ENANTIOSELECTIVE PROCESS

Abstract

The present invention relates to novel processes for the enantioselective iridium-catalysed hydrogenation of oximes and oxime ethers to provide compounds of formula (II) and salts thereof formula (I) and (II).

##STR00001##

Claims

1. A process for the hydrogenation of oximes of formula (I) in the presence of an iridium catalyst and an acid to produce hydroxylamines of formula (II): ##STR00170## wherein the position labelled with the asterisk is an asymmetric centre and one stereoisomer of hydroxylamine of formula (II) is produced in excess; R.sup.1 and R.sup.2 are each independently C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8hydroxyalkyl, C.sub.1-C.sub.8cyanoalkyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.8cycloalkyl, phenyl, phenylC.sub.1-C.sub.3alkyl, phenylsulfonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.6alkoxycarbonyl, a bridged carbocyclyl, heterocyclyl or heteroaryl, wherein the cycloalkyl, phenyl, heterocyclyl and heteroaryl moieties are each optionally substituted with 1 to 5 groups selected from hydroxyl, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, phenyl, heteroaryl, C.sub.1-C.sub.6alkoxycarbonyl, acylamino, amido, cyano, nitro, azido, and C.sub.2-C.sub.6alkenyl; or a single group selected from pinacolborane, phenylsulfonyl, phenylC.sub.1-C.sub.3alkyl, or phenylC.sub.1-C.sub.3alkoxy; R.sup.3 is hydrogen, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8hydroxyalkyl, C.sub.1-C.sub.8cyanoalkyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.8cycloalkyl, phenylC.sub.1-C.sub.3alkyl, heterocyclylC.sub.1-C.sub.3alkyl or heterobicyclylC.sub.1-C.sub.3alkyl, wherein the cycloalkyl and heterocyclyl moieties are each optionally substituted with 1 to 5 groups selected from hydroxyl, halogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, phenyl, heteroaryl, C.sub.1-C.sub.6alkoxycarbonyl, acylamino, amido, cyano, azido, nitro and C.sub.2-C.sub.6alkenyl; and wherein R.sup.1 and R.sup.2 cannot be the same; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached may form a 4- to 9-membered saturated or partially saturated asymmetric cycloalkyl or asymmetric heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic monocyclic ring which comprises 1, 2 or 3 heteroatoms, wherein the heteroatoms are individually selected from N, O and S; or R.sup.1 and R.sup.3 together with the carbon and oxygen atoms to which they are respectively attached, may form a 5- to 8-membered non-aromatic heterocyclyl ring, or an 8- to 10-membered partially saturated heterobicyclyl; wherein the iridium catalysts of formula (IIIa) and (IIIb) are: ##STR00171## wherein ##STR00172## represents an optionally substituted cyclopentadienyl ligand; ##STR00173## represents a bidentate chelating ligand comprising at least one carbon atom which coordinates to iridium and at least one nitrogen atom which coordinates to iridium; X represents an anionic group; Y represents a neutral ligand; and Z represents an anionic group.

2. The process according the claim 1, wherein the iridium catalyst is of the formula (IIIa-1) or (IIIb-1) or the corresponding enantiomeric formula (IIIa-1-ent) or (IIIb-1-ent): ##STR00174## wherein R.sup.4, R.sup.5, and R.sup.6 are each independently hydrogen or C.sub.1-C.sub.3alkyl; R.sup.7 and R.sup.8 are each independently hydrogen, hydroxyl, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, C.sub.3-C.sub.8cycloalkyl, phenyl, phenoxy, naphthyl, benzyl, or tert-butyldiphenylsilyloxy, wherein the aromatic ring of each phenyl, naphthyl, or benzyl moiety is optionally substituted with 1 to 5 groups selected from C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl and C.sub.1-C.sub.6alkoxy.

3. The process according the claim 1, wherein the iridium catalyst is of the formula (IIIa-2) or (IIIb-2) or the corresponding enantiomeric formula (IIIa-2-ent) or (IIIb-2-ent): ##STR00175## wherein R.sup.4, R.sup.5, and R.sup.6 are each independently hydrogen or C.sub.1-C.sub.3alkyl; R.sup.7 and R.sup.8 are each independently hydrogen, hydroxyl, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, C.sub.3-C.sub.8cycloalkyl, phenyl, phenoxy, naphthyl, benzyl, or tert-butyldiphenylsilyloxy, wherein the aromatic ring of each phenyl, naphthyl, or benzyl moiety is optionally substituted with 1 to 5 groups selected from C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl and C.sub.1-C.sub.6alkoxy; R.sup.32 and R.sup.33 are each independently hydrogen, halogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkoxy; R.sup.34 is halogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkoxy; or R.sup.32 and R.sup.33, or R.sup.33 and R.sup.34, or R.sup.32 and R.sup.34 together with the carbon atoms to which they are attached may form a 5- to 10-membered carbocyclyl or heterocyclyl ring, wherein the heterocyclic moiety is a monocyclic ring which comprises 1, 2 or 3 heteroatoms, wherein the heteroatoms are individually selected from N, O and S.

4. The process according to claim 1, wherein the bidentate chelating ligand is a ligand of structure (IVc): ##STR00176## wherein R.sup.18, R.sup.19A, R.sup.19B, R.sup.20, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 are each independently hydrogen, halogen, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8haloalkoxy, or C.sub.1-C.sub.8alkoxycarbonyl, wherein each C.sub.1-C.sub.8alkoxy moiety is optionally substituted by 1 or 2 groups selected from hydroxy, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxycarbonyl and phenyl; R.sup.21 is hydrogen, C.sub.1-C.sub.8alkyl or phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C.sub.1-C.sub.8alkyl and C.sub.1-C.sub.8alkoxy; or R.sup.20 and R.sup.21 together with the carbon atoms to which they are attached may form a 6- to 8-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring which comprises 1 or 2 heteroatoms, and wherein the heteroatoms are individually selected from N, O and S.

5. The process according to claim 1, wherein the bidentate chelating ligand is a ligand of structure (IVe): ##STR00177## wherein, R.sup.19A, R.sup.19B, R.sup.20, R.sup.23, R.sup.24 and R.sup.15 are each independently hydrogen, C.sub.1-C.sub.8alkyl, or C.sub.1-C.sub.8alkoxy; R.sup.21 is hydrogen, C.sub.1-C.sub.8alkyl or phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C.sub.1-C.sub.8alkyl and C.sub.1-C.sub.8alkoxy; or R.sup.20 and R.sup.21 together with the carbon atoms to which they are attached may form a 6- to 8-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring which comprises 1 or 2 heteroatoms, and wherein the heteroatoms are individually selected from N, O and S; R.sup.26 is a derivative of the following structure: ##STR00178## wherein R.sup.27, R.sup.28, R.sup.29, R.sup.30, and R.sup.31 are each independently selected from hydrogen, C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.6cycloalkyl, and phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C.sub.1-C.sub.3alkyl, halogen and C.sub.1-C.sub.3alkoxy, and wherein either, R.sup.27 and R.sup.28 may not be the same, or R.sup.29 and R.sup.30 may not be the same; or R.sup.29 and R.sup.30 together with the carbon to which they are attached form and oxo (═O) group.

6. The process according to claim 1, wherein X represents an anionic group of the formula R.sup.14—SO.sub.2O— or R.sup.15—C(O)O—, wherein R.sup.14 is halogen, hydroxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkyl, or phenyl, wherein the phenyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R.sup.16; R.sup.16 is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, nitro, or halogen; R.sup.15 is C.sub.1-C.sub.6haloalkyl or phenyl, wherein the phenyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R.sup.17; and R.sup.17 is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, nitro or halogen.

7. The process according to claim 1, wherein Z is R.sup.14—SO.sub.2O.sup.−, mesylate, sulfate, hydrogensulfate, tetrafluoroborate, hexafluorophosphate, tetraphenylborate, or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

8. The process according to claim 1, wherein the acid is methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid, trifluoroacetic acid or triflic acid.

9. The process according to claim 1, wherein Y is H.sub.2O or MeCN.

10. The process according to claim 1, wherein the oxime of formula (I) is N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-imine (I-1).

11. The process according to claim 1, wherein the iridium catalyst is a compound of formula (III-1), (III-2), (III-3), (III-4), (III-15), (III-16), or (III-24): ##STR00179## ##STR00180##

12. The process according to claim 1, wherein the hydroxylamine of formula (II) is (2R)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1).

13. The process according to claim 12, in which the (2R)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1) is further reacted with 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride (XII) to provide 4-(difluoromethyl)-N-methoxy-1-methyl-N-[(1R)-1-methyl-2-(2,4,6-trichlorophenyl) ethyl]pyrazole-3-carboxamide (XIII-1): ##STR00181##

14. The process according to claim 1, wherein the iridium catalyst is a compound of formula (III-1-ent), (III-2-ent), (III-3-ent), (III-4-ent), (III-15-ent), (III-16-ent), or (III-24-ent): ##STR00182## ##STR00183##

15. The process according to claim 1, wherein the hydroxylamine of formula (II) is (2S)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1-ent).

16. The process according to claim 15, in which the (2S)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1-ent) is further reacted with 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride (XII) to provide 4-(difluoromethyl)-N-methoxy-1-methyl-N-[(1S)-1-methyl-2-(2,4,6-trichlorophenyl) ethyl]pyrazole-3-carboxamide (XIII-1-ent): ##STR00184##

17. A compound of formula (IIIc), (IIId), (IIIc-ent) or (IIId-ent): ##STR00185## ##STR00186## wherein, R.sup.4, R.sup.5, and R.sup.6 are each independently hydrogen or C.sub.1-C.sub.3alkyl; R.sup.7 and R.sup.8 are each independently hydrogen, hydroxyl, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, C.sub.3-C.sub.8cycloalkyl, phenyl, phenoxy, naphthyl, benzyl, or tert-butyldiphenylsilyloxy, wherein the aromatic ring of each phenyl, naphthyl, or benzyl moiety is optionally substituted with 1 to 5 groups selected from C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl and C.sub.1-C.sub.6alkoxy; R.sup.18, R.sup.19A, R.sup.19B, R.sup.20, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 are each independently hydrogen, halogen, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8haloalkoxy, C.sub.1-C.sub.8alkoxycarbonyl, wherein each C.sub.1-C.sub.8alkoxy moiety is optionally substituted by 1 to 2 groups selected from hydroxyl, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxycarbonyl and phenyl; R.sup.21 is hydrogen, C.sub.1-C.sub.8alkyl or phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C.sub.1-C.sub.8alkyl and C.sub.1-C.sub.8alkoxy; or R.sup.20 and R.sup.21 together with the carbon atoms to which they are attached may form a 6- to 8-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring which comprises 1 or 2 heteroatoms, and wherein the heteroatoms are individually selected from N, O and S; X is mesylate, tosylate, nosylate, sulfate, hydrogensulfate, triflate or trifluoroacetate; Y is H.sub.2O, PhCN or MeCN; and Z is mesylate, tosylate, nosylate, sulfate, hydrogensulfate, triflate tetrafluoroborate, hexafluorophosphate, tetraphenylborate or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

18. A compound of formula (IIIe) or (If): ##STR00187## wherein each R is independently hydrogen or C.sub.1-C.sub.8alkyl; Preferably, R.sup.19A, R.sup.19B, R.sup.20, R.sup.22, R.sup.23, R.sup.24 and R.sup.15 are each independently hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, or C.sub.1-C.sub.6alkoxycarbonyl, wherein each C.sub.1-C.sub.6alkoxy moiety is optionally substituted by 1 or 2 groups selected from hydroxy, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxycarbonyl and phenyl; R.sup.21 is hydrogen, C.sub.1-C.sub.8alkyl or phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C.sub.1-C.sub.8alkyl and C.sub.1-C.sub.8alkoxy; or R.sup.20 and R.sup.21 together with the carbon atoms to which they are attached may form a 6- to 8-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring which comprises 1 or 2 heteroatoms, and wherein the heteroatoms are individually selected from N, O and S; R.sup.26 is a derivative of the following structure: ##STR00188## wherein R.sup.27, R.sup.28, R.sup.29, R.sup.30, and R.sup.31 are each independently selected from hydrogen, C.sub.1-C.sub.8alkyl, C.sub.3-C.sub.6cycloalkyl, and phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C.sub.1-C.sub.3alkyl, halogen and C.sub.1-C.sub.3alkoxy; and wherein either, R.sup.27 and R.sup.28 may not be the same, or R.sup.29 and R.sup.30 may not be the same.

19. A compound of formula (IIIg), (IIIh), (IIIg-ent) or (IIIh-ent): ##STR00189## ##STR00190## wherein, R.sup.4, R.sup.5, and R.sup.6 are each independently hydrogen or C.sub.1-C.sub.3alkyl; R.sup.7 and R.sup.8 are each independently hydrogen, hydroxyl, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, C.sub.3-C.sub.8cycloalkyl, phenyl, phenoxy, naphthyl, benzyl, or tert-butyldiphenylsilyloxy, wherein the aromatic ring of each phenyl, naphthyl, or benzyl moiety is optionally substituted with 1 to 5 groups selected from C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl and C.sub.1-C.sub.6alkoxy; R.sup.18, R.sup.19A, R.sup.19B, R.sup.20, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 are each independently hydrogen, halogen, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8haloalkoxy, or C.sub.1-C.sub.8alkoxycarbonyl, wherein each C.sub.1-C.sub.8alkoxy moiety is optionally substituted by 1 or 2 groups selected from hydroxy, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkoxycarbonyl and phenyl, preferably each C.sub.1-C.sub.8alkoxy moiety is optionally substituted by 1 or 2 groups selected from hydroxy, C.sub.1-C.sub.8alkoxy, C.sub.1-C.sub.8alkyl, and phenyl; R.sup.21 is hydrogen, C.sub.1-C.sub.8alkyl or phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C.sub.1-C.sub.8alkyl and C.sub.1-C.sub.8alkoxy; or R.sup.20 and R.sup.21 together with the carbon atoms to which they are attached may form a 6- to 8-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring which comprises 1 or 2 heteroatoms, and wherein the heteroatoms are individually selected from N, O and S; R.sup.32 and R.sup.33 are each independently hydrogen, halogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkoxy; R.sup.34 is halogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkoxy; or R.sup.32 and R.sup.33, or R.sup.33 and R.sup.34, or R.sup.34 and R.sup.34 together with the carbon atom to which they are attached may form a 5- to 10-membered carbocyclyl or heterocyclyl ring, wherein the heterocyclic moiety is a monocyclic ring which comprises 1, 2 or 3 heteroatoms, wherein the heteroatoms are individually selected from N, O and S; X is mesylate, tosylate, nosylate, sulfate, hydrogensulfate, triflate or trifluoroacetate; Y is H.sub.2O, PhCN or MeCN; and Z is mesylate, tosylate, nosylate, sulfate, hydrogensulfate, triflate tetrafluoroborate, hexafluorophosphate, tetraphenylborate or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

20. A compound of formula (III-1), (III-2), (III-3), (III-4), (III-15), (III-16), (III-24), (III-1-ent), (III-2-ent), (III-3-ent), (III-4-ent), (III-16-ent), (III-24-ent) or (III-15-ent): ##STR00191## ##STR00192## ##STR00193## ##STR00194##

Description

EXAMPLES

[0336] The Examples which follow serve to illustrate the invention.

[0337] The following abbreviations are used: s=singlet; bs=broad singlet; d=doublet; br d=broad doublet, dd=double doublet, dt=double triplet, t=triplet, tt=triple triplet, q=quartet, hept=heptet, m=multiplet, ddd=doublet of doublet of doublets, dtd=doublet of triplet of doublets, dddt=doublet of doublet of doublet of triplets, RT=room temperature, Rt=retention time, MH.sup.+=mass of the molecular cation+proton.

[0338] .sup.1H, .sup.13C and .sup.19F NMR spectra were recorded on a Bruker Avance III 400 spectrometer (400 MHz) and Bruker DRX600 (600 MHz) spectrometer.

[0339] Melting points were measured on a Büchi melting point apparatus, model B-540, and are uncorrected.

[0340] Infrared spectroscopy was recorded on an Alpha-P Bruker FT-IR Spectrometer. Only strong and relevant absorptions are reported.

[0341] Optical Rotations were measured on a Polartronic M polarimeter using a 0.5 cm cell with a Na 589 nm filter.

[0342] HRMS measurements were recorded on an Agilent LC-MS TOF mass spectrometer (ESI). High resolution mass are given in m/z with only molecular ions [M-I]+, [M-OMs]+, [M+H]+ and [M+Na]+ being reported.

[0343] If not otherwise specified, chiral analysis was conducted on a Waters UPLC—HClass, Waters SFC Acquity UPC.sup.2/QDa, Agilent HPLC and Shimadzu UPLC system.

[0344] Chiral cyclopentadienyl iridium iodide dimer complexes (VI) were prepared according to the following literature procedures: Angew. Chem. Int. Ed. 2015, 54, 12149; Angew. Chem. Int. Ed. 2018, 57, 5459; Organometallics (DOI:10.1021/acs.organomet.9b00365). The opposite enantiomers of (VI-ent) were prepared according the identical procedures but starting from the opposite enantiomer of the starting materials. Methanesulfonic acid was purchased from Sigma Aldrich as >99% extra pure grade and stored in a desiccator.

Example 1: General Procedure 1: Preparation of Chiral Cyclopentadienyl Iridium Iodide Dimer Complex (VI-1-ent)

[0345] ##STR00044##

[0346] The chiral cyclopentadienyl ligand (prepared according to J. Am. Chem. Soc. 2015, 137, 12478; mixture of double bond isomers, 350 mg, 0.629 mmol, 1.00 eq.) was dissolved in benzene (4.0 mL, degassed by pump-freeze-thaw, 3 cycles) and thallium ethoxide (220 mg, 0.880 mmol, 1.40 eq.) was added as a solution in benzene (2.0 mL, degassed) under a nitrogen atmosphere and in the absence of light at room temperature. The mixture was heated to 80° C. in a sealed tube for 2 h. In parallel, ethylene gas was bubbled through a suspension of [Ir(coe).sub.2Cl].sub.2 (394 mg, 0.440 mmol, 0.70 eq.) in THE (6.0 mL) at 0° C. until a clear yellow solution was obtained. This solution of ‘in situ’ generated [Ir(ethylene).sub.2Cl].sub.2 was added to the above prepared reaction mixture at room temperature under a nitrogen atmosphere and was stirred for 18 h. The resulting red emulsion was purified by flash column chromatography (SiO2; nHex:toluene 70:30 to 0:100) to yield the corresponding [Cp.sup.xIr(ethylene).sub.2] complex (409 mg) as a pale yellow gum/solid. The [Cp.sup.xIr(ethylene).sub.2] complex (409 mg, 0.491 mmol, 1.00 eq.) was dissolved in toluene (3.0 mL) and a solution of iodine (137 mg, 0.540 mmol, 1.1 eq.) in toluene (2.00 mL) was added at 0° C. under a nitrogen atmosphere. The resulting brown solution was stirred for 30 min at 0° C. n-Hexane (15 mL) was added and the dark precipitate was filtered off, washing with pentane (3×5 mL) and re-dissolving it in dichloromethane. After removal of the solvent, the chiral cyclopentadienyl iridium iodide dimer complex (VI-1-ent) was obtained as a bright dark brown solid (489 mg, 78% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): δ.sub.H=8.08 (d, J=8.2 Hz, 2H), 7.94-7.88 (m, 2H), 7.87 (d, J=0.8 Hz, 2H), 7.83 (s, 2H), 7.49 (dddd, J=17.5, 8.1, 6.8, 1.2 Hz, 4H), 7.36-7.27 (m, 8H), 7.14-7.10 (m, 2H), 7.10-7.03 (m, 8H), 7.02-6.96 (m, 2H), 6.76 (d, J=8.6 Hz, 4H), 5.17-5.12 (m, 2H), 4.73 (t, J=2.2 Hz, 2H), 4.59 (t, J=1.7 Hz, 2H), 3.96 (s, 6H), 3.84 (s, 6H), 3.79 (d, J=14.1 Hz, 2H), 3.73 (d, J=16.2 Hz, 2H), 3.59 (d, J=14.0 Hz, 2H), 3.16 (d, J=16.1 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ.sub.C=159.41, 158.79, 140.93, 139.49, 138.17, 136.41, 133.86, 132.75, 132.68, 132.60, 132.51, 132.00, 131.69, 131.53, 131.00, 130.73, 129.95, 129.56, 128.17, 128.02, 126.77, 126.63, 126.58, 126.55, 114.30, 114.23, 95.79, 90.76, 84.02, 80.65, 68.04, 55.75, 55.64, 30.22, 27.73; HRMS (ESI.sup.+): m/z calcd for C.sub.82H.sub.62I.sub.3Ir.sub.2O.sub.4 [M-I].sup.+ 1877.1041, found 1877.1048.

