MXPA06011280A

MXPA06011280A - Preparation of p-chirogenic phospholanes and their use in asymetric synthesis

Info

Publication number: MXPA06011280A
Application number: MXPA/A/2006/011280A
Authority: MX
Inventors: Garrett Stewart Hoge
Original assignee: Pfizer Inc
Priority date: 2004-04-01
Filing date: 2006-09-29
Publication date: 2007-04-20

Abstract

Materials and methods for preparing P-chirogenic monophospholanes and bisphospholanes are disclosed. The methods employ stereoselective cyclization to generate the phospholane rings followed by pyramidal inversion to access a variety of P-chirogenic phospholanes. When bound to transition metals such as rhodium, the disclosed P-chirogenic phospholanes may be used as catalysts in asymmetric synthesis of valuable pharmaceutical chemical entities, including pregabalin.

Description

PREPARATION OF P-CHIROGENIC PHOSPHOLANES AND THEIR USE IN ASYMMETRIC SYNTHESIS FIELD OF THE INVENTION This invention relates to materials and methods for the preparation of phospholane P-quirogénic ligands and to their use in asymmetric syntheses, including the enantioselective hydrogenation of prochiral olefins to prepare pharmaceutically useful compounds such as pregabalin.

BACKGROUND OF THE INVENTION Asymmetric catalysis is often the most efficient method for the synthesis of enantiomerically enriched compounds because a small amount of a chiral catalyst can be used to produce a large amount of a chiral target molecule. During the last two decades, more than half a dozen commercial industrial processes have been developed that use asymmetric catalysis as the key step in the production of enantiomerically pure compounds with much effort focused on the development of new asymmetric catalysts for these reactions. See, for example, J.D. Morrison ed., Asymmetríc Synthesis 5 (1985); B. Bosnich ed., Asymmetríc Catalysis (1986); H. Brunner, Synthesis 645 (1988); R. Noyori & M. Kitamura, in R. Scheffold, ed., Modern Synthetic Methods 5: 115 (1989); W. A. Nugent et al., Science 259: 479 (1993); I. Ojima, ed., Catalytic Asymmetric Synthesis (1993); R. Noyori, Asymmetric Catalysis In Organic Synthesis (1994). For more recent examples, see "Special Feature Section: Homogeneous Transition Metal-Catalyzed Reactions", Organic Process Research and Development 7 (3): 341-445 (2003). Chiral phosphine ligands have played an important role in the development of new asymmetric reactions catalyzed by transition metal to produce enantiomeric excess of compounds with desired activities. The first successful attempts at asymmetric hydrogenation of enamide substrates were achieved in the last 70 years using chiral bisphosphines as transition metal ligands. See, for example, B. D. Vineyard et al., J. Am. Chem. Soc. 99 (18): 5946-52 (19JJ); W. S. Knowles et al., J. Am Chem. Soc. 97 (9): 2567-68 (1975). From these first published reports, there has been a continuing expansion of research in relation to the synthesis of novel chiral bisphosphine ligands for asymmetric hydrogenations and other chiral catalytic transformations. See I. Ojima, ed., Catalytic Asymmetric Synthesis (1993); D. J. Ager, ed., Handbook of Chiral Chemicals (1999). Much of the current interest in new ligands and chiral catalysts results from their use in the preparation of enantiomerically enriched or enantiopure drugs. A drug of this type is pregabalin, (S) -3-aminomethyl-5-methyl-hexanoic acid, which is the active pharmaceutical ingredient in LYRICA®. Pregabalin is related to the endogenous inhibitory neurotransmitter α-aminobutyric acid (GABA), which is involved in the regulation of brain neuronal activity. Pregabalin shows anti-epilepsy activity, as described in U.S. Patent No. 5,563,175 of R.B. Silverman et al., And is believed to be useful for the treatment, among other conditions, of pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, and various psychiatric disorders, including mania and bipolar disorder. See, respectively, U.S. Patent No. 6,242,488 to L. Bueno et al., U.S. Patent No. 6,326,374 to L. Magnus & C. A. Segal, and US Pat. No. 6,001, 876 to L. Singh; U.S. Patent No. 6,194,459 to H. C. Akunne et al .; U.S. Patent No. 6,329,429 to D. Schrier et al .; U.S. Patent No. 6,127,418 to L. Bueno et al .; U.S. Patent No. 6,426,368 to L. Bueno et al .; U.S. Patent No. 6,306,910 to L. Magnus & C. A. Segal; and U.S. Patent No. 6,359,005 to A. C. Pande. A recent US patent describes a method of preparing pregabalin and other chiral compounds by asymmetric hydrogenation of a cyano substituted olefin to produce a chiral cyano precursor of (S) -3-aminomethyl-5-methyl-hexanoic acid. See U.S. Patent No. 6,605,745 to G. S. Hoge, II & O. P. Goel (the patent 745), which is assigned to Warner-Lambert Company LLC. The cyano precursor is subsequently reduced by giving the pregabalin enantiomerically enriched in high yield. According to the '745 patent, the asymmetric hydrogenation uses a chiral catalyst, which is comprised of a transition metal (e.g., rhodium) linked to a bisphospholane P-chitogenic ligand, such as 1,2-bis ((1R, 2R) -2-benzylphospholanyl) ethane, In addition to alkanediyl, such as ethanediyl in formula I, patent 745 discloses other bridges that join phosphorus atoms, including substituted and unsubstituted phen-1,2-diyl bridges as shown in the compound of formula 2, The '745 patent describes numerous methods for the preparation of bisphospholane P-quirogénic ligands. A useful method uses an oxidative coupling promoted by CuCl2 of a methyl anion of the compound of formula 3, which is obtained by treatment of the compound of formula 3 with a strong base, such as s-BuLi. Although this approach is useful for the preparation of P-chirogenic bisphospholanes similar to the compound of formula 1, such approaches are less useful for ligands exemplified by formula 2. Therefore, it would be desirable to develop a general technique for the preparation of bisphospholane P-chirogenic .

BRIEF DESCRIPTION OF THE INVENTION The present invention provides materials and methods for the preparation of monophospholanes (formula 9) and bisphospholanes (formula 10) P-quirogénicos by stereoselective cyclization of a phosphine precursor (formula 6) to generate the phospholane rings. The pyramidal inversion of the phosphine residues allows access to a variety of diastereoisomers of phospholane P-quirogénicos. When they are attached to transition metals such as rhodium, the P-chirogenic phospholanes described as catalysts in asymmetric synthesis of pharmaceutical chemical entities valuable, including pregabalin. One aspect of the present invention provides a method of preparation of compounds of formula 9, or formula 10, or opposing enantiomers thereof, in which R is C-t-β alkyl, C 1 -C 6 haloalkyl, C 3-8 cycloalkyl. C3-8 haloalkyl, alkanoyl, C6-6 alkoxy, C6-6 alkoxyC1-6alkyl, C6alkoxycarbonyl, aryl, arylC1-6alkyl, aryloxy, arylalkoxy C? -6, aryloxycarbonyl, aryl-alkoxycarbonyl C -? - 6, or carboxy, and each of the C3-8 aryl and cycloalkyl moieties are independently substituted or unsubstituted, and X is C? -? 2 alkyl, C? - | 2 alkanoyl, or phen-1,2-diyl, wherein fen-1,2-diyl is substituted or unsubstituted, the method comprising the epimerization of compounds of formula 7, 7 or formula 8, or opposite enantiomers thereof, to give the compounds of formula 9, or formula 10, or the opposite enantiomers thereof, respectively, wherein R and X in formula 7 and formula 8 are as defined in formula 9 and formula 10. In the claimed method, the epimerization of the compounds typically comprises heating a reaction mixture containing the compounds of formula 7 or formula 8 or opposite enantiomers thereof, at a temperature greater than or approximately equal to 100 ° C and less than or approximately equal to the decomposition temperature of the compounds of formula 7 or formula 8, which is typically about 250 ° C. This corresponds to the heating of the mixture of reaction at a temperature greater than or approximately equal to 100 ° C, 110 ° C, 120 ° C, 130 ° C, 140 ° C, 150 ° C, 160 ° C, 170 ° C, 180 ° C, 190 ° C, 200 ° C, 210 ° C, 220 ° C, 230 ° C, 240 ° C or 250 ° C, and less than or equal to 110 ° C, 120 ° C, 130 ° C, 140 ° C, 150 ° C , 160 ° C, 170 ° C, 180 ° C, 190 ° C, 200 ° C, 210 ° C, 220 ° C, 230 ° C, 240 ° C or 250 ° C. In some cases, the epimerization of the compounds comprises heating a reaction mixture containing the compounds of formula 7 or formula 8 or opposite enantiomers thereof, at a temperature greater than or approximately equal to 140 ° C and less than or approximately equal to 210 ° C or at a temperature greater than or approximately equal to 190 ° C and less than or approximately equal to 210 ° C. In the claimed method , the compounds of formula 7 or formula 8 or their opposite enantiomers, are generally epimerized in the absence of oxygen or when the reaction mixture contains less than about 1%, 0.1% or 0.01% oxygen by mass. Another aspect of the present invention provides a method of preparing compounds of formula 7, or formula 8, 8 or opposing enantiomers thereof, wherein R and X are as defined above in formula 9 and formula 10, the method comprising: (a) treatment of a compound of formula 6, X (PH2) n 6, with a first base generating a first intermediate, wherein n in formula 6 is 1 or 2 and X is as defined in formula 9 and formula 10; (b) reacting the first intermediate with a compound of formula 5, or an opposite enantiomer thereof, giving a second intermediate; and (c) treating the second intermediate with a second base to give the compounds of formula 7, or formula 8, or opposite enantiomers thereof, wherein R in formula 5 is as defined in formula 7 and formula 8, and the first and second bases are the same or different. In the methods for the preparation of compounds of formula 7 to formula 10, R is typically C? -6 alkyl, C1-6 alkoxy-C1-6 alkyl or C? -6 arylalkyl, and X is typically alkyl of C? -6, alkanediyl of C1-2, or phen-1,2-diyl. Thus, useful Rs include methyl, ethyl, isopropyl, methoxymethyl or benzyl, and useful X include methyl, methylene, ethanediyl, or phen-1,2-diyl. A further aspect of the present invention provides compounds of formula 7, or formula 8, 8 or opposing enantiomers thereof, wherein R and X are as defined above in formula 9 and formula 10, and with the proviso that R in formula 7 is not methyl. A further aspect of the present invention provides compounds of formula 11, or formula 12, or opposite enantiomers thereof, wherein R and X are as defined above in formula 9 and formula 10, and with the proviso that R in formula 11 is not methyl. Another aspect of the present invention provides compounds of formula 5, or opposite enantiomers thereof, wherein R is as defined above in formula 9 and formula 10. In each of the compounds of formula 5 and formulas 7, 8, 11 and 12, R is typically C-alkyl. -6, C6-C6-alkoxy-C6-alkyl or aryl-C6-C6alkyl, and X is typically C1-6alkyl) C3-2alkanediyl, or phen-1, 2- say it Under the conditions related to the compounds of formula 7 and formula 11, useful Rs thus include methyl, ethyl, isopropyl, methoxymethyl or benzyl, and useful X include methyl, methylene, ethanediyl, or phen-1,2-diyl. Particularly useful compounds include: (4S) -4-benzyl-1,2,2-dioxathiepane-2,2-dioxide; 2,2-dioxathiepane 2,2-dioxide (4R) -4-methyl-1, 2,2-dioxide; 2,2-dioxathiepane-2,2-dioxide (4S) -4- (methoxymethyl) -1,2-dioxide; (1 R, 2R) -1-phenyl-2-benzylphospholane; (1 R, 2R) -1-phenyl-2- (methoxymethyl) phospholane; 1, 2-bis ((1 R, 2R) -2-benzylphospholane) benzene; 1, 2-bis ((1 R, 2S) -2-methylphospholane) benzene; 1, 2-bis ((1 S, 2R) -2-benzylphospholane) ethane; (1S, 2R) -1-phenyl-2- (methoxymethyl) phospholane; (1S, 2R) -1-phenyl-2-benzylphospholane; 1 - ((1 R, 2 S) -2-methylphospholan-1-yl) -2 - ((1 S, 2 S) -2-methylphospholan-1-yl) -benzene; 1 - ((1 R, 2R) -2-benzylphospholan-1-yl) -2 - ((1 S, 2R) -2-benzylphospholan-1-yl) -benzene; 1 - ((1 R, 2R) -2-benzylphospholan-1-yl) -2 - ((1 S, 2R) -2-benzylphospholan-1-yl) -ethane; opposing enantiomers thereof; and complexes, salts, solvates or hydrates thereof. The scope of the present invention includes all complexes, salts, solvates, hydrates, polymorphs, esters, amides and prodrugs of the claimed and described compounds, including compounds of formulas 5, 7, 8, 11 and 12, whether pharmaceutically acceptable or not.

