PROCESS FOR THE PREPARATION OF A CHIRAL TRIOL

Abstract

The invention comprises a process for the preparation of a chiral triol of formula I

##STR00001## wherein, R.sup.1 is hydrogen or halogen by way of an asymmetric hydrogenation of a ketone compound of formula IIa

##STR00002## wherein, R.sup.1 is hydrogen or halogen and R.sup.2 is C.sub.1-6-alkyl; with hydrogen in the presence of an iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst). The chiral triols of formula I are versatile building blocks for the preparation of various pharmaceutically active drug substances such as for instance for statins.

Claims

1. Process for the preparation of a chiral triol of formula I ##STR00041## wherein R.sup.1 is hydrogen or halogen and denotes either a dashed bond (a) or a wedged bond (b) a) b) . comprising the asymmetric hydrogenation of a ketone compound of formula IIa ##STR00042## wherein R.sup.1 is hydrogen or halogen and R.sup.2 is C.sub.1-6-alkyl; with hydrogen in the presence of an iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) of the formula IIIa or IIIb, or enantiomers thereof, ##STR00043## wherein R.sup.4a, R.sup.4b, R.sup.4c and R.sup.4d independently of each other are hydrogen or C.sub.1-6-alkyl; the dotted ring signifies an aromatic ring when Q.sup.1 is nitrogen and Q.sup.2 is carbon and the dotted ring signifies a cycloalkane ring wherein Q.sup.1 and Q.sup.2 are sulfur; X.sup.1 is either a coordinated ligand or a counter anion selected from halogen, C.sub.1-6-alkoxy, tetrahalogeno borate, hexahalogenoborate, tetrakis(3,5-bis(trihalogeno-C.sub.1-6-alkyl)phenyl)borate, acetylacetonate, hexahalogenophosphate, p-tolylsulfonate (OTs) or trihalogeno methanesulfonate and Z is phenyl, optionally substituted by one or more groups selected from C.sub.1-8-alkyl, C.sub.1-8-halogenalkyl or phenyl; C.sub.3-8-cycloalkyl, optionally substituted by one or more C.sub.1-8-alkyl groups or di-C.sub.1-8-alkyl phosphinyl.

2. Process of claim 1, wherein the Ir-SpiroPAP catalyst is selected from the compounds IIIa or IIIb, or enantiomers thereof, wherein R.sup.4a, R.sup.4b, R.sup.4c and R.sup.4d independently of each other are hydrogen or C.sub.1-4-alkyl; the dotted ring signifies an aromatic ring when Q.sup.1 is nitrogen and Q.sup.2 is carbon and the dotted ring signifies a cycloalkane ring wherein Q.sup.1 and Q.sup.2 are sulfur; X.sup.1 is either a coordinated ligand or a counter anion selected from halogen, methoxy, tetrafluoroborate (BF4), hexafluoroborate (BF6), tetrakis(3,5-bis(trifluoromethyl) phenyl)borate (barf), acetylacetonate (acac), hexafluorophosphate (PF6), p-tolylsulfonate (OTs) or trifluoromethanesulfonate (OTf) and; Z is phenyl, optionally substituted by one or more groups selected from C.sub.1-6-alkyl, C.sub.1-4-halogenalkyl or phenyl or is C.sub.4-7-cycloalkyl.

3. Process of claim 1, wherein the Ir-SpiroPAP catalyst is selected from the compounds IIIa or IIIb, or enantiomers thereof R.sup.4a, R.sup.4b, R.sup.4c and R.sup.4d independently of each other are hydrogen or C.sub.1-4-alkyl; the dotted ring signifies an aromatic ring when Q.sup.1 is nitrogen and Q.sup.2 is carbon and the dotted ring signifies a cycloalkane ring wherein Q.sup.1 and Q.sup.2 are sulfur; X.sup.1 is halogen; Z is phenyl, optionally substituted by one or two groups selected from C.sub.1-6-alkyl, C.sub.1-4-halogenalkyl or phenyl or is cyclopentyl or cyclohexyl.

4. Process of claim 1, wherein the Ir-SpiroPAP catalyst is selected from the compounds ##STR00044## wherein; R.sup.4a, R.sup.4b, R.sup.4c and R.sup.4d independently of each other are hydrogen or C.sub.1-4-alkyl; X.sup.1 is halogen; Z is phenyl optionally substituted by one or two groups selected from C.sub.1-6-alkyl, C.sub.1-4-halogenalkyl or phenyl or is cyclopentyl or cyclohexyl.

5. Process of claim 1, wherein the asymmetric hydrogenation is performed in the presence of an organic solvent and a base at a hydrogen pressure of 5 bar to 100 bar and at a reaction temperature of 10 C. to 90 C.

6. Process of claim 1, wherein the organic solvent is an aliphatic alcohol, a halogen substituted alcohol, an ether or an aromatic solvent or is a mixture thereof.

7. Process of claim 1, wherein the base is an inorganic base selected from alkali or earth alkali-carbonates orhydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formates or organic bases selected from amines, alkali alcoholates or amidines.

8. Process of claim 1, wherein the substrate to catalyst ratio is selected in a range of 100 to 10,000.

9. Process of claim 1, wherein the Ir-SpiroPAP catalyst of formula IIIa or IIIb is prepared in situ in the course of the asymmetric hydrogenation reaction by bringing together a Iridium-pre catalyst complex with a spiro-pyridylamidophosphine ligand of the formula ##STR00045## wherein R.sup.4a, R.sup.4b, R.sup.4c and R.sup.4d, Q.sup.1 and Q.sup.2 and Z have the meanings as outlined above.

10. Process of claim 9, wherein the Iridium-pre catalyst complex is selected from [Ir(cod).sub.2]BF.sub.4, [IrCl(COD)].sub.2, [Ir(acac)(COD)], [Ir(OMe)(COD)].sub.2, [Ir(cod).sub.2]BARF, [Ir(cod).sub.2]PF6.

11. Process of claim 1, wherein the asymmetric hydrogenation of the ketone of formula IIa in a first step is performed in the presence of the Ir-PEN catalyst of formula IVa or IVb, or enantiomers thereof, ##STR00046## wherein, R.sup.5 is C.sub.1-6-alkylsulfonyl wherein the alkyl group is optionally substituted with one or more halogen atoms; with a 7,7-dimethyl-2-oxobicyclo[2.2.1] heptane-1-yl group or phenyl sulfonyl, wherein the phenyl group is optionally substituted by one or more C.sub.1-6-alkyl groups and X.sup.2 is either a coordinated ligand or a counter anion selected from a C.sub.1-6-alkylsulfonyloxy group which is optionally substituted with one or more halogen, atoms; from halogen, C.sub.1-6-alkoxy, tetrahalogenoborate, hexahalogenoborate, tetrakis(3,5-bis(trihalogeno-C.sub.1-6-alkyl)phenyl)borate, acetylacetonate, hexahalogenophosphine, p-tolylsulfonate (OTs) or trihalogenomethanesulfonate; to form the ketone of formula IIb, ##STR00047## wherein R.sup.1 and R.sup.2 are as above, and in a subsequent step the ketone of formula IIb is further subjected to an asymmetric hydrogenation in the presence of an Ir-SpiroPAP catalyst of the formula IIIa or IIIb, or enantiomers thereof, to form the chiral triol of formula I.

