Background of the invention Chiral 2, 2'-bis-Diphenylphosphino-1, 1'bi-2-naphtol (BINAP) introduced by Noyori (J.

Am. Chem. Soc. 1980, 102, 7932) in 1980 has found wide application as a chiral ligand in asymmetric catalysis from laboratory up to industrial scale.

The major drawbacks of the Noyori-BINAP synthesis are a bromination reaction at 240° to 320° C and a late resolution step of a BINAP precursor by crystallization with either camphorsulfonic acid or 2, 3-O-dibenzoyltartaric acid as resolving agent, providing a overall low yield of the desired reagent (Nachr. Chem. Techn. Lab. 1996, 44, 996).

A new procedure by Verhoeven (US Patent 5, 399, 771) circumvents the tedious introduction of the diphenylphosphino group and provides a simpler preparation of BINAP via nickel catalyzed phosphinylation of the corresponding ditriflate of 1, 1'-Bi-2- naphtol (BINOL).

Nevertheless their improved synthesis of BINAP is still based on the resolution of BINOL with trans-1, 2-Diaminocyclohexane as a resolving agent (J. Org. Chem. 1986, 51, 629).

Although steroids are potentially interesting compounds for asymmetric catalysis due to their rigid backbone the synthesis of 4, 4'-bis (steroids) and any application thereof as chiral ligands in asymmetric catalysis is unprecedented so far.

The present invention describes the diastereoselective synthesis of (Ra)-and (Sa)- 4, 4'-bis (3-Diphenylphosphinoestra-1, 3, 5 (10), 6, 8-pentaene) and the application of these new bisphosphines as chiral ligands in metal complexes for the enantioselective hydrogenation of-ketoesters, a--unsaturated acids and dehydroaminoacids.

Detailed description of the invention.

Bissteroidal compounds of general formula I

in which R1 stands for hydrogen, alkyl, acyl, fluorine, and X1 R5, where X1 stands for oxygen and sulfur and R5 can either be hydrogen, alkyl, aryl, R2 stands for hydrogen and alkyl ; the stereochemistry of C-13, C-14 and C-17 may either be a or b, X stands for oxygen, hydroxyl, trifluormethylsulfonyloxy, or (R6) 2P, where R6 can be aryl, alkyl and cycloalkyl, R3 stands for hydrogen, alkyl, aryl, trialkylsilyl, fluorine and X2R6, where X2 stands for oxygen and sulfur and R6 stands for hydrogen, trifluormethylsulfonyl, alkyl, cyloalkyl or aryl.

R4 can either be a substituent in the 6 or 7 position of the steroid with the meaning of hydrogen, alkyl, aryl, fluorine, and X3R7, where X3 stands for oxygen, sulfur or trialkylsilyl and R7 stands for hydrogen, trifluormethylsulfonyl, alkyl or aryl, and the B-ring of the steroid contains none or two double bonds.

Enantio-and Diastereomeric derivatives of compounds of general formula 1.

The alkyl radical of R1-R7 have the meaning of lower alkyl substituents, for example the methyl-, ethyl-, propyl-, 2-methylethyl-, 2-methyl-propyl-, 3-methyl-propyl-, 2, 2- dimethyl-ethyl-or butyl group. The acyl radical of R1 have the meaning of C1-C6- groups, per example acyl-, propionylic-, butyric or hexanoic group. The aryl group radical of R3, R4, R5, R6 and R7 have the meaning of phenyl-, benzyl-or 4-methyl- phenyl substituents. The cycloalkyl radical of R6 has the meaning of a cyclopentyl-or cyclohexyl group. The trialkylsilyl radical of R3 or X3 have the meaning of trimethyl-or tert.-butyldimethylsilyl.

3-Hydroxy-1, 3, 5 (10) 6, 8-estrapentaen-17-one (Equilenin) 1 is submitted to the standard conditions of a Wolff-Kishner reduction (J. Am. Chem. Soc. 1946, 68, 2487) giving Estra-1, 3, 5 (10), 6, 8-pentaen-3-ol 2 in 80-85% yield.

The targets (Ra)-and (Sa)-4, 4'-bis (Estra-1, 3, 5 (10), 6, 8-pentaen-3-ol) (bisequilenol) 3 are prepared from Estra-1, 3, 5 (10), 6, 8-pentaen-3-ol 2 via metal catalyzed phenolic coupling.

The coupling is performed with catalytic amounts of a copper-amine complex in methylenechloride under an oxygen atmosphere (Tetrahedron Lett. 1994, 35, 7983). generating the diastereomers S-3 and R-3. In contrast to the Noyori BINOL synthesis these two diastereomers can be easily separated by flash chromatography thus avoiding the lengthy resolution of enantiomers with an additional resolution agent.

The absolute configuration of the new ligands (Ra)-and (Sa)-4, 4'-bis (Estra- 1, 3, 5 (10), 6, 8-pentaen-3-ol) 3, (Ra)-and (Sa)-4, 4'-bis (Estra-1, 3, 5 (10)-trien-3-ol) 5 and (Ra)-and (Sa)-4, 4'-bis (3-diphenylphosphinoestra-1, 3, 5 (10), 6, 8-pentaene) 7 were determined by CD spectroscopy in comparison to the CD spectra of the ligand (Ra)- bis (17-beta-Methoxyestra-1, 3, 5 (10)-trien-3-ol) R-4 whose absolute configuration was determined by X-ray crystallography.

Furthermore the diastereoselectivity of the coupling shows a temperature dependance favouring the R-isomer at room temperature with a diasteromeric excess of 50%. At lower temperature the selectivity is inverted, favouring the S-isomer with almost the same diasteromeric excess (Table 1). In order to make both isomers available the coupling is performed at 0° C providing both diastereomers in a combined yield of 92-96%.

Table 1. Dependence of the diasteroselectivity of the copper mediated coupling on the temperature Temperature (° C) S-3R-3 +20 1 3 0 1 1, 5 -20 3 1

The intriguing feature of these new compounds R-3 and S-3 is that they behave as true enantiomers in any type of asymmetric reactions despite of their diastereomeric nature.

This was first shown testing the set of bissteroids 3-5 in enantioselective reductions of acetophenone following the Noyori protocol (J. Am. Chem. Soc. 1979, 101, 3129) ; (Table 2).

