Background to the Invention The list of available chiral ligands for asymmetric catalytic transformations continues to grow at a rapid pace, and yet many desirable reactions remain impractical due to the limitations of currently available catalyst systems. In particular, achieving both high rates and high enantioselectivites in catalysis remains a serious challenge that continues to present the principal obstacle to the development of cost-effective asymmetric catalytic processes.

Burk, in Handbook of Chiral Chemicals, ed. Ager, Marcel Dekker, Inc., New York (1999), Chapter 18: 339-59, and references cited therein, reports that ligands composed of 2,5-disubstituted phospholane groups may bestow significant advantages in terms of enantioselectivities in asymmetric catalytic hydrogenation reactions. Unfortunately, catalysts that rendered the highest selectivities (e. g. DuPHOS-Rh and BPE-Rh) often displayed low catalytic rates in the hydrogenation of certain functional groups (e. g. ketones, hindered alkenes, etc.). Burk and Gross, Tet. Lett. 35: 9363 (1994), report that reaction rates could be accelerated by the introduction of more flexible ligand backbones (e. g. 1,3-propano and 1, l'-ferrocenyl bridges), but enantioselectivities fell.

WO-A-98/02445 describes chiral phosphetane ligands as defined by general formula 1, or the opposite enantiomer thereof, wherein R groups are each independently H, alkyl, cycloalkyl, aryl or alkaryl, provided that Rl and R2 are both not H, and X is any group capable of forming a stable bond to phosphorus. In particular, WO-A-98/02445 highlights the synthetic utility of rhodium complexes of monophosphetanes of formula 2, wherein R'= R2, in comparison with five-membered ring analogues of formula 3

WO-A-99/02444 (published after the priority dates claimed in this Application) describes an improved process for the preparation of cyclic phosphines. This involves the addition of strong base to a preformed mixture or reaction product of a primary phosphine and an alkylating agent.

Summary of the Invention Novel ligands according to the present invention are bis (dialkylphosphetano) ferrocenes of formula 4 wherein R is linear or branched alkyl (including the opposite enantiomers thereof).

Unexpectedly, it has been found that these bis (dialkylphosphetano) ferrocenes have especial utility as components of catalysts for asymmetric synthesis. In particular, their transition metal complexes give superior performance in the asymmetric hydrogenation of certain prochiral substrates, in terms of improved enantioselectivity and catalytic activity, when compared with equivalent complexes of alternative known chiral phosphine ligands.

Description of the Invention Preferred ligands of the present invention are those where R is linear alkyl, e. g.

Iinear C, 4 alkyl, more preferably methyl or ethyl, and rhodium (I) complexes thereof. It will be understood by those skilled in the art that the term"alkyl"does not necessarily comprise C and H only, provided that any substituents have no effect on the function of the ligands.

This invention involves asymmetric hydrogenation which is applicable to a variety of substrates, especially those that might otherwise require forcing conditions, or where other ligands give no or little conversion. Examples of such substrates are those with C=C bonds, e. g. tetrasubstituted alkenes and also itaconic acid derivatives such as esters (whether or not p-substituted or ß, ß'-disubstituted), those with C=O bonds, e. g. ketones and a-ketoacids, and those with C=N bonds, e. g. oximes and imines that can be converted to chiral hydroxylamines and chiral amines, respectively. As is evident from the Examples

below, a particular class of substrates that can be hydrogenated according to this invention, has the partial formula C=C (C=O)-C-C=O, especially C=C (COOH)-C-C=O.

The hydrogenation reaction may be conducted under conditions that are known to, or can be determined by, those skilled in the art. Examples are given below.

The novel 1,1'-bis (phosphetano) ferrocenes may be prepared by known procedures, or as generally disclosed in WO-A-99/02444. Suitable reactants are of the formulae which may be reacted in the presence of an alkyllithium, in THF. The cyclic sulfates may be prepared starting from enantiomerically pure 1,3-diols. These diols may be prepared through asymmetric hydrogenation of 1,3-diketones using well-documented procedures involving catalysts such as Ru-BINAP catalysts; see Noyori et al, JACS 110: 629 (1988).

Subsequently, the diols may be converted to 1,3-diol cyclic sulfates through treatment with thionyl chloride followed by Ru-catalyzed oxidation with sodium periodate. Reaction between the cyclic sulfates cyclic sulfates and 1,1'-bis (phosphino) ferrocene in the presence of a strong base such as s-BuLi gives the desired ligands (4). For utilisation as catalysts in asymmetric hydrogenation, rhodium complexes of (4) are of the form [Rh (4) (COD)] BF4, which are prepared by sequential reaction ofRh (COD) acac with COD (1,5-cyclooctadiene), HBF4-OEt2 and the ligand (4).

