facilitate understanding of this invention, specific terms are defined below. Further definitions of these and other terms are set forth throughout the specification.

[0085] In this invention, unless explicitly stated otherwise in the text, the term "a" may be understood as "at least one". As used in this invention, the term "or" may be understood as "and / or". In this invention, the terms "comprising" and "including" may be understood as including individual components or steps, either alone or together with one or more additional components or steps. In this invention, the term "comprising" and variations thereof are not intended to exclude other added ingredients, components, integers, or steps.

[0086] As used herein, the terms “about” and “approximately” are used as equivalents. Unless otherwise stated, the terms “about” and “approximately” are to be understood as allowing standard variations as understood by one of ordinary skill in the art. The ranges provided herein include endpoints. Any numbers used in this invention, with or without “about” / “approximately”, are intended to cover any normal fluctuations as understood by one of ordinary skill in the relevant art. In some embodiments, the terms “approximately” or “about” refer to a value falling 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 than the stated reference value in any direction (greater or less than), unless otherwise stated or clearly apparent from the context (unless the number exceeds 100% of the possible value).

[0087] The definitions of specific functional groups and chemical terms will be described in more detail below.

[0088] For the purposes of this invention, chemical elements are identified according to the periodic table (CAS edition, *Handbook of Chemistry and Physics*, 75th edition, inner cover), and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as specific functional parts and reactivity, are referenced in the following literature: *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito, 1999; *March's Advanced Organic Chemistry*, 5th edition, John Wiley & Sons, New York, 2001; *Comprehensive Organic Transformations*, VCH Publishing, New York, 1989; *Some Modern Methods of Organic Synthesis*, 3rd edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of these are incorporated herein by reference.

[0089] Some compounds of the present invention may contain one or more asymmetric centers, and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. Therefore, the compounds and compositions thereof of the present invention may be in the form of a single enantiomer, diastereomer, or geometric isomer, or in the form of a mixture of stereoisomers. In some embodiments, the compounds of the present invention are enantiopure compounds. In some other embodiments, the compounds of the present invention are mixtures of enantiomers or diastereomers.

[0090] Furthermore, unless otherwise stated, some compounds described herein may have one or more double bonds and may exist as Z or E isomers. The invention also includes compounds as individual isomers, substantially free of other isomers, or as mixtures of various isomers, such as racemic mixtures of enantiomers. In addition to the compounds themselves, the invention also includes compositions comprising one or more of the compounds.

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

[0092] In some embodiments where specific enantiomers are preferred, the compound may be substantially free of the opposite enantiomers and may be referred to as "optical enrichment." "Optical enrichment" as used herein means that the compound consists of a significantly larger proportion of one enantiomer. In some embodiments, the compound consists of at least about 90% by weight of one enantiomer. In some embodiments, the compound consists of at least about 95%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, or 99.9% by weight of one enantiomer. In some embodiments, the enantiomeric excess of the provided compounds is at least about 90%, 95%, 97%, 98%, 99%, 99.5%, 99.7%, 99.8%, or 99.9%. In some embodiments, the enantiomeric compounds can be separated from the racemic mixture by any method known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), formation and crystallization of chiral salts, or preparation by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience Database, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL., Stereochemistry of Carbon Compounds (McGraw Hill, New York, 1962); Wilen, SH., Tables of Resolving Agents and Optical Resolutions, p. 268 (Ellie Liel, Ed., University of Notre Dame Press, University of Notre Dame, 1972).

[0093] As used in this article, the terms "halo" and "halogen" refer to atoms selected from fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (bromine, -Br), and iodine (iodinated, -I).

[0094] As used herein, the term "aliphatic" or "aliphatic group" refers to a hydrocarbon moiety that can be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spirofused polycyclic rings), and can be fully saturated or contain one or more unsaturated units, but is not an aromatic hydrocarbon. Unless otherwise stated, an aliphatic group contains 1-30 carbon atoms. In some embodiments, the aliphatic group contains 1-12 carbon atoms. In some embodiments, the aliphatic group contains 1-8 carbon atoms. In some embodiments, the aliphatic group contains 1-6 carbon atoms. In some embodiments, the aliphatic group contains 1-5 carbon atoms; in some embodiments, the aliphatic group contains 1-4 carbon atoms; in some other embodiments, the aliphatic group contains 1-3 carbon atoms; and in some other embodiments, the aliphatic group contains 1-2 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight-chain or branched alkyl, alkenyl, and alkynyl groups, as well as their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0095] As used herein, the term "heteroaliphatic group" or "heteroaliphatic group" 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 in this article, the term "unsaturated" refers to a portion having one or more double or triple bonds.

[0097] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group derived by removing a single hydrogen atom from an aliphatic portion containing one to six carbon atoms. Unless otherwise stated, alkyl groups contain 1 to 12 carbon atoms. In some embodiments, alkyl groups contain 1 to 8 carbon atoms. In some 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 some other embodiments, alkyl groups contain 1 to 3 carbon atoms; and in some 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] As used herein, the term "alkenyl" refers to a monovalent group derived by removing a single hydrogen atom from a straight-chain or branched aliphatic portion having at least one carbon-carbon double bond. Unless otherwise stated, alkenyl groups contain 2-12 carbon atoms. In some embodiments, alkenyl groups contain 2-8 carbon atoms. In some embodiments, alkenyl groups contain 2-6 carbon atoms. In some embodiments, alkenyl groups contain 2-5 carbon atoms; in some embodiments, alkenyl groups contain 2-4 carbon atoms; in some other embodiments, alkenyl groups contain 2-3 carbon atoms; and in some other embodiments, alkenyl groups contain 2 carbon atoms. Examples of alkenyl groups include vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc.

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

[0100] As described herein, the compounds of the present invention may comprise an "optionally substituted" group portion. Generally, regardless of whether the term "optionally" is preceding it, the term "substituted" means that one or more hydrogens of the specified portion are substituted by a suitable substituent. Unless otherwise stated, the "optionally substituted" group may have a suitable substituent at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from a particular group. The combinations of substituents contemplated in this invention are preferably those that result in the formation of stable or chemically viable compounds. The term "stable" as used herein refers to a compound that is substantially unchanged under production, detection, and, in some embodiments, substantially unchanged during recovery, purification, and use for one or more purposes of the invention herein.

