WO2006016116A1

WO2006016116A1 - Process for asymmetric catalytic hydrogenation

Info

Publication number: WO2006016116A1
Application number: PCT/GB2005/003017
Authority: WO
Inventors: Mark William Pennington; Anne Hodgson
Original assignee: Phoenix Chemicals Limited
Priority date: 2004-08-11
Filing date: 2005-08-02
Publication date: 2006-02-16
Also published as: GB2417244A; GB0515909D0; GB0417824D0

Abstract

The invention provides a process for preparing optically active 1,2-haloalcohols from an α-haloketone by asymmetric catalytic hydrogenation of a-haloketones comprising providing a substrate comprising an a-haloketone and contacting the substrate with a hydrogenation reagent under conditions effective for hydrogenation of the substrate in the presence of a catalyst comprising ruthenium or rhodium coordinated to a bisphosphine ligand.

Description

PROCESS FOR ASYMMETRIC CATALYTIC HYDROGENATION

The present invention relates to a process for preparing optically active 1 ,2- haloalcohols from α-haloketones by asymmetric catalytic hydrogenation, using bisphosphine catalysts.

A number of catalysts comprising bisphosphine ligands have been found suitable for certain asymmetric hydrogenation reactions. Ligands used in these catalysts include:

P

BoPhoz

Phanephos is known in particular for the Ru-catalysed hydrogenation of C=O bonds and for the Rh-catalysed hydrogenation of C=C bonds. P-Phos is known in connection with the Ru-catalysed hydrogenation of C=O and C=C bonds. BINAM-P and Spiro-P have been found effective for the Rh-catalysed hydrogenation of C=C bonds, whilst BoPhoz is known to be effective in the Rh- catalysed hydrogenation of both C=O and C=C bonds. Ruthenium based catalysts, having the metal coordinated to both nitrogen and phosphorus, have been developed and known for some time in connection with the asymmetric enantioselective catalytic hydrogenation of ketones:

>98%

Ph

(R)-XyIyI-BINAP (S)-DAIPEN (S₁S)-DPEN

Phanephos-Ru-DPEN (immediately below) has been suggested to be more active than BINAP complexes. Catalysts of this type are also thought to be adaptable (or "tunable") for use wittm diiferef*teHfo$trates»va*iM-l^^

Turnover numbers (TONs) of up to 100,000 and turnover frequencies (TOFs) of up to 60 sec^"1 have been reported (Org. Lett. 2000, 4173) in this connection.

Xylyl-P-Phos and P-Phos-Ru-DPEN (immediately below) have also been found to be competitive with BINAP complexes. TONs of up to 100,000 have been reported {J.Org.Chem. 2002, 7908).

EP-A-1346972 discloses a process for preparing an optically active halohydrin compound in which an α-haloketone is asymmetrically hydrogenated in the presence of a group 9 transition metal compound having a substituted or unsubstituted cyclopentadienyl group and an optically active diamine compound.

Wang et al in J. Org Chem. 69(5) 1629-1633, 2004, disclose the use of certain BINAP catalysts in the hydrogenation of chloroketones. Rotella describes the reduction of chloroketones with hydride reducing agents in Tetrahedron Letters, Vol. 36, No. 31, pp5453-5456, 1995.

It is an object of the present invention to provide an improved process for the asymmetric hydrogenation of α-haloketones. In particular it is an object of the invention to provide a high diastereomeric excess (d.e) in the resulting hydrogenation product. A further object is to provide a process for the asymmetric hydrogenation of α-haloketones which proceeds with a high turnover number (TON). Another object is to provide a process for the asymmetric hydrogenation of α-haloketones which proceeds with a high turnover frequency (TOF). Yet another object of the invention is to provide a process for the asymmetric hydrogenation of α-haloketones which can proceed with a high substrate to catalyst (s/c) ratio.

According to the present invention there is provided a process for the enantioselective catalytic hydrogenation of α-haloketones comprising providing a substrate comprising an α-haloketone and contacting the substrate with a hydrogenation reagent under conditions effective for hydrogenation of the substrate in the presence of a catalyst comprising ruthenium or rhodium coordinated to a bisphosphine ligand other than BINAP, the hydrogenation product being at least predominantly a (2R, 3S) diastereomer.

