WO2012113889A1

WO2012113889A1 - Processes for the stereoselective preparation of p-chiral four -coordinated phosphorus borane compounds and p-chiral three-coordinated phosphorus compounds

Info

Publication number: WO2012113889A1
Application number: PCT/EP2012/053111
Authority: WO
Inventors: Declan G. GILHEANY; Jaya Satyanarayana KUDAVALLI; Adam D. MOLLOY; Kirill NIKITIN; Kamalraj V. RAJENDRAN
Original assignee: University College Dublin
Priority date: 2011-02-23
Filing date: 2012-02-23
Publication date: 2012-08-30
Also published as: GB201103092D0

Abstract

Processes for the stereoselective preparation of P-chiral four-coordinated phosphorus borane compounds and P-chiral three-coordinated phosphorus compounds.

Description

PROCESSES FOR THE STEREOSELECTIVE PREPARATION OF P-CHIRAL FOUR -COORDINATED PHOSPHORUS BORANE COMPOUNDS AND P-CHIRAL

THREE-COORDINATED PHOSPHORUS COMPOUNDS

Field of the Invention The present invention relates to processes for preparing stereoisomerically enriched phosphorus containing compounds, and processes for racemic conversion of phosphine oxides to phosphine boranes.

Background 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 's L-dopa process (Knowles, 1986); Anic and Monsanto Aspartame process (Kagan, 1988) Syntex naproxen process (Noyori, 1989) and Takasago L-menthol process (Kagan, 1998). 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.

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 compounds such as phosphine oxides and phosphine sulfides continues to be of prime importance (Pietrusiewicz et al., 1994).

A number of strategies have been employed in the synthesis of chiral phosphines. In principle, the most direct route to optically active phosphines is to resolve the racemic phosphine by making disatereomeric 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 from 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 phosphorates (Valentine, 1984) is hindered by the availability of suitable phosphonites, which have low optical stability compared with phosphines. 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-coordinated 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-thiophosphoryl disulfides is discussed in Perlikowska et al, 2001.

Statements of the Invention

According to a first aspect of the present invention there is provided a process for the stereoselective preparation of a P-chiral four-coordinated phosphorus borane compound, the process comprising

(i) reacting a first reactant comprising a P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P- atom with a second reactant selected from the group consisting of a chiral alcohol, chiral amine or chiral thiol, to provide a diastereomeric P-chiral four-coordinated chiral alloxy-, chiral amino-, or chiral tbio- substituted phosphonium salt; and

(ii) reacting said diastereomeric substituted phosphonium salt with a metal borohydride to provide a P-chiral four-coordinated phosphorus borane compound.

In one embodiment of this first aspect of the invention, the process further comprises converting said P-chiral four-coordinated phosphorus borane compound to a P-chiral three-coordinated phosphorus compound.

In one embodiment of this first aspect of the invention, said P-chiral four-coordinated phosphosphonium salt compound having a leaving group attached to the P-atom is prepared by a process comprising reacting a P-chiral three-coordinated phosphorus compound with an electrophile.

In an alternative embodiment of this first aspect of the invention, when said P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P-atom is a P-chiral four-coordinated halo-phosphonium salt compound, said compound is prepared by a process comprising reacting a P-chiral phosphine oxide or a P-chiral phospine sulfide with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfunyl halide and methane sulfonyl halide.

According to a second aspect of the present invention there is provided a process for the stereoselective preparation of a P-chiral three-coordinated phosphorus compound, the process comprising

(i) reacting a first reactant comprising a P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P- atom, with a second reactant selected from the group consisting of a chiral alcohol, chiral amine or chiral thiol, to provide a diastereomeric P-chiral four-coordinated chiral alkoxy-, chiral amino-, or chiral thio- substituted phosphonium salt; and

(ii) reducing said diastereomeric substituted phosphonium salt compound preferably with a reducing agent, such as LiAlH₄ or sodium bis (2- methoxyethoxy) aluminium hydride, to provide a P-chiral three- coordinated borane compound.

In one embodiment of this second aspect of the invention, said P-chiral four- coordinated phosphosphonium salt compound having a leaving group attached to the P-atom is prepared by a process comprising reacting a P-chiral three-coordinated phosphorus compound with an electrophile.

In an alternative embodiment of this second aspect of the invention, when said P- chiral four-coordinated phosphosphonium salt compound having a leaving group attached to the P-atom is a P-chiral four-coordinated halo-phosphonium salt compound, said compound is prepared by a process comprising reacting a P-chiral phosphine oxide or a P-chiral phosphine sulfide with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfonyl halide, and methane sulfonyl halide. According to a third aspect of the present invention there is provided a process for the stereoselective preparation of a P-chiral phosphine oxide or sulphide compound, the process comprising (i) reacting a P-chiral phosphine oxide or a P-chiral phosphine sulfide with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfonyl halide, and methane sulfonyl halide to provide a P-chiral four-coordinated halo-phosphonium salt compound, and (ii) reacting said P- chiral four-coordinated halo-phosphonium salt compound with a reactant selected from the group consisting of a chiral alcohol, or chiral thiol to provide a stereospecific P-chiral phosphine oxide or sulphide compound. Alternatively, the P-chiral four- coordinated halo-phosphonium salt compound is reacted with a chiral amine and subsequently hydrolysed, e.g. with sodium hydroxide, to provide a stereospecific P- chiral phosphine oxide.

According to a fourth aspect of the present invention there is provided a process for the preparation of a four-coordinated phosphorus borane compound, the process comprising (i) reacting a phosphine oxide compound or a phosphine sulphide compound with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfonyl halide, and methane sulfonyl halide to afford a four-coordinated halo-phosphonium salt compound, and (ii) treating said four- coordinated halo-phosphonium salt compound with a metal borohydride to provide a four-coordinated phosphorus borane compound.

Preferably, the process of the fourth aspect is a stereoselective process for the preparation of a P-chiral four-coordinated phosphorus borane compound. According to a fifth aspect of the present invention there is provided a process for the stereospecific preparation of a P-chiral four-coordinated phosphorus borane compound, the process comprising (i) reacting a P-chiral phosphine oxide compound or a P-chiral phosphine sulfide compound with an alkylating agent to afford a P-chiral four-coordinated alkoxyphosphonium salt compound, and (ii) reducing said P-chiral four-coordinated alkoxyphosphonium salt compound with a metal borohydride or LiAlEU to provide a P-chiral four-coordinated phosphorus borane compound.

In this fifth aspect of the invention, treatment with a metal borohydride or LiAlEU yields a P-chiral four-coordinated phosphorus borane compound with inversion of configuration but without adversely affecting any stereoisomeric ratio present in the starting P-chiral phosphine oxide or sulfide.

In a preferred embodiment, the alkylating agent is a compound of formula [R₃0]BF₄, such as Meerwein's salt, [Et₃0]BF₄.

According to a sixth aspect of the present invention there is provided a process for the stereoselective preparation of a P-chiral four-coordinated alkoxyphosphonium salt compound, the process comprising:

(i) reacting a three-coordinated halophosphine compound with a chiral alkoxy Grignard reagent to afford a diastereomerically enriched P-chiral three-coordinated alkoxyphosphorus compound; and

(ϋ) reacting said diastereomerically enriched P-chiral three- coordinated alkoxyphosphorus compound with an alkyl halide or an alkyl triflate to afford a diastereomeric P-chiral four- coordinated alkoxyphosphonium salt compound.

In one embodiment of the sixth aspect of the present invention, the process further comprises treating said diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound with a metal borohydride to afford a P-chiral four-coordinated phosphorus borane compound.

In an alternative embodiment of the sixth aspect of the present invention, the process further comprises treating said diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound with L1AIH₄ to afford a P-chiral three coordinated phosphorus compound. In yet a further alternative embodiment of the sixth aspect of the present invention, the process further comprises converting said P-chiral four-coordinated alkoxyphosphonium salt compound to a P-chiral phosphine oxide. According to a seventh aspect of the invention is provided a process for preparing an enantiomerically enriched chiral phosphonium salt compound comprising reacting a P-chiral four-coordinated chiral alkoxy-, chiral amino-, or chiral thio-substituted phosphonium salt compound with a Grignard reagent to provide an enantiomerically enriched chiral phosphonium salt compound.

Detailed Description

Stereoselective reactions can generally be of two types: enantioselective, in which selection is between two enantiomeric products; and diastereoselective, in which selection is between diastereomeric products.

The term stereoselective preparation refers to a preparation that yields predominantly one entantiomer or one diastereomer. Similarly, the term stereospecific refers to a product that is predominantly in the form of one entantiomer or one diastereomer. The present invention is primarily concerned with stereoselective reactions involving compounds with a single P-chiral centre and therefore with enantioselective preparations. However, the skilled person would readily appreciate that the methods described herein are equally applicable to compounds possessing one or more additional chiral centres (either at P or C) and that corresponding reactions involving such compounds would therefore be diastereoselective preparations. Accordingly, terms such as enantiomeric excess and enantiomerically enriched, and the like, may when the context requires it mean diastereomeric excess and diastereomerically enriched, and the like. Preferably the enantiomeric excess (ee) is greater than 25%, more preferably greater than 30%, more preferably greater than 50%, more preferably greater than 60%, more preferably greater than 70%, more preferably greater than 80%. The term P-chiral refers to a phosphorus containing compound wherein a chiral centre resides on the phosphorus atom.

As used herein, the term "hydrocarbyl" refers to a group comprising at least C and H. If the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the hydrocarbyl group may contain heteroatoms. Suitable heteroatoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen, oxygen, phosphorus and silicon. Preferably, the hydrocarbyl group is an aryl, heteroaryl, alkyl, carbocycle, heterocycloalkyl, aralkyl or alkenyl group.

As used herein, the term "alkyl" includes both saturated straight chain and branched alkyl groups which may be substituted (mono- or poly-, preferably 1 to 3 substituents, more preferably one substituent) or unsubstituted. In one embodiment the alkyl group is a Ci-20 alkyl group. In another embodiment the alkyl group is a C_1-15. In another embodiment the alkyl group is a C]_-12 alkyl group. In another embodiment the alkyl group is a Ci_-6 alkyl group. Suitable substituents include, for example, a group selected from halogeno, N0₂, CN, (CH₂)_mOR^a, where m is 0, I, 2 or 3, 0(CH₂)„OR^b, where n is 1, 2, or 3, NR^cR^d, CF₃, COOR^e, CONR^fR^e, COR^h, S0₃H, S0₂R S0₂NRⁱR^k, heterocycloalkyl or heteroaryl, wherein said heterocycloalkyl and heteroaryl may be optionally substituted by one or more substituents selected from R^m and COR"; and R^a"n are each independently H or alkyl. As used herein, the term "carbocycle" refers to a mono- or multi-ringed carbocyclic ring system which may be substituted (mono- or poly-, (mono- or poly-, preferably 1 to 3 substituents, more preferably one substituents)) or unsubstituted. Preferably the multi-ringed carbocycle is bi- or tri-cyclic. Preferably the carbocycle is a C_3-20 carbocyclic group. More preferably the carbocycle is a C_3-i₂ carbocyclic group. More preferably the carbocycle group is a C_3-7 carbocyclic group. Suitable substituents include, for example, a group selected from halogeno, N0₂, CN, (CH₂)_mOR^a, where m is 0, 1, 2 or 3, 0(CH₂)_nOR^b, where n is 1, 2, or 3, NR^cR^d, CF₃, COOR^e, CONR'R⁵, COR^h, S0₃H, S0₂R, S0₂NR^jR^k, heterocycloalkyl or heteroaryl, wherein said heterocycloalkyl and heteroaryl may be optionally substituted by one or more substituents selected from R^m and COR"; and R^a~" are each independently H or alkyl. 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-, preferably 1 to 3 substituents, more preferably one substituent)) or unsubstituted. Preferably the multi-ringed cyclic alkyl group is bi- or tri-ringed. Preferably the cycloalkyl group is a C_3-2o 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. Suitable substituents include, for example, a group selected from halogeno, N0₂, CN, (CH₂)_mOR^a, where m is 0, 1, 2 or 3, 0(CH₂)_nOR^b, where n is 1, 2, or 3, NR°R^d, CF₃, COOR⁶, CONR^fR , COR^h, S0₃H, S0₂R', S0₂NRⁱR^k, heterocycloalkyl or heteroaryl, wherein said heterocycloalkyl and heteroaryl may be optionally substituted by one or more substituents selected from R^m and COR"; and R^a~" are each independently H or alkyl. Preferably the substituents are selected from halogeno, (CH₂)_mOR^a, where m is 0, 1, 2 or 3, NR°R^d, COOR^e, CONR^fR^s, COR^h. 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, 1 ,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 sp³ hybridized nitrogen heteroatom. Preferred heterocycloalkyl groups include piperazine, morpholine, piperidine and pyrrolidine.

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-, preferably 1 to 3 substituents, more preferably one substituent) or unsubstituted. In one embodiment the alkenyl group is a C_2-20 alkenyl group. In another embodiment the alkenyl group is a C_2-15 alkenyl group. In another embodiment the alkenyl group is a C_2-i₂ alkenyl group. In another embodiment the alkenyl group is a C_2-6 alkenyl group. Suitable substituents include, for example, a group selected from halogeno, N0₂, CN, (CH₂)_mOR^a, where m is 0, 1, 2 or 3, 0(CH₂)_nOR^b, where n is 1, 2, or 3, NR^cR^d, CF₃, COOR^e, CONR^fR^g, COR^h, S0₃H, SO₂R', SC^NR'R¹', heterocycloalkyl or heteroaryl, wherein said heterocycloalkyl and heteroaryl may be optionally substituted by one or more substituents selected from R^m and CORⁿ; and R^a~" are each independently H or alkyl. 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^s, COR^h.