DETAILED DESCRIPTION OF THE INVENTION Definitions and abbreviations Unless otherwise indicated, this description uses the definitions provided below. Some of the definitions and formulas may include a "-" (ray) to indicate a bond between atoms or a point of attachment to a named or unnamed atom or group of atoms. Other definitions and formulas may include a "=" (equal sign) or "=" (identity sign) to indicate a double or triple link, respectively. "Substituted" groups are those in which one or more hydrogen atoms have been replaced with one or more other hydrogen groups, with the proviso that the valence requirements are met and that the substitution results in a chemically stable compound. "Alkyl" refers to straight and branched chain saturated hydrocarbon groups, which generally have a specified number of carbon atoms (ie, C?-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, / -propyl, n-butyl, s-butyl, / -butyl, 1-butyl, pent-1-yl, pent-2-yl, pent -3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2- ilo, 2,2,2-trimethylethyl-1-yl, n-hexyl and the like. "Alkenyl" refers to straight and branched chain hydrocarbon groups that have one or more unsaturated carbon-carbon bonds, and generally have a specified number of carbon atoms. Examples of alkenyl groups include, without limitation, ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl , 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2 -propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like. "Alkynyl" refers to straight or branched chain hydrocarbon groups having one or more triple carbon-carbon bonds, and generally have a specified number of carbon atoms. Examples of alkynyl groups include, without limitation, ethinyl, 1-propin-1-yl, 2-propin-1-yl, 1-butin-1-yl, 3-butin-1-yl, 3-butin-2-yl , 2-butin-1-yl, and the like. "Alkaneldiol" refers to divalent straight chain and branched aliphatic hydrocarbon groups, which generally have a specified number of carbon atoms. Examples include, without limitation, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1, 9-nonanediyl, 1, 10-decanediyl, 1, 11-undecannediyl, 1, 12-dodecanediyl and the like. "Phenyl-1,2-diyl" refers to a divalent phenyl group, which is attached to a parent group or substrate by adjacent ring carbon atoms. "Alkanoyl" and "alkanoylamino" refer, respectively, to alkyl-C (O) - and alkyl-C (O) -NH-, where alkyl is defined above, and generally includes a specified number of carbon atoms, including the carbonyl carbon. Examples of alkanoyl groups include, without limitation, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like. "Alkoxy", "alkoxyalkyl", "alkoxycarbonyl" and "alkoxycarbonylamino" refer, respectively, to alkyl-O-, alkyl-O-alkyl, alkyl-OC (O) - and alkyl-OC (0) -NH-, where alkyl was defined above. Examples of alkoxy groups include, without limitation, methoxy, ethoxy, n-propoxy, / '-propoxy, n-butoxy, s-butoxy, i-butoxy, n-pentoxy, s-pentoxy and the like. "Alkylamino", "alkylaminocarbonyl", "dialkylaminocarbonyl", "alkylsulfonyl", "sulfonylaminoalkyl" and "alkylsulfonylaminocarbonyl" refer, respectively, to alkyl-NH-, a-quyl-NH-C (O) -, alkyl2-NC (0) -, alkyl-S (O) 2-, HS (O) 2-, NH-alkyl- and alkyl-S (O) -NHC (0) -, where alkyl was defined above. "Aminoalkyl" and "cyanoalkyl" refer, respectively to NH2-alkyl, and N = C-alkyl, where alkyl was defined above. "Cycloalkyl" refers to monocyclic and saturated bicyclic hydrocarbon rings, which generally have a specified number of carbon atoms comprising the ring (ie, C3-7 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members). The cycloalkyl may be attached to a parent group or to a substrate at any ring atom, unless such binding violates the valence requirements. Likewise, cycloalkyl groups can include one or more substituents other than hydrogen unless such substitution violates the valence requirements. Useful substituents include, without limitation, alkyl, alkoxy, alkoxycarbonyl, and alkanoyl, as defined above, and hydroxy, mercapto, nitro, halogen, and amino. Examples of monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of bicyclic cycloalkyl groups include, without limitation, bicyclo [1.1.O-butyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.O-pentyl, bicyclo [2.1.1] hexyium, bicyclo [3.1.Oxhexyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.0] heptyl, bicyclo [3.1.1] heptyl, bicyclo [4.1.0] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [4.1.1] octyl, bicyclo [3.3.0] octyl, bicyclo [4.2.0] octyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.0] nonyl, bicyclo [3.3.2] decyl, bicyclo [4.2.2] decyl, bicyclo [4.3.1] decyl, bicyclo [4.4.0] decyl, bicyclo [3.3.3] undecyl, bicyclo [4.3.2] undecyl, bicyclo [4.3.3] dodecyl, and the like. "Cycloalkanoyl" refers to cycloalkyl-C (O) -, where cycloalkyl is defined above, and generally includes a specified number of carbon atoms, excluding the carbonyl carbon. Examples of cycloalkanoyl groups include, without limitation, cyclopropanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl and the like. "Halo" and "halogen" can be used interchangeably, and refer to fluoro, chloro, bromo and iodo. "Haloalkyl", "halocycloalkyl" and "haloalkanoyl" refer, respectively, to alkyl, cycloalkyl or alkanoyl groups substituted with one or more halogen atoms, wherein alkyl, cycloalkyl and alkanoyl were defined above. Examples of haloalkyl and haloalkanoyl groups include, without limitation, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, trifluoroacetyl, trichloroacetyl, pentafluoropropionyl, pentachloropropionyl, and the like. "Hydroxyalkyl" and "oxoalkyl" refer, respectively, to HO-alkyl and 0 = alkyl, where alkyl was defined above. Examples of hydroxyalkyl and oxoalkyl groups include, without limitation, hydroxymethyl, hydroxyethyl, 3-hydroxypropyl, oxomethyl, oxoethyl, 3-oxopropyl, and the like. "Aryl" and "arylene" refer to monovalent and divalent aromatic groups, respectively. Examples of aryl groups include, without limitation, phenyl, naphthyl, biphenyl, pyrenyl, anthracenyl, fluorenyl and the like, which may be unsubstituted or substituted with 1 to 4 substituents. Such substituents include, without limitation, alkyl, alkoxy, alkoxycarbonyl, alkanoyl, and cycloalkanoyl, as defined above, and hydroxy, mercapto, nitro, halogen, and amino. "Arylalkyl" refers to aryl-alkyl, wherein aryl and alkyl are defined above. Examples include, without limitation, benzyl, fluorenylmethyl, and the like. "Arylalkanoyl" refers to aryl-alkanoyl, where aryl and alkanoyl were defined above. Examples include, without limitation, benzoyl, phenylethanoyl, phenylpropanoyl, and the like. "Aryloxy" refers to aryl-O-, where aryl was defined above.

Examples include, without limitation, phenoxy and the like. "Aryloxycarbonyl" refers to aryl-O-C (O) -, where aryl was defined above. Examples include, without limitation, phenoxycarbonyl and the like. "Arylalkoxy" refers to aryl-alkoxy, where aryl and alkoxy are defined above. Examples of arylalkoxy include, without limitation, benzyloxy, fluorenylmethoxy, and the like. "Arylalkoxycarbonyl" refers to aryl-alkoxycarbonyl, where aryl and alkoxycarbonyl are defined above. Examples include, without limitation, phenoxycarbonyl, benzyloxycarbonyl (CBz) and the like. "Carboxi" refers to HOOC-. "Heterocycle" and "heterocyclyl" refer to monocyclic or saturated bicyclic, partially unsaturated, or unsaturated rings having 5 to 7 or 7 to 11 ring members, respectively. These groups have ring members of carbon atoms and from 1 to 4 heteroatoms which are independently nitrogen, oxygen or sulfur, and can include any bicyclic group in which any of the monocyclic heterocycles defined above are fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring can be linked with a parent group or with a substrate at any heteroatom or carbon atom unless such binding violates the valence requirements. Likewise, any of the carbon or nitrogen ring members may include a substituent other than hydrogen unless such substitution violates the valence requirements.