The invention is further illustrated by the following Examples. Examples 1-5 describe the preparation ofligands offormula (4). Examples 6-10 describe the preparation of the corresponding rhodium complexes. Examples 11-15 describe the use of the complexes as catalysts for asymmetric hydrogenation processes and include comparisons with rhodium complexes of other chiral ligands. Hydrogenation conditions for these examples are shown in individual equations (80 psi = 550 kPa). In all cases, rhodium complexes are of the form [Rh (Ligand) (COD)] BF4 wherein Ligand is a chiral diphosphine ligand. Ligands are denoted by acronyms, as follows: Fc-4-Me, Fc-4-Et, Fc4-Pr, Fc-4-i-Pr and Fc4-t-Bu are ligands (4) of the present invention; and

Fc-5-Me and Fc-5-Et are analogues of (4) containing five-membered phospholane rings, as described by Burk and Gross, supra.

For definitions ofBINAP, bppm, DIPAMP and DuPHOS, see Noyori, in Catalytic Asymmetric Synthesis, ed. Ojima, VCH Inc., New York (1993).

For a definition of PHANEPHOS, see Pye et al., JACS 119: 6207 (1997).

General Procedure 1 Ligands A 500 ml three-necked flask was equipped with magnetic stirrer bar, a dropping funnel on the middle neck, a reflux condenser with bubbler and a septum on the third neck.

In this flask was made up under nitrogen a solution of 8.4 mmol of the cyclic sulphate in 250 mL of THF. The flask was immersed in an ice bath, and the solvent was degassed by bubbling nitrogen through it using a capillary bleed. In the dropping funnel was prepared a solution of 35.2 mmol of s-BuLi in 50 mL of pentane under nitrogen. After 45 minutes of solvent degassing, 2.0 g (8 mmol) of 1,1'-bis (phosphino) ferrocene was added via a syringe to the THF-solution. Then vigorous stirring was started, and the diluted solution ofthe s-BuLi was added dropwise into the vortex. At the end of the addition, the reaction was quenched by the addition of ca. 3 mL of methanol, and the solvent was removed in vacuum. To the residue was added water (ca. 150 mL), and then the ligand was extracted into pentane (2 x 100 mL). Evaporation of the solvent from the dried combined organic layers provided the crude product which was purified further by recrystallisation from methanol.

Example 1 1,1'-Bis ((2R, 4R)-2, 4-dimethyl-phosphetano) ferrocene (referred to herein as (R, R)- Fc-4-Me) was prepared by General Procedure 1, in a crude yield of 3.00 g.

Recrystallisation from ca. 15 mL of methanol gave 0.85 g (27.5%) of yellow plates. 31p NMR (CDC13,162 MHz) 8 16.01.

Example 2 1,1'-Bis ((2R, 4R)-2,4-diethyl-phosphetano) ferrocene (referred to herein as (R, R)- Fc-4-Et) was prepared by General Procedure 1, in a crude yield of 3.2 g. Recrystallisation from 30 mL of methanol gave 1.06 g (30%) as very fine yellow needles. 3lP-NMR (CDCI3, 162 MHz) 8 13.10.

Example 3 1,1'-Bis ((2R, 4R)-2, 4-di-n-propyl-phosphetano) ferrocene (referred to herein as (R, R)-Fc-4-Pr) was prepared by General Procedure 1, in a crude yield of 3.2 g.

Recrystallisation from a mixture of methanol and ethanol gave 1.34 g (33%) as a yellow solid. 3lP-NMR (CDC13,162 MHz) 8 16.04.

Example 4 1,1'-Bis ((2R, 4R)-2, 4-diisopropyl-phosphetano) ferrocene (referred to herein as (R, R)-Fc-4-i-Pr) was prepared by General Procedure 1, in a crude yield of 4.0 g.

Recrystallisation from 20 mL of methanol gave 2.85 g (71.5%) as very fine yellow needles.

3IP-NMR (CDCI3,162 MHz) 8 9.74.

Example 5 1,1'-Bis ((2R, 4R)-2,4-di-tert-butyl-phosphetano) ferrocene (referred to herein as (R, R)-Fc-4-t-Bu) was prepared by General Procedure 1, in a crude yield of 3.4 g.

Recrystallisation from 50 mL of methanol gave 1.12 g (25%) as very fine yellow needles.

3'P-NMR (CDC13,162 MHz) 8 7.63.