Table 2. Enantioselective reductions of acetophenone induced by bissteroid ligands Li and % ee/Confi uration Tem erature (°C) Conversion (%) a R-3 92, 5/R-45 > 95 S-3 67/S-45 > 95 R-4 96, 5/R-90 > 95 R-5 85, 2/R-50-30 > 95

a) determined by GC The results in table 2 show that the new bissteroids are as powerful as reducing agents as Noyori's BINOL. The lower enantiomeric excess for the ligands 3 and 5 are due to solubility problems at very low temperatures which prevent the reduction to be carried out at-90° C as in the Noyori protocol. With ligand 4, which is completely soluble at-90° C the same enantiomeric excess in the reduction of acetophenone is achieved as Noyori.

The absolute configuration of the reduction products is also the same as in the Noyori reduction.

As expected the reduction with the two diasteromeric ligands R-3 and S-3 produce the opposite enantiomers of the reduction product.

The bissteroids R-/S-4 and R-/S-5 were prepared by copper mediated coupling (Tetrahedron 1992, 48, 2579) of the lithiated 4-Bromo-17p-methoxy-3- methoxymethoxyestra-1, 3, 5 (10)-triene (Tetrahedron 1991, 47, 2871) 11 and 4-Bromo- 3-methoxymethoxyestra-1, 3, 5 (10)-triene 14.

Furthermore the diasteromeric ligands R-3 and S-3 were incorporated into the chiral titanium catalysts R-Ti-1 and S-Ti-1 (Tetrahedron Lett. 1991, 32, 6571). These catalysts were then applied as chiral lewis acids for the enantioselective cyclization of Methylsecone, yielding 3-Methoxyestra-1, 3, 5 (10), 8, 14-pentaene-17-one in remarkably high yield and enantiomeric excess (Table 3).

R-Ti-l X=BF4 S-Ti-l X=BF4

Table 3. Enantioselective cyclization of methyl-secone with R-Ti-1 and S-Ti-1. catal st ield % ee (%)/configuration R-Ti-1 72 70/S S-Ti-1 60 54/R

Most interestingly, the catalysts R-Ti-1 and S-Ti-1 afford the product 3-Methoxyestra- 1, 3, 5 (10), 8, 14-pentaene-17-one due to their diastereomeric nature with a different chemical and optical yield each.

The synthesis of (Ra)-and (Sa)-4, 4'-bis (3-Trifluoromethylsulfonyloxyestra- 1, 3, 5 (10), 6, 8-pentaene) 6 was accomplished by triflation of R-/S-3 with triflic acid anhydride in the presence of pyridine in quantitative yield.

R-/S-3 R-/S-6 The triflate 6 was then converted into the bisphoshine 7 without any isomerisation of the diastereomers in 83% yield.

R-/S-6 R-/S-7 Starting with Equilinin 1 both bisphosphines R-7 and S-7 are available in 4 chemical steps in an overall yield of 64%.

The epimeric phosphines Epi-R-7 and Epi-S-7 are available according to a similar synthetic sequence starting with 14-Epi-equilenine 14-Epi-1 (Tetrahedron Lett. 1971, 4179).

14-epi-1 14-epi-R-/S-6 14-epi-R-/S-6 14-epi-R-/S-7

The new phosphines R-7 and S-7 were tested as chiral ligands in a ruthenium complex for the asymmetric hydrogenation of methyl-acetoacetate, N-acetyl-cinnamic acid and tiglic acid as representative examples (Table 3).

The chiral ruthenium complex is prepared by heating the bisphosphines R-/S-7 with [RuCI2 (benzene)] 2 in DMF (Tetrahedron Lett. 1991, 32, 4163).

Table 3. Asymmetric hydrogenation of Methyl-acetoacetate and N-Acetyl-cinnamic acid Substrate R-7 (% ee) S-7 (% ee) conversion (yield) BINAP (conv%) methyl-acetoacetate > 99* > 99* 100 (98) >98 (100) * N-acetyl-cinnamic acid 85, 7** 85, 7** 100 (96) 77 (90) **** tiglic acid 90, 5*** 90, 5*** >96 (92) 87, 5 (44) ***

*1 h/100 atm/100°C ; **48h/7atm ; ***24 h/4atm ; ****96h/7 atm ; The new chiral complexes synthesized from [RuCl2 (benzene)] 2 and the bissteroidal ligands 7 are more powerful than the state-of-the-art BINAP-ruthenium complexes of

Noyori as they are of broader applicability and allow the preparation of a range of substrates of extraordinary high enantiomeric purity in a quantitative yield.

In addition the new bissteroidal ligands 3-5 have proven to be highly effective for the enantioselective reduction of ketones exemplified by the reduction of acetophenone and to be highly effective chiral lewis acids exemplified by the enantioselective cyclization of methyl-secone.

Preparative Examples Optical rotations were measured on a Perkin Elmer 241 Polarimeter, melting points are not corrected ; 1 H-NMR (300 MHz), and 13C-NMR (75 MHz) spectra were taken on General Electric QE 300 in CDC13 as a solvent and internal reference (7. 28 ppm, 81. 9 ppm) ; J values are given in Hz ; IR spectra were taken on Nicolet 20 SBX ; Mass spectra were recorded on TRI02 ; TLC were performed on Merck 60 F 254. Silica gel 60G (240-400 mesh) was used for column chromatography. All reactions were carried out under dry nitrogen or argon.

1. Synthesis of the phosphines R-/S-7 : 1. A suspension of 53, 15 g 3-Hydroxy-1, 3, 5 (10) 6, 8-estrapentaen-17-one 1 (0, 199 mmoles) in 36, 3 mi hydrazine hydrate, 435 ml diethyleneglycol and 36, 5 g NaOH (0, 91 mole) is heated on an oil bath to 120° C. After stirring at this temperature for 0, 5 hour the temperature is increased to 180°-190° C and stirred for additional 8 hrs. After cooling to room temperature the solution is added to 500 ml of ice cooled water and then acidified with conc. HCI to pH 0. The precipitate is filtered off, dried and the crude product is recrystallized from water-ethanol 1 : 1 (100 ml each) giving 42, 7 g Estra- 1, 3, 5 (10), 6, 8-pentaen-3-ol 2 (85%) ; mp = 136, 5°-139°C ; [a] 365 = + 228. 7° (c=10. 2 in THF).