As used herein, the term "aryl" refers to a mono- or multi- ringed aromatic group which may be substituted (mono- or poly-, preferably 1 to 3 substituents, more preferably one substituent) 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_6-12 aromatic group. Typical examples include phenyl and naphthyl etc. Suitable substituents include, for example, a group selected from halogeno, N0₂, CN, (CH₂)_mOR^a, where m is 0, 1, 2 or 3, 0(CH₂)_nOR^b, where n is 1, 2, or 3, NR°R^d, CF₃, COOR^e, CONR^fR⁸, COR^h, S0₃H, SC^R*, S0₂NR^JR^k, heterocycloalkyl, aryl or heteroaryl, wherein said heterocycloalkyl and heteroaryl may be optionally substituted by one or more substituents selected from R^m and COR"; and R^a"n are each independently H or alkyl. Preferably the substituents are selected from halogeno, (CH₂)_mOR^a, where m is 0, 1, 2 or 3, NR^cR^d, COOR^e, CONR^fR⁸, COR^h.

As used herein, the term "heteroaryl" refers to a C_4-12 aromatic, substituted (mono- or poly-, preferably 1 to 3 substituents, more preferably one substituent) or unsubstituted group, which comprises one or more heteroatoms, preferably 1 to 3 heteroatoms, more preferably one heteroatom, 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. Suitable substituents include, for example, a group selected from halogeno, N0₂, CN, (CH₂)_mOR^a, where m is 0, 1, 2 or 3, 0(CH₂)_nOR^b, where n is 1, 2, or 3, NR^cR^d, CF₃, COOR^e, CONR R^g, COR^h, S0₃H, S0₂R\ S0₂NRⁱR^k, heterocycloalkyl or heteroaryl, wherein said heterocycloalkyl and heteroaryl may be optionally substituted by one or more substituents selected from R^m and COR"; and R^a"n are each independently H or alkyl. Preferably the substituents are selected from halogeno, (CH₂)_mOR^a, where m is 0, 1, 2 or 3, NR°R^d, COOR^e, CO R^fR^g, COR^h.

The term cyclic alcohol, as used herein to define a group or a part of a group, unless otherwise stated, refers to a saturated or unsaturated mono or multi-ringed cyclic group containing from 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3-7 carbon atoms, substituted by at least one hydroxyl group and optionally substituted by one or more substituents. Suitable substituents include aryl, heteroaryl, alkyl, carbocycle, heterocycloalkyl, aralkyl and alkenyl groups. Preferably, the cyclic alcohol is substituted by 1 to 3 substituents, more preferably one or two substituents. Preferably the mono or multi-ringed cyclic group is saturated. Preferably the multi- ringed group is tricyclic or bicyclic. The stereoselectivity of the reaction is generally improved if the alcohol has a bulky substituent at the a position relative to the -OH. In one embodiment, the bulky substituent has 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 9 carbon atoms. Examples of such bulky substituents include phenyl and isopropyl, cyclohexanol and dimethyl benzyl.

Examples of suitable cyclic alcohols include menthol, 8-phenylmenthol, trans-2-tert- butylcyclohexanol, isomenthol, 2-benzoylcyclohexanol and trans-2- phenylcyclohexanol .

Preferred organometallic groups are selected from the group consisting of ferrocenyl, ruthenacenyl, (bisindenyl)titanyl, (bisindenyl)zirconyl, (bisindenyl)hafnyl, (bisindenyl)niobyl, (bisindenyl)tantalyl, (bisindenyl)molybdenyl, and (bisindenyl)tungstenyl. As used herein, the term alcohol refers to any organic molecule comprising at least one hydroxy group bonded to a carbon atom.

The P-chiral compounds of the present invention (three or four coordinated) may, in addition, be chiral at at least one other site, for example, another phosphorus atom and/or another carbon atom. Some embodiments of the present invention use an Appel, Castro or Evans type reaction. A skilled person would readily appreciate that modifications of these well known reactions also fall within the scope of the present invention.

The Appel reaction is based on a reaction system comprising a three-coordinated phosphine compound and polyhalogenoalkanes such as carbon tetrachloride (Appel et al., 1979; Appel, 1975). The first report of the use of a mixture of triphenylphosphine and carbon tetrachloride to effect the conversion of alcohols to alkyl halides (one of the best known uses of the most common version of the Appel system) was by Downie, Holmes and Lee in 1966 (Downie et al., 1966).

PR₃ + R'— OH + CCI₄ *~ R'- CI + O=PR₃ + HCCI₃

Example of an Appel reaction

The halogen group of the electrophile acts as an electrophile, associating with the phosphine to form a quaternary phosphonium salt which then undergoes nucleophilic attack. The specific system based on tris(dimethylamino)phosphine was studied in the late 60s and early 70s by Castro and co-workers (Castro et al., 1969; Castro et al., 1971) and his name is sometimes associated with this variant of Appel. Related systems for the conversion, amongst others, of diols to cyclic ethers, were reported by Evans (Barry et al., 1981; Robinson et al., 1985). As well as its most significant conversions, namely conversion of alcohols to alkyl halides and ester and amide formation, these systems are useful for an extremely wide variety of other organic chemical transformations ( olodiazhnyi, 1998; Appel, 1975; Cadogan, 1979) including the preparation of 1,1-dichloroalkenes from aldehydes, ketones and epoxides; acid halides from the parent acid; imidoyl halides from carboxamides and carbodiimides from N,N -disubstituted ureas. In all of the reactions promoted by Appel, Castro and Evans, conditions, the ultimate function of the phosphorus species is to collect a Group 15 or 16 atom (for example, an oxygen, sulfur or nitrogen atom) from the system. In the formation of alkyl halides from alcohols, for example, the oxygen of the alcohol ends up attached to the phosphorus atom.

In these reactions the formation of the e.g., phosphine oxide or sulphide is seen as a by-product of the process. Indeed, it can be a nuisance in certain cases if it cannot be easily removed from the desired product of the reaction.

Thus, according to a first aspect of the present invention there is provided a process for the stereoselective preparation of a P-chiral four-coordinated phosphorus borane compound, the process comprising

(i) reacting a first reactant comprising a P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P- atom with a second reactant selected from the group consisting of a chiral alcohol, chiral amine or chiral thiol, to provide a diastereomeric P-chiral four-coordinated chiral alkoxy-, chiral amino-, or chiral thio- substituted phosphonium salt; and

First Reactant

The first reactant is a P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P-atom.

The leaving group attached to the P-chiral may be any group that is readily substituted by the second reactant to provide the required P-chiral four-coordinated substituted phosphonium salt compound. For example, the leaving group may be a halide, an alkoxide or a phenoxide. Preferably, the leaving group is a halide, more preferably the leaving group is a chloride.

Accordingly, in a preferred embodiment of the first aspect of the present invention, step (i) involves reacting a first reactant comprising a P-chiral four-coordinated halo- phosphonium salt compound with a second reactant selected from the group consisting of a chiral alcohol, chiral amine, or chiral thiol, to provide a diastereomeric P-chiral four-coordinated chiral alkoxy-, chiral amino-, or chiral thio-substituted phosphonium salt compound. The P-chiral four-coordinated halo-phosphonium salt compound may be a compound of the following structure:

wherein Hal is a halogen atom, preferably chlorine or fluorine, more preferably chlorine;

wherein X , X and X are each independently absent, -O- or -N(R )-; and

wherein R¹, R², R³ and R⁵ may be any inorganic or organic moiety.

Preferably R¹, R², R³ and R⁵ are each independently hydrogen, halogen, hydrocarbyl or an organometallic group.

In one embodiment R¹, R², R³ and R⁵ are each independently an aryl, heteroaryl, alkyl, carbocycle, heterocycloalkyl, aralkyl, or alkenyl group.

Preferably R⁵ is hydrogen, halogen or alkyl.

Preferably, R⁵ is an alkyl group. When R¹, R^z, or R³ is an aralkyl group, the phosphorus, oxygen or nitrogen may be directly bonded to either the alkyl component or the aryl component of said aralkyl group.

1 9 ^

In one embodiment X , X and X are absent.

1 9 ^

In another embodiment X , and X are absent and X is present.

In any of the embodiments described above, the P-chiral four-coordinated halo- phosphonium salt compound may be a P-chiral four-coordinated chloro-phosphonium salt compound.

Furthermore, the P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P-atom is preferably a halide salt compound, more preferably a chloride salt compound. In a further preferred embodiment, it is a P- chiral four-coordinated halo-phosphonium halide salt compound, preferably a chloride salt compound.

Second Reactant

The second reactant is selected from the group consisting of a chiral alcohol, chiral amine or chiral thiol.

In one embodiment the second reactant is a chiral alcohol. The chiral alcohol may be an aliphatic alcohol or an aromatic alcohol.

When the alcohol is an aromatic alcohol it may have the following formula:

Wherein Ar is H or an aryl group, preferably Ar is phenyl substituted with one or more (preferably two) Ci_-6 alkyl groups, preferably methyl, wherein the alkyl group is optionally substituted with one or more halo-groups. For example, Ar is a 3,5- disubstitutedphenyl such as 3,5-dimethylphenyl or 3,5-bis(trifluoromethyl)phenyl.

Chiral aromatic alcohols suitable for use in this aspect of the invention include (S)- or (R)-l,l-binepthalene-2,2'-diol (BINOL) and derivatives thereof.

Alternatively, when the chiral alcohol is aromatic it may have the following formula:

Wherein R is an alkyl or aryl group.

Generally, the chiral alcohol may have the formula:

' ^m

wherein R, R", and R are each independently hydrogen or hydrocarbyl with the proviso that R, R", and R cannot be identical.

In a preferred embodiment, two of R, R", and R together with the carbon atom bearing the hydroxyl group form a carbocyclic or heterocycloalkyl ring system.

In one embodiment the alcohol is a mono-alcohol, that is it contains one OH group.

Preferably, the chiral alcohol comprises a chiral centre that resides on the hydroxy carbon.

Preferably, the alcohol is a cyclic alcohol. In one embodiment the chiral alcohol is a secondary or tertiary alcohol. In one embodiment the chiral alcohol is a primary alcohol.

In one embodiment the chiral alcohol is a diol.

In one embodiment, the chiral alcohol used in the present invention is selected from the group comprising (-)-menthol, (-)-S-phenylmenthol, {-)-trans-2-tert- butylcyclohexanol, (+)-neomenthol, (+)-isomenthol, (S)-l-Octyn-3-ol, (R)-3-methyl- 2-butanol, (S)-l -phenyl- 1-butanol, (lR,2R)-2-benzoylcyclohexanol, (-)- isopinocampheol, cholesterol, (lS,2S,5R)-2-isopropyl-l,5-dimethylcyclohexanol, (-)- 10-dicyclohexylsulfamoyl-D-isoborneol, (-) trara-2-phenylcyclohexanol, (+)-fenchyl alcohol, (-)-benzenesulfonyl-N-(3,5-dimemylphenyl)amino-2-borneol, (S)-l,l '- binaphthalene-2,2'-diol, (R)-l, -binaphthalene-2,2'-diol, a fructose derivative including but not limited to l,2:4,5-Di-0-isopropylidene-D-fructopyranoside, cyclohexandiol, (5)-(-)-2-amino-l,l-diphenyl propanol , (5)-(-)-2-amino-l,l-diphenyl propanol, (5)-(-)-2-amino-3 -methyl- 1 , 1 -diphenyl-butan- 1 -ol, (i?)-(+)-2-arnino-(l ,1,3)- triphenyl-propan- 1 -ol, (_JS)-(-)-2-amino-4-methyl- 1 , 1 -diphenyl-pentan- 1 -ol, (-)-trans- 2-phenylcyclohexanol, diacetone-D-glucose and (-)-l,2-dicyclohexyl-l,2-ethanediol, or the corresponding enantiomers thereof.

For example, the chiral alcohol may be selected from the following compounds:

For example, the chiral alcohol may be selected from the following compounds:

A particularly preferred chiral alcohol is (-)-menthol, which generally provides an increased enantiomeric selectivity.

In one embodiment said first reactant is a chiral amine.

Preferably the chiral amine has the formula:

wherein R, R", and R are each independently hydrogen or hydrocarbyl with the proviso that R, R", and R cannot be identical. In a preferred embodiment, two of R, R", and R together with the carbon atom bearing the hydroxyl group form a carbocyclic or heterocycloalkyl ring system.

In one embodiment said first reactant is a chiral thiol In one embodiment the chiral thiol has the formula:

wherein R, R", and R are each independently hydrogen or hydrocarbyl with the proviso that R, R", and R cannot be identical. In a preferred embodiment, two of R, R", and R together with the carbon atom bearing the thiol group form a carbocyclic or heterocycloalkyl system. In one embodiment, the chiral thiol used in the present invention is (+)-neomenthane thiol.

Reducing Agent

In one embodiment, the metal borohydride is NaBH₄ or L1BH₄.

In this aspect of the present invention, delaying addition of the metal borohydride increases the enantiomeric excess of the P-chiral four-coordinated phosphorus borane compound, but decreases the yield of the reaction. This is believed to be because the minor diastereomer of the P-chiral four-coordinated halo-phosphonium salt compound converts faster to the corresponding phosphine oxide via Arbuov collapse.

This aspect of the invention provides a process for preparing an enantiomerically enriched P-chiral four-coordinated phosphorus borane compound. As seen above, in one embodiment the process involves a step of reducing a diastereomeric

alkoxyphosphonium salt (DAPS), which itself has been prepared from a P-chiral four coordinated halo-phosphonium salt (HPS). It has been observed that the % ee of the final borane product is the same as the % ee of its immediate precursor (i.e. DAPS). Thus, it is believed that the % ee is not determined during the course of the reduction step. In contrast, it has been observed that the % ee of the DAPS increases as the reaction of step (i) progresses. This observation is equally applicable to the other embodiments of the same aspect of the invention.

