PROCESS

This invention relates to a process for the cyanation of aldehydes, particularly to the asymmetric cyanation of aldehydes, including the synthesis of chiral cyanohydrins and 5 derivatives thereof, such as chiral O-acyl cyanohydrins.

The synthesis of chiral intermediates such as chiral cyanohydrins and derivatives is an important process for use in the manufacture of fine chemicals, agrochemicals and pharmaceuticals. Enantiomerically pure cyanohydrins and derivatives are known to be versatile intermediates for the synthesis of a wide range of commercially important .0 compounds. For example chiral cyanohydrins and derivatives are intermediates for the synthesis of: α-hydroxy-acids, α-amino alcohols, and 1 ,2-diols. In addition, chiral cyanohydrins are themselves components of highly successful pyrethroid insecticides.

There are a number of synthetic routes available for the asymmetric synthesis of cyanohydrins and derivatives, virtually all of which involve the use of a chiral catalyst to

.5 induce the asymmetric addition of a cyanide source to a prochiral aldehyde or ketone.

The available catalysts include enzymes, cyclic peptides and transition metal complexes.

However, all of these methods suffer from one or more significant disadvantages which have negated their commercial exploitation. Many of the methods employ highly toxic and hazardous HCN, require very low (ca. -8O ⁰ C) reaction temperatures, and/or give products io with low to moderate enantiomeric excesses.

Processes for the asymmetric synthesis cyanohydrins and derivatives are disclosed by M.North, Synlett, 1993, 807-20; F.Effenberger, Angew. Chem. Int. Ed. Engl. 1994, 33, 1555; M.North, Comprehensive Organic Functional Group Transformations ed. Katritzky, A.R.; Meth-Cohn, O.; Rees, C.W.; Pattenden, G.; Pergamon Press, Oxford, >5 1995, vol. 3, chapter 18; Y.Belokon ¹ et al, Tetrahedron Asymmetry, 1996, 7, 851-5; Y.Belokon ¹ et al, J. Chem. Soc, Perkin Trans. 1 , 1997, 1293-5; Y.N.Belokon ¹ et al, Izvestiya Akademii Nauk. Seriya Khimicheskaya, 1997, 2040: translated as Russian Chem. Bull., 1997, 46, 1936-8; V.I.Tararov et al, Chem. Commun., 1998, 387-8; Y.N.Belokon' et al, J. Am. Chem. Soc, 1999, .121, 3968-73; V.I.Tararov et al, Russ. 50 Chem. Bull., 1999, 48, 1128-30; Y.N.Belokon' et al, Tetrahedron Lett., 1999, 40, 8147-50; Y.N.Belokon' et al, Eur. J. Org. Chem., 2000, 2655-61; Y.N.Belokon ¹ , M.North, and T.Parsons; Org. Lett., 2000, 2, 1617-9; M.North, Tetrahedron Asymmetry 2003, 147-176 and J. M. Brunei and I. P. Holmes Angewandte Chemie, International Edition, 2004, 2752- 2778. 5 J. Am. Chem. Soc, 1999, 121, 3968-73 discloses the use of titanium salen ligand based catalysts in the reaction of TMSCN with aldehydes and ketones. However, whilst the chemistry is academically interesting, it is of little commercial relevance due to the prohibitive cost of trimethylsilyl cyanide. Additionally, trimethylsilyl cyanide is highly volatile and hazardous to handle.

WO02/10095 and WO03/099435 disclose alternate processes which use certain cyanides sources and which involve reaction with a substrate susceptible to nucleophilic attack.

According to a first aspect of the present invention, there is provided a process for cyanating an aldehyde which comprises reacting the aldehyde with a cyanating agent in the presence of i) a chiral catalyst; and ii) less than a stoichiometric amount of an ionic cyanide source.

Aldehydes which can be employed in the process of the present invention have the chemical formula R-CHO, wherein R is a substituted or unsubstituted hydrocarbyl group, including perhalogenated hydrocarbyl groups. Hydrocarbyl groups which may be represented by R include alkyl, alkenyl, aryl and heterocyclic groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups. Alkyl groups which may be represented by R include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprise up to 10 branched chain carbon atoms, preferably up to 4 branched chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups. Additional examples of alkyl groups which may be represented by R include pentyl, hexyl, heptyl and octyl groups.

Alkenyl groups which may be represented by R include C _2-2 o. and preferably C ₂ .β alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups.

Aryl groups which may be represented by R may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups. A further example of an aryl group which may be represented by R is methoxyphenyl.

Perhalogenated hydrocarbyl groups which may be represented by R include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl grdups which may be represented by R include -CF ₃ and -C ₂ F ₅ .

Heterocyclic groups which may be represented by R include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will

contain at least one heterocyclic ring, commonly comprising from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups. When R is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R above. One or more substituents may be present.

Cyanating agents which can be employed in the process of the present invention include TMSCN, dicyanogen, sulfonyl cyanides, for example tosyl cyanide and mesyl cyanide. The cyanating agent preferably comprises a P-CN bond or a 0-(C=O)-CN moiety. Cyanating agents comprising a 0-(C=O)-CN moiety which can be employed in the process of the present invention include organic cyanides having the formula R ³ -0- CO-CN, where R ³ is H or a substituted or unsubstituted hydrocarbyl group as described above, commonly a C _1-6 alkyl group. Preferably, R ³ is a C _1-6 alkyl group. More preferably, R ³ is selected from the group comprising: methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t- butyl and t-pentyl. Most preferably, R ³ is ethyl. Cyanating agents comprising a P-CN bond which can be employed in the process of the present invention include phosphorous cyanides having the formula R ⁴ R ⁵ R ⁶ P(O) _x CN wherein x=0 or x=1 and R ^4'6 each independently is a substituted or unsubstituted hydrocarbyloxy group wherein the substituted or unsubstituted hydrocarbyl or the hydrocarbyloxy group is as described above, and is commonly a Ci _-6 alkyl group, where x=1, one of R ⁴ , R ⁵ or R ⁶ is absent. Preferably, R ⁴ , R ⁵ and R ⁶ are an independently chosen Ci _-6 alkyl group. More preferably R ⁴ , R ⁵ and R ⁶ are independently selected from the group comprising: methyloxy, ethyloxy, propyloxy, 2-propyloxy, butyloxy, 2-butyloxy, t-butyloxy and t-pentyloxy. Most preferably, R ⁴ , R ⁵ and R ⁶ are independently ethyloxy.