In the process of the invention, the α-haloketone preferably has the Formula (I):

or its enantiomer, wherein:

X is selected from Cl and Br; R is selected from optionally substituted aryl groups; and

R' is selected from NHR² and NR²R³, wherein R² and R³ are the same or different and are independently selected from hydrogen or from optionally substituted alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryi and heteroalkyl groups, or from COR⁴, OCOR⁴ and SO₂R⁴, wherein R⁴ is selected from hydrogen or from optionally substituted alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryi and heteroalkyl groups.

Preferably, R' is NHR², wherein R² is OCOR⁴, wherein R⁴ is selected from hydrogen or from optionally substituted alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryi and heteroalkyl groups. Particularly preferred R⁴ include t-butyl and benzyl.

In yet another particularly preferred process of the invention, R' is NHR², in which case R² is preferably a protecting group, such as Boc or cBz. R² may for example be an alkoxycarbonyl group such as terf-butoxycarbonyl.

In one particularly preferred process of the invention, X is Cl.

In another particularly preferred process of the invention, R is phenyl or a substituted phenyl.

One particularly preferred product of the process of the invention is:

(2R,3S)-3-tert-butoxy-carbonylamino-1-chloro-2-hydroxy-4-phenylbutane

Preferably, the process of the invention yields the above (2R, 3S) product in significant diastereomeric excess with respect to its diastereomer:

(2S,3S)-3-tert-butoxy-carbonylamino-1-chloro-2-hydroxy-4-phenylbutane

In this case, the starting material in the process of the invention is:

(3S)-3-tert-butoxy-carbonylamino-1-chloro-4-phenyl-2-butanone Therefore, according to a preferred process in accordance with the invention, there is provided a process for the asymmetric catalytic hydrogenation of α- haloketones comprising providing a substrate of Formula (II):

Formula (II)

or its enantiomer, wherein X is Cl or Br, R comprises an optionally substituted aromatic group and wherein R" comprises a protecting group, and contacting the substrate with a hydrogenation reagent in the presence of a catalyst comprising ruthenium or rhodium coordinated to a bisphosphine ligand under conditions effective for asymmetric hydrogenation of the substrate.

One preferred substrate for use in the process of the invention is a BocHaloketone, more preferably a BocChloroketone.

Thus, one preferred process in accordance with the invention concerns the asymmetric enantioselective catalytic hydrogenation of a BocChloroketone, in accordance with the following reaction scheme:

The catalyst used in the process of the invention preferably comprises at least one bisphosphine ligand exhibiting both planar and carbon centre chirality. One preferred ligand is a Bophoz ligand. One preferred Bophoz ligand is:

h,

Me-BoPhoz with R = CH ₃

Another preferred catalyst for use in the process of the invention comprises at least one bisphosphine ligand exhibiting axial chirality. One preferred ligand is a P-Phos ligand. One preferred P-Phos ligand is:

The invention thus provides the use of a catalyst comprising ruthenium or rhodium coordinated to at least one chiral bisphosphine ligand in the catalytic asymmetric hydrogenation of an α-chloro- or bromoketone of formula (I) to yield a hydrogenation product being predominately the

(2R, 3S) diastereomer. Certain preferred chiral bisphosphine ligands may contain biaryl axial chirality preferably through a 3,3'-bipyridyl structure. Other preferred chiral bisphosphine ligands may contain both planar chirality, for example through a di-substituted ferrocenyl structure, and a centre of asymmetry, for example in the side chain. The or each bisphosphine catalyst may be enantiomerically pure, or may be present as an enantiomeric mixture.

The process of the invention preferably utilises a catalyst which has been immobilised in a reaction zone in which the hydrogenation reaction takes place. Various immobilisation techniques are known in the art.

The hydrogenation reaction in the process of the invention preferably proceeds with high a TON, for example of at least about 50,000, preferably at least about 75,000, more preferably at least about 100,000, and most preferably at least about 125,000.

The hydrogenation reaction in the process of the invention preferably proceeds with high a TOF, for example of from at least about 30sec^'1 , preferably at least about 50sec^"1 , more preferably at least about 60 sec^"1 , and most preferably at least about 75sec^"1.

The s/c ratio in the reaction mixture in the process of the invention is preferably at least about 100/1 , more preferably at least about 250/1 , yet more preferably about 500/1 and most preferably at least about 1000/1. In a continuous process according to the invention (see below) the s/c ratio may be even higher, for example at least about 10000/1 , even at least about 12000/1 - for example at least about 15000/1.