Thus, in one embodiment, it is the aim to increase the % ee of the final P-chiral four- coordinated phosphorus borane compound. Preferably, this is achieved by delaying the addition of the metal borohydride in step (ii). Preferably, the metal borohydride is added 5 minutes or greater after the addition of the second reactant, more preferably 10 minutes or greater, more preferably 20 minutes or greater, more preferably 30 minutes or greater, more preferably 40 minutes or greater, more preferably 3 hours or greater, more preferably 24 hours or greater, more preferably 48 hours or greater. It has also been observed that delaying the addition of the metal borohydride to the reaction decreases the yield of the reaction. In one embodiment it is the aim to maintain an acceptable product yield. Preferably, this is achieved by adding the metal borohydride less than or equal to 40 minutes after addition of the second reactant, more preferably less than or equal to 3 hours, more preferably less than or equal to 24 hours, more preferably less than or equal to 48 hours.

Also, in one embodiment the aim of the process is to achieve a balance between reaction yield and % ee of the final product. Preferably, this is achieved by adding the metal borohydride at a time after addition of the second reactant that provides this.

For example, such a time could be within a time range having a lower limit as referred to above in the context of the embodiment aiming to increase % ee of the final product, i.e. greater than 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 3 hours, or 24 hours, and having an upper limit as referred to above in the context of the embodiment aiming to maintain an acceptable reaction yield, i.e. less than 20 minutes,

30 minutes, 40 minutes, 3 hours, 24 hours or 48 hours.

Preferably, the P-chiral four-coordinated phosphorus borane compound that is the product of this process has the formula:

wherein X 1', X2 and X 3 _, R 1 , IT 2, R 3^J and R 5^J are as described above.

The chiral alcohol, chiral amine or chiral thiol employed in the process is preferably regenerated. In one embodiment of this aspect of the present invention, the process further comprises converting said P-chiral four-coordinated phosphorus borane compound to a P-chiral three-coordinated phosphorus compound, by methods known to those skilled in the art, such as, but not limited to, treatment with a secondary amine (e.g. morpholine or diathylamine) or treatment with an alcohol (e.g. ethanol).

Thus, this embodiment provides a dynamic process for resolving a racemic P-chiral three-coordinated phosphorus compound by conversion to an enantiomerically enriched P-chiral three-coordinated phosphorus compound.

Preparation of Starting Material from P-Chiral Phosphorus Compound

In one embodiment of this aspect of the invention, said P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P-atom is prepared by a process comprising reacting a P-chiral three-coordinated phosphorus compound with an electrophile.

Preferably, the P-chiral three-coordinated phosphorus compound used in this preparation step has the formula:

wherein X¹ , X² and X³, R¹ , R², R³ and R⁵ are as described above.

Electrophile

In one embodiment the electrophile is a halide, preferably a haloalkane. Preferably the electrophile is selected from the group comprising, hexahaloacetone, hexahaloethane and N-halosuccinimide or CX4, wherein X is a halogen. Preferably the halo component is a chlorine or bromine atom. More preferably the halo component is a chlorine atom. In one embodiment the electrophile is selected from the group comprising carbon tetrachloride, hexachloroacetone, hexachloroethane, N-chlorosuccinimide, 2,3,4,5,6,6- hexachloro-2,4-cyclohexadiene-l-one and trichloroacetonitrile. A particularly preferred electrophile is hexachloroacetone.

Preferred electrophiles for tertiary non-aminophosphines (i.e., when X , X and X are absent) are hexachloroacetone and N-cUorosuccinirnide. A particularly preferred electrophile is hexachloroacetone. A particularly preferred electrophile for aminophosphines (i.e., when X , X and/or X are present) is carbon tetrachloride.

In one embodiment the electrophile is a peroxide or a disulfide, preferably diethylperoxide or bis(2-pyridyl)sulfide.

Accordingly, in one embodiment the invention provides a process for the stereoselective preparation of a P-chiral four-coordinated phosphorus borane compound, the process comprising the steps of:

(a) stereoselectively preparing a P-chiral four coordinated diastereomeric chiral alkoxy-, chiral amino- or chiral thio-substituted phosphonium salt compound, said preparation comprising reacting a first reactant selected from the group consisting of chiral alcohol, chiral amine or chiral thiol, with a second reactant comprising a P-chiral three-coordinated phosphorus compound, in the presence of an electrophile, and

(b) reducing said P-chiral four coordinated diastereomeric substituted phosphonium salt compound with a metal borohydride.

Preferably, the process is a one-pot synthesis. Preparation of Starting Material from a Phosphine Oxide/Sulfide

In an alternative embodiment of the first aspect of the invention, when said P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P-atom is a P-chiral four-coordinated halo-phosphonium compound, such compound is prepared by a process comprising reacting a P-chiral phosphine oxide or a P-chiral phosphine sulfide with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfonyl halide, and methane sulfonyl halide. Preferably, the P-chiral phosphine oxide or P-chiral phosphine sulfide has the formula:

wherein X¹, X² and X³ _, R¹, R², R³ and R⁵ are as described above.

An example of a suitable phosphine oxide is ortAo-tolylmethylphenyl phosphine oxide. In one embodiment, the oxalyl halide is oxalyl chloride.

Preferably, about one molar equivalent or greater of the halogenating agent is added to the reaction mixture based on the molar amount of phosphine oxide starting material. Preferably, from one to three molar equivalents are added or greater than two molar equivalents are added. It has been observed that the use of such molar equivalents results in cleaner generation of the halo/chloro-phosphonium salt compound.

The process of this aspect of the present invention is stereoselective. It provides a dynamic process for converting a P-chiral phosphine oxide to an enantiomerically enriched P-chiral four-coordinated phosphorus borane compound. Accordingly, in one embodiment the invention provides a process for the stereoselective preparation of a P-chiral four-coordinated phosphorus borane compound, the process comprising the steps of:

(a) stereoselectively preparing a P-chiral four coordinated diastereomeric chiral alkoxy-, chiral amino- or chiral thio-substituted phosphonium salt compound, said preparation comprising reacting a halogenating agent with a P-chiral phosphine oxide or P-chiral phosphine sulfide compound and a reactant selected from the group consisting of a chiral alcohol, chiral amine or chiral thiol, to provide a P-chiral four coordinated diastereomeric chiral alkoxy-, chiral amino- or chiral thio-substituted phosphonium salt compound, and

Preferably, the process is one-pot synthesis.

(ii) reducing said diastereomeric substituted phosphonium salt compound preferably with a reducing agent, such as L1AIH₄ or sodium bis (2- methoxyethoxy) aluminium hydride, to provide a P-chiral three- coordinated phosphorus compound. First Reactant

The first reactant is a P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P-atom. The leaving group attached to the P-chiral may be any group that is readily substituted by the second reactant to provide the required chiral four-coordinated substituted phosphonium salt compound. For example, the leaving group may be a halide, an alkoxide or a phenoxide. Preferably, the leaving group is a halide, more preferably the leaving group is a chloride.

Accordingly, h a preferred embodiment of the first aspect of the present invention, step (i) involves reacting a first reactant comprising a P-chiral four-coordinated halo- phosphonium salt compound with a second reactant selected from the group consisting of a chiral alcohol, chiral amine, or chiral thiol, to provide a diastereomenc P-chiral four-coordinated substituted phosphonium salt compound. The P-chiral four- coordinated halo-phosphonium salt compound may be of the following structure:

wherein Hal is a halogen atom, preferably fluorine or chlorine, more preferably chlorine;

wherein Χ', Χ² and X³ are each independently absent, -O- or -N(R⁵)-; and

wherein R¹, R², R³ and R⁵ may be any inorganic or organic moiety. Preferably R¹, R², R³ and R⁵ are each independently hydrogen, halogen, hydrocarbyl or an organometallic group.

Preferably R is hydrogen, halogen or alkyl.

Preferably, R⁵ is an alkyl group. When R¹, R², or R³ is an aralkyl group, the phosphorus, oxygen or nitrogen may be directly bonded to either the alkyl component or the aryl component of said aralkyl group.

In one embodiment X 1 , X2 and X 3 are absent.

In another embodiment X 1 and X2 are absent and X 3 is present. In any of the embodiments described above, the P-chiral four-coordinated halo- phosphonium salt compound is a P-chiral four-coordinated chloro-phosphonium salt compound.

Furthermore, the P-chiral four-coordinated halo-phosphonium salt compound is preferably a P-chiral four-coordinated halo-phosphonium halide salt compound, preferably a chloride salt compound.

Second Reactant

When the alcohol is a chiral aromatic alcohol it may have the following formula:

Wherein Ar is H or an aryl group, preferably Ar is phenyl substituted with one or more (preferably two) C_1-6 alkyl groups, preferably methyl, wherein the alkyl group is optionally substituted with one or more halo-groups. For example, Ar is a 3,5- disubstitutedphenyl such as 3,5-dimethylphenyl or 3,5-bis(trifluoromethyl)phenyl.

Chiral aromatic alcohols suitable for use in this aspect of the invention include (S)- or (R)-l ,1 -binepthalene-2,2'-diol (BINOL) and derivatives thereof.

Wherein R is an alkyl or aryl group.

Generally, the chiral alcohol may have the formula:

Preferably, the alcohol is a cyclic alcohol.

In one embodiment the chiral alcohol is a secondary or tertiary alcohol. In one embodiment the chiral alcohol is a primary alcohol. In one embodiment the chiral alcohol is a diol. In one embodiment, the chiral alcohol used in the present invention is selected from the group comprising (-)-menthol, (-)-8-phenylmenthol, (-)-trans-2-tert- butylcyclohexanol, (+)-neomenthol, (+)-isomenthol, (S)-l-Octyn-3-ol, (R)-3-methyl- 2-butanol, (S)-l -phenyl- 1-butanol, (lR,2R)-2-benzoylcyclohexanol, (-)- isopinocampheol, cholesterol, (lS,2S,5R)-2-isopropyl-l,5-dimethylcyclohexanol, (-)- 10-dicyclohexylsulfamoyl-D-isoborneol, (-) tr<ms-2-phenylcyclohexanol, (+)-fenchyl alcohol, (-)-berizenesulfonyl-N-(3,5-dimethylphenyl)amino-2-borneol, (S)-l,l '- binaphthalene-2,2'-diol, (R)-l,l'-binaphthalene-2,2'-diol, a fructose derivative including but not limited to l,2:4,5-Di-0-isopropylidene-D-f uctopyranoside, cyclohexandiol, (5)-(-)-2-amino-l,l-diphenyl propanol , (S)-(-)-2-amino-l,l-diphenyl propanol, (<S)-(-)-2-amino-3 -methyl- 1,1-diphenyl-butan-l-ol, (i?)-(+)-2-amino-(l,l,3)- triphenyl-propan- 1 -ol, (5)-(-)-2-amino-4-methyl- 1 , 1 -diphenyl-pentan- 1 -ol, (-)-trans- 2-phenylcyclohexanol, diacetone-D-glucose and (-)-l,2-dicyclohexyl-l,2-ethanediol, or the corresponding enantiomers thereof. For example, the chiral alcohol may be selected from the following compounds:

Other examples of suitable chiral alcohols include the following compounds:

In one embodiment said first reactant is a chiral amine.

Preferably the chiral amine has the formula:

Reducing Agent

The reduction step of the process is carried out using LiAlH₄ or sodium bis methoxyethoxy) aluminium hydride

In a preferred embodiment, dilute LiAlELi is employed, preferably 0.1M L1AIH₄. The use of dilute LiAlHLj provides an increase in enantiomeric excess and/or yield. Preferably, reduction with L1AIH₄ should be carried out soon after the formation of the P-chiral four-coordinated substituted phosphonium salt, e.g. up to one day, preferably from about 10 to about 30 minutes, after the formation of the P-chiral four- coordinated substituted phosphonium salt. Preparation of Starting Material from F '-Chiral Phosphorus Compound

wherein X', X and X _, R , R R^J and R^J are as described above. Electrophile

In one embodiment the electrophile is a halide, preferably a haloalkane. Preferably the electrophile is selected from the group comprising, hexahaloacetone, hexahaloethane and N-halosuccinimide or C¾, wherein X is a halogen. Preferably the halo component is a chlorine or bromine atom. More preferably the halo component is a chlorine atom. In one embodiment the electrophile is selected from the group comprising carbon tetrachloride, hexachloroacetone, hexachloroethane, N-chlorosuccinimide, 2,3,4,5,6,6- hexachloro-2,4-cyclohexadiene-l-one and trichloroacetonitrile. A particularly preferred electrophile is hexachloroacetone. Preferred electrophiles for tertiary non-aminophosphines (i.e., when X¹, X² and X³ are absent) are hexachloroacetone and N-chlorosuccinimide. A particularly preferred electrophile is hexachloroacetone.

A particularly preferred electrophile for aminophosphines (i.e., when X , X and/or X are present) is carbon tetrachloride.

In one embodiment the electrophile is a peroxide or a disulfide, preferably diethylperoxide or bis(2-pyridyl)sulfide. Accordingly, in one embodiment the invention provides a process for the stereoselective preparation of a P-chiral three-coordinated phosphorus compound, the process comprising the steps of:

(a) stereoselectively preparing a diastereomeric P-chiral four coordinated chiral alkoxy-, chiral amino-, or chiral thio-substituted phosphonium salt compound, said preparation comprising reacting a first reactant selected from the group consisting of chiral alcohol, chiral amine or chiral thiol, with a second reactant comprising a P-chiral three-coordinated phosphorus compound, in the presence of an electrophile, and (b) reducing said P-chiral four coordinated diastereomeric substituted phosphonium salt compound with a reducing agent such as L1AIH₄ or sodium bis(2-methoxyethoxy)aluminium hydride. Preferably, the process is a one-pot synthesis.

Preparation of Starting Material from a Phosphine Oxide/Suljide

In an alternative embodiment of the same aspect of the invention, when said P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P-atom is a P-chiral four-coordinated halo-phosphonium compound, such compound is prepared by a process comprising reacting a P-chiral phosphine oxide or a P-chiral phosphine sulfide with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfonyl halide, and methane sulfonyl halide.

Preferably, the P-chiral phosphine oxide or the P-chiral phosphine sulfide has the formula:

An example of a suitable phosphine oxide is ort/zo-tolylmethylphenyl phosphine oxide.

