WO2010004278A1 - Method for increasing the enantiomeric excess of chiral phosphine oxides, sulphides, imides and boranes - Google Patents

Abstract

The present invention relates to a method for increasing the enantiomeric excess of a chiral phosphine oxide, a chiral phosphine sulphide, a chiral phosphine-borane and a chiral phosphine imide said method comprising the steps of: (a) contacting said chiral phosphine oxide, sulphide, imide or borane with a solvent to form a slurry; (b) partitioning the phosphine oxide, sulphide, imide or borane either into the solvent or as an insoluble product; and (c) optionally, isolating the partitioned phosphine oxide, sulphide, imide or borane.

Description

METHOD FOR INCREASING THE ENANTIOMERIC EXCESS OF CHIRAL PHOSPHINE OXIDES, SULPHIDES, IMIDES AND BORANES

The present invention relates to a method for increasing the enantiomeric excess of neutral four-coordinated chiral phosphorus compounds, the use of said method and the phosphorus-containing compounds obtainable by said method.

BACKGROUTSro TO THE INVENTION

The use of chiral non-racemic phosphorus compounds for catalytic asymmetric synthesis has grown enormously in the last three decades, such compounds providing many of the most successful ligands for metal-based catalysts (Ojima, 2000; Brunner et al., 1993).

Asymmetric reactions making use of metal catalysts with chiral phosphine ligands include alkene hydrogenations, hydroformylations and hydrosilylations, allylamine isomerisations, allylic substitutions and a number of cross coupling procedures. Some of these processes have gained industrial significance, e.g. Monsanto L-dopa process

(Knowles, 1986); Anic and Monsanto Aspartame process (Kagan, 1988) Syntex naproxen process (Noyori, 1989) and Takasago L-menthol process (Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008). Chiral phosphorus compounds have been found to be useful non-metallic catalysts in their own right (Noyori, 1989).

Most of these catalysts involve the use of C-chiral, rather than P-chiral, phosphorus ligands, primarily because they are more easily prepared. However, P-chiral ligands can be of great value in catalytic asymmetric synthesis, as exemplified by the rhodium/diPAMP catalyst, developed by Knowles, which is one of the most successful catalysts used for the L-dopa and Aspartame syntheses. diPAMP

In light of the beneficial properties of P-chiral phosphorus compounds in asymmetric synthesis, the search for efficient methods for the synthesis of P-chiral, non-racemic phosphines and related neutral four-coordinated phosphorus compounds such as phosphine oxides, phosphine sulfides, phosphine imides and phosphine boranes continues to be of prime importance (Pietrusiewicz et al., 1994).

A number of strategies have been employed in the synthesis chiral phosphines. In principle, the most direct route to optically active phosphines is to resolve the racemic phosphine by making diastereomeric transition metal complexes. However, problems associated with the separation of the complexes, the synthesis of optically active ligands and the recycling of expensive metals have prevented this method irom being generally applied. Another method used to resolve phosphorus compounds is the formation of phosphonium salts using a chiral counterion (Horner et al., 1964). However, this route has a number of limitations, especially in cleavage reactions of the resultant non-racemic salts where the stereochemical outcome cannot be guaranteed (Valentine, 1984).

The generation of chiral phosphines oxides from phosphinate esters has been widely used (Valentine, 1984), but the success of this method heavily depends on the availability of chiral phosphinate esters, and much effort has been expended in the search for methods to generate these esters, with only limited success. Likewise, the synthesis of chiral phosphines by the electrophilic substitution of chiral phosphonites (Valentine, 1984) is hindered by the availability of suitable phosphonites, which have low optical stability compared with phosphines. Additionally, the enantioselective lithiation and electrophilic trapping of prochiral phosphine-boranes using chiral lithium amide bases (Muci, 1995) is often insufficiently enantioselective for industrial applicability.

Reduction of chiral four coordinated phosphorus compounds such as phosphine oxides is perhaps the most common route to chiral phosphines and can be achieved by a number of reagents including hydrides, boranes and silanes, the choice of which is determined by the sensitivity of the compound to reduction and the stereochemistry required in the product phosphine. At present, the preferred reductants for phosphine oxides are silanes. However, the use of such reduction methods has merely pushed the stereoselectivity problem back to an earlier stage in the synthesis, i.e. a source of a chiral four-co-ordinated phosphorus compound is now required, such as a chiral phosphine oxide. The synthesis of enantiomerically enriched phosphine oxides and phosphine sulfides based on the kinetic resolution of P-chiral three-coordinate phosphorus compounds using pure bis-phosphoryl or bis-tbiophosphoryl disulfides is discussed in Perlikowska et al, 2001.

WO2005118603 (University College Dublin), the disclosure of which is incorporated herein by reference, relates to the preparation of stereoisomerically enriched phosphorus containing compounds. P-chiral- three- and four-coordinated phosphorus compounds are generated by the disclosed process.

There remains a clear need for methods for the generation of resolved (partitioned) neutral four-coordinated phosphorus derivatives such as phosphine oxides, phosphine sulfides, phosphine imides and phosphine-boranes. As mentioned above, such compounds can be converted to the corresponding P-chiral three-coordinated phosphorus compounds by reduction or coupled to form, for example, bis-phosphine oxides that may be subsequently reduced to the bis-phosphines; phosphine sulfides and phosphine-boranes may be similarly coupled to form alternative bis-phosphine precursors. In addition, the phosphine oxides have important uses in pharmaceutical and agrochemical applications in their own right.

STATEMENTS OF THE INVENTION One aspect of the present invention relates to a method for increasing the enantiomeric excess of a neutral four-coordinated phosphorus compound selected from a chiral phosphine oxide, a chiral phosphine sulfide, a chiral phosphine imide and a chiral phosphine-borane, said method comprising the steps of: (a) contacting said chiral phosphine oxide, sulfide, imide or borane with a solvent to form a heterogeneous mixture (i.e. a slurry);

(b) partitioning the chiral phosphine oxide, sulfide, imide or borane either into the solvent or as an insoluble product; and

(c) optionally, isolating the partitioned chiral phosphine oxide, imide, sulfide or borane.

Another aspect relates to use of the method according to the present invention for increasing the enantiomeric excess of a chiral phosphine oxide, a chiral phosphine sulfide, a chiral phosphine imide or a chiral phosphine borane.

Yet another aspect relates to the phosphine oxides, phosphine sulfides, phosphine imides, phosphine-boranes, phosphines, bis-phosphine oxides, bis-phosphine sulfides, bis(phosphine-boranes), or bis-phosphines obtainable by the method of the present invention.

DETAILED DESCRIPTION

The preferred embodiments set out below are applicable to all the above-mentioned aspects of the invention.

As mentioned above, one aspect of the present invention relates to a method for increasing the enantiomeric excess of a neutral four-coordinated phosphorus compound selected from a chiral phosphine oxide, a chiral phosphine sulfide, a chiral phosphine imide and a chiral phosphine-borane, said method comprising the steps of: (a) contacting said chiral phosphine oxide, sulfide, imide or borane with a solvent to form a heterogeneous mixture (i.e. a slurry); (b) partitioning the chiral phosphine oxide, sulfide, imide or borane either into the solvent or as an insoluble product; and (c) optionally, isolating the partitioned chiral phosphine oxide, sulfide, imide or borane.

As used herein, the term "partitioning" refers to increasing the enantiomeric purity of a chiral phosphine oxide, sulfide, imide or borane. Increasing the enantiomeric purity of a chiral phosphine oxide is also known as increasing the enantiomeric excess (ee) of the compound. Percent enantiomeric excess can be represented by the following formula (J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4^th Edition, Wiley-Interscience, 1992):

[R] - [S]

Percent enantiomeric excess = — — ^ x 100 = % R - % S

IN ⁺ l^J

The enantiomeric excess of the chiral phosphine oxide, sulfide, imide or borane may be increased as follows: (a) the chiral phosphine oxide, sulfide, imide or borane is partitioned into the solvent. This means that some or all of the desired enantiomer of the phosphine oxide, sulfide, imide or borane is preferentially dissolved in the solvent and some or all of the other enantiomer preferentially remains as a solid. (b) the chiral phosphine oxide, sulfide, imide or borane is partitioned as an insoluble product. This means that some or all of _. the desired enantiomer preferentially remains as a solid while some or all of the other enantiomer is preferentially dissolved in the solvent.

As described above, the chiral phosphine oxide, sulfide, imide or borane is contacted with a solvent to form a heterogeneous mixture (i.e. a slurry) in which some or all of one of the enantiomers dissolves in the solvent and some or all of the other enantiomer remains as a solid. Thus, at no stage in the claimed process is the phosphine oxide, sulfide, imide or borane completely dissolved in the solvent. As used herein, the following terms are used interchangeably: "phosphine oxide" and "phosphinoyl"; "phosphine sulfide" and "thiophosphinoyl"; "phosphinimine", "phosphine imine" and "phosphine imide."

