Chiral chlorothionate compounds and use thereof for separating a mixture of enantiomers or antipodes of an alcohol and / or for deoxygenating a mixture of enantiomers or antipodes of an alcohol

Abstract

The present invention relates to chiral chlorothionate compounds, derived from chiral binols, which are of great use in the total synthesis of molecules of interest, to the method of preparation thereof, to the use thereof for the separation of a racemic or enantioenriched mixture of enantiomers or of antipodes of an alcohol, to a method for separating a racemic or enantioenriched mixture of enantiomers or of antipodes of an alcohol using such chiral chlorothionate compounds, to the use of chiral chlorothionate compounds for deoxygenating a racemic or enantioenriched mixture of enantiomers or of antipodes of an alcohol into an enantiopure corresponding alkane, in particular via the Barton-McCombie reaction, and to a method for deoxygenating an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or of antipodes, to form alkanes in the form of enantiopure compounds.

Description

chiral chlorothionate compounds and their use in separating a mixture of enantiomers or antipodes of an alcohol and / or in deoxygenating a mixture of enantiomers or antipodes of an alcohol

[0001] The present invention relates to chiral chlorothionate compounds, derived from chiral binols, which are of great utility in the total synthesis of molecules of interest; their preparation process; their use for the separation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol; a process for separating a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol using such chiral chlorothionate compounds; the use of chiral chlorothionate compounds for the deoxygenation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol into corresponding enantiopure alkanes, in particular via the Barton-McCombie reaction; and a process for deoxygenating an alcohol in the form of a racemic or enantioenriched mixture. of enantiomers or antipodes, to form alkanes in the form of enantiopure compounds.

[0002] The multi-step synthesis of chiral molecules of interest very often requires obtaining strictly enantiopure molecules, and in particular the use of enantiopure alcohols.

[0003] To obtain enantiopure alcohols, it is known to use liquid chromatography with a chiral stationary phase. Another solution is to esterify an alcohol in the form of a racemic mixture with a chiral carboxylic acid, such as (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid), to form a diastereomeric mixture of activated esters which are then separated by conventional silica gel liquid chromatography or reversed-phase liquid chromatography.

[0004] Other chiral carboxylic acids were described in Harada, Molecules, 2016, 21, 1328, 1-37 and are listed below with the acid MαNP: .

[0005] In general, separating enantiomers or diastereomers composed of carbon, hydrogen, and oxygen atoms by chromatography is quite difficult, especially when they include aliphatic chains. Furthermore, as reported by Harada, depending on the racemic alcohol used, chromatographic separation of diastereomers is not always efficient. Therefore, there is a need for new chiral compounds capable of separating racemic mixtures of alcohols.

[0006] Furthermore, when it is necessary to synthesize an enantiopure alkane from a racemic alcohol in a multi-step synthesis, the aforementioned separation of diastereomers must be followed by a deprotection step to form the enantiopure alcohol, which is then reduced to the enantiopure alkane, as shown by Harada in the synthesis scheme below: .

[0007] This can involve a large number of steps, especially when the alcohol includes one or more groups sensitive to the conditions of alcohol reduction to alkane, thus making it necessary to protect such groups beforehand.

[0008] There is therefore a need for new chiral compounds that allow both the splitting of enantiomers and the transformation of an alcohol into an alkane to form enantiopure alkanes from a racemic mixture of alcohols.

[0009] The invention has as its first object a chiral chlorothionate compound, derived from a chiral binol, characterized in that it corresponds to the following formula (I) or (I'): ,in which:* R 1 is an alkyl group or an aryl group,* R 2 is a hydrogen atom, a halogen atom, an alkyl group, an aryl group, or a carbonyl group -C(=O)-R 3 , in which R 3 is a heteroalkyl, alkyl, or aryl group.

[0010] Thanks to this chiral chlorothionate compound, it is possible to carry out multi-step syntheses involving both racemic or enantioenriched alcohols that we wish to separate and a deoxygenation reaction to obtain the corresponding enantiopure alkanes.

[0011] A binol is also called 1,1'-bi-2-naphthol. It is a derivative of a naphthalene dimer exhibiting axial chirality of the atropoisomeric type, that is to say that rotation around the single naphthyl-naphthyl bond is blocked due to the steric hindrance of the hydroxyl groups in the ortho position relative to this bond.

[0012] Chlorothionate compounds (I) and (I') are chiral compounds, and more specifically atropoisomers. Compound (I) is a derivative of (R)-binol and compound (I') is a derivative of (S)-binol.

[0013] The compound chlorothionate (I) or (I') is a binaphtyl chiral skeleton that can be substituted by an R group 2 in the ortho position of naphthols. It has proven particularly useful, firstly, for forming activated thiocarbonate-type compounds that are easily separable and also readily reducible to alkanes. This allows, in a total synthesis of molecules of interest, the transformation of alcohols into a racemic mixture or an enantiomerically enriched enantiopure alkanes.

[0014] The present invention provides a practical and simple solution for separating enantiomers during a multi-step sequence including a Barton-McCombie reaction on a racemic or enantioenriched intermediate having an alcohol function (for example, splitting of enantiomers in the case of a Barton-McCombie reaction).

[0015] General definitions

[0016] According to the invention, the term "alkyl" refers to saturated, linear or branched, hydrocarbon aliphatic groups comprising, unless otherwise specified, from 1 to 20 carbon atoms, and preferably from 1 to 10 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl groups.

[0017] According to the invention, the term "heteroalkyl" refers to saturated, linear or branched, hydrocarbon aliphatic groups comprising, unless otherwise specified, from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms; and comprising at least one heteroatom such as an oxygen atom or a nitrogen atom. Examples include alkoxy groups or amine groups.

[0018] According to the invention, the term "cycloalkyl" refers to saturated cyclic or polycyclic aliphatic hydrocarbon groups comprising, unless otherwise specified, from 3 to 30 carbon atoms, and preferably from 5 to 20 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0019] According to the invention, the term "heterocycloalkyl" refers to saturated cyclic or polycyclic aliphatic hydrocarbon groups comprising, unless otherwise specified, from 3 to 30 carbon atoms, preferably from 5 to 20 carbon atoms; and comprising at least one heteroatom such as an oxygen or nitrogen atom. Examples include tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, etc.

[0020] According to the invention, the term "aryl" refers to cyclic or polycyclic aromatic groups comprising, unless otherwise specified, from 5 to 20 carbon atoms. Examples of aryl groups include phenyl and naphthyl groups.

[0021] According to the invention, the term "heteroaryl" refers to cyclic or polycyclic aromatic groups comprising, unless otherwise stated, from 5 to 20 atoms, and comprising at least one heteroatom such as an oxygen atom, a sulfur atom, or a nitrogen atom. Examples include the pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, and 1,2,3-triazinyl imidazolyl, thiazolyl, oxazolyl, furanyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, benzothazolyl, quinolineinyl, and isoquinolineinyl groups.

[0022] The groups "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl" can be substituted by one or more substituents. Examples of these substituents include: amino, hydroxy, thiol, oxo, halogen, alkyl, alkoxy, alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl, carboxy, and carboxyalkyl.

[0023] Definition of R 1

[0024] The alkyl group can be a linear or branched alkyl group.