[0101] In the "optionally substituted" group, the suitable monovalent substituents on the substituted carbon atom are independently halogens; -(CH2) 0-4 R o ;-(CH2) 0-4 OR o -O-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 CH(OR o )2;-(CH2) 0-4 SR o ;-(CH2) 0-4 Ph can be used with R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph can be used with R o Substitution; -CH=CHPh, can be used with R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)NR o 2; -N(R) o )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(Ro )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)N(R o )2;-(CH2) 0-4 C(O)SR o ;-(CH 2)0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR-;SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ;-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0- 4S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)R o ;-N(Ro )S(O)2NR o 2; -N(R) o )S(O)2R o ;-N(OR) o )R o ;-C(NH)NR o 2; -P(O)2R o ;-P(O)R o 2; -OP(O)R o 2; -OP(O)(OR o )2; SiR o 3; -(C 1-4 (linear or branched alkylene) ON(R) o )2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R) o )2, where each R o It can be replaced according to the following definition and is independently hydrogen, C 1-8 Aliphatic, -CH2Ph, -O(CH2) 0- 1Ph, or a 5-6 saturated or partially unsaturated aromatic ring, or an aromatic ring having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur, or, despite the above definitions, two independently occurring R atoms. o They combine with the atoms in between to form 3-12 saturated, partially unsaturated, or monocyclic aryl groups or polycyclic groups with 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, which can be substituted according to the following definition.

[0102] R o (or through two independently occurring R) o Suitable monovalent substituents on the ring formed by the atoms in between are independently halogens, -(CH2). 0-2 R · 、-(haloR · -(CH2) 0-2 OH, -(CH2) 0-2 OR · -(CH2) 0-2 CH(OR · )2、-O(haloR · -CN, -N3, -(CH2) 0-2 C(O)R · -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · -(CH2) 0-4 C(O)N(Ro 2、-(CH2) 0-2 SR · -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR · -(CH2) 0-2 NR · 2, -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · -(C 1-4 (straight-chain or branched alkylene)C(O)OR · or SSR · , where each R · It is unsubstituted, or it is preceded by "halogenated" and is substituted by only one or more halogens, and is independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph is either a 5-6 saturated or partially unsaturated aromatic ring, or an aromatic ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R o Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0103] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include: =O, =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2)) 2-3 O-, or -S(C(R) * 2)) 2-3 S-, where each independently occurring R * Selected from hydrogen, C can be substituted according to the following definition 1-6 The aliphatic group, or an unsubstituted 5-6 member saturated or partially unsaturated group, or an aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on adjacent substituted carbon atoms of the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * Selected from hydrogen, C can be substituted according to the following definition 1-6It is an aliphatic compound, or an unsubstituted 5-6 saturated or partially unsaturated compound, or an aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0104] R * Suitable substituents on aliphatic groups include halogens, R · 、-(haloR · -OH, -OR · -O(haloR) · -CN, -C(O)OH, -C(O)OR · -NH2, -NHR · -NR · 2, or -NO2, where each R · It is unsubstituted, or it is preceded by "halogenated" and is substituted by only one or more halogens, and is independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph is either a 5-6 saturated or partially unsaturated aromatic ring, or an aromatic ring with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0105] Suitable divalent substituents on the substituted nitrogen atom in the "optionally substituted" group include: -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 ; where each R C that is independently selected from hydrogen and can be substituted according to the following definition 1-6 Aliphatic, unsubstituted -OPh, or unsubstituted 5-6 saturated or partially unsaturated, or aromatic rings having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur, or, despite the above definitions, two independently occurring R... They combine with the atoms in between to form unsubstituted 3-12 saturated, partially unsaturated, or monocyclic aryl groups or bicyclic groups with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0106] R Suitable substituents on the aliphatic group are independently selected from halogens, -R· 、-(haloR · -OH, -OR · -O(haloR) · -CN, -C(O)OH, -C(O)OR · -NH2, -NHR · -NR · 2, or -NO2, where each R · It is unsubstituted, or it is preceded by "halogenated" and is substituted by only one or more halogens, and is independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph is either a 5-6 saturated or partially unsaturated aromatic ring, or an aromatic ring with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0107] The term “substantially” as used in this article refers to a qualitative assessment that the feature or performance of interest exhibits all or nearly all of its characteristics. Attached Figure Description

[0108] In the accompanying drawings, the same parts in different views are represented by the same reference numerals. Furthermore, the drawings are not necessarily drawn to scale, but are generally intended to emphasize the principles of the compositions and methods of the invention and are not intended to be limiting. For clarity, not every part is labeled in the drawings. In the following description, various embodiments are described with reference to the following drawings, wherein:

[0109] Figure 1 shows a representative product prepared according to one embodiment of the preparation method of the present invention. 1 H NMR spectrum. Detailed Implementation

[0110] On one hand, the present invention provides a method for preparing 1-O-substituted rhamnose by converting it into 1-O-substituted ascaridose, comprising:

[0111] Provide 1-O-substituted rhamnose as a raw material;

[0112] A monosulfonate ester is formed at the 3-OH position of the raw material; and

[0113] The monosulfonate is treated with a hydride source to form 1-O-substituted ascaridose. In some embodiments of the invention, the monosulfonate is formed on a rhamnose raw material without hydroxyl protecting groups at the 2-OH or 4-OH positions. In some embodiments of the invention, the method includes contacting the raw material with a sulfonating agent (e.g., sulfonyl halide, sulfonic anhydride, or similar reagent) in the presence of a Lewis acid.

[0114] In some embodiments of the invention, the Lewis acid comprises a tin compound. In some embodiments, the Lewis acid comprises an acid having the chemical formula R. 1 R 2 Tin compounds of SnX2. Among them, R... 1 and R 2 Each is independently selected from C 1-40 aliphatic, C 1-40 At least one of heteroaliphatic, optionally substituted aromatic, and optionally substituted heteroaromatic, wherein R 1 and R 2 Optionally, they collectively form an optionally substituted ring; and each X is independently selected from halogen or OR. 3 Or, two X groups can form a carbonyl group together, where each R group... 3 Selected independently from C 1-40 aliphatic, C 1-40 At least one of the acyl group, optionally substituted aromatic group, or when both -OR groups are present. 3 When the group is R 3 The groups together form an optionally substituted ring.

[0115] In some embodiments of the present invention, R 1 R 2 Each independently is C 1-20 aliphatic, C 2-12 aliphatic, C 2-8 aliphatic, C 1-6 aliphatic, or C 1-4 Aliphatic. In some implementations, R 1 and R 2 Same. In some implementations, R 1 R 2 Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, n-octyl, and C 9-24 Straight-chain alkyl groups. In some embodiments, R 1 =R 2 = n-Butyl. In some implementations, R 1 =R 2 = n-octyl.

[0116] In some embodiments, each X is a halogen atom. In some embodiments, each X is Cl. In some embodiments, each X is an alkoxide, and in some embodiments, the alkoxide is C. 1-8A straight-chain alkoxide. In some embodiments, each X is independently selected from at least one of methoxide, ethoxide, n-propoxide, i-propoxide, n-butoxide, and i-butoxide. In some embodiments, each X is an acyl group, and in some embodiments, the acyl group is C. 1-16 Straight-chain or branched-chain acyl groups. In some embodiments, each X is independently selected from at least one of acetate, propionate, butanoate, ethylhexanoate, octanoate, and long-chain fatty acyl groups.