In one embodiment, the oxalyl halide is oxalyl chloride. Preferably, about one molar equivalent or greater of the halogenating agent, preferably oxalyl halide/chloride is added to the reaction mixture based on the molar amount of phosphine oxide starting material.

The process of this aspect of the present invention is stereoselective. It provides a dynamic process for converting a P-chiral phosphine oxide compound to an enantiomerically enriched P-chiral three-coordinated phosphorus compound.

Accordingly, in one embodiment the invention provides a process for the stereoselective preparation of a P-chiral three-coordinated phosphorus compound, the process comprising the steps of:

(a) stereoselectively preparing a P-chiral four coordinated diastereomeric chiral alkoxy-, chiral amino- or chiral thio-substituted phosphonium salt compound, said preparation comprising reacting an oxalyl halide with a P-chiral phosphine oxide compound and subsequently reacting with a reactant selected from the group consisting of a chiral alcohol, chiral amine or chiral thiol, to provide a P-chiral four coordinated diastereomeric substituted phosphonium salt compound, and

(b) reducing said P-chiral four-coordinated diastereomeric substituted phosphonium salt compound with a reducing agent such as LiAlEU or sodium bis(2-methoxyethoxy)aluminium hydride.

Preferably, the process is one-pot synthesis.

The process of this aspect of the present invention is stereoselective. It provides both a dynamic process for resolving a racemic P-chiral three-coordinated phosphorus compound and a dynamic process for converting a racemic phosphine oxide to an enantiomerically enriched P-chiral three-coordinated phosphorus compound. The chiral alcohol, chiral amine or chiral thiol employed in the process is regenerated.

The enantiomerically enriched P-chiral three-coordinated phosphorus compound end product of this process may subsequently by converted to a enantiomerically enriched P-chiral four-coordinated phosphorus borane compound. For example, this conversion may be carried out by treating the enantiomerically enriched P-chiral three-coordinated phosphorus compound with borane THF complex to provide the corresponding phosphine borane adduct.

According to a third aspect of the present invention there is provided a process for the stereoselective preparation of a P-chiral phosphine oxide or sulphide compound, the process comprising (i) reacting a P-chiral phosphine oxide or a P-chiral phosphine sulfide with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfonyl halide, and methane sulfonyl halide to provide a P-chiral four-coordinated halo-phosphonium salt compound, and (ii) reacting said P- chiral four-coordinated halo-phosphonium salt compound with a reactant selected from the group consisting of a chiral alcohol, or chiral thiol to provide a stereospecific P-chiral phosphine oxide or sulphide compound. Alternatively, the P-chiral four- coordinated halo-phosphonium salt compound is reacted with a chiral amine and subsequently hydrolysed, e.g. with sodium hydroxide, to provide a stereospecific P- chiral phosphine oxide.

P-Chiral Phosphine Oxide or P ^~ -Chiral Phosphine Sulphide (Starting Material)

Preferably, the P-chiral phosphine oxide or P-chiral phosphine sulphide used as starting material in this process has the formula:

wherein X¹, X² and X³ are each independently absent, -O- or -N(R⁵)-; and

wherein R¹, R², R³ and R⁵ may be any inorganic or organic moiety.

In one embodiment R¹, R², R³ and R⁵ are each independently an aryl, heteroaryl, alkyl, carbocycle, heterocycloalkyl, aralkyl, or alkenyl group. Preferably R is hydrogen, halogen or alkyl. Preferably, R⁵ is an alkyl group.

When R¹, R², R³ or R⁴ is an aralkyl group, the phosphorus, oxygen or nitrogen may be directly bonded to either the alkyl component or the aryl component of said aralkyl group.

In one embodiment X 1 , X2 and X 3 are absent. In another embodiment X¹, X² are absent and X³ is present.

First Reactant

The first reactant is a P-chiral four-coordinated halo-phosphonium salt compound (HPS), such as a compound of the following structure:

wherein X¹, X² and X³ are each independently absent, -O- or -N(R⁵)-; and

wherein R 1 , R , R 3 and R 5 may be any i ·norganic or organi *c moi ·ety. Preferably R¹, R², R³ and R⁵ are each independently hydrogen, halogen, hydrocarbyl or an organometallic group. In one embodiment R¹, R², R³ and R⁵ are each independently an aryl, heteroaryl, alkyl, carbocycle, heterocycloalkyl, aralkyl, or alkenyl group.

Preferably R⁵ is hydrogen, halogen or alkyl. Preferably, R⁵ is an alkyl group.

When R^,, R², R³ or R⁴ is an aralkyl group, the phosphorus, oxygen or nitrogen may be directly bonded to either the alkyl component or the aryl component of said aralkyl group.

In one embodiment X , X and X are absent.

In another embodiment X , X are absent and X is present. In any of the embodiments described above, the P-chiral four-coordinated halo- phosphonium salt compound is a P-chiral four-coordinated chloro-phosphonium salt compound.

Chiral Reactant

The reactant employed in the process of this aspect of the invention is selected from the group consisting of a chiral alcohol, chiral amine or chiral thiol.

In one embodiment the second reactant is a chiral alcohol. The chiral alcohol may be an aliphatic alcohol or an aromatic alcohol. When the alcohol is an aromatic alcohol it may have the following formula:

Wherein Ar is H or an aryl group, preferably Ar is phenyl substituted with one or more (preferably two) C_1-6 alkyl groups, preferably methyl, wherein the alkyl group is optionally substituted with one or more halo-groups. For example, Ar is a 3,5- disubstitutedphenyl such as 3,5-dimethylphenyl or 3,5-bis(trifluoromethyl)phenyl. Chiral aromatic alcohols suitable for use in this aspect of the invention include (S)- or (R)-l,l-binepthalene-2,2'-diol (BINOL) and derivatives thereof.

Wherein R is an alkyl or aryl group.

Generally, the chiral alcohol may have the formula:

Preferably, the alcohol is a cyclic alcohol.

In one embodiment the chiral alcohol is a secondary or tertiary alcohol.

In one embodiment the chiral alcohol is a primary alcohol. In one embodiment the chiral alcohol is a diol.

In one embodiment, the chiral alcohol used in the present invention is selected from the group comprising (-)-menthol, (-)-8-phenylmenthol, (-)-trans-2-tert- butylcyclohexanol, (+)-neomenthol, (+)-isomenthol, (S)-l-Octyn-3-ol, (R)-3-methyl- 2-butanol, (S)- 1 -phenyl- 1-butanol, (lR,2R)-2-benzoylcyclohexanol, (-)- isopinocampheol, cholesterol, (lS,2S,5R)-2-isopropyl-l,5-dimethylcyclohexanol, (-)- 10-dicyclohexylsulfamoyl-D-isoborneol, (-) tra¾s-2-phenylcyclohexanol, (+)-fenchyl alcohol, (-)-benzenesulfonyl-N-(3 ,5-dimethylphenyl)amino-2-borneol, (S)- 1 , 1 ' - binaphthalene-2,2'-diol, (R)-l,l '-binaphthalene-2,2'-diol, a fructose derivative including but not limited to l,2:4,5-Di-0-isopropylidene-D-fructopyranoside, cyclohexandiol, (S)-(-)-2-amino-l,l-diphenyl propanol , (S)-(-)-2-amino-l,l-diphenyl propanol, (5)-(-)-2-amino-3 -methyl- 1 , 1 -diphenyl-butan- 1 -ol, (i?)-(+)-2-amino-( 1,1,3)- triphenyl-propan- 1 -ol, (5)-(-)-2-amino-4-methyl- 1 , 1 -diphenyl-pentan- 1 -ol, (-)-trans- 2-phenylcyclohexanol, diacetone-D-glucose and (-)-l,2-dicyclohexyl-l ,2-ethanediol, or the corresponding enantiomers thereof.

For example, the chiral alcohol may be selected from the following compounds:

Other examples of suitable chiral alcohols include the following compounds:

A particularly preferred chiral alcohol is (-)-menthol, which generally provides an increased enantiomeric selectivity. In one embodiment said first reactant is a chiral amine.

Preferably the chiral amine has the formula:

In a preferred embodiment, two of R , R", and R together with the carbon atom bearing the thiol group form a carbocyclic or heterocycloalkyl system.

In one embodiment, the chiral thiol used in the present invention is (+)-neomenthane thiol. Phosphine Oxide/Sulfide (End Product).

Preferably the enantiomerically enriched P-chiral phosphine oxide or sulphide compound provided by the process has the formula:

Preferably, the process of the fourth aspect is a stereoselective process for the preparation of a P-chiral four-coordinated phosphorus borane compound.

Phosphine Oxide/Sulfide (Starting Material)

Preferably, the phosphine oxide is a P-chiral phosphine oxide compound, or the phosphine sulphide is a P-chiral phosphine sulphide compound.

In one embodiment, the phosphine oxide or phosphine sulphide used in this preparation step has the formula:

wherein X¹, X² and X³ are each independently absent, -O- or -N(R⁵)

wherein R , R , R and R may be any inorganic or organic moiety.

In one embodiment R , R , R and R are each independently an aryl, heteroaryl, alkyl, carbocycle, heterocycloalkyl, aralkyl, or alkenyl group.

Preferably R⁵ is hydrogen, halogen or alkyl.

Preferably, R⁵ is an alkyl group. When R¹, R², R³ or R⁴ is an aralkyl group, the phosphorus, oxygen or nitrogen may be directly bonded to either the alkyl component or the aryl component of said aralkyl group. In one embodiment X¹, X² and X³ are absent.

In another embodiment X , X are absent and X is present.

The phosphine oxide or sulfide starting material may be a tertiary or secondary phosphine oxide or sulfide.

Four-coordinated Halo-phosphonium Salt Compound

The first step of the process described above involves the preparation of a four- coordinated halo-phosphonium salt compound. Preferably, the four-coordinated halo- phosphonium salt compound is P-chiral.

In one embodiment, the four-coordinated halo-phosphonium salt compound is a compound of the following structure:

wherein X¹, X and X^J, R', R\ R^J and R^J are the same as defined above.

In any of the embodiments described above, the P-chiral four-coordinated halo- phosphonium salt compound is a P-chiral four-coordinated chloro-phosphonium salt compound. Furthermore, the P-chiral four-coordinated halo-phosphonium salt compound is preferably a P-chiral four-coordinated halo-phosphonium halide salt compound, preferably a chloride salt compound.

Four-coordinated Phosphorus Borane Compound

Preferably, the four-coordinated phosphorus borane compound provided by this process is P-chiral.

In one embodiment, the four-coordinated phosphorus borane compound has the formula:

wherein X¹, X and X R , R R^J and R are as described above.

The process of the fourth aspect provides a means for converting a phosphine oxide or phosphine sulphide compound to a four-coordinated phosphorus borane compound. In previous attempts, it has proved especially difficult to achieve this reduction without the loss of one or more substituents which are not attached to the P-atom by a carbon atom. As a result, in a preferred embodiment of the fourth aspect of the invention, the process involves compounds in which one or more or all of the substituents attached to the P-atom are not attached to the P-atom by a carbon atom. For example, wherein one or more, or all ofX\ X^z and X^J are each independently -O- or -N(R ) -.

According to a fifth aspect of the present invention there is provided a process for the stereospecific preparation of a P-chiral four-coordinated phosphorus borane compound, the process comprising (i) reacting a P-chiral phosphine oxide compound or a P-chiral phosphine sulfide compound with an alkylating agent to afford a P-chiral four-coordinated alkoxyphosphonium salt compound, and (ii) reducing said P-chiral four-coordinated alkoxyphosphonium salt compound with a metal borohydride or L1AIH4 to provide a P-chiral four-coordinated phosphorus borane compound.

In a preferred embodiment, when the reducing agent is L1AIH₄, the counterion on the alkoxyphosphonium salt is fluoroborate.

P-Chiral Phosphine Oxide/Sulfide (Starting Material)

The first reactant is a P-chiral phosphine oxide or sulfide compound, preferably having the following formula:

wherein X¹, X² and X³ are each independently absent, -O- or -N(R⁵)-; and

Preferably R⁵ is hydrogen, halogen or alkyl. Preferably, R⁵ is an alkyl group. When R¹, R², R³ or R⁴ is an aralkyl group, the phosphorus, oxygen or nitrogen may be directly bonded to either the alkyl component or the aryl component of said aralkyl group. In one embodiment X 1 , X2 and X 3 are absent.

In another embodiment X , X are absent and X is present. In this aspect of the invention, treatment with a metal borohydride or LiAlFLf yields a P-chiral four-coordinated phosphorus borane compound with inversion of enatiomeric configuration but without adversely affecting any stereoisomeric ratio present in the starting P-chiral phosphine oxide or sulfide. Reducing Agent

The reduction step of the process is carried out with a metal borohydride or L1AIH₄. The metal borohydride may be for example NaBH4 or LiBHj. Particularly preferred reducing agents are NaB¾ and LLA.IH4, more preferably NaBHU. Alkylating Agent

The process employs an alkylating agent. Suitable alkylating agents include alkyl triflates, such as methyl triflate, and compounds of formula [R₃0]BF₄, wherein R is an alkyl group, preferably CI -2 alkyl. For example, the alkylating agent can be [Me₃0]BF₄ or Meerwein's salt, [Et₃0]BF₄, i.e. triethyloxonium tetrafluoroborate.

Solvent

A particularly preferred solvent for use in this process is toluene.

P-chiral Four-coordinated Alkoxyphosphonium Salt Compound

In one embodiment, the P-chiral four-coordinated alkoxyphosphonium salt compound has the following formula:

wherein X', X% X R, R , R R are as described above. Borane end product

This process provides an enantiomerically enriched P-chiral four-coordinated phosphorus borane compound. Preferably, the eneatiomerically enriched P-chiral four-coordinated phosphorus borane compound has the following formula:

Reaction Temperature

In a preferred embodiment, the process is carried out at a temperature from about 15°C to about 35°C, preferably from about 20 °C to about 30 °C, more preferably at about 25°C (i.e. at ambient temperature).