2. To a solution of Estra-1, 3, 5 (10), 6, 8-pentaen-3-ol 2 (10g, 20mmol) in CH2CI2 (300 ml) was added CuCI (OH)-TMEDA (0. 800 g, 0. 35 mmol) and the solution was stirred at 0°C for 10-15 min while bubbling oxygen through the mixture. The reaction was monitored by TLC. At the end of the reaction HCI (10%, 5 ml) was added to the mixture and stirred for additional 15 min (the colour was changed from blue to yellow).

The mixture was filtered and the residue was dried under vacuum to give crude product (5 g). From the filtrate after extraction with CH2CI2 (3 X 10 ml) was isolated additionally 4. 8 g product which was combined with the first fraction. The crude mixture was separated to give 5. 9 g (Ra)-4, 4'-bis (estra-1, 3, 5 (10), 6, 8-pentaen-3-ol) 3 (59%) as main isomer ; m. p. 207, 4-207, 5°C ; [a] 365 = + 303. 13° (c=1. 6 in THF) ; 1 H-NMR : 8. 15 (1H, d, J=10. 0 Hz), 7. 38 (1H, d, J=10. 0 Hz), 7. 09 (1H, d, J=7. 5 Hz), 7. 01 (1H, d, J=7. 5 Hz), 4. 98 (1H, s, OH), 0. 70 (3H, s) ; 13C-NMR : 151. 3 (s), 135. 2 (s), 131. 8 (s), 130. 9 (s), 127. 6 (s), 126. 5 (d), 126. 1 (d), 122. 0 (d), 116. 8 (d), 111. 7 (s), 49. 7 (d), 40. 4 (s), 38. 7 (t), 35. 8 (t), 25. 2 (t), 24. 7 (t), 20. 9 (t), 16. 2 (q) ; MS-CI : 520 (100, M+ + 1+ NH3), 503 (90, M+) ; MS-EI : 502 (100, M+), 389 (5), 235 (10), 195 (5), 157 (7) ;

and 3. 7 g (Sa)-4, 4'-bis (Estra-1, 3, 5 (10), 6, 8-pentaen-3-ol) 3 as minor isomer (37%), m. p. 287, 0°C decomp. (Hexane) ; [a] 365 =+ 145. 18° (c=1. 4 in THF) ; 1H-NMR : 8. 10 (1H, d, J=9. 0 Hz), 7. 32 (1H, d, J=9. 0 Hz), 7. 05 (1H, d, J=6. 0 Hz), 6. 98 (1H, d, J=6. 0 Hz), 5. 10 (1H, s, OH), 0. 70 (3H, s) ; 13C-NMR : 151. 3 (s), 135. 1 (s), 131. 6 (s), 130. 9 (s), 127. 6 (s), 126. 5 (d), 126. 1 (d), 121. 8 (d), 116. 8 (d), 111. 7 (s), 49. 7 (d), 40. 4 (s), 38. 7 (t), 35. 8 (t), 25. 2 (t), 24. 7 (t), 20. 9 (t), 16. 2 (q) ; MS-CI : 520 (88, M+ + 1+ NH3), 503 (100, M+) ; MS-EI : 502 (100, M+), 389 (5), 251 (6), 235 (10), 195 (5), 157 (7) ; 3. To a solution of (Sa)-4, 4'-bis (Estra-1, 3, 5 (10), 6, 8-pentaen-3-ol) 3 (1. 8 g, 3. 6 mmol) in toluene-pyridine 15 : 1 (30 ml) was added over period of 30 min dropwise triflic anhydride and mixture was stirred for additional 30 min. The solution was diluted with water, the organic layer was washed with brine, dried with Na2SO4 and the solvent was evaporated. The residue was filtered through Si02 to yield crude product (2. 8 g) which after crystallisation from hexane gave 2, 5 g pure triflate (Sa)-4, 4'-bis (3- Trifluoromethylsulfonyloxyestra-1, 3, 5 (10), 6, 8-pentaene) 6 (90%), m. p. =+168. 2°C ; [a] D=-97. 6° (c= 1. 7 in THF), 1H-NMR : 8. 25 (1H, d, J=10. 0 Hz), 7. 58 (1H, d, J=10. 0 Hz), 7. 12 (1H, d, J=9. 0 Hz), 7. 01 (1H, d, J=9. 0 Hz), 0. 65 (3H, s) ; 13C-NMR : 144. 3 (s), 138. 5 (s), 131. 6 (s), 130. 9 (s), 130. 7 (s), 126. 9 (d), 126. 6 (d), 124. 3 (d), 123. 5 (s), 118. 2 (d), 49. 9 (d), 40. 3 (s), 38. 6 (t), 35. 6 (t), 24. 9 (t), 24. 7 (t), 20. 8 (t), 16. 2 (q) ; 19F- NMR : 87. 12 ; MS-CI : 784 (3, M+ + 1+ NH3), MS-EI : 766 (100, M+), 633 (7) 483 (85), 389 (6), 309 (7), (Ra)-4, 4'-bis (3-Trifluoromethylsulfonyloxyestra-1, 3, 5 (10), 6, 8-pentaene) 6 : The compound was synthezised according to the same procedure as (Sa)-4, 4'-bis (3- Trifluoromethylsulfonyloxyestra-1, 3, 5 (10), 6, 8-pentaene) 6 to give after recrystallisation pure compound ; m. p. =201. 9°C. [a] D=-88. 2° (c= 1. 0 in THF), 1 H-NMR : 8. 25 (1 H, d, J=10. 0 Hz), 7. 59 (1H, d, J=10. 0 Hz), 7. 12 (1 H, d, J=9. 0 Hz), 7. 01 (1H, d, J=9. 0 Hz), 0. 66 (3H, s) ; 13C-NMR : 144. 3 (s), 138. 5 (s), 131. 6 (s), 131. 0 (s), 130. 7 (s), 126. 9 (d), 126. 8 (d), 124. 3 (d), 123. 5 (s), 118. 2 (d), 49. 9 (d), 40. 3 (s), 38. 6 (t), 35. 6 (t), 24. 9 (t), 24. 7 (t), 20. 8 (t), 16. 2 (q) ; 19F-NMR : 87. 12 ; MS-CI : 784 (8, M+ + 1+ NH3), MS-EI : 766 (100, M+), 633 (7) 483 (75), 389 (6), 309 (7), 4. To solution of NiCl2dppe (0. 070 g, 0. 13 mmol) in dimethyl acetamide (2 ml) was added diphenylphosphine (0. 13 ml, 0. 75 mmol) at room temperature, and the solution was heated to 100°C. After 45 min, a solution of triflate (Ra)-or (Sa)-4, 4'-bis (3- Trifluoromethylsulfonyloxyestra-1, 3, 5 (10), 6, 8-pentaene) (1g, 1. 3mmol) and 1, 4- diazabicyclo [2. 2. 2] octane (0. 62 g, 5. 5 mmol) in dimethyl acetamide (4 ml) was added at once, the resulting green solution was kept at 100°C and three additional portions of