Useful substituents include, without limitation, alkyl, alkoxy, alkoxycarbonyl, alkanoyl, and cycloalkanoyl, as defined above, and hydroxy, mercapto, nitro, halogen, and amino. Examples of heterocycles include, without limitation, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxathiolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2 - /, 6f / -1, 5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3 / - / - indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl , phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxyazinyl, phentazinyl, piperazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H -pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1, 2,5-thiadiazinium, 1, 2,3-thiadiazolyl, 1,4-thiadiazolyl, 1 , 2,5-thiadiazolyl, 1,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,4-triazolyl, 1,2 ,5- triazolyl, 1,4-triazolyl and xanthenyl. "Heteroaryl" and "heteroarylene" refer, respectively, to monovalent and divalent heterocyclic or heterocyclyl groups, as defined above, which are aromatic. Heteroaryl and heteroarylene groups represent a subset of aryl and arylene groups, respectively. "P-quirogenic" refers to a molecule that has at least one phosphorus atom that is a stereocenter. "Phospholane ring" refers to a 5-membered cyclic structure in which at least one atom is phosphorus. "Leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. The leaving groups can be nucleophilic, in which the group leaves with a pair of electrons that previously served as the bond between the leaving group and the molecule, or they can be electrophoretic, in which the group leaves without the pair of electrons. The ability of a nucleofugal leaving group to leave depends on its strength as a base, with the strongest bases being the weakest outgoing groups. Common nucleophilic leaving groups include nitrogen (for example, of diazonium salts); sulfonates, including alkylsulfonates (e.g., mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and arylsulfonates (e.g., tosylate, brosylate, and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions and alkoxides. Some stronger bases, such as NH2"and OH" can be made into better leaving groups by treatment with an acid. Common electrofugal leaving groups include the proton, CO2 and metals. "Enantiomeric excess" or "ee" is a measure, for a given sample, of the excess of an enantiomer in a racemic sample of a chiral compound and is expressed as a percentage. The enantiomeric excess is defined as 100 x (er - 1) / (er + 1), where "er" is the ratio of the most abundant enantiomer to the least abundant enantiomer. "Diastereomeric excess" or "ed" is a measure, for a given sample, of the excess of a diastereomer in a sample having equal amounts of diastereomers and is expressed as a percentage. The diastereomeric excess is defined as 100 x (dr - 1) / (dr + 1), where "dr" is the ratio of a more abundant diastereomer to a less abundant diastereomer. "Stereoselective", "enantioselective", "diastereoselective" and variants thereof, refer to a given procedure (e.g., hydrogenation) that gives more than one stereoisomer, enantiomer or diastereomer than another, respectively. "High level of stereoselectivity", "high level of enantioselectivity", "high level of diastereoselectivity", and variants thereof, refer to a given procedure that gives products having an excess of a stereoisomer, enantiomer or diastereoisomer, which comprises at least about 90% of the products. For a pair of enantiomers or diastereomers, a high level of enantioselectivity or diastereoselectivity would correspond to an ee or ed of at least about 80%. "Stereoisomerically enriched", "enantiomerically enriched", "diastereomerically enriched" and variants thereof, refer, respectively, to a sample of a compound having more than one stereoisomer, enantiomer or diastereomer than another. The degree of enrichment can be measured by% of the total product, or by a pair of enantiomers or diastereomers, by ee or ed. "Substantially pure stereoisomer", "substantially pure enantiomer", "substantially pure diastereomer" and variants thereof, refer, respectively, to a sample containing a stereoisomer, enantiomer, or diastereomer, comprising at least about 95% of the sample. For pairs of enantiomers and diastereomers, a substantially pure enantiomer or diastereomer would correspond to samples having an ee or ed of about 90% or greater. A "pure stereoisomer", "pure enantiomer", "pure diastereomer" and variants thereof, refer, respectively, to a sample containing a stereoisomer, enantiomer or diastereomer, comprising at least about 99.5% of the sample. For pairs of enantiomers and diastereomers, a pure enantiomer or diastereomer pure would correspond to samples that have an ee or ed of approximately 99% or higher. "Opponent enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, which can be obtained by reversing all the stereogenic centers of the reference molecule. For example, if the reference molecule has absolute stereochemical configuration S, then the opposite enantiomer has absolute stereochemical configuration R. Similarly, if the reference molecule has absolute stereochemical configuration S, S, then the opposite enantiomer has stereochemical configuration R, R, and so on. "Cis" in the context of a pair of monophospholane ring substituents, refers to a configuration in which both substituents are located on the same side of the ring. "Trans" in the context of a pair of monophospholane ring substituents refers to a configuration in which substituents are located on opposite sides of the ring. The terms "cis / cis", "cis / trans" and "trans / trans" refer to the arrangement of each phospholane ring within a molecule of a bisphospholane. "Around" or "approximately", when used in relation to a measurable numerical variable, refer to the indicated value of the variable and all the values of the variable that fall within the experimental error of the indicated value (for example, within of the 95% confidence interval for the mean) or within 10 percent of the indicated value, which be greater. "Solvate" describes a molecular complex comprising a compound (e.g., pregabalin) and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g., ethanol). "Hydrate" describes a solvate comprising a compound (e.g., pregabalin) and a stoichiometric or non-stoichiometric amount of water. "Pharmaceutically acceptable complexes, salts, solvates or hydrates" refer to complexes, acid or base addition salts, solvates or hydrates of claimed and described compounds, which are within the scope of medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like, which provide a reasonable benefit / risk ratio and are effective for their intended use. "Treat" refers to reversing, alleviating, inhibiting the progress of, or preventing a disorder or condition to which such term applies, or to preventing one or more symptoms of such disorder or condition. "Treatment" refers to the act of "treating" as defined immediately above. Table 1 provides a non-exhaustive list of abbreviations that can be used in the specification.

TABLE 1 List of abbreviations In some of the following reaction schemes and examples, certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at sites that would otherwise be reactive. Protective groups can also be used to improve the solubility or otherwise modify the physical properties of a compound. For a discussion of protective group strategies, a description of materials and procedures for installation and removal of groups protectants, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and the like, see T. W. Greene and P.G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000). In addition, some of the following schemes and examples may omit details of common reactions, including oxidations, reductions, and the like, which are known to those skilled in the art of organic chemistry. The details of such reactions can be found in a number of treatises, including Richard Larock, Comprehensive Organic Transformations (1999); M.B. Smith and J. March, March's Advanced Organic Chemistry (fifth edition, 2001); and the multi-volume series edited by Michael B. Smith et al., Compendium of Organic Synthetic Methods (1974-2004). In general, starting materials and reagents can be obtained from commercial sources or are derived from the methods of the literature. The present invention provides materials and methods for the preparation of P-chirogenic compounds represented by formula 9 and formula 10, above. Additionally, the present invention provides materials and methods for the preparation of P-chirogenic compounds having opposite stereochemical configuration (ie, opposite enantiomers) of the compounds represented by formula 9 and formula 10. In general, and unless expressly indicate or otherwise clarify in the context of the text, a reference to a formula that shows a compound that has a certain stereochemical configuration includes the opposite enantiomer of the compound. Useful compounds of formula 9 and formula 10 include monophospholanes and bisphospholanes in which R is C? 6 alkyl, halo-C-? 6 alkyl, C3-8 cycloalkyl > halo C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, aryl, or aryl C 1-6 alkyl, and X is C 1 -2 alkyl, C 1 alkanediyl. - | 2, or phen-1,2-diyl, which may be substituted or unsubstituted. Other useful compounds of formula 9 and formula 10 include monophospholanes and bisphospholanes in which R is C? -6 alkyl, C3-8 cycloalkyl, C-i alkoxy. 6, C 1-6 alkoxy-6-alkyl, aryl, or aryl-C 1-6 alkyl, and X is C? -6 alkyl, C 1-6 alkanediyl, or phen-1,2-diyl. Particularly useful compounds of formula 9 and formula 10 include monophospholanes and bisphospholanes in which R is C? -6 alkyl, C? -6 alkoxy-C1-6 alkyl or aryl-C-? -6 alkyl, and X is alkyl of C -6, C1-2 alkanediyl, or phen-1,2-diyl. These latter compounds include those in which R is methyl, ethyl, isopropyl, methoxymethyl or benzyl, and X is methyl, methylene, ethanediyl, or phen-1,2-diyl. Scheme A and Scheme B show the preparation of monophospholans and bisphospholans P-quirogénicos of formula 9 and formula 10. Scheme A illustrates a method of preparing a chiral cyclic sulfate (formula 5), which is subsequently reacted with a monophosphine or bisphosphine (formula 6) in the presence of a strong base giving a cis monophospholane (formula 7) or a cis / cis bisphospholane (formula 8) respectively. As shown in scheme A, a chiral 1,4-diol (formula 4) is reacted with thionyl chloride to give a cyclic sulfite of 1-4. corresponding diol (not isolated), which is subsequently oxidized with Nal0 and a catalytic amount of RuCI3 giving the cyclic sulfate of formula 5 as a crystalline oil or solid. The substituent R in formula 4 and formula 5 is as defined above in formula 9 and formula 10, and the chiral 1,4-diol of formula 4 can be obtained from L-glutamic acid and (S) -2.3 - epoxypropylbenzene using known procedures. See, for example, G. Hoge, J. Am. Chem. Soc. 125: 10219 (2003); C. Herdeis, Synthesis, 232 (1986); H. Brunner & H. Lautenschlager, Synthesis, 706 (1989); K. Mori, Tetrahedron 31: 3011 (1975); U. Ravid et al., Tetrahedron 34: 1449 (1978); H. Nemoto et al., J. Org. Chem. 50: 2764 (1985); X. Cai et al., Organic Process Research and Development 3:73 (1999).