[0025] The alkyl group as group R 1 is preferably an alkyl group comprising from 1 to 10 carbon atoms, particularly preferably from 1 to 5 carbon atoms, and most particularly preferably is a methyl group.

[0026] The aryl group as an R group 1 can be a cyclic or polycyclic aromatic group.

[0027] The aryl group as an R group1 is preferably an aryl group comprising 5 to 12 carbon atoms, particularly preferably 5 to 10 carbon atoms, more particularly preferred is a phenyl, naphthyl or anthracenyl group, and even more particularly preferred is a phenyl group.

[0028] aryl group substituted

[0029] The aryl group can be substituted by at least one substituent chosen from an alkyl group or a halogen atom.

[0030] A phenyl group substituted in ortho or meta position(s) is preferred.

[0031] The alkyl group as a substituent of the aryl group can be a linear or branched alkyl group.

[0032] The alkyl group as a substituent of the aryl group can comprise from 1 to 5 carbon atoms, and more particularly preferred is a methyl or isopropyl group.

[0033] The halogen atom as a substituent of the aryl group can preferentially be a fluorine atom.

[0034] According to a preferred embodiment of the invention, the aryl group as group R 1 is a phenyl group or a phenyl group substituted in ortho or meta position(s) by a substituent as defined above.

[0035] In a particularly preferred embodiment, the R group 1 is an alkyl group.

[0036] Definition of R 2

[0037] The halogen atom is preferably a fluorine, iodine, bromine or chlorine atom, and particularly preferably a fluorine atom.

[0038] The alkyl group can be a linear or branched alkyl group.

[0039] The alkyl group as group R 2is preferably an alkyl group comprising from 1 to 10 carbon atoms, particularly preferably from 1 to 5 carbon atoms, and most particularly preferably is a methyl, ethyl, or isopropyl group.

[0040] The aryl group as an R group 2 is preferably an aryl group comprising from 5 to 12 carbon atoms, particularly preferably from 5 to 10 carbon atoms, and most particularly preferably is a phenyl group.

[0041] aryl group substituted

[0042] The aryl group can be substituted by at least one substituent chosen from an alkyl group or a halogen atom, and preferably by a halogen atom.

[0043] A phenyl group substituted in ortho or meta position(s) is preferred.

[0044] The alkyl group as a substituent of the aryl group can be a linear or branched alkyl group.

[0045] The alkyl group as a substituent of the aryl group can comprise from 1 to 5 carbon atoms, and more particularly preferred is a methyl or isopropyl group.

[0046] The halogen atom as a substituent of the aryl group can be an iodine, chlorine, fluorine, or bromine atom, and preferably a fluorine atom.

[0047] According to a preferred embodiment of the invention, the aryl group as group R 2 is a phenyl group or a phenyl group substituted in ortho or meta position(s) by a substituent as defined above.

[0048] In the carbonyl group -C(=O)-R 3 as group R 2 , the R group 3 is a group heteroalkyl, alkyl or aryl.

[0049] The alkyl group can be a linear or branched alkyl group.

[0050] The alkyl group as group R 3is preferably an alkyl group comprising from 1 to 10 carbon atoms, particularly preferably from 1 to 5 carbon atoms, and most particularly preferably is a methyl group.

[0051] The heteroalkyl group can be a linear or branched heteroalkyl group.

[0052] The heteroalkyl group as the R group 3 is preferably a heteroalkyl group comprising from 1 to 10 carbon atoms and at least one heteroatom selected from one oxygen atom and one nitrogen atom, particularly preferably comprising from 1 to 5 carbon atoms and at least one heteroatom selected from one oxygen atom and one nitrogen atom, and particularly preferably is a methoxy group.

[0053] The aryl group as an R group 3is preferably an aryl group comprising 5 to 12 carbon atoms, particularly preferably 5 to 10 carbon atoms, more particularly preferably is a phenyl group.

[0054] aryl group substituted

[0055] The aryl group can be substituted by at least one substituent chosen from an alkyl group or a halogen atom.

[0056] A phenyl group substituted in ortho or meta position(s) is preferred.

[0057] The alkyl group as a substituent of the aryl group can be a linear or branched alkyl group.

[0058] The alkyl group as a substituent of the aryl group can comprise from 1 to 5 carbon atoms, and more particularly preferred is a methyl or isopropyl group.

[0059] The halogen atom as a substituent of the aryl group can preferentially be a fluorine atom.

[0060] According to a preferred embodiment of the invention, the aryl group as group R 3 is a phenyl group or a phenyl group substituted in ortho or meta position(s) by a substituent as defined above.

[0061] In a particularly preferred embodiment, the R group 3 is a heteroalkyl group.

[0062] In a particularly preferred embodiment, the R group 2 is a hydrogen atom or an alkyl group.

[0063] According to a more particularly preferred embodiment of the invention, the chiral chlorothionate compound (I) (respectively (I')) is such that:* R 1 is an alkyl group, and* R 2 is a hydrogen atom or an alkyl group.

[0064] More specifically, the chiral chlorothionate compound of the invention (I) or (I') is selected from the following compounds: .

[0065] The invention has as its second object a process for preparing a chlorothionate compound (I) or (I') according to the first object of the invention, characterized in that it comprises at least one step i) of reacting a chiral substituted alcohol, derived from a chiral binol, in the presence of thiophosgene and a strong base, said chiral substituted alcohol corresponding to the following formula (II) or (II'): , in which R 1 and R 2 are as defined in the first object of the invention.

[0066] The strong base can be chosen from NaH, KH, or LiHMDS.

[0067] Step i) can be carried out in a polar aprotic solvent, preferably chosen from tetrahydrofuran or diethyl ether.

[0068] Step i) is preferably carried out at room temperature (e.g., approximately 18-25°C).

[0069] Step i) is preferably carried out with a slight excess of strong base, e.g. 1.1-1.2 equivalents relative to the chiral substituted alcohol.

[0070] Step i) is preferably carried out with an excess of thiophosgene, e.g. 2-4 equivalents relative to the chiral substituted alcohol.

[0071] The chiral substituted alcohol corresponding to formula (II) or (II') can be obtained beforehand via one or more steps which will depend on the nature of the R groups 1 and R 2 choose. In particular, when R 2 is a hydrogen atom, the process may further include a step i0) in which one of the hydroxyl groups of (R)-binol or (S)-binol is protected by an R group 1 as defined in the invention. When R 2is different from a hydrogen atom, the process may further comprise a step i01) in which the ortho positions of the (R)-binol or (S)-binol are substituted by an R group 2 as defined in the invention, then one of the hydroxyl functions of the (R)-binol or the (S)-binol substituted at ortho positions is protected by an R group 1 as defined in the invention according to step i02).

[0072] Step i0) or i02) can be carried out in the presence of an alkyl halide R 1 -X, in which R 1 is an alkyl group as defined in the invention, and X is a halogen atom such as an iodine atom; and a base such as K2CO3, preferably by heating to a temperature of 40 to 100°C (e.g., about 60°C).

[0073] When R 1is a phenyl group, step i0) or i02) can be carried out by using a hypervalent iodine-based reagent after mono-deprotonation of the phenol with a strong base, followed by a coupling reaction mediated by iodonium-type reagents.