diphenylphosphine (3 X 0. 13 ml) were added at 1, 3 and 5 h later. The reaction was kept at 100°C for six days and then the dark brown solution was diluted with MeOH.

The desired product was filtered and the filter cake was washed with MeOH and dried under vacuum. The crude product (0. 820 g, 80%) was recrystallised from MeOH/Tol 10 : 1 to give 0. 78 g pure phosphine (Ra)-4, 4'-bis (3-Diphenylphosphinoestra-1, 3, 5 (10), 6, 8-pentaene) 7 : (70%), 1H-NMR : 8.

05 (1H, d, J=10. 0 Hz), 7. 42 (1H, brd, J=10. 0 Hz), 7. 3-6. 9 (10H, m) 6. 50 (2H, ABq, J=8. 0 Hz), 3. 30 (2H, brd, J=8. 5Hz), 2. 63 (1H, dd, J= 5. 1, 11. 0 Hz), 2. 2-1. 3 (7H, m), 0. 70 (3H, s) ; 13C-NMR : 145. 8 (s), 138. 8 (s), 137. 4 (s), 133. 6 (s), 132. 6 (s), 131. 6 (s), 130. 6 (s), 130. 1 128. 3, 128. 2, 127. 6, 125. 7, 124. 9, 123. 3, 50. 3 (d), (each d), 40. 7 (s), 39. 0 (t), 36. 1 (t), 25. 4 (t), 24. 9 (t), 21. 2 (t), 16. 8 (q) ; 31 P-NMR :-15. 42 (s) ; MS-CI : 784 (8, M+ + 1+ NH3), MS-EI : 766 (100, M+), 633 (7) 483 (75), 389 (6), 309 (7), (Sa)-4, 4'-bis (3-Diphenylphosphinoestra-1, 3, 5 (10), 6, 8-pentaene) 7 : (70%), [a] D = ~ 97. 6° (c = 0. 17 in THF), 1H-NMR : 7. 92 (1H, d, J=10. 0 Hz), 7. 39 (1H, brd, J=10. 0 Hz), 7. 3-6. 9 (1 OH, m), 6. 75 (2H, ABq, J=8. 0 Hz), 3. 38 (1 H, dd, 5. 6, 21. 0 Hz), 3. 22 (1 H, m), 2. 72 (1H, dd, 6. 5, 11. 6 Hz), 2. 12 (2H, m), 1. 9-1. 3 (5H, m), 0. 55 (3H, s) ; 13C-NMR : 146. 2 (s), 137. 6 (s), 133. 5 (s), 133. 1 (s), 132. 5 (s), 131. 8 (s) 131. 5 (s), 130. 0 (d), 129. 9 (s), 127. 6, 127. 5, 126. 9, 125. 5, 124. 8, 122. 9 50. 0 (each d), 40. 3 (s), 38. 7 (t), 35. 8 (t), 25. 0 (t), 24. 6 (t), 20. 8 (t), 16. 4 (q) ; 31P-NMR :-14. 42 (s) ; MS-CI : 784 (8, M+ + 1+ NH3), MS-EI : 766 (100, M+), 633 (7) 483 (75), 389 (6), 309 (7).

2. Synthesis of the phosphines Epi-R-/S-7 : 1. To a suspension of 14-Epi-3-hydroxy-1, 3, 5 (10) 6, 8-estrapentaen-17-one 14- Epi-1 (10g, 38mmol) in CH2CI2 (300 ml) was added CuCI (OH)-TMEDA (0. 800 g, 0. 35 mmol) and the solution was stirred at 0°C for 10-15 min while bubbling oxygen through the mixture. The reaction was monitored by TLC. At the end of the reaction HCI (10%, 5 ml) was added to the mixture and stirred for additional 15 min (the colour was changed from blue to yellow). The organic layer was washed with brine, dried and the solvent was evaporated. The crude mixture (9. 9 g) was separated to give 5. 2 g (Ra)- 4, 4'-bis (14-Epi-3-hydroxy-1, 3, 5 (10) 6, 8-estrapentaen-17-one) (52%) ; m. p. 293°C decomp. ; [a] 365 = + 139. 5° (c=2. 4 in THF) ; 1 H-NMR : 8. 17 (1 H, d, J=9. 3 Hz), 7. 38 (1H, d, J=9. 3 Hz), 7. 07 (1H, d, J=8. 5 Hz), 6. 98 (1H, d, J=8. 5 Hz), 4. 85 (1H, s, OH), 1. 50 (3H, s) ; MS-CI : 520 (100, M+ + 1+ NH3), 503 (90, M+) ; MS-EI : 530 (100, M+), 474 (15), 209 (20), 181 (25), 165 (20) ; and 4. 3 g (Sa)-4, 4'-bis (14-Epi-3-hydroxy-1, 3, 5 (10) 6, 8-estrapentaen-17-one) (43%), m. p. 180°C decomp. (Hexane) ; [a] 365 = + 154. 0° (c=2. 0 in THF) ;