SCHEME A SCHEME B 1. n-BuLi (n eq) X (PH2) n - 6 2. Cyclic sulfate (5) 3. n-BuLi (n eq) As indicated above and as shown in the diagram B, the monophospholanes and bisphospholans P-quirogénicos of formula 9 and formula 10 are obtained by first reacting a monophosphine (formula 6, n = 1) or bisphosphine (formula 6, n = 2) with a strong first base which is able to deprotonate a P-H bond, such as MeLi, n-BuLi, PhLi or LDA. The resulting anion is reacted with the chiral cyclic sulfate (formula 5) producing a carbon-phosphorus bond on each phosphorus atom. The subsequent treatment with a strong second base (which may be the same as or different from the strong first base) removes the remaining proton in each of the phosphorus atoms, which results in a second carbon-phosphorus bond and generates , by displacement of the sulfate group, a cis monophospholan (formula 7) or a cis / cis bisphospholane (formula 8). The reaction can be carried out in an organic solvent, such as THF, Et 2 O, dimethoxyethane, and the like, in an inert atmosphere (for example, nitrogen or argon) and at a temperature between about 0 ° C and reflux conditions. Cyclization is usually carried out at ambient pressure. The delations illustrated in Scheme B generally provide good cis-to-trans ratios of monophospholanes (formula 7) and cis / cis-to-cis / trans ratios of the bisphospholanes (formula 8). As described in the examples section, in many cases, the cis and cis / cis diastereomers can be isolated from the mixtures of cis and trans isomers and from cis / cis and cis / trans isomer mixtures by crystallization or column chromatography. of borane adducts or sulfur adducts of the phosphines. As also described in the examples section, the procedure shown in Scheme B does not appear to generate trans / trans isomers. The cis and cis / cis stereochemistry observed for monophospholanes (formula 7) and bisphospholanes (formula 8) is surprising. While researchers have recently studied cis stereoselectivity in a cyclization, the elucidation of the stereoselectivity mechanism in these studies was complicated by the existence of many chiral substituents in the cyclization precursor. See E. Vedejs & O. Daugulis, J. Am. Chem. Soc. 121: 5813 (1999); E. Vedejs, O. Daugulis, J. Am. Chem. Soc. 125: 4166 (2003). Scheme C compares the stereoselective cycling mechanism of Vedejs & Daugulis (formula 13 and formula 14) with a stereoselective cyclization mechanism proposed for the formation of phospholane shown in Scheme B. Vedejs & Daugulis credited interactions 1, 3 for the observation that the isolated pair "a" in formula 13 was favored for the displacement of the sulfate group. The resulting product (formula 14) is analogous to the cis monofosfolanes (formula 7) and cis / cis bisphospholanes (formula 8) illustrated in scheme B since the group Ar (aryl) at the phosphorus atom in formula 14 is cis with respect to the condensed 5-membered carbocyclic ring. By analogy, an intermediate in the system of the inventors is presumably represented by formula 15. Given the lack of interactions 1, 3 in formula 15, the lower energy approach of the isolated pair "a" to displace the sulfate group is attributed to the steric interaction of the phenyl substituent with a phospholane ring structure in transition state of lesser unknown energy.

SCHEME C 13 14 15 As shown in scheme B, the trans (trans) trans (formula 9) and bisphospholane (formula 10) monophosphenes are prepared from the corresponding monophospholanes (formula 7) and cis bisphospholanes (formula 8) by epimerization. Pyramidal inversion is a well-known phenomenon for phosphines, as well as for other atoms. See, for example, H. Hommer & B. Gordillo, Phosphorous, Sulfur, and Silicon 177: 465 (2002); W. Egan et al., J. Am. Chem. Soc. 92: 1442 (1970); S. E. Cremer et al., Tetrahedron Lett. 55: 5799 (1968). See also, J.B. Lambert, Topics in Stereochemistry, 6:19 (1971); A. Rauk et al., Angew. Chem. International Edition 9: 400 (1970). However, this subtle transformation has been underutilized in the practical synthesis of P-chirogenic phosphines. Epimerization by pyramidal inversion represents an ideal reaction in terms of atomic efficiency and processing. As shown in scheme B, the monophospholanes (formula 7) and bisphospholanes (formula 8) cis can be epimerized to the trans monofosfolanes (formula 9) and trans / trans bisphospholanes (formula 10), respectively, by heating the compounds of formula 7 or formula 8 to a temperature below the decomposition temperature of the reactants and products. For reasonable reaction times the epimerization substrate is heated to a temperature between about 100 ° C and 250 ° C, inclusive. Reagents and solvent are not necessary to promote epimerization. Although not necessary, epimerization can be carried out in the absence of oxygen to minimize oxide formation. In general, maintaining the oxygen content in the headspace above the reaction mixture by less than about 1% based on the mass is sufficient. As shown in the examples, the epimerization yields can reach 100%. When epimerized products are desired (formula 8 and formula 9) it is convenient to cyclize and then epimerize by a single container procedure. The solvent can be removed from the cyclization reactions in vacuo and the resulting residue (a mixture predominantly of cis or cis / cis phospholanes and sulfate salts) is heated to the appropriate temperature without a solvent in an oil bath under a nitrogen atmosphere. Without being bound by any particular theory, the epimerization mechanism can be explained using a monophospholane (formula 16) shown in scheme D. The mechanism probably involves a transition state that presents an sp2 phosphorus atom (formula 17) which is in balance with each form of the phospholane (formula 16 and formula 18). The reaction is conducted to the more thermodynamically stable trans phospholane (formula 18). As indicated in the examples, certain bisphospholanes (formula 8, R = Me, X = phen-1, 2-diyl, and R = Bn, X = ethanediyl) and monophospholans (formula 7, R = Me, X = phenyl) undergo incomplete epimerization. This is probably the result of similar energies of cis to trans isomers due to reduced steric effects of the small methyl substituents. In addition, the bisphospholane substituted with benzyl (formula 8, R = Bn, X = ethanediyl) is probably difficult to epimerize because the phosphorus atom sp2 in the transition state is not stabilized with an aryl group that acts as a bridge between the two phospholane groups.

SCHEME D 16 17 18 Scheme E shows the preparation of a chiral precursor (formula 21) of pregabalin using a chiral catalyst (formula 19) comprised of a bisphospholane P-quirogenic ligand (formula 2) and rhodium.

As shown in scheme E, the bisphospholane ligand was transformed into a cationic rhodium complex (formula 19) by reaction with [Rh (COD) 2] + OTf in MeOH. The rhodium complex was subsequently used to catalyze the asymmetric hydrogenation of a cyano substituted prochiral olefin (formula 20) to give the chiral precursor (formula 21), which was the single hydrogenation product (96% ee).

SCHEME E t-BuNlV 21 E / Z (1: 5.7) 96% ee FIG. 5 In general, the chemical transformations described throughout the specification can be carried out using substantially stoichiometric amounts of reagents, although certain reactions can benefit from the use of an excess of one or more of the reagents. From In addition, many of the reactions described throughout the specification can be carried out at about room temperature, but certain reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields and the like. In addition, any reference in the description to a stoichiometric range, a temperature range, a pH range etc., includes the indicated end points. Further desired enantiomers of any of the compounds described in this invention can be enriched by classical resolution, chiral chromatography or recrystallization. For example, compounds having stereogenic centers can be reacted with an enantiomerically pure compound (eg, acid or base) to give a pair of diastereomers, each consisting of a single enantiomer, which are separated by fractional recrystallization or chromatography. The desired enantiomer is subsequently regenerated from the appropriate diastereomer. Additionally, the desired enantiomer can often be further enriched by recrystallization from a suitable solvent when it is available in sufficient quantity (e.g., typically not much less than about 85% ee, and in some cases, not much less than about 90% ee). Many of the compounds described in this description are capable of forming pharmaceutically acceptable salts. These salts include, without limitation, acid addition salts (including diacids) and basic salts.

Pharmaceutically acceptable acid addition salts include non-toxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as non-toxic salts derived from organic acids, such as acids aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts therefore include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate.oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate and the like. Basic pharmaceutically acceptable salts include non-toxic salts derived from bases, including metal cations, such as alkali metal or alkaline earth metal cations, as well as amines. Examples of suitable metal cations include, without limitation, sodium cations (Na +), potassium cations (K +), magnesium cations (Mg2 +), calcium cations (Ca2 +) and the like. Examples of suitable amines include, without limitation, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine,? / -methylglucamiene, and procaine. For a discussion of useful acid addition and basic salts, see S. M. Berge et al., "Pharmaceutical Salts ", 66 J. of Pharm. Sci., 1-19 (1977), see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002) .A pharmaceutically acceptable acid addition salt can be prepared. acceptable (or basic salt) by contacting a free base of the compound (or free acid) with a sufficient amount of a desired acid (or base) to produce a non-toxic salt.The salt can then be isolated by filtration if it precipitates The solution, or by evaporation to recover the salt, can also regenerate the free base (or free acid) by contacting the acid addition salt with a base (or the basic salt with an acid). physical properties of the free base (or free acid) and its respective acid addition salt (or basic salt) may differ (eg, solubility, crystal structure, hygroscopicity, etc.), a free base of the compound and the salt of addition of acid (or its free acid and basic salt) are otherwise the same for the purposes of this description. Additionally, certain compounds of this disclosure may exist as an unsolvated form or as a solvated form, including hydrated forms. Pharmaceutically acceptable solvates include hydrates and solvates in which the crystallization solvent may be substituted isotopically, for example D2O, d6-acetone, d6-DMSO, etc. Generally, for the purposes of this description, solvated forms, including hydrated forms, are the same as unsolvated forms. Therefore, unless expressly indicated, all references to the free base, the free acid or the unsolvated form of a compound also it includes the corresponding acid addition salt, basic salt or solvated form of the compound. The disclosed compounds also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass normally found in nature. Examples of suitable isotopes for inclusion in the disclosed compounds include, without limitation, hydrogen isotopes, such as 2H and 3H; carbon isotopes, such as 13C and 14C; nitrogen isotopes, such as 15N; oxygen isotopes, such as 17O and 18O; phosphorus isotopes, such as 31P and 32P; isotopes of sulfur, such as 35S; isotopes of fluorine, such as 18F; and chlorine isotopes, such as 36CI. The use of isotopic variations (for example, deuterium, 2H) can give certain therapeutic advantages resulting from greater metabolic stability, for example, greater half-life in vivo at lower dosage requirements. Additionally, certain isotopic variations of the disclosed compounds may incorporate a radioactive isotope (e.g., tritium, 3 H, or 14 C), which may be useful in drug and / or substrate tissue distribution studies.

EXAMPLES The following examples are intended to be illustrative and not limiting, and represent specific embodiments of the present invention.