12. Process of claim 11, wherein R.sup.5 is methylsulfonyl, trifluoromethylsulfonyl, 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-yl; tolylsulfonyl or 1,3,5-tri-i-propylphenyl sulfonyl; X.sup.2 is either a coordinated ligand or a counter anion selected from a methylsulfonyloxy group which is optionally substituted with one or more fluoro atoms; from halogen, methoxy, tetrafluoroborate (BF4), hexafluoroborate (BF6), tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (barf), acetylacetonate (acac), hexafluorophosphine (PF6), p-tolylsulfonate (OTs) or trifluoromethanesulfonate (OTf.

13. Process of claim 11, wherein the iridium-phenylendiamine catalyst (Ir-PEN catalyst) are of the formula IVa, or enantiomers thereof, wherein, R.sup.5 is methylsulfonyl, trifluoromethylsulfonyl, 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-yl; tolylsulfonyl or 1,3,5-tri-i-propylphenyl sulfonyl; X.sup.2 is a trifluoromethylsulfonyl oxy group; or are of the formula IVb, or enantiomers thereof, wherein, R.sup.5 is methylsulfonyl, trifluoromethylsulfonyl, 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-yl; tolylsulfonyl or 1,3,5-tri-i-propylphenyl sulfonyl.

14. Process of claim 11, wherein the asymmetric hydrogenation of the ketone of formula IIa is performed in the presence of an organic solvent at a hydrogen pressure of 5 bar to 100 bar and at a reaction temperature of 10 C. to 90 C.

15. Process of claim 14, wherein the organic solvent is an aliphatic alcohol, a halogen substituted alcohol, an ether or an aromatic solvent or is a mixture thereof.

16. Process of claim 14, wherein the substrate to catalyst ratio is selected in a range of 100 to 1000.

17. Process of claim 1, wherein the asymmetric hydrogenation of the ketone of formula IIa takes place in the presence of a mixture of an Ir-Spiro PAP catalyst of the formula IIIa or IIIb, or of an enantiomer thereof, and an Ir-PEN catalyst of the formula IVa or IVb, or of an enantiomer thereof.

18. Process of claim 17 wherein the reaction is performed in the presence of an organic solvent and a base at a hydrogen pressure of 5 bar to 100 bar and at a reaction temperature of 10 C. to 90 C.

19. Process of claim 17, wherein the organic solvent is an aliphatic alcohol, a halogen substituted alcohol, an ether or an aromatic solvent or is a mixture thereof.

20. Process of claim 17, wherein the base is an inorganic base selected from alkali or earth alkali-carbonates orhydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formiates or organic bases selected from amines, alkali alcoholates or amidines.

21. Process of claim 17, wherein the substrate to Ir-PEN catalyst ratio is selected in a range of 100 to 10000, and the substrate to Ir-Spiro PAP catalyst ratio is selected in a range of 100 to 10000.

22. Process of claim 1, wherein the intermediates in the asymmetric hydrogenation of the ketone of formula IIa to the chiral triol of formula I of the formula ##STR00048## wherein R.sup.1 and R.sup.2 are as above, are individually isolated and individually be subjected to the asymmetric hydrogenation in the presence of an Ir-Spiro PAP catalyst of the formula IIIa or IIIb.

23. Process of claim 1, wherein the chiral triol has the formula Ia ##STR00049## R.sup.1 is hydrogen or halogen.

24. Process of claim 23, wherein R.sup.1 is halogen.

25. Process of claim 1, wherein the chiral triol has the formula Ib ##STR00050##

Description

EXAMPLES

Abbreviations

[0133]

TABLE-US-00001 EtOH Ethanol iPr.sub.2O Diisopropyl ether MeOH Methanol DCM Dichloromethane Dioxane 1,4-Dioxane iPrOH 2-Propanol iPrOAc Isopropyl acetate tAmOH tert-Amylalcohol TFE Trifluoroethanol THF Tetrahydrofuran DBU Diazabicycloundecene DABCO 1,4-Diazabicyclo(2.2.2)octane MTBD Triazabicyclodecene DBN 1,5-Diazabicyclo(4.3.0)non-5-ene BIPY Biypridine COD Cyclooctadiene rt Room temperature IPC In process control T Temperature P Hydrogen pressure eq Equivalent rct Reaction time con Conversion exp Experiment S/C Substrate-to-Catalyst ratio S/L Substrate-to-Ligand ratio S/B Substrate-to-Base ratio S/Ir Substrate-to-Iridium ratio

TABLE-US-00002 1 4-(4-Chlorophenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester (Note: 1H-NMR spectra data of 1 in D6-EtOH or CD.sub.2Cl.sub.2 confirmed the structure to be assigned as: 4-(4-chlorophenyl)-2-hydroxy-4-keto- butyric-2-en-acid ethyl ester. No hint was found for the presence of 4-(4- Chlorophenyl)-2-diketo-butyric acid ethyl ester) (R)-3 = (2R)-3 (2R)-4-(4-Chlorophenyl)-2-hydroxy-4-keto-butyric acid ethyl ester (R,R)-4 = trans-(2R, 4R)-4 (2R,4R)-4-(4-Chlorophenyl)-2,4-dihydroxy-butyric acid ethyl ester trans-4 mix of (R,R)-4 and (S,S)-4 cis-4 mix of (R,S)-4 and (S,R)-4 (R,R)-5 = cis-(3R,5R)-5 (3R,5R)-5-(4-Chlorophenyl)-3-hydroxy-butyrolactone cis-5 mix of (R,R)-5 and (S,S)-5 trans-5 mix of (R,S)-5 and (S,R)-5 (R,R)-6 = trans-(2R, 4R)-6 (2R,4R)-4-(4-Chlorophenyl)-butane-1,2,4-triol trans-6 mix of (R,R)-6 and (S,S)-6 cis-6 mix of (R,S)-6 and (S,R)-6 7 4-(Phenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester (Note: 1H-NMR spectra data of 7 in CD.sub.2Cl.sub.2 confirmed the structure to be assigned as: 4-(Phenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester. No hint was found for the presence of 4-(Phenyl)-2-diketo-butyric acid ethyl ester) (R,R)-8 = trans-(2R, 4R)-8 (2R,4R)-4-(Phenyl)-butane-1,2,4-triol trans-8 mix of (R,R)-8 and (S,S)-8 cis-8 mix of (R,S)-8 and (S,R)-8

##STR00018##

##STR00019##

[0134] Pre-Catalysts, Catalyst and Ligands:

[0135] 627-630 and 6051-6056 were prepared according to T. Ohjuma et al. Organic Letters, 2007, 9, 2565. All other (pre-) catalysts and ligands were commercially available e.g. from Strem, Sigma Aldrich, Jiuzhou Pharma.