1 H-NMR : 8. 15 (1H, d, J=9. 3 Hz), 7. 42 (1H, d, J=9. 3 Hz), 7. 15 (1H, d, J=8. 6 Hz), 7. 05 (1H, d, J=8. 6 Hz), 4. 98 (1H, s, OH), 1. 19 (3H, s) ; MS-CI : 520 (88, M+ + 1+ NH3), 503 (100, M+) ; MS-EI : 530 (100, M+), 474 (15), 209 (36), 181 (38), 165 (40) ; 2. To a solution of (Sa)-4, 4'-bis (14-Epi-3-hydroxy-1, 3, 5 (10) 6, 8-estrapentaen-17- one) (2. 2 g, 4. 2 mmol) and N-ethyldiisopropylamine (4ml, 23 mmol) in Toluene (60 ml) was added over period of 30 min dropwise triflic anhydride (3. 6 mi, 10 mmol). The mixture was stirred for 30 min. at room temperature and then heated to 60°C and kept at this temperature for 3 hours. At the end of the reaction the mixture was cooled down and the upper (toluene) layer was separated and washed with water, 2N HCI and brine, dried with Na2SO4 and the solvent was evaporated. The residue was dissolved in ethanol (30 ml) and exposed to hydrogen (1 atm) in the presence of PtO2 (0. 2 g) for 2h. The mixture was filtered through a pad of celite, the solvent was evaporated and the crude product was dissolved in ethyl acetate. The solution was washed with NaHCO3, brine and dried with Na2SO4. The solvent was evaporated and the crude product was separated on a Si02 to yield (Sa)-4, 4'-bis (14-Epi-3- trifluoromethylsulfonyloxyestra-1, 3, 5 (10), 6, 8-pentaene) 14-Epi-S-6 (2. 6 g) (86%), mp=115-116°C ; [a] D= + 128. 8° (c= 0. 1 in THF), 1 H-NMR : 8. 28 (1 H, d, J=10. 0 Hz), 7. 60 (1H, d, J=10. 0 Hz), 7. 12 (1H, d, J=9. 0 Hz), 6. 98 (1H, d, J=9. 0 Hz), 1. 10 (3H, s) ; 3C-NMR : 144. 8 (s), 139. 2 (s), 132. 0 (s), 131. 4 (s), 130. 7 (d), 130. 4 (s), 126. 6 (d), 124. 5 (d), 120. 3 (s), 118. 5 (d), 50. 7 (d), 40. 7 (t), 39. 3 (s), 35. 4 (t), 31. 4 (t), 25. 7 (q), 23. 2 (t), 22. 7 (t) ; MS-CI : 784 (100, M+ + 1+ NH3), MS-EI : 766 (80, M+), 633 (17) 483 (100), 387 (21), 308 (17), (Ra)-4, 4'-bis (14-Epi-3-trifluoromethylsulfonyloxyestra-1, 3, 5 (10), 6, 8-pentaene) 14-Epi- R-6 : The compound was synthesised according to the same procedure as (Sa)-4, 4'-bis (14- Epi-3-trifluoromethylsulfonyloxyestra-1, 3, 5 (10), 6, 8-pentaene) 14-Epi-S-6 to give after recrystallisation pure compound ; m. p. =204-204. 5°C, [a] D=-23. 9° (c=0. 1 in THF), 1 H- NMR : 8. 28 (1H, d, J=10. 0 Hz), 7. 60 (1H, d, J=10. 0 Hz), 7. 11 (1H, d, J=9. 0 Hz), 7. 01 (1H, d, J=9. 0 Hz), 1. 10 (3H, s) ; 13C-NMR : 144. 3 (s), 139. 2 (s), 132. 0 (s), 131. 4 (s), 130. 8 (d), 130. 5 (s), 127. 0 (d), 124. 6 (d), 124. 9 (s), 118. 5 (d), 50. 6 (d), 40. 6 (t), 39. 6 (s) 35. 4 (t), 31. 5 (t), 25. 7 (q), 23. 3 (t), 22. 8 (t), MS-CI : 784 (88, M+ + 1+ NH3), MS-EI : 766 (100, M+), 633 (17) 483 (75), 389 (26), 309 (7), 3. To solution of NiCl2dppe (0. 070 g, 0. 13 mmol) in dimethyl acetamide (2 ml) was added diphenylphosphine (0. 13 ml, 0. 75 mmol) at room temperature, and the solution was heated to 100°C. After 45 min, a solution of triflate (Ra)-or (Sa)-4, 4'-bis (14-Epi-3-

trifluoromethylsulfonyloxyestra-1, 3, 5 (10), 6, 8-pentaene) (1g, 1. 3mmol) and 1, 4- diazabicyclo [2. 2. 2] octane (0. 62 g, 5. 5 mmol) in dimethyl acetamide (4 mi) was added at once, the resulting green solution was kept at 100°C and three additional portions of diphenylphosphine (3 X 0. 13 ml) were added at 1, 3 and 5 h later. The reaction was kept at 100°C for six days and then the dark brown solution was diluted with MeOH.

The desired product was filtered and the filter cake was washed with MeOH and dried under vacuum. The crude product (0. 820 g, 80%) was recrystallised from MeOH/Tol 10 : 1 to give 0. 78 g pure phosphine.

(Sa)-4, 4'-bis (14-Epi-3-diphenylphosphinoestra-1, 3, 5 (10), 6, 8-pentaene) 14-pi-7 : (89%), [a] D =-79. 3° (c = 0. 13 in THF), 1H-NMR : 7. 98 (1H, d, J=10. 0 Hz), 7. 36 (1H, brd, J=10. 0 Hz), 7. 3-6. 9 (10H, m), 6. 52 (2H, s), 3. 12 (1H, dt, 3. 2, 21. 0 Hz), 2. 95 (1H, m), 2. 52 (1H, t, 7. 5 Hz), 2. 1 (2H, m), 1. 7 (1H, m), 1. 9-1. 3 (5H, m), 0. 98 (3H, s) ; 13C-NMR : 146. 4 (s), 146. 0 (s), 138. 2 (s), 133. 1 (s), 132. 8 (s), 132. 0 (s) 129. 5 (s), 129. 9 (s), 130. 3 128. 8, 128. 3, 127. 9, 127. 4, 125. 6, 123. 2 50. 0 (each d), 40. 3 (s), 38. 7 (t), 35. 8 (t), 25. 0 (t), 24. 6 (t), 20. 8 (t), 16. 4 (q) ; 31 P-NMR :-15. 2 (s) ; 3. Synthesis of (Ra)-bis (17 beta-Methoxyestra-1, 3, 5 (10)-trien-3-ol) 4 and (Ra)-4, 4'- bis (Estra-1, 3, 5 (10)-trien-3-ol) 5