In one embodiment, the chiral phosphine oxide is a compound of formula (Ia):

In one embodiment, the chiral phosphine sulfide is a compound of formula (Ib):

In one embodiment, the chiral phosphine imide is a compound of formula (Ic):

In one embodiment, the chiral phosphine-borane is a compound of formula (Id):

In each of the above compounds of formula (Ia), (Ib), (Ic) and (Id), Rj and R₂, are independently selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl and an alkenyl group; R₃ is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, and -A-PPQR₁R₂, wherein A is selected from alkyl, heteroalkyl, aryl, alkylaryl, -(hetero)-(aryl)_r, maleic anhydride, succinic anhydride, maleimide and succinimide, X is absent (lone pair), O, S, BH₃ or NR₄, and R₁, R₂ and R4 are as herein described; and

R₄ is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, NR^aR^b, SO₂R⁰, SO₂NR^dR^e, P(0)R^fR^εR^b, wherein R^a"h axe each independently selected from H, alkyl and alkylaryl.

The star (*) as illustrated in the structural formulae above represents a chiral centre.

As used herein, the term "alkyl" includes both saturated straight chain and branched alkyl groups which may be substituted (mono- or poly-) or unsubstituted. In one embodiment, the alkyl group is a C_1-2O alkyl group. In another embodiment, the alkyl group is a Ci_-15. hi another embodiment, the alkyl group is a Gi_-12 alkyl group. In

- another -embodiment, the. alkyl group is-a Ci_-6 aikyl group. Preferred alkyl groups include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl. The alkyl group may be optionally substituted by one or more substituents selected from halogeno (preferably, F, Cl, Br, I), NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, CONR^fR^ε, COR^h, SO₃H, SO₂R', SO₂NR^jR^k, alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and CORⁿ; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R^a"π are each independently selected from H, alkyl and alkylaryl.

The term "heteroalkyl" refers to an alkyl group as defined above containing one or more heteroatoms selected from Si, O, N and S. In one embodiment, the heteroatom is S, N or O. hi another embodiment, the heteroatom is Si or O. More preferably, the heteroalkyl group is a C_1-2O heteroalkyl. In another embodiment, the heteroalkyl group is a C _l-i ₅ heteroalkyl group, hi yet another embodiment, the heteroalkyl group is a C_1-12 heteroalkyl group. Preferably the heteroalkyl group contains one to three heteroatoms preferably one herteroatom.

As used herein, the term "carbocycle" refers to a mono- or multi-ringed carbocyclic ring system which may be substituted (mono- or poly-) or unsubstituted. Preferably, the multi-ringed carbocycle is bi- or tri-cyclic. Preferably, the carbocycle is a C_3-2O carbocyclic group. More preferably, the carbocycle is a C_3-12 carbocyclic group. More preferably the carbocycle group is a C_3-7 carbocyclic group. The carbocycle may be optionally substituted with one or more substituents selected from halogeno (preferably, F, Cl, Br, I), NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, CONR^fR^g, COR^h, SO₃H, SO₂R*, SO₂NR^JR^k, alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said alkylaryl, aryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and COR^π; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R^a"n are each independently selected from H, alkyl and alkylaryl. Preferably, the substituents are selected from halogeno, (CH₂)_mOR^a, where m is 0, 1, 2 or 3, NR^cR^d, COOR^e, CONR^fR^g, COR^h. Preferably the carbocycle is a carbocycle ring. Preferably, the carbocycle is a cycloalkyl.

As used herein, the term "cycloalkyl" refers to a mono- or multi-ringed cyclic alkyl group which may be substituted (mono- or poly-) or unsubstituted. Preferably, the multi-ringed cyclic alkyl group is bi- or tri-ringed. Preferably, the cycloalkyl group is a C_3-20 cycloalkyl group. More preferably, the cycloalkyl group is a C_3-12 cycloalkyl group. More preferably, the cycloalkyl group is a C_3-7 cycloalkyl group. The cycloalkyl group may be optionally substituted by one or more substituents selected from halogeno (preferably, F, Cl, Br, F), NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, CONR^fR^g, COR^h, SO₃H, SO₂R*, SO₂NR*R^k, alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and COR"; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R^a"n are each independently selected from H, alkyl and alkylaryl. As used herein the term "heterocycloalkyl" refers to a cycloalkyl group containing one or more heteroatoms selected from O, N and S. Examples of heterocycloalkyl include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, pyrrolidinyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl, l,2-pyrazolidin-2-yl, 1,3-pyrazolidin-l-yl, thiomorpholinyl, 1,2- tetrahydrothiazin-2-yl, l,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, 1,2- tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-l-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Thus, one of ordinary skill in the art will understand that the connection of said heterocycloalkyl rings is through a carbon or a sp hybridized nitrogen heteroatom. Preferred heterocycloalkyl groups include piperazine, morpholine, piperidine and pyrrolidine. In a preferred embodiment, the heterocycloalkyl group may be optionally substituted by one or more substituents selected from halogeno (preferably ,F, Cl, Br, F), NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, C0NR^fR^ε, COR^h, SO₃H, SO₂R¹, SO₂NR¹R*, -alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and CORⁿ; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R^a~n are each independently selected from H, alkyl and alkylaryl.

As used herein, the term "alkenyl" refers to a group containing one or more carbon- carbon double bonds, which may be branched or unbranched, substituted (mono- or poly-) or unsubstituted. In one embodiment, the alkenyl group is a C_2-20 alkenyl group. In another embodiment, the alkenyl group is a C_2-I5 alkenyl group. In another embodiment the alkenyl group is a C_2-12 alkenyl group, hi another embodiment, the alkenyl group is a C_2-6 alkenyl group. The alkenyl group may be optionally substituted by one or more substituents selected from selected from halogeno (preferably, F, Cl, Br, I), NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, C0NR^fR^ε, COR^h, SO₃H, SO₂R*, SO₂NR^jR^k, alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and CORⁿ; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R^a"π are each independently selected from H, alkyl and alkylaryl.

As used herein, the term "aryl" refers to a mono- or multi- ringed aromatic group which may be substituted (mono- or poly-) or unsubstituted. Preferably, the multi- ringed aromatic group is bi- or tri-ringed. Preferably, the aromatic group is a C_5-20 aryl group. More preferably, the aryl group is a C_6-I₂ aromatic group. Typical examples include phenyl and naphthyl etc. The aryl group may be optionally substituted by one or more substituents selected from halogeno (preferably, F, Cl, Br, I), NO₂, CN, (CH₂)_mOR^a, O(CH₂)nOR^b, (CH^aryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, CONR^fR^g, COR^h, SO₃H, SO₂R¹, SO₂NR^jR^k, alkyl, heterocycloalkyl, aryl, alkylaryl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl may be optionally substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and COR"; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R^a"n are each independently selected from H, alkyl and alkylaryl. In one embodiment, the aryl group is optionally substituted by one or more substituents selected from phenyl, benzyloxy, methyl, iso- propyl, hydroxy and methoxy.

The term "alkylaryl" is used as a conjunction of the terms "alkyl" and "aryl" as given above. Preferably, the alkylaryl group is -CH₂Ph.

The term "heteroalkylaryl" is used as a conjunction of the terms "heteroalkyl" and "aryl" as given above. Preferably, the heteroalkylaryl group is -OCH₂Ph.

As used herein, the term "heteroaryl" refers to a C_4-I2 aromatic, substituted (mono- or poly-) or unsubstituted group, which comprises one or more heteroatoms independently selected from N, O and S. Preferably, the heteroatom is N or S. Preferred heteroaryl groups include pyrrole, pyrazole, pyrimidine, pyrazine, pyridine, quinoline, triazole, tetrazole, thiophene, furan imidazole and oxazolidine. The heteroaryl group may be optionally substituted by one or more substituents selected from halogeno (preferably, F, Cl, Br, I), NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, CONR^fR^g, COR^h, SO₃H, SO₂R*, SO₂NR*R^k, alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said aryl, alkylaryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH2)_raOR^a, R^m and COR"; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R^{a n} are each independently selected from H, alkyl and alkylaryl.

In one embodiment, the heteroaryl group is optionally substituted by one or more substituents selected from phenyl, phenyloxy, benzyloxy, methyl, iso-propyl, hydroxy and methoxy.

The term "-(hetero)-(aryl)_r" refers to a groups wherein one or two aryl groups (as defined above) are covalently bonded to a heteroatom. Preferably, the heteroatom is N, O or S. More preferably, the heteroatom is N (in which case two aryl groups are covalently bonded) or O (where one aryl group is covalently bonded). Most preferably, the group is -O-aryl and even more preferably, -OPh.

In one embodiment, Ri and R₂ are independently selected from aryl, alkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2 and heteroalkyl.

In one embodiment, R₃ is selected-from alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, and -A-P(X)RiR₂, wherein A is selected from Ci-3alkyl, Cijheteroalkyl, C_3-7aryl, -CH₂-aryl, -(hetero)-(phenyl), maleic anhydride, succinic anhydride, maleimide and succinimide, X is absent (lone pair), O, S, BH₃ or NR₄, and Ri , R₂ and R₄ are as herein described.

In one embodiment of the compound of formula (Ia): X is selected from absent (lone pair), O, S, BH₃ and NR₄, preferably X is selected from absent, O, S and BH₃, more preferably X is absent, O or S, most preferably X is absent or O.