TABLE-US-00001 TABLE 1 Physical data of compounds (VI) prepared according to the General Procedure 1: Cpd. No. Structure Characterization Data (VI-3-ent) [00045] Bright dark brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): δ.sub.H = 8.10-7.10 (m, 48H), 4.96 (s, 2H), 4.55 (s, 2H), 4.08 (s, 2H), 3.79 (br. d, J = 14.3 Hz, 2H), 3.73 (d, J = 16.2 Hz, 2H), 3.64 (d, J = 13.9 Hz, 2H), 3.26 (d, J = 16.1 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) 6c = 141.25, 139.81, 138.16, 137.88, 136.50, 133.94, 133.35, 132.76, 132.66, 132.64, 132.58, 131.91, 131.76, 131.43, 130.04, 129.56, 128.88, 128.87, 128.80, 128.77, 128.49, 128.31, 128.15, 128.09, 128.07, 127.79, 127.05, 126.98, 126.80, 126.75, 126.66, 125.93, 125.73, 83.49, 30.34, 27.66; HRMS (ESI.sup.+): m/z calcd for C.sub.94H.sub.62I.sub.3Ir.sub.2 [M − I].sup.+ 1957.1244, found 1957.1250. [00046]

Example 2: General Procedure 2A, Synthesis of Ligands of Formula (IV)

[0347] ##STR00047##

[0348] A round-bottom flask, equipped with a condenser, was charged with the aniline (IV-aniline) (1 eq.), ketone (IV-keto) (1 eq.), molecular sieves 4 Å and dry toluene. The reaction mixture was stirred and refluxed for 20 h. After cooling to room temperature, the mixture was filtered through a short pad of Celite. The resulting filtrate was concentrated under reduced pressure to afford the crude imine, which was purified by either trituration in hexane:Et.sub.2O or by flash column chromatography to afford the desired imine product (IV).

Example 2: General Procedure 2B, Alternative Synthesis of Ligands of Formula (IV)

[0349] A flame-dried round-bottom flask was charged with the aniline (IV-aniline) (1 eq), ketone (IV-ketone) (1 eq), triethylamine (2.5 eq) and dry dichloromethane under a nitrogen atmosphere. After cooling to −78° C., a solution of titanium tetrachloride (0.5 eq) in dichloromethane was added dropwise and the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched by addition of sat. aq. Na.sub.2CO.sub.3 solution. After dilution with dichloromethane, the solids were filtered off and the phases were separated. Aqueous layer was extracted twice with dichloromethane.

[0350] Organic layers were combined, dried, filtered and evaporated to afford the crude imine, which was purified by either trituration in hexane:Et.sub.2O or flash column chromatography to afford the desired imine product (IV).

Example 3: Preparation of (E)-4-methoxy-N-(7-(2-methoxyethoxy)-3,4-dihydro naphthalen-1(2H)-ylidene)-3,5-dimethylaniline (IV-8)

[0351] ##STR00048##

[0352] Step 1: a flame-dried sealed tube was charged with 7-hydroxy-1-tetralone (100 mg, 0.617 mmol) and dry potassium carbonate (256 mg, 1.850 mmol). DMF (1.2 mL) was added and the mixture was stirred for 10 min at room temperature. 1-bromo-2-methoxyethane bromide (0.12 mL, 1.233 mmol) was added and the reaction mixture was stirred for 16 h at 65° C. The reaction mixture was partitioned between water and diethyl ether. The aqueous phase was extracted three times with diethyl ether, the combined organic layers washed twice with water, then brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the crude product (IV-8-keto) (139 mg) as a brown oil. Rf 0.15 (SiO.sub.2; nHex:EtOAc 90:10); .sup.1H NMR (400 MHz, CDCl.sub.3): δ=7.51 (d, J=2.8 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.11 (dd, J=8.4, 2.8 Hz, 1H), 4.17-4.14 (m, 2H), 3.77-3.73 (m, 2H), 3.45 (s, 3H), 2.89 (t, J=6.1 Hz, 2H), 2.63 (dd, J=7.2, 5.8 Hz, 2H), 2.11 (p, J=6.5 Hz, 2H).

[0353] Step 2: following the General Procedure 2A, 4-methoxy-3,5-dimethylaniline (30.0 mg, 0.198 mmol) was reacted with 7-(2-methoxyethoxy)-3,4-dihydronaphthalen-1(2H)-one (IV-8-keto) (43.7 mg, 0.198 mmol) and molecular sieves (4 Å) in dry toluene (2.0 mL) stirring at reflux for 20 h. The crude imine product was purified by flash column chromatography (SiO.sub.2; nHex:Et.sub.2O:Et.sub.3N 80:20:1 to 60:40:1) to afford the title compound (50 mg, 71%>95:5 E:Z) as a pale yellow solid. Rf 0.4 (nHex:Et.sub.2O:Et.sub.3N 60:40:1); m.p.=86-88° C.; IR (neat, cm-1): v.sub.max=2927, 1627, 1600, 1492, 1480, 1219; .sup.1H NMR (400 MHz, CDCl.sub.3): δ=7.81 (d, J=2.8 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.00 (dd, J=8.4, 2.8 Hz, 1H), 6.44 (s, 2H), 4.21-4.16 (m, 2H), 3.77-3.73 (m, 2H), 3.72 (s, 3H), 3.44 (s, 3H), 2.82 (t, J=6.1 Hz, 2H), 2.55-2.49 (m, 2H), 2.27 (s, 6H), 1.88 (p, J=6.3 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ=165.44, 157.43, 152.97, 147.22, 134.87, 134.16, 131.32, 129.93, 119.76, 119.65, 109.19, 71.19, 67.47, 59.99, 59.27, 29.88, 29.30, 23.36, 16.30; HRMS (ESI+): m/z calculated for C.sub.22H.sub.28NO.sub.3 [M+H]+ 354.2064, found 354.2060.

Example 4: Preparation (S,E)-4-methoxy-N-(7-(2-methoxy-1-phenylethoxy)-3,4-dihydro-naphthalen-1(2H)-ylidene)-3,5-dimethylaniline (IV-12)

[0354] ##STR00049##

[0355] Step 1: In a flame-dried round-bottom flask, methanesulfonyl chloride (37 μL, 0.473 mmol) was added dropwise to a solution of (R)-2-methoxy-1-phenylethanol (60 mg, 0.394 mmol) and triethylamine (66 μL, 0.473 mmol) in anhydrous dichloromethane (2.0 mL) at 000. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was partitioned between H.sub.2O and CH.sub.2Cl.sub.2. The aqueous phase was further extracted twice with CH.sub.2Cl.sub.2. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure to afford the crude product (R)-2-methoxy-1-phenylethyl methanesulfonate (85 mg), which was used in the next step without further purification.

[0356] Step 2: A flame-dried sealed tube was charged with 7-hydroxy-1-tetralone (40 mg, 0.247 mmol) and dry caesium carbonate (121 mg, 0.370 mmol). Anhydrous 1,4-dioxane (1.0 mL) was added and the mixture was stirred for 10 mi at room temperature. A solution of (R)-2-methoxy-1-phenylethyl methanesulfonate (85 mg) in 1,4-dioxane (0.5 mL) was added and the reaction mixture was stirred for 24 h at 100° C. The solvent was removed under reduced pressure. The remaining residue was partitioned between water and diethyl ether. The aqueous phase was extracted three times with diethyl ether, the combined organic layers were washed twice with water, then brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO.sub.2; nHex:EtOAc 90:05 to 80:20) to afford ketone (IV-12)-keto (20 mg, 28% over 2 steps) as a colourless oil. R.sub.f0.35 (SiO.sub.2; nHex:EtOAc 80:20); .sup.1H NMR (400 MHz, CDCl.sub.2) δ 7.53-7.48 (m, 1H), 7.42-7.37 (m, 2H), 7.36-7.30 (m, 2H), 7.29-7.22 (m, 1H), 7.08 (d, J=1.6 Hz, 2H), 5.41 (dd, J=7.8, 3.5 Hz, 1H), 3.81 (dd, J=10.8, 7.8 Hz, 1H), 3.63 (dd, J=10.9, 3.5 Hz, 1H), 3.44 (s, 3H), 2.83 (t, J=6.1 Hz, 2H), 2.59-2.52 (m, 2H), 2.10-1.99 (n, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 198.16, 156.69, 138.15, 137.36, 133.41, 129.97, 128.78, 128.23, 126.64, 122.74, 112.70, 79.56, 59.53, 39.08, 28.98, 23.51. Chiral HPLC: Chiralpak IA column, 4.6×250 mm; nHex:iPrOH 90:10, flow=1.0 mL/min; T=25° C.; λ=254 nm. t.sub.R,A=9.1 min (minor), t.sub.R,B=19.4 min (major); 94:6 er.

[0357] Step 3: Following the General Procedure 2A, 4-methoxy-3,5-dimethylaniline (10.2 mg, 0.067 mmol) was reacted with (S)-7-(2-methoxy-1-phenylethoxy)-3,4-dihydronaphthalen-1(2H)-one (IV-12-keto) (20.0 mg, 0.067 mmol) and molecular sieves (4 Å) in dry toluene (0.7 mL) stirring at reflux for 20 h. The crude imine product was purified by flash column chromatography (SiO; nHex:Et.sub.2O:EtN 80:20:1 to 60:40:1) to afford the title compound (IV-12) (9 mg, 31%>95:5 E:Z) as a pale yellow oil. R.sub.f 0.5 (nHex:Et.sub.2O:Et.sub.3N 60:40:1); .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (d, J=2.8 Hz, 1H), 7.45-7.39 (m, 2H), 7.36-7.30 (m, 2H), 7.29-7.22 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.92 (dd, J=8.4, 2.7 Hz, 1H), 6.40 (s, 2H), 5.44 (dd, J=7.6, 3.7 Hz, 12H), 3.80 (dd, J=10.8, 7.6 Hz, 1H), 3.72 (s, 3H), 3.64 (dd, J=10.8, 3.7 Hz, 12H), 3.43 (s, 3H), 2.75 (t, J=6.1 Hz, 2H), 2.54-2.39 (m, 2H), 2.27 (s, 6H), 1.83 (p, J=6.4 Hz, 2H).

TABLE-US-00002 TABLE 2 Physical data of further compounds of Formula (IV) prepared according to the General Procedures 2A or 2B: Cpd. No. Structure Characterization Data (IV-4) [00050] Synthesized according to General Procedure 2A. m.p. = 97-99° C.; IR (neat, cm.sup.−1): v.sub.max = 2937, 1626, 1595, 1495, 1479, 1248, 1220; .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 8.23 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 8.8, 2.6 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 6.44 (s, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 2.86 (t, J = 6.1 Hz, 2H), 2.52 (dd, J = 7.2, 5.6 Hz, 2H), 2.27 (s, 6H), 1.89 (p, J = 6.5 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 164.96, 161.49, 152.82, 147.46, 143.18, 131.22, 128.36, 127.34, 119.92, 113.05, 112.77, 60.01, 55.43, 30.51, 29.92, 23.24, 16.32; HRMS (ESI+): m/z calcd for C.sub.20H.sub.24NO.sub.2 [M + H]+ 310.1802, found 310.1811. (IV-15) [00051] Synthesized according to General Procedure 2A. Beige solid. m.p. = 138-140° C.; .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 8.33 (d, J = 8.8 Hz, 1H), 7.82 (dd, J = 8.5, 3.0 Hz, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.45 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.38 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 7.04 (dd, J = 8.6, 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.7 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 3.87 (s, 3H), 2.88 (t, J = 6.1 Hz, 2H), 2.53 (dd, J = 7.1, 5.6 Hz, 2H), 1.91 (p, J = 6.3 Hz, 2H). .sup.13C NMR (151 MHz, CDCl.sub.3) δ = 165.58, 161.68, 149.66, 143.47, 134.33, 130.37, 128.85, 128.52, 127.86, 127.29, 127.11, 126.28, 124.30, 121.37, 115.44, 113.16, 112.82, 55.47, 30.48, 30.18, 23.19. HRMS (ESI+); m/z calcd for C.sub.21H.sub.20NO [M + H]+ 302.1539, found 302.1537. (IV-5) [00052] Synthesized according to General Procedure 2A. .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 7.81 (d, J = 2.8 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.95 (dd, J = 8.4, 2.8 Hz, 1H), 6.45 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 2.83 (t, J = 6.1 Hz, 2H), 2.53 (ddd, J = 7.4, 5.4, 1.5 Hz, 2H), 2.28 (s, 6H), 1.89 (p, J = 6.7 Hz, 2H). (IV-14-keto) [00053] Synthesized from hydroxy-1-benzosuberone (Chem. Commun. 2017, 53, 1490) according to Example 3 (Step 1). Yellow oil. Rf 0.35 (SiO.sub.2; nHex:EtOAc 80:20); .sup.1H NMR (400 MHz, CDCl.sub.3); δ = 7.27 (d, J = 2.8 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.3, 2.8 Hz, 1H), 4.13 (ddd, J = 6.2, 4.5, 1.2 Hz, 2H), 3.74 (ddd, J = 5.6, 3.2, 1.3 Hz, 2H), 3.44 (s, 3H), 2.86 (dd, J = 6.9, 5.1 Hz, 2H), 2.72 (td, J = 6.6, 5.0, 1.3 Hz, 2H), 1.88-1.74 (m, 4H); .sup.13C NMR MHz, CDCl.sub.3) δ = 205.69, 157.57, 139.54, 134.34, 131.18, 119.98, 112.91, 71.09, 67.58, 59.32,40.92, 31.81, 25.47, 21.00. (IV-14) [00054] Synthesized from (IV-14-keto) according to General Procedure 2A. Yellow oil. Mixture of E/Z-diastereoisomers in a 90:10 E:Z ratio. Rf 0.2 (nHex:Et.sub.2O:Et.sub.3N 70:30:1); .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z stereoisomers in a 0.9:0.1 ratio): δ = 7.29 (d, J = 2.8 Hz, 0.9H), 7.04 (d, J = 8.3 Hz, 0.9H), 7.00 (d, J = 8.2 Hz, 0.1H), 6.90 (dd, J = 8.3, 2.8 Hz, 0.9H), 6.65 (dd, J = 8.3, 2.7 Hz, 0.1H), 6.45 (s, 1.8H), 6.28 (s, 0.2H), 6.23 (d, J = 2.7 Hz, 0.1H), 4.18-4.14 (m, 1.8H), 3.81-3.77 (m, 0.2H), 3.77-3.73 (m, 1.8H), 3.72 (s, 2.7H), 3.61 (s, 0.3H), 3.55-3.52 (m, 0.2H), 3.45 (s, 2.7H), 3.35 (s, 0.3H), 2.90-2.75 (m, 2H), 2.75-2.67 (m, 0.2H), 2.51-2.46 (m, 1.8H), 2.28 (s, 5.4H), 2.10 (s, 0.6H), 2.02-1.94 (m, 0.2H), 1.83-1.75 (m, 1.8H), 1.68-1.59 (m, 1.8H), 1.34-1.27 (m, 0.2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 174.51 (Z), 173.84 (E), 157.51 (E), 156.58 (Z), 153.16 (Z), 152.95 (E), 147.02 (E), 146.24 (Z), 141.75 (E), 140.25 (Z), 132.52 (E), 132.32 (Z), 131.36 (E), 131.19 (Z), 130.65 (Z), 130.48 (E), 121.18 (Z), 119.04 (E), 116.75 (E), 115.09 (Z), 113.36 (E), 113.24 (Z), 71.22 (E), 70.81 (Z), 67.51 (E), 67.38 (Z), 59.99 (E), 59.83 (Z), 59.30 (E), 59.21 (Z), 32.45 (E), 31.75 (E), 31.71 (Z), 27.59 (Z), 26.38 (E), 24.48 (E), 22.78 (Z), 16.34 (E), 16.16 (Z), 11.75 (Z). HRMS (ESI+): m/z calcd for C.sub.23H.sub.30NO.sub.3 [M + H]+ 368.2220, found 368.2223 (IV-13-keto) [00055] Synthesized from 6-hydroxychroman-4-one (Bioorg. Med. Chem. Lett. 1999, 9, 2773) according to Example 3 (Step 1). Brown oil. .sup.1H NMR (400 MHz, CDCl.sub.3); δ = 7.31 (d, J = 3.1 Hz, 1H), 7.13 (dd, J = 9.0, 3.2 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 4.48 (dd, J = 7.0, 5.9 Hz, 2H), 4.10 (td, J = 5.5, 4.5, 1.2 Hz, 2H), 3.75-3.71 (m, 2H), 3.43 (s, 3H), 2.77 (t, J = 6.5 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 191.95, 156.83, 153.31, 125.98, 121.16, 119.31, 108.39, 71.05, 67.96, 67.20, 59.31, 37.82. (IV-13) [00056] Synthesized from (IV-13-keto) according to General Procedure 2B. IR (neat, cm.sup.−1); v.sub.max = 2924, 1633, 1609, 1487, 1434, 1278; .sup.1H NMR (400 MHz, CDCl.sub.3); δ = 7.64 (d, J = 3.1 Hz, 1H), 7.02 (dd, J = 9.0, 3.2 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.46 (s, 2H), 4.22 (dd, J = 6.6, 5.6 Hz, 2H), 4.16-4.11 (m, 2H), 3.77-3.70 (m, 5H), 3.44 (s, 3H), 2.70 (t, J = 6.1 Hz, 2H), 2.27 (s, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 159.63, 153.41, 153.36, 153.34, 146.10, 131.46, 122.42, 121.89, 120.27, 118.74, 108.40, 71.23, 67.97, 66.28, 60.01, 59.31, 28.97, 16.33. HRMS (ESI+); m/z calcd for C.sub.21H.sub.26NO.sub.4 [M + H].sup.+ 356.1856, found 356.1861. (IV-17-keto) [00057] Synthesized from 7-hydroxy-1-tetralone according to Example 3 (Step 1). Rf = 0.15 (SiO.sub.2; n-Hex:EtOAc 80:20); .sup.1H NMR (400 MHz, CDCl.sub.3); δ = 7.44 (d, J = 2.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 8.4, 2.9 Hz, 1H), 4.67 (s, 2H), 3.79 (s, 3H), 2.89 (t, J = 6.1 Hz, 2H), 2.62 (dd, J = 7.3, 5.8 Hz, 2H), 2.10 (p, J = 6.5 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 198.10, 169.19, 156.56, 138.31, 133.48, 130.43, 122.41, 109.86, 65.27, 52.39, 39.02, 28.99, 23.48. (IV-17) [00058] Synthesized from (IV-17-keto) according to General Procedure 2B (T = 0° C., reaction time = 5 h). .sup.1H NMR (400 MHz, CDCl.sub.3); δ = 7.71 (d, J = 2.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.9 Hz, 1H), 6.36 (s, 2H), 4.62 (s, 2H), 3.73 (s, 3H), 3.65 (s, 3H), 2.76 (t, J = 6.1 Hz, 2H), 2.48-2.41 (m, 2H), 2.21 (s, 6H), 1.82 (h, J = 6.3, 5.8 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 169.55, 165.18, 156.43, 153.04, 147.15, 135.10, 135.04, 131.39, 130.22, 119.66, 119.60, 109.43, 65.43, 60.03, 52.35, 29.84, 29.33, 23.28, 16.34. HRMS (ESI+): m/z calcd for C.sub.22H.sub.26NO.sub.4 [M + H].sup.+ 368.1856, found 368.1859.