TABLE-US-00003 (Pre-) Catalysts and Ligands Number Abbreviation Structure 627 [Ir(cp*)((S,S)-Ms-DPEN-2H)] CAS No 937378-51-3 [00020] 628 [Ir(cp*)((S,S)-Ms-DPEN-H)(OTf)] CAS No 917756-11-7 [00021] 629 [Ir(cp*)((R,R)-Ms-DPEN-2H)] CAS No 1263000-75-4 [00022] 630 [Ir(cp*)((R,R)-Ms-DPEN-H))(OTf)] CAS No 1201686-18-1 [00023] 6051 [Ir(cp*)((R,R)-Ts-DPEN-2H)] CAS No 401479-02-5 [00024] 6052 [Ir(cp*)((R,R,R)-Cs-DPEN-2H)] CAS No 895579-52-9 [00025] 6053 [Ir(cp*)((S,S)-TFMs-DPEN-2H)] CAS No 1807637-08-6 [00026] 6054 [Ir(cp*)((S,S)-TIPBs-DPEN-2H)] CAS No. 1073339-77-1 [00027] 6055 [Ir(cp*)((S,S)-Ts-1,3,5-MeDPEN-2H)] CAS No 2376389-13-6 [00028] 6056 [Ir(cp*)((R,R)-Ts-DACH-2H)] CAS No. 1099830-96-2 [00029] 680 [IrClH.sub.2((S)-DTB-SpiroPAP-3-Me)] CAS No 1418483-59-6 Available from Jiuzhou Pharma, CN Catalogue No. JZ-S033-2 [00030] 682 [IrClH.sub.2((S)-DTB-SpiroSAP)] CAS No not available Available from Jiuzhou Pharma, CN Catalogue No. JZ-S034-2 [00031] 6046 [IrClH.sub.2((S,S,S)-DTB-PSpiroPAP-3-Me)] CAS No not available Available from Jiuzhou Pharma, CN Catalogue No. JZ-S036-1 [00032] 6048 [IrClH.sub.2((S)-DTB-SpiroPAP)] CAS No not available Available from Jiuzhou Pharma, CN Catalogue No. not available [00033] 6049 [IrClH.sub.2(R)-DTB-SpiroPAP-4-tBu)] CAS No not available Available from Jiuzhou Pharma, CN Catalogue No. not available [00034] 6050 [IrClH.sub.2((R)-DTB-SpiroPAP-6-Me)] CAS No not available Available from Jiuzhou Pharma, CN Catalogue No. not available [00035] 1508 (S)-DTB-SpiroPAP-3-Me CAS No not available Available from Jiuzhou Pharma, CN Catalogue No. JZ-S022-2 [00036] 600 [Ir(cod).sub.2]BF.sub.4 CAS No 35138-23-9 [00037] 601 [IrCl(COD)].sub.2 CAS No 12112-67-3 [00038] 650 [Ir(acac)(COD)] CAS No 12154-84-6 [00039] 657 [Ir(OMe)(COD)].sub.2 CAS No 12148-71-9 [00040]

[0136] Analytical Methods

[0137] a) Achiral LC Method to Determine the Conversion and Purifies of 1, 3 and the Cis- and Trans-Isomers of 4-6

TABLE-US-00004 Stationary phase Kinetex (2.6 m PFP 100 , LC Column 50 4.6 mm) Eluent: A) Acetonitrile B) H2O + 5% Acetonitrile D) TBAHS Puffer (1 g TBAHS in 800 mL Acetonitrile und 200 mL H2O). Pump program (gradient): 10 A:80 B:10 D .fwdarw. 80 A:10 B:10 D Run time: 16 min Flow: 1 mL/min Column oven temperature 40 C. Injection volume: 5 uL Detection: DAD 210 nm Retention Times: 1, 13.23 min; 3, 6.91 min; trans-4, 6.04 min; cis-4, 5.73 min; trans-5, 5.49 min; cis-5, 5.19 min; trans-6 2.40 min; cis-6 2.18 min

[0138] b) Chiral LC Method to Determine the Enantiomeric Purity of 3

TABLE-US-00005 Stationary Daicel Chiralpak IC-3, L = 150 mm, ID = 4.6 mm, 3.0 phase: m Eluent: A) H2O + 5% Acetonitrile B) Acetonitrile C) 6.25-6.35 g ammonium formate in 950.0 mL Water adjusted to pH 9.0 with ammonium hydroxide solution (25%) + 50.0 mL acetonitrile pump program (isocratic): 60 A:30 B:10 C Run time: 20 min Flow: 1 mL/min Column oven 30 C. temperature: Injection 2.5 uL volume: Detection: DAD 254 nm Retention (S)-3, 10.60 min; (R)-3, 12.20 min Times:

[0139] c) Chiral LC Method to Determine the Enantiomeric Purifies of 3, 4, 5 and 6

TABLE-US-00006 Stationary Daicel Chiralpak IB-N; L = 150 mm, ID = 4.6 mm, phase: 3.0 m Eluent: A) CO2 B) Isopropanol, pump program (isocratic): 90 A:10 B Run time: 9 min Flow: 3 mL/min Column oven 20 C. temperature: Injection 5 uL volume: Detection: DAD 220 nm Retention 1, 1.19 min; (R)-3, 1.85 min; (S)-3, 1.95 min; (R,R)-4, Times: 2.24 min; (S,S)-4, 2.58 min; (R,S)-4, 3.09 min; (S,R)-4, 3.93 min; (R,R)-5, 3.08 min; (S,S)-5, 3.92 min; (R,S)-5, 2.33 min; (S,R)-5, 2.33 min; (R,R)-6, 5.11 min; (S,S)-6, 5.78 min; (R,S)-6, 6.37 min; (S,R)-6, 6.95 min

[0140] 1. Preparation of (R)-3 Via Asymmetric Hydrogenation of 1

Example 1.1

[0141] In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (20.0 g, 78.5 mmol), 630 (60.2 mg, 78.310.sup.6 mol, S/C 1,000) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line, pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken after 1 h (50% conversion) and 2 h (>99.9% conversion) to follow the progress of the reaction. After a total reaction time of 2.5 h, the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to yield crude (R)-3 (19.9 g) with 96.7 area-% purity and 94.3% ee. 0.9% of trans-4 was detected as major impurity (note: trans-4 demonstrated to have limited stability and converted during handling and storage gradually into trans-5).