[0117] In some embodiments, the Lewis acid comprises a dialkyltin dihalide. In some embodiments, the Lewis acid comprises R 1 R 2 SnCl2, where R 1 R 2 As defined above, and within the scope of the genera and subgenera described herein. In some embodiments, the Lewis acid includes (R 1 )2SnCl2, i.e. R 1 =R 2 In some embodiments, the Lewis acid comprises (R... 1 )2SnCl2, where R 1 It is an alkyl group. In some embodiments, the Lewis acid includes dibutyltin dichloride.

[0118] In some embodiments, the Lewis acid comprises a boron compound. Suitable boron compounds include, but are not limited to, boron halides (e.g., BF3) and their complexes, alkyl boron compounds, boronates and similar boronic acid derivatives, aminoboranes, boron complexes of amino alcohols, and other nitrogen-boron complexes, as well as any combination of the above.

[0119] In some embodiments, the Lewis acid is used in a catalytic amount (i.e., less than 1 molar equivalent relative to the rhamnose feedstock). In some embodiments, the molar ratio of the Lewis acid to the 1-O-substituted rhamnose is 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 some embodiments, the molar ratio of the Lewis acid to the 1-O-substituted rhamnose is about 1:10 to about 1:200. In some embodiments, the molar ratio of the Lewis acid to the 1-O-substituted rhamnose is about 1:50 to about 1:100, about 1:100 to about 1:400, or about 1:200 to about 1:500. In some embodiments, the molar ratio of the Lewis acid to the 1-O-substituted rhamnose is about 1:100. In some embodiments, the molar ratio of the Lewis acid to the 1-O-substituted rhamnose is about 1:200.

[0120] In some embodiments, sulfonation of the 1-O-substituted rhamnose includes treatment with a base. In some embodiments, the base is an organic base, such as a nitrogen-containing heterocycle or a trialkylamine. In some embodiments, the base is an inorganic base, such as a metal hydroxide, carbonate, or hydride. In some embodiments, the base includes an amine. In some embodiments, the base includes a Hünig's base (diisopropylethylamine). In some embodiments, the base includes triethylamine. In some embodiments, the base includes an alkali metal salt. In some embodiments, the base includes an alkali metal hydroxide or an alkali metal carbonate. In some embodiments, the base includes at least one selected from sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, lithium hydroxide, and lithium carbonate.

[0121] There are no particular limitations on the characteristics of the sulfonates formed at the 3-position. In some embodiments, the sulfonate includes p-toluene sulfonate. In some embodiments, the sulfonate includes methyl sulfonate. In some embodiments, the sulfonate includes trifluoromethyl sulfonate. In addition, the sulfonate may include any of a large number of other sulfonates known in the art that are frequently used to activate alcohols for nucleophilic displacement. Those skilled in the art can select the type of sulfonate used, and the large number of commercially available sulfonating agents allows them to test various sulfonates according to the methods described herein and select those that provide the best results and / or the lowest cost.

[0122] Rhamnose (methyloxane-2,3,4,5-tetrol) is a sugar with the structure shown in Formula I. 1-O-substituted rhamnose refers to rhamnose with a non-H-substituted group at the hydrogen atom position of the hydroxyl group at the 1-position (i.e., the position of the H in "1-OH" in Formula I). ​​Rhamnose (and the corresponding 1-O-substituted rhamnose) can be L-form or D-form. In some embodiments, the method provided by this invention relates to L-form (naturally occurring form) rhamnose (and 1-O-substituted rhamnose).

[0123]

[0124] The 1-O-substituted rhamnose is shown in Formula II below, where Z represents "1-OH substituent".

[0125]

[0126] This invention does not particularly limit the characteristics of the substituent (“Z”) in the 1-OH group of the rhamnose raw material that replaces hydrogen. Preferably, the substituent does not contain any functional group or feature that interferes with the reagents and reaction conditions used in the deoxygenation process of this invention. In some 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 hydroxyl protecting groups described in, in whole or in part, the book *Protecting Groups in Organic Synthesis* (Peter GMWuts, ISBN: 9781118057483), the entire contents of which are incorporated herein by reference. In some embodiments, when the ascaridose is to be further converted into a final product having a 1-O-substitution, it is ideal and effective to use a rhamnose starting material having the same substituent at the 1-OH position as the desired substituent of the target ascaridose (or its enantiomer or isomer), or a convenient synthetic precursor having the desired substituent at the 1-OH position of the rhamnose starting material. In some embodiments, the substituent is a side chain of a naturally occurring ascaridosin. In some embodiments, the substituent has the following structure: Among them, R 4 C can be optionally replaced 1-40 Aliphatic groups. In some embodiments, R 4 C 1-40 The carboxylic acid chain, wherein C 1-40 The carboxylic acid chain may optionally be unsaturated at one or more positions, or R 4 It is an ester or orthoester derivative of the above-mentioned carboxylic acid chain. In some embodiments, R 4 C 1-40 α-olefins. In some embodiments, the substituents have the following structure: Among them, R 4 As defined above, and falling within the genus and subgenus defined therein. In some embodiments, the substituent is C. 1-40 The carboxylic acid chain has the following structure: Where n is an integer from 1 to 40; and R y Selected from -H, metal cations, carboxyl protecting groups, and optionally substituted C groups. 1-20 The substituent comprises at least one of an aliphatic group, an optionally substituted aromatic group, and a biomolecular residue, wherein the biomolecular residue may be, for example, a glycoside, an amino acid, a peptide, a nucleotide, or a derivative thereof. In some embodiments, the substituent is C. 1-40 Esters or orthoesters of carboxylic acid chains, having the following structure: Where n is an integer from 1 to 40; and R10 Selected from C which can be optionally replaced 1-20 At least one of an aliphatic group and optionally a substituted aromatic group. In some embodiments, the substituent is C. 1-40 Esters or orthoesters of carboxylic acid chains, having the following structure: Where n' is an integer from 1 to 38; and R 10 Selected from C which can be optionally replaced 1-20 At least one of an aliphatic group and optionally substituted aromatic groups. In some embodiments, the substituent has the following structure: Where x is an integer from 1 to 30.