GENERAL PROCEDURES AND MATERIALS All reactions and manipulations were carried out under nitrogen in conventional laboratory glass instruments. The recrystallization of the rhodium complex and the asymmetric hydrogenation were carried out in a glove box filled with nitrogen. THF (anhydrous, 99.9%), acetonitrile (99.8% anhydrous), ether (99.8% anhydrous), methyl alcohol (99.8% anhydrous) and dichloromethane (99.8% anhydrous) were purchased from Aldrich Chemical Co Thionyl chloride (99.5%), ruthenium chloride (III) hydrate (99.98%), sodium periodate (99%) and n-BuLi (2.5 M in hexanes) were purchased from Aldrich Chemical Co. , 5-cyclooctadiene) rhodium (I), trifluoromethanesulfonate (99%), 1,2-bis (phosphino) benzene (+ 98%), 1,2-bis (phosphino) ethane (99%), and phenylphosphine (99%) ) at Strem Chemicals Inc. Hydrogen gas was used from a reading bottle supplied by Specialty Gas. Hydrogenations were carried out in a Griffin-Worden pressure vessel supplied by Kimble / Kontes.

EXAMPLE 1 Preparation of (4S) -4-benzyl-1,3,2-dioxathiepane-2,2-dioxide (formula 5, R = Bn) It was dissolved in a 250 ml round bottom flask (S) -5-phenyl-pentan-1,4-diol (formula 4, R = Bn, 8.97 g, 49.8 mmol) in CH2Cl2 (150 ml) and then placed in N2 and cooled to 0 ° C. Thionyl chloride (4.54 ml, 62.2 mmol) was added at once via syringe. No exotherm was observed. The reaction was warmed to room temperature and stirred for 30 minutes. HCl gas evolution was observed from the solution. The solution was clear brown. The reaction was then placed in an oil bath and subjected to open reflux in the air for 15 hours. CH2Cl2 was then removed in a rotary evaporator. The light brown residue was redissolved in CH2CI (150 ml) and CH3CN (150 ml). To this solution was added H2O (300 ml). The resulting solution was cooled to 0 ° C and stirred in air. RuCI3 x H2O (0.112 g, 0.498 mmol) was added in one portion and then sodium periodate (21.3 g, 99.5 mmol) was added portionwise until it became apparent that the reaction was not exothermic. The reaction was stirred for 5 hours during which it turned from light brown to black. The reaction was transferred to a separatory funnel and the lower black phase was separated. The upper aqueous phase was then extracted with ethyl ether (300 ml). The ether phase was combined with the lower black phase and the resulting solution was filtered through a short pad of silica gel washing with ethyl ether to produce a clear yellow solution. The leak was necessary to eliminate salts of Ru. The volatile compounds were removed in a rotary evaporator leaving a light green oil. The oil recristallizó after resting for 20 minutes. A small amount of ethyl ether was added and then the crystals were collected and washed with hexane to yield a white crystalline product (4.83 g). A second batch formed in the mother liquors after addition of hexane (from the washings) gives additional white crystals (3.30 g). The white crystalline product was stable in air for more than 6 months. The remaining ruthenium salts in the crystalline product (as observed by the appearance of green solids after redissolving the crystals in THF) can be removed by redissolution of the product in THF, the suspension is filtered through a short bed of silica, and the filtrate is recrystallized. Yield: 67%; [a] 24D = + 16.0 ° (c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl 3) d 1.97 (m, 4 H), 2.92 (dd, J = 13.91, 7.08 Hz, 1 H), 3.14 (dd, J = 14.03, 6.22 Hz, 1 H), 4.34 (m, J = 12.08, 3.42, 3.29 Hz, 1 H), 4.45 (m, J = 11.83, 11.83, 1.46 Hz, 1 H), 4.83 (m, 1 H), 7.22 (m, 2 H), 7.29 (m, 3 H) ); 13 C NMR (101 MHz, CDCl 3) d 27.41, 32.02, 41.J9, 71.91, 85.19, 127.45, 128.95, 129.73, 135.57. Analysis calculated for CnH? 4O4S: C, 54.53, H, 5.82. Found: C, 54.60; H, 5.77.

EXAMPLE 2 Preparation of (4R) -4-methyl-1,3,2-dioxathiepane-2,2-dioxide (formula 5. R = Me) The title compound was prepared from (R) -pentan-1,4-diol and SOCI2 using a method similar to the procedure of Example 1. The resulting oil was chromatographed on silica gel (25% ethyl acetate). hexanes) providing the title compound. Yield: 48%; e.g. normal 117.2 ° C; [a] 24D = -6.1 ° (c 1.0, CHCI3); 1 H NMR (400 MHz, CDCl 3) d 1.43 (d, J = 6.34 Hz, 3 H), 1.94 (m, 3 H), 2.11 (m, 1 H), 4.35 (m, 1 H), 4.44 (td, J = 11.90, 1.34 Hz, 1 H), 4.79 (m, J = 15.10, 6.30, 6.30, 3.05 Hz, 1 H); 13 C NMR (101 MHz, CDCl 3) d 21.65, 27.42, 34.68, 72.01, 82.06. HRMS (El): (M + H) + 167.0337 ((M + H) +, exact mass calculated for C5H11O.4S: 167.0378).

EXAMPLE 3 Preparation of (4S) -4- (methoxymethyl) -1,3,2-dioxathiepane-2,2-dioxide (formula 5, R = methoxymethyl) The title compound was prepared from (S) -5-methoxy-pentane-1,4-diol and SOCI2 using a method similar to the process of Example 1. The resulting oil was chromatographed on silica gel (25% ethyl acetate / hexanes) to give the title compound. Performance: 53% yield; [a] 24D = -9.8 ° (c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl 3) d ppm 2.00 (m, 3H), 2.10 (m, 1 H), 3.39 (d, J = 2.68 Hz, 3 H), 3.50 (dd, J = 10.86, 4.76 Hz, 1 H ), 3.59 (dd, J = 10.74, 5.37 Hz, 1 H), 4.38 (m, 1 H), 4.46 (td, J = 11.71, 1.46 Hz, 1 H), 4.71 (m, 1 H); 13 C NMR (101 MHz, CDCl 3) d ppm 27.14, 29.50, 59.61, 72.12, 73.65, 82.61. Analysis calculated for C6H12O5S: C, 36.73, H, 6.16. Found: C, 36.74; H, 6.01.

EXAMPLE 4 Preparation of (1R, 2R) -1-phenyl-2-benzylphospholane (formula 7, R = Bn, X = Ph) It was added to a 25 ml round bottom flask equipped with a magnetic stirring bar phenylphosphine (0.300 g, 2.73 mmol). The THF flask (10 ml) was added via syringe and the reaction mixture was placed under nitrogen and cooled to 0 ° C. To the solution was added n-BuLi (1.0 eq., 1.0 ml of a 2.5 M solution in hexanes) and the reaction mixture was stirred for 1 hour at 0 ° C. The reaction solution was yellow, which was indicative of phosphine anion formation. A solution of (4S) -4-benzyl-l, 3,2-dioxathiepane 2,2-dioxide in THF (5 ml) was then added via a syringe. The reaction was stirred for 30 minutes at 0 ° C and then for 30 minutes at room temperature. The reaction was again cooled to 0 ° C and then n-BuLi (1.15 eq., 1.25 ml of a 2.5 M solution in hexanes) was added dropwise over five minutes. The reaction was stirred for 30 minutes at 0 ° C and then warmed to room temperature and stirred for 45 minutes. The reaction was stopped with MeOH (1 ml) yielding a white thick solution. The volatile compounds were removed in vacuo and then the white oily solid was triturated with ethyl ether and then filtered off with the sulfate salts. The solvent was then removed in the filtrate in vacuo to give a clear oil (603 mg). Yield: 82%; cis: trans = 9.4: 1; 31 P NMR (162 MHz, CDCl 3) d ppm -7.0 (s).

EXAMPLE 5 Preparation of (1R, 2R) -1-phenyl-2-benzylphospholanoborate (formula 22) 22 (1R, 2R) -1-phenyl-2-benzylphospholane (Example 4) was transformed into its borane phosphine derivative, (1R, 2R) -1-phenyl-2-benzylphospholane borane, for characterization purposes. The phospholane was dissolved in THF (10 ml) under nitrogen and waved with a magnetic stir bar. To this solution was added BH3-Me2S (0.273 ml of a 10.0 M solution) by syringe. The reaction was stirred for 30 minutes and then the volatile compounds were removed in a rotary evaporator yielding a white solid. The white solid was recrystallized from hot ethyl acetate (15% in hexanes) to yield white crystals (440 mg). Yield: 61% of (4S) -4-benzyl-1,2,2-dioxathiepane-2,2-dioxide; [a] 20D = -1.3 ° (c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl 3) d 0.86 (m, 3 H), 1.55 (m, 1 H), 1.J 9 (m, 1 H), 2.04 (m, 2 H), 2.24 (m, 3 H), 2.40 (m , 1 H), 2.67 (m, 1 H), 6.98 (m, 2H), 7.18 (m, 3H), 7.51 (m, 3H), 7.73 (m, 2H); 13 C NMR (101 MHz, CDCl 3) d 25.13, 25.46 (d, J = 36.85 Hz), 33.73, 35.82, 42.24, 126.54, 127.74 (d, J = 43.76 Hz), 128.67 (d, J = 18.43 Hz), 128.92 (d, j = 9.21 Hz), 128.96, 131.75 (d, J = 2.30 Hz), 133.25 (d, J = 8.45 Hz), 140.04 (d, J = 10.75 Hz); 31P NMR (162 MHz, CDCl 3) d 32.76. Analysis calculated for C17H22BP: C, 76.15, H, 8.27. Found: C, 73.16; H, 8.29.

EXAMPLE 6 Preparation of (1R, 2S) -1-phenyl-2-methylphospholane (formula 7, R = Me, X = Ph) The title compound was prepared from 2,2-dioxide of (4R) -4-methyl-1, 3,2-dioxathiepane and phenylphosphine using a method similar to the procedure of Example 4. Yield: 72%, cis: trans = 7.0: 1; 31 P NMR (162 MHz, CDCl 3) d ppm -5.80 (s).