Example 5: General Procedure 3, Synthesis of Chiral Catalysts of Formula (III)

[0358] ##STR00059##

[0359] Step (1)—Method A: A flame-dried sealed tube was charged with iridium complex (VI) (1.0 eq dimer), sodium acetate (20 eq) and the corresponding imine ligand (IV) (2.2 eq). 1,2-DCE (0.015-0.100 M) was added under a nitrogen atmosphere and the reaction mixture was heated to 50-80° C. stirring for 20 h. After cooling to room temperature, the mixture was directly purified by flash column chromatography to afford the corresponding Cp*Ir(III)-iodide complex (VII) (typically a mixture of diastereoisomers).

[0360] Step (1)—Method B: A flame-dried sealed microwave tube was charged with iridium complex (VI) (1.0 eq dimer), sodium acetate (10 eq), silver acetate (2.0 eq) and the corresponding imine ligand (IV) (3.0 eq). 1,2-DCE (0.015-0.100 M) was added under a nitrogen atmosphere and the reaction mixture was heated to 100° C. in a microwave reactor stirring for 3 h. After cooling to room temperature, the mixture was directly purified by flash column chromatography to afford the corresponding Cp*Ir(III)-iodide complex (VII) (typically a mixture of diastereoisomers).

[0361] Step (2): A flame-dried sealed tube, wrapped in aluminium foil, was charged with the iridium-iodide complex (VII) (1.0 eq) and AgOMs (1.0 to 2.0 eq). Chloroform (0.015 to 0.100 M) was added under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 20 h. The mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the corresponding CpIr(III)-OMs complex (III) (typically as one species, or as a mixture of mesylate complex (IIIa) and aqua complex (IIIb, also aqua-III)), which was used as catalyst in the oxime reductions without further purification.

Example 6: Preparation of [(R)-BINOL-diPh]CpIr[(E)-4-methoxy-N-(7-(2-methoxy ethoxy)-3,4-dihydronaphthalen-1(2H)-ylidene)-3,5-dimethylaniline] methanesulfonate (III-3)

[0362] ##STR00060##

[0363] Following General Procedure 3 (step 1—method B), the corresponding chiral cyclopentadienyl iridium iodide dimer [(R)-BINOL-diPh]CpIrI.sub.2].sub.2 (200 mg, 0.106 mmol; Angew. Chem. Int. Ed. 2015, 54, 12149) was reacted with NaOAc (87 mg, 1.062 mmol), AgOAc (36 mg, 0.212 mmol) and (E)-4-methoxy-N-(7-(2-methoxyethoxy)-3,4-dihydronaphthalen-1(2H)-ylidene)-3,5-dimethylaniline (113 mg, 0.319 mmol) in 1,2-DCE (2.1 mL) at 100° C. stirring for 3 h. After cooling to room temperature, the mixture was directly purified by flash column chromatography (SiO.sub.2; nHex:Et.sub.2O 80:20 to 65:35) to afford the corresponding iridium-iodide complex (VII-3) (200 mg, 81%, 85:15 dr) as an orange solid. R.sub.f 0.35 (SiO.sub.2; nHex:Et.sub.2O 60:40); [α].sub.D.sup.20=+151.6 (c=0.1, CHCl.sub.3); IR (neat, cm.sup.−1): v.sub.max=2925, 1588, 1566, 1480, 1447, 1402, 1228, 1211, 704; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of diastereoisomers in a 0.85:0.15 ratio; the peaks correspond to the major diast. unless otherwise stated): δ=7.99 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J=2.6 Hz, 1H), 7.56-7.44 (m, 4H), 7.38-7.29 (m, 3H), 7.17 (ddd, J=8.3, 6.8, 1.3 Hz, 1H), 7.09 (ddt, J=8.7, 7.5, 2.5 Hz, 4H), 6.81 (dd, J=8.3, 3.2 Hz, 2H), 6.73 (d, J=8.0 Hz, 1H), 6.60-6.48 (m, 3H), 6.00 (s, 0.15H, minor diast.), 5.79 (t, J=1.7, 1.3 Hz, 1H), 5.60 (d, J=2.7 Hz, 1H), 4.86 (t, J=2.2 Hz, 0.15H, minor diast.), 4.79 (t, J=2.2 Hz, 1H), 4.21 (t, J=1.6 Hz, 1H), 4.07 (dd, J=7.1, 2.9 Hz, 2H), 3.67-3.61 (m, 2H), 3.31 (s, 3H), 3.30 (s, 3H), 3.24 (s, 0.45H, minor diast.), 3.20 (s, 0.45H, minor diast.), 2.93-2.78 (m, 2H), 2.78-2.67 (m, 3H), 2.65-2.52 (m, 1H), 2.16 (s, 3H), 2.14 (s, 0.3H), 2.05 (d, J=13.5 Hz, 1H), 1.80-1.62 (m, 2H), 1.02 (s, 0.45H, minor diast.), 1.00 (s, 3H); .sup.13C NMR (151 MHz, CDCl.sub.3) (mixture of diastereoisomers in a 0.85:0.15 ratio; the peaks correspond to the major diast. unless otherwise stated; some peaks corresponding to the minor diast. are missing due to low intensity) δ.sub.C=183.50, 160.82, 160.02 (minor diast.), 155.06, 152.10, 151.64 (minor diast.), 146.88 (minor diast.), 146.32, 145.70, 145.38 (minor diast.), 141.74, 140.87, 140.57, 139.85, 138.06, 137.99, 135.28, 133.32, 132.58, 132.19, 132.17, 131.95, 131.83, 131.25, 130.42, 129.83, 129.77, 129.74, 129.47, 128.51, 128.07, 128.05, 128.01, 127.23, 126.77, 126.51, 126.41, 126.30, 126.27, 126.17, 125.98, 125.67 (minor diast.), 122.58, 122.19, 115.70 (minor diast.), 115.27, 107.16 (minor diast.), 106.36, 90.67 (minor diast.), 90.16, 86.73, 81.45, 71.88, 71.71 (minor diast.), 68.16, 64.14, 59.70, 58.91, 34.40 (minor diast.), 32.11 (minordiast.), 31.49, 30.60, 30.46, 28.88, 25.64, 24.10, 22.85 (minor diast.), 21.37 (minor diast.), 15.86, 15.30, 14.29 (minor diast.); HRMS (ESI+): m/z calcd for C.sub.61H.sub.53IrNO.sub.3 [M-I].sup.+ 1040.3655, found 1040.3654.

[0364] Then, following General Procedure 3 (step 2), iridium-iodide complex (VII-3) (180 mg, 0.154 mmol) was reacted with AgOMs (32 mg, 0.154 mmol) in CDCl.sub.3 (3.1 mL) stirring at room temperature for 20 h. The mixture was filtered through a short pad of Celite®. The filtrate was concentrated under reduced pressure to afford the corresponding iridium-methanesulfonate complex (III-3) (168 mg, 96%, 90:10 NMR mixture of (III-3):(aqua-III-3) as a light brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) (the peaks correspond to (III-3) unless otherwise stated): 6=7.97 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.55-7.44 (m, 4H), 7.38-7.28 (m, 3H), 7.24-7.15 (m, 3H), 7.08 (dddd, J=8.4, 6.9, 3.3, 1.4 Hz, 2H), 6.93 (d, J=8.1 Hz, 1H), 6.88 (d, J=8.1 Hz, 0.15H, (aqua-III-3)), 6.78 (d, J=8.5 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 6.63-6.47 (m, 3H), 6.10 (t, J=2.0 Hz, 0.85H), 6.00 (s, 0.10H, (aqua-III-3)), 5.59 (d, J=2.5 Hz, 1H), 5.44 (t, J=2.3 Hz, 0.85H), 4.85 (t, J=2.2 Hz, 0.10H, (aqua-III-3)), 4.54 (s, 1H), 4.18-4.09 (m, 1H), 3.99-3.91 (m, 1H), 3.74-3.62 (m, 2H), 3.33 (s, 2.5H), 3.31 (s, 3H), 3.30 (s, 0.3H, (aqua-III-3)), 2.90 (d, J=16.2 Hz, 1H), 2.86 (d, J=13.9 Hz, 1H), 2.79-2.68 (m, 2H), 2.66-2.43 (m, 2H), 2.17-2.11 (m, 4H), 2.08 (d, J=13.5 Hz, 1H), 2.01 (s, 2.5H), 1.98 (s, 0.3H, (aqua-III-3)), 1.84-1.66 (m, 2H), 1.02 (d, J=2.7 Hz, 3H); .sup.11C NMR (151 MHz, CDCl.sub.3) (the peaks correspond to both species (III-3) and (aqua-III-3); some peaks of the (aqua-III-3) complex might be missing due to low intensity) 6=185.87 (aqua-III-3)), 183.60 (III-3), 160.13, 160.01, 155.15, 154.90, 153.90, 148.18, 146.84, 145.36, 144.43, 141.72, 141.50, 140.86, 140.56, 140.53, 139.94, 139.91, 138.07, 138.04, 137.94, 137.55, 135.25, 135.22, 133.28, 132.85, 132.57, 132.23, 132.18, 132.11, 131.89, 131.84, 131.57, 131.50, 130.63, 130.53, 130.18, 129.87, 129.78, 129.75, 129.62, 129.43, 128.60, 128.52, 128.50, 128.34, 128.06, 128.00, 127.91, 127.22, 127.19, 126.77, 126.75, 126.50, 126.44, 126.40, 126.37, 126.29, 126.24, 126.03, 125.96, 125.67, 124.48, 124.44, 124.03, 123.00, 122.19, 122.10, 115.59, 114.33, 107.63, 107.13, 90.69, 83.21, 82.89, 82.78, 73.86, 71.75, 71.68, 71.08, 68.10, 67.58, 67.23, 66.08, 64.01, 59.71, 59.05, 58.89, 31.17, 30.45, 30.08, 29.72, 28.80, 28.69, 25.81, 24.04, 23.90, 22.82, 22.78, 15.93, 15.82, 15.30, 15.27, 14.29; HRMS (ESI+): m/z calcd for C.sub.61H.sub.53IrNO.sub.3 [M-OMs]+1040.3655, found 1040.3662.