According to a sixth aspect of the present invention there is provided a process for the stereoselective preparation of a P-chiral four-coordinated aUcoxyphosphonium salt compound, the process comprising:

0) reacting a three-coordinated halophosphine compound with a chiral alkoxy Grignard reagent to afford a diastereomerically enriched P-chiral three-coordinated alkoxyphosphorus compound; and

Three-coordinated Chlorophosphine Compound (Starting Material) The starting material of the present process is a three-coordinated chlorophosphine compound, such as a compound having the following formula:

wherein X 1 , and X2 are each independently absent, -O- or -N(R 5 )-; and

wherein R¹, R², and R⁵ may be any inorganic or organic moiety.

Preferably R , R , and R are each independently hydrogen, halogen, hydrocarbyl or an organometallic group.

In one embodiment R¹, R², and R⁵ are each independently an aryl, heteroaryl, alkyl, carbocycle, heterocycloalkyl, aralkyl, or alkenyl group.

Preferably R⁵ is hydrogen, halogen or alkyl.

Preferably, R⁵ is an alkyl group.

When R , or R , is an aralkyl group, the phosphorus, oxygen or nitrogen may be directly bonded to either the alkyl component or the aryl component of said aralkyl group.

In one embodiment X 1 , and X 2 are absent.

In another embodiment X , is absent and X is present.

Grignard Reagent

The chiral alkoxy Grignard reagent used may be any suitable Grignard reagent, such as a compound of formula R*OMX, wherein R* is a chiral moiety and X is a halide, preferably chloride or bromide and M is Mg, Li or Na. Preferably, R* has the formula:

R'R"R"'C- wherein R, R", and R are each independently hydrogen or hydrocarbyl with the proviso that R, R", and R cannot be identical.

P-chiral three coordinated alkoxyphosphorus compound

The product of step (i) above is a diastereomerically enriched P-chiral three coordinated alkoxyphosphorus compound, such as a compound of the following formula:

Wherein Rl, R2 and R* are as described above. Alkyl Halide/Triflate

The alkyl halide or alkyl triflate introduces an alkyl group (R₃) to the phosphorus compound.

Preferably, the alkyl halide that can be employed in step (ii) of the process is a C1-C4 alkyl halide. The alkyl halide may be an alkyl chloride or bromide, preferably alkyl chloride. The alkyl halide is a methyl halide. Most preferably, the alkyl halide is methyl chloride.

Preferably, the alkyl triflate that can be employed in step (ii) of the process is a C1-C4 alkyl triflate, more preferably the alkyl triflate is methyl triflate. Diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound

The diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound provided by step (ii) of the process can be a compound having the following formula:

wherein X¹, X and X , R*, R , R , R^J and R^J are as described above, and

wherein Hal is a halogen such as chlorine or fluorine, preferably chlorine.

Conversion to P-chiral four-coordinated phosphorus borane compound

In one embodiment of the above aspect of the present invention, the process further comprises the following step:

0) treating said diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound with a metal borohydride to afford a P-chiral four-coordinated phosphorus borane compound.

The metal borohydride employed in step (iii) above may be NaB¾ or L1BH₄.

Step (iii) above provides a enantiomerically enriched P-chiral four-coordinated phosphorus borane compound, such as a compound having the following formula:

Conversion to P-chiral three coordinated phosphorus compound

In an alternative embodiment of the above aspect of the present invention, the process further comprises the following step:

treating said diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound with LiAlHU to afford a P- chiral three coordinated phosphorus compound.

The P-chiral three coordinated phosphorus compound provided by the above step is enantiomerically enriched. Preferably, the P-chiral three coordinated phosphorus compound has the following formula:

wherein X¹, X² and X³ _, R¹, R², and R³ are as described above.

Conversion to P-chiral phosphine oxide

In yet a further alternative embodiment of the above aspect of the present invention, the process further comprises

(iii) converting said P-chiral four-coordinated alkoxyphosphonium salt compound to a P-chiral phosphine oxide. The P-chiral phosphine oxide provided by the above step (iii) is enantiomerically enriched and preferably has the following formula:

wherein X¹, X² and X³ _, R¹, R², R³ and R⁵ are as described above.

According to a seventh aspect of the invention is provided a process for preparing an enantiomerically enriched chiral phosphonium salt compound comprising reacting a P-chiral four-coordinated chiral alkoxy-, chiral amino-, or chiral thio-substituted phosphonium salt compound with a Grignard reagent to provide an enantiomerically enriched chiral phosphonium salt compound.

Grignard Reagent

The Grignard reagent used may be any alkyl or aryl Grignard reagent, such as a compound of formula R*MX, wherein R* is an alkyl or aryl moiety and X is a halide, preferably chloride or bromide and M is Mg, Li or Na.

Preferably, R* has the formula: R'R"R"'C- wherein R, R", and R are each independently hydrogen or hydrocarbyl with the proviso that R, R", and R cannot be identical. In a preferred embodiment, two of R, R", and R together with the carbon atom bearing the hydroxyl group form a carbocyclic or heterocycloalkyl ring system.

Diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound The diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound provided by step (ii) of the process can be a compound having the following formula:

wherein R* is as defined above;

wherein X¹, X² and X³ are each independently absent, -O- or -N(R⁵)-; and

wherein R¹, R², R³ and R⁵ may be any inorganic or organic moiety.

In one embodiment R¹, R², R³ and R⁵ are each independently an aryl, heteroaryl, alkyl, carbocycle, heterocycloalkyl, aralkyl, or alkenyl group. Preferably R⁵ is hydrogen, halogen or alkyl.

Preferably, R⁵ is an alkyl group.

When R¹, R², or R³ is an aralkyl group, the phosphorus, oxygen or nitrogen may be directly bonded to either the alkyl component or the aryl component of said aralkyl group.

In one embodiment X , X and X are absent. In another embodiment X¹ and X² are absent and X³ is present. Further preferred features and embodiments of the present invention will now be described by way of non-limiting examples.

Representative Reactions

A. Enantioselective Synthesis of Non-Racemic P-Chiral Phosphines and Non- Racemic P-Chiral Phosphine Boranes from Racemic Phosphines.

In the first and second aspects of the present invention there are provided processes for the stereoselective preparation of non-racemic P-chiral four-coordinated phosphorus borane compounds (phosphine boranes) and non-racemic P-chiral three- coordinated phosphorus compounds (phosphines). In one embodiment of each, the common starting material of each is prepared from a racemic phosphine. One example of each is provided here along with results from further examples in Tables A1/A2. An overview of the process is shown in Scheme 1. Diastereomeric alkoxyphosphonium salts (DAPS) are generated from the racemic phosphines with hexachloroacetone (HCA) via the reactive chlorophosphonium salts (CPS). Subsequent reaction (Example Al) of the DAPS with NaBH gives the enantio- enriched phosphine borane directly. Alternatively (Example A2) if LiAlFU is used, the product is the enantio-enriched phosphine itself, whose enantiomeric excesss is determined by conversion of a sample to the phosphine borane with BH₃.THF.

Scheme 1. Synthesis of non-racemic P-stereogenic phosphine boranes from the corresponding racemic phosphines.

Example Al (NaBH.i A standard solution of methylphenyl(o-tolyl)phosphine (0.110 M) was prepared in anhydrous toluene in a sealed vessel under nitrogen. Standard solutions of (-)-menthol (0.132 M) and HCA (0.110 M) were prepared in a similar manner. HCA solution (10.0 niL) and (-)-menthol solution (10.0 mL) were added to a dry flask under nitrogen. The resulting solution was cooled to -78 °C under nitrogen, and allowed to stir at this temperature for 10 minutes. After this time the phosphine solution (10 mL) was added steadily over 2 minutes. The temperature was maintained for a further half

31 an hour, at which point the formation of the diastereomeric salt was confirmed by P NMR (showing two peaks at δ = 65.7 and δ = 67.4 ppm). Then NaB¾ solution (11 mL, 0.5 M in diglyme, 5 mol equiv) was added dropwise. After the addition was complete the vessel was removed from the cooling bath and allowed to warm to room temperature. The reaction was stirred for a further 60 min, when the diastereomeric

31

salt was shown by P NMR to have been consumed and the phosphine borane formed (peak at δ 10.1 ppm). A portion of the reaction mixture was removed, evaporated under reduced pressure, diluted in HPLC mobile phase, filtered though a 0.2 μΜ Millipore Acrodisc and directly injected (10 μL) onto the HPLC system for ee analysis. The remaining reaction mixture was diluted with ethyl acetate (15 mL) and water (10 mL), the organic layer was separated, and the aqueous layer was extracted with AcOEt. The combined extracts were dried over MgS0₄, and evaporated under reduced pressure. The residue was passed through a column of basic alumina using degassed ether. The solvent was removed under vacuum and column chromatography was carried out on silica gel (ethyl acetate 100%, R_f 0.11) yielding the enantioenriched phosphine borane as a white solid (0.19 g, 94%).

The procedure was repeated using a series of different phosphines and alcohols giving the results shown in the following Table Al.

Table Al. Enantiomeric excesses'-*¹ of phosphine boranes (ArPhMePBH₃) prepared from NaBH₄ treatment of diastereomerically enriched alkoxyphosphonium salts'^

Ar alkoxyphosphonium salts % ee Config

derived from: on

o-anisyl (-)-menthol 50 (R) -anisyl (+)-menthol -50 (S)

o-tolyl (-)-menthol 75 (R)

o-tolyl (+)-menthol -72 (S)

o-biphenylyl (-)-menthol 66 (R)

o-tertbutylphenyl (+)-menthol -63 (S)

o-trifluoromethyl)phenyl (-)-menthol 71 (R)

o-wopropylphenyl (-)-menthol 41 (R)

o-z^'sopropylphenyl (+)-menthol -40 OS)

[a] Determined by CSP HPLC of the boranes, negative ee denotes that the major enantiomer was eluted second; [b] Reaction conditions: Phosphine (0.11 mM), alcohol (1.2 equiv), HCA (1 equiv), NaB¾ (5 equiv.), yields >95% (as judged by ³¹P NMR)

Example A2 (L1AIH4)

A standard solution of methylphenyl(o-tolyl)phosphine (0.110 M) was prepared in anhydrous toluene in a sealed vessel under nitrogen. Standard solutions of (-)-menthol (0.132 M), HCA (0.1 10 M) and LAH (0.11 M) were prepared in a similar manner. HCA solution (10.0 mL) and (-)-menthol solution (10.0 mL) were added to a dry flask under nitrogen. The resulting solution was cooled to -78 °C under nitrogen, and allowed to stir at this temperature for 10 minutes. After this time the phosphine solution (10 mL) was added steadily over 2 minutes. The temperature was maintained for a further half an hour, at which point the formation of the diastereomeric salt was confirmed by ^{3 I}P NMR (showing two peaks at δ = 65.7 and δ = 67.4 ppm). Then LiAlHU solution (10.0 mL, 0.11M in toluene) was added dropwise. After the addition was complete the vessel was removed from the cooling bath and allowed to warm to room temperature. The reaction was stirred for a further 60 min, when the

31

diastereomeric salt was shown by P NMR to have been consumed and the phosphine re-formed (signal at δ -36.2 ppm) and then BH₃-THF complex (2.0 M solution in THF, 1.5 mmol) was added. ^{3 I}P NMR of the clear solution revealed one peak for the phosphine borane (at δ 10.1 ppm). A portion of the reaction mixture was removed, evaporated under reduced pressure, diluted in HPLC mobile phase, filtered though a 0.2 μΜ Millipore Acrodisc and directly injected (10 μΐ,) onto the HPLC system for ee analysis. The remaining reaction mixture was diluted with ethyl acetate (15 mL) and water (10 mL), the organic layer was separated, and the aqueous layer was extracted with AcOEt. The combined extracts were dried over MgS0₄, and evaporated under reduced pressure. The residue was passed through a column of basic alumina using degassed ether. The solvent was removed under vacuum and column chromatography was carried out on silica gel (ethyl acetate 100%, Rf 0.11) yielding the enantioenriched phosphine borane as a white solid (0.2 g, 96%). The procedure was repeated using a series of different phosphines and alcohols giving the results shown in Table A2.

Table A2. Enantiomeric excesses¹*¹ of phosphines (ArPhMeP) prepared from LAH treatment of diastereomerically enriched alkoxyphosphonium salts^M

Ar alkoxyphosphonium salts % ee Configur derived from: ation

0-anisyl (-)-menthol 48 (R)

o-anisyl (+)-menthol -47 (S)

o-anisyl (-)- 8 -phenylmenthol 76 (R)

o-tolyl (-)-menthol 78 (R)

o-tolyl (+)-menthol -76 (S)

o-fertbutylphenyl (-)-menthol 65 (R)

0-fertbutylphenyl (+)-menthol -63

o-methyl,/>-fluorophenyl (-)-menthol 66 (S)

o, ?-dimethylphenyl (-)-menthol 65 (R)

o ?-dimethylphenyl (+)-menthol -63 (S)

ο, 7-dimethylphenyl (+)-neomenthol -48 (S)

ο,/7-dimethylphenyl (+)-isomenthol -53 (S)

( 9-trifiuoromethyl)phenyl (-)-menthol 70 (R) [a] Determined by CSP HPLC of the derived boranes, negative ee denotes that the major enantiomer was eluted second; [b] Reaction conditions: Phosphine (1.0 equiv), alcohol (1.2 equiv), HCA (1 equiv), LAH (1.5 equiv), yields >95% (as judged by ³¹P NMR).

B. Stereoselective Synthesis of Phosphine Boranes and Phosphines from Racemic Phosphine Oxide

In the first and second aspects of the present invention are provided processes for the stereoselective preparation of P-chiral four-coordinated phosphorus borane compounds (phosphine boranes) and P-chiral three-cordinated phosphorus compounds (phosphines). In one embodiment of each, the common starting material of each is prepared from a racemic phosphine oxide. Examples of such reactions are provided here.