The reaction between the aldehyde and the cyanating agent occurs in the presence of less than a stoichiometric amount of an ionic cyanide source. Ionic cyanide sources include ammonium cyanide salts, particularly quaternary ammonium salts such as tetraalkyl, preferably tetra C _1-6 alky!-ammonium salts; and inorganic cyanides, preferably metal cyanides or an in situ source of inorganic cyanide such as acetone cyanohydrin. Preferred ionic cyanide sources are metal cyanides comprising transition metal, alkali metal and alkaline earth metal cyanides, for example, lithium, sodium, potassium, rubidium, caesium, magnesium, calcium and titanium cyanides, and mixed metal cyanides such as potassium ferrocyanide and potassium ferricyanide. More preferably, ionic cyanide sources are metal cyanides comprising alkali metal and alkaline earth metal

cyanides, for example, lithium, sodium, potassium, rubidium, caesium, magnesium, calcium and cyanides. The most preferred ionic cyanide source is potassium cyanide.

When the ionic cyanide source is a metal cyanide source, preferably the metal cyanide is a metal cyanide ligand complex wherein the metal is optionally complexed by ligands. Examples of ligands that may optionally complex the metal include ethers, polyethers, cryptands, aza-crowns, calixarenes, cyclodextrins and preferably crown ethers. The most preferred ligand is 18-crown-6.

Metal cyanide ligand complexes can be formed in situ, for example by the addition of ligands to a solution of metal cyanide either just prior to reaction and used without isolation or by addition of ligands during reaction. Alternatively, metal cyanide ligand complexes can be pre-formed, for example by prior reaction of the metal cyanide with ligands, the isolated metal cyanide ligand complexes can optionally be stored prior to addition to the reaction mixture.

Chiral catalysts that can be employed in the process of the present invention are those known in the art for catalysing the addition of a cyanide group to a carbonyl group, and include enzymes and cyclic peptides. Preferably, the chiral catalysts are metal complexes of metals, for example B, Mg, Al ₁ Sn, Bi, particularly transition-metal complexes comprising a chiral ligand, for example Re and lanthanides. In many embodiments, the transition metal is a Lewis acid capable of forming tetra coordinate complexes with chiral ligands. Preferred transition metal complexes are complexes of titanium and vanadium, especially titanium (IV), vanadium (IV) and vanadium (V). The chiral ligands are preferably tetradentate and commonly coordinate via oxygen and/or nitrogen atoms. Examples include binol, taddol, sulfoximines, salicylimines and tartrates, especially tartrate esters. However, the most preferred class of ligands are chiral Salen ligands and derivatives thereof.

Particularly preferably, the chiral catalyst employed in the process according to the present invention is a catalyst of formula 1.

wherein each R ¹ and R ² independently is H, a substituted or unsubstituted hydrocarbyl group; a substituted or unsubstituted hydrocarbyloxy group; halogen; nitro; amino (including a substituted or unsubstituted mono or di-hydrocarbylamino group); or amido group. Substituted or unsubstituted hydrocarbyl groups are as described above.

When a catalyst of formula 1 is employed, the catalyst may also be a mixed catalyst containing one vanadium and one titanium ion in each bimetallic catalyst unit.

Further catalysts that may be employed in the process according to the present invention include catalysts of formula (2):

wherein each R ¹ and R ² independently is H, a substituted or unsubstituted hydrocarbyl group; a substituted or unsubstituted hydrocarbyloxy group; halogen; nitro; amino (including a substituted or unsubstituted mono or di-hydrocarbylamino group); or amido group. Substituted or unsubstituted hydrocarbyl groups are as described above. In formulae 1 and 2 above, preferably R ¹ and R ² are independently selected from: hydrogen; halogen; cyano; nitro; hydroxy; amino; thiol; hydrocarbyl including alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl or any combination thereof, such as aralkyl, arylcycloalkyl, aralkenyl, arylcycloalkenyl, alkaryl, cycloalkaryl, alkenylaryl and cycloalkenylaryl; heterocyclyl; hydrocarbyloxy including alkyloxy, cycloalkyloxy, alkenyloxy, cycloalkenyloxy, aryloxy, aralkyloxy, arylcycloalkoxy, aralkenyloxy, arylcycloalkenyloxy, alkaryloxy, cycloalkaryloxy, alkenylaryloxy and cycloalkenylaryloxy; mono or di-hydrocarbylamino, including mono- or di-alkylamino, mono- or di- cydoalkylamino, mono- or di-alkenylamino, mono- or di- cycloalkenylamino, mono- or di- arylamino, mono- or di-aralkylamino, mono- or di-arylcycloalkylamino, mono- or di- aralkenylamino, mono- or di-arylcycloalkenylamino, mono- or di-alkarylamino, mono- or di- cycloalkarylamino, mono- or di-alkenylarylamino and mono- or di-cycloalkenylarylamino; hydrocarbylthio, including alkylthio, cycloalkylthio, alkenylthio, cycloalkenylthio, arylthio, araikylthio, arylcycloalkylthio, aralkenylthio, arylcycloalkenylthio, alkarylthio, cycloalkarylthio, alkenylarylthio and cycloalkenylarylthio; acyl; ester; carbonate; amide; sulphonyl or sulphonamido group, or comprise part of a fused ring; wherein each of the hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di- hydrocarbylamino, hydrocarbylthio, acyl, ester, carbonate, amide, sulphonyl and sulphonamido groups may be optionally independently substituted on any carbon atom