The process of the invention preferably proceeds with a diastereomeric excess (d.e.) of the (2R, 3S) asymmetric hydrogenation product over the (2S, 3S) hydrogenation product. Preferably, the d.e. in respect of the desired diastereomer is at least about 90%, more preferably at least about 95%, and most preferably at least about 97%.

The process of the invention may be operated as a batch or as a continuous process.

Accordingly, in one preferred process of the invention there is provided a continuous process for the asymmetric hydrogenation of an α-haloketone of Formula (I) comprising providing reaction zone and continuously supplying to the reaction zone a substrate comprising the α-haloketone to be hydrogenated, a hydrogenation reagent effective for hydrogenating the α-haloketone, and a catalyst comprising Ru or Rh coordinated to a bisphosphine ligand other than BINAP, maintaining the reaction zone under conditions effective for asymmetric hydrogenation of the α-haloketone, and continuously withdrawing from the reaction zone a product stream comprising asymmetrically hydrogenated α- haloketone, or a product derived therefrom. Preferably, the product stream in such a continuous process is treated to remove the desired product and at least part of any remaining unreacted materials or catalyst may be returned to the reaction zone.

Whether the process of the invention is batch or continuous, the hydrogenation reagent preferably comprises hydrogen.

The temperature conditions effective for hydrogenation of the α-haloketone will vary to some extent for different substrates and for different catalysts. However, generally temperatures of from about 15°C to about 120⁰C, preferably from about 25°C to about 100°C, more preferably from about 35°C to about 85°C, and most preferably from about 45° to about 75°C, are preferred.

The pressure conditions effective for hydrogenation of the α-haloketone will vary to some extent for different substrates and for different catalysts. However, generally pressures of from about 1 bar to about 100 bar, preferably from about 2 bar to about 75 bar, more preferably from about 3 bar to about 50 bar, and most preferably from about 5 bar to about 40 bar, are preferred.

The solvent or solvent mixture used in the process of the invention is preferably compatible with the substrate to be hydrogenated, and optimal solvent conditions are therefore likely to be different for different substrates. However, generally polar solvents will be preferred, in particular alcohols, substituted alcohols and furans. Particularly preferred solvents include methanol, ethanol, propanol, isopropyl alcohol, butanol, THF, DCE, and compatible mixtures of two or more thereof.

Also provided in accordance with the invention is the use of a catalyst comprising ruthenium or rhodium coordinated to at least one bisphosphine ligand other than BINAP in the catalytic asymmetric hydrogenation of an α-haloketone.

The inventors have conducted a substantial research program with the aim of identifying certain types of catalyst, and preferred process conditions under which such catalysts are found to be most effective in the asymmetric catalytic hydrogenation process of the invention. Initially, a preferred substrate was chosen and a number of different catalysts were screened for initial activity. Subsequently, studies were conducted to identify preferred conditions (including temperature and solvent environment) for optimal operation of the process of the invention.

Optimisation of reaction conditions may be further enhanced by investigation of such parameters as:

- solvents - s/c ratio

- temperature

- substrate concentration

- pressure

- additives Bisphosphine ligands considered for use (when suitably coordinated) in the process of the invention include, but are not limited to:

H8-BINAMP SpirOP

Phanephos Xyl-Phanephos MeOXyl-Phanephos Cy-Phanephos 'Pr- Phanepho

DIPFc Me-DUPHOS

DIPAMP

MeBoPhoz p-Fluorophenyl-MeBoPhoz

EtBoPhoz

Ligand A

Ligand B

Ligand C

Ligand D

These ligands may suitably be coordinated in the form [Rh(bisphosphine)(NBD)]BF₄, although other types of coordination unit and counterions may be used. These coordinated ligands are found to be effective in the asymmetric enantioselective catalytic hydrogenation of haloketones generally, of which BocChloroketone is a preferred example in the process of the invention.

Screening of a number of Ru-bisphosphine- based catalysts (some of the results of which are reported below) demonstrated, inter alia, that Ru(S-XyI-P- Phos)CI2(dmf)2 gave 98% conversion, 94% d.e. in 1-butanol. Ru(R-p-F- phenylMeBoPhoz)CI2(dmf)2 gave 96% conversion and 94% de in ethanol. Use of sodium trifluoroacetate as an additive with this catalyst gave an increase in reaction rate.