In one embodiment of the compound of formula (Ib): X is selected from absent (lone pair), O, S, BH₃ and NR₄, preferably X is absent, O, S or BH₃, more preferably X is absent, O or S, most preferably X is absent or S. In one embodiment of the compound of formula (Ic): X is selected from absent (lone pair), O, S, BH₃ and NR₄, preferably X is absent, O, S or BH₃, more preferably X is absent, O or BH₃, most preferably X is absent or BH₃.

In one embodiment of the compound of formula (Id): X is selected from absent (lone pair), O, S, BH₃ and NR4, preferably X is absent, O, S or NR4, more preferably X is absent, O or NR₄, most preferably X is absent or NR₄.

In another embodiment, Ri and R₂ are independently selected from C_5-20 aryl, C_4-I2 heteroalkylaryl, Ci_-20 alkyl, C_1-20 heteroalkyl and -(hetero)-(Cs_-2o aryl)_r, wherein the C_5-2O aryl, C_4-12 heteroalkylaryl, Ci_-20 alkyl, Ci_-20 heteroalkyl and -(hetero)-(Cs_-2o aryl)_r groups are optionally substituted by one or more substituents selected from halogeno, NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, C0NR^fR^ε, COR^h, SO₃H, SO₂R¹, SO₂NR^jR^k, alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said alkylaryl, aryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and COR"; wherein m is O, 1, 2, or 3; n is 1, 2, or 3; r is 1 or 2 and R^{a" n} are each independently selected from H, alkyl and alkylaryl.

In yet another embodiment, R₁ and R₂ are independently selected from C_5-20 aryl, Gμ₁₂ heteroalkylaryl, Ci_-20 alkyl, Ci_-20 heteroalkyl and -(hetero)-(Cs_-2o aryl)_r, wherein the C5-20 aryl, C_4-12 heteroalkylaryl, Ci_-20 alkyl, C]_-20 heteroalkyl and -(hetero)-(C₅-2o aryl)_r, groups are optionally substituted by one or more substituents selected from (CH₂)_mOR^a, COOR^e, O(CH₂)_naryl, alkyl, aryl and alkylaryl; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3; r is 1 or 2 and R^a and R^e are independently selected from H, alkyl and alkylaryl.

In another embodiment, Ri and R₂ are independently selected from phenyl, phenyloxy, naphthyl and tert-butyl wherein each group is optionally substituted by one or more methoxy, benzyloxy, hydroxy, phenyl, wo-propyl and methyl groups.

In another embodiment, R₃ is a C_1-20 alkyl group which is optionally substituted by one or more substituents selected from halogeno, NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, CONR^fR^g, COR^h, SO₃H, SO₂R*, SO₂NR^JR^k, alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said alkylaryl, aryl, heterocycloalkyl and heteroaryl may be optionally further substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and COR"; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3 and R^{a n} are each independently selected from H, alkyl and alkylaryl.

In another embodiment, R₃ is selected from alkyl, aryl, heteroalkylaryl, heteroalkyl, -(hetero)-(aryl)_r, where r is 1 or 2.

In another embodiment, R₃ is -A-P(X)RiR₂, wherein A is selected from Ci-₃alkyl, Ci-sheteroalkyl, phenyl, -O-phenyl, maleic anhydride, succinic anhydride, maleimide and succinimide, X is absent (lone pair), O, S, BH₃ or NR₄, and R₁, R₂ and R₄ are as herein described.

In another embodiment, R₃ is -A-P(X)R₁R₂, wherein A is selected from C_1-3alkyl, C_1-3heteroalkyl, phenyl, -O-phenyl, X is absent (lone pair), O, S, BH₃ or NR₄, and R₁, R₂ and R₄ are as herein described.

In one embodiment, R₄ is selected from alkyl, aryl, suifonyl-(SO₂R^c) and phosphoryl (P(O)R^fR^gR^h). In another embodiment R₄ is alkyl. Preferably R₄ is selected from alkyl, aryl, sulfonyl (SO₂R^C) and phosphoryl (P(O)R^fR⁸R^h).

In another embodiment, the compound of formula (Ia) to (Id) is selected from: l-methoxy-2-(methyl-phenyl-phosphinoyl)-benzene; 1 ,4-dimethoxy-2-(methyl-phenyl-phosphinoyl)-benzene; l,3-dimethoxy-2-(methyl-phenyl-phosphinoyl)-benzene; l-(methyl-phenyl-phosphinoyl)-naphthalene;

2-methoxy- 1 -(methyl-phenyl-phosphinoyl)-naphthalene; l-(ter^buryl-methyl-phosphmoyl)-2-methoxy-benzene; 2-(methyl-phenyl-phosphinoyl)-biphenyl; l-isopropyl-2-(methyl-phenyl-phosphinoyl)-benzene; methyl-2-(methyl-phenyl-phosphinoyl)-benzene; l-methoxy-2-(methyl-phenyl-thiophosphinoyl)-benzene; l,4-dimethoxy-2-(methyl-phenyl-thiophosphinoyl)-benzene; l,3-dimethoxy-2-(methyl-phenyl-thiophosphinoyl)-benzene; l-(methyl-phenyl-thiophosphinoyl)-naphthalene;

2-methoxy- 1 -(methyl-phenyl-thiophosphinoyl)-naphthalene; l-(fert-butyl-methyl-thiophosphinoyl)-2-methoxy-benzene; 2-(methyl-phenyl-tbiophosphinoyl)-biphenyl; l-isopropyl-2-(methyl-phenyl-thiophospbinoyl)-benzene; methyl-2-(methyl-phenyl-tbiophosphinoyl)-benzene;

(2-methoxyphenyl)-methyl-phenyl-phosphane-borane;

(2,5-dimethoxyphenyl)-methyl-phenyl-phosphane-borane; (2,6-dimethoxyphenyl)-methyl-phenyl-phosphane-borane; methyl-naphthalen- 1 -yl-phenyl-phosphane-borane;

(2-methoxy-naphthalen- 1 -yl)-methyl-phenyl-phosphane-borane; fcrt-butyl-(2-methoxyphenyl)-methyl-phosphane-borane; biphenyl-2-yl-methyl-phenyl-phosphane-borane; (2-isopropylphenyl)-methyl-phenyl-phosphane-borane; methyl-phenyl-o-tolyl-phosphane-borane; and

2- { [(di-tert-butyl-phosphanyl)-methyl] -methyl-phosphanyl } -2-methyl-propane ('trichickenfootphos-bisborane').

In yet another embodiment, the chiral phosphine oxide, sulfide, imide or borane of step (a) is present as a non-racemic mixture. Preferably, the non-racemic mixture has an enantiomeric excess of greater than about 1%; more preferably, greater than about 25%; yet more preferably, greater than about 50% and most preferably, greater than about 75%.

In another embodiment, the chiral phosphine oxide, sulfide, imide or borane of step (a) is present as a racemate. As is commonly known in the art, a "racemate" or "racemic mixture" relates to enantiomers of compounds present in equal amounts.

In yet another embodiment, the partitioned phosphine oxide, sulfide, imide or borane has an enantiomeric excess from about 1% to greater than about 99%; preferably, from about 60% to greater than about 99%; more preferably, from about 75% to greater than about 99% and most preferably, from about 95% to greater than about 99%. In another embodiment, the solvent is selected from at least one of alkanes, cycloalkanes, heteroalkanes, heterocycloalkanes, alkyl esters, aromatics, heteroaromatics, alcohols or mixtures thereof.

"Alkanes", "cycloalkanes", "heteroalkanes", "heterocycloalkanes" and the "alkyl" groups of "alkyl esters" should be construed in line with the definitions for "alkyl", "cycloalkyl", "heteroalkyl" and "heterocycloaJkyl" given above providing that the resulting substance acts as a solvent. A "solvent" is a substance capable of dissolving or dispersing one or both of the enantiomers of the chiral phosphine oxide, sulfide, imide or borane.

Preferably, the heteroalkane is an ether i.e. the heteroatom is O.

Preferably, the solvent is selected from at least one of C_1-2O alkanes, C_3-20 cycloalkanes, C_1-20 heteroalkanes, C_3-2O heterocycloalkanes, C_1-2O alkyl esters, C_6-20 aromatics, C_4-2O heteroaromatics and Ci_-2O alcohols, or mixtures thereof.

More ^preferably, the. solvent is selected from at least one of C_1-I5 alkanes,. C_3-H cycloalkanes, C_M5 heteroalkanes, C_3-12 heterocycloalkanes, C_1-15 alkyl esters, Cβ-io aromatics, C_4-I0 heteroaromatics and Ci_-15 alcohols, or mixtures thereof.

Yet more preferably, the solvent is selected from at least one of C_1-6 alkanes, C_3-7 cycloalkanes, Q-β heteroalkanes, C_3-7 heterocycloalkanes, Ci_-6 alkyl esters, C_6-S aromatics, C_4-5 heteroaromatics and C_1-I₀ alcohols, or mixtures thereof.

Suitable aromatic solvents include benzene, xylene, chlorobenzene, dichlorobenzne, toluene.

Suitable heteroaromatic solvents or co-solvents include furan, pyrrole and pyridine.