General Procedure 2 Rh (I)-tetrafluoroborate catalysts In a Schlenk flask was made up, under nitrogen, a ca. 0.5 N solution of one equivalent of [Rh (COD) acac] in THF. To this solution was added two equivalents of 1,5- cyclooctadiene, and when the mixture had warmed to 50°C, one equivalent of HBF4-OEt2 was added dropwise as a ca. 1 N solution in THF. A slurry of [Rh (COD) 2 BF4 was formed, and to this was added dropwise a solution of one equivalent of the ligand. The [Rh (COD) 2 BF4 dissolved gradually, and the colour of the solution changed from brown to bright red-orange. When the addition was complete, the mixture was kept stirring for another ten minutes. Then ether was added dropwise to the stirred solution until the mixture become turbid. When the catalyst had started to crystallise, more ether was added into the reaction mixture to complete the precipitation of the catalyst. The product was filtered off under nitrogen, washed with a mixture of THF/ether 6: 4 v: v until the filtrate was colourless, and the filtered solid was then dried in vacuo to constant weight.

Example 6 (2R, 4R)-Fc-4-Me-(1, 5-cyclooctadiene)-rhodium (I) tetrafluoroborate was obtained by General Procedure 2, from 0.5 g of ligand in a yield of 0.57g (64.3%). 31P NMR (CDC13,162 MHz) 8 61.46 (d, Jan = 146.5 Hz).

Example 7 (2R, 4R)-Fc4-Et- (1, 5-cyclooctadiene)-rhodium (l) tetrafluoroborate was obtained by General Procedure 2, from 0.6 g of ligand in a yield of 0.90 g (89%)."P-NMR (CDC'3 162 MHz): 8 72.15 (d, JpRh= = 146 Hz).

Example 8 (2R, 4R)-Fc4-Pr-(1, 5-cyclooctadien*rhodiuma) tetrafluoroborate was obtained by General Procedure 2, from 1.1 g of ligand in a yield of 0.40 g (21%). 31P NMR (CDC13 162 MHz): 8 53.27 (d, JpRh = 146 Hz).

Example 9 (2R, 4R)-Fc-4-i-Pr-(1, 5-cyclooctadiene)-rhodium (I) tetrafluoroborate was obtained by General Procedure 2, from 1.0 g of ligand in a yield of 1.35 g (84%). 31p NMR (CDC13 162 MHz): 8 43.86 (d, JpRh = 145.6 Hz).

Example 10 (2R, 4R)-Fc-4-t-Bu- (1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate was obtained by General Procedure 2, from 1.12 g of ligand in a yield of 0.92 g (53%). ³¹P- NMR (CDC13 162 MHz): 8 38.27 (d, Jp,Rh = 141 Hz).

Example 11 Hydrogenation of a-acetamidocinnamic acid H2, MeOH, RT NHAc NHAc s/c 100 * NHAc <02H Rh (Ligand) (COD) ] BF4 ISJ CO2H Table 1 entry Ligand % 1 R, R-Fc-4-Me 75 2 (R,R)-Fc-5-Me 69 3 (R,R)-Fc-4-Et 90 4 R, R-Fc-5-Et 58 As shown in table 1, rhodium complexes containing the ligands (R, R)-Fc-4-Me and (R,R)-Fc-4-Et (entries 1 and 3) gave superior enantioselectivities for this process, compared to those containing (R, R)-Fc-5-Me and (R, R)-Fc-5-Et (entries 2 and 4).

Example 12 Hydrogenation of dimethyl itaconate H2 (80 psi), MeOH (1 M), RT, 1 hr ! t s/c 200-1000 Me s/c 200-1000 Me COzMe Rh (Ugand) (COD)] BF4 MeO2C CO2Me

Table 2 entry Ligand % ee 1 R-Fc-4-Me 91 2 (R, R)-Fc-4-Et 96 3 (R, R)-Fc4-Pr 4 S,-Fc-4-i-Pr 78 5 S,-Fc-5-Me 70 6 S,-Fc-5-Et 66 7 Et-DuPHOS 97 8 DIPAMP 85 9 PHANEPHOS 12 10 bppm 69 Table 2 shows that ligands of the invention, especially Fc-4-Et and Fc-4-Pr (entries 2-3), are very effective for this transformation, affording the product with enantioselectivity comparable to that achieved with Et-DuPHOS (entry 7). All other ligands gave inferior performance. A striking difference is observed between results achieved with the novel ligands, especially n-alkyl variants, and the structural analogues Fc-5-Me and Fc-5-Et (entries 5-6). The advantages conferred by the phosphetane ligands are evident, although the reason for such a significant increase in selectivity upon moving from a five-membered ring to a four-membered phosphorus heterocycle is unclear.