3. 1 Synthesis of (Ra)-bis (17 beta-Methoxyestra-1, 3, 5 (10)-trien-3-ol) 4 : 1. To solution of 4-Bromo-3-hydroxyestra-1, 3, 5 (10)-trien-17-one 8 (20g, 51 mmol) in dimethyl formamide (250 ml) was added t-BuOK (7. 7g, 74 mmol) at 0°C. The mixture was stirred for 5 min and then a solution of methoxymethyl chloride (5. 5 g, 68 mmol) in dimethyl formamide (15 ml) was added dropwise at the same temperature and stirred for additional 1 h. The reaction was quenched with saturated NH4CI and diluted with water (130 ml). The crude product was filtered and recrystallized from ethanol to give 21. 5 g pure 4-Bromo-3-methoxymethoxyestra-1, 3, 5 (10)-trien-17-one 9 (95. 5%) ; m. p. 172° ; 2. 4-Bromo-3-methoxymethoxyestra-1, 3, 5 (10)-trien-17-one 9 (20 g) was reduced with 10, 6 g NaBH4 (15 mmoles) in 300 ml methanol to give the alcohol 4-Bromo-3- methoxymethoxyestra-1, 3, 5 (10)-trien-17-beta-ol 10 (20g) which was used without purification for the next step.

3. To solution of 4-Bromo-3-methoxymethoxyestra-1, 3, 5 (10)-trien-17 beta-ol 10 (20g, 50 mmol) in DMF (250 ml) was added t-BuOK (7. 9 g, 75 mmol) at 0°C. The mixture was stirred for 5 min and then a solution MeJ (9. 2 g, 65 mmol) in dimethyl formamide (15 ml) was added dropwise at the same temperature and stirred for additional 15 h. The reaction was quenched with saturated NH4CI and diluted with water (130 ml). The crude product was filtered and recrystallized from ethanol to yield 19. 7 g 4-Bromo-17 beta-methoxy-3-methoxymethoxyestra-1, 3, 5 (10)-trien 11 (94%) ; [a] 365 = + 49, 6° (c=1 in THF) ; 1H-NMR : 7. 18 (1H, d, J=9. 0 Hz), 6. 95 (1H, d, J=9. 0 Hz), 5. 22 (2H, s), 3. 52 (3H, s), 3. 48 (3H, s), 3. 30 (1 H, t, J=7. 5 Hz), 2. 98 (1 H, dd, J=5. 8, 19. 5 Hz), 2. 70 (1H, m), 0. 75 (3H, s) ; 13C-NMR : 151. 3 (s), 137. 3 (s), 135. 8 (s), 124. 4 (d), 115. 9 (s), 113. 0 (d), 94. 9 (t), 90. 4 (d), 57. 4 (d), 55. 9 (s), 49. 9 (d), 43. 8 (d), 42. 8 (s), 37. 6 (t), 37. 4 (d), 30. 8 (t), 27. 4 (t), 27. 1 (t), 26. 3 (t), 22. 7 (t), 11. 1 (q) ; Anal. Calcd. (C21 H2903Br) C-61. 75, H-7. 16, O- 11. 76, Br-19. 52 ; Found : C-60. 95, H-7. 80, 0-11. 72, Br-19. 60.

4. To solution of 4-Bromo-17-beta-methoxy-3-methoxymethoxyestra-1, 3, 5 (10)- trien 11 (10 g, 24. 4 mmol) in THF (250 ml) was added BuLi (16 ml, 1. 6 M, 26 mmol) at -60°C. The mixture was stirred for 30 min and then a suspension of CuCN (1. 1 g, 12 mmol) in THF (25 ml) was added at the same temperature. The stirring was continued for additional 2. 5 h until no CuCN was visible at the bottom of the flask. After cooling to -100°C dry oxygen was passed through the mixture for 15 min. which resulted in a deep purple colour. The oxygen flow was disconnected and the reaction mixture was stirred for additional 30 min at this temperature and then quenched with saturated NH4CI and diluted with diethyl ether (100 ml). The organic layer was washed with brine, dried with Na2SO4 and the solvent was evaporated. The crude mixture (7. 8 g) was crystallized from ethyl acetate-hexanes 8 : 1. The solid product was filtered and dried to give 2. 9 g of pure isomer (Ra)-4, 4'-bis (17-beta-Methoxy-3- methoxymethoxyestra-1, 3, 5 (10)-triene) 12 (36%). The filtrate was evaporated and the residue was separated by chromatography on Si02 (hexane : diethyl ether-6 : 1) to give additional product (0. 2 g, 2%) which was combined with a first one and used without further purification.

1 H-NMR (crude) : 7. 28 (1H, d, J=9. 0 Hz), 7. 05 (1H, d, J=9. 0 Hz), 5. 09 (1H, d, J=6. 0 Hz), 4. 95 (1 H, d, J=6. 0 Hz), 3. 48 (3H, s,), 3. 30 (1 H, t, J=8. 5 Hz), 3. 30 (3H, s), 0. 80 (3H, s) ; 13C-NMR : 151. 7 (s), 136. 1 (s), 134. 1 (s), 126. 3 (s), 124. 6 (d), 111. 9 (d), 94. 2 (t), 81. 5 (d), 55. 2 (d), 52. 9 (s), 50. 0 (d), 44. 0 (d), 42. 9 (t), 37. 9 (d), 36. 5 (t), 30. 3 (t), 26. 9 (t), 25. 9 (t), 22. 7 (t), 16. 2 (q) ;