[0074] Step i01) can be carried out in several steps, including the protection of the hydroxyl functions of (R)-binol or (S)-binol and then the substitution of the ortho positions by an R group 2 as defined in the invention but different from a hydrogen atom, then the deprotection of the hydroxyl functions.

[0075] The protecting group of the hydroxyl functions of (R)-binol or (S)-binol can be an alkoxyalkyl ether such as methoxymethyl ether.

[0076] The protection of the hydroxyl functions by the alkoxyalkyl ether is obtained by the reaction of the phenolate in the presence of a halogenodialkyl ether, preferably a chlorodialkyl ether such as chloromethyl ether.

[0077] Substituting ortho positions with a group R 2 can be carried out in the presence of an alkyl halide R 2 -X, in which R 2 is an alkyl group as defined in the invention, and X is a halogen atom such as an iodine atom; and a strong base such as BuLi.

[0078] The installation of a carbonyl group as an R group 2 perhaps carried out in the same way, namely by the formation of an organolithium from the bis-protected phenol, preferably in the form of methoxymethyl ether, followed by its trapping by a bis-alkyl carbonate or by a chloroalkyl carbonate (in order to form the esters), or by its trapping by an aliphatic or aromatic aldehyde followed by oxidation of the transient alcohol to access the corresponding ketones.

[0079] The invention has as its third object the use of a chiral chlorothionate compound (I) or (I') according to the first object of the invention, for the separation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol.

[0080] The chiral chlorothionate compound (I) or (I') according to the first object of the invention is particularly useful for separating a racemic mixture of an alcohol. The chiral chlorothionate compound (I) or (I') according to the first object of the invention thus makes it possible to separate two enantiomers or two antipodes of a racemic or enantioenriched mixture of an alcohol, or in other words, to perform a resolution.

[0081] In the invention, the term "racemic or enantiomerically enriched mixture of an alcohol" means a compound having an alcohol group in the form of two enantiomers, the relative proportion of each enantiomer being variable, for example, 50% by mole of one enantiomer and 50% by mole of the other enantiomer for a racemic mixture, and x% by mole of one enantiomer and y% by mole of the other enantiomer, with 0% < x < 100% and 0% < y < 100%. The alcohol in the form of two enantiomers comprises at least one asymmetric carbon atom (denoted -C*). The alcohol may comprise other asymmetric carbons so as to form a racemic or enantiomerically enriched mixture of two antipodes. The asymmetric carbon atom is not necessarily bonded to the alcohol group.

[0082] An asymmetric carbon or center is also referred to in the invention as a chiral or stereogenic carbon or center.

[0083] Alcohol can be primary, secondary, or tertiary, and is preferentially secondary. Alcohol is preferentially aliphatic.

[0084] The alcohol may be an alcohol of formula (III) as defined below in the fourth object of the invention.

[0085] The R group 2 on the compound of formula (I) or (I') allows to modulate the separation coefficient of the diastereomers formed by coupling and to optimize the separation of the racemic mixture of said alcohol.

[0086] The invention has as its fourth object a method for separating a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol, characterized in that it comprises at least the following steps: a) coupling an alcohol, in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, with a chiral chlorothionate compound (I) or (I') according to the first object of the invention, to form two corresponding thiocarbonate diastereomers, and b) separating the two corresponding thiocarbonate diastereomers.

[0087] Coupling a) can be carried out under buffered or thermodynamic conditions, in the presence of a weak basis, or under kinetic conditions, in the presence of a strong basis.

[0088] The thermodynamic conditions are particularly suitable in the case of an alcohol that is not too crowded.

[0089] The kinetic conditions are particularly suitable in the case of a crammed alcohol.

[0090] The base is generally used in excess (e.g., 5 equivalents compared to the alcohol).

[0091] The weak base can be chosen from pyridine, 2,6-di-tert-butylpyridine, and 2,6-dimethylpyridine.

[0092] Under thermodynamic conditions, step a) is preferably carried out in an aprotic, polar or nonpolar solvent, such as dichloromethane, dimethylformamide, or acetonitrile.

[0093] The strong base can be LiHMDS or KHMDS.

[0094] Under kinetic conditions, step a) is preferably carried out in a polar aprotic solvent such as tetrahydrofuran or diethyl ether.

[0095] Step a) preferably employs an excess of chiral chlorothionate compound (I) or (I') relative to the alcohol, and particularly preferably of 1.5 to 3.5 equivalents relative to the alcohol (e.g., 2 equivalents).

[0096] The two thiocarbonates obtained at the end of step a) are easily separable according to step b).

[0097] Step b) is carried out using conventional methods, in particular by liquid chromatography, possibly under high pressure, and preferably by silica gel chromatography.

[0098] Alcohol can be primary, secondary, or tertiary, and is preferentially secondary. Alcohol is preferentially aliphatic.

[0099] Alcohol can notably be denoted R*-OH, with the asterisk representing at least one stereogenic or chiral center within the alcohol R*-OH.

[0100] The thiocarbonates obtained at the end of step b) are new in themselves and can in this case correspond to the following formula (IV) or (IV'): , in which R 1 and R 2 are as defined in the first object of the invention and the R group is a remnant of a primary, secondary or tertiary alcohol chosen from molecules of interest, such as, for example, molecules with therapeutic aims, the asterisk designating at least one stereogenic center within the R group.

[0101] When the chiral chlorothionate (I) according to the first object of the invention is used in the process according to the fourth object of the invention, a thiocarbonate compound of formula (IV) is obtained at the end of step a) in the form of a mixture of two diastereomers. When the chiral chlorothionate (I') according to the first object of the invention is used in the process according to the fourth object of the invention, a thiocarbonate compound of formula (IV') is obtained at the end of step a) in the form of a mixture of two diastereomers. Then, at the end of step b), the diastereomers are separated.

[0102] These thiocarbonates of formula (IV) or (IV') have the advantage of being easily deoxygenated, in particular via the Barton-McCombie reaction.

[0103] The process preferably uses in step a) an alcohol corresponding to the following formula (III): , in which: - compound (III) is in the form of a racemic or enantiomerically enriched mixture of enantiomers or antipodes, - R 4 is chosen from an alkyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, or a polycyclic aryl group, or together form a cycloalkylene group or a heterocycloalkylene group, and- R 5 and R 6, identical or different, are chosen, independently of each other, from a hydrogen atom, an alkyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, or a polycyclic aryl group, - said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylene, heterocycloalkylene, polycyclic aryl group, being able to be substituted by one or more substituents chosen from an alkyl group, a cyano group (CN), a carboxylic acid group (COOH), an alkyl ester group, a phosphonic acid group (PO(OH)2), an alkyl ester group of phosphonic acid, a sulfonic acid group (SO3H), an alkyl ester group of sulfonic acid, a dialkyl or monoalkyl amide group.

[0104] The alcohol is preferentially a primary or secondary alcohol (i.e., at least one of the R groups). 5 or R 6 is a hydrogen atom), and preferably still a secondary alcohol (R 5is a hydrogen atom and R 6 is different from a hydrogen atom or vice versa).

[0105] In one particular embodiment, the alcohol is chosen from menthol and any other primary or secondary complex alcohol present in the form of two antipodes.