where valence allows by one or more compatible optional groups independently selected from the group comprising: halogen; cyano; nitro; hydroxy; amino; thiol; acyl; hydrocarbyl including alkyl, cycloalkyl, alkenyl, aryl or any combination thereof, such as aralkyl, arylcycloalkyl, aralkenyl, arylcycloalkenyl, alkaryl, cycloalkaryl, alkenylaryl and cycloalkenylaryl; heterocyclyl; hydrocarbyloxy including alkyloxy, cycloalkyloxy, alkenyloxy, cycloalkenyloxy, aryloxy, aralkyloxy, arylcycloalkoxy, aralkenyloxy, arylcycloalkenyloxy, alkaryloxy, cycloalkaryloxy, alkenyiaryloxy and cycloalkenylaryloxy; mono or di- hydrocarbylamino, including mono- or di-alkylamino, mono- or di-cycloalkylamino, mono- or di-alkenylamino, mono- or di-cycloalkenylamino, mono- or di-arylamino, mono- or di- aralkylaminp, mono- or di-arylcycloalkylamino, mono- or di-aralkenylamino, mono- or di- arylcycloalkenylamino, mono- or di-alkarylamino, mono- or di-cycloalkarylamino, mono- or di-alkenylarylamino and mono- or di-cycloalkenylarylamino; hydrocarbylthio, including alkylthio, cycloalkylthio, alkenylthio, cycloalkenylthio, arylthio, aralkylthio, arylcycloalkylthio, aralkenylthio, arylcycloalkenylthio, alkarylthio, cycloalkarylthio, alkenylarylthio and cycloalkenylarylthio; esters; carbonates; amides; sulphonyl and sulphonamido groups.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "hydrocarbyl" is used to refer generally to organic groups comprised of carbon chains to which hydrogen and optionally other groups are attached. The term "hydrocarbyl" includes straight chain, branched chain and cyclic structures or combinations thereof. For example, the term "hydrocarbyl" is used to refer to alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl or any combination thereof, such as aralkyl, arylcycloalkyl, aralkenyl, arylcycloalkenyl, alkaryl, cycloalkaryl, alkenylaryl and cycloalkenylaryl groups.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "alkyl" includes linear and branched alkyl groups Alkyl groups include Ci _-20 alkyl, preferably C _1-7 alkyl, more preferably C^s alkyl. When the alkyl groups are branched, the groups often comprise up to 10 branched chain carbon atoms, preferably up to 4 branched chain atoms. Examples of alkyl groups which may be represented by R ¹ and R ² include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl, n-pentyl, t-pentyl, n-hexyl, n-heptyl and n-octyl. Preferably, alkyl groups which may be represented by R ¹ and R ² include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and t-pentyl. The alkyl group may be optionally substituted by from 1 to 5 independently chosen halogen atoms. Examples of alkyl groups substituted by one or more halogens include -CF ₃ , -C ₂ F ₅ and -C ₂ F ₃ CI ₂ .

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "cycloalkyl" refers to a cyclic alkyl group. Cycloalkyl groups have a hydrocarbon ring. Preferably, the hydrocarbon ring has between 3 and 10 atoms in the largest ring. Cycloalkyl groups can include straight chain is and branched portions. Cycloalkyl groups may optionally feature one or more bridging rings. Examples of cycloalkyl groups which may be represented by R ¹ and R ² include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and