[0142] Next, crude (R)-3 (5.00 g) was dissolved in iPr.sub.2O (25 mL) at 60 C. The clear solution was allowed to cool to 0 C. within 6 h and stirred at this temperature for another 1.5 h. The formed white crystals were filtered, washed with 9 mL of ice cold iPr.sub.2O and dried for 1 h at 40 C. under vacuum (10 mbar) to afforded pure (R)-3 (4.15 g, 82% yield) with 99.9 area-% purity and 99.6% ee.

[0143] Analytical Data for 3

[0144] LC-MS ESI (m/z): 256.0 [M+]

[0145] .sup.1H-NMR (CDCl.sub.3, 600 MHz): ppm 7.89 (d, J=8.8 Hz, 2H), 7.41-7.50 (m, 3H), 4.65 (td, J=5.8, 3.8 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.46-3.53 (m, 1H), 3.38-3.45 (m, 1H), 3.27 (d, J=5.6 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H)

[0146] Analytical Data for Trans-4

[0147] GC-MS ESI (m/z): 258.0 [M+]

[0148] 1H NMR (DMSO-D6, 600 MHz): ppm 7.35-7.38 (m, 2H), 7.32-7.35 (m, 2H), 5.44 (br s, 2H), 4.73 (br d, J=9.6 Hz, 1H), 4.25 (br d, J=8.6 Hz, 1H), 4.06 (q, J=7.1 Hz, 2H), 1.53-1.78 (m, 1H), 1.45-1.99 (m, 1H), 1.17 (t, J=7.1 Hz, 3H)

Example 1.2

[0149] In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (20.0 g, 78.5 mmol), 629 (48.4 mg, 78.310.sup.6 mol, S/C 1,000) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line, pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. A reaction sample was taken after 3.5 h (98% conversion) to follow the progress of the reaction. After a total reaction time of 4 h, the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to yield crude (R)-3 (20.0 g) with 94 area-% purity and 94.5% ee. 1.3% of trans-4 was detected as major impurity. Next, crude (R)-3 (20.0 g) was dissolved in iPr.sub.2O (200 mL) at 40 C. The clear solution was then allowed to cool to 0 C. within 6 h and stirred at this temperature for another 1.5 h. The formed white crystals were filtered, washed with 45 mL of ice cold iPr.sub.2O and dried for 1 h at 40 C. under vacuum (10 mbar) to afforded 15.62 g of pure (R)-3 (15.62 g, 78% yield) with 99.2 area-% purity and 99.8% ee.

Examples 1.3-1.6

[0150] In analogy to Example 1.1, 1 (0.5 g, 1.96 mmol) was hydrogenated for 20 h in EtOH (5 mL) and the presence of the catalysts as listed in Table 1 at 30 C. and an initial hydrogen pressure of 70 bar H.sub.2.

TABLE-US-00007 TABLE 1 conv 3 (R)-3 trans-4 exp catalyst [%] [area-%] [% ee] [area-%] 1.3 629 >99.9 90 95.0 7 1.4 6051 >99.9 95.8 95.0 2.2 1.5 6052 >99.9 94 92 1.9 1.6 6053 60 40 63 (S) 0

Examples 1.7-1.10

[0151] In analogy to Example 1.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 2 h in EtOH (5 mL) and the presence of the catalysts as listed in Table 2 at 30 C. and an initial hydrogen pressure of 70 bar H.sub.2.

TABLE-US-00008 TABLE 2 conv 3 (R)-3 trans-4 exp catalyst [%] [area-%] [% ee] [area-%] 1.7 629 59 52 95.0 0 1.8 6054 21 9 n.d. 0 1.9 6055 9 7 n.d. 0 1.10 6056 42 38 15 0

Examples 1.11-1.14

[0152] In analogy to Example 1.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 2 h in EtOH (5 mL) at 30 C. in the presence of the catalysts (S/C 1,000) and initial hydrogen pressures as listed in Table 3.

TABLE-US-00009 TABLE 3 p conv 3 (R)-3 trans-4 exp catalyst [bar] 1%] [area-%] [% ee] [area-%] 1.11 629 30 75 71 n.d. 0 1.12 629 50 89 87 n.d. 0 1.13 630 30 >99.9 96.5 95.7 0 1.14 630 50 >99.9 95.9 95.7 0.4

Examples 1.15-1.20

[0153] In analogy to Example 1.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 2 h in EtOH (5 mL) at 30 C. and an initial hydrogen pressures of 70 bar in the presence of various amounts of catalysts and DBU as base as listed in Table 4.

TABLE-US-00010 TABLE 4 DBU conv 3 (R)-3 trans-4 exp catalyst S/C [eq] [%] [area-%] [% ee] [area-%] 1.15 630 1000 >99.9 96.3 95.6 0.3 1.16 630 1000 10 95.0 94.5 96.5 0 1.17 630 500 50 >99.9 97 n.d. 1.4 1.18 630 1000 50 98.3 96.9 96.4 0 1.19 630 2000 50 56 55 n.d. 0 1.20 630 2000 46 46 n. d. 0

[0154] 2. Preparation of (R,R)-6 Via Asymmetric Hydrogenation of 1

Examples 2.1

[0155] In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (10.0 g, 39.3 mmol), 680 (38.4 mg, 39.310.sup.6 mol, S/C 1,000), DBU (597.8 mg, 3.93 mmol, S/B 10) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to yield crude 6 (9.0 g) with 98.4 area-% purity (DBU not integrated) and a trans cis ratio of 7.7. (R,R)-6 was obtained with 98.8% ee.

[0156] Analytical Data for Cis-5

[0157] GC-MS ESI (m/z): 212.0 [M+]

[0158] .sup.1H-NMR (DMSO-D6, 600 MHz): 7.47-7.51 (m, 2H), 7.42 (d, J=8.3 Hz, 2H), 6.02 (br s, 1H), 5.40 (dd, J=10.8, 5.4 Hz, 1H), 4.62 (dd, J=10.7, 8.6 Hz, 1H), 2.89 (ddd, J=12.2, 8.2, 5.4 Hz, 1H), 1.93 (dt, J=12.1, 11.0 Hz, 1H)

[0159] Analytical Data for Trans-5

[0160] GC-MS ESI (m/z): 212.0 [M+]

[0161] 1H-NMR (DMSO-D6, 600 MHz): 7.47 (d, J=8.7 Hz, 2H), 7.40-7.42 (m, 2H), 6.18 (br d, J=5.2 Hz, 1H), 5.68 (t, J=6.7 Hz, 1H), 4.38 (dt, J=7.0, 4.9 Hz, 1H), 2.44-2.48 (m, 1H), 2.36-2.42 (m, 1H)

[0162] Analytical Data for Trans-6

[0163] GC-MS ESI (m/z): 216.0 [M+]

[0164] .sup.1H NMR (400 MHz, DMSO) 7.40-7.31 (m, 4H), 5.23 (d, J=4.9 Hz, 1H), 4.75 (dd, J=9.9, 4.8 Hz, 1H), 4.50 (dd, J=6.5, 5.5 Hz, 2H), 3.68-3.67 (m, 1H), 3.30-3.24 (m, 2H), 1.67-1.61 (m, 1H), 1.44-1.39 (m, 1H).