This provides a new, simple, and effective method for obtaining enantioriched P- stereogenic phosphines or phosphine boranes from racemic P-stereogenic phosphine oxide through dynamic resolution. An overview of the process is shown in Scheme 2.

e

Scheme 2. Synthesis of non-racemic P-stereogenic phosphine boranes from the corresponding racemic phosphine oxides. In the case of methylphenylo-tolylphosphine oxide as the starting oxide, the chlorophosphonium salt (CPS, ³¹P NMR 70 ppm) can be obtained easily by reaction with oxalyl chloride. The CPS is then reacted with chiral non-racemic alcohol to produce the diastereomeric alkoxyphosphonium salts (DAPS), which, in the case of (- )-menthol as the alcohol, show as a narrow unequal pair of signals at 67.8 and 67.3 ppm in the P NMR spectrum of the reaction mixture. Subsequent reaction with NaB¾ (Example Bl) gives the enantio-enriched phosphine borane directly. Alternatively (Example B2) if L1AIH₄ is used, the product is the enantio-enriched phosphine itself, whose enantiomeric excesss is determined by conversion of a sample to the phosphine borane with BH₃.THF. Initially NaBH was added to DAPS at -78 °C, later we discovered that the addition of NaBFL at room temperature drop wise gave the same selectivity as -78 °C addition.

Example Bl (NaBHLQ

A standard solution of the methylphenyl(o-tolyl)phosphine oxide (0.110 M) was prepared in anhydrous toluene in a sealed vessel under nitrogen. Standard solutions of (-)-menthol (0.132 M) and oxalyl chloride (0.110 M) were prepared in a similar manner. Oxalyl chloride solution (10.0 mL, 0.11M, 1 equiv) was added drop wise at room temperature to the phosphine oxide solution (10.0 mL, 0.11M, 1 equiv) in a flame dried degassed Schlenk tube. 31 P NMR was taken identify the chlorophosphonium salt at 70 ppm. Following addition of alcohol solution (10.0 mL, 0.132 M, 1.2 equiv) at -78 °C, the formation of the diastereomeric alkoxy phosphonium salts was confirmed by 3 ^J 1^,P NMR ( δ = 67.8 and 67.3 ppm). NaB¾ solution (11.0 mL, 0.5 M in diglyme, 5 mol equiv) was added dropwise at -78 °C, the vessel was removed from the cooling bath and allowed to warm to room temperature. The reaction was stirred for a further 60 min, when the diastereomeric salt was shown by P NMR to have been consumed and the phosphine borane formed (peak at δ 10.2 ppm). The reaction mixture was evaporated under reduced pressure, the reaction mixture diluted with ethyl acetate (100 mL) and water added (100 mL), the organic layer was separated, and the aqueous layer was extracted with (50 mL). The combined extracts were dried over MgS0₄, and evaporated under reduced pressure. The solvent was removed under vacuum and column chromatography was carried out on silica gel (ethyl acetate: hexane 50: 50 %) yielding phosphine borane as a colourless oil (0.24 g, 94%). CSP HPLC analysis revealed it to have 76% ee.

The procedure was repeated using a series of different phosphines oxide and alcohols giving the results shown in Table B 1 Table Bl. Enantiomeric excesses^ of phosphine boranes (ArMePhPBH₃) obtained from racemic phosphine oxides by treatment with oxalyl chloride, chiral non-racemic alcohol and NaB¾, according to Scheme 3. ^M

Ar Alcohol % ee

(Config) o-tolyl (-)-menthol 76 (R) o-tolyl (+)-menthol -74 (S) o-tolyl (+)-isomenthol -66 (S) o-tolyl (+)-neomenthol -61 (S) o-tolyl R-BINOL 46 (R) o-anisyl (-)-menthol 40 (R) o-anisyl (+)-menthol -42 (S) o-anisyl (-)-8-phenylmenthol 64 (R) o-anisyl (+)-isomenthol -46 (S) o-anisyl (+)-neomenthol -62 (S) o-trifluoromethylphenyl (-)-menthol 74 (R) o-trifluoromethylphenyl (+)-menthol -76 (S) o-trifluoromethylphenyl^[c] (+)-isomenthol -84 (S) o-trifluoromethylphenyl^[c] (+)-neomenthol -76 (S) o-biphenylyl (-)-menthol 52 (R) o-biphenylyl (+)-menthol -52 (S) o-methyl, 7-fluorophenyl (-)-menthol 60 (R)

[a] Determined by CSP HPLC, negative ee denotes that the major enantiomer was eluted second; [b] Reaction conditions: Phosphine oxide (1 equiv), oxalyl chloride (1 equiv), alcohol (1.2 equiv), NaB¾ (5 equiv), yields >85% except were noted (as judged by ³¹P NMR), for the o-trifluoromethylphenyl cases, reaction was warmed to get full conversion from oxide to chlorophosphonium salt, [c] 60-65% of phosphine borane and 35-40% of phosphine oxide which is also enantio enriched. Example B2 (XiAlFL)

A standard solution of memylphenyl(o-tolyl)phosphine oxide (0.110 M) was prepared in anhydrous toluene in a sealed vessel under nitrogen. Standard solutions of (-)- menthol (0.132 M) and oxalyl chloride (0.110 M) were prepared in a similar manner. Oxalyl chloride solution (10.0 mL, 0.11M, 1 equiv) was added dropwise at room temperature to the phosphine oxide solution (10.0 mL, 0.11M, 1 equiv) in a flame dried degassed Schlenk tube. 31 P NMR was taken identify the chlorophosphonium salt at 70 ppm. Following the addition of (-)-menthol solution (10.0 mL, 0.132 M, 1.2 equiv) at -78 °C, the formation of the diastereomericalkoxy phosphonium salts was confirmed by ³¹P NMR ( δ = 67.8 and 67.3 ppm). LiAlH* solution (10.0 mL, 0.11M in toluene, 1 mol equiv) was added dropwise at -78 °C, the vessel was removed from the cooling bath and allowed to warm to room temperature. The reaction was stirred for a further 60 min, when the diastereomeric salt shown by 31 P NMR to have been consumed (phosphine δ = -36.2 ppm). B¾-THF complex (2.0 M solution in THF, 1.5 mmol) was added and ³¹P NMR of the clear solution revealed one peak at δ_ρ +10.2 ppm (phosphine borane). The reaction mixture was evaporated under reduced pressure, the reaction mixture diluted with ethyl acetate (100 mL) and added water (100 mL), the organic layer was separated, and the aqueous layer was extracted with (50 mL). The combined extracts were dried over MgS0₄, and evaporated under reduced pressure. The solvent was removed under vacuum and column chromatography was carried out on silica gel (ethyl acetate: hexane 50: 50 %) yielding phosphine borane as a colourless oil (0.23 g, 91%). CSP HPLC analysis revealed it to have 76% ee.

C. Method for Conversion of Racemic Phosphine Oxide to Non-Racemic Phosphine Oxides.

This process is overviewed in Scheme 3. The same DAPS formed in Section B are not further reacted but instead allowed to collapse by internal Arbusov reaction to reform the oxide from which they were generated but which is now non-racemic. e

Scheme 3. Conversion of racemic P-stereogenic phosphine oxides to non- racemic P- stereogenic phosphine oxides.

Example CI Methylphenyl-o-tolylphosphine oxide

A standard solution of the phosphine (0.110 M) was prepared in anhydrous toluene in a sealed vessel under nitrogen. Standard solutions of (-)-menthol (0.132 M) and oxalyl chloride (0.110 M) were similarly prepared. Oxalyl chloride solution (10.0 mL, 0.11M, 1 equiv) was added dropwise at room temperature to the phosphine oxide solution (10.0 mL, 0.11M, 1 equiv) in a flame dried degassed Schlenk tube. ³¹P NMR was taken identify the chlorophosphonium salt at 70 ppm. Following addition of alcohol solution (10.0 mL, 0.132 M, 1.2 equiv) at -78 °C, the formation of the diastereomericalkoxy phosphonium salts was confirmed by ^J1P NMR ( δ = 67.8 and 67.3 ppm). The reaction was stirred for 30 min at -78 °C and refluxed for 2 hrs for the DAPS to collapse to oxide. The solvent was removed under vacuum and column chromatography was carried out on silica gel (ethyl acetate 100%,) yielding phosphine oxide as a white solid (0.24 g, 95%). A portion (0.5 mL) of the sample was removed, diluted to 2 mL with HPLC solvent (HPLC grade solvents purchased from Aldrich were used as supplied) and filtered through a PTFE syringe filter into a HPLC vial. High-performance liquid chromatography was performed on a Agilent Technologies 1200 series connected with 6 column switcher. HPLC (CHIRALPAK® IA column, 80:20 Heptane/EtOH, 1 mL/min): Rt = 7.4(5), 8.3(i?) min, and showed the oxide to have 76% ee. Example C2A Ethylphenyl-o-tolylphosphine oxide of (j?)-configuration.

Oxalyl chloride (0.1 mL neat, 2 equiv) was added dropwise at room temperature to a solution of racemic ethylphenyl-o-tolylphosphine oxide (146 mg, 1 equiv) in 31 dichloromethane (3 mL) in a flame dried degassed Schlenk tube after which P NMR identified the presence of the derived P-chlorophosphonium chloride at 78 ppm. The solution was stirred for 30 min and the solvent was removed in vacuo to give the P- chlorophosphonium chloride as a glassy white solid. This was taken up in dichloromethane (2.4 ml) followed by the addition of a solution of (-)-menthol in toluene (5.5 mL, 0.132 M, 1.2 equiv) at -82 °C. After 1 h at -82 °C the formation of

31

the diastereomeric alkoxyphosphonium salts was confirmed by ^J,P NMR (δ = 71.2 and 71.4ppm). The reaction mixture as above was stirred for 30 min at 0 °C after which time t-butyl alcohol (3 mL) was added and the mixture was stirred at 60 °C for 2 hrs for the DAPS to collapse to oxide. The solvent was removed under vacuum and column chromatography was carried out on silica gel (ethyl acetate 100%,) yielding the (R)- phosphine oxide as a white solid (0.142 g, 97%). A 1.0 mg/ml solution of this sample was filtered through a PTFE syringe filter into a HPLC vial. High-performance liquid chromatography was performed on an Agilent Technologies 1200 series connected with 6 column switcher and UV-spectrophotometry integrator. HPLC (CHIRALPAK® IA column, 80:20 Heptane/EtOH, 1 mL/min): Rt = 6.04 (S), 7.50 (R) min and showed the oxide to have enantiomeric purity of 92% ee.

Example C2B Ethylphenyl-o-tolylphosphine oxide of (^-configuration.

Oxalyl chloride (0.1 mL neat, 2 equiv) was added dropwise at room temperature to a solution of racemic ethylphenyl-o-tolylphosphine oxide (146 mg, 1 equiv) in dichloromethane (3 mL) in a flame dried degassed Schlenk tube after which P NMR identified the presence of the derived P-chlorophosphonium chloride at 78 ppm. The solution was stirred for 30 min and the solvent was removed in vacuo to give the P- chlorophosphonium chloride as a glassy white solid. This was taken up in dichloromethane (2.4 ml) followed by the addition of a solution of (-)-menthol in toluene (5.5 mL, 0.132 M, 1.2 equiv) at -82 °C. After 1 h at -82 °C the formation of

31

the diastereomeric alkoxyphosphonium salts was confirmed by ^J1P NMR (δ = 71.2 and 71.4ppm). The reaction mixture as above was stirred for 30 min at 0 °C after which time the solvent was removed in vacuo and acetonitrile (7 mL) was added followed by aqueous sodium hydroxide solution (1 M, 3.6 mL, 6 equiv). The mixture was stirred at 60 °C for 2 hrs, concentrated in vacuo and diluted with ethyl acetate (10 mL) and washed with water. The solvent was removed and column chromatography was carried out on silica gel (ethyl acetate 100%,) yielding the (iS)-phosphine oxide as a white solid (0.14 g, 96%). A 1.0 mg/ml solution of this sample was filtered through a PTFE syringe filter into a HPLC vial. High-performance liquid chromatography was performed on an Agilent Technologies 1200 series connected with 6 column switcher and UV- spectrophotometry integrator. HPLC (CHIRALPAK® IA column, 80:20 Heptane EtOH, 1 mL/min): Rt = 6.04 (5), 7.50 (R) min and showed the oxide to have enantiomeric purity of 87% ee.

D. Method for Conversion of Phosphine Oxides and Sulfides to Phosphine Boranes Using Sodium Borohydride (or Lithium aluminium hydride)

The fourth and fifth aspects of the present invention provide processes for the conversion of phosphine oxides to phosphane boranes via different intermediates, both racemically and stereospecifically. General procedures for such reactions are provided here.

A B

Scheme 4. Conversion of racemic P-stereogenic phosphine oxides (and sulfides) to racemic P-stereogenic phosphine boranes (Reaction A, Example Dl) and non-racemic P-stereogenic phosphine oxides (and sulfides) to non-racemic P-stereogenic

phosphine boranes (Reaction B, Example D2/D3)

Example Dl General Procedure for Racemic Conversion of Phosphine Oxides and Sulfides to Phosphine Boranes To a stirred solution of phosphine oxide/sulfide (0.11 M in toluene, 1 equiv.) was added a solution of oxalyl chloride (0.13 M in toluene, 1.0 equiv.) dropwise at room temperature under a nitrogen atmosphere. After 30 min, sodium borohydride (0.5 M diglyme, 1.7 mol equiv.) was added dropwise to the reaction mixture. This mixture was stirred for 1 h. The reaction mixture was then washed twice with deionised water (2 xlO mL) and the isolated toluene layer was dried over anhydrous MgS0₄. The drying agent was removed by filtration, and the solvent was removed in vacuo to give a colourless oil, which was eluted through a silica plug with 50:50 cyclohexane/ethylacetate. Solvent removal in vacuo yielded the pure phosphine borane, characterization data as shown in Table Dl below.