EXAMPLE 7 (1R, 2S) -1-Phenyl-2-methylphospholane borane (formula 23) 2. 3 (1 R, 2S) -1-phenyl-2-methylphospholane (example 6) was converted into its borane phosphine derivative, (1 R, 2S) -1-phenyl-2-methylphospholane borane, for characterization purposes, by reaction with BH3-Me2S in a manner similar to the procedure of example 5. The resulting diastereoisomers were isolated as an oil, but were inseparable by column chromatography on silica gel. 1 H NMR (400 MHz, CDCl 3) d 0.84 (m, 3 H), 0.83 (dd, J = 14.41, 6.59 Hz, 3 H), 1.53 (m, 1 H), 1.85 (m, 1 H), 2.19 (m, 5H), 7.48 (m, 3H), 7.68 (m, 2H); 13 C NMR (101 MHz, CDCl 3) d 14.06, 25.09 (d, J = 36.08 Hz), 34.64, 35.07 (d, J = 36.08 Hz), 36.10, 128.79 (m, J = 9.21 Hz), 131.48, 133.09 (d, J = 8.44 Hz); 31 P NMR (162 MHz, CDCl 3) d 33.84 (m). HRMS (El): (M-BH3 + H) + 179.1136 ((M-BH3 + Hf, exact mass calculated for CnH16P: 179.0990).

EXAMPLE 8 Preparation of (1R, 2R) -1-phenyl-2- (methoxymethyl) phospholane (formula 7, R = methoxymethyl, X = Ph) The title compound was prepared from (4S) -4- (methoxymethyl) -1,2,2-dioxathiepane and phenylphosphine 2,2-dioxide using a method similar to the procedure of Example 4. Yield: 70%; cis.'trans = 16.5: 1; 31 P NMR (162 MHz, CDCl 3) d ppm - 10.7 (s).

EXAMPLE 9 Preparation of (1R, 2R) -1-phenyl-2- (methoxymethyl) phospholanesulfide (formula 24) 24 (1 R, 2R) -1-phenyl-2- (methoxymethyl) phospholane was transformed into its phosphinsulfide derivative, (1 R, 2R) -1-phenyl-2- (methoxymethyl) phospholanesulfide, for characterization purposes. The crude phospholane was dissolved from the cyclization process in toluene and then sulfur (1.25 eq. Based on (4S) -4- (methoxymethyl) -1,2,2-dioxathiepane-2,2-dioxide) was added in one portion. The reaction was heated to 50 ° C and stirred under nitrogen for 12 hours and then the volatiles were removed in vacuo yielding a clear oil. The oil was chromatographed on silica gel (30% ethyl acetate in hexanes) yielding the title compound as a single diastereomer. Yield: 31% from 2,2-dioxide (4S) -4- (methoxymethyl) -1,2,2-dioxathiepane; e.g. 171.3 ° C; [a] 24D = + 56.2 ° (c 1.0, CHCI3); 1 H NMR (400 MHz, CDCl 3) d 1.60 (m, 1 H), 2.23 (m, 4 H), 2.63 (m, 2 H), 2.97 (m, 1 H), 2.97 (s, 3 H), 3.12 (m, 1 H), 7.48 (m, 3H), 7.86 (m, 2H); 13 C NMR (101 MHz, CDCl 3) d ppm 24.32 (d, J = 4.61 Hz), 30.99 (d, J = 9.21 Hz), 34.16 (d, J = 54.51 Hz), 50.00 (d, J = 52.21 Hz), 58.66, 71.25 (d, J = 3.07 Hz), 128.52 (d, J = 11.52) Hz), 128.88 (d, J = 11.52 Hz), 130.27 (d, J = 67.56 Hz), 131.82 (d, J = 9.98 Hz); 31 P NMR (162 MHz, CDCl 3) d ppm 60.72 (s). Analysis calculated for C-, 2H20BOP: C, 59.98, H, 7.13. Found: C, 59.95; H, 7.07.

EXAMPLE 10 Preparation of 1,2-bis ((1R, 2R) -2-benzylphospholane) benzene (formula 8, R ~ Bn, X = phen-1,2-diyl) To a 25 ml round bottom flask equipped with a magnetic stirring bar 1, 2-bis (phosphino) benzene (0.330 g, 2.33 mmol) was added. THF (15 ml) was added to the flask by syringe and the reaction was placed under nitrogen and cooled to 0 ° C. To the solution was added n-BuLi (1.0 eq., 1.9 ml of a 2.5 M solution in hexanes) and the reaction was stirred for 1 hour at 0 ° C. The reaction solution was yellow, which was indicative of the formation of phosphine anion. A solution of (4S) -4-benzyl-l, 3,2-dioxathiepane 2,2-dioxide in THF (5 ml) was then added via syringe. The reaction mixture was stirred for 30 minutes at 0 ° C and then for 30 minutes at room temperature. The reaction mixture was again cooled to 0 ° C and then n-BuLi (2.3 eq., 2.1 ml of a 2.5 M solution in hexanes) was added dropwise over five minutes. The reaction was stirred for 30 minutes at 0 ° C and then warmed to room temperature and stirred for 45 minutes. The reaction was stopped with MeOH (1 ml) yielding a white thick solution. The volatiles were removed in vacuo and then the white oily solid was triturated with ethyl ether and then filtered to remove the sulfate salts. The solvent was then removed in the vacuum filtrate yielding the title compound as a clear oil (780 mg). Yield: 78%; cis / cis: cis / trans = 4.2: 1. The product can be recrystallized with hot 10: 1 MeOH / CHCl3 yielding the pure cis / cis diastereomer (60% recovery). 1 H NMR (400 MHz, CDCl 3) d 1.40 (m, 2 H), 1.61 (m, 4 H), 1.80 (dd, J = 13.68, 11.72 Hz, 2H), 2.00 (m, 6H), 2.46 (m, 2H), 3.00 (d, J = 13.68, 3.66 Hz, 2H), 6.97 (m, 4H), 7.06 ( m, 2H), 7.14 (m, 4H), 7.29 (m, 2H), 7.37 (m, 2H); 13 C NMR (101 MHz, CDCl 3) d ppm 24.07, 26.09, 32.70, 38.59 (t, J = 3.84 Hz), 42.62 (t, J = 7.68 Hz), 128.32 (m, J = 5.37 Hz), 128.45, 128.92, 131.64 (t, J = 1.54 Hz), 142.59 (t, J = 3.84 Hz), 143.99; 31 P NMR (162 MHz, CDCl 3) d -16.53 (s).

EXAMPLE 11 Preparation of 1,2-bis ((1R, 2S) -2-methylphospholane) benzene (formula 8, R = Me, X = phen-1,2-diyl) The title compound was prepared from 2,2-dioxide of (4R) -4-methyl-1, 3,2-dioxathiepane and 1,2-bis (phosphino) benzene using a method similar to the procedure of Example 10. Yield: 52%; cis / cis: cis / trans = 6.1: 1; 31 P NMR (162 MHz, CDCl 3) d ppm -15.1 (s).

EXAMPLE 12 Preparation of 1,2-bis ((1 R, 2S) -2-methylphospholanesulfide) -benzene (formula 25) 1, 2-bis ((1 R, 2S) -2-methylphospholane) benzene was transformed into its phosphinsulfide derivative, 1,2-bis ((1 R, 2S) -2-methylophospholansulfide) benzene, for characterization purposes, by reaction with sulfur (2.2 eq) of a Similar to the procedure of Example 9. The resulting white solid was recrystallized from hot toluene yielding the title compound as a single diastereomer. Yield: 44% from 2,2-dioxide (4R) -4-methyl-1, 3,2-dioxathiepane; [a] 24D = + 2.3 ° (c 1.0, CHCI3); 1 H NMR (400 MHz, CDCl 3) d 0.98 (dd, J = 19.29, 7.57 Hz, 6H), 1.76 (m, 2H), 1.96 (m, 2H), 2.25 (m, 4H), 2.45 (m, 2H) , 3.14 (s, 4H), 7.50 (m, 2H), 7.64 (m, 2H); 3 C NMR (101 MHz, CDCl 3) d 18.47, 23.30 (t, J = 3.84 Hz), 33.16, 42.60 (d, J = 52.98 Hz), 130.50, 132.99 (t, J = 9.21 Hz), 135.93 (dd, J = 66.03, 6.91 Hz); 31 P NMR (162 MHz, CDCl 3) d 71.84 (s); HRMS (El): (M + H) + 343.0887 ((M + H) +, exact mass calculated for C 16 H 25 P 2 S: 343.0873).

EXAMPLE 13 Preparation of 1,2-bis ((1S, 2R) -2-benzylphospholane) ethane (formula 8, R = Bn, X = ethanediyl) The title compound was prepared from 2,2-dioxide of (4S) -4-benzyl-1, 3,2-dioxathiepane and 1,2-bis-phosphanyl-ethane using a method similar to the procedure of Example 10. Yield: 49%; cis / cis: cis / trans = 6.1: 1; J1P NMR (162 MHz, CDCl3) d ppm -13.3 (s).

EXAMPLE 14 Preparation of 1,2-bis ((1S, 2R) -2-benzylphospholane borane) -ethane (formula 26) 26 1, 2-bis ((1S, 2R) -2-benzylphospholane) ethane was transformed into its bis-borane derivative, 1,2-bis ((1S, 2R) -2-benzylphospholanoborane) ethane, for characterization purposes, by reaction with BH3-Me2S (2 eq) in a manner similar to the procedure of example 5. Recrystallization of the product from isopropanol afforded the title compound as a single diastereomer. Yield: 35%; [a] 24D = -25.3 ° (c 1, 0, CHCl3); 1 H NMR (400 MHz, CDCl 3) d 0.69 (m, 6H), 1.42 (m, 2H), 1.68 (m, 6H), 2.01 (m, 8H), 2.33 (m, 2H), 2.52 (m, 2H) , 3.00 (m, 2H), 7.21 (m, 10H); 13 C NMR (101 MHz, CDCl 3) d 16.46 (d, J = 25.34 Hz), 24.64, 24.96 (d, J = 34.55 Hz), 33.05, 34.70, 40.48 (d, J = 33.01 Hz), 126.85, 128.79 , 128.83, 139.51 (d, J = 9.98 Hz); 31 P NMR (162 MHz, CDCl 3) d 36.78 (s); Analysis calculated for C 24 H 38 B 2 P 2: C, 70.29; H, 9.34. Found: C, 70.15; H, 9.45.