TABLE-US-00003 TABLE 3 Physical data of further compounds of Formula (III) prepared according to General Procedure 3: Cpd. No. Structure Characterization Data (III-1) [00061] Brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3); δ = 7.91 (br d, J = 8.1 Hz, 1H), 7.28-7.80 (m, 6H), 6.70-7.24 (m, 9H), 6.60-6.68 (m, 1H), 5.85 (bs, 1H), 5.33 (s, 1H), 5.26 (bs, 1H), 5.02 (bs, 2H); 3.93 (s, 3H); 3.93 (s, 3H); 3.43-3.53 (m, 6H); 3.25-3.30 (m, 4H); 2.83 (br d, J = 13.8 Hz, 1H); 2.28 (bs, 3H); 2.23 (s, 3H); 1.84 (br d, J = 14.7 Hz, 1H); 1.63 (br d, J = 13.8 Hz, 1H) ppm. (III-2) [00062] Brown solid. [α].sub.D.sup.25= −101.0 (c = 0.18, CHCl.sub.3); IR (neat, cm.sup.−1); v.sub.max = 2930, 1618, 1596, 1568, 1451, 1228, 749; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of (III-2 and (aqua-III-2) in a 0.9:0.1 ratio; the peaks correspond to (III-2) unless otherwise stated): δ = 7.86 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.59 (br. s, 1H), 7.41 (ddd, J = 8.5, 6.6, 1.2 Hz, 1H), 7.31 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.14 (d, J = 9.2 Hz, 2H), 7.05 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 6.97 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 6.85 (d, J = 7.8 Hz, 2H), 6.79 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.46 (br. s, 1H), 5.97 (t, J = 2.0, 1.6 Hz, 0.1H, (aqua-III-2), 5.90 (s, 1H), 5.29 (s, 1H), 5.03 (s, 1H), 4.22 (dt, J = 10.3, 5.0 Hz, 1H), 4.08-4.00 (m, 1H), 3.93 (s, 3H), 3.79-3.73 (m, 2H), 3.46 (s, 3H), 3.42 (s, 3H), 3.29-3.22 (m, 4H), 2.92-2.51 (m, 6H), 2.35 (s, 3H), 2.22 (s, 3H), 1.97-1.86 (m, 2H), 1.82-1.69 (m, 1H), 0.94 (s, 3H); .sup.13C NMR (151 MHz, CDCl.sub.3) (the peaks correspond to both (III- 2) and (aqua-III-2) δ = 185.04, 182.71, 160.45 (aqua-III-2), 159.98 (III-2), 155.97, 155.58, 155.12, 154.92, 147.96, 146.83, 144.15, 143.32, 138.06, 137.91, 137.80, 136.61, 136.09, 135.88, 133.76, 133.65, 127.68, 127.30, 127.24, 126.94, 126.90, 126.87, 126.76, 126.57, 126.57, 126.37, 126.08, 124.86, 124.55, 124.21, 124.06, 123.85, 123.57, 122.66, 119.78, 116.45, 105.71, 104.19, 104.05, 96.20, 88.76, 85.55, 82.95, 73.50, 73.09, 71.91, 70.26, 69.08, 68.33, 59.75, 59.15, 59.04, 55.65, 55.59, 54.84, 54.72, 37.20, 32.07, 32.04, 31.57, 31.54, 30.46, 29.52, 29.48, 29.24, 29.02, 25.03, 24.90, 24.28, 24.08, 22.87, 22.08, 16.38, 16.29, 14.33, 14.28; HRMS (ESI+); m/z calcd for C.sub.51H.sub.49IrNO.sub.5 [M − OMs].sup.+ 948.3240, found 904.3246. (III-4) [00063] Brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.81 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.39 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.31-7.27 (m, 1H), 7.12 (s, 1H), 7.01 (ddd, J = 8.2, 6.7, 1.2 Hz, 1H), 6.93 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 6.84-6.78 (m, 2H), 6.71 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 2.3 Hz, 1H), 5.76 (t, J = 2.3 Hz, 1H), 5.35 (s, 1H), 5.23 (s, 1H), 4.73 (p, J = 6.0 Hz, 1H), 4.37 (p, J = 6.0 Hz, 1H), 4.21 (ddd, J = 10.4, 7.2, 3.3 Hz, 1H), 4.04-3.97 (m, 1H), 3.82-3.69 (m, 2H), 3.41 (s, 3H), 3.41 (s, 3H), 3.26 (d, J = 14.9 Hz, 1H), 2.83 (d, J = 13.3 Hz, 1H), 2.80-2.70 (m, 1H), 2.66-2.48 (m, 2H), 2.25 (s, 3H), 2.21 (s, 3H), 1.94-1.66 (m, 4H), 1.54-1.48 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H), 1.41 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.0 Hz, 3H), 0.93-0.88 (m, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) 185.37, 160.03, 155.06, 154.92, 153.44, 151.38, 148.30, 143.77, 138.39, 136.72, 135.96, 133.71, 133.64, 132.09, 129.16, 128.03, 127.96, 127.81, 127.29, 127.02, 126.91, 126.73, 126.71, 126.36, 125.88, 124.37, 124.11, 123.59, 123.02, 115.29, 110.05, 109.07, 107.00, 90.56, 83.28, 71.90, 71.82, 70.09, 69.88, 67.88, 59.67, 59.09, 37.01, 31.28, 28.88, 25.42, 24.08, 22.40, 22.32, 22.11, 21.87, 21.85, 16.21, 14.30, 1.16. HRMS (ESI+); m/z calcd for C.sub.55H.sub.57IrNO.sub.5 [M − OMs].sup.+ 1004.3866, found 1004.3861. (III-6) [00064] Brown solid. [α].sub.D.sup.25 = −29.6 (c = 0.06, CHCl.sub.3); IR (neat, cm.sup.−1); v.sub.max = 2935, 2177, 1736, 1594, 1563, 1543, 1505, 1454, 1463, 1243, 1227; .sup.1H NMR (400 MHz, CDCl.sub.3); δ = 7.90 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.49 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.32 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.17-7.08 (m, 3H), 6.97 (td, J = 8.2, 6.8, 0.7 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.79-6.70 (m, 2H), 6.40 (d, J = 2.3 Hz, 1H), 5.87 (t, J = 2.3 Hz, 1H), 5.28 (d, J = 14.6 Hz, 2H), 5.05 (q, J = 8.8, 8.1 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.47 (s, 3H), 3.30 (s, 3H), 2.93-2.68 (m, 3H), 2.60 (ddd, J = 16.9, 12.1, 4.6 Hz, 1H), 2.49 (dt, J = 17.1, 4.1 Hz, 1H), 2.23 (s, 3H), 1.92 (dt, J = 8.4, 4.3 Hz, 1H), 1.82 (d, J = 14.5 Hz, 1H), 1.78-1.66 (m, 1H); .sup.13C NMR (151 MHz, CDCl.sub.3) δ = 182.66, 164.32, 162.12, 157.39, 155.81, 155.35, 145.07, 141.18, 140.28, 139.81, 138.03, 136.02, 135.72, 133.90, 133.62, 128.03, 127.96, 127.24, 127.15, 127.08, 127.03, 126.77, 126.75, 126.71, 126.52, 126.41, 126.36, 126.21, 126.01, 125.92, 123.85, 121.36, 119.93, 109.95, 109.90, 107.18, 106.99, 105.55, 105.50, 104.01, 103.95, 96.17, 90.12, 85.56, 85.18, 72.09, 70.85, 67.44, 55.52, 55.45, 55.39, 55.14, 55.06, 54.56, 31.97, 30.74, 29.68, 29.32, 24.38, 24.14, 23.81, 22.69, 21.89, 14.19; HRMS (ESI+): m/z calcd for C.sub.47H.sub.41IrNO.sub.4 [M − OMs].sup.+ 876.2665, found 876.2656. (III-8) [00065] Brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 7.86 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 9.6 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.15 (s, 1H), 7.11 (s, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 5.99 (t, J = 2.6, 1.8 Hz, 1H), 5.24 (s, 1H), 5.15 (s, 1H), 5.02 (s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.46 (s, 3H), 3.27 (s, 3H), 2.93-2.49 (m, 6H), 2.21 (s, 6H), 1.98-1.65 (m, 4H), 0.97 (s, 3H); .sup.13C NMR (151 MHz, CDCl.sub.3) δ = 182.81, 165.10, 162.27, 155.86, 155.52,155.05, 145.14, 143.27, 140.43, 138.02, 135.89, 133.77, 133.67, 127.59, 127.27, 126.93, 126.81, 126.60, 126.11, 124.69, 124.21, 123.89, 123.67, 121.51, 110.49, 107.36, 105.75, 104.13, 88.16, 84.34, 74.93, 66.95, 59.76, 55.61, 55.55, 54.79, 38.58, 30.92, 29.83, 24.58, 24.05, 22.23, 16.35, 14.36, 14.29; HRMS (ESI+): m/z calcd for C.sub.49H.sub.45IrNO.sub.4 [M − OMs].sup.+ 904.2978, found 904.2975. (III-10) [00066] Brown solid. [α].sub.D.sup.25 = −55.1 (c = 0.37, CHCl.sub.3); IR (neat, cm.sup.−1); v.sub.max = 2928, 2240, 1729, 1618, 1595, 1561, 1545, 1243, 1227, 1195, 746, 731; .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 8.04 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.69 (t, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 7.33-7.17 (m, 4H), 7.11-7.03 (m, 2H), 6.95 (q, J = 7.3 Hz, 2H), 6.73 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 6.01 (s, 1H), 5.76 (d, J = 8.2 Hz, 1H), 5.56 (s, 1H), 5.19 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.34 (s, 3H), 3.29 (d, J = 7.6 Hz, 1H), 2.99-2.63 (m, 4H), 2.51 (d, J = 14.6 Hz, 2H), 2.24 (s, 3H), 1.98-1.86 (m, 1H), 1.86-1.69 (m, 3H); .sup.13C NMR (151 MHz, CDCl.sub.3) δ = 183.64, 165.42, 162.52, 156.00, 155.37, 145.55, 144.53, 140.13, 138.16, 135.81, 133.86, 133.61, 131.69, 131.14, 129.58, 127.77, 127.64, 127.51, 127.26, 127.12, 126.89, 126.84, 126.71, 126.68, 126.09, 125.82, 125.66, 124.33, 123.87, 123.50, 121.67, 121.25, 109.69, 107.49, 105.65, 104.25, 88.53, 84.77, 74.71, 67.03, 55.59, 55.49, 54.90, 38.61, 30.81, 24.53, 24.02, 21.46, 14.29; HRMS (ESI+): m/z calcd for C.sub.50H.sub.41IrNO.sub.3 [M − OMs].sup.+ 896.2716, found 896.2725. (III-12) [00067] Brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 7.86 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.59 (br. s, 1H), 7.42 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.32 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 7.14 (d, J = 10.2 Hz, 2H), 7.05 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 6.97 (ddd, J = 8.2, 5.9, 1.3 Hz, 1H), 6.90-6.82 (m, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.21 (s, 1H), 5.92 (t, J = 2.4 Hz, 1H), 5.26 (s, 1H), 5.03 (s, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.46 (s, 3H), 3.27 (s, 3H), 3.22 (d, J = 14.7 Hz, 1H), 2.92-2.79 (m, 2H), 2.75 (d, J = 13.8 Hz, 1H), 2.69-2.50 (m, 3H), 2.31 (br. s, 3H), 2.22 (s, 3H), 2.00-1.68 (m, 4H), 0.94 (s, 3H); .sup.13C NMR (151 MHz, CDCl.sub.3) δ = 182.77, 161.12, 155.87, 155.58, 154.91, 146.58, 137.73, 137.21, 135.84, 133.70, 133.46, 128.68, 127.53, 127.30, 127.22, 127.14, 126.91, 126.83, 126.42, 126.03, 124.88, 124.07, 123.81, 122.69, 116.94, 105.62, 103.95, 85.60, 59.75, 57.99, 55.66, 54.75, 31.59, 29.16, 25.08, 24.25, 22.00, 16.29, 14.32; HRMS (ESI+): m/z calcd for C.sub.49H.sub.45IrNO.sub.4 [M − OMs].sup.+ 904.2978, found 904.2976. (III-15) [00068] Brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 7.73-7.49 (br. m, 2H), 7.48-7.28 (br. m, 3H), 7.14-6.87 (br. m, 2H), 6.76-6.50 (br. m, 2H), 5.73-5.38 (br. m, 0.5H), 5.25-5.04 (br. m, 0.5H), 4.19-3.88 (br. m, 1H), 3.75 (s, 3H), 3.67-3.28 (br. m, 4H), 3.11-2.46 (br. m, 4H), 2.34 (s, 6H), 1.91-1.71 (br. m, 2H), 1.48 (s, 15H); HRMS (ESI+); m/z calcd for C.sub.38H.sub.45IrNO.sub.3 [M − OMs].sup.+ 756.3029, found 756.3032. (III-16- [00069] Brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.58 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.83-6.69 (m, 6H), 6.43-6.38 (m, 1H), 5.79 (t, J = 2.3 Hz, 1H), 5.41 (s, 1H), 4.21 (ddd, J = 10.4, 6.8, 3.6 Hz, 1H), 4.01 (dt, J = 10.6, 3.8 Hz, 1H), 3.79-3.71 (m, 5H), 3.69 (s, 3H), 3.63 (s, 3H), 3.58 (s, 3H), 3.43 (s, 3H), 3.12 (s, 3H), 3.07 (d, J = 14.9 Hz, 1H), 2.86-2.72 (m, 2H), 2.67-2.58 (m, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.03 (s, 3H), 1.89 (tt, J = 9.0, 4.4 Hz, 1H), 1.80 (d, J = 13.8 Hz, 1H), 1.77-1.70 (m, 2H). HRMS (ESI+); m/z calcd for C.sub.45H.sub.49IrNO.sub.7 [M − OMs].sup.+ 908.3138, found 908.3136. (III-18) [00070] Brown solid. [α].sub.D.sup.25 = −52.5 (c = 0.34, CHCl.sub.3); IR (neat, cm.sup.−1); v.sub.max = 2931, 1618, 1596, 1560, 1450, 1226, 749; .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 7.85 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 7.41 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.31 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.14 (d, J = 2.8 Hz, 2H), 7.04 (ddd, J = 8.2, 6.7, 1.2 Hz, 1H), 6.96 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 6.85 (t, J = 7.4 Hz, 2H), 6.74 (t, J = 8.4 Hz, 2H), 6.40 (s, 1H), 5.88 (s, 1H), 5.29 (s, 1H), 5.08 (s, 1H), 4.27-4.19 (m, 1H), 4.04-3.97 (m, 1H), 3.93 (s, 4H), 3.83-3.70 (m, 2H), 3.44 (s, 3H), 3.42 (s, 3H), 3.31 (s, 3H), 3.25 (d, J = 14.8 Hz, 1H), 3.10 (dt, J = 16.1, 8.2 Hz, 1H), 2.88 (dt, J = 15.3, 4.4 Hz, 1H), 2.74 (d, J = 13.7 Hz, 1H), 2.70-2.64 (m, 2H), 2.37 (s, 2H), 2.23 (s, 4H), 1.95-1.87 (m, 1H), 1.84 (d, J = 13.7 Hz, 1H), 1.77 (d, J = 14.8 Hz, 1H), 1.74-1.61 (m, 1H), 0.95 (s, 3H); .sup.13C NMR (151 MHz, CDCl.sub.3) mixture of (III)-18 and aqua-(III)-18) δ = 189.78, 187.51, 160.30, 159.90, 155.97, 155.63, 155.59, 155.31, 155.11, 154.89, 150.59, 149.49, 145.21, 144.27, 138.56, 137.92, 137.67, 137.26, 136.10, 135.87, 133.75, 133.73, 133.61, 133.53, 132.29, 131.54, 129.27, 128.96, 128.12, 127.75, 127.66, 127.54, 127.52, 127.39, 127.27, 127.23, 127.17, 126.94, 126.90, 126.87, 126.81, 126.78, 126.48, 126.31, 126.05, 126.00, 125.65, 125.34, 124.80, 124.46, 124.15, 123.99, 123.82, 122.04, 121.61, 117.35, 114.57, 105.67, 105.62, 104.50, 104.29, 89.39, 86.33, 84.32, 83.84, 73.18, 72.63, 71.95, 71.86, 69.68, 67.97, 59.75, 59.13, 59.02, 55.65, 55.59, 55.10, 55.01, 31.84, 31.66, 30.97, 30.89, 30.45, 25.75, 25.57, 25.11, 25.02, 23.17, 22.84, 22.52, 21.89, 16.42, 16.33, 14.39, 14.34; HRMS (ESI+); m/z calcd for C.sub.52H.sub.51IrNO.sub.5 [M − OMs].sup.+ 962.3396, found 962.3401 (III-19) [00071] Brown solid. [α].sub.D.sup.25 = −146.7 (c = 0.30, CHCl.sub.3); IR (neat, cm.sup.−1); v.sub.max = 2932, 1730, 1598, 1560, 1245; .sup.1H NMR (400 MHz, CDCl.sub.3) (complex mixture of 4 different species): δ = 8.05 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.90-7.79 (m, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.48-7.27 (m, 2H), 7.22 (t, J = 5.0 Hz, 1H), 7.15 (d, J = 3.9 Hz, 1H), 7.11 (dd, J = 10.2, 7.9 Hz, 1H), 7.08-6.93 (m, 3H), 6.90 (d, J = 8.6 Hz, 1H), 6.87-6.79 (m, 1H), 6.79-6.69 (m, 1H), 6.61-6.50 (m, 1H), 6.47 (s, 1H), 6.37 (s, 1H), 6.34 (s, 1H), 6.27 (s, 1H), 6.20-6.09 (m, 1H), 6.00 (t, J = 2.4 Hz, 1H), 5.99-5.96 (m, 1H), 5.95-5.89 (m, 1H), 5.54-5.50 (m, 1H), 5.49-5.45 (m, 1H), 5.45-5.42 (m, 1H), 5.39-5.34 (m, 1H), 5.01 (s, 1H), 4.97 (s, 1H), 4.94 (s, 1H), 4.69 (s, 1H), 4.38-4.19 (m, 1H), 4.19-4.03 (m, 1H), 4.03-3.84 (m, 3H), 3.80-3.58 (m, 3H), 3.49-3.44 (m, 3H), 3.44-3.39 (m, 3H), 3.34 (d, J = 5.4 Hz, 1H), 3.11-3.05 (m, 2H), 2.87-2.70 (m, 1H), 2.64-2.50 (m, 1H), 2.26-1.86 (m, 4H), 0.88 (td, J = 7.0, 5.9, 3.0 Hz, 3H); HRMS (ESI+): m/z calcd for C.sub.50H.sub.47IrNO.sub.6 [M − OMs].sup.+ 950.3033, found 950.3025. (III-22-ent) [00072] Brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of (III)-21: aqua-(III)-21 in a 0.8:0.2 ratio) (only peaks corresponding to (III)-21 are shown unless otherwise stated) δ = 7.95 (d, J = 8.9 Hz, 2H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.46 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 7.32 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.27-7.21 (m, 3H), 7.18-7.12 (m, 4H), 7.08-7.01 (m, 3H), 6.94 (d, J = 8.1 Hz, 1H), 6.75 (dd, J = 8.2, 2.8 Hz, 2H), 6.49 (d, J = 8.5 Hz, 1H), 6.13 (d, J = 2.7 Hz, 1H), 6.07 (d, J = 8.2 Hz, 2H), 5.62 (d, J = 2.6 Hz, 1H), 5.46 (t, J = 2.2 Hz, 1H), 4.92 (t, J = 2.3 Hz, 0.2H, aqua-(III)-22), 4.69 (s, 1H), 4.21-4.10 (m, 1H), 4.01-3.94 (m, 4H), 3.78-3.58 (m, 5H), 3.34 (s, 3H), 3.31 (s, 3H), 2.96-2.86 (m, 2H), 2.79-2.71 (m, 1H), 2.64-2.45 (m, 2H), 2.17 (s, 3H), 2.15-2.06 (m, 2H), 2.00 (s, 3H), 1.92-1.59 (m, 2H), 1.03 (s, 3H). HRMS (ESI+): m/z calcd for C.sub.63H.sub.57IrNO.sub.5 [M − OMs].sup.+ 1100.3866, found 1100.3875. (III-23-ent) [00073] Brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) shows a complex mixture of different isomers/species. HRMS (ESI+): m/z calcd for C.sub.69H.sub.57IrNO.sub.3 [M − OMs].sup.+ 1140.3968, found 1140.3962. (III-24-ent) [00074] Brown solid. [α].sub.D.sup.25 = −69.7 (c = 0.50, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 8.01-7.95 (m, 2H), 7.85-7.76 (m, 3H), 7.56-7.45 (m, 5H), 7.39-7.28 (m, 4H), 7.24-7.14 (m, 4H), 7.11-7.04 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.62-6.55 (m, 1H), 6.53 (d, J = 8.5 Hz, 1H), 6.21 (t, J = 1.7 Hz, 1H), 5.60-5.55 (m, 2H), 4.58 (d, J = 10.2 Hz, 1H), 4.51 (d, J = 1.9 Hz, 1H), 3.71 (s, 3H), 3.40-3.32 (m, 4H), 2.93 (d, J = 16.0 Hz, 1H), 2.85 (d, J = 13.6 Hz, 1H), 2.80-2.71 (m, 1H), 2.66-2.45 (m, 2H), 2.35-2.21 (m, 1H), 2.15 (s, 3H), 2.01 (s, 3H), 1.88-1.62 (m, 2H), 1.04 (s, 3H). HRMS (ESI+): m/z calcd for C.sub.61H.sub.51IrNO.sub.4 [M − OMs].sup.+ 1054.3447, found 1054.3443.

Example 7: General Procedure 4: Synthesis of Oxime Ether Substrates (I)

[0365] ##STR00075##

[0366] In a Teflon-capped sealed tube, the alkoxylammonium chloride (H) (1.2 to 3.0 eq) was added to a solution of the ketone (K) (1.0 eq) in EtOH (0.3 M). Water (0.33 v/v) was added and the mixture was stirred at room temperature for 5 min. Sodium acetate (1.5 to 4.0 eq) was added portion-wise and the reaction mixture was stirred at 7000 for 16 h. After cooling to room temperature, the reaction mixture was partitioned between CH.sub.2Cl.sub.2 and water. The aqueous phase was extracted twice with CH.sub.2Cl.sub.2. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product (typically a mixture of E/Z diastereoisomers) was purified by flash column chromatography to afford the desired E or Z oxime ether product.

Example 8: General Procedure 5: Synthesis of 4-substituted-1H-2,3-benzoxazines (I-31) and (I-32) Via Cyclodehydration of N-(benzyloxy)carboxamides (XV-31) and (XV-32)

[0367] ##STR00076##

[0368] Step 1: In a round-bottom flask, the corresponding acyl chloride [A] (1.1 eq.) was added dropwise to a solution of O-benzylhydroxylamine hydrochloride [H] (1.0 eq.) and trimethylamine (2.2 eq.) in dichloromethane (0.2 M) at 0° C. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was washed with H.sub.2O, dried over Na.sub.2SO.sub.4, filtered, and the solvent removed under reduced pressure to afford the crude product. Filtration through a short silica plug, eluting with pent:EtOAc 50:50 afforded the pure N-(benzyloxy)carboxamide product (XV) in a quantitative yield (XV-31; Synth. Commun. 2005, 731) (XV-32; Bioorg. Med. Chem. Lett. 2015, 4933).

[0369] Step 2: In aflame-dried Schlenk tube, under a nitrogen atmosphere, trifluoromethanesulfonic anhydride (1.1 eq.) was added dropwise to a stirred mixture of the corresponding N-(benzyloxy)carboxamide (XV) (1.0 eq.) and 2-chloropyridine (1.2 eq.) in dichloromethane (0.25 M) at −78° C. After 5 min, the reaction mixture was placed in an ice-water bath and warmed to 0° C. After 15 min, the reaction mixture was stirred at room temperature for further 2 h. The reaction was quenched with NaHCO.sub.3 (sat., aq.). The aqueous phase was extracted twice in CH.sub.2Cl.sub.2, the combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent removed under reduced pressure to afford the crude product. Purification by flash column chromatography (SiO.sub.2, pent:EtOAc 99:1 to 90:10) afforded the pure product (I-31, 60% yield; I-32, 65% yield). Experimental data of compounds (I-31) and (I-32) included in Table 4.