Examples

In the following examples, the substrate chosen for illustration of the process of the invention was (3S)-3-tert-butoxy-carbonylamino-1-chloro-4-phenyl-2-butanone which was asymmetrically hydrogenated to (2R,3S)-3-tert-butoxy-carbonylamino- 1-chloro-2-hydroxy-4-phenylbutane according to the following reaction scheme:

[examples were, unless otherwise indicated, conducted using an Argonaut Endeavour hydrogenation unit and following standard protocols for its use.] Example 1

Hvdroαenation Using Chiral Ru -bisphosphine-Based Catalysts (P-Phos ligands)

A series of experiments were carried out with the following ligands coordinated to ruthenium:

Some results of this study are shown in Table 1 :

Table 1

Reaction conditions: 1mmol substrate, S/C ratio = 100/1 , 4mL MeOH, unoptimized reaction time 20 hrs.

Example 2 Influence of the solvent on the hvdroqenation of BocChloroketone using Ru(P-

Some results of this study are shown in Table 2:

Table 2

^aReaction conditions: O.δmmol substrate, S/C ratio = 100/1 , 3mL solvent, 5O⁰C, 10 bar, unoptimized reaction time 20 hrs.

Example 3 Ru-BoPhoz-based catalyst for the hydroqenation of BocChloroketone.

A series of experiments were carried out with an aforementioned ligand and with the following ligands coordinated to ruthenium:

MeBoPhoz EtBoPhoz

Some results of this study are shown in Table 3

Table 3.

a) O.δmmol BocChloroketone, S/C = 500/1 , 3mL 1-BuOH, O.OOlmmol catalyst, 50⁰C, 10bar H₂, 20 hrs; b) 1mmol BocChloroketone, S/C = 750/1 , 6mL 1-BuOH, 0.0013mmol catalyst, 50-55⁰C₁ 10bar H₂, 24 hrs, reaction performed in a Parr reactor; c) 1mmol BocChloroketone, S/C = 1000/1 , 6mL 1-BuOH, O.OOlmmol catalyst, 50-55⁰C, 10bar H₂, 48hrs, reaction performed in a Parr reactor. Example 4

Influence of the solvent on the Ru-fffl-Me-BoPhoz-Cbfclmffc-catalyzed asymmetric hvdroqenation of BocChloroketone

Some results of this study are shown in Table 4 Table 4.

catalyst, 6mL solvent, 50⁰C, 10 bar, reaction time 20 hrs. ^b 1 mmol substrate, S/C ratio = 750/1 , 0.0013mmol catalyst, 6mL solvent, 50⁰C, 10 bar, reaction time 20 hrs, reaction performed in a Parr reactor.

Example 5

Influence of the substrate concentration on the hvdroqenation of BocChloroketone using Ru-fffl-MeBoPhoz-CUdmf^catalvst

Some results of this study are shown in Table 5 Table 5.

S/C = 750, 50 C, 10bar H₂, 20 hrs

Example 6

Asymmetric hvdrogenation of BocChloroketone using BoPhoz-Ru catalysts

A series of experiments were carried out certain BoPhoz ligands coordinated to ruthenium. Some results of this study are shown in Table 6.

Table 6

Entry Catalyst S/c Time Conv. (%) de (%)

1 (R)MeBoPhoz-RuCI₂-d mf 500 18 >99 93

2 (R)MeBoPhOz-RuCI₂-PPh₃ 500 18 >99 92.5

3 (R)MeBoPhoz-RuCI₂-dmf 1000 56 >99 93

4 (R)MeBoPhoz-RuCI₂-dmf 1000 56 89 92

5 (R)MeBoPhoz-Ru (acac)₂ 1000 18 55 92

6 (R)MeBoPhOz-RuCI₂ (TFA)₂ 1000 18 69 88

Reaction conditions: Endeavor catalyst system; EtOH (2 ml/mmol), H₂ (145 psi), 55 oC. Conversion analysed by HPLC, de measured by chiral HPLC.

Example 7 Asymmetric hydrogenation of BocChloroketone using p-Fluorophenyl (R)- MeBoPhoz-RuCI?-dmf catalyst.