[0127] In some other embodiments of the invention, it is desirable to use a rhamnose starting material having a Z-substituent at the 1-OH position that functions as a protecting group, and the Z-substituent can be removed to provide unsubstituted ascaridose, or the 1-OH position can be substituted with another substituent (e.g., with the side chain of ascaridin, or similar natural products containing ascaridose, or derivatives thereof). Suitable protecting groups can be found in *Protecting Groups in Organic Synthesis* (Peter GMWuts, ISBN: 9781118057483). In some embodiments, the 1-OH substituent is a hydroxyl protecting group. In some embodiments, the 1-OH substituent is a methyl group.

[0128] The method of the present invention can begin with a direct reaction of 1-O-substituted rhamnose, or the method can include a first step of converting rhamnose to 1-O-substituted rhamnose. The methods for converting OH to OZ and preparing 1-O-substituted rhamnose depend on the Z substituent and are well known in the art.

[0129] Ascaris sugar can be described by the following formula III.

[0130]

[0131] As described above, in some embodiments, the method of the present invention provides 1-O-substituted ascaridose, as shown in Formula V below. In some embodiments, the method further includes reacting the 1-O-substituted ascaridose (e.g., including but not limited to removing Z as a protecting group (to prepare, for example, ascaridose), and optionally further functionalizing the 1-OH position of the ascaridose to obtain modified ascaridose).

[0132]

[0133] The method of preparing 1-O-substituted ascaridoses by treating rhamnose-derived monosulfonates with a hydride source in this invention is unexpectedly easy and yield-efficient. The feasibility of this step is particularly surprising, given prior art reports that treatment of such mono-tosylates often results in a rearrangement of the sugar into a five-membered ring. For example, Baer et al. reported in the Canadian Journal of Chemistry (1985, Vol. 63, p. 432, DOI: 10.1139 / v85-072) that treatment of 2-p-tosylates of the same matrix resulted in the following rearrangement:

[0134]

[0135] Similarly, Ito et al. reported that sulfonated sugars closely associated with hydride reduction yielded poor yields of the corresponding deoxysaccharides, because the reaction was more inclined towards ring contraction or OS bond cleavage than the reductive removal of the tosyloxy group (Chemical and Pharmaceutical Bulletin, 1991, Vol. 39, No. 8, 1983-1989). Likewise, Binkley (J. Org. Chem.) 50, 5646 (1985) reported that hydrogenation of similar matrices having more than one sulfonate produced a complex mixture of products including a large number of ring-constricting products. In contrast, the inventors of this invention provide a method that unexpectedly yields the desired high yield of the 3-deoxy product without significant rearrangement.

[0136] Therefore, in one aspect, the present invention provides a method for synthesizing 3-deoxyrhamnose and its derivatives, including the high-yield reductive cleavage of 3-sulfonate derivatives of rhamnose. In some embodiments, the method includes: providing a 1-O-substituted 3-sulfonate of rhamnose having the structure shown in Formula IV as a starting material, wherein Z is as defined above and falls within the genus and subgenus range defined therein, and Q is optionally a substituted aliphatic or aromatic group:

[0137]

[0138] The monosulfonate was then treated with a strong base and a hydride source to form 1-O-substituted ascaridose.

[0139] In some embodiments, Q includes an optionally substituted aliphatic group. In some embodiments, Q is selected from methyl, ethyl, C... 3-8 Alkyl, -CF3 and C 3-8At least one of fluoroalkyl groups. In some embodiments, Q is methyl. In some embodiments, Q includes optionally substituted aryl groups. In some embodiments, Q is selected from phenyl, p-toluyl, m-toluyl, o-toluyl, bromophenyl, methoxyphenyl, or nitrophenyl. In some embodiments, Q is p-toluyl.

[0140] In some embodiments, the method provided by the present invention is characterized by a 3-deoxy product yield greater than 50% (based on a starting 1-O-substituted rhamnose 3-sulfonate feedstock) provided by hydride treatment. In some embodiments, the method provided by the present invention is characterized by a 3-deoxy product yield greater than 30%, greater than 40%, 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% provided by hydride treatment. In some embodiments, the method provided by the present invention is characterized by hydride treatment producing less than 40% of the ring-contraction rearrangement product. In some embodiments, the method provided by the present invention is characterized by hydride treatment producing less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% of the ring-contraction rearrangement product.

[0141] In some embodiments, treating the monosulfonate with a hydride source includes contacting the monosulfonate with aluminum hydride. In some embodiments, the hydride source includes LiAlH4. In some embodiments, the hydride source includes diisobutylaluminum hydride. In some embodiments, treating the monosulfonate with a hydride source includes contacting the monosulfonate with boron hydride. In some embodiments, the hydride source includes NaBH4. In some embodiments, the hydride source includes LiBH4. In some embodiments, the hydride source includes alkylboron hydride. In some embodiments, the hydride source includes lithium triethylborohydride.

[0142] In some embodiments, treating the monosulfonate with a hydride source comprises contacting the monosulfonate with the hydride source in the presence of a strong base. In some embodiments, the strong base comprises an alkali metal hydride; in some embodiments, the strong base comprises sodium hydride. In some embodiments, the strong base comprises an alkaline earth metal hydride; in some embodiments, the strong base comprises calcium hydride. In some embodiments, the strong base comprises an alkali metal oxide or an alkali metal alkoxide. In some embodiments, the strong base comprises potassium alkoxide. In some embodiments, the strong base comprises sodium alkoxide. In some embodiments, the strong base comprises potassium tert-butoxide. In some embodiments, the strong base comprises sodium tert-butoxide. In some embodiments, the strong base contains a nitrogen anion. In some embodiments, the strong base containing the nitrogen anion includes alkali metal amides (e.g., sodium diisopropylamide or potassium bis(trimethylsilyl)amide).

[0143] In some embodiments, the strong base contains sodium ions. In some embodiments, the strong base contains potassium ions. In some embodiments, the strong base contains rubidium ions or cesium ions. In some embodiments, the strong base is not a lithium salt. In some embodiments, the strong base is not an aluminum salt.

[0144] In some embodiments, the strong base is added in solid form. In some embodiments, the strong base is dissolved in an organic solvent and added in solution form. In some embodiments, the strong base is added in suspension form.

[0145] In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with an aluminum hydride compound and a strong base. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with aluminum hydride and an alkali metal hydride or an alkaline earth metal hydride. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with lithium aluminum hydride and an alkali metal hydride. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with lithium aluminum hydride and sodium hydride. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with lithium aluminum hydride and an alkaline earth metal hydride. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with lithium aluminum hydride and calcium hydride.

[0146] In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with an aluminum hydride compound and an alkali metal oxide or alkali metal alkoxide. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with lithium aluminum hydride and an alkali metal hydroxide. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with lithium aluminum hydride and sodium alkoxide. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with lithium aluminum hydride and potassium alkoxide. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with lithium aluminum hydride and potassium tert-butoxide. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with lithium aluminum hydride and sodium tert-butoxide.