[0106] According to this embodiment using alcohol (III), the thiocarbonate obtained at the end of step b) corresponds to any one of the following formulas (IVa), (IVb), (IVa'), (IVb'): ,in which R 1 , R 2 , R 4 , R 5 , and R 6 are as defined in the invention, and the asterisk denotes at least one stereogenic center within the -CR group 4 R 5 R 6 .

[0107] Thiocarbonates (IVa) and (IVb) [respectively thiocarbonates (IVa') and (IVb')] are distinguished from each other by the inverted configuration of one or all of the stereogenic centers within the -CR group 4 R 5 R 6 . In other words, for a thiocarbonate (IVa) [respectively a thiocarbonate (IVa')] having a stereogenic center of configuration (S) within the -CR 4 R 5 R 6 , the thiocarbonate (IVb) [respectively thiocarbonate (IVb')] then has a stereogenic center of configuration (R) within the -CR group 4 R 5 R 6 ; for a thiocarbonate (IVa) [respectively a thiocarbonate (IVa')] having several stereogenic centers of configurations (1S, 2R, 3S) within the -CR group 4 R 5 R 6 , the thiocarbonate (IVb) [respectively the thiocarbonate (IVb')] then has several stereogenic centers of configurations (1R, 2S, 3R) within the -CR group 4R 5 R 6 .

[0108] When the chiral chlorothionate (I) according to the first object of the invention is used in the process according to the fourth object of the invention, two diastereomers of formulas (IVa) and (IVb) are obtained at the end of step a) and are separated according to step b). When the chiral chlorothionate (I') according to the first object of the invention is used in the process according to the fourth object of the invention, two diastereomers of formulas (IVa') and (IVb') are obtained at the end of step a) and are separated according to step b).

[0109] The two thiocarbonates (IVa) and (IVb) obtained at the end of step a) [respectively the two thiocarbonates (IVa') and (IVb') obtained at the end of step a)] are easily separable according to step b).

[0110] The process may further include a step c) of deprotection of at least one of the diastereomers recovered in step b) to form said alcohol (e.g. said alcohol (III)), in an enantiopure form (i.e. a single enantiomer or a single antipode).

[0111] Deprotection (c) can be achieved by saponification, particularly using an alcohol such as methanol or ethanol as a solvent, and a weak base, for example, one chosen from carbonates and bicarbonates. The use of a stronger base such as sodium methoxide or sodium ethoxide may also be considered.

[0112] When the alcohol carries the stereogenic center (i.e., the carbon of the hydroxyl group is a stereogenic center), step c) can lead to one of the following enantiopure alcohols: ,with R 4 , R 5 , and R 6being as defined in the invention, and the asterisk denotes the stereogenic center.

[0113] The thiocarbonates corresponding to the formulas (IVa), (IVb), (IVa') and (IVb'), obtained at the end of step b) have the advantage of being able to be easily deoxygenated, in particular via the Barton-McCombie reaction, once the separation of the two diastereomers has been carried out while preserving their stereochemistry.

[0114] Thus, the invention has as its fifth object the use of a chiral chlorothionate compound (I) or (I') according to the first object of the invention, for the deoxygenation of an alcohol in the form of a racemic or enantiomerically enriched mixture of enantiomers or antipodes in corresponding enantiopure alkanes, in particular via the Barton-McCombie reaction.

[0115] In particular, alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes is deoxygenated to a corresponding enantiopure alkane, via the formation of a key thiocarbonate intermediate as defined in the invention which is in the form of two diastereomers which are on the one hand easily separable and on the other hand easily reduced after separation.

[0116] Alcohol or alcohol (III) can be a primary, secondary or tertiary alcohol and preferentially a primary or secondary alcohol.

[0117] The alcohol is preferably an alcohol of formula (III) as defined in the invention, and even more preferably in which: - the alcohol (III) is a primary alcohol (i.e., R 5 = R 6 = a hydrogen atom) and at least one asymmetric carbon is carried by the R group 4 ;- Alcohol (III) is a secondary alcohol (i.e. R 5= a hydrogen atom) and at least one asymmetric carbon is attached to R 4 , R 5 or the carbon bearing the hydroxyl group; or - alcohol (III) is a tertiary alcohol (i.e., R 5 and R 6 (each are different from a hydrogen atom), R 5 and R 6 are identical and R 4 includes at least one asymmetric carbon.

[0118] One of the two thiocarbonates of formula (IV) or one of the two thiocarbonates of formula (IV'), and in particular one of the thiocarbonates of formula (IVa), (IVb), (IVa'), or (IVb'), obtained from the chlorothionate compound (I) or (I') according to the first object of the invention, can be deoxygenated while preserving the initial stereochemistry by: - ​​radical reaction on the thiocarbonate function in the presence of a hydride donor such as Bu3SnH and a radical initiator such as AIBN, or - by any alternative method to the Barton-McCombie such as those involving silane hydrides.

[0119] The so-called "Barton-McCombie" reaction is a transformation frequently used in multi-step synthesis, particularly in syntheses aimed at producing complex molecules. To date, only achial reagents have been used in such a reaction. The chlorothionate compounds (I) and (I') of the invention are stable and allow for the efficient deoxygenation of aliphatic alcohols.

[0120] The sixth object of the invention is a process for deoxygenating an alcohol, in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, to form alkanes in the form of enantiopure compounds, characterized in that it comprises at least the following steps: a) coupling an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, with a chiral chlorothionate compound (I) or (I') according to the first object of the invention, to form two corresponding thiocarbonate diastereomers, b) separating the two corresponding thiocarbonate diastereomers, and d) reducing at least one of the two thiocarbonate diastereomers in the presence of a hydride donor.

[0121] The alcohol can be an alcohol of formula (III) as defined in the invention.

[0122] The alcohol is preferably an alcohol of formula (III) in which: - the (III) alcohol is a primary alcohol (i.e., R 5= R 6 = a hydrogen atom) and at least one asymmetric carbon is carried by the R group 4 ;- Alcohol (III) is a secondary alcohol (i.e. R 5 = a hydrogen atom) and at least one asymmetric carbon is attached to R 4 , R 5 or the carbon bearing the hydroxyl group; or - alcohol (III) is a tertiary alcohol (i.e., R 5 and R 6 (each are different from a hydrogen atom), R 5 and R 6 are identical and R 4 includes at least one asymmetric carbon.

[0123] Step d) is preferably a radical reaction on the thiocarbonate function in the presence of a hydride donor such as Bu3SnH and a radical initiator such as AIBN, or any alternative method to the Barton-McCombie such as those involving silane hydrides.

[0124] Chlorothionates (I) or (I') thus have a dual purpose: they allow the separation of racemic alcohols by simple purification on silica gel, but also to deoxygenate these alcohols during the subsequent step of reduction under radical conditions.

[0125] The invention thus makes it possible to anticipate the asymmetric synthesis of molecules of interest more effectively through strategies based on a Barton-McCombie deduplication step. This can be particularly relevant in the field of synthesis of complex bioactive molecules; a field that often employs Barton-McCombie reactions and requires the production of strictly enantiopure molecules.