A series of experiments were carried out with the following ligands coordinated to

ruthenium:

MeBoPhoz p-Fluorophenyl-MeBoPhoz

Some results of this study are shown in Table 7

Table 7

Entry S/c Time Conv. (%) de (%)

1 500 5 >99 94

2 1000 12 >99 93.5

3 2000 55 75 93

^a Reaction conditions: Endeavor catalyst system; EtOH (2 ml/mmol), H₂ (145 psi), 55 ⁰C. Conversion and de measured by chiral HPLC.

Example 8

Asymmetric Hydrogenation of BocChloroketone using (f?)MeBoPhoz-RuCI?-PPhj with different additives The Some results of study of effect of additives on the reaction are summarised in Tables 8, 8a and 8b

Table 8 Asymmetric Hydrogenation of BocChloroketone using (R)MeBoPhOZ- RuCI₂-PPh₃ with different additives (20 mol%)

Entr y Additive Conv. (%) de (%)

" i" - ^">98 ^{"" ""}93^"

2 MgBr₂OEt 75 93.5

3 NH₄CI 60 93

4 Na(CO₂CF₃) >99 93^C

5 Ag(OTf)₂ 31 90

6 AgBF₄ 15 -

7 NaOAc 16.5 83

^a Reaction conditions: Endeavor catalyst system; EtOH (2 ml/mmol), H₂ (145 psi), 55 ⁰C, 18 hrs. Conversion and de measured by chiral HPLC. ^c reaction complete after 5 hrs.

Table 8a. Asymmetric hydrogenation of BocChloroketone using BoPhoz-Ru catalysts with different levels of sodium trifluoroacetate as additive. ^a

^"Entry ~~ Catalyst Na(CO₂CF₃) ContTJ%) ~de (%)^"

(mol%)

1 ^{' "} (R)MeBoPhOZ-RuCI₂- PPh₃ ^{" ' "} - ^" 73 92.5

2 5 99 93 3 10 97 93 4 20 90 91 5 50 81.5 90 6 100 44 87 7 p-F-Ph-(f?)MeBoPhoz-RuCI₂-dmf 2.5 >99 93.5

>99 93.5 ^a Reaction conditions: Endeavor catalyst system; s/c 1000, 12h, EtOH (2 ml/mmol), H₂ (145 psi), 55 ⁰C. Conversion analysed by HPLC₁ de measured by chiral HPLC.

Table 8b. Asymmetric hydrogenation of BocChloroketone using BoPhoz-Ru catalysts with sodium trifluoroacetate as additive under different conditions.⁸

Entry Catalyst Na(TFA): S/c Temp Conv. de

Catalyst (⁰C)

1 (/?)MeBoPhoz-RuCI₂-dmf - 1000 55 82 92

2 25:1 1000 55 98 92.4

3 50:1 1000 55 99 94

P-F-Ph-(R)MeBoPhOz-

4 94 RuCI₂-dmf 25:1 1000 55 99

5 25:1 1000 45 99 94

6 25:1 1000 35 93 94

7 25:1 1500 55 99 94 δ 25:1 2000 55 98 94

9 50:1 2000 55 78 94

10 25:1 2500 55 95 92

^a Reaction conditions: Endeavor catalyst system; 18h, EtOH (2 ml/mmol), H₂ (145 psi), Na(TFA):Catalyst molar ratio. Conversion analysed by HPLC, de measured by chiral HPLC.

Example 9

Asymmetric hvdroαenation of BocChloroketone using BoPhoz-Ru catalysts with sodium trifluoroacetate as additive using a 50 ml Parr autoclave.⁸

To a 50 ml Glass liner was added catalyst (5.4mg, δμmol s/c 1000; or 2.7mg, 3 μmol, s/c 2000), sodium trifluoroacetate (20.4 mg, 0.15mmol, s/cϊOOO; or 10.2mg, 0.075mmol, s/c 2000) and substrate (1.79 g, 6 mmol). This was placed in the autoclave and the flushed with Nitrogen. Ethanol (12 ml) was added to the autoclave. The autoclave was placed in an oil bath (oil bath temperature 69⁰C) and left to equilibrate for 10 minutes. The autoclave was then pressurised with hydrogen (10 bar) and left for 18 hrs. The internal temperature of the autoclave was measured as being 4O⁰C. A pressure drop of 50 psi was noted over 18 hrs. The autoclave was removed from the oil bath, cooled, depressurised and the contents analysed by HPLC. The results of this and a similar study are shown in Table 9.