5. To solution of (Ra)-4, 4'-bis (17-beta-Methoxy-3-methoxymethoxyestra-1, 3, 5 (10)- triene) 12 (2g, 3 mmol) in Methanol/THF/H2O 1 : 1 : 0. 2 (20 ml) was added concentrated HCI (3mi) the mixture was stirred for 25 h at rt. The reaction mixture was neutralized with saturated NaHC03 and diluted with ethyl ether (50 ml). The organic layer was washed with brine, dried with Na2SO4 and the solvent was evaporated. The crude product (1. 3 g, 78%) was recrystalised from Hexane ethyl ether 1 : 1 to give 1. 1 g (Ra)- bis (17-beta-Methoxyestra-1, 3, 5 (10)-trien-3-ol) 4 (70%) ; m. p. 181°C, [a] 365 =-96. 30° (c=1. 54 in THF) ; 1H-NMR : 7. 25 (1H, d, J=10. 0 Hz), 6. 82 (1H, d, J=10. 0 Hz), 4. 72 (1H, s, OH), 3. 38 (3H, s), 3. 32 (1H, t, J=7. 5 Hz),, 0. 80 (3H, s) ; 13C-NMR : 150. 7 (s), 136. 6 (s), 133. 3 (s), 126. 8 (d), 124. 6 (s), 112. 9 (d), 90. 4 (d), 57. 5 (d), 50. 0 (s), 43. 8 (d), 42. 8 (t), 37. 8 (d), 37. 6 (t), 27. 3 (t), 26. 9 (t), 26. 7 (t), 22. 6 (t), 11. 2 (q) ; Anal. Calcd.

(C38H5004) C-79. 96, H-8. 83, Found : C-79. 46, H-7. 90.

3. 2 Synthesis of (Ra)-4, 4'-bis (Estra-1, 3, 5 (10)-trien-3-ol) 5 : 1. To solution of 4-Bromo-3-hydroxy-estra-1, 3, 5 (10)-triene (20g, 60 mmol) in dimethyl formamide (250 ml) was added t-BuOK (9. 3g, 89 mmol) at 0°C. The mixture was stirred for 5 min and then a solution methoxymethyl chloride (6. 3 g, 78 mmol) in DMF (15 ml) was added dropwise at the same temperature and stirred for additional 1 h. The reaction was quenched with saturated NH4CI and diluted with water (130 ml).

The crude product was filtered and recrystallized from ethanol to give 20. 4 g 4-Bromo- 3-methoxymethoxy-estra-1, 3, 5 (10)-triene 14 (90%) ; m. p. 85. 2°C, [a] p = + 50, 8° (c=1 in THF) ; 1 H-NMR : 7. 22 (1H, d, J=9. 0 Hz), 6. 97 (1 H, d, J=9. 0 Hz), 5. 22 (2H, s,), 3. 55 (3H, s,), 0. 72 (3H, s) ; 13C-NMR : 151. 3 (s), 135. 2 (s), 131. 8 (s), 130. 9 (s), 127. 6 (s), 126. 5 (d), 94. 2 (t), 81. 5 (d), 55. 2 (d), 52. 9 (s), 50. 0 (d), 44. 0 (d), 42. 9 (t), 37. 9 (d), 36. 5 (t), 30. 3 (t), 26. 9 (t), 25. 9 (t), 22. 7 (t), 16. 2 (q) ; MS-CI : 398, 396 (100, M+ + 1+ NH3) ; MS-EI : 380, 378 (30, M+), 350, 348 (25), 251 (6), 173 (10) ; Anal. Calcd.

(C2oH2702Br) C-63. 33, H-7. 17, 0-8. 44, Br-21. 06 ; Found : C-63. 28, H-7. 20, Br-21. 00 ; 2. To solution of 4-Bromo-3-methoxymethoxy-estra-1, 3, 5 (10)-triene 14 (12 g, 31. 7 mmol) in THF (250 ml) was added BuLi (24 ml, 1. 6 M, 38 mmol) at-60°C. The mixture was stirred for 30 min and then a suspension of CuCN (1. 5 g, 17mmol) in THF (25 ml) was added at the same temperature. The mixture was stirred for additional 2. 5 h until no CuCN was visible at the bottom of the flask. After cooling to-100° dry oxygen was passed through the mixture for 15 min. The oxygen flow was disconnected and the reaction mixture was stirred for additional 30 min at this temperature and then quenched with saturated NH4CI and diluted with diethyl ether (100 ml). The organic

layer was washed with brine, dried with Na2SO4 and the solvent was evaporated. The residue (10 g) was dissolved in DMF (30 ml) and to the solution was added t-BuOK (1. 9 g, 18 mmol) at 0°C. The mixture was stirred for 5 min and then a solution of TBDMSCI (2. 5 g, 65 mmol) in DMF (15 ml) was added at the same temperature and stirred for additional 30 min. The reaction was quenched with saturated NH4CI and diluted with ethyl ether (50 ml). The organic layer was washed with brine, dried with Na2SO4 and the solvent was evaporated. The crude mixture (11 g) was separated by chromatography on Si02 (hexane : diethyl ether-6 : 1) to give 2 g of crystalline product (Ra)-4, 4'-bis (3-Methoxymethoxyestra-1, 3, 5 (10)-triene) 15 (21 %) which was used without purification for the next step.

3. To solution of (Ra)-4, 4'-bis (3-Methoxymethoxyestra-1, 3, 5 (10)-triene) 15 (2g, 3. 3 mmol) in Methanol/THF/H2O 1 : 1 : 0. 2 (20 ml) was added conc. HCL (3ml) and stirred for 25 h at room temperature. The reaction mixture was neutralized with saturated NaHC03 and diluted with ethyl ether (50 ml). The organic layer was washed with brine, dried with Na2SO4 and the solvent was evaporated. The crude product (1. 3 g, 78%) was recrystallised from hexane/ethyl ether 1 : 1 to give 1, 3 g (Ra)-4, 4'-bis (Estra- 1, 3, 5 (10)-trien-3-ol) 5 (76%), m. p. 162. 5°C, [a] 365 =-96. 30° (c=1. 54 in THF) ; 1H- NMR : 7. 25 (1H, d, J=10. 0 Hz), 6. 82 (1H, d, J=10. 0 Hz), 4. 72 (1H, brs, OH), 0. 72 (3H, s) ; 13C-NMR : 150. 8 (s), 136. 7 (s), 133. 6 (s), 126. 8 (d), 111. 8 (s), 112. 3 (d), 53. 3 (d), 43. 9 (d), 40. 7 (s), 40. 2 (t), 38. 5 (t), 38. 3 (d), 27. 6 (t), 27. 1 (t), 26. 4 (t), 24. 8 (t), 20. 2 (t), 14. 8 (q) ; MS-CI : 520 (100, M+ + 1+ NH3), 503 (92, M+ + 1) ; MS-EI : 520 (100, M+), 251 (4), 235 (6) ; Anal. Calcd. (C36H4602) C-84. 66, H-9. 08, Found : C-84. 94 H-9. 12, 0-6. 20.