Table Dl. ³¹P NMR Characterisation data for phosphine boranes obtained from racemic phosphine oxides (and sulfides) by treatment with oxalyl chloride and NaB¾, according to Scheme 4.

# PO PO^a (ppm) CPS^b (ppm) PB^C (ppm)

X = 0 25.2

PlV ^Ph 64.4 21.5

X = S 42.1

X OMe X= O 28.5

70.5 8.4

X= S 35.2

a : PO: phosphine oxide; : CPS: chlorophosphonium salt; c : PB phosphine borane, yield > 95% (by ³¹P NMR). Example D2 Stereospecific Conversion of Methylphenylo-tolylphosphine oxide to the corresponding phosphine borane using alkylating agents and NaBHU

To a stirred solution of solution of alkylating agent (10 mL, 0.13 M in toluene, 1.2 equiv.) phosphine oxide (10 mL, 0.11 M in toluene, 1 equiv.) was added dropwise at room temperature under a nitrogen atmosphere and the mixture refluxed gently for 2 hrs. Then sodium borohydride (11 mL, 0.5 M in diglyme, 5 mol equiv) was added dropwise to the reaction mixture. This mixture was refluxed gently for 2 h. The reaction mixture was washed twice with deiomsed water, and the isolated toluene layer was dried over anhydrous MgS0₄. The drying agent was removed by filtration, and the solvent was removed in vacuo to give a colourless oil, which was eluted through a silica plug using 50:50 cyclohexane/ethylacetate as eluting solvent. Solvent removal in vacuo yielded the pure phosphine borane, characterisation data as shown in Table D2 below.

Table D2. Enantiomeric excesses in methylphenylo-tolylphosphine borane obtained from the corresponding non-racemic (94% ee) phosphine oxide by treatment with alkylating agents (including Meerwein's salt) and NaBLL;, according to Scheme 4.

Entry⁸ Alkylating Agent Yield (%) % ee° (config)

^"F [Et₃0]BF₄ 65 94 (5)

2^e [Et₃0]BF₄ 75 94 (5)

3^f [Et₃0]BF₄ 80 94 (5)

4 [Me₃0]BF₄ 75 94 (S)

5^g MeOTf 78 94 (S) a Unless specified the addition of alkylating agent and NaB¾ was carried at room temperature followed by refluxing. ^b by ^3,P NMR; ^c by CSP HPLC; ^d Addition of NaB¾ at -78 °C; ^e Addition of NaBLLj at -40°C; ^f ethoxyphosphonium salt was observed by at 75.9 ppm (³¹P NMR); ^E methoxyphosphonium salt was observed at at 71.7 ppm (^3IP NMR);

Example D3 Stereospecific Conversion of Methylphenylo-tolylphosphine oxide to the corresponding phosphine borane using Meerwein's salt and LAI I

To a stirred solution of Meerwein's salt (10 mL, 0.13 M in DCM, 1.2 equiv.), methylphenyl(o-tolyl)phosphine oxide (10 mL, 0.11 M in DCM, 1 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The reaction mixture was refluxed gently for 2 hrs at which point P NMR showed the complete conversion of phosphine oxide to the alkoxyphosphonium salt (peak at δ 71.8 ppm) then cooled to room temperature. LAH (10 mL, 0.13 M in toluene, 1.2 mol equiv.) was added dropwise to the reaction mixture which was then stirred for 30 min. 31 P NMR of the reaction mixture showed that the phosphine borane had formed (peak at δ 10.1 ppm). A portion of the reaction mixture was removed, evaporated under reduced pressure, diluted in HPLC mobile phase, filtered though a 0.2 μΜ Millipore Acrodisc and directly injected (10 μί) onto the HPLC system for ee analysis. The reaction mixture was evaporated under reduced pressure, then diluted with ethyl acetate (50 mL) and water added (50 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (25 mL). The combined extracts were dried over MgS0₄ and the solvent was removed under vacuum. Column chromatography was carried out on silica gel (ethyl acetate: cyclohexane 50: 50) yielding methylphenyl(o- tolyl)phosphine borane as a colourless oil (0.22 g, 90%).

Table D3. Enantiomeric excesses in methylphenylo-tolylphosphine borane obtained from the corresponding non-racemic (94% ee) phosphine oxide by treatment with Meerwein's salt and LAH, according to Scheme 4.

Entry Alkylating Agent Yield (%) % ee (config)

_ [_Et3o]BF₄ 90 94 (5)

E. Method for Conversion of Secondary and Tertiary Amino Phosphine Oxide to Phosphine Borane using Oxalyl Chloride and Sodium Borohydride.

The fourth aspect of the invention described above also provides a convenient method for converting an aminophosphine oxide to an aminophosphine borane via a P-chiral halophosphonium salt compound, Scheme 5. The method is exemplified in the following Table El. The procedure is the same as for Example Dl.

X CI BH₃ oxalyl chloride | θ NaBhL

R¹ _R'₂ R³ room temp. ^r1 _R'₂ R^{3 room tem}P- ^r1 _R2 ^r3 ^x = °> ^s CPS > 95 % yield

Scheme 5. Conversion of aminophosphine oxides to aminophosphine boranes Table El. 3 IP NMR Characterisation data for aminophosphine boranes obtained from racemic phosphine oxides (and sulfides) by treatment with oxalyl chloride and NaBHL}, according to Scheme 5.

a :

0 : PB phosphine borane, yield > 95% (by ³¹P NMR).

F. Method for Conversion of Phosphonate. Phosphinate and Phosphate to the Corresponding Phosphonic, Phosphinic and Phospho Boranes using Meerwein's Salt and Lithium Aluminium Hydride

The fifth aspect of the present invention described above provides a convenient method for converting a phosphonate to a four-coordinated phosphonic borane compound, Scheme 6. This process is exemplified below.

Scheme 6. Reduction of Phosphonate using Meerweins salt and LAH Example Fl Reduction of diethylphenylphosphonate

To a stirred solution of Meerwein's salt (10 mL, 0.13 M in DCM, 1.2 equiv.), diethylphenylphosphonate (10 mL, 0.11 M in DCM, 1 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The reaction mixture was refluxed gently for 2 hrs at which point P NMR showed the complete conversion of phosphonate to the intermediate salt (peak at δ 29.2 ppm) then cooled to room temperature. LAH (10 mL, 0.13 M in toluene, 1.2 mol equiv.) was added dropwise to the reaction mixture which was then stirred for 30 min. 31 P NMR of the reaction mixture showed that the phosphonic borane had formed (peak at δ 129.6 ppm). The reaction mixture was evaporated under reduced pressure, then diluted with ethyl acetate (50 mL) and water added (50 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (25 mL). The combined extracts were dried over MgS0₄ and the solvent was removed under vacuum. Column chromatography was carried out on silica gel (ethyl acetate: cyclohexane 50: 50) yielding diethylphenylphosphonic borane as a colourless oil (0.12 g, 52%).

Table Fl. P NMR Characterisation data for phosphonic boranes obtained from phosphonates by treatment with Meerwein's salt and LAH, according to Scheme 6.

G. Time Delayed Addition of Reducing Agent as Studied by ³¹P NMR

The DAPS intermediates in Example Al were studied by P NMR. It was found that one (often the minor one) collapsed more quickly by internal Arbusov reaction than the other. This provides a method to enrich the enantiomeric excess of the produced phosphine oxides and also the phosphine boranes produced by NaBH₄ reaction, if a time delay is introduced before addition of the NaB¾. Initial studies were carried out on ort zo-tolylmethylphenylphosphine in combination with (-)-menthol. By sampling the reactions using Schlenk NMR techniques it was possible to observe the diastereomeric alkoxyphosphonium salts (DAPS) by ³¹P NMR as two unequal peaks (Figure Gl), the major one at 67.3 and the minor one at 67.8 ppm (the peak at 32.2 ppm corresponds to the phosphine oxide formed form Arbuzov collapse of DAPS).

Figure Gl. P-NMR Spectrum of DAPS generated from ortho- tolylmethylphenylphosphine in combination with (-)-menthol. Further studies with several other phosphines showed that the diastereomeric ratio of DAPS as observed by ^JXP NMR 5 min after the start of the reaction equals the enantiomeric ratio of the phosphine oxide at the end of the reaction (see Table Gl).

Table Gl. Similarity between the DAPS de and phosphine oxide ee.

_Ra) Alcohol % de^b) % ee^c)

Me (-)-menthol 80 80

Me (+)-isomenthol 64 64

OMe (-)-menthol 50 50

OMe (+)-8-Ph-menthol 70 70

CF₃ (-)-menthol 70 70

Phenyl (-)-menthol 64 64

a Corresponds to different ortho substituents on arylmethyl phenyl phosphanes. ' 5 min after the start of the reaction the reaction was sampled for ³¹ P-NMR under the Schlenk NMR techniques to calculate the % de of DAPS. ^c) % ee of phosphane oxide was determined by CSP HPLC.

Further studies again with ort/zo-tolylmethylphenylphosphine in which the reaction mixture was sampled at different time periods indicated that the minor DAPS isomer collapses more rapidly to the phosphine oxide than the major one (see Figure G2 and Table G2)

1

Figure G2. P-NMR Spectrum of DAPS from ort/20-tolylmethylphenylphosphine and (-)-menthol at different time intervals, showing unequal collapse of the major and minor DAPS.

Table G2. Collapse of DAPS derived from r/¾o-tolylmethylphenylphosphine in combination with different chiral alcohols at various time intervals.

a⁾ To the solution of HCA and chiral alcohol, phosphine was added at -78 °C and reaction was sampled at various time intervals. The DAPS P NMR signals at 67.3 and 67.8 ppm were integrated at various time intervals. ^c) The % conversion of phosphine oxide from DAPS was calculated by integration of the P NMR signals at various time intervals.

These observations allow for the application of a time-delay methodology to the formation of phosphine boranes by reduction of DAPS with NaBHzj. By allowing the collapse of predominantly minor isomer of DAPS to phosphine oxide before treatment with NaB¾ it is possible to enhance the ee of the resulting phosphine borane as this corresponds to the de of DAPS (see Scheme 7 and Table G3). This is possible because NaBH* does not react with phosphine oxides.

Scheme 7. Enantioselective synthesis of phosphine boranes by time delay

Table G3. Reduction of (OTMPP) DAPS at various time intervals

Time^a) % % ee^c) % ee^d)

(PO/PB)^b)

(PB) (PO)

5 min 13/87 74(R) 72(S)

3 hrs 58/42 80(R) 74(R)

24 hrs 76/24 82(R) 70(R)

48 hrs 80/20 90(R) 72(R) a⁾To the solution of HCA and (-)-menthol (OTMPP) phosphine was added at -78 °C and the reaction sampled for reduction using NaB¾ at various time intervals. ^ After the reduction of DAPS using NaB¾ % yield of Phosphine oxide (PO) /Phosphine borane (PB) was obtained by integration of the ³¹P-NMR signals ^c) Obtained from CSP HPLC analysis of phosphine borane formed from reduction of DAPS. ^d) After the reduction of DAPS using NaBH₄ % ee of phosphine oxide in the reaction mixture was determined using CSP HPLC. Example Gl Monitoring of DAPS

The phosphine solution (0.11 M, 1 equiv.) and alcohol solution (0.132 M, 1.2 equiv.) were syringed into flame dried degassed Schlenk flask fitted with a stirring bar. A rubber septum was put over the Schlenk arm and the Schlenk flask was then immersed in a dry ice/acetone bath and cooled to -78°C. HCA stock solution (0.11 M, 1 equiv.) (0.1 mL/min approx.) was added via syringe. When all the HCA had been added, the reaction was stirred at -78 °C for 5 min. The reaction was sampled for NMR under N₂ using Schlenk techniques. The CDC1₃ used as the NMR solvent was stored under an atmosphere of N₂ over activated 4A molecular sieves. The reaction was then allowed to warm to room temperature and subsequent sampling carried out at further time intervals.

Reduction of DAPS. 5 min after the start of the reaction, the reaction mixture was sampled carefully into a flame dried degassed Schlenk tube, the Schlenk flask was then immersed in a dry ice/acetone bath and cooled to -78°C. NaB¾ (0.5 M diglyme, 5 equiv.) was added dropwise to the reaction mixture and once all NaBHj was added the reaction was allowed to stir at -78°C for 1 hr. The cooling was removed and the mixture allowed to stirrer at room temperature for 30 min. A portion (0.5 mL) of the mixture was removed, diluted to 2 mL with HPLC solvent (HPLC grade solvents, purchased from Aldrich, were used as supplied) and filtered through a PTFE syringe filter into a HPLC vial for analysis by CSP HPLC.

A similar procedure of reduction was followed by sampling the reaction at various time intervals.

H. Method for Independent Generation of Diastereomeric Alkoxyphosphonium Salts (DAPS) enabling enantioselective synthesis of phosphine oxide or phosphine or phosphine borane. The sixth aspect of the process provides the same DAPS species that has been the significant intermediate species in most of the above examples but in this aspect it is synthesised in another way, Scheme 8

racemic diastereomeric DAPS

I NaBH₄

Scheme 8. Enantioselective synthesis of phosphine oxide, phosphine or phosphine borane by independent generation of the requisite DAPS species and subsequent Arbusov collapse or reduction with a metal hydride.

Example HI

0-(-)Menthyl-P-o-anisylphenylphosphinite was prepared by the following method: to a solution of dicUorophenylphosphine in anhydrous THF was added ort/zo-anisyl magnesium bromide by drop wise addition at low temperature using a CCh/acetone cooling bath. The reaction mixture was analysed by 3 IP NMR and showed the expected peaks for a mixture of ort/zo-anisylphenylphosphinous chloride and bromide as the major products. The reaction mixture was re-cooled and a solution of menthoxymagnesium halide, freshly prepared by addition of methylmagnesium chloride to a solution of (-)-menthol, was added dropwise. The reaction mixture was allowed to warm overnight. P NMR analysis showed two predominant peaks provisionally identified as the -epimeric mixture of (-)-menthyl P-o- arnsylphenylphosphinite with a diastereomeric excess of ~32 %. A sample of this mixture was removed and at room temperature an excess of methyl iodide was added and the reaction allowed to stir overnight at room temperature. 3 IP NMR analysis of the mixture showed a single peak corresponding to literature and previous experimental data for PAMPO (phenyl(o-anisyl)methylphosphine oxide) with a small number of minor impurities. HPLC analysis of the mixture confirmed the presence of PAMPO with an ee of 30%. This independent synthesis of the diastereomeric alkoxyphosphonium salt intermediates (DAPS) and their Arbuzov collapse without loss of chiral information supports the observed behaviour of the breakdown of DAPS in the reaction manifold proceeding with preservation of d.e. as e.e according to Example Gl .