[0165] .sup.13C NMR (101 MHz, DMSO) 146.6, 131.3, 128.4, 127.9, 68.7, 68.6, 66.8, 44.3.

[0166] Analytical Data for Cis-6

[0167] GC-MS ESI (m/z): 216.0 [M+]

[0168] .sup.1H-NMR (CDCl.sub.3, 600 MHz): ppm 7.31-7.34 (m, 2H), 7.32 (s, 2H), 4.98 (dd, J=9.9, 2.5 Hz, 1H), 4.04 (br d, J=2.4 Hz, 1H), 3.45-3.70 (m, 2H), 2.76 (s, 1H), 1.65-1.95 (m, 2H), 1.08 (s, 2H).

[0169] .sup.13C-NMR (CDCl.sub.3, 151 MHz) 142.7, 133.3, 128.7, 127.1, 73.82, 72.3, 66.7, 41.6.

Examples 2.2

[0170] In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (10.0 g, 39.3 mmol), 601 (29.4 mg, 19.610.sup.6 mol, S/Ir 1,000), 1508 (13.2 mg, 39.310.sup.6 mol, S/L 1,000), DBU (597.8 mg, 3.93 mmol, S/B 10) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to yield crude 6 (9.1 g) with 96.5 area-% purity (DBU not integrated) and a trans/cis ratio of 8.3. (R,R)-6 was obtained with >99.9% ee.

[0171] Specified impurity: trans-5 (0.8%)

Examples 2.3

[0172] In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (10.0 g, 39.3 mmol), 601, 29.4 mg, 19.610.sup.6 mol, S/Ir 1,000), 1508 (13.2 mg, 39.310.sup.6 mol, S/L 1,000), KOtBu (437.6 mg, 3.93 mmol, S/B 10) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 42 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to yield crude 6 (9.0 g) with 84.2 area-% purity and a trans/cis ratio of 8.0. (R,R)-6 was obtained with 98.6% ee.

[0173] Specified impurity: trans-5 (0.9%)

Examples 2.4-2.8

[0174] In analogy to Example 2.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 20 h in EtOH (5 mL) at 30 C. and an initial hydrogen pressure of 70 bar in the presence KOtBu (4.910.sup.5 mol, S/B 20) and of the catalysts (S/C 1,000) as listed in Table 5.

TABLE-US-00011 TABLE 5 6 6 conv 3 trans-4 trans-5 [area- (R,R)-6 trans/ exp cat [%] [area-%] [area-%] [area-%] %] [% ee] cis] 2.4 682 >99.9 0 51 27 15 99.9 35 2.5 6046 85 67 0 0 0 2.6 6048 >99.9 0.3 0 1.2 93 99.9 7.8 2.7 6049 99.1 1.1 0 1.4 88 99.8 7.2 2.8 6050 77 56 0.4 0 0

Examples 2.9-2.16

[0175] In analogy to Example 2.2, 1 (0.25 g, 0.98 mmol) was hydrogenated for 20 h in EtOH (5 mL) at 30 C. and an initial hydrogen pressure of 70 bar in the presence of 1508 (0.9810.sup.6 mol, S/L 1,000), the presence or absence of DBU (0.9810.sup.4 mol, S/B 10) and the presence of a pre-catalyst (S/Ir 1,000) as listed in Table 6.

TABLE-US-00012 TABLE 6 pre- conv 3 trans-4 trans-5 6 (R,R)-6 6 exp catalyst base [%] [area-% [area-%] [area-%] [area-%] [% ee] [trans/cis] 2.9 600 DBU 99.5 0 1.0 1.5 93 99.9 8.3 2.10 601 DBU 99.6 0 0 0.7 96.7 99.6 7.5 2.11 650 DBU 99.7 0 0 0.8 96.0 99.6 7.3 2.12 657 DBU 99.3 0 0 0.7 97.3 99.5 6.9 2.13 600 82 69 1.0 0 0 2.14 601 95 52 7 1.7 0 2.15 650 75 64 0.6 0 0 2.16 657 >99.9 20 70 0.5 0

Examples 2.17-2.29

[0176] In analogy to Example 2.1, 1 (0.10 g, 0.39 mmol or 0.25 g, 0.98 mmol) was hydrogenated for 20 h in EtOH (2 mL for 0.10 g scale experiments, resp. 4 mL for 0.25 g experiments) at 30 C. and an initial hydrogen pressure of 70 bar in the presence of 680 (9.810.sup.7 mol, S/C 1,000), the presence of a base (S/B 10) as listed in Table 7.

TABLE-US-00013 TABLE 7 3 trans-4 trans-5 6 (R,R)-6 6 exp base conv [%] [area-% [area-%] [area-%] [area-%] [% ee] [trans/cis] 2.17 8 6 0 0 0 2.18 KOtBu >99.9 0 1.6 0 85 99.9 13 2.19 NaHCO.sub.3 79 67 2.4 0 0 2.20 DBU >99.9 0 3.5 0 91 99.9 20 2.21 NEt.sub.3 >99.9 0 62 34 0.7 2.22 KH.sub.2PO.sub.4 25 20 0 0 0 2.23 Cs.sub.2CO.sub.3 96.7 0 0 0 85 99.6 12 2.24 NaOCHO 51 40 0 0 0 2.25 NaOAc 57 46 0 0 0 2.26 DABCO 93 86 3.4 0 0 2.27 DBN >99.9 0 26 50 17 n.d. 38 2.28 BIPY 6 11 0 0 0 2.29 MTBD >99.9 0 0 0.6 96.3 99.9 8.3

Examples 2.30-2.42

[0177] In analogy to Example 2.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 20 h at 30 C. and an initial hydrogen pressure of 70 bar in the presence of 680 (either 0.9810.sup.6 mol, S/C 1,000 or 0.2010.sup.6 mol, S/C 5,000), the presence of KOtBu (0.98 mmol, S/B 10) and a solvent or solvent mixtures (5 mL) as listed in Table 8.