EXAMPLES 15 TO 20 Preparation of trans monophospholans (formula 9) and trans / trans bisphospholanes (formula 10) Sequential cyclization and epimerization in a single container. After stopping the cyclization reaction in Example 4, 6, 8, 10, 11 and 13 with MeOH and removing the solvent, each of the crude cis monophospholanes (formula 7) and cis / cis bisphospholanes (formula 8) was placed. in N2 and heated in an oil bath to 190 ° C for 8 hours (cyclization products of example 4, 6, 8, 10 and 11) or 205 ° C for 20 hours (cyclization products of example 13). After cooling to room temperature the vacuum connection was quickly replaced by a septum and the flask was immediately placed in N2. Care was taken to cool the epimerization product before exposing it to air for a short period to avoid oxidation. Ethyl ether (15 ml) was added to the flask by syringe and the product, which had a gelatinous consistency, was vigorously ground. The ethyl ether was collected using a syringe equipped with a 15.24 cm needle and filtered through a 0.20 micron SFCA syringe filter into another round bottom flask under N2. White solid left in the flask (salts sulfate). The crushing was repeated twice. By combining the ether extracts and evaporating the solvent using a vacuum pump an oily product was obtained. 31P NMR of an aliquot of the oil showed clean conversion predominantly to trans and trans / trans products in ratios described below.

EXAMPLE 15 (1S, 2S) -1-Phenyl-2-methylphospholane (formula 9, R = Me, X = Ph) The title compound was prepared by epimerization of (1 R, 2S) -1-phenyl-2-methylphospholane (formula 7, R = Me, X = Ph). Cis: trans = 1: 3.2; 3 P NMR (162 MHz, CDCl 3) d 2.2 (s).

EXAMPLE 16 (1S, 2R) -1-Phenyl-2- (methoxymethyl) phospholane (formula 9, R = methoxymethyl, X = Ph) The title compound was prepared by epimerization of (1R, 2R) -1-phenyl-2- (methoxymethyl) phospholane (formula 7, R = methoxymethyl, X = Ph). Cis: trans = 1: 7.1; 31P NMR (162 MHz, CDCl 3) d -6.2 (s).

EXAMPLE 17 (1S.2R) -1-Phenyl-2-benzylphospholane (formula 9, R = Bn, X = Ph) The title compound was prepared by epimerization of (1 R, 2R) -1-phenyl-2-benzylphospholane (formula 7, R = Bn, X = Ph). 100% Trans; 31 P NMR (162 MHz, CDCl 3) d -2.9 (s).

EXAMPLE 18 Preparation of 1,2-bis ((1S, 2S) -2-methylphospholane) benzene (formula 10, R = Me, X = phen-1,2-diyl) The title compound was prepared by epimerization of 1,2-bis ((1R, 2S) -2-methylphospholane) benzene (formula 8, R = Me, X = phen-1,2-diyl). Cis / trans: trans / trans = 1: 4; 31P NMR (162 MHz, CDCl 3) d -6.2 (s).

EXAMPLE 19 Preparation of 1,2-bis ((1S, 2R) -2-benzylphospholane) benzene (formula 8, R = Bn, X = phen-1,2-diyl) The title compound was prepared by epimerization of 1, 2-bis ((1 R, 2R) -2-benzylphospholane) benzene (formula 8, R = Bn, X = phen-1,2-diyl). Trans / 100% trans; 31 P NMR (162 MHz, CDCl 3) d -8.1 (s).

EXAMPLE 20 Preparation of 1,2-bis ((1R, 2R) -2-benzylphospholane) ethane (formula 10, R = Bn, X = ethanediyl) The title compound was prepared by epimerization of 1,2-bis ((1S, 2R) -2-benzylphospholane) ethane (formula 8, R = Bn, X = ethanediyl). Cis / trans: trans / trans = 1: 2.3; 4% of the cis / cis isomer remained uncimerized).

EXAMPLE 21 Preparation of (1S, 2S) -1-phenyl-2-methylphospholane borane (formula 27) 27 (1S, 2S) -1-phenyl-2-methylphospholane was transformed into its borane derivative, (1S, 2S) -1-phenyl-2-methylphospholane borane, for characterization purposes using a method similar to the procedure of Example 5. Resulting diastereomers were isolated as an oil, but were not separable by column chromatography on silica gel. Yield: 72% from 2,2-dioxide (4R) -4-methyl-1, 3,2-dioxathiepane; 1 H NMR (400 MHz, CDCl 3) d 0.83 (m, 3 H), 1.27 (dd, J = 16.36, 7.08 Hz, 3 H), 1.62 (m, 1 H), 1.86 (m, 1 H), 2.20 (m, 5H), 7.46 (m, 3H), 7.68 (m, 2H); 13 C NMR (101 MHz, CDCl 3) d 14.40 (d, J = 5.37 Hz), 26.18, 26.94 (d, J = 38.39 Hz), 35.28 (d, J = 35.32 Hz), 36.29 (d, J = 6.91 Hz), 129.03 (d, J = 9.98 Hz), 131.48, 131.73 (d, J = 24.57 Hz) , 131.67 (d, J = 9.21 Hz); HRMS (El): (M-BH3 + H) + 179.1136 ((M-BH3 + H) +, exact mass calculated for CnH16P: 179.0990).

EXAMPLE 22 Preparation of (1S, 2R) -1-phenyl-2- (methoxymethyl) phospholanesulfide (formula 28) 28 (1S, 2R) -1-phenyl-2- (methoxymethyl) phospholane was converted to its phosphinsulfide derivative, (1S, 2R) -1-phenyl-2- (methoxymethyl) phospholanesulfide, for characterization purposes using a method similar to Method of Example 9. Column chromatography on silica gel (30% ethyl acetate in hexanes) provided a clear oil as a single diastereomer. Yield: 31% from (4S) -4- (methoxymethyl) -1,3,2-dioxathiepane 2,2-dioxide; e.g. 155.6 ° C; 1 H NMR (400 MHz, CDCl 3) d 1.84 (m, 2 H), 2.27 (m, 3 H), 2.47 (m, 1 H), 2.63 (m, 1 H), 3.29 (s, 2 H), 3.56 (m, 1 H), 3.75 (m, 1 H), 7.48 (m, 3H), 7.86 (m, 2H); 13 C NMR (101 MHz, CDCl 3) d 25.11 (d, J = 3.84 Hz), 30.41 (d, J = 9.98 Hz), 36.84 (d, J = 55.28 Hz), 43.33 (d, J = 52.98 Hz), 59.20 , 71.84 (d, J = 4.61 Hz), 128.88 (d, J = 11.52 Hz), 130.59 (d, J = 10J5 Hz), 131.69 (d, j = 3.07 Hz), 133.95 (d, J = 71.40 Hz); 31 P NMR (162 MHz, CDCl 3) d 60.69 (s). Analysis calculated for C12H20BOP: C, 59.98; H, 7.13. Found. C, 59.321; H, 6.85.

EXAMPLE 23 Preparation of (1S, 2R) -1-phenyl-2-benzylphospholane-borane (formula 29) 29 (1S, 2R) -1-phenyl-2-benzylphospholane was transformed into its borane derivative, (1S, 2R) -1-phenyl-2-benzylphospholane borane, for characterization purposes using a method similar to the procedure of example 5. isolated the product as a solid, which was recrystallized from ethyl acetate (15% in hexanes) to give the title diastereomer. Yield: 61%; 1 H NMR (400 MHz, CDCl 3) d 1.02 (m, 3 H), 1.65 (m, 1 H), 1.80 (m, 1 H), 2.14 (m, 4 H), 2.47 (m, 1 H), 2.81 (m, 1 H), 3.12 (m, 3 H), 7.16 (m, 5 H), 7.44 (m, 3 H), 7.64 (m, 2H); 13 C NMR (101 MHz, CDCl 3) d 26.00, 27.02 (d, J = 39.16 Hz), 33. 51 (d, J = 6.91 Hz), 35.46 (d, J = 6.91 Hz), 42.96 (d, J = 33.01 Hz), 126.44, 128.57, 128.98, 129.09, 131.35 (d, J = 2.30 Hz), 140.62 (d. d, J = 12.28 Hz); 31 P NMR (162 MHz, CDCl 3) d 34.02 (s).

EXAMPLE 24 Preparation of 1,2-bis ((1S, 2S) -2-methylphospholanesulfide) -benzene (formula 30) 1, 2-bis ((1S, 2S) -2-methylphospholane) benzene was converted into its phosphinesulfide derivative, 1,2-bis ((1S, 2S) -2-methylphospholanesulfide) benzene, for characterization purposes by reaction with sulfur (2.25 eq) in a manner similar to the procedure of Example 9. The resulting white solid was recrystallized from ethyl acetate (70% in hexanes) to give the title compound as a single diastereomer. Yield: 21% yield from 2,2-dioxide (4R) -4-methyl-1, 3,2-dioxathiepane; [α] 20 D = -179.2 ° (c 1, 0, CHCl 3); 1 H NMR (400 MHz, CDCl 3) d 1.54 (dd, J = 17.95, 6.72 Hz, 6H), 1. 65 (m, 4H), 2.14 (m, 4H), 2.29 (m, 2H), 2.58 (m, 2H), 4.45 (m, 2H), 7.48 (m, J = 1 J1 Hz, 2H), 7.64 (m, m, 2H); 13 C NMR (101 MHz, CDCl 3) d 15.39, 24.30, 34.08, 37.11 (d, j = 50.67 Hz), 38.88 (d, J = 54.51 Hz), 131.21 (dt, J = 8.64, 4.61, 4.41 Hz), 132.72 (dd, J = 10.37 Hz), 139.60 (dd, J = 66.41, 8.06 Hz); 31 P NMR (162 MHz, CDCl 3) d 67.39 (s), HRMS (El): (M + H) + 343.0866 ((M + H) +, exact mass calculated for C? 6H25P2S2: 343.0873).

EXAMPLE 25 Preparation of 1,2-bis ((1S, 2R) -2-benzylphospholane borane) benzene (formula 31) 1, 2-bis ((1S, 2R) -2-benzylphospholane) benzene was converted into its bis-borane, 1,2-bis ((1S, 2R) -2-benzylphospholaneborane) benzene derivative, for characterization purposes, by reaction with BH3-Me2S (2 eq) in a manner similar to the procedure of example 5. Recrystallization of the product from THF gave the title compound as white crystals.