Table 9.

Entry Catalyst Na(TFA): s/c Temp Conv. de Catalyst (^ (%) {%)___

_Λ P-F-Ph-(R)MeBoPhOz-RuCI_{2 QO Ωo}

¹ dmf 25:1 1000 48 88 92

2 " 25:1 2000 40 96 94

^a Reaction conditions: 50 ml Parr Autoclave; 18h, EtOH (2 ml/mmol), H₂ (145 psi), Na(TFA):Catalyst molar ratio. ^b Internal temperature of autoclave measured using temperature probe inserted into sampling well of autoclave. Conversion analysed by HPLC, de measured by chiral HPLC.

Example 10

Influence of Pressure on Asymmetric Hvdroqenation of BocChloroketone using BoPhoz-Ru catalysts.

Some results of this study are shown in Table 10 and 10a. Table 10

Entry Catalyst S/c Pressure Conv. (%) De (%)

(psi) . _________ __ _

94 94

2 (R)MeBoPhoz-RuCI₂-dmf 1000 145 98 93

3 p-F-Ph-(f?)MeBoPhoz-RuCI₂ dmf 1000 70 98 96

4 P-F-Ph-(R)MeBoPhOZ-RuCI₂ dmf 1000 145 98 94

Reaction conditions: Endeavor catalyst system; EtOH (2 ml/mmol), H₂, 55 ⁰C. Conversion analysed by HPLC, de measured by chiral HPLC.

Table 10a. Asymmetric hydrogenation of BocChloroketone using BoPhoz-Ru catalysts with sodium trifluoroacetate as additive using a 50 ml Parr autoclave.⁸

Entry Catalyst Na(TFA): s/c Temp Conv. de

QataJyst _ _ (°^c) _ (^0/?) (T⁰I

_Λ P-F-Ph-(R)MeBoPhOz-R [uUCCII₂₂ dmf 25:1 1000 48 88 92 2 25:1 2000 40 96 94 3 25:1 2500 45 93 93

Example 11

Reduction of BocChloroketone with (RHRuCI(benzene)(MeBoPhoz)lCI

A Parr vessel was charged with (R)-[RuCI(benzene)(MeBoPhoz)]CI (98mg), sodium trifluoroacetate (366mg) and (3S)-3-t-butoxycarbonylamino-1-chloro-4- phenyl-2-butanone (33g) and 220ml of degassed ethanol. After purging cycle, the vessel was heated to 55⁰C and pressurised with hydrogen to 4.5 atm. After completion of reaction (41 h), HPLC analysis showed 96.5% conversion and a 93.7% de in favour of the desired (2R.3S) chloroalcohol.

Example 12 (Comparative)

The reduction of BocChloroketone with a BINAP catalyst (R)-[RuCI2(BINAP)]n at 4.5bar hydrogen (65psi) at 55°C in ethanol, substrate/catalyst ratiol 000:1 gave negligible reaction after 16h. 97.4% starting material, 1.05% product, de 58% in favour of R₁S (dr 3.8:1). The result suggests that Ru-BINAP is not an efficient catalyst for this conversion and the selectivity is poor.

Example 13

Screening of other Ru catalysts

Further screening was carried out using the following ligands:

Ligand B

Ligand C

Ligand D

In a 10ml Schlenk flask (set under an atmosphere of argon) metal precursor (1 equiv) and ligand (1.05 equivalents) were placed and dissolved in 1 ml of freshly distilled solvent. The solution was stirred at room temperature for 30 minutes. BOC Chloroketone was dissolved in solvent to give a 0.5M solution in a tube suitable for parallel screening. The catalyst solution was transferred into the tube and placed in parallel reactor. The autoclave was closed, set under the desired hydrogen pressure and temperature was adjusted to the desired value. After the given reaction time, the reaction was stopped and a sample of the reaction mixture was diluted and directly analyzed by HPLC. Some results of this study are shown in Table 13. Table 13

Ru^* [RuCI₂(p-cymene)]2 Ru^$ [Rul₂(p-cymene)]2

Example 14

fRh(bisphosphine)(NBD)lBF4 - Catalyzed. Asymmetric Hydroqenation of

BocChloroketone

The following ligands coordinated to rhodium were chosen for initial experimental

studies.