Examples of applications : 1. Reduction of acetophenone with ligand R-4 : A dry 50 ml Schlenk tube containing a Teflon coated stirring bar was charged with solution of LiAIH4 in THF (1. 5 ml, 0. 98 M) and then a solution of ethyl alkohol in THF (0. 9 ml, 1. 7 M) was added dropwise for a period of ca. 10 min. Subsequently a THF solution of R-4 (3 ml, 0. 53 M) was added dropwise for a period of 30 min. After stirring for additional 30 min. at room temperature the reducing agent was cooled to-90°C. A solution of acetophenone (0. 45 ml, 0. 7 M) in THF was added slowly (for a period of 20 min). The mixture was stirred for additional 3 h at this temperature and at-78°C for 16 h. After addition of methanol (0. 5 ml) at-78°C the mixture was warmed up to room temperature, neutralized to pH=6 with HCL (5%) and extracted with ethyl ether (2 X10

ml). GC analysis (25 m FS-Hydrodex-B-PM, 110 isoterm, 1 bar Hydrogen, t° detector=280°C, t° column = 280°C) of the extract shows 96. 5% ee and complete conversion.

2. Hydrogenation of olefins and b-Ketoesters and with ligand R-4 : A dry 50 ml Schlenk tube containing a Teflon coated stirring bar was charged with [RuCl2 (benzene)] 2 (0. 018 g, 0. 036 mmol), S-4 (0. 07 g, 0. 073 mmol) and DMF (1 ml).

The resulting brown suspension was heated at 100°C under argon for 30 min to give a clear reddish brown solution. The reaction mixture was cooled and concentrated at 1 mm Hg and then at 0. 05 mm Hg for 1h to give RuCI2 (S-4) (DMF) 2.

a) Hydrogenation of methyl acetoacetate To the resulting reddish brown solid of RUC12 (S-4) (DMF) 2 was added a solution of methyl acetoacetate (7. 3 g, 63 mmol) in degassed methanol (40 mi) and stirred for 5 min. Then the solution was transferred to 125 ml stainless steel autoclave and kept 1h at 100°C and under hydrogen (100 atm) and then 10 h at room temperature and same pressure. After the excess hydrogen had been blown off, the apparatus was disassembled. The content was concentrated. Distillation (110°C, 46 mmHg) afforded methyl (S)-3-hydroxybutanoate (7. 22 g, 98%, [a] D =-50. 5 c= 1. 4, [a] 546 =-58. 3 c= 1. 4 in CHCI3), in 99% ee assayed as MTPA ester. b) Hydrogenation of acrylic acid : To the resulting reddish brown solid of RuCI2 (S-4) (DMF) 2 was added a solution of a- acetamidocinnamic acid (3. 6 g, 17 mmol) in degassed methanol (40 ml) and stirred for 5 min. Then the solution was transfered in to 125 ml stainless steel autoclave and kept 48h at room temperature and under hydrogen (4 atm). After the excess hydrogen had been blown off, the apparatus was disassembled. The content was concentrated to give 3. 6 g crude product. A small amount from the crude product (0. 05 g) was treated with excess of diazomethane (solution in ethyl ether) to yield the corresponding methyl ester for determination of the enantiomeric excess. GC analysis (25 m Chiralsil-DEX, 150° isoterm, 1 bar hydrogen, t° detector=280°C, t° colum = 280°C) of this ester shows an ee of 85. 7% and no trace of the starting material. The rest of the product was dissolved in hot water (200 ml) and extracted with toluene (2X30 ml). The water was evaporated and the residue was dried under vacuum to give 3. 48 g (96%) (-)-N-acetyl- phenyl alanine, [a] D =-33. 7 (c= 1. 0 in methanol). c) Hydrogenation of tiglic acid : To the resulting reddish brown solid of RuCI2 (S-4) (DMF) 2 was added a solution of tiglic acid (1. 2 g, 17 mmol) in degased methanol (30 ml) and stirred for 5 min. Then the solution was transferred to 200 ml stainless steel autoclave and kept 24h at r. t and under hydrogen (4 atm). After the excess hydrogen had been blown off, the aparatus was disassembled. The content was concentrated to give 3. 6 g crude product. A small amount from the crude product (0. 05 g) was treated with exess of diazomethane (solution in ethyl ether). GC analysis (25 m Chiralsil-DEX, 150° isoterm, 1 bar Hydrogen, t° detector=280°C, t° colum = 280°C) of this solution shows 90. 5 % ee and

no trace of the starting material. Distillation (78°C, 24 mmHg) afforded methyl (R)-2- methylbutyric acid (1. 15 g, 92%, [a] p =-17. 2 (neat).

3. Enantioselective Cyciization of methyl-secone with R-Ti-1 and S-Ti-1 : To a solution of either R-3 or S-3 (0. 094g, 0. 19mmol) in dry toluene (5ml) was added 4A molecular sieves (0. 600 g, beads 1 mm) and AgBF4 (0. 075 g, 0. 39 mmol) under argon and the mixture was sonificated for 10 minutes in the dark. Then a solution of (i- PrO) 2TiCI2 (0. 62 ml, 0. 302 M in toluene, 0. 19 mmol) was added and the resulting dark red solution was stirred at room temperature in the dark for one hour. The mixture was cooled to-22°C and a solution of Methyl-secone (0. 300 g, 1 mmol) in toluene (1 ml) was added dropwise. The reaction mixture was then allowed to stand at-20°C (freezer) for 3 days. The reaction mixture was quenched with 20% Na2CO3. Work up in a usual way followed by column chromatography gave 14-beta-Hydroxy-3- methoxyestra-1, 3, 5 (10), 8-tetraene-17-one (0. 06 g, 20%, 36% ee), mp. = 162. 5-163°C (EtOH) ; [a] D = +26. 9° (c=0. 2 in THF) and 3-Methoxyestra-1, 3, 5 (10), 8, 14-pentaene-17- one (0. 17 g, 72%, 70% ee), mp. = 108. 3°C (EtOH), [a] D =-70. 6° (c=0. 12 in THF).