In one embodiment, the solvent is selected from at least one of hexane, heptane, cyclohexane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethyl acetate, toluene and methanol, or mixtures thereof. Preferably, the solvent is diethyl ether. In another embodiment, the solvent is a mixture of a C_1-2O heteroalkane, preferably diethyl ether, with a second solvent. Preferably, the second solvent is selected from tetrahydrofuran, cyclohexane, heptane and a C_1-3 alcohol, preferably methanol. In an alternative embodiment the solvent is a mixture of a C_1-6 alkyl ester, preferably ethyl acetate, with a second solvent. Preferably, the second solvent is selected from tetrahydrofuran, cyclohexane, heptane and a C_1-3 alcohol, preferably methanol.

In another embodiment, the alcohol solvent or co-solvent employed may contain a chiral centre. Preferably, the enantiomeric excess of the alcohol is greater than 10%, more preferably greater than 50%, yet more preferably, greater than 90%. Preferred chiral alcohols include (-)-menthol, (-)-trans-2-tertbutylcyclohexanol, (+)-neomenthol, cholesterol, (+)-fenchyl alcohol, (-)-(l,2)-cyclohexanediol, (-)-trans-2- phenylcyclohexanol, diacetone-D-glucose, and the corresponding enantiomers thereof.

Suitably, the ratio of diethyl ether or ethyl acetate to the second solvent is from about 1:100 to about 100:1 v/v; preferably, from about 1:50 to about 50:1 v/v; more preferablyrfrom abθut-l:10^~to-about-10:l v/v; yet more preferably, from about _L:2 to about 2:1 v/v and most preferably about 1 : 1 v/v.

hi another embodiment, the ratio of solvent to the chiral phosphine oxide, sulfide, imide or borane of step (a) is from about 1 ml/g to about 1000 ml/g. Preferably, the ratio is from about 1 ml/g to about 500 ml/g; more preferably, from about 1 ml/g to about 100 ml/g and most preferably, from about 1 ml/g to about 50 ml/g.

In yet another embodiment, the present method further comprises reducing the partitioned phosphine oxide or sulfide to the corresponding phosphine. Suitable reducing agents include trichlorosilane, trichlorosilane/amine combinations, hexachlorodsilane or phenylsilane (Edmundson, 1992). The phosphine may optionally be protected as a borane complex for example using BH₃.THF or BH₃-Me₂S, such phosphine-boranes being suitable for conversion to a protected bisphosphine. In another embodiment, the present method further comprises converting the partitioned phosphine oxide to the bis-phosphine oxide. Suitable methods are described in Edmundson, 1992. Preferably, the bis-phosphine oxide is selected from:

1 ,2-bis[(2,5-dimethoxyphenyl)(phenyl)phosphinoyl]ethane; l,2-bis[(2-methoxyphenyl)(phenyl)phosphinoyl]ethane; l,2-bis[phenyl-(2-hydroxyphenyl)phosphinoyl]ethane;

1 ,2-bis [phenyl-(2-benzyloxyphenyl)phosphinoyl] ethane; and l,2-bis[phenyl-(2-biphenylyl)phosphinoyl]ethane.

In another embodiment, the present method further comprises converting the partitioned phosphine sulfide to the bis-phosphine sulfide. This may be carried out according to methods described for the coupling of phosphine oxides (Edmundson,

1992).Preferably, the bis-phosphine sulfide is selected from:

l,2-bis[(2,5-dimethoxyphenyl)(phenyl)thiophosphinoyl]ethane;

1 ,2-bis [(2-methoxyphenyl)(phenyl)thiophosphinoyl] ethane; l,2-bis[phenyl-(2-hydroxyphenylthiophosphinoyl]ethane;

1 ,2-bis[phenyl-(2-ben2yloxyphenyl)thiOphosphinoyl]eihane; and 1 ,2-bis[phenyl-(2-biphenylyl)thiophosphinoyl]ethane.

In yet another embodiment, the present method further comprises reducing the bis- phosphine oxide or sulfide to the corresponding bis-phosphine, using similar methods to those described above for the corresponding monophosphine oxides and sulfides (Edmundson 1992). Preferably, the bis-phosphine is selected from:

l,2-bis[(2,5-dimethoxyphenyl)(phenyl)phosphino]ethane; l,2-bis[(2-methoxyphenyl)(phenyl)phosphino]ethane; l,2-bis[phenyl-(2-hydroxyphenyl)phosphino]ethane; l,2-bis[phenyl-(2-benzyloxyphenyl)phosphino]ethane; and l,2-bis[phenyl-(2-biphenylyl)phosphino]ethane.

In yet another embodiment, the present method further comprises converting the partitioned phosphine borane to the bis(phosphine-borane), such bis(phosphine- boranes) being readily deboronated to afford bis-phosphines. Suitable methods are described in Wada, 2004. Preferably, the phosphine borane is selected from:

l,2-bis[boronato(2,5-dimethoxyphenyl)(phenyl)phosphino]ethane; 1 ,2-bis[boronato(2-methoxyphenyl)(phenyl)phosphino]ethane; l₅2-bis[boronato-phenyl-(2-hydroxyphenyl)phosphino]ethane; 1 ,2-bis[boronato-phenyl-(2-benzyloxyphenyl)phosphino]ethane; and l,2-bis[boronato-phenyl-(2-biphenylyl)phosphino]ethane.

In another embodiment, the present method further comprises converting the partitioned phosphine imide to the phosphine oxide. This transformation may generally be accomplished by hydrolysis under acidic conditions. The phosphine oxide may be further converted to the phosphine or the bis-phosphine oxide.

As mentioned above, another aspect relates to use of the method according to the present invention for enhancing the enantiomeric excess of a chiral phosphine oxide, sulfide, imide or borane.

Yet- another aspect relates to the phosphine oxides, phosphine sulfides, phosphine imides, phosphine-boranes, phosphines, bis-phosphine oxides, bis-phosphine sulfides, bis(phosphine-boranes), or bis-phosphines obtainable by the method of the present invention.

Further preferred features and embodiments of the present invention will now be described by way of non-limiting examples.

EXAMPLES

The phosphine oxides used as starting material in the following examples may be prepared according to the methods described in WO2005/118603 or according to the methods described in (Juge, S., Genet, J. P., Tetrahedron letters. 1989, 30, 2783- 2786).

Example 1 - Synthesis of ^.S-dimethoxy'-DiPAMP

Step 1 — Enhancement of ee with scalemic phenyl-methyl-(2.,5- dimethoxyphenvDphosphine oxide

Scalemic (R)-phenyl-methyl-(2,5-dimethoxyphenyl)phosphine oxide (54% ee) was purified by trituration with diethylether. This gave pure (R)-phenyl-methyl-(2,5- dimethoxyphenyl)phosphine oxide (5.28 g, 48 %, ee _= 95%). HPLC: Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 80/20, 1 mL/min, UV detection (254, 230, 210 nm); retention times 11.4 (S), 14.4 min (R).

Step 2 - Synthesis of (R,R)-L2-bis[(2..5-dimemoxyphenvπ(rjhenyl)phosphinoyl] ethane

A solution of LDA (4.8 mmol) in THF (4 ml) was added dropwise to a solution of pure (R)-phenyl-methyl-(2,5-dimethoxyphenyl)-phosphine oxide (1.1 g, 4 mmol) in THF (4 ml) over a period of lOmins at O⁰C, ice bath cooling. The reaction was stirred for lhr at O⁰C then Cu(I)Cl (480 mg, 4.8 mmol) was added, stirred for 30 mins, then Cu(II)Cl₂ (626 mg, 4.8 mmol) was added. The suspension was stirred for a further 30 mins at O⁰C then allowed to warm to ambient temperature and stirred for 3hrs. After this time, cone. HCl (2 ml) was added followed by chloroform (30 ml). Layers shaken and separated. The organic layer was washed with sat. ammonium hydroxide (4 x 20 ml) until no further blue colour was apparent in the aqueous washings. Organic layer washed further with brine (2 x 20 ml), dried (anh. Na₂SO₄), filtered and the solvent evaporated to give an off-white solid. The crude solid was slurried in warm ethyl acetate and filtered to give pure (R₅R)- l,2-bis[(2,5- dimethoxyphenyl)(phenyl)phosphinoyl]ethane (570 mg, 51 %, ee > 99%). HPLC: , Daicel Chiralpak IA (250 x 4.6 mm) + Daicel IA guard cartridge, heptane/EtOH 50/50, 1 mL/min, UV detection (254, 230, 210 ran); retention times 7.4 (R₁R), 10.6 (rnesό), UA mJn (S₁S).