TABLE-US-00014 TABLE 8 conv 3 trans-4 trans-5 6 (R,R)-6 6 exp solvent S/C [%] [area-%] [area-%] [area-%] [area-%] [% ee] [trans/cis] 2.30 EtOH 1000 >99.9 0 1.6 0 85 99.8 13 2.31 MeOH 1000 >99.9 0 0 0 92 97.0 4.0 2.32 EtOH 5000 53 14 0 0 0 2.33 MeOH 5000 68 20 5 0 0 2.34 iPrOH 5000 23 5 0 0 0 2.35 tAmOH 5000 15 2.0 0 0 0 2.36 DCM 5000 22 6 0 0 0 2.37 THF 5000 19 8 0 0 0 2.38 toluene 5000 16 4.4 0 0 0 2.39 TFE 5000 52 16 2.9 0 0 2.40 dioxane 5000 3.8 0 0 0 0 2.41 EtOH/ 5000 99.0 47 0 0 0 H.sub.2O 95:5 2.42 EtOH/ 5000 28 6 0 0 0 dioxane 1:1

Examples 2.43-2.51

[0178] In analogy to Example 2.1, 1 (0.20 g, 0.79 mmol) was hydrogenated for 20 h in EtOH (5 mL) the presence of 680 (either 0.7910.sup.6 mol, S/C 9,000 or 0.1610.sup.6 mol S/C 5,000), the presence of various amounts of KOtBu, different temperatures and initial hydrogen pressures all as listed in Table 9.

TABLE-US-00015 TABLE 9 p conv 3 trans-4 trans-5 6 (R,R)-6 6 exp S/C S/B T [bar] [%] [area-%] [area-%] [area-%] [area-%] [% ee] [trans/cis] 2.43 1000 1000 30 70 30 25 0 0 0 2.44 1000 100 30 70 75 65 0 0 0 2.45 1000 10 30 70 >99.9 0 0 0 87 98.8 7.3 2.46 1000 1000 60 70 85 76 0 0 0 2.47 1000 100 60 70 >99.9 0 0 0 88 97.9 7.3 2.48 1000 10 60 70 >99.9 0 0 0 8 96.5 5.2 2.49 5000 1 30 70 17 0 1.2 0 13 99.9 7.8 2.50 5000 1 30 100 16 0 1.3 0 12 99.9 8.0 2.51 5000 1 90 100 >99.9 0 4.6 0 0

Example 2.52

[0179] In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 629 (1.21 mg, 1.9610.sup.6 mol, S/C 2,000), 680 (1.92 mg, 1.9610.sup.6 mol, S/C 2,000), DBU (59.8 mg, 3.9310.sup.4 mol, S/B 10) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 10) to follow the progress of the reaction.

TABLE-US-00016 TABLE 10 ret conv 3 trans-4 trans-5 6 (R,R)-6 6 [h] [%] [area-%] [area-%] [area-%] [area-%] [% ee] [trans/cis] 1 16 11 0 0 0 2 51 46 0.1 0 0.2 4 96.4 76 11 7 0.3 6 95.9 0.7 30 41 17 99.9 48 8 97.5 0 2.0 14 74 99.9 55 24 >99.9 0 0 0.8 98.4 99.9 14

Example 2.53

[0180] In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 629 (2.42 mg, 3.9310.sup.6 mol, S/C 1,000), 680 (0.77 mg, 0.7910.sup.6 mol, S/C 5,000), DBU (30.0 mg, 1.9710.sup.4 mol, S/B 20) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 11) to follow the progress of the reaction.

TABLE-US-00017 TABLE 11 ret conv 3 trans-4 trans-5 6 (R,R)-6 6 [h] [%] [area-%] [area-%] [area-%] [area-%] [% ee] [trans/cis] 1 52 50 0 0 0 2 84 82 0.3 0 0 4 99.1 76 16 6 0 6 98.5 23 46 24 1.2 8 97.7 3.8 49 28 13 n.d. n.d. 22 >99.9 0 0.9 2.7 94 99.9 32

Example 2.54

[0181] In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 629 (2.42 mg, 3.9310.sup.6 mol, S/C 1,000), 680 (0.77 mg, 0.7910.sup.6 mol, S/C 5,000), DBU (5.98 mg, 3.9310.sup.5 mol, S/B 100) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 12) to follow the progress of the reaction.

TABLE-US-00018 TABLE 12 ret conv 3 trans-4 trans-5 6 (R,R)-6 6 [h] [%] [area-%] [area-%] [area-%] [area-%] [% ee] [trans/cis] 1 15 13 0 0 0 2 49 47 0 0 0 4 83 76 1.1 0 0 6 98.3 81 9 1.6 0.4 8 98.9 2.3 28 14 53 99.9 55 22 >99.9 0 0 0 98.0 99.9 16

Example 2.55

[0182] In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 630 (3.00 mg, 3.9310.sup.6 mol, S/C 1,000) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 30 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 30 bar for 4 h. Afterward the pressure was released to 1-2 bar and the autoclave returned to the glove box where under argon atmosphere it was opened and charged with 680 (0.77 mg, 0.7910.sup.6 mol, S/C 5,000), DBU (30.0 mg, 1.9710.sup.4 mol, S/B 20). The autoclave was sealed again and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. The reaction was continued for 18 h at to 70 bar and heated to 30 C. Reaction samples were taken at different time points (see Table 13) to follow the progress of the reaction.

TABLE-US-00019 TABLE 13 3 trans-4 trans-5 6 (R,R)-6 6 ret [h] conv [%] [area-%] [% ee] [area-%] [area-%] [area-%] [% ee] [trans/cis] 1 54 52 0 0 0 2 87 85 95 0 0 0 4 >99.9 93 95.2 0.4 0 0 6 >99.9 31 19 18 0.7 23 >99.9 0.8 23 10 56 99.9 78

Example 2.56

[0183] In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 630 (3.00 mg, 3.9310.sup.6 mol, S/C 1,000), 680 (0.77 mg, 0.7910.sup.6 mol, S/C 5,000), DBU (12.0 mg, 7.8610.sup.5 mmol, S/B 50) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 30 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 30 bar for 4 h. Afterward the pressure was increased to 70 bar and the reaction carried out for additional 19 h. Reaction samples were taken at different time points (see Table 14) to follow the progress of the reaction.

TABLE-US-00020 TABLE 14 3 trans-4 trans-5 6 (R,R)-6 6 ret [h] conv [%] [area-%] [% ee] [area-%] [area-%] [area-%] [% ee] [trans/cis] 1 34 34 2 48 48 92.4 4 67 66 91.9 0.2 6 74 73 91.1 0.3 23 >99.9 0.9 3.8 0.3 92 >99.9 20

Example 2.57

[0184] In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 630 (3.00 mg, 3.9310.sup.6 mol, S/C 1,000), 680 (0.77 mg, 0.7910.sup.6 mol, S/C 5,000), DBU (12.0 mg, 7.8610.sup.5 mmol, S/B 50) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar for 23 h. Reaction samples were taken at different time points (see Table 15) to follow the progress of the reaction.

TABLE-US-00021 TABLE 15 3 trans-4 trans-5 6 (R,R)-6 6 ret [h] conv [%] [area-%] [% ee] [area-%] [area-%] [area-%] [% ee] [trans/cis] 1 30 30 2 62 61 92.6 4 96.0 91 92.7 3.9 6 >99.9 43 40 16 0.4 23 >99.9 98.1 >99.9 15

Example 2.58

[0185] In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 630 (3.00 mg, 3.9310.sup.6 mol, S/C 1,000), 680 (0.77 mg, 0.7910.sup.6 mol, S/C 5,000), DBU (30.0 mg, 1.9710.sup.4 mol, S/B 20) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar for 23 h. Reaction samples were taken at different time points (see Table 16) to follow the progress of the reaction.