TABLE-US-00004 TABLE 4 Physical data of compounds (I) prepared according to the General Procedure 4: Cpd. No. Structure Characterization Data (E-I-1) [00077] The analytical data are in accordance with WO2013/127764 A1. Colourless solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.33 (s, 2H), 3.79 (s, 2H), 3.78 (s, 3H), 1.80 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 153.09, 136.79, 133.27, 132.18, 128.24, 61.59, 36.96, 13.86. (Z-I-1) [00078] The analytical data are in accordance with WO2013/127764 A1. Pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.35 (s, 2H), 4.00 (s, 2H), 3.90 (s, 3H), 1.60 (s, 3H). (E-I-2) [00079] Colourless solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 8.19 (s, 1H), 7.33 (s, 2H), 3.78 (s, 2H), 1.91 (s, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 154.43, 136.54, 133.45, 131.95, 128.26, 36.98, 13.88. (E-I-3) [00080] Pale yellow oil. IR (neat, cm−1): v.sub.max = 2923, 1581, 1548, 1453, 1439, 1369, 1018, 854, 696; .sup.1H NMR (400 MHz, CDCl.sub.3) (E isomer): δ = 7.36-7.26 (m, 7H), 5.01 (s, 2H), 3.79 (s, 2H), 1.85 (s, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 153.57, 138.35, 136.77, 133.19, 132.26, 128.30, 128.15, 127.71, 75.74, 37.02, 14.30; HRMS (EI+): m/z calcd for C16H15Cl3NO [M + H]+ 342.0214, found 342.0211. (E-I-4) [00081] Colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.31 (s, 2H), 3.76 (s, 2H), 1.83 (s, 3H), 1.15 (s, 9H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 150.71, 136.64, 133.04, 132.78, 127.91, 78.05, 37.37, 27.64, 14.10. (E-I-5) [00082] Colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.32 (s, 2H), 5.10 (t, J = 4.3 Hz, 1H), 4.01 (d, J = 4.3 Hz, 2H), 3.99-3.85 (m, 4H), 3.78 (s, 2H), 1.86 (s, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 154.08, 136.74, 133.29, 132.05, 128.21, 102.14, 74.26, 65.18, 36.93, 14.24. (E-I-6) [00083] The analytical data are in accordance with Chem. Commun., 2017, 53, 12189. Colourless liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.17-7.10 (m, 2H), 6.87-6.81 (m, 2H), 3.88 (s, 3H), 3.79 (s, 3H), 3.40 (s, 2H), 1.72 (s, 3H). (E-I-7) [00084] Colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.60-7.53 (m, 1H), 7.30-7.22 (m, 2H), 7.13-7.07 (m, 1H), 3.89 (s, 3H), 3.67 (s, 2H), 1.78 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 155.75, 136.78, 133.06, 130.76, 128.50, 127.69, 125.13, 61.52, 41.58, 13.87. (Z-I-7) [00085] Colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.56 (dd, J = 7.9, 1.3 Hz, 1H), 7.29-7.22 (m, 1H), 7.19 (dd, J = 7.7, 1.9 Hz, 1H), 7.11 (td, J = 7.7, 1.9 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 2H), 1.75 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 155.16, 136.52, 132.96, 130.79, 128.39, 127.77, 125.15, 61.48, 35.78, 19.73. (E-I-8) [00086] Colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 6.85 (s, 2H), 3.84 (s, 3H), 3.53 (s, 2H), 2.29 (s, 6H), 2.26 (s, 3H), 1.67 (s, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 156.11, 137.45, 136.15, 130.56, 129.21, 61.40, 35.47, 20.99, 20.47, 13.06. (I-9) [00087] Colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.7:0.3 ratio) δ = 7.41-7.15 (m, 10H, E + Z), 5.99 (s, 0.3H, Z), 5.08 (s, 0.7H, E), 3.93 (s, 2.1H, E), 3.89 (s, 0.9H, Z), 1.88 (s, 2.1H, E), 1.80 (s, 0.9H, Z). .sup.13C NMR (101 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.7:0.3 ratio) δ = 158.10 (E), 157.30 (Z), 140.54 (E), 140.34 (Z), 129.22 (Z), 129.18 (E), 128.56 (Z), 128.51 (E), 126.88 (E), 126.80 (Z), 61.60 (E), 61.56 (Z), 56.82 (E), 49.25 (Z), 19.04 (Z), 13.88 (E). (E-I-10) [00088] Colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.35-7.27 (m, 4H), 7.25-7.18 (m, 1H), 3.93 (s, 3H), 1.56 (s, 3H), 1.48 (s, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 162.09, 146.64, 128.48, 126.37, 126.22, 61.50, 45.31, 26.98, 12.46. (E-I-11) [00089] Compound described in Chem. Commun. 2007, 1530; no characterization data given. Colourless liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 3.81 (s, 3H), 2.20-2.09 (m, 1H), 1.84-1.62 (m, 7H), 1.38-1.09 (m, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 161.164, 61.13, 44.61, 30.28, 26.17, 26.15, 11.74. (E-I-12) [00090] The analytical data are in accordance with J. Am. Chem. Soc. 1996, 118, 5138. (E-I-13) [00091] The analytical data are in accordance with J. Chem. Soc., Perkin Trans. 1, 2000, 3250. (E-I-14) [00092] Compound described in Chem. Commun. 2007, 1530; no experimental data given. Colourless liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 3.82 (s, 3H), 2.05-1.98 (m, 3H), 1.78-1.63 (m, 15H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 163.79, 61.16, 39.62, 38.99, 36.96, 28.35, 9.59. (Z-I-15) [00093] Colourless solid; m.p. = 71-73° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 4.18 (d, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.12 (t, J = 7.0 Hz, 1H), 2.06- 1.99 (m, 3H), 1.79-1.62 (m, 12H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 165.92, 61.78, 56.03, 38.92, 38.49, 36.73, 28.03. (Z-I-16) [00094] Colourless solid; m.p. = 80-82° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.84-7.78 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.58 (s, 2H), 3.67 (s, 3H), 2.46 (s, 3H), 2.03-1.95 (m, 3H), 1.76-1.58 (m, 12H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 157.57, 144.92, 132.75, 129.73, 128.42, 61.72, 58.47, 39.32, 38.69, 36.60, 28.08, 21.81. (E-I-17) [00095] The analytical data are in accordance with J. Org. Chem. 2006, 71, 3998. (I-18) [00096] 50:50 E:Z mixture. The analytical data are in accordance with Org. Lett. 2018, 20, 4994-4997 and ACS Catal. 2016, 6, 3890-3894. (E-I-19) [00097] Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.31 (dd, J = 8.9, 2.7 Hz, 2H), 6.87 (dd, J = 8.9, 2.7 Hz, 2H), 3.91 (s, 3H), 3.81 (s, 3H), 3.19 (tt, J = 12.2, 3.1 Hz, 1H), 1.81-1.62 (m, 5H), 1.47 (qd, J = 11.8, 2.5 Hz, 2H), 1.33 (qt, J = 12.4, 3.0 Hz, 2H), 1.16 (qt, J = 12.9, 3.0 Hz, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 163.82, 159.87, 129.42, 128.82, 113.62, 61.75, 55.42, 39.01, 29.61, 26.51, 26.18. (Z-I-19) [00098] Colourless solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.22-7.15 (m, 2H), 6.95-6.87 (m, 2H), 3.82 (s, 3H), 3.80 (d, J = 1.1 Hz, 3H), 2.44 (tt, J = 11.3, 2.6 Hz, 1H), 1.89-1.70 (m, 4H), 1.70-1.60 (m, 1H), 1.38-1.06 (m, 5H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ 161.93, 159.42, 129.09, 126.74, 113.58, 61.65, 55.32, 44.46, 30.94, 26.39, 26.19. (I-20) [00099] 45:55 E:Z mixture. Colourless liquid; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.45:0.55 ratio) δ = 7.42-7.30 (m, 4H, E + Z), 7.22-7.17 (m, 1H, E + Z), 3.94 (s, 1.35H, E), 3.80 (s, 1.65H, Z), 3.23 (tt, J = 12.2, 3.2 Hz, 0.45H, E), 2.46 (ddq, J = 11.3, 7.7, 3.3 Hz, 0.55H), 1.92-1.60 (m, 5H, E + Z), 1.54-1.07 (m, 5H, E + Z); .sup.13C NMR (101 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.45:0.55 ratio) δ = 164.20 (E), 162.48 (Z), 136.27, 134.67, 128.42, 128.19, 128.16, 128.12, 127.53, 61.82, 61.68, 44.38, 38.85, 30.77, 29.56, 26.44, 26.30, 26.12. (I-21) [00100] 50:50 E:Z mixture. (E-isomer): colourless liquid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.30 (ddd, J = 8.2, 7.4, 1.8 Hz, 1H), 7.09 (dd, J = 7.4, 1.8 Hz, 1H), 6.93 (td, J = 7.4, 1.0 Hz, 1H), 6.88 (dd, J = 8.3, 1.0 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 3.12 (tt, J = 11.6, 3.4 Hz, 1H), 1.88-1.77 (m, 2H), 1.74-1.58 (m, 2H), 1.38-1.14 (m, 5H), 1.08 (at, J = 12.9, 3.5 Hz, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 163.70, 157.62, 130.65, 129.76, 125.40, 120.36, 110.90, 61.74, 55.43, 39.31, 28.91, 26.34, 26.21. (Z-isomer): colourless liquid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.34- 7.27 (m, 1H), 7.01-6.91 (m, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 2.43 (tt, J= 11.4, 3.4 Hz, 1H), 1.93-1.81 (m, 2H), 1.81-1.67 (m, 2H), 1.67-1.59 (m, 1H), 1.36-1.06 (m, 5H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 160.90, 155.87, 129.42, 128.55, 124.38, 120.32, 111.23, 61.67, 55.82, 44.16, 30.46, 26.35, 26.18. (I-22) [00101] Compound described in U.S. Pat. No. 5,354,865; no characterization data given, 40:60 E:Z mixture. Pale yellow solid; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.4:0.6 ratio) δ = 7.92-7.81 (m, 4H, E + Z), 7.59- 7.45 (m, 3H, E + Z), 7.36-7.26 (m, 1H, E + Z), 7.05-6.94 (m, 2H, E + Z), 6.88-6.77 (m, 1H, E + Z), 5.25 (s, 0.8H, E), 5.24 (s, 1.2H, Z), 3.98-3.88 (m, 3.2H, E + Z), 3.80 (s, 1.8H, Z), 3.49-3.29 (m, 2.4H, E + Z), 2.64 (tt, J = 8.7, 5.9 Hz, 0.6H, Z), 1.86 (dtd, J = 13.4, 12.2, 4.5 Hz, 1H, E + Z), 1.70-1.54 (m, 3H, E + Z); .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 161.83, 160.04, 158.65, 158.58, 136.93, 135.21, 134.43, 134.37, 133.42, 133.39, 133.20, 129.51, 128.57, 128.06, 128.04, 127.86, 126.56, 126.49, 126.42, 126.39, 126.27, 126.23, 125.40, 125.37, 120.80, 120.17, 115.25, 114.97, 114.95, 114.50, 70.36, 70.33, 68.04, 67.81, 62.01, 61.91, 41.29, 36.13, 30.38, 29.07. (I-23) [00102] Compound described in Bioorg. Med. Chem. Lett. 2007 3894; no characterization data given. 50:50 E:Z mixture. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 1:1 ratio) δ = 7.70-7.57 (m, 4H), 7.53-7.44 (m, 2H), 7.34- 7.27 (m, 2H), 3.95 (s, 3H), 3.79 (s, 3H), 3.23 (tt, J = 12.1, 3.1 Hz, 1H, E), 2.46 (tq, J = 11.6, 3.3 Hz, 1H, Z), 1.90-1.62 (m, 10H), 1.51-1.06 (m, 10H); .sup.19F NMR (376 MHz, CDCl.sub.3) δ = −62.73, −62.74; .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 162.93, 161.24, 139.90, 138.38, 131.03, 130.71, 130.42, 130.38, 130.10, 129.77, 128.58, 128.25, 128.20, 128.04, 125.23, 125.19, 125.15, 125.11, 122.84, 122.79, 120.14, 120.08, 62.07, 61.84, 44.19, 38.74, 30.67, 29.53, 26.39, 26.21, 26.07, 26.04. (I-24) [00103] 50:50 E:Z mixture. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 1:1 ratio) δ = 7.48-7.33 (m, 6H), 7.23-7.17 (m, 2H), 6.74 (dd, J = 17.6, 10.9 Hz, 2H), 5.79 (ddd, J = 17.6, 1.8, 0.9 Hz, 2H), 5.29 (ddd, J = 10.9, 1.7, 0.9 Hz, 2H), 3.96 (s, 3H), 3.82 (s, 3H), 3.23 (tt, J = 12.3, 3.1 Hz, 1H), 2.48 (tt, J = 11.2, 3.3 Hz, 1H), 1.93- 1.63 (m, 10H), 1.57-1.08 (m, 10H); .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 163.82, 162.19, 137.71, 137.50, 136.54, 136.51, 135.70, 134.03, 128.34, 127.85, 126.01, 125.98, 114.52, 114.45, 61.86, 61.72, 44.33, 38.90, 30.80, 29.55, 26.47, 26.31, 26.15, 26.13. (I-25) [00104] 60:40 E:Z mixture. Pale yellow oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.6:0.4 ratio) δ = 8.28 (t, J = 2.0 Hz, 0.6H, E), 8.21-8.12 (m, 1.4H, E + Z), 7.77 (dt, J = 7.8, 1.3 Hz, 0.6H, E), 7.59 (dt, J = 7.7, 1.4 Hz, 0.4H), 7.56-7.45 (m, 1H, E + Z), 3.15 (tt, J = 12.2, 3.3 Hz, 0.6H, E), 2.52 (tt, J = 10.9, 3.4 Hz, 0.4H, Z), 1.90-1.54 (m, 5H, E + Z), 1.42-1.10 (m, 14H, E + Z). .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 159.29 (E), 157.12 (Z), 148.12, 148.05, 139.32, 136.71, 134.54, 133.97, 129.00, 128.83, 123.29, 122.92, 122.87, 122.82, 79.10, 78.85, 44.01, 39.26, 30.90, 29.27, 27.68, 27.53, 26.61, 26.23, 26.20. (I-26) [00105] 55:45 E:Z mixture. Yellow oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.55:0.45 ratio) δ = 7.40-7.35 (m, 1.1H, E), 7.24-7.17 (m, 0.9H, Z), 7.06-7.02 (m, 0.9H, Z), 7.02-6.98 (m, 1.1H, E), 3.93 (s, 1.65H, E), 3.79 (s, 1.35H, Z), 3.19 (tt, J = 12.2, 3.1 Hz, 0.55H, E), 2.50-2.37 (m, 0.45H, Z), 1.89-1.61 (m, 5H, E + Z), 1.52- 1.07 (m, 5H, E + Z). .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 163.21 (E), 161.40 (Z), 140.27, 139.95, 133.05, 131.15, 129.66, 129.28, 118.83, 118.79, 61.90, 61.75, 44.29, 38.87, 30.81, 29.55, 26.44, 26.29, 26.12. (I-27) [00106] 50:50 E:Z mixture. Colourless oil; .sup.1H NMR (600 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 1:1 ratio) δ = 7.85-7.80 (m, 2H), 7.80-7.75 (m, 2H), 7.37- 7.33 (m, 2H), 7.20-7.15 (m, 2H), 3.93 (s, 3H), 3.77 (s, 3H), 3.20 (tt, J = 12.3, 3.2 Hz, 1H, E), 2.44 (tq, J = 11.1, 3.4 Hz, 1H, Z), 1.89- 1.61 (m, 10H), 1.49-1.05 (m, 34H). .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 164.10 (E), 162.63 (Z), 138.98, 137.61, 134.58, 134.53, 127.47, 126.82, 83.97, 61.87, 61.70, 44.29, 38.82, 30.71, 29.54, 26.44, 26.26, 26.13, 26.09, 25.01, 24.99. (I-28) [00107] 45:55 E:Z mixture. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.45:0.55 ratio) δ = 7.49 (ddd, J = 7.7, 4.6, 1.1 Hz, 1H, E + Z), 7.28-7.23 (m, 0.55H, Z), 7.20 (dd, J = 3.7, 1.0 Hz, 0.45H, E), 7.08 (dd, J = 5.2, 3.9 Hz, 0.55H, Z), 7.00 (dd, J = 5.1, 3.7 Hz, 0.45H, E), 4.02 (s, 1.65H, Z), 3.94 (s, 1.35H, E), 3.54 (p, J = 9.1 Hz, 0.45H, E), 3.27 (p, J = 8.0 Hz, 0.55H, Z), 2.05-1.58 (m, 8H). .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 157.56 (E), 151.76 (Z), 139.28, 133.05, 129.83, 129.24, 127.03, 126.49, 126.28, 125.58, 62.10, 61.88, 43.69, 38.72, 31.43, 30.07, 26.75, 25.49. (I-29) [00108] 60:40 E:Z mixture. Colourless solid; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.60:0.40 ratio) δ = 7.92-7.83 (m, 2.4H, E + Z), 7.65- 7.57 (m, 1H, E + Z), 7.51 (tt, J = 8.2, 1.3 Hz, 2H, E + Z), 7.31 (t, J = 1.9 Hz, 0.6H, E), 7.13 (dd, J = 3.4, 2.3 Hz, 0.4H, Z), 7.11 (dd, J = 3.3, 2.2 Hz, 0.6H, E), 6.56 (dd, J = 3.4, 1.6 Hz, 0.4H, Z), 6.50 (dd, J = 3.3, 1.6 Hz, 0.6H, E), 3.93 (s, 1.2H, Z), 3.87 (s, 1.8H, E), 3.06 (tt, J = 11.9, 3.7 Hz, 0.6H, E), 2.45 (tt, J = 11.5, 3.1 Hz, 0.4H, Z), 1.90-1.51 (m, 6H, E + Z), 1.46-1.14 (m, 4H, E + Z). .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 157.52 (E), 152.93 (Z), 138.90, 138.81, 134.22, 134.15, 129.63, 129.60, 127.11, 127.07, 124.63, 124.05, 121.00, 119.99, 119.96, 119.30, 114.24, 113.68, 62.04, 61.89, 42.63, 38.78, 31.75, 29.28, 26.72, 26.51, 26.30, 26.12. (Z-I-30) [00109] The analytical data are in accordance with Tetrahedron 2004, 60, 3893. (I-31) [00110] Synthesized according to General Procedure 5. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.49-7.36 (m, 3H), 7.18-7.12 (m, 1H), 4.84 (s, 2H), 2.88 (tt, J = 11.5, 3.2 Hz, 1H), 2.05-1.93 (m, 2H), 1.91-1.80 (m, 2H), 1.80-1.70 (m, 1H), 1.59- 1.21 (m, 5H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 163.36, 133.12, 131.53, 128.42, 124.51, 123.19, 122.45, 66.69, 39.49, 31.22, 26.58, 26.30. (I-32) [00111] Synthesized according to General Procedure 5. The analytical data are in accordance with Org. Biomol. Chem., 2018, 16, 6284. (E-I-33) [00112] Compound described in Org. Lett. 2017 3199; no characterization data given. Colourless liquid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.78 (dd, J = 5.4, 3.1 Hz, 2H), 7.65 (dd, J = 5.5, 3.0 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 4.44 (t, J = 5.2 Hz, 2H), 4.05 (t, J = 5.2 Hz, 2H), 3.29-3.23 (m, 5H), 2.68 (t, J = 7.4 Hz, 1H), 1.62- 1.42 (m, 4H). .sup.19F NMR (376 MHz, CDCl.sub.3) δ = −62.78; .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 168.33, 158.04, 139.04, 134.28, 133.99, 132.27, 131.26, 130.94, 130.62, 130.30, 126.58, 125.37, 125.34, 125.30, 125.26, 123.25, 72.35, 70.79, 58.63, 38.06, 29.63, 26.23, 23.04. (I-34) [00113] 65:35 E:Z mixture. Pale yellow oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.65:0.35 ratio) δ = 8.29 (ddd, J = 7.8, 1.3, 0.7 Hz, 0.35H, Z), 7.74-7.70 (m, 0.65H, E), 7.43-7.24 (m, 3H, E + Z), 4.06 (dd, J = 9.4, 4.1 Hz, 0.65H, E), 4.03 (s, 1.05H, Z), 3.98 (s, 1.95H, E), 3.95 (dd, J = 8.6, 4.3 Hz, 0.35H, Z), 3.77 (s, 1.05H, Z), 3.71 (s, 1.95H, E), 3.46-3.28 (m, 1.35H, E + Z), 3.15 (ddq, J = 17.2, 4.3, 0.8 Hz, 0.65H, E): .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 172.72 (Z), 172.47 (E), 159.22 (E), 156.87 (Z), 146.96 (Z), 146.03 (E), 135.30 (E), 132.85 (Z), 131.47 (Z), 130.81 (E), 129.42 (Z), 127.63 (E), 127.26 (Z), 125.44 (E), 125.39 (Z), 122.03 (E), 62.79 (Z), 62.48 (E), 52.62 (Z), 52.38 (E), 46.64 (Z), 44.83 (E), 34.2 (E), 33.49 (Z). (I-35) [00114] Compound described in J. Org. Chem. 2010, 914; no characterization data given. 70:30 E:Z mixture. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of E:Z isomers in a 0.70:0.30 ratio) δ = 8.17 (d, J = 7.8 Hz, 0.3H, Z), 7.55 (d, J = 7.6 Hz, 0.7H, E), 7.28-7.07 (m, 3H, E + Z), 3.88 (s, 0.9H, Z), 3.85 (s, 2.1H, E), 3.33 (pd, J = 7.3, 2.0 Hz, 0.7H, E), 3.15 (dt, J = 16.7, 8.3 Hz, 1H, E + Z), 2.98 (pd, J = 7.1, 4.1 Hz, 0.3H, Z), 2.53 (dd, J = 16.5, 4.2 Hz, 0.3H, Z), 2.49-2.40 (m, 0.7H, E), 1.20 (d, J = 7.0 Hz, 0.9H, Z), 1.15 (d, J = 7.2 Hz, 2.1H, E); .sup.13C NMR (101 MHz, CDCl.sub.3) (E + Z isomers) δ = 166.17 (E), 162.92 (Z), 147.65 (Z), 146.81 (E), 135.52 (E), 133.38 (Z), 130.99 (Z), 130.38 (E), 129.53 (Z), 127.10 (E), 126.85 (Z), 125.83 (E), 125.57 (Z), 121.89 (E), 62.26 (Z), 62.06 (E), 38.30 (E), 38.10 (Z), 36.42 (Z), 34.52 (E), 20.45 (Z), 18.61 (E). (Z-I-36) [00115] Colourless liquid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 4.30 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 2.68 (hept, J = 6.9 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.14 (d, J = 7.0 Hz, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 164.14, 156.62, 62.25, 61.40, 31.07, 19.65, 14.37. (E-I-37) [00116] Synthesized according to Tetrahedron: Asymmetry 1997, 2649, Experimental data are in accordance with the referred publication.

Example 9: Synthesis of Enantioenriched (2R)-N-methoxy-1-(2,4,6-trichlorophenyl) propan-2-amine (II-1) Via Asymmetric Oxime Hydrogenation

[0370] ##STR00117##

[0371] A 50 mL Hastelloy reactor with glass inlet was charged with (E)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-imine (I-1) (267 mg), catalyst (III-1) (9.5 mg), iPrOH (5 mL, anhydrous, degassed with argon), and methanesulfonic acid (144 mg) under argon. The reactor was purged with hydrogen (3×5 bar), pressurized to 50 bar H.sub.2 and stirred for 16 h at 23° C. Hydrogen was released and the reactor was purged with argon. GC and NMR analysis of the crude reaction mixture indicated full conversion. The reaction mixture was added slowly onto sat. NaHCO.sub.3 solution (15 mL) and water (10 mL), and was extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and evaporated. The crude product was further purified by column chromatography (silica, ethyl acetate-cyclohexane gradient) to give 250 mg of the desired product (II-1). Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.32 (s, 2H), 5.47 (br. s, 1H), 3.55 (s, 3H), 3.44 (dp, J=8.0, 6.4 Hz, 1H), 3.16 (dd, J=13.4, 5.9 Hz, 1H), 2.91 (dd, J=13.4, 8.0 Hz, 1H), 1.08 (d, J=6.5 Hz, 3H). Chiral SFC analysis: Column=Daicel Chiralpak IA 3×100 mm, particle size=3μ, λ=220 nm, CO.sub.2:iPrOH 85:15, flow=2.0 ml/min, T=40° C.; t.sub.R,A=0.45 min (minor enantiomer, 34%), t.sub.R,B=0.51 min (major enantiomer, 66%).

TABLE-US-00005 TABLE 5 Synthesis of enantioenriched N-methoxy-1-(2,4,6-trichlorophenyl)propan-2- amine (III-1) via asymmetric hydrogenation of oxime ether (I-1); screeening of catalysts (III); [00118] [00119]

[0372] Standard conditions: according to the general procedure 4, E-oxime (E-I-1) was reacted with 1.5 eq of methanesulfonic acid, iPrOH solvent (0.5 mol oxime/1 L solvent), 1 mol % catalyst (III), 50 bar H.sub.2, RT, 20 h, unless otherwise indicated. In all reactions high selectivity towards the desired product (>95%) was observed.