[0147] In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with a boron hydride compound and a strong base. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with a boron hydride compound and an alkali metal hydride or an alkaline earth metal hydride. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with sodium borohydride (or lithium borohydride) and an alkali metal hydride. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with sodium borohydride (or lithium borohydride) and sodium hydride. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with sodium borohydride (or lithium borohydride) and an alkaline earth metal hydride. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with sodium borohydride (or lithium borohydride) and calcium hydride.

[0148] In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with a boron hydride compound and an alkali metal oxide (or alkali metal alkoxide). In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with sodium borohydride (or lithium borohydride) and an alkali metal alkoxide. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with sodium borohydride (or lithium borohydride) and sodium tert-butoxide. In some embodiments, the method provided by the present invention includes treating the monosulfonate ester with sodium borohydride (or lithium borohydride) and potassium tert-butoxide.

[0149] There is no particular limitation on the amount of strong base used in the hydride reduction step. In some embodiments, the strong base is provided in an approximately equimolar amount relative to the mono-sulfonate ester substrate. In some embodiments, the strong base is provided in an approximately molar excess relative to the mono-sulfonate ester substrate. In some embodiments, the strong base is provided in an approximately equimolar amount relative to the hydride reducing agent. In some embodiments, the strong base is provided in an approximately equimolar amount or a higher proportion relative to the free -OH groups present on the mono-sulfonate ester substrate. In some embodiments, the base is provided in an approximately equimolar amount relative to the free -OH groups present on the substrate.

[0150] On one hand, the present invention provides a method for converting 1-O-methylrhamnose to 1-O-methylascaridose. In some embodiments, the method includes: contacting 1-O-methylrhamnose with a sulfonating agent in the presence of a Lewis acid catalyst to selectively sulfonate the 3-OH group of the 1-O-methylrhamnose, followed by treatment of the monosulfonate with a hydride source to obtain 1-O-methylascaridose in a yield greater than 50%. In some embodiments, the Lewis acid catalyst is a tin compound, for example, a dialkyltin dihalide. In some embodiments, the Lewis acid catalyst is a dialkyltin dichloride, for example, dibutyltin dichloride. In some embodiments, the sulfonating agent includes sulfonyl chloride, for example, p-toluene sulfonyl chloride. In some embodiments, the hydride source includes an aluminum hydride reducing agent, for example, lithium aluminum hydride. In some embodiments, treating the monosulfonate with a hydride reducing agent comprises contacting the monosulfonate with a strong base; the strong base may be, for example, an alkali metal hydride or an alkaline earth metal hydride (e.g., NaH or CaH2), an alkali metal oxide, or an alkali metal alkoxide. In some embodiments, treating the monosulfonate with a hydride reducing agent comprises first adding at least one molar equivalent of a strong base to the monosulfonate matrix, and then treating the matrix with at least one molar equivalent of a hydride reducing agent. In some embodiments, treating the monosulfonate with a hydride reducing agent comprises first adding a strong base to the monosulfonate matrix, the amount of which is equal to or greater than the molar equivalents of free -OH groups present on the matrix, and then treating the resulting mixture with at least one molar equivalent of a hydride reducing agent.

[0151] In some embodiments, the method is characterized by the elimination of the need for chromatographic purification to obtain a substantially pure product. Hereinafter, the term "substantially pure" means a product purity of about 85% or higher, about 88% or higher, about 90% or higher, about 95% or higher, about 98% or higher, about 99% or higher, or about 99.5% or higher. In some embodiments, the 1-O-methylascaridose is purified by replacing the 2-hydroxyl and 4-hydroxyl groups with substituents that make the product hydrophobic. The resulting hydrophobic derivative can be purified, for example, by extraction into a nonpolar organic solvent. Therefore, in some embodiments, the method includes the additional step of treating the product obtained from hydride reduction to attach substituents to the 2-hydroxyl and 4-hydroxyl groups. In some embodiments, such substituents are cleavable, allowing the compound having hydroxyl groups at the 2- and 4-positions to be regenerated if desired (e.g., after purification). The above substitution of 2-hydroxy and 4-hydroxy can also achieve manipulation of 1-O-substituents (e.g., removal and replacement of 1-O-substituents in 1-O-substituted ascaridose products) or manipulation of 1-O-substituents (e.g., through carbon-carbon bond formation reactions or manipulation of the functional groups of substituents). In some embodiments, these additional steps enable the method provided by the present invention to prepare valuable ascarosides glycosides, such as ascr#18 or ascr#7, which may have efficacy in the fields of agriculture or human health (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, the contents of which are incorporated herein by reference).

[0152]

[0153] In some embodiments, the method includes acylation of the 2- and 4-positions of the 1-O-substituted ascaridose product. In some embodiments, the 2- and 4-positions are substituted with the same acyl group. In some embodiments, the 2- and 4-positions may be substituted with different acyl groups. In some embodiments, the acyl group is selected from optionally substituted C... 1-5Acyl groups, acetates, propionates, methyl butyrate, pivalate, ethyl hexanoate, octanoate, trifluoroacetate, and optionally substituted C groups. 5-20 At least one of acyl, benzoate, and substituted benzoate. In some embodiments, the 2- and 4-positions are converted to their benzoate esters. In some embodiments, the 2- and 4-positions are converted to substituted benzoate esters (e.g., chlorobenzoate, nitrobenzoate, methoxybenzoate, p-tert-butylbenzoate, etc.). In some embodiments, the method includes a "one-pot" acylation of the 2- and 4-positions of the 1-O-substituted ascaridose product (e.g., after hydride reduction of the sulfonated matrix, without the need for product inspection and separation). In some embodiments, after the hydride reduction step, an acylation agent (e.g., acyl chloride or acid anhydride) is added to the reaction vessel. The above additions may include a quenching step (e.g., added directly to the reaction mixture), or may be performed after the initial quenching step (e.g., adding a quenching agent such as water to consume excess hydride reducing agent, and / or neutralizing other reactive substances present in the reaction mixture).

[0154] In some embodiments, the method includes substituting the 2-hydroxyl and 4-hydroxyl groups of the 1-O-substituted ascaridose product, wherein the 2- and 4-positions are substituted with substituents other than acyl groups. Suitable substituents include hydroxyl protecting groups as described in Protecting Groups in Organic Synthesis (Peter GMWuts, ISBN: 9781118057483).