TABLE-US-00022 TABLE 16 3 trans-4 trans-5 6 (R,R)-6 6 ret [h] conv [%] [area-%] [% ee] [area-%] [area-%] [area-%] [% ee] [trans/cis] 1 22 19 2 88 85 94.3 1.6 4 97 77 93.6 11 4.2 6 >99.9 9 54 30 5 23 >99.9 1.7 0.4 96.2 >99.9 24

Example 2.59

[0186] In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (15.0 g, 59 mmol), 630 (45.1 mg, 5.910.sup.5 mol, S/C 1,000), 680 (11.5 mg, 1.210.sup.5 mol, S/C 5,000), DBU (179.3 mg, 1.2 mmol, S/B 50) and EtOH (300 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 17) to follow the progress of the reaction. After a total reaction time of 48 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (200 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to afford crude 6 (12.1 ga higher yield would be achievable when omitting IPC sampling) with 99.4 area-% purity and a trans cis ratio of 15. (R,R)-6 was obtained with >99.9% ee.

[0187] Specified impurities: cis-6 (6.1%), trans-4 (0.2%), trans-5 (0.1%)

[0188] Next, crude (R,R)-6 (12.1 g) was suspended in iPrOAc (100 mL) and the slurry stirred for 2 h at 50 C. The suspension was cooled to 0 C. and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold iPrOAc (60 ml) in 3 portions to afford after drying (25 C., 10 mbar) pure 6 (9.8 g, 77% yield) with 99.5 area-% purity and a trans cis ratio of 104. (R,R)-6 was obtained with >99.9% ee.

[0189] Specified impurity: cis-6 (0.95%)

[0190] Subsequently, (R,R)-6 (9.8 g) from above was dissolved in iPrOAc (78 ml) at 90 C. The colorless solution was cooled to 25 C. within 2 h whereby the product started to crystallize. The formed suspension was kept at 25 C. for 2 h and cooled to 0 C. within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25 C., 10 mbar) off-white, crystalline 6 (9.0 g, 71% yielda higher yield would be achievable when omitting IPC sampling during the hydrogenation run) with >99.9 area-% purity and a trans cis ratio of 713. (R,R)-6 was obtained with >99.9% ee.

[0191] Specified impurity: cis-6 (0.14%)

TABLE-US-00023 TABLE 17 3 trans-4 trans-5 6 (R,R)-6 6 ret [h] conv [%] [area-%] [% ee] [area-%] [area-%] [area-%] [% ee] [trans/cis] 2 89 88 94 0.4 0 0 4 >99.9 85 93 11 0 0.1 6 >99.9 34 92 44 19 0.4 20 >99.9 0 0.9 0.2 96.4 >99.9 18 23 >99.9 0 0.7 0.1 97.0 >99.9 18 46 >99.9 0 0.2 0.1 96.8 >99.9 15

Example 2.60

[0192] In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (15.0 g, 59 mmol), 630 (45.1 mg, 5.910.sup.5 mol, S/C 1,000), 680 (11.5 mg, 1.210.sup.5 mol, S/C 5,000), DBU (179.3 mg, 1.2 mmol, S/B 50) and EtOH (300 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 18) to follow the progress of the reaction. After a total reaction time of 23 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (200 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to afford crude 6 (12.4 ga higher yield would be achievable when omitting IPC sampling) with 98.7 area-% purity and a trans/cis ratio of 14. (R,R)-6 was obtained with >99.9% ee.

[0193] Specified impurities: cis-6 (6.5%), trans-4 (0.2%), trans-5 (0.4%)

[0194] Next, crude (R,R)-6 (12.4 g) was suspended in DCM (100 mL) and the slurry stirred for 2 h at 50 C. The suspension was cooled to 0 C. and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold DCM (60 ml) in 3 portions to afford after drying (25 C., 10 mbar) pure 6 (11.0 g, 91% yield) with 99.8 area-% purity and a trans/cis ratio of 65. (R,R)-6 was obtained with >99.9% ee.

[0195] Specified impurity: cis-6 (1.52%)

[0196] Subsequently, (R,R)-6 (11.0 g) from above was dissolved in iPrOAc (88 ml) at 90 C. The colorless solution was cooled to 25 C. within 2 h whereby the product started to crystallize. The formed suspension was kept at 25 C. for 2 h and cooled to 0 C. within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25 C., 10 mbar) off white, crystalline 6 (9.0 g, 75% yielda higher yield would be achievable when omitting IPC sampling during the hydrogenation run) with >99.9 area-% purity and a trans/cis ratio of 713. (R,R)-6 was obtained with >99.9% ee.

[0197] Specified impurity: cis-6 (0.14%)

TABLE-US-00024 TABLE 18 3 trans-4 trans-5 6 (R,R)-6 6 ret [h] conv [%] [area-%] [% ee] [area-%] [area-% [area-%] [% ee] [trans/cis] 2 89 87 95 0.4 0 0 4 >99.9 95 93 4.5 0.1 0.2 23 >99.9 0.2 0.4 98.1 >99.9 14

Example 2.61

[0198] In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (15.0 g, 59 mmol), 630 (45.1 mg, 5.910.sup.5 mol, S/C 1,000), 680 (11.5 mg, 1.210.sup.5 mol, S/C 5,000), DBU (179.3 mg, 1.2 mmol, S/B 50) and EtOH (300 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 23 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (200 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to afford crude 6 (13.2 g) with 99.4 area-% purity and a trans cis ratio of 18. (R,R)-6 was obtained with >99.9% ee.

[0199] Specified impurities: cis-6 (5.1%), trans-5 (0.3%)

[0200] Next, crude (R,R)-6 (13.2 g) was suspended in iPrOAc (106 mL) and the slurry stirred for 2 h at 50 C. The suspension was cooled to 0 C. and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold iPrOAc (60 ml) in 3 portions to afford after drying (25 C., 10 mbar) pure 6 (10.6 g, 83% yield) with 99.8 area-% purity and a trans cis ratio of 91. (R,R)-6 was obtained with >99.9% ee.

[0201] Specified impurity: cis-6 (1.1%)

[0202] Subsequently, (R,R)-6 (10.6 g) from above was dissolved in iPrOAc (85 ml) at 90 C. The colorless solution was cooled to 25 C. within 2 h whereby the product started to crystallize. The formed suspension was kept at 25 C. for 2 h and cooled to 0 C. within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25 C., 10 mbar) off-white, crystalline 6 (9.8 g, 77% yield) with >99.9 area-% purity and a trans cis ratio of 249. (R,R)-6 was obtained with >99.9% ee.