TABLE-US-00006 TABLE 6 Stereospecific asymmetric hydrogenation of E or Z-oxime ethers (I-1) and (I-7) to yield enantioenriched alkoxylamines (II-1) and (II-7); variations of solvents and acids: Deviation from the Conversion R:S-Enantiomeric Catalyst standard conditions of (I-1) ratio of (II-1) (III-1) — >95% 66:34 (III-6) — >95% 67:33 (III-8) — >95% 78:22 (III-10) — >95% 71:29 (III-12) — >95% 83:17 (III-2) — >95% 90:10 (III-4) — >95% 92:8  (III-4) 0.01 mol % Ir   94% 87:13 (III-16-ent) — >95% 10:90 (III-3-ent) — >95%  4:96 (III-3-ent) 4 h >95%  4:96 (III-3-ent) 0.01 mol % Ir   40% 17:83 (III-3-ent)  0.01 mol % Ir,   73% 18:82 c = 1.0M (III-18) — >95% 92:18 (III-19) — >95% 85:15 (III-15) — >95% 67:33 (III-22-ent) — >95%  5:95 (III-23-ent) — >95%  7:93 (III-24-ent) — >95% 10:90

[0373] Conditions: according to the general procedure 4, the F or Z oxime (I-1) was reacted with acid, solvent (0.5 mol oxime/1 L solvent), 1 mol % (III-3-ent), 50 bar H.sub.2, RT, 20 h, unless otherwise indicated. In all reactions high selectivity towards the desired product (>95%) was observed.

TABLE-US-00007 R:S- Conversion Enantiomeric Oxime Solvent Acid (eq.) of (I-1) ratio of (II-1) E-(I-1) MeOH MsOH (1.5 eq.) >95% 15:85 E-(I-1) iPrOH MsOH (1.5 eq.) >95%  4:96 E-(I-1) tAmylOH MsOH (1.0 eq.) >95%  4:96 Z-(I-1) tAmylOH MsOH (1.0 eq.) >95% 88:12 E-(I-1) tAmylOH TFA (5.0 eq.)   80% 15:85 E-(I-7) iPrOH MsOH (1.5 eq.) >95% 14:86 E-(I-7) tAmylOH MsOH (1.5 eq.) >95% 13:87 E-(I-7) tAmylOH MsOH (1.0 eq.) >95%  9.5:90.5 E-(I-7) tAmylOH H.sub.2SO.sub.4 (1.0 eq.) >95% 20:80 E-(I-7) tAmylOH PTSA•H.sub.2O (1.0 eq.) >95% 14:86 E-(I-7) tAmylOH HBF.sub.4 (1.0 eq.) >95% 17:83 E-(I-7) tAmylOH TFA (1.0 eq.)   63%  7:93 E-(I-7) tAmylOH TFA (5.0 eq.) >95     7:93

Example 10: Synthesis of 4-(difluoromethyl)-N-methoxy-1-methyl-N-[(1R)-1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-3-carboxamide (XIII-1)

[0374] ##STR00120##

[0375] A reaction vial was charged with N-methoxy-1-(2,4,6-trichlorophenyl) propan-2-amine (II-1) (made according to Example 10; 25 mg, 66:34 R:S) and dichloromethane (0.4 mL). Triethylamine (0.027 mL), followed by 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride (XII) (20 mg) dissolved in dichloromethane (0.2 mL) were added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane, extracted with aq. HCl (1M), aq. NaHCO.sub.3, brine, dried over sodium sulfate and evaporated under vacuum. The product was isolated by flash column chromatography (SiO.sub.2; ethyl acetate-cyclohexane gradient) to give 20 mg of the desired product (XIII-1). Analytical data corresponds to that reported in WO14/206855. Chiral SFC analysis: Daicel SFC Chiralpak IC column 3×100 mm, wavelength: 220 nm, solvent: λ=CO.sub.2, B=EtOH, gradient: 50% B in 1.8 min, injection volume: 1 μl, flow: 2.0 ml/min, retention time=0.90 minutes (minor (S)-enantiomer, 33.3%), 1.41 minutes (major (R)-enantiomer, 66.7%).

Example 11: General Procedure 6: Asymmetric Hydrogenation of Oxime Ethers Using Catalysts of the Invention to Produce Enantioenriched N-alkoxylamines

[0376] ##STR00121##

[0377] A flame-dried test tube, equipped with a magnetic stirring bar and a septum seal, was charged with the corresponding catalyst (1 mol %) and the oxime substrate (1 eq.). Dry ROH solvent (0.5 M; R=t-Amyl, i-propyl, ethyl, methyl) was added followed by a dropwise addition of either trifluoroacetic or methanesulfonic acid (1.0-5.0 eq.). A needle was inserted in the septum and test tube was placed in a high-pressure reactor. The reactor was purged with hydrogen (3×5 bar), pressurized to 50 bar of H.sub.2 and the reaction mixture was stirred at 25° C. for 16 h. Hydrogen was released and the reaction mixture was added slowly onto NaHCO.sub.3 (aq., sat.) and extracted three times with CH.sub.2Cl.sub.2. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure to afford the crude N-alkoxylamine product (typically with >95% NMR purity). Purification by flash column chromatography afforded the pure product. The enantiomeric excess of the product was determined by chiral stationary phase HPLC.

Example 12: General Procedure 7: N-alkoxyamine Product Derivatization by N-acylation with Benzoyl Chloride

[0378] ##STR00122##

[0379] In a test tube, triethylamine (2.0 eq) and benzoyl chloride (1.2 eq) were added to a solution of N-alkoxyamine (II) in CH.sub.2Cl.sub.2 at room temperature. The reaction mixture was stirred for 1-16 h at room temperature. The reaction mixture was directly purified by flash column chromatography to afford the corresponding N-benzoyl-N-alkoxyamine product (II-Bz). The enantiomeric excess of the product was determined by chiral stationary phase HPLC.

TABLE-US-00008 TABLE 7 Synthesis of hydroxylamines (II) via asymmetric hydrogenation of oximes (I) using catalyst (III-3-ent), substrate, scope: [00123]

[0380] Reaction conditions: according to General Procedure 4, 1 eq. of oxime (I), 1.0-5.0 eq. of MsOH or TFA acid, ROH solvent (0.5 mol oxime/1 L solvent; R=t-Amyl, i-propyl, ethyl, methyl), 1 mol % catalyst (III-3-ent), 50 bar H.sub.2, room temperature, 16 h, unless otherwise stated. In all reactions high selectivity towards the desired product (>95%) was observed.