[0155] In some embodiments, the 2- and 4-positions are converted to ethers. In some embodiments, the 2- and 4-positions are converted to benzyl ether, allyl ether, or tbutyl ether. In some embodiments, the 2- and 4-positions are converted to silyl ethers (e.g., trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl, and similar substances). In some embodiments, the 2- and 4-positions are converted to acetal or ketal derivatives. In some embodiments, the 2- and 4-positions of the 1-O-substituted ascaridose product can be efficiently converted to 2-,4-monosubstituted or disubstituted ethers, silyl ethers, acetals, or ketals in a "one-pot" manner (e.g., without needing to examine and separate the product from previous reactions). In some embodiments, after the hydride reduction is complete, a suitable reagent (e.g., a haloalkane, silyl chloride, aldehyde, or ketone) is added to the reaction vessel. Depending on the reactivity of the reagent used, the addition may include a quenching step (e.g., added directly to the reaction mixture), or it may be carried out after the initial quenching step (e.g., adding a quencher to consume excess hydride reducing agent, and / or neutralizing other reactive substances present in the reaction mixture before adding the reagent).

[0156] In some embodiments, the method includes substituting the 2-hydroxyl and 4-hydroxyl groups of the 1-O-substituted ascaridone in the product, wherein the method includes separating the prepared 2-4-substituted 1-O-substituted ascaridone using a nonpolar solvent. Separation using a nonpolar solvent allows for substantial product purification because many reagents and byproducts in the method are substantially insoluble in nonpolar solutions and can be separated during the extraction process. In some embodiments, the nonpolar solvent used for the extraction includes hydrocarbon solvents, such as petroleum ether, pentane, hexane, heptane, and similar substances. In some embodiments, the nonpolar solvent used for the extraction includes aromatic solvents, such as benzene, toluene, chlorobenzene, and similar substances. In some embodiments, the nonpolar solvent may include ethers, such as t-butyl dimethyl ether, dioxane, diphenyl ether, and similar substances. In some embodiments, the extraction product contains a product of sufficient purity to allow crystallization from the extraction product. In some embodiments, the method includes concentration, cooling, or adding a non-solvent to the extract to affect the crystallization of the ascarid sugar derivative product.

[0157] In some embodiments, the method provided by the present invention is characterized by the quantity of raw materials used or the quantity of product prepared. Although the synthesis of ascaridone sugars and their derivatives from rhamnosyl raw materials has been reported in the prior art, large-scale production of such preparations has not been reported. Existing processes are generally unsuitable for large-scale production due to the cost of reagents used, the use of difficult reaction conditions (e.g., low temperatures), and / or the need for chromatographic purification of intermediates or final products. In contrast, the preparation method provided by the present invention can be used in multi-kilogram quantities. Therefore, in some embodiments, the method provided by the present invention is characterized by providing raw materials in quantities 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 some embodiments, the method provided by the present invention is characterized by producing the 1-O-substituted ascaridone sugar product in quantities 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.

[0158] Example

[0159] The following examples illustrate certain implementations of the invention, but are not intended to be limiting.

[0160] Example 1: Conversion of L-rhamnose to benzoylated-methyl-ascarylose:

[0161]

[0162] 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 equivalence) was added. The reaction mixture was heated under reflux (oil bath, 90 °C) for 5 days. The reaction mixture was cooled and concentrated under vacuum to approximately 20 mL, and iPr₂EtN (1 mL) was added to quench any residual acid. The reaction mixture was concentrated to dryness and dissolved in MeCN (100 mL). iPr₂EtN (8.4 g, total 70 mmol, 1.3 equivalence) was added, followed by Bu₂SnCl₂ (836 mg, 2.8 mmol, 0.1 equivalence), and finally pTsCl (11.5 g, 60.2 mmol, 1.1 equivalence). The reactants were stirred at room temperature for 2 h, quenched with 100 mL of saturated NaHCO3 aqueous solution, and extracted with EtOAc (100 mL × 3). The organic layers were combined, filtered through a 1.5-inch silica mat, and concentrated. The resulting clear oil was dissolved in 100 mL of THF, and NaH (4.4 g, 110 mmol, 2.0 equivalent) was carefully added in small amounts (about 10 parts) to avoid rapid exothermic reaction or H2 gas release. The resulting yellow suspension was stirred for 15 min, and LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalent) was carefully added in a similar manner (about 10 parts) to avoid rapid gas or heat release. When the suspension became thick foam and stirring was stopped, another 100 mL of THF was added. A reflux condenser was connected to the flask, and the reactants were heated under reflux (oil bath, 90 °C) for 1 h. The reaction was cooled to room temperature, and saturated Na2SO4 aqueous solution was added dropwise until no more bubbles were produced. AcOH was added until the pH of the crude reaction mixture was approximately 7, then filtered through a 1.5-inch silica pad. The resulting product was a mixture of a yellow liquid (target product) and a two-phase clear oil (from NaH), which could be removed by washing with hexane. The target yellow oil was dissolved in pyridine (100 mL), and BzCl (15 mL, 129 mmol, 2.3 equivalences) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 24 h and then heated to room temperature. A saturated aqueous solution of NaHCO3 (200 mL) was added, the mixture was stirred for 2 h, evaporated under vacuum, and extracted with hot hexane. The hexane layer was dried over Na2SO4, filtered, and evaporated to dryness to give benzoyl-methyl-ascaridose (9.1 g, 24.7 mmol, 45% yield) as a clear oil, which was further purified by column chromatography (1:9, EtOAc:Hex). This method utilizes rhamnose to prepare benzoyl-methyl-ascaridose, with a yield of 38%-45%. 1H NMR: CDC13(600mHz): δ8.11(d,J=7.1Hz,2H),8.03(d,J=7.2Hz,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=9.7,6.3Hz,1H),3.48(s,3H),2.42(dt,J=13.4,3. 7, 3.4Hz, 1H), 2.20 (ddd, J=13.5, 11.4, 3.2Hz, 1H), 1.31 (d, J=6.3Hz, 3H).

[0163] Example 2: Modified conversion of L-rhamnose to benzoyl-methyl-ascaridose:

[0164]

[0165] 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 equivalence) was added. The reaction mixture was heated under reflux (oil bath, 90 °C) for 3 days. 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 equivalence) was added, followed by Bu₂SnCl₂ (836 mg, 2.8 mmol, 0.1 equivalence), and finally pTsCl (11.5 g, 60.2 mmol, 1.1 equivalence). The reaction mixture was stirred at room temperature for 2 h, quenched with saturated NaHCO₃ aqueous solution (100 mL), and extracted with EtOAc (100 mL × 3). The organic layers were combined and concentrated. The resulting oil was dissolved in THF (100 mL), and a small amount (approximately 10 parts) of NaH (4.4 g, 110 mmol, 2.0 equivalent) was added to avoid exothermic release or H2 gas release. The resulting yellow suspension was stirred for 15 min, and LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalent) was added in a similar manner (approximately 10 parts) to avoid rapid gas or heat release. When the suspension became a thick foam and stirring was stopped, another 100 mL of THF was added. A reflux condenser was connected to the flask, and the reaction mixture was heated under reflux (oil bath, 90 °C) for 1 h. The reaction was cooled to room temperature, and 30 mL of water was added dropwise to the resulting mixture, followed by neutralization with 1.0 M HCl until the mixture separated into a complete bilayer at a pH of approximately 9. The mixture was extracted with EtOAc (100 mL × 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 equivalence) was added dropwise at room temperature, with stirring for 24 h. A saturated NaHCO3 aqueous solution (200 mL) was added, and the mixture was stirred for 2 h. The mixture was then evaporated under vacuum and extracted with hot hexane. The hexane layer was dried on Na2SO4, filtered, and evaporated to dryness to give benzoyl-methyl-ascaridose (9.1 g, 24.7 mmol, yield 45%) as a clear oil. This oil was further purified by column chromatography (1:9, EtOAc:Hex) using rhamnose to obtain purified benzoyl-methyl-ascaridose in a 21% yield.