[0203] Specified impurity: cis-6 (0.41%)

[0204] Analytical Data for Trans-6

[0205] GC-MS ESI (m/z): 216.0 [M+]

[0206] NMR (400 MHz, DMSO) 7.27-7.42 (m, 4H), 5.21 (d, J=4.8 Hz, 1H), 4.69-4.82 (m, 1H), 4.48 (br d, J=4.6 Hz, 2H), 3.62-3.75 (m, 1H), 3.20-3.31 (m, 2H), 1.59-1.73 (m, 1H), 1.42 (ddd, J=13.9, 9.5, 2.2 Hz, 1H).

[0207] 3. Preparation of (R,R)-6 Via Asymmetric Hydrogenation of (R)-3

Example 3.1

[0208] In a glove box under argon atmosphere, a 185 mL autoclave was charged with (R)-3 (1.00 g, 3.91 mmol, quality: 99.9% ee, 99.8 area-% purity), 680 (3.83 mg, 3.9110.sup.6 mol, S/C 1,000) and DBU (59.5 mg, 3.9110.sup.4 mol, S/B 10) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 19) to follow the progress of the reaction.

TABLE-US-00025 TABLE 19 ret conv trans-4 trans-5 6 (R,R)-6 6 [h] [%] [area-%] [area-%] [area-%] [% ee] [trans/cis] 1 46 14 7 0.8 n.d. 2 99.2 19 19 54 99.9 84 3 >99.9 0.4 1.1 94 99.9 49 4 >99.9 0 0.2 95 99.9 40 5 >99.9 0 0 95.5 99.9 37 6 >99.9 0 95.7 95.7 99.9 38

Example 3.2-3.3

[0209] In analogy to Example 3.1, 3 (0.25 g, 0.98 mmol) was hydrogenated in the presence of 680 (0.19 mg, 0.2010.sup.6 mol, S/C 5,000) for 23 h in EtOH (4 mL) at 30 C. and the presence of DBU as base in amounts as listed in Table 20.

TABLE-US-00026 TABLE 20 conv trans-4 trans-5 6 (R,R)-6 6 Exp base S/B [%] [area-%] [area-%] [area-%] [% ee] [trans/cis] 3.2 DBU 20 >99.9 0.3 0.1 94 >99.9 39 3.3 DBU 50 >99.9 0.1 0.1 97.2 >99.9 36

Example 3.4

[0210] In a glove box under argon atmosphere, a 185 mL autoclave was charged with (R)-3 (6.0 g, 23.0 mmol, quality: 99.9% ee, 99.8 area-% purity) 680 (22.9 mg, 2.310.sup.5 mol, S/C 1,000) and DBU (71.2 mg, 4.710.sup.4 mol, S/B 50) and EtOH (120 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 23 h (99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 250 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to yield crude (R,R)-6 (5.2 g) with 98.7 area-% purity and a trans/cis ratio of 28. (R,R)-6 was obtained with >99.9% ee.

[0211] Specified impurities: cis-6 (3.40%), 3 (0.10%)

[0212] Next, crude (R,R)-6 (5.2 g) was suspended in iPrOAc (52 mL) and the slurry stirred for 2 h at 50 C. The suspension was cooled to 0 C. and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold iPrOAc (30 ml) in 3 portions to afford after drying (25 C., 10 mbar) pure 6 (4.1 g, 81% yield) with 99.5 area-% purity and a trans/cis ratio of 125. (R,R)-6 was obtained with >99.9% ee.

[0213] Specified impurity: cis-6 (0.79%)

[0214] Subsequently, (R,R)-6 (4.1 g) from above was dissolved in iPrOAc (34 ml) at 90 C. The colorless solution was cooled to 25 C. within 2 h whereby the product started to crystallize. The formed suspension was kept at 25 C. for 2 h and cooled to 0 C. within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (14 ml) in 2 portions to afford after drying (25 C., 10 mbar) off white, crystalline 6 (3.7 g, 73% yield) with >99.9 area-% purity and a trans/cis ratio of 586. (R,R)-6 was obtained with >99.9% ee.

[0215] Specified impurity: cis-6 (0.17%)

[0216] 4. Preparation of (R,R)-6 Via Asymmetric Hydrogenation of (R,R)-5

Example 4.1

[0217] In a glove box under argon atmosphere, a 185 mL autoclave was charged with (R,R)-5 (1.00 g, 4.71 mmol; quality: 99.9% ee, 99.9 area-% purity), 680 (4.62 mg, 4.7110.sup.6 mol, S/C 1,000), DBU (71.7 mg, 4.7110.sup.4 mol, S/B 10) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. A reaction sample was taken at different time points (see Table 21) to follow the progress of the reaction.

TABLE-US-00027 TABLE 21 rct conv 6 (R,R)-6 6 [h] [%] [area-%] [% ee] [trans/cis] 1 90 82 99.9 >100 2 >99.9 98.2 99.9 >100

Example 4.2

[0218] In analogy to Example 4.1, (R,R)-5 (0.25 g, 1.18 mmol; quality: 99.9% ee, 99.9 area-% purity) was hydrogenated in the presence of 680 (0.23 mg, 2.3610.sup.7 mol, S/C 5,000) and DBU (9.0 mg, 0.5910.sup.4 mol, S/B 20) in EtOH (5 mL) to yield after 20 h at 30 C. and an initial hydrogen pressure of 70 bar crude (R,R)-6 with 96.7% purity and >99.9% ee (99% conversion; trans cis ratio >100)

[0219] 5. Preparation of (R,R)-8 Via Asymmetric Hydrogenation of 7

Examples 5.1

[0220] In a glove box under argon atmosphere, a 35 mL autoclave was charged with 7 (250 mg, 1.1 mmol), 680 (1.1 mg, 1.110.sup.6 mol, S/C 1,000), KOtBu (12.1 mg, 1.110.sup.4 mol, S/B 10) and EtOH (5 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h, the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (5 mL) from the autoclave into a 50 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 C./10 mbar to constant weight to yield crude trans-8 (presumable major enantiomer: (R,R)-8, 245 mg) with >95% LC/MS purity.

[0221] Analytical Data for Trans-8

[0222] GC-MS ESI (m/z): 182.1 [M+]

[0223] .sup.1H-NMR (CDCl.sub.3, 600 MHz): ppm 7.30-7.42 (m, 1H), 7.28-7.42 (m, 3H), 5.03 (br d, J=3.8 Hz, 1H), 3.98 (br s, 1H), 3.44-3.64 (m, 2H), 3.03-3.44 (m, 2H), 2.38-2.86 (m, 1H), 1.72-2.03 (m, 3H)

[0224] .sup.13C-NMR (CDCl.sub.3, 151 MHz): ppm 144.2, 128.5, 127.5, 125.5, 71.4, 69.4, 66.8, 41.0 ppm