P-Phos ) <yl-P-Phos H8-BINAMP SpirOP

Phanephos Xyl-Phanephos MeOXyl-Phanephos Cy-Phanephos 'Pr- Phanepho

DIPFc Me-DUPHOS

DlPAMP

Some results of this study are shown in Table 14.

Table 14

Reaction conditions: 1mmol substrate, S/C ratio = 100/1 , 4ml_ MeOH, unoptimized reaction time 20 hrs.

Example 15

Asymmetric hvdroqenation of BocChloroketone catalyzed by in situ- rRh(bisphosphine)(COD)1OTf

The following ligands coordinated to rhodium were chosen for experimental studies:

,PPh₂

MeBoPhoz EtBoPhoz PCycoBoPhoz ProBoPhoz

Some results of this study are shown in Table 15.

Table 15

Entry Ligand Solvent Conv (%) (HPLC) Product (HPLC) d.e (%) j config

1 (S-Me-BoPhoz) MeOH 98 72 i 2R,3S

2 (S-Et-BoPhoz) MeOH 94 83 I 2R,3S

3 (R-Xyl-PhanePhos) MeOH 100 59 I 2R.3S

Reaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1 , 4mL MeOH, 65°C, 10 bar, unoptimized reaction time 20 hrs. Example 16

Influence of the solvent on the hvdrogenation of BocChloroketone in the presence of rRh(COD21OTf/BoPhoz systems

Some results of this study are shown in Table 16.

Table 16

^aReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1 , 4mL solvent, 65^°C, 10 bar, unoptimized ^• reaction time 20 hrs.

Example 17

Influence of the solvent on the hvdrogenation of BocChloroketone in the presence of fRh(COD21OTf/Xyl-PhanePhos systems Some results of this study are shown in Table 17.

Table 17

Reaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1 , 4mL solvent, 50°C, 10 bar, unoptimized reaction time 20 hrs.

Example 18

Influence of the solvent on the hvdrogenation of BocChloroketone in the presence of rRh(COD2lOTf/Xyl-PhanePhos systems

Some results of this study are shown in Table 18:

Table 18

^aReaction conditions: 1mmol substrate, catalyst generated in situ from the corresponding Rh precursor and R-Xyl-PhanePhos. S/C ratio = 100/1 , 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.

Claims

1. A process for preparing optically active 1 ,2-haloalcohols from an α-haloketone by asymmetric catalytic hydrogenation of α-haloketones comprising: providing a substrate comprising an α-haloketone having the Formula (I):

Formula (I) or its enantiomer, wherein:

X is selected from Cl and Br;

R is selected from optionally substituted aryl groups;

R' is selected from NHR² and NR²R³, wherein R² and R³ are the same or different and are independently selected from hydrogen or from optionally substituted alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups, or from COR⁴, OCOR⁴ and

SO₂R⁴, wherein R⁴ is selected from hydrogen or from optionally substituted alkyl, alkenyl, aryl, alkaryl, alkenaryl, aralkyl, aralkenyl, cycloalkyl, heteroaryl and heteroalkyl groups; and contacting the substrate with a hydrogenation reagent under conditions effective for hydrogenation of the substrate in the presence of a catalyst comprising ruthenium or rhodium coordinated to two phosphine groups on one or more ligands other than BINAP to yield a hydrogenation product being at least predominantly a (2R, 3S) diastereomer.

2. A process according to claim 1 wherein the catalyst comprises a bisphosphine ligand, and the ruthenium or rhodium is coordinated to the two phosphine groups on the bisphosphine ligand.

3. A process according to claim 1 or claim 2 wherein the hydrogenation catalyst comprises a ligand exhibiting both planar and carbon centre chirality.

4. A process according to any one of claims 1 to 3 wherein the hydrogenation catalyst comprises a ligand exhibiting axial chirality.

5. A process according to any one of claims 1 to 4 wherein the two phosphine groups are attached, directly or indirectly, to an aromatic or non-aromatic ring or, respectively, to two different aromatic or non-aromatic rings which may themselves be connected together directly or indireptly through none- phosphine groups, the or each ring to which the phosphine groups are attached not being itself or themselves directly connected to any other aromatic ring (if any) in the ligand compound.

6. A process according to any one of claims 1 to 5 wherein the two phosphine groups are respectively attached, directly or indirectly, to two different aromatic rings which are themselves linked together directly or through non- phosphine substituents thereon, and which are not themselves attached directly to any other aromatic ring (if any) in the compound.