[0166] Example 3:

[0167] The method of Example 1 was followed, except that the preparation scale was increased by using 1 kg of starting L-rhamnose and the amount of all other reagents was increased proportionally.

[0168] Example 4:

[0169] The method is the same as in Example 1, except that methane sulfonic anhydride is used instead of benzoyl chloride (BzCl), and calcium hydride is used instead of sodium hydride (NaH).

[0170] Example 5:

[0171] The method is the same as in Example 1, except that methanesulfonic anhydride is used instead of benzoyl chloride, and calcium hydride is used instead of sodium hydride.

[0172] Example 6:

[0173] The method is the same as in Example 1, except that the amount of Bu2SnCl2 used is reduced to 1 mol relative to 1-O-methylrhamnose.

[0174] Example 7:

[0175] The method is the same as in Example 2, except that ferric chloride (Fe in the +3 valence) is used instead of Bu2SnCI2.

[0176] Example 8:

[0177] The method is the same as in Example 2, except that an excess of potassium carbonate is used to replace iPr2EtN.

[0178] Example 9: Deoxygenation of medium-chain 1-O-substituted rhamnose derivatives

[0179]

[0180] Compound 5a was dissolved in MeCN (100 mL), followed by the addition of iPr2EtN (8.4 g, total 70 mmol, 1.3 equivalents), then Bu2SnCl2 (836 mg, 2.8 mmol, 0.1 equivalents), and finally pTsCl (11.5 g, 60.2 mmol, 1.1 equivalents). The reaction mixture was stirred at room temperature for 2 h, quenched with saturated NaHCO3 aqueous solution (100 mL), and extracted with EtOAc (100 mL × 3). The organic layers were combined and concentrated. The resulting oil was dissolved in THF (100 mL), and a small amount (approximately 10 parts) of NaH (4.4 g, 110 mmol, 2.0 equivalents) was added. The resulting yellow suspension was stirred for 15 min, and LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalents) was added in a similar manner as described above. Add 100 mL of THF, connect a reflux condenser to the flask, and heat the reaction mixture under reflux (oil bath, 90 °C) for 1 h. Cool the reaction to room temperature, add 30 mL of water dropwise to the resulting mixture, and then neutralize with 1.0 M HCl until the mixture separates into a complete bilayer. Extract the mixture with EtOAc (100 mL × 3) and concentrate under vacuum. Wash the product with hexane to remove mineral oil. Dissolve the crude product in pyridine (100 mL), and add BzCl (15 mL, 129 mmol, 2.3 equivalence) dropwise at room temperature, stirring for 24 h. Add saturated NaHCO3 aqueous solution (200 mL), stir for 2 h, evaporate under vacuum, and extract with hot hexane. Dry the hexane layer on Na2SO4, filter, and evaporate to dryness to give compound 5b, which is an oil and further purified by column chromatography (1:9, EtOAc:Hex).

[0181] Example 10: Deoxygenation of long-chain 1-O-substituted rhamnose derivatives

[0182]

[0183] Compound 6a was dissolved in MeCN (100 mL), followed by the addition of iPr2EtN (10 g, total 70 mmol, 1.3 equivalents), then Bu2SnCl2 (836 mg, 2.8 mmol, 0.1 equivalents), and finally pTsCl (11.5 g, 60.2 mmol, 1.1 equivalents). The reaction mixture was stirred at room temperature for 2 h, quenched with saturated NaHCO3 aqueous solution (100 mL), and extracted with EtOAc (100 mL × 3). The organic layers were combined and concentrated. The resulting oil was dissolved in THF (100 mL), and a small amount (approximately 10 parts) of NaH (4.4 g, 110 mmol, 2.0 equivalents) was added. The resulting yellow suspension was stirred for 15 min, and LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalents) was added in a similar manner as described above. Add 100 mL of THF, connect a reflux condenser to the flask, and heat the reaction mixture under reflux (oil bath, 90 °C) for 1 h. Cool the reaction to room temperature, add 30 mL of water dropwise to the resulting mixture, and then neutralize with 1.0 M HCl until the mixture separates into a complete bilayer. Extract the mixture with EtOAc (100 mL × 3) and concentrate under vacuum to give compound 6b as an oil.

[0184] Example 11:

[0185] 1-Methyl-L-rhamnose (10.0 g, 55 mmol) was dissolved in MeCN (100 mL), followed by iPr2EtN (8.4 g, total 70 mmol, 1.3 equivalents), then Bu2SnCl2 (84 mg, 0.3 mmol, 0.01 equivalents), and finally pTsCl (11.5 g, 60.2 mmol, 1.1 equivalents). The reaction mixture was stirred at room temperature for 2 h, quenched with saturated NaHCO3 aqueous solution (100 mL), and extracted with EtOAc (100 mL × 3). The organic layers were combined and concentrated. The resulting oil was dissolved in THF (200 mL), and a small amount of NaH (4.4 g, 110 mmol, 2.0 equivalents) was added. The resulting yellow suspension was stirred for 60 min, and LiAlH4 (2.4 g, 63.2 mmol, 1.1 equivalents) was added in a similar manner (approximately 10 times) to avoid rapid release of gas or heat. The reactants were heated under reflux (oil bath, 90 °C) for 1 h. The reaction mixture was cooled to room temperature, and 50 mL of water was added dropwise to the resulting mixture, followed by 50 mL of 4N NaOH. THF was separated under reduced pressure, and 50 mL of toluene was added. Most of the added toluene was removed by heating under reduced pressure, and then another 100 mL of toluene was added. Benzoyl chloride (200 mmol) and tetrabutylammonium chloride (5 mmol, as a phase transfer catalyst) were added to the resulting bilayer mixture. The bilayer mixture was stirred vigorously for 16 h and then allowed to stand. The toluene layer was separated, and the aqueous residue was extracted with additional toluene (3 × 50 mL). The combined toluene was dried over Na₂SO₄, filtered, and evaporated to dryness to give benzoyl-methyl-ascaridose.