adamantyl groups. Preferably, the cycloalkyl group is selected from cyclohexyl and adamantyl groups.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "alkenyl" refers to an straight or branched hydrocarbon having one or more carbon-carbon double bonds therein. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Alkenyl groups which may be represented by R ¹ and R ² include C _2-2O alkenyl groups, and preferably C _2-6 alkenyl groups. Examples of alkenyl groups include vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl and hexadienyl. Preferably, the alkenyl group is a vinyl group. An alkenyl group can be unsubstituted or substituted with one, two or more substituents. Preferably, the alkenyl group is substituted with one or more phenyl substituents. An example of an aikenyl group substituted with phenyl substituents include styryl.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "cycloalkenyl" refers to straight or branched chain hydrocarbon groups which connect to form one or more non-aromatic rings containing a carbon-carbon double bond, which can be fused or isolated. Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl groups. An example of a cycloalkenyl group is an indenyl group.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "aryl" is used to refer to aromatic groups which have at least one ring having a conjugated pi electron system. Aryl groups which may be represented by R ¹ and R ² may contain 1 ring or 2 or more fused rings which may include aryl or heterocyclic rings. In the definition of R ¹ and R ² , the term "aryl" includes heterocyclic aryl, biaryl and heterocyclic biaryl. Examples of aryl groups which may be represented by R ¹ and R ² phenyl, naphthyl, ferrocenyl and anisyl groups. The aryl group can be optionally substituted by one or more groups. For example, the phenyl group can be optionally substituted by one or more groups selected from the group comprising: alkyl, halogen and haloalkyl. Examples of substituted phenyl groups include tolyl, fluorophenyl, chlorophenyl, bromophenyl and trifluoromethylphenyl, groups.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "aralkyl" is used to refer to an alkyl group substituted with an aryl group. The term "aralkyloxy" refers to an alkoxy group substituted with an aryl group. "Mono- or di-aralkylamino" refers to a mono or di-alkylamino group substituted with an aryl group. "Aralkylthio" refers to an alkylthio group substituted with an aryl group.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "arylcycloalkyl" is used to refer to a cycloalkyl group substituted with an aryl group. The term "arylcycloalkyloxy" refers to a cycloalkyloxy group. substituted with an aryl group. "Mono- or di-arylcycloalkylamino" refers to a mono or di-cycloalkylamino group substituted with an aryl group. "Arylcycloalkylthio" refers to a cycloalkylthio group substituted with an aryl group.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "aralkenyi" is used to refer to an alkenyl group substituted with an aryl group. The term "aralkenyloxy" refers to an alkenyloxy group substituted with an aryl group. "Mono- or di-aralkenylamino" refers to a mono or di-alkenylamino group substituted with an aryl group. "Aralkenylthio" refers to an alkenylthio group substituted with an aryl group.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "arylcycloalkenyl" is used to refer to a cycloalkenyl group substituted with an aryl group. The term "arylcycloalkenyloxy" refers to a cycloalkenyloxy group substituted with an aryl group. "Mono- or di-arylcycloalkenylamino" refers to a mono or di-cycloalkenylamino group substituted with an aryl group. "Arylcycloalkenylthio" refers to a cycloalkenylthio group substituted with an aryl group.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "alkaryl" is used to refer to an aryl group substituted with an alkyl group. "Alkaryloxy" therefore refers to an aryloxy group substituted with an alkyl group. "Mono- or di-alkarylamino" refers to a mono- or di-arylamino group substituted with an alkyl group. "Alkarylthio" refers to an arylthio group substituted with an alkyl group.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "cycloalkaryl" is used to refer to an aryl group substituted with a cycloalkyl group. "Cycloalkaryloxy" therefore refers to an aryloxy group substituted with a cycloalkyl group. "Mono- or di- cycloalkarylamino" refers to a mono- or di-arylamino group substituted with a cycloalkyl group. "Cycloalkarylthio" refers to an arylthio group substituted with a cycloalkyl group.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "alkenylaryl" is used to refer to an aryl group substituted with an alkenyl group. "Alkenylaryloxy" therefore refers to an aryloxy group substituted with an alkenyl group. "Mono- or di- alkenylarylamino" refers to a mono- or di-arylamino group substituted with an alkenyl group. "Alkenylarylthio" refers to an arylthio group substituted with an alkenyl group.

In the definition of R ¹ and R ² in formulae 1 and 2 above, the term "cycloalkenylaryl" is used to refer to an aryl group substituted with a cycloalkenyl group. "Cycloalkenylaryloxy" therefore refers to an aryloxy group substituted with a cycloalkenyl group. "Mono- or di-cycloalkenylarylamino" refers to a mono- or di- arylamino group substituted with a cycloalkenyl group. "Cycloalkenylarylthio" refers to an arylthio group substituted with a cycloalkenyl group.

Heterocyclyl groups which may be represented by R ¹ and R ² in formulae 1 and 2 above include aromatic, saturated and partially unsaturated ring systems and may constitute single or fused rings, for example 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclyl group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is an atom other than carbon, for example N, O, S or P. Examples of heterocyclyl groups which may be represented by

R ¹ and R ² include pyridyl, pyrimidyl, pyrrolyl, thienyi, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl, triazoyl, pyrazinyl, isoxazolyl, isothiazolyl and pyrazolyl groups. Preferably, the heterocyclyl groups which may be represented by R ¹ and R ² include pyridyl, pyrimidyl, pyrrolyl, thienyi, furanyl, indolyl, quinolyl, isoquinolyl, imidazolyl and triazoyl. In one embodiment of the compounds of formulae 1 and 2, R ¹ and R ² are independently selected from the group comprising: C _1-2O alkyl, C _3-10 cycloalkyl, C _∑ . _∑ Q alkenyl, C _4- - _I o cycloalkenyl, C _1-7 alkyl aryl, aryl Ci _-7 alkyl, C _1-7 alkyl heterocyclyl, heterocyclyl Ci_7 alkyl, aryl and heterocyclyl.

In a related embodiment of the compounds of formulae 1 and 2, R ¹ and R ² are independently chosen C _1-7 alkyl groups. More preferably, R ¹ and R ² are independently chosen C _1-5 alkyl groups. More preferably, R ¹ and R ² are independently selected from the group comprising: methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and t-pentyl. Most preferably, R ¹ = t-butyl. Most preferably, R ² = t-butyl.

In another related embodiment of the compounds of formulae 1 and 2, R ¹ and R ² are independently Cs _-10 cycloalkyl groups. Preferably, R ¹ and R ² are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In another related embodiment of the compounds of formulae 1 and 2, R ¹ and R ² are independently chosen C _∑ -β alkenyl groups. More preferably, R ¹ and R ² are independently selected from the group comprising: vinyl, ally!, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl and hexadienyl groups.

In another related embodiment of the compounds of formulae 1 and 2, R ¹ and R ² are independently chosen C ₄ - ₁ 0 cycloalkenyl groups. Preferably, R ¹ and R ² are independently cyclopentenyl, cyclohexenyl or indenyl groups.

In another related embodiment of the compounds of formulae 1 and 2, R ¹ and R ² are independently selected from the group comprising: substituted or unsubstituted Ci_ ₇ alkyl aryl or aryl groups wherein the aryl groups comprise 1 ring or 2 or more fused rings which may include aryl or heterocyclic rings. Preferably, R ¹ and R ² are independently substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indenyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted phenanthrenyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted ferrocenyl or substituted or unsubstituted anisyl groups.