Step 3 - Synthesis of π^RVL2-Bis[(2.5-dimemoxyphenyl)fphenyDphosphino^"|ethane

To a solution of pure (R₃R)-1, 2-Bis[(2,5-dimethoxyphenyl)(phenyl)phosphinoyl]- ethane (1.93 g, 3.5 mmol) and tributylamine (8.4 ml, 35 mmol) in acetonitrile (14 ml) under nitrogen gas at 7O⁰C was added trichlorosilane (3.15 ml, 31.15 mmol) dropwise over ~10 mins. After 2hrs heating at 7O⁰C the reaction was allowed to cool to ambient temperature. The solution was added dropwise to ice cold 25%w/v NaOH (aq, 30 ml). Toluene (20 ml) was added and the layers stirred and separated. The aqueous layer was extracted further with toluene (2 x 10 ml). Organics were combined, washed with brine (20 ml), dried (anh. Na₂SO₄), filtered and the solvent evaporated to give a sticky solid. The solid was slurried in ice cold methanol (25 ml), filtered, washing with ice cold methanol. Filtrate evaporated to give pure (R₅R)- l,2-Bis[(2,5-di-o- methoxyphenyl)(phenyl) phosphinojethane (1.68 g, 93 %, ee > 99%)

Step 4 - Synthesis of (Tl,R)-1.2-BisPx)ranatof2.5-dimemQX\ρhenyl)(phen.v-l^*) phosphinoiethane

To pure (R₅R)-1, 2-bis[(2,5-dimethoxyphenyl)(phenyl)phosphino]ethane (1.56 g, 3 mmol) in THF (20 ml) under nitrogen gas atmosphere was added borane-THF complex (IM in THF, 10 ml, 10 mmol) dropwise over ~5 mins. After lhr stirring at ambient temperature dilute IM HCl (5 ml) was added carefully, followed by DCM (40 ml). Layers shaken and separated. The aqueous layer was extracted further with DCM (2 x 15 ml). Organics combined, washed with brine (20 ml), dried (anh. Na₂SO₄), filtered and the solvent evaporated to give a white solid. The solid was recrystallised from hot toluene to give pure (R₅R)- l,2-bis[boranato(2,5- dimethoxyphenyl)(phenyl)phosphino]ethane (1.05 g, 64 %, ee > 99 %). ¹H NMR (CDCl₃, 300MHz): δ/ppm, 7.67-7.38 (12H, Ar-H, m), 6.99 (2H, Ar-H, d J - 9 Hz), 6.77 (2H, Ar-H, d J = 9 Hz), 3.78 (6H, -OCH₃, s), 3.59 (6H, -OCH₃, s), 2.59 (4H, - CH₂-P, ap. br. s); ³¹P NMR (CDCl₃, 105MHz, ¹H decoupled): δ/ppm, 20.6 (br. m) HPLC: Daicel Chiralpak IB (250 x 4.6 mm) + Daicel IB guard cartridge, heptane/EtOH 97/03, 0.5 mL/min, UV detection (254, 230, 210 nm); retention times 21.6 (meso), 24.8 (R,R), 26.0 min (S,S).

(S,S) Ligand made in a similar fashion.

Example 2: Partitioning of phosphine oxides

1. 1 -Methoxy-2-(metfayl-phenyl-phosphinoylVbenzene (PAMPO)

Crude (J?)-PAMPO (16.0 g) of 68% ee was stirred overnight in diethyl ether (100 mL). Filtration afforded solid near-racemic PAMPO (ee <20%) and a filtrate which was concentrated to afford (R)-PAMPO as a white solid (9.3 g, ee (HPLC) >98%). ¹H NMR (300 MHz, CDCl₃): δ 7.97 (IH, dd, J = 13.2, 8.0 Hz, Ar-H), 7.74 (2H, dd, J = 11.7, 7.0 Hz, Ar-H)₅ 7.55-7.37 (4H, m, Ar-H), 7.11 (IH, t, J = 7.0, Ar-H), 6.89 (IH, dd, J = 8.0, 5.5 Hz, Ar-H), 3.73 (3H, s, -OCH₃), 2.07 (3H, d, ²J_P-H = 14.1 Hz, P(O)CH₃); ³¹P(¹H) NMR (121.4 MHz, CDCl₃): δ 29.48 (s).

HPLC: Daicel Chiralpak IA (250 x 4.6 mm) + Daicel IA guard cartridge, heptane/ElOH 90/10, 1.0 mL/min, UV detection J(254 nm); retention times 14.9 (JR), 16.5 min (S).

2. l,4-Dimethoxy-2-rmethyl-phenyl-phosphinoyl)-benzene (^"2,5-dimethoxy-

PAMPO)

(i?)-2,5-Dimethoxy-PAMPO (8.5 g) of 54% ee was stirred with diethyl ether (70 ml); filtration afforded solid 2,5-dimethoxy-PAMPO (15% ee) and a filtrate which was concentrated to afford (i?)-2,5-dimethoxy-PAMPO (5.3 g, ee (HPLC) 95%). ¹H NMR (300 MHz, CDCl₃): δ 7.80-7.69 (2H, m, Ar-H), 7.57 (IH, dd, J = 14.1, 2.9 Hz, Ar-H), 7.51-7.37 (3H, m, Ar-H), 7.04 (IH, dd, J = 8.8, 2.9 Hz, Ar-H), 6.83 (IH, dd, J = 8.8, 6.4 Hz, Ar-H), 3.82 (3H, s, -OCH₃), 3.66 (3H, s, -OCH₃), 2.08 (3H, d, ²J_P-H - 14.6 Hz, P(O)CH₃); ³¹P(¹H) NMR (121.4 MHz, CDCl₃): δ 29.65 (s).

HPLC: Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 80/20, 1 mL/min, UV detection (254, 230, 210 nm); retention times UA (S), 14.4 min (R). 3. 1.3 -Dimethoxy-2-(metfayl-phenyl-phosphinoyl)-benzene (2,6-dimethoxy-

PAMPO)

Crude (Λ)-2,6-dimethoxy-PAMPO of 76% ee was stirred with THF (50 ml/g), affording a heterogeneous mixture whose supernatant liquid contained (R)-2,6- dimethoxy-PAMPO of 89% ee (HPLC). ¹H NMR (300 MHz, CDCl₃): δ 7.72-7.63 (2H, m, Ar-H), 7.45-7.35 (4H, m, Ar-H), 6.53 (2H, dd, J = 8.2, 4.1 Hz, Ar-H), 3.61 (6H, s, -OCH₃), 2.02 (3H, d, ²J_P._H = 14.4 Hz, P(O)CH₃); ³¹P{1H} NMR (121.4 MHz, CDCl₃): δ 29.07 (s).

HPLC: Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 95/05, 1 mL/min, UV detection (254 nm); retention times 15.6 (R), 24.0 min (S).

4. 1 -(Methyl-phenyl-phosphinoyl)-naphthalene (naphthyl-P AMPO)

(5)-Naphthyl-PAMPO (63% ee) was stirred with diethyl etheπTHF (10:1) (40 ml/g), affording on filtration near-racemic solid naphthyl-PAMPO and a filtrate containing (5)jiaphthyl-PAMPO of 94% ee (HPLC). Spectral data- consistent with literature values (Perlikowska, W.; Gouygou, M.; Mikolajczyk, M.; Daran, J.-C; Tetrahedron: Asymmetry, 2004, vol. 15, 3519).

HPLC: Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 95/05, 1 mL/min, UV detection (254, 210 nm); retention times 20.2 (R), 23.5 min (S).

5. 2-Methoxy- 1 -(methyl-phenyl-phosphinoyl Vnaphthalene (2-methoxynaphthyl- PAMPO)

Crude (i?)-2-methoxynaphthyl-PAMPO of 38% ee was stirred with diethyl ether (30 ml/g), affording a heterogeneous mixture that on filtration gave a solid consisting of (i?)-2-methoxynaphthyl-PAMPO of 60% ee (HPLC). Spectral data consistent with literature values (Serreqi, A. N.; Kazlauskas, R. J.; J. Org. Chem., 1994, vol. 59, 7609). HPLC: Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 90/10, 1 mL/min, UV detection (254 nm); retention times 11.2 (S), 14.6 min (R).

6. 1 -(ferf-Butyl-methyl-phosphinoylV2-methoxy-benzene (/-butyl-anisyl -PAMPO^*)

Crude f-butyl-PAMPO (43% ee of unknown configuration) was stirred with diethyl ether (5 ml/g), affording a heterogeneous mixture from which further crystallisation occurred on standing to afford, after filtration, solid t-butyl-anisyl-PAMPO of 70% ee (HPLC, unknown configuration). ¹H NMR (300 MHz, CDCl₃): δ 8.00 (IH, ddd, J = 11.7, 7.6, 1.8 Hz, Ar-H), 7.49 (IH, t, J = 7.6, Ar-H), 7.10 (IH, t, J = 7.6), 6.95-6.88 (IH, m, Ar-H), 3.82 (3H, s, -OCH₃), 1.79 (3H, d, ²J_P-H = 13.5 Hz, P(O)CH₃), 1.79 (9H, d, ³JP-H = 15.2 Hz, C(CH₃)₃); ³¹P(¹H) NMR (121.4 MHz, CDCl₃): δ 49.84 (s). HPLC: Daicel Chiralpak IA (250 x 4.6 mm) + Daicel IA guard cartridge, heptane/EtOH 95/05, 1 mL/min, UV detection (254 nm); retention times 12.0, 16.0 min (configurations unknown).

7. 2-fMethyl-phenyl-phosphinoylVbiphenyl (biphenyl-P AMPO)

(Λ)-Biphenyl-PAMPO (12.0 g, 75% ee) was stirred in diethyl etheπcyclohexane (1:1, 50 mL) to afford a precipitate of near-racemic biphenyl-PAMPO and a supernatant liquid which was concentrated to afford (Λ)-biphenyl-PAMPO (10.0 g, ee (HPLC) 99%). ¹H NMR (300 MHz, CDCl₃): δ 7.92 (IH, ddd, J = 13.1, 7.6, 1.0, Ar-H), 7.58- 7.50 (IH, m, Ar-H), 7.49-7.16 (HH, m, Ar-H), 7.15-7.08 (2H, m, Ar-H), 1.58 (3H, d, ²Jp_-H = 13.3 Hz; ³¹P(¹H) NMR (121.4 MHz, CDCl₃): δ 32.52 (s).