Yield: 44% from (4S) -4-benzyl-1,2,2-dioxide, 3,2-dioxathiepane as a single diastereomer; [a] 20D = -99.4 ° (c 1.1, CHCl3); 1 H NMR (400 MHz, CDCl 3) d 1.02 (m, 6 H), 1.54 (m, 2 H), 1.70 (m, 2 H), 1.94 (s, 2 H), 2.12 (m, 4 H), 2.70 (s, 2 H) , 2.92 (s, 2H), 3.35 (m, 2H), 3.52 (s, 2H), 7.27 (s, 10H), 7.49 (s, 2H), 7.63 (s, 2H); 13 C NMR (101 MHz, CDCl 3) d 25.72, 27.80 (d, J = 33.78 Hz), 32.94 (d, J = 7.68 Hz), 37.06 (d, J = 5.37 Hz), 44.80 (d, J = 33J8 Hz) , 126.79, 128.95 (d, J = 9.98 Hz), 130.37 (d, J = 6.91 Hz), 133.19, 136.85 (d, J = 6.14 Hz), 137.24 (d, J = 5.38 Hz), 140.43 (d, J = 13.82 Hz); 31 P NMR (162 MHz, CDCl 3) d 42.74 (s). Analysis calculated for C28H38B2P2: C, 73.40; H, 8.36. Found: C, 73.36; H, 8.61.

EXAMPLE 26 Preparation of rRh (1,2-bis (1S, 2R) -2-benzylphospholane) benzene) - (COD) r OTf (formula 19) 1, 2-bis ((1S, 2R) -2-benzylphospholane) benzene (200 mg, 0.465 mmol) was dissolved in THF (5 ml) and was given dropwise with stirring to a solution of [Rh (COD) 2 ] + OTf (211 mg, 0.451 mmol) in MeOH (5 mL). The metal solution turned from dark red to orange. The reaction was stirred for 45 minutes and then the volatiles were removed in vacuo. The remaining orange paste was washed with ether and hexane producing a solid in orange crust form. The product was dissolved in the minimum amount of THF. The addition of a small amount of hexane immediately produced small red crystals. The recrystallization medium was allowed to stand for two hours and then the solvent was removed with a pipette. The orange crystals were washed three times with hexane and the crystals were dried in vacuo (224 mg). Yield: 61%; 1 H NMR (400 MHz, CDCl 3) d 1.56 (m, 2 H), 1.85 (m, 4 H), 2.05 (m, 2 H), 2.32 (m, 4 H), 2.54 (m, 8 H), 2.87 (m, 4 H) , 3.14 (m, 2H), 5.31 (d, J = 102.33 Hz), 6.73 (d, J = 7.08 Hz), 6.97 (m, 6H), 7.44 (m, 2H), 7.57 (m, 2H); 13 C NMR (101 MHz, CDCl 3) d 14.06, 14.40 (d, J = 5.37 Hz), 25.09 (d, J = 36.08 Hz), 26.18, 26.94 (d, J = 38.39 Hz), 35.08 (d, J = 36.08 Hz), 35.27 (d, J = 35.32 Hz), 36.11, 36.29 (d, J = 6.91 Hz), 128.79 (d, J = 9.21 Hz), 129.04 (d, J = 9.98 Hz), 131.27 (d, J = 2.30 Hz), 131.61 (d, J = 46.07 Hz), 131.49 (d, J = 2.30 Hz), 131.67 (d, J = 9.21 Hz), 133.09 (d, J = 8.44 Hz); 31 P NMR (162 MHz, CDCl 3) d 63.05 (d, J = 148.33 Hz).

Determination of isomeric phospholane ratios of cyclization and epimerization cis: trans ratios of monophospholanes were measured (formula 7 and formula 9) by integration of their respective 31P NMR signals. The cis / cis: cis / trans ratios were measured by integration of 31P NMR signals either of the free bisphospholanes after reactions of cyclization (formula 8) or corresponding sulfur or borane adducts (e.g., formula 25 and 26). Similarly, cis / trans: trans / trans ratios were measured by integrating 31P NMR signals either of the free bisphospholanes after epimerization reactions (formula 10) or corresponding sulfur or borane adducts (eg, formula 30 to 31). ). While the cis / cis and trans / trans products of the reactions of the cyclization and epimerization reactions were isolated and characterized, this was not the case for the cis / trans derivatives. However, cis / trans derivatives were easily identified in the 31 P NMR spectrum by observation of two 31 P NMR signals with equal coupling constants.

Assignment of relative and absolute stereochemistry of cyclized and epimerized products All cis (formula 7) and cis / cis (formula 8) products were assigned by analogy to the relative and absolute stereochemistry of 1,2-bis ((1 R, 2S) -2-methylphospholane) benzene, which was demonstrated by the crystal structure of its bis-sulfide derivative (formula 25). All trans and trans / trans products were assigned by analogy to the relative and absolute stereochemistry of (1S, 2R) -1-phenyl-2-benzylphospholane, which was demonstrated by the crystal structure of its borane derivative (formula 29). It should be noted that, as used in this specification and in the appended claims, singular items such as "a" and "he" may refer to an object or a plurality of objects unless the context clearly indicate otherwise. Thus, for example, reference to a composition containing "a compound" may include a single compound or two or more compounds. The above description is intended to be illustrative and not restrictive. Many modalities will be apparent to those skilled in the art upon reading the above description. The scope of the invention should not be determined, therefore, with reference to the appended claims.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A method for making compounds of formula 9, or formula 10, or opposing enantiomers thereof, wherein R is C 1 alkyl, haloalkyl C3-8 cycloalkyl, C3-8 halocycloalkyl, alkanoyl, C1-6 alkoxy, C6-6 alkoxy-C-? 6 alkyl, C6-6 alkoxycarbonyl, aryl, C1-6 arylalkyl, aryloxy, C? -6 arylalkoxy, aryloxycarbonyl, Ci-β-, or carboxy arylalkoxycarbonyl, and each of the C3-8 aryl and cycloalkyl moieties are independently substituted or unsubstituted and X is C? -? 2 alkyl, C1-12 alkanediyl, or phen-1,2-diol, in which phen-1,2-diyl is substituted or unsubstituted, the method comprising the epimerization of compounds of formula 7, or formula 8, 8 or opposite enantiomers thereof, giving the compounds of formula 9, or formula 10, or the opposite enantiomers thereof, respectively, wherein R and X in formula 7 and formula 8 are as defined in formula 9 and formula 10.

2. The method according to claim 1, further characterized in that it comprises treatment of a compound of formula 6, X (PH2) n 6, with a first base generating a first intermediate, wherein n in the Formula 6 is 1 or 2 and X is as defined in formula 9 and formula 10; reacting the first intermediate with a compound of formula 5, 5 or an opposite enantiomer thereof, giving a second intermediate; and treating the second intermediate with a second base to give the compounds of formula 7, or formula 8, or opposite enantiomers thereof, wherein R in formula 5 is as defined in formula 9 and formula 10, and the first and second bases are the same or different.

3. A method for preparing compounds of formula 7 or formula 8, or opposite enantiomers thereof, wherein R is C? -6 alkyl, C1-6 haloalkyl, C8 cycloalkyl, C3-8 halocycloalkyl, alkanoyl, C6-C6 alkoxy, C6-6alkoxy, C6-6 alkoxycarbonyl, aryl, C6-6 arylalkyl, aryloxy, C6 arylalkoxy, aryloxycarbonyl, C6-6 arylalkoxycarbonyl. -, or carboxy, and each of the C3-8 aryl and cycloalkyl moieties are independently substituted or unsubstituted, and X is C? -? 2 alkyl, C-M2I O-phen-1,2-diyl alkanediyl, wherein fen-1, 2-diyl is substituted or unsubstituted, the method comprising: treating a compound of formula 6, X (PH2) n 6, with a first base generating a first intermediate, wherein n in the Formula 6 is 1 or 2 and X is as defined in formula 9 and formula 10; reacting the first intermediate with a compound of formula 5, or an opposite enantiomer thereof, giving a second intermediate; and treating the second intermediate with a second base to give the compounds of formula 7, or formula 8, or opposite enantiomers thereof, wherein R in formula 5 is as defined in formula 7 and formula 8, and the first and second bases are the same or different.

4. The methods according to claims 1 and 3, further characterized in that R is C?-6 alkyl, C alco?-6-alkoxy d-6 alkyl, or arylalkyl of C? -6, and X is C1-6alkyl, C-? -2alkanediyl, or phen-1,2-diyl.

5. The methods according to claim 4, further characterized in that R is methyl, ethyl, isopropyl, methoxymethyl, or benzyl, and X is methyl, methylene, ethanediyl, or phen-1,2-diyl. 6.- Compounds of formula 7, or formula 8, Or opposing enantiomers thereof, or complexes, salts, solvates or hydrates thereof, wherein R is methyl, ethyl, isopropyl, methoxymethyl or benzyl, and X is methyl, methylene, ethanediyl or phen-1, 2- say it, with the proviso that R in formula 7 is not methyl. 7.- Compounds of formula 11, eleven or formula 12, or opposite enantiomers thereof, or complexes, salts, solvates or hydrates thereof, wherein R is methyl, ethyl, isopropyl, methoxymethyl or benzyl, and X is methyl, methylene, ethanediyl or phen-1, 2- say it, with the proviso that R in formula 11 is not methyl. 8.- Compounds of formula 5, or complexes, salts, solvates or hydrates thereof, wherein R is methyl, ethyl, isopropyl, methoxymethyl or benzyl. 9. The compounds of claims 6, 7 or 8, selected from: (4S) -4-benzyl-l, 3,2-dioxathiepane-2,2-dioxide; (4R) -4-methyl-1,2,2-dioxetane-2,2-dioxide; 2,2-dioxathiepane-2,2-dioxide (4S) -4- (methoxymethyl) -1,2-dioxide; (1 R, 2R) -1-phenyl-2-benzylphospholane; (1 R, 2R) -1-phenyl-2- (methoxymethyl) phospholane; 1, 2-bis ((1 R, 2R) -2-benzylphospholane) benzene; 1, 2-bis ((1 R, 2S) -2-methylphospholane) benzene; 1, 2-bis ((1 S, 2R) -2-benzylphospholane) ethane; (1S, 2R) -1-phenyl-2- (methoxymethyl) phospholane; (1S, 2R) -1-phenyl-2-benzylphospholane; 1 - ((1 R, 2S) -2-methylphospholan-1-yl) -2 - ((1S, 2S) -2- methylphospholan-1-yl) -benzene; 1 - ((1R, 2R) -2-benzylphospholan-1-yl) -2 - ((1S, 2R) -2-benzylphospholan-1-yl) -benzene; 1 - ((1 R, 2R) -2-benzylphospholan-1-yl) -2 - ((1S, 2R) -2-benzylphospholan-1-yl) -ethane; opposing enantiomers thereof; and complexes, salts, solvates or hydrates thereof.