In yet another related embodiment of the compounds of formulae 1 and 2, R ¹ and R ² are independently chosen Ci _-7 alkyl heterocyclyl or heterocyclyl groups, comprising 1 to 3 fused rings. Preferably, R ¹ and R ² are independently chosen C ₃ - ₁₀ heterocyclyl groups. More preferably, R ¹ and R ² are independently selected from the group comprising: pyridyl, pyrimidyl, pyrrolyl, thienyi, ^■ furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl, triazoyl, pyrazinyl, isoxazolyl, isothiazolyl and pyrazolyl groups. Most preferably, R ¹ and R ² are independently selected from the group comprising: pyridyl,

pyrimidyl, pyrrolyl, thienyi, furanyl, indolyl, quinolyl, isoquinolyl, imidazolyl and triazoyl group.

Preferably, R ¹ and R ² = CMe ₃

Further preferred catalysts that may be employed in the process according to the present invention include catalysts of formula (3a) and (3b):

(3a) (3b) wherein,

R ⁷ and R ⁸ are independently hydrogen, halogen, cyano, nitro, hydroxy, amino, thiol, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted mono or di-hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or comprise part of a fused ring; R ⁹ and R ¹⁰ are independently halogen, cyano, nitro, hydroxy, amino, thiol, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted mono or di-hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or R ⁹ and R ¹⁰ optionally are linked in such a way as to form an optionally substituted ring(s); Y ¹ is a neutral ϋgand; and X is an anion.

Hydrocarbyl groups which may be represented by R ^7"10 independently include alkyl, alkenyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups

Alkyl groups which may be represented by R ^7'10 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprise up to 10 branched chain carbon atoms, preferably up to 4 branched chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging

rings. Examples of alkyl groups which may be represented by R ^7"10 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl, t-pentyl, cyclohexyl and adamantyl groups.

Alkenyl groups which may be represented by R ^7"10 include C _2-2 o, and preferably

C ₂ .6 alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents.

Examples of alkenyl groups which may be represented by R ^7'10 include vinyl, styryl and indenyl groups.

Aryl groups which may be represented by R ^7"10 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R ^7"10 include phenyl, toiyl, fluorophenyl, chlorophenyl, bromophenyl, trifiuoromethylphenyl, anisyl, πaphthyl and ferrocenyl groups.

Perhalogenated hydrocarbyl groups which may be represented by R ^7"10 include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R ^7"10 include -CF ₃ and -C ₂ F ₅ .

Heterocyclic groups which may be represented by R ^7"10 include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, commonly comprising from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R ^7"10 include pyridyl, pyrimidyl, pyrrolyl, thienyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.

When R ⁹ and R ¹⁰ are linked in such a way as to form an optionally substituted ring(s), commonly comprising from 5 to 7 ring atoms. When R ^7"10 is a substituted hydrocarbyl, heterocyclic group, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, acyl, ester, carbonate, amide, sulphonyl or sulphonamido group, or R ⁹ and R ¹⁰ are linked in such a way as to form a substituted ring(s) the substituent(s) should be such so as not to adversely affect the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di- hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined above for R ^7"10 . One or more substituents may be present.

Neutral ligands which may be represented by Y ¹ include water, C _1-4 alcohols, C _1-4 thiols, C _1-8 ethers, C _1-8 thioethers, Ci _-8 primary, secondary or tertiary amines, and aromatic amines for example pyridine. A preferred ligand represented by Y ¹ is water.

Anions which may be represented by X include, halide, sulphate, alkylsulphate, perchlorate, PF ₆ ^" , acetate, tosylate, triflate, tetrafluoroborate, nitrate and cyanide.

in one embodiment of the compounds of formulae 3a and 3b, R ⁷ is defined in the same way as. R ¹ is defined above and R ⁸ is defined in the same way as R ² is defined above.

In one embodiment of the compounds of formulae 3a and 3b, R ⁷ and R ⁸ are independently selected from the group comprising: C ₁ . ₂ 0 alkyl, C _3- - _I0 cycloalkyl, C _2-2 o alkenyl, C _4-I0 cycloalkenyl, C _1-7 alkyl aryl, aryl C _L7 alkyl, Ci _-7 alkyl heterocyclyl, heterocyclyl Ci- ₇ alkyl, aryl and heterocyclyl.

In a related embodiment of the compounds of formulae 3a and 3b, R ⁷ and R ⁸ are independently chosen C ₁ . _? alkyl groups. Preferably, R ⁷ and R ⁸ are independently chosen C ₁ . ₅ alkyl groups. More preferably, R ⁷ and R ⁸ are independently selected from the group comprising: methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and t-pentyl.

In an alternative embodiment, R ⁷ or R ⁸ are independently alkyl groups, preferably methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl, t-pentyl, and cyclohexyl groups.

More preferably R ⁷ and R ^a are independently 2-propyl, butyl, 2-butyl, t-butyl, t- pentyl and cyclohexyl groups.

Most preferably R ⁷ and R ⁸ are independently t-butyl, t-pentyl and cyclohexyl groups.

Preferably R ⁹ and R ¹⁰ are independently halogen, cyano, nitro, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted di- hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or R ⁹ and R ¹⁰ optionally being linked in such a way as to form an optionally substituted ring(s) In one embodiment of the compounds of formulae 3a and 3b, R ⁹ is defined in the same way as R ¹ is defined above and R ¹⁰ is defined in the same way as R ² is defined above.

In one embodiment, R ⁹ and R ¹⁰ are independently selected from the group comprising C _1-20 alkyl, C3- ₁ 0 cycloalkyl, C _2-2 o alkenyl, C _4-10 cycloalkenyl, Ci _-7 alkyl aryl, aryl, C _L7 alkyl heterocyclyl or heterocyclyl groups; or R ⁹ and R ¹⁰ together with the carbons to which they are attached form an optionally substituted ring containing from 4 to 8 members and optionally including a N, S or O atom in the ring. Preferably, R ⁹ and R ¹⁰ together with the carbons to which they are attached form an optionally substituted carbocylic ring having from 4 to 8 ring atoms. More preferably, R ⁹ and R ¹⁰ together with the carbons to which they are attached form a carbocylic ring of 5 to 7. Most preferably R ⁹ and R ¹⁰ together with the carbons to which they are attached form a cyclohexyl ring.