HPLC: Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 80/20, 1.0 mL/min, UV detection (254 nm); retention times 7.0 (S), 9.5 min (R).

8. 1 -Isopropyl-2-(methyl-phenyl-phosphinoyl^')-benzene (isopropyl-P AMPO)

Crude (i?)-isopropyl-PAMPO (48% ee) was stirred with diethyl ether (approx. 10 ml/g), affording a heterogeneous mixture in which the supernatant liquid contained (fl)-isopropyl-PAMPO of 74% ee (HPLC). ¹H NMR (300 MHz, CDCl₃): δ 7.83-7.61 (3H, m, Ar-H), 7.56-7.40 (4H, m, Ar-H), 7.32-7.26 (2H, m, Ar-H), 3.47 (IH, quin., J = 6.7 Hz, CHMe₂), 2.05 (3H, d, ²J_P-H = 13.0 Hz, P(O)CH₃), 1.14 (3H, d, J = 6.6 Hz, CH₃), 0.85 (3H, d, J = 6.6 Hz, CH₃); ³¹P(¹H) NMR (121.4 MHz, CDCl₃): «531.50 (s). HPLC: Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 90/10, 1.0 mL/min, UV detection (254 nm); retention times 7.3 (S), 8.2 min (R).

9. Methyl-2-(methyl-phenyl-phosphinoylVbenzene (tolyl-P AMPO)

(Λ)-Tolyl-PAMPO (71% ee) was stirred in a variety of solvents (Table 1) to afford heterogeneous mixtures whose supernatant liquid was in all cases further enriched with (Λ)-tolyl-PAMPO, and in most cases >90% ee (HPLC). ¹H NMR (300 MHz, CDCl₃): δ 7.72-7.60 (2H, m, Ar-H), 7.54-7.39 (4H, m, Ar-H), 7.34-7.19 (2H, m, Ar- H), 2.38 (3H, s, Ar-CH₃), 2.04 (3H, d, ²J_P-H = 13.5 Hz, P(O)CH₃); ³¹P(¹H) NMR (121.4 MHz, CDCl₃): δ 32.59 (s).

HPLC: Daicel Chiralpak IA (250 x 4.6 mm) + Daicel IA guard cartridge, heptane/EtOH 80/20, 1.0 mL/min, UV detection (254. 230, 210 nm); retention times 7.9 (S), 8.8 min (R).

Table 1: Enhancement of ee of enantioenriched tolyl-PAMPO in various solvents.

Example 3: Partitioning of phosphine sulfides

1. l-Memoxy-2-(memyl-phenyl-tMophosphinoyl)-benzene (PAMP=S) (low ee)

A mixture of (S)-PAMPO (98% ee) (0.98 g, 4 mmol) and Lawesson's reagent (0.89 g, 2.2. mmol) in toluene (5 mL) was heated at 90 °C for 5 h. After aqueous workup (water/EtOAc), drying (MgSO4) and concentrating, the mixture was purified by column chromatography on silica (Rf 0.2, 25% EtOAc/cyclohexane) to afford (S)-PAMP=S (1.2 g) in 12% ee.

(S)-PAMP=S of 12% ee (1.2 g) was stirred with diethyl ether (20 mL) for 30 min, affording a heterogeneous mixture whose supernatant contained (S)-PAMP=S of 31% ee. Spectral data consistent with literature values (Uziel, J.; Darcel, C; Moulin, D.;

Bauduin, C; Juge, S. Tetrahedron: Asymm., 2001, 12, 1441).

HPLC: Daicel Chiralpak IA (250 x 4.6 mm) + Daicel IA guard cartridge, heptane/EtOH 80/20, 1.0 mL/min, UV detection (254, 230, 210 nm); retention times 6.4 (R), 7.1 min (S).

2. l-Methoxy-2-(methyl-phenyl-thiophosphinoyl)-benzene (PAMP=S) (moderate ee)

(i?)-PAMP-BH₃ (99% ee) (0.49 g, 2 mmol), DABCO (0.24 g, 2.14 mmol) and sulfur (0.07 g, 2.18 mmol as S) in toluene (5 mL) were heated at 50 °C overnight. After concentrating, the mixture was purified by column chromatography on silica (Rf 0.2, 25% EtOAc/cyclohexane) to afford (S)-PAMP=S (0.34 g) in 99% ee.

Racemic PAMP (0.23 g, 1 mmol) and sulfur (0.03 g, 1 mmol as S) were stirred in toluene (2 mL) for 1 h. After concentrating, the mixture was purified by column chromatography on silica (Rf 0.2, 25% EtOAc/cyclohexane) to afford racemic PAMP=S (0.17 g). A sample of (S)-P AMP=S was mixed with racemic PAMP=S to afford a mixture with 70% ee (R). 150 mg of this mixture was stirred with 1:1 toluene/cyclohexane (1 mL), affording a heterogeneous mixture whose supernatant contained (S)-P AMP=S of 77% ee.

Example 4: Partitioning of phosphine boranes

1. (2-MethoxyphenylVmethyl-phenylphosphane-borane fP AMP-BHY)

(R)-P AMP-B H₃ of 63% ee (0.27 g) was stirred in a heptane/isopropanol mixture (9:1, 4 mL) for 1 h, affording a mixture whose supernatant contained (^)-PAMP-BH₃ of 58% ee. Upon filtration, the solid (R)-P AMP-BH₃ collected was of 67% ee. Spectral data consistent with literature values (Al-Masum, M.; Kumaraswamy, G.; Livinghouse, T. J Org. Chem., 2000, 65, 4776). HPLC: Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 98/02, 1.0 mL/min, UV detection (254, 230, 210 nm); retention times 12.3 (Λ), 13.3 min (5;.

2. fcrf-Butyl-memyl-phenylphosphane-borane (PfBMP-BH^Y

PrBMP-BH₃ of 50% ee (configuration not determined) was stirred with pentane for 1 h min, affording a heterogeneous mixture whose supernatant contained P/BMP-BH₃ of 62% ee. Spectral data consistent with literature values (Stankevic, M.; Pietmsiewicz, K. M. J. Org. Chem., 2007, 72, 816). HPLC: Daicel Chiralcel OJ-H (250 x 4.6 mm) + Daicel OJ-H guard cartridge, heptane/EtOH 70/30, 1.0 mL/min, UV detection (254, 230, 210 nm); retention times 8.5 (major), 11.6 min (minor).

Example 5: Partitioning of 2-fr(di-fer/-butyl-phosphanyI)-methvH-methyl- phosphanyl}-2-methyl-propane ('trichickenfootphos-bisborane'. 'TCFP-BHs')

A suspension of (S)-TCFP-BH₃ (86.1% ee, 1.07 g) in cyclohexane (60 ml/g, 64 ml) at ambient temperature was stirred rapidly for 2hrs. After this time the suspension was filtered off, washing with cyclohexane (2 x 10 ml). The residue was collected (370 mg) and the filtrate was evaporated to give a white solid (554 mg, 60% mass recovery); ¹H NMR (300MHz, CDCl₃), δ/ppm 1.88 (t J= 12 Hz₅ 2H, P-CH₂), 1.56 (d J= 10 Hz, 3H, P-CH₃), 1.33 (d J= 13 Hz, 9H, P-C(CH₃)₃), 1.27 (d J= 13 Hz, 9H, P- C(CHs)₃), 1.19 (d J - 13 Hz, 9H, P-C(CH₃)₃), 0.61 (m, 6H, 2 x BH₃); ³¹P NMR (121MHz, CDCl₃) δ/ppm 49.25-48.78 (m), 32.65-32.11 (m). A small amount of the evaporated filtrate (~20 mg) was converted into the corresponding disulfide to determine enantiomeric excess (ee > 99%), using the following procedure;

To TCFP-BH₃ (1 eq), DABCO (1.5 eq) and elemental sulphur (5 eq) in a flame dried crimped-top vial was added nitrogen-purged dry toluene (2 ml). The suspension was heated to 85⁰C and stirred for 2hrs under dry nitrogen gas. After this time the reaction was allowed to cool to ambient temperature and filtered through a 5μm syringe filter.

The enantiomeric excess of the resulting solution of disulfide was determined by

HPLC. HPLC: Daicel Chiralpak AS-H (250 x 4.6 mm) + Daicel AS-H guard cartridge, heptane/EtOH 97/03, 1.0 mL/min, UV detection (210 nm); retention times 5.77 (R),

8.00 min (S).