TABLE-US-00009 Cpd. No. Structure Structure & Characterization Data (S)- (II-1) [00124] Synthesized from (E-I-1) according to General Procedure 6 using i- PrOH, 1.0 eq. of MsOH; >95% yield. The analytical data are in accordance with WO2014/206855 A1. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.32 (s, 2H), 5.47 (br. s, 1H), 3.55 (s, 3H), 3.44 (dp, J = 8.0, 6.4 Hz, 1H), 3.16 (dd, J = 13.4, 5.9 Hz, 1H), 2.91 (dd, J = 13.4, 8.0 Hz, 1H), 1.08 (d, J = 6.5 Hz, 3H). Chiral SFC: Column = Daicel Chiralpak IA 3 × 100 mm, particle size - 3μ, λ = 220 nm, CO.sub.2:iPrOH 85:15, flow = 2.0 ml/min, T = 40° C.; t.sub.RA = 0.45 min (major enantiomer, 96%), t.sub.RB = 0.51 min (minor enantiomer, 4%). (R)- (II-2) [00125] Synthesized according to General Procedure 6 using (III-3), i-PrOH, 1.0 eq. of MsOH; >95% yield. Colourless solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.32 (s, 2H), 4.76 (br. s, 2H), 3.40 (h, J = 6.6 Hz, 1H), 3.15 (dd, J = 13.6, 6.9 Hz, 1H), 2.92 (dd, J = 13.6, 7.0 Hz, 1H), 1.15 (d, J = 6.5 Hz, 3H). Chiral HPLC: Chiralpak IF column, 4.6 × 250 mm; nHex:iPrOH 95:05, flow = 1.0 mL/min; T = 25° C.; λ = 230 nm, t.sub.RA = 15.6 min (minor enantiomer, 18%), t.sub.RB = 17.0 min (major enantiomer, 82%). (R)- (II-3) [00126] Synthesized according to General Procedure 6 using (III-3), i-PrOH, 1.0 eq. of MsOH; >95% NMR yield. Colourless oil; IR (neat, cm.sup.−1): v.sub.max = 3248, 2969, 1580, 1546, 1452, 1439, 1372, 855, 697; .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 7.38-7.27 (m, 7H), 5.53 (br. S, 1H), 4.72 (s, 2H), 3.47 (dtd, J = 7.8, 6.5, 6.1 Hz, 1H), 3.18 (dd, J = 13.4, 6.1 Hz, 1H), 2.92 (dd, J = 13.4, 7.8 Hz, 1H), 1.11 (d, J = 6.5 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 137.83, 136.50, 134.53, 132.69, 128.57, 128.47, 128.35, 127.94, 76.88, 55.81, 35.49, 17.90; HRMS (EI.sup.+): m/z calcd for C.sub.16H.sub.17Cl.sub.3NO [M + H].sup.+ 344.0370, found 344.0370; The crude product (II-3) was converted to the N-benzoyl derivative (II-3-Bz) according to the General Procedure 7, for chiral HPLC analysis: [00127] IR (neat, cm.sup.−1): v.sub.max = 294.0, 1598, 1359, 1175, 975, 553; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.51 (d, J = 7.3 Hz, 2H), 7.45 (tt, J = 7.6, 1.1 Hz, 1H), 7.41-7.32 (m, 5H), 7.31-7.16 (m, 4H), 5.01-4.54 (m, 3H, 3.28 (d, J = 7.3 Hz, 2H), 1.33 (d, J = 6.8 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 170.78, 136.76, 135.04, 133.31, 133.24, 130.75, 129.46, 128.81, 128.58, 128.40, 128.30, 127.99, 78.30, 55.73 (br.), 34.82, 17.47; HRMS (EI.sup.+): m/z calcd for C.sub.23H.sub.21Cl.sub.3NO.sub.2 [M + H].sup.+ 448.0632, found 448.0642; Chiral HPLC: Chiralpak IG column, 4.6 × 250 mm; nHex:iPrOH 90:10, flow = 1.0 mL/min; T = 25° C.; λ = 230 nm, t.sub.RA = 26.7 min (minor enantiomer, 8%), t.sub.RB = 28.4 min (major enantiomer, 92%). (S)- (II-4) [00128] Synthesized according to General Procedure 6 using i-PrOH, 1.0 eq. of MsOH; >95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.30 (s, 2H), 4.68 (br. s, 1H), 3.30 (dp, J = 7.7, 6.4 Hz, 1H), 3.15 (dd, J = 13.3, 6.5 Hz, 1H), 2.82 (dd, J = 13.3, 7.7 Hz, 1H), 1.12 (s, 9H), 1.07 (d, J = 6.4 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 136.49, 135.06, 132.44, 128.23, 76.89, 56.31, 35.69, 26.90, 18.40. Chiral SFC: Column = Daicel Chiralpak IG 3 × 100 mm, particle size = 3μ, λ = 210 nm, CO.sub.2:MeOH 80:20, flow = 2.0 ml/min, T = 40° C.; t.sub.RA = 0.77 min (major enantiomer, 97%), t.sub.RB = 0.87 min (minor enantiomer, 3%). (S)- (II-5) [00129] Synthesized according to General Procedure 6 using i-PrOH, 1.0 eq. of MsOH; >95% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.30 (s, 2H), 5.69 (d, J = 5.4 Hz, 1H), 5.06 (t, J = 4.1 Hz, 1H), 4.03-3.83 (m, 4H), 3.77 (d, J = 4.1 Hz, 2H), 3.51-3.39 (dp, J = 7.9, 6.4 Hz, 1H), 3.14 (dd, J = 13.4, 6.1 Hz, 1H), 2.90 (dd, J = 13.4, 7.9 Hz, 1H), 1.08 (d, J = 6.4 Hz, 3H). The crude product (II-5) was converted to the N-benzoyl derivative (II-5-Bz) according to the General Procedure 7, for chiral HPLC analysis: [00130] .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.51-7.39 (m, 3H), 7.39-7.31 (m, 2H), 7.29-7.20 (m, 2H), 5.21-5.06 (br. m, 1H), 4.75-4.55 (br. m, 1H), 4.08-3.82 (m, 6H), 3.38-3.22 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 170.87, 136.75, 134.65, 133.25, 130.89, 128.39, 128.32, 127.94, 101.31, 76.63, 65.27, 65.22, 55.92, 34.65, 17.26; Chiral HPLC: Chiralpak IG column, 4.6 × 250 mm; nHex:iPrOH 70:30, flow = 1.0 mL/min; T = 25° C.; λ = 230 nm, t.sub.RA = 19.6 min (minor enantiomer, 7%), t.sub.RB = 24.5 min (major enantiomer, 93%). (S)- (II-6) [00131] Synthesized according to General Procedure 6 using t-AmylOH, 2.0 eq. of TFA; >95% yield. Compound described in J. Med. Chem. 1965 100; Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.12-7.07 (m, 2H), 6.87-6.79 (m, 2H), 3.78 (s, 3H), 3.54 (s, 3H), 3.18 (h, J = 6.5 Hz, 1H), 2.73 (dd, J = 13.6, 7.0 Hz, 1H), 2.55 (dd, J = 13.6, 6.5 Hz, 1H), 1.06 (d, J = 6.4 Hz, 2H). The crude product (II-6) was converted to the N-benzoyl derivative (II-6-Bz) according to the General Procedure 7, for chiral HPLC analysis: [00132] Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.40-7.33 (m, 1H), 7.32-7.23 (m, 2H), 7.17 (d, J = 7.7 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.83-6.76 (m, 2H), 4.46-4.21 (br. m, 1H), 3.79 (s, 3H), 3.71 (br. s, 3H), 3.04 (dd, J = 13.7, 8.9 Hz, 1H), 2.65 (dd, J = 13.8, 5.9 Hz, 1H), 1.37 (d, J = 6.7 Hz, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 170.54, 158.48, 135.28, 130.59, 130.36, 130.27, 128.12, 127.49, 113.92, 64.12, 58.47, 55.42, 39.29, 18.43. Chiral HPLC: Chiralpak IG column, 3 × 100 mm; nHex:iPrOH 80:20, flow = 1.0 mL/min; T = 35° C.; λ = 254 nm, t.sub.RA = 7.9 min (major enantiomer, 78%), t.sub.RB = 10.1 min (minor enantiomer, 22%). (S)- (II-7) [00133] Synthesized from (E-I-7) according to General Procedure 6 using t- AmylOH, 5 eq. of TFA; >95% yield, 93:7 er. Product enantio- enriched to 99:1 er (81% yield) by crystallization of the 4- nitrobenzenesulfonic acid salt in iPrOH/cHex as the racemate. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.61-7.54 (m, 1H), 7.31-7.21 (m, 2H), 7.11 (ddd, J = 8.0, 5.1, 3.8 Hz, 1H), 5.59 (br. s, 1H), 3.59 (s, 3H), 3.37 (h, J = 6.7 Hz, 1H), 3.03 (dd, J = 13.4, 6.9 Hz, 1H), 2.75 (dd, J = 13.4, 6.8 Hz, 1H), 1.15 (d, J = 6.4 Hz, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 138.63, 133.14, 131.70, 128.15, 127.46, 125.06, 62.77, 56.08, 40.38, 17.95. Chiral HPLC: Chiralpak IA column, 3 × 100 mm; nHex:iPrOH 99.5:0.5, flow = 0.5 mL/min; T = 25° C.; λ = 210 nm. t.sub.RA = 9.2 min (minor enantiomer, 1%), t.sub.RB = 10.7 min (major enantiomer, 99%). (S)- (II-8) [00134] Synthesized according to General Prodcedure 6 using t-AmylOH, 1.0 eq. of TFA, 2 mol % (III-3); 60% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 6.85 (s, 2H), 5.46 (br. s, 1H), 3.57 (s, 3H), 3.24 (h, J = 6.6 Hz, 1H), 2.88 (dd, J = 13.8, 6.8 Hz, 1H), 2.59 (dd, J = 13.8, 7.4 Hz, 1H), 2.31 (s, 6H), 2.26 (s, 3H), 1.11 (d, J = 6.3 Hz, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 137.02, 135.55, 132.88, 129.25, 62.79, 56.69, 33.74, 20.92, 20.49, 18.32. The Crude product (II-8) was converted to the N-benzoyl derivative (II-8-Bz) according to the General Procedure 7, for chiral HPLC analysis: [00135] Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.40-7.32 (m, 1H), 7.30-7.23 (m, 2H), 7.22-7.10 (m, 2H), 6.74 (s, 2H), 4.49-4.28 (m, 1H), 3.78 (s, 3H), 3.02 (dd, J = 14.0, 7.5 Hz, 1H), 2.80 (dd, J = 14.0, 6.8 Hz, 1H), 2.23 (s, 3H), 2.11 (s, 6H), 1.36 (d, J = 6.8 Hz, 3H). Chiral HPLC: Chiralpak IG column, 3 × 100 mm; nHex:iPrOH 80:20, flow = 1.0 mL/min; T = 35° C.; λ = 254 nm, t.sub.RA = 4.7 min (major enantiomer, 97%), t.sub.RB = 6.2 min (minor enantiomer, 3%). (S)- (II-9) [00136] Synthesized according to General Procedure 6 using MeOH, 1.5 eq. of MsOH; 94% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.40-7.35 (m, 2H), 7.35-7.25 (m, 6H), 7.24-7.15 (m, 2H), 5.65 (br. s, 1H), 3.88 (d, J = 10.5 Hz, 1H), 3.78 (dq, J = 10.5, 6.1 Hz, 1H), 3.51 (s, 3H), 1.14 (d, J = 6.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 142.63, 142.18, 129.05, 128.73, 128.38, 128.11, 126.91, 126.60, 62.92, 59.15, 55.49, 17.38. Chiral SFC: Column = Daicel Chiralpak IG 3 × 100 mm, particle size = 3μ, λ = 220 nm, CO.sub.2:iPrOH 90:10, flow = 2.0 ml/min, T = 40° C.; t.sub.RA = 1.23 min (major enantiomer, 93%), t.sub.RB = 1.39 min (minor enantiomer, 7%). (S)- (II-10) [00137] Synthesized according to General Procedure 6 using MeOH, 1.5 eq. of MsOH; 38% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.41-7.29 (m, 4H), 7.24-7.18 (m, 1H), 5.21 (br. s, 1H), 3.44 (s, 3H), 3.18 (q, J = 6.4 Hz, 1H), 1.34 (s, 3H), 1.30 (s, 3H), 1.07 (d, J = 6.4 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 147.88, 128.38, 126.23, 126.16, 64.53, 62.25, 40.49, 26.53, 23.27, 13.97. Chiral HPLC: Chiralpak IG column, 4.6 × 250 mm; nHex:iPrOH 99.9:0.1, flow = 1.0 mLmin; T = 25° C.; λ = 210 nm, t.sub.RA = 10.6 min (major enantiomer, 77%), t.sub.RB = 12.9 min (minor enantiomer, 22%). (S)- (II-11) [00138] Synthesized according to General Procedure 6 using iPrOH, 1.0 eq. of MsOH; >95% NMR yield (analytical data are in accordance with Chem. Commun. 2007, 1530). The cruded product was converted to the N-benzoyl derivative (II-11-Bz) according th the general procedure 7, for chiral HPLC analysis: [00139] .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.67-7.50 (m, 2H), 7.50-7.31 (m, 3H), 3.93 (br. s, 1H), 3.65 (s, 3H), 1.90 (dtd, J = 13.4, 4.6, 4.2, 2.3 Hz, 1H), 1.79-1.56 (m, 5H), 1.33 (d, J = 6.8 Hz, 3H), 1.29-1.01 (m, 3H), 0.97-0.75 (m, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 170.51, 135.55, 130.41, 128.32, 127.95, 63.96, 61.02, 41.16, 30.30, 30.20, 26.31, 26.28, 26.10, 16.58. Chiral HPLC: Chiralpak IC column, 4.6 × 250 mm; nHex:iPrOH 80:20, flow = 1.0 mL/min; T = 25° C.; λ = 254 nm. t.sub.RA = 11.1 min (minor enantiomer, 14%), t.sub.RB = 13.8 min (major enantiomer, 86%). (R)- (II-12) [00140] Synthesized according to General Procedure 6 using (III-3), iPrOH, 1.0 eq. of MsOH; >95% NMR yield (analytical data are in accordance with Chem. Commun. 2007, 1530). The crude product was converted to the N-benzoyl derivative (II-12-Bz) according to the general procedure 7, for chiral HPLC analysis: [00141] IR (neat, cm.sup.−1): v.sub.max = 2927, 2851, 1645, 1448, 1384, 697; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.72-7.55 (m, 2H), 7.51-7.37 (m, 3H), 7.37- 7.27 (m, 3H), 7.15 (s, 2H), 4.77 (br. s, 2H), 4.07 (br. s, 1H), 2.03- 1.86 (m, 1H), 1.84-1.67 (m, 4H), 1.67-1.57 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.29-1.03 (m, 3H), 1.02-0.76 (m, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 170.86, 135.71, 134.96, 130.41, 129.46, 128.74, 128.51, 128.31, 128.12, 78.26, 53.55, 41.23, 30.37, 30.22, 26.32, 26.25, 26.08, 167.67; HRMS (EI.sup.+): m/z calcd for C.sub.22H.sub.28NO.sub.2 [M + H].sup.+ 338.2115, found 338.2120. Chiral HPLC: Chiralpak IG column, 4.6 × 250 mm; nHex:iPrOH 70:30, flow = 1.0 mL/min; T = 25° C.; λ = 230 nm, t.sub.RA = 12.70 min (minor enantiomer, 16%), t.sub.RB = 22.90 min (major enantiomer, 84%). (S)- (II-13) [00142] Synthesized according to General Procedure 6 using iPrOH, 1.0 eq. of MsOH; >95% NMR yield. The crude methoxyamine methanesulfonic acid salt was converted directly to the N-benzoyl derivative (II-13-Bz) according to the general procedure 7 (using 3 eq. of triethylamine), for chiral HPLC analysis: [00143] Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.64 (s, 2H), 7.48- 7.29 (m, 3H), 4.63 (br. s, 1H), 3.46 (br. s, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.00 (br. s, 9H). Chiral HPLC: Chiralpak IC column, 4.6 × 250 mm; nHex:iPrOH 80:20, flow = 1.0 mL/min; T = 25° C.; λ = 254 nm, t.sub.RA = 9.4 min (minor enantiomer, 13%). t.sub.RB = 10.6 min (major enantiomer, 87%). (S)- (II-14) [00144] Synthesized according to General Procedure 6 using t-AmylOH, 1.0 eq. of MsOH, 74% yield. Analytical data are in accordance with Chem. Commun. 2007, 1530. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 5.48 (br. s, 1H), 3.48 (s, 3H), 2.51 (q, J = 6.7 Hz, 1H), 1.95 (p, J = 3.3 Hz, 3H), 1.73- 1.56 (m, 9H), 1.49 (dq, J = 12.2, 2.6 Hz, 3H), 1.03 (d, J = 6.5 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 64.74, 61.86, 39.03, 37.36, 35.17, 28.64, 12.58. The product (II-14) was converted to the N-benzoyl derivative (II- 14-Bz) according to the General Procedure 7, for chiral HPLC analysis: [00145] Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (mixture of 2 rotamers A:B in a 0.65:0.35 ratio) δ = 7.84-7.47 (br. m, 2H, rot, A + B), 7.47- 7.33 (m, 3H, rot. A + B), 4.49 (br. m, 1H, rot. A + B), 3.82 (br. s, 1.05H, rot. B), 3.40 (br. s, 1.95H, rot. B), 2.02-1.89 (br. m, 3H, rot. A + B), 1.81-1.41 (br. m, 12H, rot. A + B), 1.32 (d, J = 7.0 Hz, 3H, rot. A + B). Chiral HPLC: Chiralpak IC column 4.6 × 250 mm; nHex:iPrOH 80:20, flow = 1.0 mL/min; T = 25° C.; λ = 254 nm, t.sub.RA = 9.2 min (minor enantiomer, 7%), t.sub.RB = 11.3 min (major enantiomer, 93%). (S)- (II-15) [00146] Synthesized according to General Procedure 6 using t-AmylOH, 1.0 eq. of MsOH, >95% yield, 91:9 er. Product enantio-enriched to 93:7 er (75% yield) by crystallization in nHex at −20° C. Colourless solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 5.99 (d, J = 5.7 Hz, 1H), 3.82-3.70 (m, 1H), 3.66-3.57 (m, 1H), 3.49 (d, J = 1.2 Hz, 3H), 2.77 (br. s, 1H), 2.46 (dtd, J = 7.8, 3.8, 1.8 Hz, 1H), 1.99-1.86 (m, 3H), 1.74-1.49 (m, 12H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 70.61, 61.82, 60.31, 39.59, 37.08, 35.13, 28.47. The product (II-15) was converted to the O-benzoyl derivative (II- 15-Bz) according to the General Procedure 7, for chiral HPLC analysis: [00147] Colourless oil; .sup.1NMR (400 MHz, CDCl.sub.3) δ 8.10-7.98 (m, 2H), 7.62-7.51 (m, 1H), 7.45 (dd, J = 8.4, 7.0 Hz, 2H), 5.83 (br. s, 1H), 4.60 (dd, J = 11.5, 4.2 Hz, 1H), 4.40 (dd, J = 11.5, 5.6 Hz, 1H), 3.51 (s, 3H), 2.72 (dd, J = 5.6, 4.3 Hz, 1H), 2.00 (p, J = 3.1 Hz, 3H), 1.83- 1.59 (m, 12H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 166.76, 133.06, 130.46, 129.73, 128.53, 68.25, 62.01, 61.65, 39.73, 37.16, 35.34, 28.57. Chiral HPLC: Chiralpak ID column 3 × 100 mm; nHex:iPrOH 98:2, flow = 1.0 mL/min; T = 25° C.; λ = 254 nm, t.sub.RA = 6.4 min (minor enantiomer, 7%), t.sub.RB = 7.0 min (major enantiomer, 93%). (S)- (II-16) [00148] Synthesized according to General Procedure 6 using MeOH:THF 2:1 v/v, 1.5 eq. of MsOH, 95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.81 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 5.61 (br. s, 1H), 4.26 (dd, J = 10.0, 3.8 Hz, 1H), 4.15 (dd, J = 10.0, 5.1 Hz, 1H), 3.37 (s, 3H), 2.50-2.46 (m, 1H), 2.44 (s, 3H), 1.99-1.86 (m, 3H), 1.73-1.54 (m, 9H), 1.54- 1.43 (m, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 144.87, 133.08, 129.91, 128.14, 67.97, 66.89, 61.34, 39.62, 36.99, 35.32, 28.45, 21.78. Chiral HPLC: Chiralpak IA column, 4.6 × 250 mm; nHex:iPrOH 98:2, flow = 1.0 mL/min; T = 25° C.; λ = 230 nm, t.sub.RA = 15.3 min (major enantiomer, 91%), t.sub.RB = 18.1 min (minor enantiomer, 9%). (R)- (II-18) [00149] Synthesized according to General Procedure 6 using iPrOH, 1.5 eq. of MsOH, 71% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.39-7.23 (m, 5H), 5.84 (br. s, 1H), 3.73 (d, J = 7.1 Hz, 1H), 3.44 (s, 3H), 2.00 (dq, J = 13.7, 6.8 Hz, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H), .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 141.09, 128.26, 128.05, 127.22, 71.62, 62.28, 31.12, 20.04, 19.16. Chiral HPLC: Chiralpak ID column, 3 × 100 mm; nHept:iPrOH 99.9:0.1, flow = 0.5 mL/min; T = 40° C.; λ = 210 nm; t.sub.RA = 5.2 min (major enantiomer, 90%), t.sub.RB = 6.3 min (minor enantiomer, 10%). (R)- (II-19) [00150] Synthesized from oxime (I-19) (50:50 E:Z mixture) according to General Procedure 6 using EtOH, 1.5 eq, of MsOH, >95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.23-7.16 (m, 2H), 6.90-6.82 (m, 2H), 5.81 (br. s, 1H), 3.80 (s, 3H), 3.68 (d, J = 7.3 Hz, 1H), 3.39 (s, 3H), 1.93-1.80 (m, 1H), 1.79-1.68 (m, 1H), 1.68- 1.54 (m, 3H), 1.54-1.41 (m, 1H), 1.35-0.71 (m, 5H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 158.72, 133.41, 129.18, 113.43, 70.27, 62.26, 55.29, 40.98, 30.59, 29.50, 26.56. 26.37, 26.31. Chiral HPLC: Chiralpak IC column, 4.6 × 250 mm; nHex:iPrOH 99.5:0.5, flow = 1.0 mL/min; T = 25° C. λ = 230 nm, t.sub.RA = 9.3 min (92%), t.sub.RB = 11.1 min (8%). (R)- (II-20) [00151] Synthesized according to General Procedure 6 using EtOH, 1.5 eq. of MsOH, >95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.38-7.19 (m, 5H), 5.86 (br. s, 1H), 3.74 (d, J = 7.3 Hz, 1H), 3.40 (s, 3H), 1.94-1.84 (m, 1H), 1.79-1.70 (m, 1H), 1.70-1.55 (m, 3H), 1.51-1.42 (m, 1H), 1.32-0.76 (m, 5H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 141.146, 128.23, 128.07, 127.17, 70.95, 62.28, 41.04, 30.54, 29.61, 26.56, 26.39, 26.34. Chiral HPLC: Chiralpak IG column, 4.6 × 250 nm; nHex:iPrOH 99.5:0.5, flow = 1.0 mL/min; T = 25° C. λ = 210 mm, t.sub.RA = 10.0 min (94%), t.sub.RB = 11.6 min (6%). (R)- (II-21) [00152] Synthesized according to General Procedure 6 using EtOH, 1.5 eq. of MsOH, >95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.30-7.24 (m, 1H), 7.21 (ddd, J = 8.1, 7.4, 1.8 Hz, 1H), 6.93 (td, J = 7.4, 1.1 Hz, 1H), 6.87 (dd, J = 8.2, 1.1 Hz, 1H), 6.14 (br. s, 1H), 4.12 (d, J = 8.1 Hz, 1H), 3.81 (s, 3H), 3.44 (s, 3H), 2.07-1.97 (m, 1H), 1.78-1.54 (m, 4H), 1.43-1.33 (m, 1H), 1.30-0.81 (m, 5H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 157.66, 129.86, 129.20, 127.88, 120.36, 110.74, 65.24, 61.81, 55.50, 40.10, 30.81, 30.11, 26.69, 26.50, 26.42, Chiral HPLC: Chiralpak IC column, 4.6 × 250 mm; nHex:iPrOH 99.5:0.5, flow = 0.7 mL/min; T = 25° C.; λ = 230 nm, t.sub.RA = 8.9 min (74%), t.sub.RB = 9.5 min (26%). (R)- (II-22) [00153] Synthesized according to General Procedure 6 using EtOH:THF 3:1 v/v, 1.5 eq. of MsOH, >95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.93-7.78 (m, 4H), 7.55 (dd, J = 8.4, 1.7 Hz, 1H), 7.52-7.45 (m, 2H), 7.30-7.22 (m, 1H), 6.98-6.92 (m, 2H), 6.88 (dt, J = 7.5, 1.3 Hz, 1H), 5.80 (br. s, 1H), 5.25 (s, 2H), 3.98-3.90 (m, 1H), 3.79 (dt, J = 11.5, 3.4 Hz, 1H), 3.70 (d, J = 7.8 Hz, 1H), 3.41 (s, 3H), 3.33 (td, J = 11.9, 2.2 Hz, 1H), 3.25-3.15 (m, 1H), 1.83 (dqd, J = 11.5, 8.1, 3.8 Hz, 1H), 1.74 (ddq, J = 13.1, 4.0, 1.9 Hz, 1H), 1.48-1.32 (m, 1H), 1.19 (td, J = 10.7, 9.4, 3.8 Hz, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 158.75, 142.21, 134.62, 133.41, 133.17, 129.36, 128.51, 128.03, 127.85, 126.52, 126.37, 126.21, 125.43, 120.89, 114.83, 113.95, 70.39, 70.23, 68.02, 67.91, 62.29, 38.44, 30.66, 29.66. Chiral HPLC: Chiralpak IC column, 3 × 100 mm; nHex:iPrOH 90:10, flow = 1.0 mL/min; T = 35° C.; λ = 245 nm, t.sub.RA = 8.5 min (minor enantiomer, 7%), t.sub.RB = 9.5 min (major enantiomer, 93%). (R)- (II-23) [00154] Synthesized according to General Procedure 6 using EtOH, 1.5 eq. of MsOH, 95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.58 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 5.87 (br. s, 1H), 3.81 (d, J = 7.3 Hz, 1H), 3.38 (s, 3H), 1.92-1.81 (m, 1H), 1.81-1.70 (m, 1H), 1.69- 1.54 (m, 3H), 1.47-1.36 (m, 1H), 1.31-0.75 (m, 5H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 145.85, 129.86, 129.54, 129.22, 128.90, 128.53, 125.79, 125.02, 124.98, 123.09, 120.38, 70.57, 62.34, 41.03, 30.32, 29.60, 26.42, 26.27, 26.22. .sup.19F NMR (376 MHz, CDCl.sub.3) δ = −62.35. Chiral HPLC: Chiralpak IA column, 4.6 × 250 mm; nHex:iPrOH 99.9:0.1, flow = 0.7 mL/min; T = 25° C.; λ = 210 nm, t.sub.RA = 12.3 min (major enantiomer, 85%), t.sub.RB = 13.5 min (minor enantiomer, 15%). (R)- (II-24) [00155] Synthesized according to General Procedure 6 using 2 mol % of (III- 3-ent), EtOH, 1.5 eq. of MsOH, 48% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.40-7.34 (m, 2H), 7.28-7.23 (m, 2H), 6.71 (dd, J = 17.6, 10.9 Hz, 1H), 5.85 (br. s, 1H), 5.73 (dd, J = 17.6, 1.0 Hz, 1H), 5.22 (dd, J = 10.9, 1.0 Hz, 1H), 3.74 (d, J = 7.3 Hz, 1H), 3.40 (s, 3H), 1.92-1.81 (m, 1H), 1.79- 1.69 (m, 1H), 1.68-1.55 (m, 3H), 1.53-1.41 (m, 1H), 1.31-0.75 (m, 5H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 141.23, 136.82, 136.53, 128.39, 125.97, 113.45, 70.66, 62.31, 41.01, 30.53, 29.58, 26.54, 26.37, 26.31. Chiral HPLC: Chiralpak IC column, 4.6 × 250 mm; nHex, flow = 1.0 mL/min; T = 25° C.; λ = 254 nm. t.sub.RA = 28.9 min (major enantiomer, 94%), t.sub.RB = 32.3 min (minor enantiomer, 6%). (R)- (II-25) [00156] Synthesized according to General Procedure 6 using 2 mol % of (III- 3-ent), MeOH, 1.5 eq. of MsOH, >95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.16-8.07 (m, 2H), 7.56 (dt, J = 7.6, 1.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 5.22 (br. s, 1H), 3.73 (d, J = 7.8 Hz, 1H), 2.05-1.94 (m, 1H), 1.76 (ddt, J = 12.8, 5.0, 2.4 Hz, 1H), 1.72-1.50 (m, 3H), 1.45-1.32 (m, 1H), 1.03 (s, 13H), 0.90-0.75 (m, 1H); Chiral HPLC: Chiralpak IB column, 4.6 × 250 mm; nHex:iPrOH 99.95:0.05, flow = 0.7 mL/min; T = 25° C., λ = 254 nm, t.sub.RA = 9.0 min (minor enantiomer, 10%), t.sub.RB = 9.5 min (major enantiomer 90%). (R)- (II-26) [00157] Synthesized according to General Procedure 6 under 20 bar H.sub.2, 1.5 eq. of MsOH in EtOH, 5 h, 80% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.31-7.27 (m, 2H), 7.02-6.96 (m, 2H), 5.84 (br. s, 1H), 3.72 (d, J = 7.3 Hz, 1H), 3.38 (s, 3H), 1.91-1.80 (m, 1H), 1.80-1.69 (m, 1H), 1.69-1.52 (m, 3H), 1.50-1.37 (m, 1H), 1.32-0.90 (m, 4H), 0.88-0.72 (m, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 138.75, 138.41, 129.60, 118.72, 70.34, 62.33, 40.99, 30.49, 29.54, 26.49, 26.31, 26.25. Chiral HPLC: Chiralpak IG column, 4.6 x 250 mm; nHex:iPrOH 99.5:05, flow = 1.0 mL/min; T = 25° C.; λ = 254 nm, t.sub.RA = 10.5 min (major enantiomer, 89%), t.sub.RB = 11.2 min (minor enantiomer 11%). (R)- (II-27) [00158] Synthesized according to General Procedure 6 using 2 mol % of (III- 3-ent) in EtOH:THF 3:1 v/v, 1.5 eq. of MsOH, 58% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.72-7.67 (m, 2H), 7.25-7.20 (m, 2H), 5.80 (br. s, 1H), 3.69 (d, J = 7.3 Hz, 1H), 3.31 (s, 3H), 1.84-1.74 (m, 1H), 1.70-1.61 (m, 1H), 1.61-1.45 (m, 3H), 1.41-1.32 (m, 1H), 1.27 (s, 12H), 1.22-0.69 (m, 5H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 144.83, 134.58, 127.71, 83.83, 71.02, 62.31, 41.04, 30.49, 29.58, 26.52, 26.36, 26.29, 25.04, 25.01. Chiral HPLC: Chiralpak IG column, 3 × 100 mm; nHex:iPrOH 99:1, flow = 0.7 mL/min; T = 35° C.; λ = 230 nm. t.sub.RA = 6.7 min (minor enantiomer; 12%), t.sub.RB = 8.3 min (major enantiomer 88%). (R)- (II-28) [00159] Synthesized according to General Procedure 6 using 2 mol % of (III- 3-ent), MeOH, 1.5 eq. of MsOH, >95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.24-7.19 (m, 1H), 6.98-6.91 (m, 2H), 5.77 (d, J = 4.2 Hz, 1H), 3.99 (dd, J = 9.4, 4.2 Hz, 1H), 3.43 (s, 3H), 2.22-2.09 (m, 1H), 1.95-1.82 (m, 1H), 1.73- 1.43 (m, 2H), 1.42-1.29 (m, 1H), 1.27-1.12 (m, 1H); Chiral HPLC: Chiralpak IG column, 4.6 × 250 mm; nHex:iPrOH 99.5:0.5, flow = 1.0 mL/min; T = 25° C.; λ = 230 nm, t.sub.RA = 8.6 min (major enantiomer, 90%), t.sub.RB = 9.5 min (minor enantiomer 10%). (R)- (II-29) [00160] Synthesized according to General Procedure 6 in EtOH:THF 3:1 v/v, 1.5 eq. of MsOH, >95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.85-7.79 (m, 2H), 7.61-7.54 (m, 1H), 7.51-7.43 (m, 2H), 7.09 (dd, J = 3.2, 2.3 Hz, 1H), 7.04 (t, J = 1.9 Hz, 1H), 6.25 (dd, J = 3.2, 1.6 Hz, 1H), 5.66 (br. s, 1H), 3.62 (d, J = 6.6 Hz, 1H), 3.33 (s, 3H), 1.80-1.45 (m, 6H), 1.29-0.66 (m, 5H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 139.24, 133.80, 129.36, 129.06, 126.77, 120.97, 119.06, 114.33, 63.94, 62.32, 39.99, 30.29, 29.12, 26.55, 26.31, 26.21. Chiral HPLC: Chiralpak IG column, 3 × 100 mm; nHex:iPrOH 90:10, flow = 1.0 mL/min; T = 35° C.; λ = 254 nm, t.sub.RA = 7.5 min (minor enantiomer, 8%), t.sub.RB = 8.4 min (major enantiomer 92%). (R)- (II-30) [00161] Synthesized according to General Procedure 6 in MeOH:THF 3:1 v/v, 1.5 eq. of MsOH, 90% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.37-7.23 (m, 5H), 5.99 (br. s, 1H), 3.77 (s, 1H), 3.41 (s, 3H), 0.92 (s, 9H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 140.78, 128.88, 127.58, 127.04, 74.30, 62.07, 33.96, 27.48. Chiral HPLC: Chiralpak IC column, 4.6 × 250 mm; nHex:iPrOH 99.9:0.1, flow = 1.0 mL/min; T = 25° C.; λ = 220 nm, t.sub.RA = 5.1 min (major enantiomer, 92%), t.sub.RB = 5.4 min (minor enantiomer 8%). (R)- (II-31) [00162] Synthesized according to General Procedure 6 in MeOH, 1.0 eq. of MsOH, 50 bar or 1 atm of H.sub.2 (g), >95% yield, 89:11 er. Product enantio-enriched to 97:3 er (80% yield) by crystallization of the 4-nitrobenzenesulfonic acid salt in THF as the racemate. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.24-7.11 (m, 3H), 7.06-6.97 (m, 1H), 5.35 (br. s, 1H), 4.88 (s, 2H), 3.76 (d, J = 5.7 Hz, 1H), 2.01-1.86 (m, 1H), 1.86-1.58 (m, 5H), 1.35-1.07 (m, 5H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 135.15, 133.84, 127.11, 126.47, 126.12, 124.52, 70.16, 62.64, 42.01, 31.06, 28.90, 26.88, 26.74, 26.54. Chiral HPLC: Chiralpak IC column, 4.6 × 250 mm; nHex:iPrOH 98:2, flow = 1.0 mL/min; T = 25° C.; λ = 220 nm, t.sub.RA = 10.1 min (minor enantiomer, 3%), t.sub.RB = 14.5 min (major enantiomer 97%). (R)- (II-33) [00163] Synthesized according to General Procedure 6 using 2 mol % of (III- 3-ent), MeOH, 1.5 eq. of TfOH, >95% yield. Colourless solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.1 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 6.14 (br. s, 1H), 4.01-3.89 (m, 2H), 3.81 (dt, J = 14.3, 4.3 Hz, 1H), 3.69 (dd, J = 5.6, 4.3 Hz, 2H), 3.29 (d, J = 6.9 Hz, 5H), 1.72 (ddt, J = 13.4, 11.2, 5.7 Hz, 1H), 1.63-1.45 (m, 3H), 1.38-1.12 (m, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 168.61, 146.54, 134.07, 132.22, 129.98, 129.66, 129.34, 129.02, 127.87, 127.59, 125.66, 125.33, 125.29, 125.25, 125.21, 123.34, 122.96, 120.25, 72.55, 71.64, 65.24, 58.66, 36.88, 33.76, 29.68, 22.79. .sup.19F NMR (376 MHz, CDCl.sub.3) δ −62.36. Chiral HPLC: Chiralpak IF column, 4.6 × 250 mm; nHex:iPrOH 90:10 flow = 1.0 mL/min; T = 25° C.; λ = 210 nm, t.sub.RA = 18 min (minor enantiomer, 40%), t.sub.RB = 21 min (major enantiomer 60%). (II-34) [00164] Synthesized according to General Procedure 6, MeOH, 1.5 eq. of MsOH, >95% yield, 98:2 trans:cis. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (peaks correspond to the trans-isomer unless otherwise stated) δ = 7.43 (d, J = 7.1 Hz, 1H), 7.32-7.20 (m, 3H), 6.16 (d, J = 6.2 Hz, 1H), 5.98 (d, J = 5.4 Hz, 0.02H, cis-isomer), 4.85 (t, J = 6.2 Hz, 0.02H, cis-isomer), 4.72 (t, J = 6.6 Hz, 1H), 3.77 (d, J = 0.8 Hz, 3H), 3.52-3.36 (m, 2H), 3.31 (s, 3H), 3.07 (dd, J = 14.6, 7.3 Hz, 1H). Chiral HPLC: Chiralpak IC column, 4.6 × 250 mm; nHex:iPrOH 98:2, flow = 1.0 mL/min; T = 25° C.; λ = 210 nm, t.sub.RA = 11.4 min (minor enantiomer, 40%), t.sub.RB = 13.7 min (major enantiomer 60%). (R,R)- (II- 35) [00165] Synthesized from oxime (R)-(I-35) according to General Procedure 6, iPrOH 1.5 eq. of MsOH, >95% yield, 97:3 cis:trans. Analytical data are in accordance with J. Org. Chem. 2010, 914, Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) (peaks correspond to the cis-isomer unless otherwise stated) δ = 7.39 (dd, J = 7.3, 1.3 Hz, 1H), 7.23-7.16 (m, 3H), 5.78 (br. s, 1H), 4.42 (d, J = 6.3 Hz, 1H), 4.12 (d, J = 5.5 Hz, 0.03H, trans), 3.57 (s, 0.09H, trans), 3.45 (s, 3H), 3.00-2.93 (m, 1H), 2.71-2.62 (m, 2H), 1.12 (d, J = 6.7 Hz, 3H). (II-36) [00166] Synthesized according to General Procedure 6 using 2 mol % of (III- 3-ent), EtOH, 1.0 eq. of MsOH, >95% yield. Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 5.93 (d, J = 11.1 Hz, 1H), 4.23-4.08 (m, 2H), 3.43 (s, 3H), 3.34 (dd, J = 11.1, 6.8 Hz, 1H), 1.86-1.69 (m, J = 6.8 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H), 0.90 (dd, J = 8.1, 6.8 Hz, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 174.09, 69.18, 61.53, 60.86, 29.21, 19.46, 19.38, 14.42. The product (II-36) was converted to the N-benzoyl derivative (II- 36-Bz) according to the General Procedure 5 (with 0.1 eq. of DMAP, DIPEA instead of Et.sub.3N, 16 h), for chiral HPLC analysis: [00167] Colourless oil; [α].sub.D.sup.25 = 19.51 (c = 2.0, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.72-7.63 (m, 2H), 7.49-7.37 (m, 3H), 4.51 (d, J = 8.8 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.62 (s, 3H), 2.53 (dhept, J = 9.5, 6.7 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 1.05 (dd, J = 16.9, 6.7 Hz, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 170.85, 169.97, 134.22, 130.89, 128.32, 128.30, 67.36, 63.62, 61.36, 28.23, 19.89, 19.77, 14.32 Chiral HPLC: Chiralpak IG column 4.6 × 250 mm; nHex:iPrOH 90:10, flow = 1.0 mL/min; T = 25° C.; λ = 254 nm. t.sub.RA = 13.9 min (major enantiomer, 90%), t.sub.RB = 16.0 min (minor enantiomer, 10%). (II-37) [00168] Synthesized according to General Procedure 6 using 2 mol % of (III- 3-ent), EtOH, 1.0 eq. of MsOH, 45% yield, 96:4 dr (absolute configuration not determined). Colourless oil; .sup.1H NMR (400 MHz, CDCl.sub.3) δ = 7.39-7.31 (m, 4H), 7.30-7.21 (m, 1H), 5.62 (br. s, 1H), 5.02 (d, J = 3.2 Hz, 1H), 3.61 (s, 3H), 3.30 (qd, J = 6.8, 3.2 Hz, 1H), 2.97 (br. s, 1H), 0.83 (d, J = 6.7 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ = 141.25, 128.34, 127.31, 126.10, 72.95, 62.74, 61.13, 10.81. Chiral HPLC: Chiralpak IG column, 4.6 × 250 mm; nHex:iPrOH 95:5, flow = 1.0 mL/min; T = 25° C.; λ = 210 nm, t.sub.RA = 14.1 min (minor enantiomer, 40%), t.sub.RB = 16.3 min (major enantiomer, 60%).