[0126] The present invention is illustrated by the following embodiments, to which it is not, however, limited. Examples

[0127] All reactions were carried out under an argon atmosphere using dry solvents in anhydrous conditions, and all reagents were purchased from commercial suppliers without further purification. Unless otherwise specified, reactions were performed at room temperature (i.e., 18–25°C, preferably around 21°C). Anhydrous dichloromethane (CH₂Cl₂, DCM) and tetrahydrofuran (THF) were obtained by filtering commercially available, pre-dried, oxygen-free formulations through activated alumina columns. Anhydrous methanol (MeOH) was purchased in the best commercial grade and used without further purification. Ethyl acetate (EtOAc), dichloromethane, diethyl ether (Et₂O), pentane, methanol (MeOH), cyclohexane, and petroleum ether (PET) were commercially available and used without anhydrous treatment.Unless otherwise stated, yields refer to materials that are homogeneous from a chromatographic and spectroscopic point of view (NMR). 1 H) The reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm Merck silica gel plates (reference "60F-254"). An ethanolic solution of phosphomolybdic acid or an aqueous solution of potassium permanganate and sodium hydroxide were used as developing agents. Merck silica gel (reference "60", particle size: 40-63 μm) was used for column chromatography.

[0128] The NMR (nuclear magnetic resonance) spectra were recorded using a reference instrument such as a Bruker DPX-300, Bruker Avance I 300 MHz, or Bruker Avance II 400 MHz, and calibrated using a non-deuterated residual solvent as an internal reference (7.26 ppm and 77.16 ppm for NMR). 1 H and 13C in CDCl3respectively). The following abbreviations have been used to describe the multiplicities: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br = large signal.

[0129] Infrared (IR) spectra were recorded between 4000 and 550 cm -1 on a reference spectrometer “FT-IR Bruker IFS55 (OPUS / IR 3.0.2)”.

[0130] Optical rotation values ​​([α]25D) were recorded on a Jasco P2000 reference digital polarimeter at 25°C using a thermostable optical glass cell (100 mm path length).

[0131] The melting points (pf) were recorded on a "Buchi B-540" digital reference device.

[0132] High-resolution mass spectrometry (HRMS) analyses using electron fogging ionization (ESI) were obtained from the Centre for Structural Study and Analysis of Organic Molecules (CESAMO) of the Institute of Molecular Sciences (ISM, CNRS-UMR 5255, Talence, France).

[0133] Example 1: Preparation of binol chlorothionate according to the invention

[0134] A first binol (I-1) chlorothionate was prepared according to the following synthetic scheme 1: .

[0135] Compound (II-1): Potassium carbonate (1.16 g, 8.38 mmol) was added to a solution of compound 1, which is (R)-BINOL (2 g, 6.98 mmols), in acetone (70 mL) at room temperature. After stirring for 1 h at this temperature, iodomethane (0.435 mL, 6.99 mmols) was added. The resulting mixture was stirred at 60°C for 16 h, then a saturated aqueous solution of NH4Cl (100 mL) was added at room temperature, and the mixture was diluted with EtOAc (140 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 30 mL). The organic phases were combined, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: EtOAc / DCM / PET - 4 / 16 / 80) to obtain the chiral(II-1) substituted alcohol (1.92 g, yield of 92%) in the form of a white solid.

[0136] Rf= 0.22 (EtOAc / DCM / PET – 4 / 16 / 80)

[0137] 1 H NMR(300 MHz, CDCl3) δ 8,08 (d,J= 9, Hz, 1H), 8,01 – 7,86 (m, 3H), 7,50 (d,J= 9,1 Hz, 1H), 7,45 – 7,22 (m, 6H), 7,12 (dd,J= 8,4, 1,3 Hz, 1H), 5,01 (s, 1H), 3,83 (s, 3H).

[0138] 13 C NMR(75 MHz, CDCl3) δ 156,09, 151,35, 134,15, 133,87, 131,12, 129,90, 129,51, 129,24, 128,25 (2C), 127,43, 126,51, 125,02, 124,92, 124,27, 123,34, 117,59, 115,46, 115,11, 113,89, 56,74.

[0139] Compound (I-1): Sodium hydride (131 mg, 3.27 mmol) was added to a solution of chiral substituted alcohol (II-1) (892 mg, 2.97 mmol) in anhydrous THF (30 mL) at room temperature. After stirring for 15 minutes at this temperature, the reaction mixture was added dropwise to a solution of thiophosgene (0.683 mL, 8.91 mmol) in anhydrous THF (30 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour before being concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent with Et2O / PET-2 / 8) to obtain the compound chlorthionate (I-1) (819 mg, 73% yield) as a yellow solid.

[0140] pf = 139-141°C

[0141] Rf = 0.71 (Et2O / DCM / PET - 3:7)

[0142] 1H NMR(300 MHz, CDCl3) δ 8.07 (dd,J= 9.0, 1.7 Hz, 2H), 7.96 (dd,J= 28.0, 8.1 Hz, 2H), 7.59 – 7.46 (m, 3H), 7.42 – 7.32 (m, 3H), 7.26 (ddd,J= 8.2, 6.7, 1.4 Hz, 1H), 7.15 (d,J= 8.6 Hz, 1H), 3.84 (s, 3H).

[0143] 13 C NMR(76 MHz, CDCl3) δ 184.65, 155.10, 150.69, 133.84, 133.52, 132.38, 130.78, 129.60, 129.03, 128.38, 128.09, 127.05, 126.78, 126.70, 126.45, 125.54, 125.40, 123.80, 120.60, 116.03, 113.34, 56.53.

[0144] HRMS (ESI)exact masses calculated for C 22 H 15 O2ClKS + :m / z417,01129 ([M + K] + ), found :m / z417,01177 ([M + K] + ).

[0145] IR(film)vmax : 3059, 3005, 2936, 2839, 1622, 1592, 1509, 1462, 1268, 1245, 1205, 1185, 1148, 1085, 1031, 1014, 810, 750 cm -1 .

[0146] Example 2: preparation of a binol chlorothionate according to the invention

[0147] A second binol (I-2) chlorothionate was prepared according to the following synthetic scheme 2: .

[0148] Compound 2: To a solution of compound 1, (R)-BINOL (3 g, 10.48 mmols) in anhydrous THF (105 mL), sodium hydride (628.7 mg, 26.20 mmols) was added at 0°C. After stirring for 15 minutes at room temperature, chloromethoxymethane (2.0 mL, 26.20 mmols) was added at 0°C. The resulting mixture was stirred at room temperature for 1 h, then a saturated aqueous solution of NH4Cl (75 mL) was added, and the mixture was diluted with EtOAc (200 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 30 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: EtOAc / DCM / PET - 4 / 16 / 80) to obtain compound 2 (3.73 g, yield of 95%) in the form of a white solid.

[0149] Rf= 0.48 (EtOAc / CH2Cl2 / PET - 6 / 24 / 70)

[0150] 1 H NMR(300 MHz, CDCl3) δ 8,04 – 7,97 (m, 1H), 7,92 (dt,J= 8,4, 1,1 Hz, 1H), 7,64 (d,J= 9,0 Hz, 1H), 7,40 (ddd,J= 8,2, 6,4, 1,7 Hz, 1H), 7,31 – 7,21 (m, 2H), 3,20 (s, 3H).