More preferably R ⁹ and R ¹⁰ are independently alkyl or aryl groups, or R ⁹ and R ¹⁰ are linked in such a way as to form an optionally substituted ring comprising from 5 to 7 ring atoms, the ring atoms preferably are carbon atoms.

More preferably when R ⁹ and R ¹⁰ are independently alkyl or aryl groups, the alkyl or aryl groups are methyl, t-butyl or phenyl groups.

More preferably when R ⁹ and R ¹⁰ are independently alkyl or aryl groups, the alkyl groups are methyl groups and the aryl groups are phenyl groups. More preferably when R ⁹ and R ¹⁰ are linked in such a way as to form an optionally substituted ring, the ring comprises 6 ring atoms and the ring atoms are preferably carbon atoms.

Most preferably R ⁹ and R ¹⁰ are linked in such a way as to form an un-substituted ring comprising 6 ring atoms and the ring atoms are carbon atoms. Preferred catalysts are those in which R ⁷ and R ⁸ are independently 2-butyl, t-butyl, t-pentyl or cyclohexyl groups, and R ⁹ and R ¹⁰ are independently methyl, t-butyl or phenyl groups, or R ⁹ and R ¹⁰ are linked in such a way as to form an optionally substituted ring comprising 6 ring atoms, the ring atoms being carbon atoms.

More preferred catalysts are those in which R ⁷ and R ⁸ are independently 2-butyl, t- butyl, t-pentyl or cyclohexyl groups, and R ⁹ and R ¹⁰ are independently methyl, t-butyl or phenyl groups, or R ⁹ and R ¹⁰ are linked in such a way as to form an optionally substituted ring comprising 6 ring atoms, the ring atoms being carbon atoms.

Most preferred catalysts are those in which R ⁷ and R ⁸ are independently 2-butyl, t- butyl, or t-pentyl groups, and R ⁹ and R ¹⁰ are linked in such a way as to form an optionally substituted ring comprising 6 ring atoms, the ring atoms being carbon atoms.

Catalysts 3(a) and 3(b) be prepared by reaction of a suitable compound of vanadium with a ligand in the presence of oxygen.

Typically vanadyl sulphate hydrate is reacted with a Salen ligand in solvent in the presence of oxygen. The process according to the present invention is commonly carried out in the presence of a solvent Preferred solvents are polar, aprotic solvents, including halocarbons, for example dichloromethane, chloroform and 1 ,2-dichloroethane; nitriles, for example acetonitrile; ketones, for example acetone and methylethylketone; ethers, for example diethylether and tetrahydrofuran; and amides, for example dimethylformamide, dimethylacetamide and N-methylpyrolidinone.

It will be recognised that when the ionic cyanide source is a metal cyanide, the reaction mixture will be heterogeneous. In such circumstances, it is therefore desirable to employ efficient agitation of the reaction mixture. Agitation means known in the art, for example mechanical stirrers and ultrasonic agitators, selected appropriately according to the scale of reaction can be employed as desired.

The process of the present invention is often carried out a temperature of from about -40 ⁰ C to about 40 ⁰ C, Lower temperatures may be employed if desired, although they are not believed to be advantageous. Commonly, the reaction is carried out a temperature of from -4O ⁰ C to ambient temperature, such as 15-25 ⁰ C.

When the cyanating agent has the general formula Q-CN, the process can be represented by the sequence:

[CNl

R-CHO + Q-CN

R O-Q

The product of the cyanation reaction can then be reacted, for example by hydrolysis, to form a cyanohydrin.

The process according to the present invention is particularly suited to the enantioselective cyanation of aldehydes. It has been found that particularly effective enantioselective cyanation of aldehydes can be achieved by employing an order of addition in which a mixture of chiral catalyst, ionic cyanide source, solvent and aldehyde are prepared, the temperature of this mixture is then adjusted to the desired reaction temperature if necessary, and the cyanating agent is added to the mixture.

This invention allows the synthesis of chiral cyanohydrin derivatives derived from a wide variety of aldehydes. The products can be transformed into other chiral compounds by standard chemistry using either of the acyl or nitrile functional groups.

The invention is illustrated, without limitation, by the following examples. In the examples, catalyst 1a has the formula:

and catalyst 1b has the formula:

General methods

¹ H NMR spectra were recorded at 250 MHz on a Bruker AM250 spectrometer, and at 400 MHz on a Bruker AMX-400 spectrometer (at 293 K, CDCI ₃ or CD ₂ Cl ₂ ). Spectra were internally referenced either to TMS or to the residual solvent peak, and peaks are reported in ppm downfield of TMS.

Infrared spectra of solutions were measured with a Nicolet Magna-750 Fourier-transform spectrometer with a resolution of 2 cm ^"1 . The spectra were recorded using a 0.06 mm KBr cell. Solvent spectra were subtracted from solution spectra using the OMNIC Nicolet program.

Optical rotations were recorded on an Optical Activity Ltd. Polar 2001 or a Perkin-Elmer 241 polarimeter, and are reported along with the solvent and concentration in g/100 mL. Elemental analyses were performed on a Carlo Erba Model 1106 or Model 1108 analyser. Chiral GC was carried out on a DP-TFA-γ-CD, fused silica capillary column (32m x 0.2 mm) using helium as the carrier gas.

Dichloromethane was distilled over CaH ₂ .