All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and system of the present invention will be apparent to those skilled in the art without departing from the spirit and scope of the present invention. Although the present invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to the skilled person in chemistry or related fields are intended to be within the scope of the following claims. REFERENCES

• Brunner, H.; Zettlmeier, W. Handbook of Enantioselective Catalysis, VCH, Weinheim, 1993 lists many hundreds of chiral phosphines used to date • Edmundson, R. S., in "The chemistry of organophosphorus compounds" (Ed. Hartley, F. R.), Vol. 2, John Wiley & Sons Ltd, Chichester, 1992, Chapter 7

• Homer et al., Pure Appl. Chem. , 1964, 9, 225

• Kagan, H.B. Bull. Chim. Soc. Fr., 1988, 846

• Knowles, W.S. J. Chem. Ed., 1986, 63, 222 • Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995, 117, 9075

• Noyori, R. Chem. Soc. Rev., 1989, 18, 187

• Ojima, I., Ed., Catalytic Asymmetric Synthesis; 2nd. Edn., Wiley- VCH, 2000

• Perlikowska, W.; Gouygou, M.; Daran, J-C; Balavoine, G.; Mikolajczyk, M. Tetrahedron Lett., 2001, 42, 7841-7845 • Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev. 1994, 94, 1375

• Valentine, in Asymmetric Synthesis (Eds. J. D. Morrison and J. W. Scott), Vol.4, Academic Press, New York, 1984, Chapter 3

• Wada, Y.; Imamoto, T.; Tsuruta, H.; Yamaguchi, K.; Gridnev, I. D. Adv. Synth. Catal. 2004, 346, 111

Claims

1. A method for increasing the enantiomeric excess of a neutral four-coordinated phosphorus compound selected from a chiral phosphine oxide, a chiral phosphine sulfide, a chiral phosphine imide and a chiral phosphine-borane, said method comprising the steps of:

(a) contacting said chiral phosphine oxide, sulfide, imide or borane with a solvent to form a heterogeneous mixture (i.e. a slurry);

(b) partitioning the phosphine oxide, sulfide, imide or borane either into the solvent or as an insoluble product; and

(c) optionally, isolating the partitioned phosphine oxide, sulfide, imide or borane.

2. A method according to claim 1 wherein the chiral phosphine oxide is a compound of formula (Ia) :

wherein, Ri, R₂ are independently selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl and an alkenyl group; and R₃ is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, and -A-P(X)RjR₂, wherein A is selected from alkyl, heteroalkyl, aryl, alkylaryl, -(hetero)-(aryl)_r, maleic anhydride, succinic anhydride, maleimide and succinimide, X is absent (lone pair), O, S, BH₃ OrNR₄.

3. A method according to claim 1 wherein the chiral phosphine sulfide is a compound of formula (Ib):

wherein,

R₁, R₂ are independently selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaiyl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl and an alkenyl group; and R₃ is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aτyl)_r, where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, and -A-PpQRiR₂, wherein A is selected from alkyl, heteroalkyl, aryl, alkylaryl, -(hetero)-(aryl)_r, maleic anhydride, succinic anhydride, maleimide and succinimide, X is absent (lone pair), O, S₃ BH₃ Or NR₄.

4. A method according to claim 1 wherein the chiral phosphine imide is a compound of formula (Ic):

wherein,

Ri, R₂ are independently selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl and an alkenyl group; and R₃ is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, and -A-P(X)R₁R₂, wherein A is selected from alkyl, heteroalkyl, aryl, alkylaryl, -(hetero)-(aryl)_r, maleic anhydride, succinic anhydride, maleimide and succinimide, X is absent (lone pair), O, S, BH₃ or NR₄; and R₄ is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)r, where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, NR^aR^b, SO₂R^C, SO₂NR^dR^e, P(O)R^fR^ER^h, wherein R^a"h are each independently selected from H, alkyl and alkylaryl.

5. A method according to claim 1 wherein the chiral phosphine-borane is a compound of formula (Id) :

wherein, Ri, R₂ are independently selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl and an alkenyl group; and R₃ is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, carbocycle, alkylaryl, an alkenyl group, and -A-P(X)R₁R₂, wherein A is selected from alkyl, heteroalkyl, aryl, alkylaryl, -(hetero)-(aryl)_r, maleic anhydride, succinic anhydride, maleimide and succinimide,. X is absent (lone pair), O, S, BH₃ or NR₄.

6. A method according to any preceding claim wherein Ri and R₂ are independently selected from aryl, alkyl, heteroalkylaryl, -(hetero)-(aryl)_r, where r is 1 or 2, and heteroalkyl.

7. A method according to any preceding claim wherein Ri and R₂ are independently selected from C_5-2O aryl, C_4-12 heteroalkylaryl, Ci_-20 alkyl, C_1-2O heteroalkyl and -(hetero)-(C_5-2o aryl)_r, wherein the C_5-2O aryl, C_4-12 heteroalkylaryl, Ci_-2O alkyl, Ci_-2O heteroalkyl and -(hetero)-(C5-2o aryl)_r groups are optionally substituted by one or more substituents selected from halogeno,

NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, CONR^fR^g, COR^h, SO₃H, SO₂R¹, SO₂NR^jR^k, alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said alkylaryl, aryl, heterocycloalkyl and heteroaryl groups may be optionally further substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and COR"; wherein m is O, 1, 2, or 3; n is 1, 2, or 3; r is 1 or 2 and R^a"n are each independently selected from H, alkyl and alkylaryl.

8. A method according to any preceding claim wherein Ri and R₂ are independently selected from Cs_-2O aryl, C_4-i2 heteroalkylaryl, Ci_-2O alkyl, Ci_-20 heteroalkyl and -(hetero)-(Cs-2o aryl)r, wherein the C5-20 aryl, C_4-12 heteroalkylaryl, Ci_-20 alkyl, Ci_-2O heteroalkyl and -(hetero)-(Cs-2o aryl)_r groups are optionally substituted by one or more substituents selected from (CH₂)_mOR^a, COOR^e, O(CH₂)_naryl, alkyl, aryl and alkylaryl; wherein m is 0, 1,

2, or 3; n is 1, 2, or 3; r is 1 or 2 and R^a and R^e are independently selected from H, alkyl and alkylaryl.

9. A method according to any preceding claim wherein Ri and R₂ are independently selected from phenyl, phenyloxy, naphthyl and tert-butyl wherein each group is optionally substituted by one or more methoxy, benzyloxy, hydroxy, phenyl, zsø-propyl and methyl groups.

10. A method according to any-preceding claim wherein R₃ is=selected from aryl, alkyl, heteroalkylaryl, heteroalkyl, -(hetero)-(aryl)_r, where r is 1 or 2, -A-

P(X)R₁R₂, wherein A is selected from Ci-₃alkyl, Ci.₃heteroalkyl, phenyl, -O- phenyl, maleic anhydride, succinic anhydride, maleimide and succinimide, X is absent (lone pair), O, S, BH₃ or NR₄.

11. A method according to any of claims 1-9 wherein R₃ is a halogen or a Ci_-20 alkyl group which is optionally substituted by one or more substituents selected from halogeno, NO₂, CN, (CH₂)_mOR^a, O(CH₂)_nOR^b, (CH₂)_naryl, O(CH₂)_naryl, NR^cR^d, CF₃, COOR^e, CONR^fR^ε, COR^h, SO₃H, SO₂R¹, SO₂NR^JR , alkyl, aryl, alkylaryl, heterocycloalkyl and heteroaryl, wherein said alkylaryl, aryl, heterocycloalkyl and heteroaryl may be optionally further substituted by one or more substituents selected from (CH₂)_mOR^a, R^m and COR"; wherein m is 0, 1, 2, or 3; n is 1, 2, or 3; and R^a'n are each independently selected from H, alkyl and alkylaryl.

12. A method according to claim 10 wherein R3 is -A-P(X)R₁R₂, wherein A is C_{1- 3}alkyl, X is absent (lone pair), O, S₃ BH₃ or NR₄.

13. A method according to any preceding claim wherein R4 is selected from alkyl, aryl, sulfonyl (SO₂R⁰) and phosphoryl (P(O)R^fR^gR^h).

14. A method according to any preceding claim wherein the compound of formula (Ia) to (Id) is selected from: l-methoxy-2-(methyl-phenyl-phosphinoyl)-benzene; 1 ,4-dimethoxy-2-(methyl-phenyl-phosphinoyl)-benzene;

1 ,3 -dimethoxy-2-(methyl-phenyl-phosphinoyl)-benzene; l-(methyl-phenyl-phosphinoyl)-naphthalene;

2-methoxy- 1 -(methyl-phenyl-phosphinoyl)-naphthalene; l-(rert-butyl-methyl-phosphinoyl)-2-methoxy-benzene; 2-(methyl-phenyl-phosphinoyl)-biphenyl; l-isopropyl-2-(methyl-phenyl-phosphinoyl)-benzene; methyl-2-(methyl-phenyl-phosphinoyl)-benzene; l-methoxy-2-(methyl-phenyl-thiophosphinoyl)-benzene; l,4-dimethoxy-2-(methyl-phenyl-thiophosphinoyl)-benzene; 1 ,3-dimethoxy-2-(methyl-phenyl-thiophosphinoyl)-benzene; l-(methyl-phenyl-thiophosphinoyl)-naphthalene;

2-methoxy- 1 -(methyl-phenyl-thiophosphinoyl)-naphthalene; l-(fert-butyl-methyl-thiophosphinoyl)-2-methoxy-benzene;

2-(methyl-phenyl-thiophosphinoyl)-biphenyl; 1 -isopropyl-2-(methyl-phenyl-thiophosphinoyl)-benzene; methyl-2-(methyl-phenyl-thiophosphinoyl)-benzene; .