[0151] 13 C NMR(76 MHz, CDCl3) δ 152,76 (2C), 134,13 (2C), 129,99 (2C), 129,50 (2C), 127,98 (2C), 126,40 (2C), 125,66 (2C), 124,17 (2C), 121,40 (2C), 117,38 (2C), 95,29 (2C), 55,91 (2C).

[0152] Compound 3: To a solution of compound 2 (749 mg, 2.00 mmol) in anhydrous THF (50 mL), n-butyllithium (5.2 mL, 1.17 M in hexanes) was added at 0°C for 5 minutes. After stirring for 2 h at room temperature, iodomethane (0.374 mL, 6 mmol) was added at 0°C. The resulting mixture was stirred at this temperature for 15 minutes, then a solution of NH4Cl and water (volume ratio: 1 / 1, 30 mL) was added, and the mixture was diluted with Et2O (100 mL). The organic phase was separated, and the aqueous phase was extracted with Et2O (2 × 15 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: Et2O / PET - 3 / 97) to obtain compound 3 (780 mg, yield of 97%) in the form of a white solid.

[0153] Rf = 0.40 (Et2O / PET - 1 / 9)

[0154] 1H NMR(300 MHz, CDCl3) δ 7.96 – 7.83 (m, 4H), 7.43 (ddd,J= 8.1, 6.4, 1.6 Hz, 2H), 7.36 – 7.23 (m, 4H), 4.73 (d,J= 5.8 Hz, 2H), 4.62 (d,J= 5.8 Hz, 2H), 2.95 (s, 6H), 2.70 (d,J= 1.0 Hz, 6H).

[0155] 13 C NMR(75 MHz, CDCl3) δ 153.24 (2C), 133.01 (2C), 131.59 (2C), 130.92 (2C), 129.75 (2C), 127.10 (2C), 126.12 (2C), 125.54 (2C), 125.35 (2C), 124.85 (2C), 98.63 (2C), 56.38 (2C), 17.85 (2C).

[0156] Compound 4: Concentrated hydrochloric acid (HCl) (4.12 mL, 135.7 mmol) was added dropwise at room temperature to a solution of compound 3 (780 mg, 1.938 mmol) in MeOH (40 mL). The resulting mixture was stirred at this temperature for 2 hours before being concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: EtOAc / Cyclohexane - 5 / 95) to obtain compound 4 (524 mg, 86% yield) as a slightly yellow solid.

[0157] Rf= 0,38 (Et2O / Pentane - 5 / 95)

[0158] 1 H NMR(300 MHz, CDCl3) δ 7,93 – 7,79 (m, 4H), 7,38 (ddd,J= 8,2, 6,8, 1,3 Hz, 2H), 7,28 (ddd,J= 8,3, 6,8, 1,3 Hz, 2H), 7,14 (dq,J= 7,6, 0,8 Hz, 2H), 5,16 (s, 2H), 2,56 (d,J= 1,0 Hz, 6H).

[0159] 13 C NMR(75 MHz, CDCl3) δ 152,19 (2C), 132,30 (2C), 130,86 (2C), 129,57 (2C), 127,69 (2C), 127,15 (2C), 126,52 (2C), 124,19 (2C), 124,05 (2C), 110,61 (2C), 17,13 (2C).

[0160] Compound (II-2): Potassium carbonate (1.42 g, 10.30 mmol) was added to a solution of compound 4 (2.70 g, 8.58 mmol) in acetone (86 mL) at room temperature. After stirring for 1 h at this temperature, iodomethane (0.534 mL, 8.58 mmol) was added. The resulting mixture was stirred at 60°C for 16 h, then a saturated aqueous solution of NH4Cl (120 mL) was added at room temperature, and the mixture was diluted with EtOAc (180 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: Et2O / Pentane - 5 / 100) to obtain the chiral(II-2) substituted alcohol (2.38 g, yield of 85%) in the form of a white solid.

[0161] Rf= 0.47 (Et2O / Pentane - 5 / 95)

[0162] 1H NMR(300 MHz, CDCl3) δ 7,92 – 7,78 (m, 4H), 7,44 (ddd,J= 8,1, 6,6, 1,4 Hz, 1H), 7,33 (ddd,J= 8,1, 6,8, 1,3 Hz, 1H), 7,28 – 7,17 (m, 3H), 7,09 (ddt,J= 8,3, 1,4, 0,7 Hz, 1H), 5,14 (d,J= 0,7 Hz, 1H), 3,40 (s, 3H), 2,58 (dd,J= 6,6, 1,0 Hz, 6H).

[0163] 13 C NMR(76 MHz, CDCl3) δ 156,75, 150,74, 132,92, 132,86, 131,93, 131,43, 130,94, 129,60, 129,12, 127,48, 127,44, 126,89, 126,19, 125,73, 125,45 (2C), 124,92, 123,37, 121,47, 114,81, 60,54, 17,35, 17,22.

[0164] Compound (I-2): Sodium hydride (219 mg, 5.48 mmol) was added at room temperature to a solution of chiral substituted alcohol (II-2) (1.64 g, 4.98 mmol) in anhydrous THF (50 mL). After stirring for 15 minutes at this temperature, this reaction mixture was added dropwise to a solution of thiophosgene (1.146 mL, 14.95 mmol) in anhydrous THF (50 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour before being concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: Et2O / Pentane 1 / 99 to 5 / 95) to obtain the compound chlorothionate(I-2) (1.42 g, 70% yield) as a white solid.

[0165] pf: 119-121°C

[0166] Rf= 0.35 (Et2O / Pentane - 2 / 98)

[0167] 1H NMR(400 MHz, CDCl3) δ 7.93 – 7.88 (m, 2H), 7.82 (t,J= 1.0 Hz, 1H), 7.79 (dt,J= 8.4, 1.0 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.34 (ddd,J= 8.1, 6.3, 1.6 Hz, 1H), 7.31 – 7.26 (m, 2H), 7.17 – 7.01 (m, 2H), 3.37 (s, 3H), 2.55 (dd,J= 13.6, 1.0 Hz, 6H).

[0168] 13 C NMR(101 MHz, CDCl3) δ 183.11, 155.78, 150.79, 132.75, 132.47, 132.22, 131.23, 130.99, 130.84, 130.23, 129.25, 127.70, 127.26, 126.62, 126.55, 126.45, 126.42, 125.76, 125.39, 124.98, 122.19, 60.58, 17.31, 17.23.

[0169] HRMS (ESI)masse molaire exacte calculée pour C 24 H 19 O2ClNaS + :m / z429.06865 ([M + Na] + ), found :m / z429,06804 ([M + Na] + ).

[0170] IR(film)vmax : 3057, 2936, 1499, 1461, 1445, 1408, 1360, 1264, 1243, 1200, 1146, 1104, 1087, 1044, 1009, 985, 884, 752 cm -1 .

[0171] Example3: use of chlorothionate (I-1) for the separation of a mixed alcohol mixture

[0172] Chlorothionate of formula (I-1) as prepared in Example 1 was used for the separation of a racemic complex alcohol according to the synthesis scheme 3 below: .