Acetic anhydride was distilled from the commercial product (99%).

Commercial potassium cyanide (98%) was thoroughly powdered and stored in vacuo over

P ₂ O ₅ .

Aliphatic and aromatic aldehydes were purified by usual methods.

Chiral ligands were prepared by refluxing 1 ,2-cyclohexyldiamines {R,R and S ₁ S) with 2,4 di-.erf-butyl salicylaldehyde.

Example 1 : O-Ethoxycarbonyl (S)-2-hydroxy-2-phenylacetonitrile

(a) Without KCN

A stirred solution of benzaldehyde (0.5g, 1 equiv., 4.72 mmol) in dichloromethane (20 mL) and (R, R)-1 (0.264g, 0.05 equiv., 2.17 x 10 ^"4 mol) was cooled to -84 °C and ethyl cyanoformate (0.95 mL, 2 equiv., 9.42 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 19 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange-brown liquid was micro- distilled to give the cyanohydrin ethyl carbonate as a clear liquid (0.87g, 90%).

(b) With KCN

A stirred solution of benzaldehyde (1 equiv., 1g, 9.43 mmol) in dichloromethane (25 mL) and (R, R)A (0.02 equiv., 229 mg, 0.1886 mmol) and KCN (0.1 equiv., 61 mg, 0.9433 mmol) was cooled to -78 ⁰ C and ethyl cyanoformate (1.2 equiv., 1.12g, 11.32 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 24 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange-brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a yellow oil (1.98g, quantitative.)

Example 2: O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-methoxy-phenyl)acetonitrile

(a) Without KCN

A stirred solution of para-methoxybenzaldehyde (0.6Og, 0.53 mL, 1 equiv., 4.39 mmol) in dichloromethane (20 mL) and (R, R)-1 (0.26g, 2.20 x 10 ^"4 mol, 5 mol%) was cooled to -84 ⁰ C and ethyl cyanoformate (0.84g, 1.04 mL, 8.78 mmol, 2 equiv.) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 20 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange- brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a clear liquid (0.95g, 92%).

(b) With KCN

A stirred solution of para-methoxybenzaldehyde (1 equiv., 1.28g, 9.43 mmol) in dichloromethane (25 mL) and (R, R)-I (0.02 equiv., 229 mg, 0.1886 mmo!) and KCN (0.1 equiv., 61mg, 0.9433 mmol) was cooled to -78 "C and ethyl cyanoformate (1.2 equiv.,

1.12g, 11.32 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 24 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange-brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a yellow oil (2.16g, 98%).

Example 3: O-Ethoxycarbonyl (S)-2-hydroxy-3, 3-dϊmethyI-butanonitrile

(a) Without KCN

A stirred solution of trimethylacetaldehyde (0.38g, 0.49 mL, 1 equiv., 4.39 mmol) in dichloromethane (20 mL) and (R, R)-1 (0.26g, 2.20 x 10 ^"4 mol, 5 mol%) was cooled to -84°C and ethyl cyanoformate (0.52g, 0.53 mL, 5.27 mmol, 1.2 equiv.) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 20 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange- brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a clear liquid (0.56g, 69%).

(b) With KCN

A stirred solution of trimethylacetaldehyde (1 equiv., 0.81g, 9.43 mmol) in dichloromethane (25 mL) and (R, R)--[ (0.02 equiv., 229 mg, 0.1886 mmol) and KCN (0.1 equiv., 61mg, 0.9433 mmol) was cooled to -78 ⁰ C and ethyl cyanoformate (1.2 equiv., 1.12g, 11.32 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 24 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange-brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a yellow oil (1.38g, 79%).

Example 4: O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-trifluoro-methylphenyl)acetonitrϊle

(a) Without KCN

A stirred solution of para-trifluoromethylbenzaidehyde (0.77g, 0.60 mL, 1 equiv., 4.43 mmol) in dichloromethane (20 mL) and (R, R)-1 (0.27g, 2.21 x 10 ^"4 mol, 5 mol%) was cooled to -84 °C and ethyl cyanoformate (0.87g, 0.87 mL, 8.79 mmoi, 2 equiv.) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 6 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange- brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a clear liquid (1.01g, 84%).

(b) With KCN

A stirred solution of para-trifluoromethylbenzaldehyde (1 equiv., 1.63g, 9.39 mmol) in dichloromethane (25 mL) and (R, R)-1 (0.02 equiv., 229 mg, 0.1886 mmol) and KCN (0.1 equiv., 61mg, 0.9433 mmol) was cooled to -78 ⁰ C and ethyl cyanoformate (1.2 equiv., 1.12g, 11.32 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 24 h. The reaction mixture was then passed through a plug of silica eluting with dichioromethane. The eluent was concentrated in vacuo and the resulting orange-brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a yellow oil (2.41 g, 94%).

Example 5: O-Ethoxycarbonyl (S)-2-hydroxy-4-phenyl-but-3-enonitrile.

(a) Without KCN

A stirred solution of trans-cinnamaldehyde (0.62g, 1 equiv., 4.72 mmol) in dichloromethane (20 mL) and (R, R)-1 (0.264g, 0.05 equiv., 2.17 x 10 ^"4 mol) was cooled to -84 "C and ethyl cyanoformate (0.53 mL, 1.2 equiv., 5.64 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 19 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange- brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a clear liquid

(0.51g, 47%).

(b) With KCN

A stirred solution of trans-cinnamaldehyde (1 equiv., 1.25g, 9.43 mmol) in dichloromethane (25 ml_) and (R, R)-1 (0.02 equiv., 229 mg, 0.1886 mmoi) and KCN (0.1 equiv., 61 mg, 0.9433 mmol) was cooled to -78 ⁰ C and ethyl cyanoformate (1.2 equiv., 1.12g, 11.32 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 24 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange-brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a yellow oil (2.05g, 94%).