Comparative Example 1: Table 8

[0381] Screening of 96 diverse homogeneous catalysts—metal precursors (Rh, Ir, Pt, Ru, neutral/cationic)/ligand classes (monodentate/bidentate, phosphine, phosphite, etc.) in two solvents (THE/TEA and MeOH) at T=60° C. and pressure H.sub.2=50 bar, at a catalyst loading of 2%. The conversion towards the desired product (II-1, labeled ‘Product’ in the table below) was determined by GC and is based on area percentages.

TABLE-US-00010 Product Metal Precursor, Ligand Solvent (II-1) A1 Rh(COD).sub.2BF.sub.4, (R)-Monophos THF/TFA   0% B1 Rh(COD).sub.2BF.sub.4, (S)-Tol-Binap THF/TFA   0% C1 Rh(COD).sub.2BF.sub.4, (R)-DM-Segphos THF/TFA   0% D1 Rh(COD).sub.2BF.sub.4, (S)-MeO-Biphep THF/TFA   0% E1 Rh(COD).sub.2BF.sub.4, (S,S,R,R)-Tangphos THF/TFA   0% F1 Rh(COD).sub.2BF.sub.4, (R,S)-Binaphos THF/TFA   0% G1 Rh(COD).sub.2BF.sub.4, (R,R)-Kelliphite THF/TFA   0% H1 Rh(COD).sub.2BF.sub.4, (R)-(+)-2-[2- THF/TFA   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A2 [Rh(COD)Cl].sub.2, (R)-Monophos THF/TFA   0% B2 [Rh(COD)Cl].sub.2, (S)-Tol-Binap THF/TFA   0% C2 [Rh(COD)Cl].sub.2, (R)-DM-Segphos THF/TFA   0% D2 [Rh(COD)Cl].sub.2, (S)-MeO-Biphep THF/TFA   0% E2 [Rh(COD)Cl].sub.2, (S,S,R,R)-Tangphos THF/TFA   0% F2 [Rh(COD)Cl].sub.2, (R,S)-Binaphos THF/TFA   0% G2 [Rh(COD)Cl].sub.2, (R,R)-Kelliphite THF/TFA   0% H2 [Rh(COD)Cl].sub.2, (R)-(+)-2-[2- THF/TFA   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A3 Ir(COD).sub.2BF.sub.4, (R)-Monophos THF/TFA 0.09% B3 Ir(COD).sub.2BF.sub.4, (S)-Tol-Binap THF/TFA   0% C3 Ir(COD).sub.2BF.sub.4, (R)-DM-Segphos THF/TFA   0% D3 Ir(COD).sub.2BF.sub.4, (S)-MeO-Biphep THF/TFA   0% E3 Ir(COD).sub.2BF.sub.4, (S,S,R,R)-Tangphos THF/TFA   0% F3 Ir(COD).sub.2BF.sub.4, (R,S)-Binaphos THF/TFA   0% G3 Ir(COD).sub.2BF.sub.4, (R,R)-Kelliphite THF/TFA   0% H3 Ir(COD).sub.2BF.sub.4, (R)-(+)-2-[2- THF/TFA   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A4 [Ir(COD)Cl].sub.2, (R)-Monophos THF/TFA 0.02% B4 [Ir(COD)Cl].sub.2, (S)-Tol-Binap THF/TFA   0% C4 [Ir(COD)Cl].sub.2, (R)-DM-Segphos THF/TFA 0.02% D4 [Ir(COD)Cl].sub.2, (S)-MeO-Biphep THF/TFA 0.03% E4 [Ir(COD)Cl].sub.2, (S,S,R,R)-Tangphos THF/TFA   0% F4 [Ir(COD)Cl].sub.2, (R,S)-Binaphos THF/TFA   0% G4 [Ir(COD)Cl].sub.2, (R,R)-Kelliphite THF/TFA   0% H4 [Ir(COD)Cl].sub.2, (R)-(+)-2-[2- THF/TFA   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A5 Pt(COD)Cl.sub.2, (R)-Monophos THF/TFA   0% B5 Pt(COD)Cl.sub.2, (S)-Tol-Binap THF/TFA   0% C5 Pt(COD)Cl.sub.2, (R)-DM-Segphos THF/TFA   0% D5 Pt(COD)Cl.sub.2, (S)-MeO-Biphep THF/TFA   0% E5 Pt(COD)Cl.sub.2, (S,S,R,R)-Tangphos THF/TFA   0% F5 Pt(COD)Cl.sub.2, (R,S)-Binaphos THF/TFA   0% G5 Pt(COD)Cl.sub.2, (R,R)-Kelliphite THF/TFA 0.02% H5 Pt(COD)Cl.sub.2, (R)-(+)-2-[2- THF/TFA   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A6 [Ru(cymene)Cl].sub.2, (R)-Monophos THF/TFA 0.02% B6 [Ru(cymene)Cl].sub.2, (S)-Tol-Binap THF/TFA   0% C6 [Ru(cymene)Cl].sub.2, (R)-DM-Segphos THF/TFA   0% D6 [Ru(cymene)Cl].sub.2, (S)-MeO-Biphep THF/TFA   0% E6 [Ru(cymene)Cl].sub.2, (S,S,R,R)-Tangphos THF/TFA   0% F6 [Ru(cymene)Cl].sub.2, (R,S)-Binaphos THF/TFA   0% G6 [Ru(cymene)Cl].sub.2, (R,R)-Kelliphite THF/TFA   0% H6 [Ru(cymene)Cl].sub.2, (R)-(+)-2- THF/TFA   0% [2-diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A7 Rh(COD).sub.2BF.sub.4, (R)-Monophos MeOH   0% B7 Rh(COD).sub.2BF.sub.4, (S)-Tol-Binap MeOH   0% C7 Rh(COD).sub.2BF.sub.4, (R)-DM-Segphos MeOH   0% D7 Rh(COD).sub.2BF.sub.4, (S)-MeO-Biphep MeOH   0% E7 Rh(COD).sub.2BF.sub.4, (S,S,R,R)-Tangphos MeOH   0% F7 Rh(COD).sub.2BF.sub.4, (R,S)-Binaphos MeOH   0% G7 Rh(COD).sub.2BF.sub.4, (R,R)-Kelliphite MeOH   0% H7 Rh(COD).sub.2BF.sub.4, (R)-(+)-2-[2- MeOH   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A8 [Rh(COD)Cl].sub.2, (R)-Monophos MeOH   0% B8 [Rh(COD)Cl].sub.2, (S)-Tol-Binap MeOH   0% C8 [Rh(COD)Cl].sub.2, (R)-DM-Segphos MeOH   0% D8 [Rh(COD)Cl].sub.2, (S)-MeO-Biphep MeOH   0% E8 [Rh(COD)Cl].sub.2, (S,S,R,R)-Tangphos MeOH   0% F8 [Rh(COD)Cl].sub.2, (R,S)-Binaphos MeOH   0% G8 [Rh(COD)Cl].sub.2, (R,R)-Kelliphite MeOH   0% H8 [Rh(COD)Cl].sub.2, (R)-(+)-2-[2- MeOH   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A9 Ir(COD).sub.2BF.sub.4, (R)-Monophos MeOH 0.02% B9 Ir(COD).sub.2BF.sub.4, (S)-Tol-Binap MeOH   0% C9 Ir(COD).sub.2BF.sub.4, (R)-DM-Segphos MeOH   0% D9 Ir(COD).sub.2BF.sub.4, (S)-MeO-Biphep MeOH   0% E9 Ir(COD).sub.2BF.sub.4, (S,S,R,R)-Tangphos MeOH   0% F9 Ir(COD).sub.2BF.sub.4, (R,S)-Binaphos MeOH   0% G9 Ir(COD).sub.2BF.sub.4, (R,R)-Kelliphite MeOH   0% H9 Ir(COD).sub.2BF.sub.4, (R)-(+)-2-[2- MeOH   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A10 [Ir(COD)Cl].sub.2, (R)-Monophos MeOH 0.75% B10 [Ir(COD)Cl].sub.2, (S)-Tol-Binap MeOH   0% C10 [Ir(COD)Cl].sub.2, (R)-DM-Segphos MeOH   0% D10 [Ir(COD)Cl].sub.2, (S)-MeO-Biphep MeOH   0% E10 [Ir(COD)Cl].sub.2, (S,S,R,R)-Tangphos MeOH   0% F10 [Ir(COD)Cl].sub.2, (R,S)-Binaphos MeOH 0.05% G10 [Ir(COD)Cl].sub.2, (R,R)-Kelliphite MeOH 0.02% H10 [Ir(COD)Cl].sub.2, (R)-(+)-2-[2- MeOH   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A11 Pt(COD)Cl.sub.2, (R)-Monophos MeOH 0.02% B11 Pt(COD)Cl.sub.2, (S)-Tol-Binap MeOH 0.04% C11 Pt(COD)Cl.sub.2, (R)-DM-Segphos MeOH   0% D11 Pt(COD)Cl.sub.2, (S)-MeO-Biphep MeOH   0% E11 Pt(COD)Cl.sub.2, (S,S,R,R)-Tangphos MeOH   0% F11 Pt(COD)Cl.sub.2, (R,S)-Binaphos MeOH   0% G11 Pt(COD)Cl.sub.2, (R,R)-Kelliphite MeOH 0.73% H11 Pt(COD)Cl.sub.2, (R)-(+)-2-[2- MeOH   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline A12 [Ru(cymene)Cl.sub.2].sub.2, (R)-Monophos MeOH   0% B12 [Ru(cymene)Cl.sub.2].sub.2, (S)-Tol-Binap MeOH   0% C12 [Ru(cymene)Cl.sub.2].sub.2, (R)-DM-Segphos MeOH   0% D12 [Ru(cymene)Cl.sub.2].sub.2, (S)-MeO-Biphep MeOH   0% E12 [Ru(cymene)Cl.sub.2].sub.2, (S,S,R,R)-Tangphos MeOH   0% F12 [Ru(cymene)Cl.sub.2].sub.2, (R,S)-Binaphos MeOH 0.04% G12 [Ru(cymene)Cl.sub.2].sub.2, (R,R)-Kelliphite MeOH   0% H12 [Ru(cymene)Cl.sub.2].sub.2, (R)-(+)-2-[2- MeOH   0% diphenylphosphino)-phenyl]- 4-isopropyl-oxazoline

[0382] These experiments demonstrate that combinations of commonly used metal precursors and ligands doesn't allow homogeneous hydrogenation of oxime substrates such as (I-1) as in all cases, the amount of product (II-1) formed was <1%.

Comparative Example 2: Table 9

[0383] ##STR00169##

[0384] Hydrogenation conditions: Temperature=60° C. and pressure H.sub.2=60 bar, Time=20 h. Reaction conditions as described in EP1862446. The conversion towards the desired product ((II-1), labeled ‘Product’ in the table below) was determined by GC and is based on area percentages.

TABLE-US-00011 Product Conditions (11-1)% Rh(COD).sub.2BF.sub.4 (1.2 mol %), SL-J002-1* (2 mol %),    0% HBF.sub.4•Et.sub.2O (4eq), THF Rh(COD).sub.2BF.sub.4 (0.12 mol %), SL-J002-1*    0% (0.2 mol %), HBF.sub.4•Et.sub.2O (4eq), THF Rh(COD).sub.2BF.sub.4 (1.2 mol %), SL-J002-1* (2 mol %),    0% CF.sub.3COOH (4eq), CF.sub.3CH.sub.2OH Rh(COD).sub.2BF.sub.4 (0.12 mol %), SL-J002-1*    0% (0.2 mol %), CF.sub.3COOH (4eq), CF.sub.3CH.sub.2OH Ir(COD).sub.2BF.sub.4 (1.2 mol %), SL-J002-1* (2 mol %), <10% HBF.sub.4•Et.sub.2O (4eq), THF Ir(COD).sub.2BF.sub.4 (0.12 mol %), SL-J002-1* Trace (0.2 mol %), HBF.sub.4•Et.sub.2O (4eq), THF (<1%) Ir(COD).sub.2BF.sub.4 (1.2 mol %), SL-J002-1* (2 mol %),    0% CF.sub.3COOH (4eq), CF.sub.3CH.sub.2OH Ir(COD).sub.2BF.sub.4 (0.12 mol %), SL-J002-1*    0% (0.2 mol %), CF.sub.3COOH (4eq), CF.sub.3CH.sub.2OH *SL-J002-1 = (R)-1-[(SP)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine

[0385] In all cases, low selectivity and no or very low yield of the desired product (II-1, labeled ‘Product’ in the table above) was observed. These experiments demonstrate that the catalysts and conditions described in EP1862446 do not allow efficient hydrogenation of oxime substrates such as (II-1).