[0173] Compounds (IVa-1) and (IVb-1): To a solution of a racemic complex alcohol (22 mg, 0.06802 mmol) in anhydrous THF (4.6 mL), lithium bis(trimethylsilyl)amide (1 M in THF, 340 µl) was added dropwise at 0°C. The resulting reaction mixture was stirred at this temperature for 20 minutes. Chlorothionate (I-1) compound (52 mg, 0.13604 mmol) was then added at this temperature. The resulting mixture was stirred at 35°C for a further 30 minutes, and then a mixture of NH4Cl and water (volume ratio: 1 / 1, 10 mL) was added at room temperature, and the mixture was diluted with EtOAc (10 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 3 ml). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure.The crude product obtained was purified by silica gel chromatography (eluent: EtOAc / PET - 5 / 5) to obtain the easily separable thiocarbonate compounds (IVa-1)(18.1 mg) and (IVb-1)(18.4 mg) as white solids, with respective yields of 40% and 41% (overall yield of 81%).

[0174] Compound(IVa-1)

[0175] pf = 132-134°C

[0176] Rf = 0.57 (EtOAc / PET - 5 / 5)

[0177] 1 H NMR(300 MHz, CDCl3) δ 8.05 – 7.96 (m, 2H), 7.97 – 7.92 (m, 1H), 7.88 – 7.81 (m, 1H), 7.51 – 7.27 (m, 7H), 7.25 – 7.19 (m, 1H), 5.57 (t,J= 2.4 Hz, 1H), 4.26 (d,J= 10.3 Hz, 1H), 4.00 – 3.86 (m, 2H), 3.83 (d,J= 10.4 Hz, 1H), 3.72 (s, 3H), 3.41 (dd,J= 10.9, 3.8 Hz, 1H), 3.13 – 3.01 (m, 1H), 2.58 (dd,J= 11.2, 4.4 Hz, 1H), 2.47 – 2.19 (m, 5H), 2.10 – 1.96 (m, 2H), 1.89 – 1.78 (m, 1H), 1.67 (d,J= 10.2 Hz, 3H), 1.56 – 1.05 (m, 7H), 0.91 – 0.78 (m, 2H).

[0178] 13C NMR(75 MHz, CDCl3) δ 193.74, 171.01, 155.30, 148.77, 133.88, 133.73, 132.19, 130.55, 129.44, 128.94, 128.36, 128.01, 126.91, 126.70 (2C), 126.02, 125.99, 125.53, 123.74, 121.83, 116.50, 113.38, 86.19, 80.04, 68.32, 62.71, 60.94, 56.45, 46.74, 44.40, 40.89, 35.96, 33.25, 30.96, 26.08, 24.00, 20.58, 20.26, 18.97, 14.27.

[0179] [α] 25 D = + 85.24 ° (c= 0.53 CHCl3)

[0180] HRMS (ESI) exact molar mass calculated for C 40 H 44 O6NS + :m / z666.28839 ([M + H] + ), trouvé :m / z666,28827 ([M + H] + ).

[0181] IR(film)vmax : 3058, 2929, 2857, 1736, 1622, 1592, 1508, 1463, 1353, 1289, 1274, 1251, 1208, 1166, 1130, 1086, 1046, 897, 811, 751 cm -1 .

[0182] Compound (IVb-1)

[0183] mp=132-134°C

[0184] Rf = 0.43 (EtOAc / PET - 5 / 5)

[0185] 1H NMR(600 MHz, CDCl3) δ 8,01 (d,J= 8,9 Hz, 1H), 7,96 (dd,J= 8,7, 5,4 Hz, 2H), 7,80 (d,J= 8,3 Hz, 1H), 7,47 (ddd,J= 13,9, 7,6, 3,4 Hz, 3H), 7,33 – 7,27 (m, 3H), 7,18 – 7,12 (m, 2H), 5,43 (d,J= 2,5 Hz, 1H), 4,28 (d,J= 10,4 Hz, 1H), 4,05 (tq,J= 7,2, 3,2 Hz, 2H), 3,94 (d,J= 10,4 Hz, 1H), 3,85 (m, 3H), 3,02 (td,J= 12,4, 3,7 Hz, 1H), 2,71 (dd,J= 11,2, 4,0 Hz, 1H), 2,57 (dd,J= 12,8, 4,7 Hz, 1H), 2,48 – 2,34 (m, 4H), 2,30 – 2,18 (m, 2H), 2,08 (s, 2H), 1,94 (td,J= 12,5, 2,8 Hz, 1H), 1,70 (dt,J= 18,3, 12,6 Hz, 4H), 1,54 – 1,09 (m, 5H), 0,99 – 0,81 (m, 2H).

[0186] 13 C NMR(151 MHz, CDCl3) δ 193,99, 171,11, 155,19, 149,22, 133,89, 133,53, 132,22, 130,58, 129,31, 129,07, 128,37, 127,86, 126,79, 126,68, 126,44, 126,34, 126,01, 125,94, 123,85, 122,37, 117,31, 113,62, 86,22, 79,97, 67,46, 62,99, 60,98, 57,23, 46,71, 44,40, 40,97, 36,08, 33,48, 30,94, 26,09, 24,01, 20,62, 20,24, 18,97, 14,31.

[0187] [α]25D= - 12,94 ° (c= 0,85 CHCl3)

[0188] HRMS (ESI) exact molar mass calculated for C 40 H 44 O6NS + :m / z666,28839 ([M + H] + ), found: m / z666,28827 ([M + H] + ).

[0189] IR(film)vmax: 2928, 2856, 1735, 1622, 1593, 1509, 1464, 1353, 1289, 1264, 1251, 1214, 1167, 1130, 1086, 1046, 902, 812, 751 cm -1

[0190] Example 4: Use of chlorothionate (I-2) for the separation of a racemic mixture of alcohols

[0191] Chlorothionate of formula (I-2) as prepared in Example 2 was used for the separation of racemic menthol according to the synthesis scheme 4 below: .

[0192] Compounds (IVa-2) and (IVb-2): To a solution of (±)-menthol6 (12.5 mg, 0.0800 mmol) in DCM (2 mL), pyridine (25.9 µl, 0.3200 mmol) and then the compound chlorothionate (I-2) (65.1 mg, 0.1600 mmol) were added at room temperature. The resulting mixture was stirred at this temperature for 48 h, and then a saturated aqueous solution of NaHCO3 (2 mL) was added at room temperature. The organic phase was separated, and the aqueous phase was extracted with DCM (2 × 2 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (eluent: Et2O / PET - 3 / 97) to obtain the easily separable thiocarbonate compounds (IVa-2)(20.6 mg) and (IVb-2)(20.9 mg) as white solids, with respective yields of 49% and 50% (overall yield of 99%).

[0193] Compound(IVa-2)

[0194] pg= 56-58°C

[0195] Rf= 0.29 (Et2O / PET - 5 / 100)

[0196] 1 H NMR(300 MHz, CDCl3) δ 7.92 – 7.84 (m, 2H), 7.76 – 7.69 (m, 2H), 7.44 (ddd,J= 8.2, 6.3, 1.7 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.25 – 7.08 (m, 3H), 4.64 (dt,J= 10.7, 5.4 Hz, 1H), 3.30 (d,J= 9.8 Hz, 3H), 2.56 – 2.45 (m, 6H), 1.84 – 1.46 (m, 5H), 1.38 – 1.20 (m, 3H), 1.13 (d,J= 7.6 Hz, 1H), 0.98 – 0.56 (m, 9H).