Example 6: O-Ethoxycarbonyl (S)-2-hydroxy-decanonitriIe

(a) Without KCN

A stirred solution of nonanal (0.67g, 1 equiv., 4.72 mmol) in dichloromethane (20 ml_) and (R, R)-1 (0.264g, 0.05 equiv., 2.17 x 10-4 mol) was cooled to -84 ⁰ C and ethyl cyanoformate (0.9 mL, 2 equiv., 9.42 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 19 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange-brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a clear liquid (0.61g, 54%).

(b) With KCN

A stirred solution of nonanal (1 equiv., 1.34g, 9.43 mmol) in dichloromethane (25 mL) and (R, R)-I (0.02 equiv., 229 mg, 0.1886 mmol) and KCN (0.1 equiv., 61 mg, 0.9433 mmol) was cooled to -78 ⁰ C and ethyl cyanoformate (1.2 equiv., 1.12g, 11.32 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 24 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange- brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a yellow oil (2.03g, 90%).

Example 7: O-Ethoxycarbonyl (S)-2-hydroxy-2-cyclohexyI-ethanonitrile.

(a) Without KCN

A stirred solution of the cyclohexane carboxaldehyde (0.52g, 1 equiv., 4.72 mmol) in dichloromethane (20 mL) and (R, R)-I (0.264g, 0.05 equiv., 2.17 x 10 ^"4 mol) was cooled to -84 ⁰ C and ethyl cyanoformate (0.53 mL, 1.2 equiv., 5.64mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 19 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange- brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a clear liquid (0.81 g, 82%).

(b) With KCN

A stirred solution of the cyclohexane carboxaldehyde(1 equiv., 1.06g, 9.43 mmol) in dichloromethane (25 mL) and (R, R)~1 (0.02 equiv., 229 mg, 0.1886 mmol) and KCN (0.1 equiv., 61mg, 0.9433 mmol) was cooled to -78 ⁰ C and ethyl cyanoformate (1.2 equiv., 1.12g, 11.32 mmol) was added in one portion. The yellow solution was then allowed to warm to -40 ⁰ C and was stirred vigorously for 24 h. The reaction mixture was then passed through a plug of silica eluting with dichloromethane. The eluent was concentrated in vacuo and the resulting orange-brown liquid was micro-distilled to give the cyanohydrin ethyl carbonate as a yellow oil (1.86g, 90%).

Example 8: Reaction of benzaldehyde and dϊethylcyanophosphσnate

(a) Without KCN

A solution of catalyst (0.12 g, 5 mol %) in dichloromethane (5 ml) was prepared. Benzaldehyde (0.20 ml, 2.0 mmol) was added to the solution, followed by diethylcyanophosphonate (0.30 ml, 2.0 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was passed through a plug of silica. The reaction has not proceeded at all, and the reactants were recovered unreacted.

(b) With KCN

A solution of catalyst (0.12 g, 5 mol %) and KCN (1 mg, 0.02 mmol) in dichloromethane (5 ml) was prepared. Benzaldehyde (0.20 ml, 2.0 mmol) was added to the solution, followed by diethylcyanophosphonate (0.30 ml, 2.0 mmol). The reaction was stirred at room

temperature overnight. The reaction mixture was passed through a plug of silica. The product was isolated as a yellow oil. (0.53 g, 99 % yield).

Example 9: Genera Procedure for Asymmetric cyanohydrin ethyl carbonate synthesis using metal cyanide ligand complex as ionic cyanide source.

KCN/18-crown-6 complex (6.6mg, 0.02 mmol, 1 mol %) and Ui(salen)O] ₂ catalyst (36mg, 0.03mmol, 1.5mol%) were dissolved in dichloromethane (5 ml). The solution was cooled to -4O ⁰ C. Aldehyde (2.0 mmol) was added by a syringe, followed by ethyl cyanoformate (0.24 ml, 2.4 mmol, 1.2 equivalents). The solution was allowed to stir overnight at -4O ⁰ C. The reaction was passed through a plug of silica, eluting with dichloromethane. The solvent was removed in vacuo and the product was analysed by chiral GC. This method was carried out using 16 different aldehydes and the products were provided with yields in the range of 48 to 100%. 13 of the 16 different aldehydes provided the product in 100% yield under the conditions specified.

Method for preparing the KCN/18-crown-6 complex (Organic syntheses, Coll. Vol. 7, p515: or vol 60, p 126)

Potassium cyanide (0.652g) was added to a solution of 18-crown-6 (2.64Og, 1 equivalent). The mixture was allowed to warm to 3O ⁰ C and stirred for 3 hours. The solvent was removed in vacuo to leave the complex as a white solid.

Example 10: Influence of potassium cyanide on the synthesis of mandolonitrile ethyl carbonate

A number of experiments were performed in dichloromethane using benaldehyde as the substrate, 1.2 equivalents of ethyl cyanoformate and 1 mol% of catalyst of formula 1 :

in which both R ¹ and R ² are tertiary butyl.

The results were as follows:

As entries 1 and 2 show, in the absence of potassium cyanide, the reaction was extremely slow under even ambient conditions. However, the addition of just 1 mol % of potassium cyanide to the reaction resulted in a significant increase in the rate at the same temperature as shown by entry 3. Entry 4 shows that by increasing the amount of potassium cyanide to 10 mol % results in the same significant increase in the rate shown by entry 2 and a significant increase in the enantioselectivity. Entry 5 shows that by reducing the reaction temperature to -40°C further improvement in the enantioselectivity is obtained yet the rate of reaction remains significantly better than that of the reaction occurring at ambient conditions without cyanide.