General Experimental

NMR Spectra The NMR spectra were recorded at 25 °C on Varian VNMRS 300, 400, 500 MHz spectrometers. ¹³C NMR spectra (³¹P decoupled) were recorded on a VNMRS 600 MHz spectrometer. All NMRs of potentially air-sensitive compounds were made up under nitrogen by syringing a small amount of the material into an NMR tube contained in a long Schlenk tube that was charged with an atmosphere of nitrogen, and then adding dry CDC1₃ to dissolve the compound which was then taken out using tweezers. CDCI₃ was purchased from Aldrich, and dried by adding to a Young's flask containing activated molecular sieves (4 A) under an atmosphere of nitrogen. It was then stored under nitrogen in the Young's flask over the molecular sieves.

HPLC Analysis of enantiomeric excesses The product four coordinated phosphorus compounds were analysed by high performance liquid chromatography on chiral stationary phases (CSP-HPLC). Typically, a 25 μΐ, sample of the reaction mixture was injected onto the HPLC column. High-performance liquid chromatography was performed on an Agilent Technologies 1200 series connected with 6 column switcher.

HPLC grade solvents, purchased from Aldrich and Lennox Supplies Ireland, were used as supplied. All samples were filtered through an Acrodisc CR 13 mm syringe filter with 0.2 μτη PTFE prior to injection. IR spectra were obtained on a Varian 3100

FTIR Excalibur series spectrometer.

General Experimental. Unless otherwise stated all the reactions were carried out under N₂ atmosphere in dry glassware using Schlenk-line techniques, all glassware was dried overnight prior to use. Air and moisture sensitive liquids and solutions were transferred via syringe. All commercially available solvents were used as supplied unless otherwise stated. All "dry" solvents were dried and distilled by standard procedures (e.g. Harwood, L.M., C.J.; Percy, J.M., Experimental Organic Chemistry, 1999, 2^nd ed, Blackwell Science Ltd, England) or were processed through a Grubbs type still, supplied by Innovative Technology Inc. Pure Solv-400-3-MD solvent purification system. Oxygen free nitrogen was obtained from BOC gases and was used without further drying. Thin layer chromatography (TLC) was performed on Merck pre-coated Kieselgel 60F₂₅₄ aluminium plates with realization by UV irradiation. Flash column chromatography was performed on Merck silica 9385, particle size 0.040-0.063 mm.

HCA was stored over molecular sieves in a Young's Flask. 4 A Molecular sieves were kept stored in an oven at 180 °C at all times. Prior to use sieves were heated to -300 °C, using a heat gun, for 2 minutes while under vacuum. They were allowed to cool to room temperature and this procedure was then repeated. Chiral alcohol, oxalyl chloride, NaBFLj (0.5 M in diglyme), silver triflate, and other reagents were purchased from Sigma-Aldrich, Fluka or Merck & Co., Inc.

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 scope and spirit 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 those skilled in biochemistry and biotechnology or related fields are intended to be within the scope of the following claims.

Claims

Claims:

1. A process for the stereoselective preparation of a P-chiral four-coordinated phosphorus borane compound, the process comprising

(i) reacting a first reactant comprising a P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P- atom with a second reactant selected from the group consisting of a chiral alcohol, chiral amine or chiral thiol, to provide a diastereomeric P-chiral four-coordinated chiral alloxy-, chiral amino-, or chiral thio- substituted phosphonium salt; and

2. The process of claim 1 further comprising converting said P-chiral four- coordinated phosphorus borane compound to a P-chiral three-coordinated phosphorus compound.

3. The process of claim 1 or claim 2 wherein said P-chiral four-coordinated phosphosphonium salt compound having a leaving group attached to the P-atom is prepared by a process comprising reacting a P-chiral three-coordinated phosphorus compound with an electrophile.

4. The process of claim 1 or claim 2 wherein when said P-chiral four-coordinated phosphonium salt compound having a leaving group attached to the P-atom is a P- chiral four-coordinated halo-phosphonium salt compound, said compound is prepared by a process comprising reacting a P-chiral phosphine oxide or a P-chiral phospine sulfide with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfunyl halide and methane sulfonyl halide.

5. The process of any one of the preceding claims, wherein the leaving group may be a halide, an alkoxide or a phenoxide, preferably, the leaving group is a halide, more preferably the leaving group is a chloride.

6. The process of claim 5 wherein step (i) involves reacting a first reactant comprising a P-chiral four-coordinated halo-phosphonium salt compound with a second reactant selected from the group consisting of a chiral alcohol, chiral amine, or chiral thiol, to provide a diastereomeric P-chiral four-coordinated chiral alkoxy-, chiral amino-, or chiral thio-substituted phosphomum salt compound.

7. The process of claim 6, wherein the P-chiral four-coordinated halo- phosphonium salt compound may be a compound of the following structure:

wherein X¹, X² and X³ are each independently absent, -O- or -N(R⁵)-; and

wherein R , R , R and R may be any inorganic or organic moiety.

8. The process of any one of the preceding claims wherein the P-chiral four- coordinated phosphonium salt compound having a leaving group attached to the P- atom is a halide salt compound, more preferably a chloride salt compound.

9. The process of any one of the preceding claims wherein the chiral alcohol is an aliphatic alcohol or an aromatic alcohol.

10. The process of any one of the preceding claims wherein the metal borohydride is NaBHU or LiBEU_.

11. The process of any one of the preceding claims wherein the process further comprises converting said P-chiral four-coordinated phosphorus borane compound to a P-chiral three-coordinated phosphorus compound.

12. A process for the stereoselective preparation of a P-chiral three-coordinated phosphorus compound, the process comprising

(ii) reducing said diastereomeric substituted phosphonium salt compound preferably with a reducing agent, such as LiAl¾ or sodium bis (2- methoxyethoxy) aluminium hydride, to provide a P-chiral three- coordinated phosphorus compound.

13. The process of claim 12 wherein the leaving group is a halide, an alkoxide or a phenoxide.

14. The process of claim 13 wherein step (i) involves reacting a first reactant comprising a P-chiral four-coordinated halo-phosphonium salt compound with a second reactant selected from the group consisting of a chiral alcohol, chiral amine, chiral thiol, to provide a diastereomeric P-chiral four-coordinated substituted phosphonium salt compound.

15. The process of claim 14 wherein the P-chiral four-coordinated halo- phosphonium salt compound has the following structure:

wherein X¹, X² and X³ are each independently absent, -O- or -N(R⁵)-; and

wherein R¹, R², R³ and R⁵ may be any inorganic or organic moiety.

16. The process of any one of claims 11 to 15 wherein the P-chiral four- coordinated halo-phosphonium salt compound is a P-chiral four-coordinated halo- phosphonium halide salt compound, preferably a chloride salt compound.

17. The process of any one of claims 11 to 16 wherein the chiral alcohol is an aliphatic alcohol or an aromatic alcohol.

18. The process of any one of claims 11 to 17 wherein said P-chiral four- coordinated phosphonium salt compound having a leaving group attached to the P- atom is prepared by a process comprising reacting a P-chiral three-coordinated phosphorus compound with an electrophile.

19. The process of any one of claims 11 to 17 wherein when said P-chiral four- coordinated phosphonium salt compound having a leaving group attached to the P- atom is a P-chiral four-coordinated halo-phosphonium compound, such compound is prepared by a process comprising reacting a P-chiral phosphine oxide or a P-chiral phosphine sulfide with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfonyl halide, and methane sulfonyl halide.

20. The process of any one of claims 11 to 19 wherein the enantiomerically enriched P-chiral three-coordinated phosphorus compound end product of the process is subsequently converted to an enantiomerically enriched P-chiral four-coordinated phosphorus borane compound.

21. A process for the stereoselective preparation of a P-chiral phosphine oxide or sulphide compound, the process comprising

(i) reacting a P-chiral phosphine oxide or a P-chiral phosphine sulfide with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfonyl halide, and methane sulfonyl halide to provide a P-chiral four-coordinated halo- phosphonium salt compound, and

(ii) either reacting said P-chiral four-coordinated halo-phosphonium salt compound with a reactant selected from the group consisting of a chiral alcohol, or chiral thiol to provide a stereo specific P-chiral phosphine oxide or sulphide compound; or reacting the P-chiral four- coordinated halo-phosphonium salt compound with a chiral amine and subsequently hydrolysing the product, e.g. with sodium hydroxide, to provide a stereospecific P-chiral phosphine oxide.

22. The process of claim 21 wherein the P-chiral phosphine oxide or phosphine sulphide used as starting material in this process has the formula:

23. The process of claim 21 or claim 22 wherein the P-chiral four-coordinated halo-phosphonium salt compound is a compound of the following structure:

wherein X\ XT and X^J are each independently absent, -O- or -N(R )-; and wherein R 1 , 2 , R 3 and R 5 may be any inorganic or organic moiety.

24. The process of any one of claims 21 to 23 wherein the P-chiral four- coordinated halo-phosphonium salt compound is a P-chiral four-coordinated halo- phosphonium halide salt compound, preferably a chloride salt compound.

25. The process of any one of claims 21 to 24 wherein the chiral alcohol is an aliphatic alcohol or an aromatic alcohol.

26. A process for the preparation of a four-coordinated phosphorus borane compound, the process comprising

(i) reacting a phosphine oxide compound or a phosphine sulphide

compound with a halogenating agent preferably selected from the group consisting of oxalyl halide, thionyl halide, sulfonyl halide, and methane sulfonyl halide to afford a four-coordinated halo- phosphonium salt compound, and

(ii) treating said four-coordinated halo-phosphonium salt compound with a metal borohydride to provide a four-coordinated phosphorus borane compound.

27. The process of claim 26 wherein the phosphine oxide or phosphine sulphide used in this preparation step has the formula:

wherein X¹, X² and X³ are each independently absent, -O- or -N(R⁵)-; and

wherein R 1 , R , R 3 and R 5 may be any inorganic or organic moiety.

28. The process of claim 26 or claim 27 wherein the P-chiral four-coordinated halo-phosphonium salt compound is a P-chiral four-coordinated halo-phosphonium halide salt compound, preferably a chloride salt compound.

29. A process for the stereospecific preparation of a P-chiral four-coordinated phosphorus borane compound, the process comprising

(i) reacting a P-chiral phosphine oxide compound or a P-chiral phosphine sulfide compound with an alkylating agent to afford a P-chiral four- coordinated alkoxyphosphonium salt compound, and

(ii) reducing said P-chiral four-coordinated alkoxyphosphonium salt compound with a metal borohydride or L1AIH4 to provide a P-chiral four- coordinated phosphorus borane compound.

30. The process of claim 29 wherein when the reducing agent is L1AIH₄, the counterion on the alkoxyphosphonium salt is fluoroborate.

31. The process of claim 29 or claim 30 wherein the P-chiral phosphine oxide or sulfide compound has the following formula:

wherein X , X and X are each independently absent, -O- or -N(R )-; and

wherein R¹, R², R³ and R⁵ may be any inorganic or organic moiety.

32. The process of any one of claims 29 to 31 wherein the reducing agent is NaBH₄ or LiAlH^ more preferably NaBH₄.

33. The process of any one of claims 29 to 32 wherein the alkylating agent is an alkyl triflates, such as methyl triflate, or a compound of formula [R₃0]BF₄, wherein R is an alkyl group, preferably CI -2 alkyl.

34. The process of any one of claims 29 to 33 wherein the solvent used is toluene.

35. The process of any one of claims 29 to 34 wherein the process is carried out at a temperature from about 15°C to about 35°C, preferably from about 20 °C to about 30 °C, more preferably at about 25°C (i.e. at ambient temperature).

36. A process for the stereoselective preparation of a P-chiral four-coordinated alkoxyphosphonium salt compound, the process comprising:

(ii) reacting said diastereomerically enriched P-chiral three- coordinated alkoxyphosphorus compound with an alkyl halide or an alkyl triflate to afford a diastereomeric P-chiral four- coordinated alkoxyphosphonium salt compound.

37. The process of claim 36 wherein the three-coordinated chlorophosphine compound is a compound having the following formula:

wherein X , and X are each independently absent, -O- or -N(R )

wherein R 1 , R2 , and R 5 may be any i *norgani■c or organic moi *ety.

38. The process of claim 36 or claim 37 wherein the Grignard reagent is a compound of formula R*OMX, wherein R* is a chiral moiety and X is a halide, preferably chloride or bromide and M is Mg, Li or Na.

39. The process of any one of claim 36 to 38 wherein the process further comprises the following step:

treating said diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound with a metal borohydride to afford a P-chiral four-coordinated phosphorus borane compound.

40. The process of any one of claims 36 to 38 wherein the process further comprises the following step:

treating said diastereomeric P-chiral four-coordinated alkoxyphosphonium salt compound with L1AIH4 to afford a P-chiral three coordinated phosphorus compound.

41. The process of any one of claims 36 to 38 wherein the process further comprises converting said P-chiral four-coordinated alkoxyphosphonium salt compound to a P-chiral phosphine oxide.

42. A process for preparing an enantiomerically enriched chiral phosphonium salt compound comprising reacting a P-chiral four-coordinated chiral alkoxy-, chiral amino-, or chiral thio-substituted phosphonium salt compound with a Grignard reagent to provide an enantiomerically enriched chiral phosphonium salt compound.