[0197] 13 C NMR(101 MHz, CDCl3) δ 192.34, 155.79, 132.85, 132.45, 132.20, 131.17, 131.04, 130.85, 130.32, 129.90, 129.73, 127.68, 127.46, 126.87, 126.52, 126.20, 126.01, 125.97, 125.84, 125.05, 124.82, 84.54, 60.61, 46.58, 38.37, 34.11, 31.09, 26.26, 23.37, 21.80, 20.61, 17.38, 17.34, 16.67.

[0198] [α] 25 D = - 57.81 ° (c= 0.8167 CHCl3)

[0199] HRMS (ESI) exact mass calculated for C 34 H 38 O3NaS + :m / z549.24339 ([M + Na] + ), trouvé :m / z549.24253 ([M + Na] + ); exact mass calculated for C34 H 38 O3KS + :m / z565.21732 ([M + K] + ), trouvé :m / z565.21659 ([M + K] + ).

[0200] IR(film)vmax : 3055, 2954, 2927, 2869, 1500, 1456, 1361, 1292, 1240, 1213, 1197, 1176, 1148, 1103, 1011, 882, 751 cm -1 .

[0201] Composé(IVb-2)

[0202] p.f.=56-58°C

[0203] Rf= 0,23 (Et2O / PET - 5 / 100)

[0204] 1 H NMR(300 MHz, CDCl3) δ 7,92 – 7,85 (m, 2H), 7,76 – 7,67 (m, 2H), 7,48 – 7,40 (m, 1H), 7,30 (dddd,J= 8,2, 6,8, 5,6, 1,4 Hz, 2H), 7,23 – 7,06 (m, 3H), 4,73 – 4,55 (m, 1H), 3,30 (d,J= 9,8 Hz, 3H), 2,55 – 2,46 (m, 6H), 2,00 (d,J= 12,3 Hz, 1H), 1,63 – 1,43 (m, 4H), 1,36 – 1,23 (m, 3H), 0,95 – 0,55 (m, 10H).

[0205] 13C NMR(101 MHz, CDCl3) δ 192.10, 155.64, 132.84, 132.48, 132.21, 131.05, 131.02, 130.85, 130.69, 130.31, 129.80, 127.69, 127.61, 126.92, 126.46, 126.11, 126.00, 125.97, 125.83, 124.95, 124.81, 84.52, 60.43, 46.86, 39.15, 34.16, 31.36, 26.07, 23.51, 22.04, 20.39, 17.34, 17.19, 16.39.

[0206] [α] 25 D = - 115.29° (c= 0.8333 CHCl3)

[0207] HRMS (ESI) exact mass calculated for C 34 H 38 O3NaS + :m / z549,24339 ([M + Na] + ), found: m / z549.24253 ([M + Na] + ) ; exact mass calculated for C 34 H 38 O3KS + :m / z565.21732 ([M + K] + ), found: m / z565.21650 ([M + K] + ).

[0208] IR(film)vmax: 3053, 2954, 2927, 2869, 1500, 1460, 1363, 1293, 1240, 1213, 1197, 1176, 1148, 1103, 1011, 890, 750 cm -1 .

[0209] Example 5: Barton-McCombie reaction from separated thiocarbonates

[0210] Each of the diastereomers (IVa-1) and (IVb-1) prepared in Example 3 was involved in the Barton-McCombie reaction to form the corresponding alkane according to the following synthetic scheme 5: .

[0211] Compound 7 [respectively compound 8]: To a solution of compound (IVa-1) [respectively compound (IVb-1)] (15 mg, 0.02253 mmol) in anhydrous toluene (3.3 mL), tributyltin hydride (121 µl, 0.45055 mmol) and then azobisisobutyronitrile (7.4 mg, 0.04506 mmol) were added at room temperature. The resulting reaction mixture was stirred at 105°C for 1 h before being quenched with KF (45 mg, 0.77457 mmol) at room temperature. The reaction mixture was stirred for a further 10 minutes at this temperature before being concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: EtOAc / PET - 2 / 8 to EtOAc / PET / Et3N - 8 / 2 / 0.01) to obtain compound 7 [respectively compound 8] (6.2 mg, yield of 90%) in the form of a colorless oil.

[0212] Rf = 0.55 (EtOAc / PET - 8 / 2)

[0213] 1H NMR(400 MHz, CDCl3) δ 4,44 (q,J= 10,4 Hz, 2H), 4,11 (q,J= 7,1 Hz, 2H), 3,92 – 3,83 (m, 1H), 3,31 – 3,14 (m, 2H), 2,70 (d,J= 11,5 Hz, 1H), 2,54 – 2,39 (m, 3H), 2,34 (td,J= 12,0, 3,5 Hz, 1H), 1,82 – 1,68 (m, 3H), 1,67 – 1,20 (m, 12H), 1,20 – 1,10 (m, 1H), 0,96 – 0,80 (m, 1H).

Claims

1. Chiral chlorothionate compound, derived from a chiral binol, characterized in that it corresponds to the following formula (I) or (I'): ,in which:* R 1 is an alkyl group or an aryl group,* R 2 is a hydrogen atom, a halogen atom, an alkyl group, an aryl group, or a carbonyl group -C(=O)-R 3 , in which R 3 is a heteroalkyl, alkyl, or aryl group.

2. Compound according to claim 1, characterized in that R 1 is an alkyl group.

3. Compound according to claim 1 or 2, characterized in that R 2 is a hydrogen atom or an alkyl group.

4. A compound according to any one of the preceding claims, characterized in that it is selected from the following compounds: .

5. A process for preparing a chlorothionate compound (I) or (I') as defined in any one of the preceding claims, characterized in that it comprises at least one step (i) of reacting a chiral substituted alcohol, derived from a chiral binol, in the presence of thiophosgene and a strong base, said chiral substituted alcohol having the following formula (II) or (II'): , in which R 1 and R 2 are as defined in any one of the preceding claims.

6. Use of a chiral chlorothionate compound (I) or (I') as defined in any one of claims 1 to 4, for the separation of a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol.

7. A method for separating a racemic or enantioenriched mixture of enantiomers or antipodes of an alcohol, characterized in that it comprises at least the following steps: a) coupling an alcohol, in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, with a chiral chlorothionate compound (I) or (I') as defined in any one of claims 1 to 4, to form two corresponding thiocarbonate diastereomers, and b) separating the two corresponding thiocarbonate diastereomers.

8. A process according to claim 7, characterized in that it further comprises a step c) of deprotection of at least one of the diastereomers recovered in step b) to form said alcohol, in an enantiopure form.

9. Use of a chiral chlorothionate compound (I) or (I') as defined in any one of claims 1 to 4, for the deoxygenation of an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes in corresponding enantiopure alkanes.

10. A process for deoxygenating an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, to form alkanes in the form of enantiopure compounds, characterized in that it comprises at least the following steps: a) coupling an alcohol in the form of a racemic or enantioenriched mixture of enantiomers or antipodes, with a chiral chlorothionate compound (I) or (I') as defined in any one of claims 1 to 4, to form two corresponding thiocarbonate diastereomers, b) separating the two corresponding thiocarbonate diastereomers, and d) reducing at least one of the two thiocarbonate diastereomers in the presence of a hydride donor.

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