[0186] It should be understood that the components, systems, apparatuses, methods, and processes of this invention include variations and adaptations developed using information from the embodiments described herein. Adaptations or modifications to the methods and processes described herein can be made by those skilled in the art.

[0187] It should be understood that the use of a header in this invention is for the convenience of the reader. The presence and / or placement of the header is not intended to limit the scope of the subject matter described herein. Unless otherwise specified, embodiments located in one part of this invention are applicable, individually or in combination, to other embodiments throughout the invention.

[0188] Throughout this specification, when a composition, compound, or product is described as having, including, or containing a specific component, or when a process or method is described as having, including, or containing a specific step, it should be considered that the articles, apparatus, and systems of the present invention are substantially composed of, or comprised of, the said components, and the processes and methods of the present invention are substantially composed of, or comprised of, the said process steps.

[0189] It should be understood that the order of steps or the order in which specific actions are performed is irrelevant, as long as the described method remains operational. Furthermore, two or more steps or operations can be performed simultaneously.

[0190] This invention provides an efficient method for preparing rhamnose and its derivatives using rhamnose. Existing methods rely on multi-step sequence hydroxyl protection and deprotection to achieve selective deoxygenation at the 3-position (e.g., *Organic Letters*, 2017, 19(11), 2837-2840, DOI:10.1021 / acs.orglett.7b01009), while this invention provides a method for efficiently deoxygenating the 3-position of rhamnose without protecting the 2- or 4-position hydroxyl groups. Other researchers have previously reported selective functionalization of the 3-OH group of rhamnose; however, a practical method for deoxygenating this position without protecting the 2- or 4-position has not been previously known. In particular, 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)) describes how such processes may result in rearrangement of the sugar backbone or the production of a mixture of products in which the desired 3-deoxy compounds are at most minor components. Therefore, the method provided by this invention offers significant advantages over prior art.

[0191] All publications and patent applications mentioned in this specification demonstrate the skill of a person skilled in the art to which this invention pertains. All publications and patent applications are incorporated herein by reference to the same extent that each individual publication or patent application is specifically and individually incorporated.

[0192] For clarity, although the invention has been described in some detail by way of illustration and example, it is apparent that certain changes and modifications may be made within the scope of the appended claims.

Claims

1. A method for preparing 1- O -The method of replacing ascarid sugar to prepare 1- O - The substituted ascarid sugar has the structure shown in Formula V, comprising: Provide a 1- having the structure shown in Formula II O - Substituted rhamnose as a starting material, where Z is a non-hydrogen substituent: Formula II Formula V A monosulfonate ester is formed at the 3-OH position of the raw material; and The monosulfonate was treated with a hydride source to form 1- O - substituted ascaridose, wherein the hydride source is LiAlH4, wherein the 1-... O The monosulfonate is formed on the substituted rhamnose; The treatment of the monosulfonate with a hydride source includes: contacting the monosulfonate with a hydride source in the presence of a strong base, wherein the strong base is sodium hydride.

2. The method according to claim 1, wherein, The formation process of the monosulfonate ester includes contacting the raw material with a sulfonyl halide or sulfonic anhydride in the presence of a Lewis acid catalyst.

3. The method according to claim 2, wherein, The Lewis acid catalyst is selected from tin compounds.

4. The method according to claim 3, wherein, The Lewis acid catalyst is selected from dialkyltin compounds.

5. The method according to claim 4, wherein, The Lewis acid catalyst is selected from dialkyltin dihalides.

6. The method according to claim 1, wherein, The raw material is 1- O 1-Methylrhamnose.

7. The method according to claim 1, wherein, In Equation II, Z represents the C that can be optionally substituted. 2-24 Aliphatic groups.

8. The method according to claim 1, wherein, In Formula II, Z is a group having the following structural formula: ， Among them, R 4 Selected from: C can be optionally replaced 1-40 Aliphatic groups; C can be optionally replaced 1-40 The carboxylic acid chain, wherein C 1-40 The carboxylic acid chain may optionally be unsaturated at one or more positions.

9. The method according to claim 1, wherein, In Equation II, Z is , where x is an integer from 1 to 30.

10. The method according to claim 9, wherein, In Equation II, Z is .

11. The method according to claim 1, wherein, Z is ,in: n is an integer from 1 to 40; and R y Selected from -H, metal cations, and carboxyl protecting groups.

12. The method according to claim 1, wherein, Z is ,in: n is an integer from 1 to 40; and R y Selected from C which can be optionally replaced 1-20 Aliphatic groups.

13. The method according to claim 1, wherein, The method further includes separating the 1- O -Replaced ascarid sugar, wherein, based on the raw material, the 1- O - The substituted ascarid sugar was isolated in a yield of at least 40%.

14. The method according to claim 1, wherein, The method uses at least 1 kg of the raw material.

15. The method according to claim 1, wherein, The monosulfonate is selected from: p-toluenesulfonate, methyl sulfonate, or trifluoromethylsulfonate.

16. The method according to claim 1, wherein, The 1- O - The yield of the substituted ascarid sugar is greater than 50%.

17. The method according to claim 16, wherein, The 1- O - The yield of the substituted ascaridose is greater than 60%.

18. The method according to claim 17, wherein, The 1- O - The yield of the substituted ascaridose is greater than 65%.

19. The method according to claim 18, wherein, The 1- O - The yield of the substituted ascaridose is greater than 70%.

20. The method according to claim 19, wherein, The 1- O - The yield of the substituted ascaridose is greater than 75%.

21. The method according to claim 20, wherein, The 1- O - The yield of the substituted ascaridose is greater than 85%.

22. The method according to claim 21, wherein, The 1- O - The yield of the substituted ascaridose is greater than 90%.

23. The method according to claim 1, wherein, The method produces less than 40% of the ring-contraction rearrangement products.

24. The method according to claim 23, wherein, The method produces less than 30% of the ring-contraction rearrangement products.

25. The method according to claim 24, wherein, The method produces less than 25% of the ring shrinkage rearrangement products.

26. The method according to claim 25, wherein, The method produces less than 20% of the ring-contraction rearrangement products.

27. The method according to claim 26, wherein, The method produces less than 15% of the ring shrinkage rearrangement products.

28. The method according to claim 27, wherein, The method produces less than 10% of the ring-shrink rearrangement products.

29. The method according to claim 28, wherein, The method produces less than 5% of the ring shrinkage rearrangement products.

30. The method according to claim 1, wherein, The 1- O - The substitute for ascaridose is ascr#18 or ascr#7.

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