Example 13 Hydrogenation of an inverse itaconate ester H2 (80 psi), MeOH (1 M), RT, 1 hr H s/c2000 Me slc 2000 Me C02H Rh (Ligand) (COD) BF4--C02H (5) Table 3 entryLigand% Conversion% ee 1 (R, R)-Me-DuPHOS 41 2 (SS)-Et-DuPHOS 3 74 3 DIPAMP 3 32 bppm 8 ; 0 25 5 PHANEPHOS >99 26 6 (R, R)-Fc4-Me >99 89 7 (RR)-Fc-4-Et >99 94 8 (R, R)-Fc4-Pr >99 95 (RJR)-Fc-5-Me >99 43 10 (R, R)-Fc-5-Et >99 33 Table 3 reports the results obtained from asymmetric hydrogenation of"inverse" itaconate (5). The term"inverse"refers to the protection pattern of the itaconate, and implies an inverse of ester/acid protection relative to standard Stobbe-derived itaconates.

It can be seen that the rhodium complexes ofDuPHOS, DIPAMP and bppm ligands were inadequate with regard to both catalytic efficiency and enantioselectivity (entries 1-4). In order to test this further, the rhodium catalyst of the PHANEPHOS ligand did render acceptable rates, although ee's were low (entry 5). Likewise, catalysts bearing the Fc-5- Me amd Fc-5-Et ligands were highly active, yet performed poorly in terms of enantioselectivity (entries 9-10). Catalysts based on the novel ligands, especially Fc-4-Et and Fc-4-Pr, were very efficient in this process (entries 6-8).

Example 14 Hydrogenation of a ß-substituted inverse itaconate ester H2 (80 psi), MeOH (1 M), RT, 16 hr f Ií slc 1000 C02H Rh (Ligand) (COD)] BF4 MeO2C * C02H (6)

Table 4

entryLigand% Conversion% ee 1 Fc-4-Et 60 91 2 Fc4-Pr 75 93.5 3 bppm 21 3 Table 4 shows results from hydrogenation of the ß-substituted inverse itaconate ester (6). Rhodium complexes of Fc-4-Et and Fc-4-Pr ligands were found to promote highly enantioselective hydrogenation with good substrate conversion (entries 1-2). In contrast the bppm catalyst was completely ineffective (entry 3).

Example 15 Hydrogenation of ß-substituted inverse itaconate amides 0 CHR O . C H2. C N COZHN * C41H O. J Rh (Ugand) (COD) BF4o. J This process was investigated, since amidosuccinate derivatives of type (8) have served as versatile peptidomimetic intermediates for the construction of various important drug candidates. The substrates represented by formula (7) are another class of "inversely"-protected itaconates.

Results are shown in Tables 5-7. For the specific substrates (9) and (10), tables 5 and 6 compare the performance of the rhodium complex of Fc-4-Et with rhodium complexes of a broad range of alternative ligands. The novel Fc-4-Et catalyst was markedly superior in terms of both rates and enantioselectivities. As shown by the results in Table 7, this catalyst can also accommodate a broad range of ß-substituents in the substrate; in each case, rapid substrate conversion and high enantioselectivity was observed. -Bu-Bu 0 f t-Bu H2 (80 psi), MeOH (1 M), RT, 1 hr O t-Bu s/c 1000, C CN ON. r"JC02H Rh (Ligand) (COD) BF4 Table 5

entryLigand% Conversion% ee 1 Fc-4-Et >99 99 2 Fc-5-Et 45 41 3 Et-DuPHOS 7 89 4 DIPAMP 50. 5 89 5 PHANEPHOS 50 69 6 bppm 98 78 OPh I HZ (80 psi), MeOH (1 M), RT, 1 hr O Ph . C_ s/c 1000 C N v'COZH N C02H oj (10) Rh (Ugarid) (COD) BF4 oj Table 6 entryLigand% Conversion% ee 1 Fc-4-Et >99 98 2 Fc-5-Et 55 70 3 Et-DuPHOS 5 85 4 DIPAMP 10 87 5 PHANEPHOS 60 62 Table 7 entry R t (min) % ee 1 Ph 60 98 2 t-Bu 60 99 3 i-Pr 30 94 4 o-Br-Ph 30 95 5 o-MeS-Ph 15 97 6 o-F-Ph 10 96 (t represents the time to full conversion)