(2-methoxyphenyl)-methyl-phenyl-phosphane-borane;

(2,5-dimethoxyphenyl)-methyl-phenyl-phosphane-borane;

(2,6-dimethoxyphenyl)-methyl-phenyl-phosphane-borane; methyl-naphthalen- 1 -yl-phenyl-phosphane-borane;

(2-methoxy-naphthalen- 1 -yl)-methyl-phenyl-phosphane-borane; ter/-butyl-(2-methoxyphenyl)-methyl-phosphane-borane; biphenyl-2-yl-methyl-phenyl-phosphane-borane;

(2-isopropylphenyl)-methyl-phenyl-phosphane-borane; methyl-phenyl-o-tolyl-phosphane-borane; and

2-{[(di-fer/-butyl-phosphanyl)-methyl]-methyl-phosphanyl}-2-methyl-propane ('trichickenfootphos-bisborane).

15. A method according to any preceding claim wherein the chiral phosphine oxide, sulfide, imide or borane of step (a) is present as a non-racemic mixture.

16. A method according to claim 14 wherein the non-racemic mixture has an enantiomeric excess of greater than about 1%.

17. A method according to claim 14 wherein the non-racemic mixture has an enantiomeric excess of greater than about 25%.

18. A method according to claim 14 wherein the non-racemic mixture has an enantiomeric excess of greater than about 50%.

19. A method according to claim 14 wherein the non-racemic mixture has an enantiomeric excess of greater than about 75%.

20. A method according to any of claims 1-13 wherein the chiral phosphine oxide, sulfide, imide or borane of step (a) is present as a racemate.

21. A method according to any preceding claim wherein the partitioned phosphine oxide, sulfide, imide or borane has an enantiomeric excess from about 1% to greater than about 99%.

22. A method according to claim 20 wherein the enantiomeric excess is from about 60% to greater than about 99%.

23. A method according to claim 20 wherein the enantiomeric excess is from about 75% to greater than about 99%.

24. A method according to claim 20 wherein the enantiomeric excess is from about 95% to greater than about 99%.

25. A method according to any preceding claim wherein the solvent is selected from at least one of alkanes, cycloalkanes, heteroalkanes, heterocycloalkanes, alkyl esters, aromatics, heteroaromatics and alcohols, or mixtures thereof.

26. A method according to any preceding claim wherein the solvent is selected from at least one Of C_1-2O alkanes, C_3-2O cycloalkanes, C_1-20 heteroalkanes, C_3-20 heterocycloalkanes, C_1-2O alkyl esters, C6-20 aromatics, C_4-20 heteroaromatics and C_1-2O alcohols, or mixtures thereof.

27. A method according to any preceding claim wherein the solvent is selected from at least one Of C_1-15 alkanes, C_3-12 cycloalkanes, Ci_-15 heteroalkanes, C_3-12 heterocycloalkanes, C_1-I₅ alkyl esters, C^_1O aromatics, C_4-10 heteroaromatics and C_1-15 alcohols, or mixtures thereof.

28. A method according to any preceding claim wherein the solvent is selected from at least one of C_1-6 alkanes, C_3-7 cycloalkanes, C_1-6 heteroalkanes, C_3-7 heterocycloalkanes; Ci-6 alkyl esters, Cβ-& aromatics, C4.₅ heteroaromatics and C_1-Io alcohols^ or mixtures thereof.

29. A method according to any preceding claim wherein the solvent is selected from at least one of hexane, heptane, cyclohexane, diethyl ether, methyl tert- butyl ether, tetrahydrofuran, ethyl acetate, toluene and methanol, or mixtures thereof.

30. A method according to any preceding claim wherein the solvent is diethyl ether.

31. A method according to any one of claims 1 to 28 wherein the solvent is a mixture of a C).₂o heteroalkane with a second solvent.

32. A method according to claim 30 wherein the C_1-2O heteroalkane is diethyl ether.

33. A method according to any one of claims 1 to 28 wherein the solvent is a mixture of a C_1-6 alkyl ester, and a second solvent.

34. A method according to claim 32 wherein the Ci_-6 alkyl ester is ethyl acetate.

35. A method according to any of claims 30 to 34 wherein the second solvent is selected from tetrahydrofuran, cyclohexane, heptane and C1-3 alcohols, or mixtures thereof.

36. A method according to claims 31 to 32 wherein the ratio of diethyl ether or ethyl acetate to the second solvent is from about 1:100 to about 100:1 v/v.

37. A method according to claims 33 to 34 wherein the ratio of ethyl acetate or ethyl acetate to the second solvent is from about 1:100 to about 100:1 v/v.

38. A method according to claim 35 or 36 wherein the ratio is from about 1:50 to about 50:1 v/v.

39. A method according to any one of claims 37 wherein the ratio is from about 1:10 to about 10:1 v/v.

40. A method according to any one of claims 37 wherein the ratio is from about 1:2 to about 2:1 v/v.

41. A method according to any one of claims 37 wherein the ratio is about 1 : 1 v/v.

42. A method according to any preceding claim wherein the ratio of solvent to the chiral phosphine oxide, sulfide, imide or borane of step (a) is from about 1 ml/g to about 1000 ml/g.

43. A method according to claim 41 wherein the ratio is from about 1 ml/g to about 500 ml/g.

44. A method according to claim 41 wherein the ratio is from about 1 ml/g to about 100 ml/g.

45. A method according to claim 41 wherein the ratio is from about 1 ml/g to about 50 ml/g.

46. A method according to any preceding claim which further comprises converting the partitioned phosphine oxide, sulfide, imide or borane to the corresponding phosphine.

47. The method of claim 46 wherein the partitioned phosphine oxide, sulfide, imide or borane is reacted with a reducing agent selected from hydrides, boranes and silanes.

48. A method according to any one of claims 1 to 45 which further comprises converting the partitioned phosphine oxide to the bis-phosphine oxide.

49. A method according to claim 48 wherein the bis-phosphine oxide is selected from: 1 ,2-bis[(2,5-dimethoxyphenyI)(phenyl)phosphinoyl]ethane; l,2-bis[(2-methoxyphenyl)(phenyl)phosphinoyl]ethane; l,2-bis[phenyl-(2-hydroxyphenyl)phosphinoyl]ethane;

1 ,2-bis[phenyl-(2-benzyloxyphenyl)phosphinoyl]ethane; and l,2-bis[phenyl-(2-biphenylyl)phosphinoyl]ethane.

50. A method according to any one of claims 1 to 45 which further comprises converting the partitioned phosphine sulfide to the bis-phosphine sulfide.

51. A method according to claim 50 wherein the bis-phosphine sulfide is selected from: l,2-bis[(2,5-dimethoxyphenyl)(phenyl)thiophosphinoyl]ethane;

1 ,2-bis [(2-methoxyphenyl)(phenyl)thiophosphinoyl] ethane; l,2-bis[phenyl-(2-hydroxyphenylthiophosphinoyl]ethane;

1 ,2-bis[phenyl-(2-benzyloxyphenyl)thiophosphinoyl]ethane; and l,2-bis[phenyl-(2-biphenylyl)thiophosphinoyl]ethane.

52. A method according to any one of claims 1 to 45 which further comprises converting the partitioned phosphine-borane to the bis(phosphine-borane).

53. A method according to claim 52 wherein the bis(phosphine-borane) is selected from: l,2-bis[boronato(2,5-dimethoxyphenyl)(phenyl)phosphino]ethane; l,2-bis[boronato(2-methoxyphenyl)(phenyl)phosphino]ethane; 1 ,2-bis [boronato-phenyl-(2-hydroxyphenyl)phosphino] ethane;

1 ,2-bis[boronato-phenyl-(2-benzyloxyphenyl)phosphino]ethane; and l,2-bis[boronato-phenyl-(2-biphenylyl)phosphino]ethane.

54. A method according to claim 48 or claim 49 which further comprises reducing the bis-phosphine oxide to the corresponding bis-phosphine.

55. A method according to claim 50 or claim 51 which further comprises reducing the bis-phosphine sulfide to the corresponding bis-phosphine.

56. A method according to claim 52 or claim 53 which further comprises converting the bis(phosphine-borane) to the corresponding bis-phosphine.

57. A method according to any one of claims 54 to 56 wherein the bis-phosphine is selected from: 1 ,2-bis[(2,5-dimethoxyphenyl)(phenyl)phosphino]ethane; l,2-bis[(2-methoxyphenyl)(phenyl)phosphino]ethane;

1 ,2-bis [phenyl-(2-hydroxyphenyl)phosphino] ethane;

1 ,2-bis[phenyl-(2-benzyloxyphenyl)phosphino]ethane; and l,2-bis[phenyl-(2-biphenylyl)phosphino]ethane.

58. Use of the method according to any one of claims 1 to 45 for increasing the enantiomeric excess of a chiral phosphine oxide, sulfide, imide or borane.

9. Phosphine oxides, phosphine sulfides, phosphine irnides, phosphine-boranes, phosphines, bis-phosphine oxides, bis-phosphine sulfides, bis(phosphine- boranes) or bis-phospbines obtainable by the method of any one of claims 1 to 57.