7. A process according to claim 6 wherein the hydrogenation catalyst comprises a ligand of the following general formula:

Phanephos Xyl-Phanephos MeOXyl-Phanephos Cy-Phanephos 'Pr-Phanephos

Ligand D or derivatives, enantiomers or diasteromers thereof.

8. A process according to claim 7 wherein the hydrogenation catalyst comprises a P-Phos ligand.

9. A process according to claim 8 wherein the ligand is:

10. A process according to any one of claims 1 to 6 wherein the two phosphine groups are respectively attached, directly or indirectly, to two different aromatic rings of a metallocene compound.

11.A process according to claim 10 wherein the hydrogenation catalyst comprises a ligand of general formula:.

Ligand B

Fe

-D P''Pr₂

DIPFc or derivatives, enantiomers or diasteromers thereof.

12. A process according to any one of claims 1 to 6 wherein the two phosphine groups are respectively attached, directly or indirectly, to one or more aromatic rings, the or each of which is not itself attached directly to any other aromatic ring (if any) in the compound.

13. A process according to claim 12 wherein the hydrogenation catalyst comprises a ligand of the following general formula:

Me-DUPHOS DIPAMP or derivatives, enantiomers or diasteromers thereof.

14. A process according to any one of claims 1 to 6, or claim 12, wherein the two phosphine groups are attached, directly or indirectly, to one aromatic ring of a metallocene compound.

15. A process according to claim 14 wherein the hydrogenation catalyst comprises a Bophoz ligand, or a ligand of the general formula:

Ligand C or derivatives, enantiomers or diasteromers thereof.

16. A process according to claim 15 wherein the Bophoz ligand has the general formula:

,>^ph₂

MeBoPhoz ProBoPhoz EtBoPhoz

PCycoBoPhoz p-Fluorophenyl-MeBoPhoz

or derivatives, enantiomers or diastereomers thereof.

17. A process according to any one of claims 1 to 6 wherein the two phosphine groups are respectively attached, directly or indirectly, to two different non- aromatic rings which are themselves linked together directly or through non- phosphine substituents thereon.

18. A process according to claim 17 wherein the hydrogenation catalyst comprises a ligand of general formula:

h₂

SpirOP

or derivatives, enantiomers or diasteromers thereof.

19. A process according to any one of claims 1 to 18 wherein X is Cl.

20. A process according to any one of claims 1 to 19 wherein R is phenyl or a substituted phenyl.

21.A process according to any one of claims 1 to 20 wherein R' is a protected amine group.

22.A process according to any one of claims 1 to 21 , which proceeds with a TON of at least about 50,000.

23. A process according to any one of claims 1 to 22, which proceeds with a TOF of at least about 30sec^'1.

24. A process according to any one of claims 1 to 23 wherein the s/c ratio in the reaction mixture is at least about 100/1.

25.A process according to any one of claims 1 to 24 wherein the hydrogenation catalyst is enantiomerically pure.

26.A process according to any one of claims 1 to 24 wherein the hydrogenation catalyst comprises a mixture of two or more enantiomers.

27. A process according to any one of claims 1 to 26 wherein the hydrogenation catalyst does not contain any naphthyl groups.

28.A process according to any one of claims 1 to 27 wherein the hydrogenation catalyst does not contain any BINAP ligands

29.A process according to any one of claims 1 to 28 wherein the hydrogenation reagent comprises hydrogen.

30. A process according to any one of claims 1 to 29 wherein the temperature conditions effective for hydrogenation of the α-haloketone are maintained at from about 15°C to about 12O⁰C.

31.A process according to any one of claims 1 to 30 wherein the pressure conditions effective for hydrogenation of the α-haloketone are maintained at from about 1 bar to about 100 bar.

32. A process according to any one of claims 1 to 31 wherein the substrate is provided in solution, the solvent or mixture of solvents being polar.

33. A process according to any one of claims 1 to 32 wherein an additive is present in the reaction mixture.

34.A process according to claim 33 wherein the additive is sodium trifluoroacetate.

35. Use of a catalyst comprising ruthenium or rhodium coordinated to at least one bisphosphine ligand other than BINAP in the catalytic asymmetric hydrogenation of an α-haloketone in a process according to any one of claims 1 to 34.