PROCESS FOR THE PREPARATION OF OPTICALLY PURE ENANTIOMERS OF CYCLIC IMINIUM SALTS AND THEIR USE AS CATALYSTS

Abstract

The present invention relates to a process for the preparation of an optically pure (+) or (?) enantiomer of an iminium salt having the formula (I), aid process comprising the following steps: a) a reduction step of an iminium salt having the formula (II), said salt being in the form of a racemic mixture, in order to obtain a compound having the formula (III) in the form of a racemic mixture, b) a step of chiral HPLC separation of the compound of formula (III) in the form of a racemic mixture, for obtaining an optically pure (+) or (?) enantiomer compound having the formula (IV), and c) an oxidation step of the compound of formula (IV) for obtaining the compound of formula (I).

Claims

1. A process for the preparation of an optically pure (+) or (?) enantiomer of an iminium salt having the following formula (I): ##STR00058## wherein: R.sup.1 is a (C.sub.6-C.sub.14)aryl group, a (C.sub.1-C.sub.6)alkyl group or a (C.sub.8-C.sub.20)cycloalkyl group, said aryl group being optionally substituted with at least one substituent chosen selected from the group consisting of: halogen, (C.sub.6-C.sub.10)aryl group, and (C.sub.1-C.sub.6)alkyl group, said alkyl group being optionally substituted with one or several phenyl group(s); or R.sup.1 is a NR.sub.aR.sub.b group, R.sub.a and R.sub.b being independently from each other selected from the group consisting of: H, (C.sub.1-C.sub.6)alkyl, and (C.sub.6-C.sub.10)aryl, or R.sub.a and R.sub.b form together with the nitrogen atom carrying them a N(CH.sub.2).sub.2+m heterocyclyl ring, m being 0 or an integer comprised from 1 to 6; R.sup.2 is H, a (C.sub.6-C.sub.10)aryl group or a (C.sub.1-C.sub.6)alkyl group; R.sup.3 is a (C.sub.1-C.sub.6)alkyl group; or R.sup.2 and R.sup.3 may together form, with the carbon atom carrying them, a (C.sub.3-C.sub.6)cycloalkyl; R.sup.5 is selected from the following groups: (C.sub.6-C.sub.20)aryl, (C.sub.1-C.sub.10)alkyl, and (C.sub.3-C.sub.12)cycloalkyl group, said alkyl group being optionally substituted with at least one substituent selected from the (C.sub.6-C.sub.10)aryl groups, and said aryl group being optionally substituted with at least one substituent selected from the group consisting of: (C.sub.1-C.sub.6)alkyl, optionally substituted with one or several phenyl group(s), (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, and (C.sub.6-C.sub.10)aryl, optionally substituted with one or several substituents selected from the group consisting of: (C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6) alkoxy, and (C.sub.1-C.sub.6)alkyl; R.sup.6 is selected from the following groups: (C.sub.6-C.sub.20)aryl, (C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.12)cycloalkyl, heteroaryl, (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, and heteroaryl(C.sub.1-C.sub.6)alkyl, said aryl group being optionally substituted with at least one substituent selected from the group consisting of: (C.sub.1-C.sub.6)alkyl, optionally substituted with one or several phenyl group(s), (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, and (C.sub.6-C.sub.10)aryl, optionally substituted with one or several substituents selected from the group consisting of: (C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6) alkoxy, and (C.sub.1-C.sub.6)alkyl; with the proviso that R.sup.6 is different from R.sup.5; or R.sup.5 and R.sup.6, taken together with the carbon atom to which they are attached, form a five-, six-, or ten-membered cycloalkyl or heterocyclyl ring; R.sup.4 is H or a (C.sub.1-C.sub.6)alkyl group; n is 0 or an integer comprised between 1 and 3; or R.sup.3 and R.sup.5, taken together with the carbon atom to which they are attached, form a six-, seven- or eight-membered cycloalkyl ring; X.sup.? is a counteranion, said salt being in the form of an optically pure (+) or (?) enantiomer, said process comprising the following steps of: a) reducing an iminium salt having the following formula (II), said salt being in the form of a racemic mixture: ##STR00059## R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, n, and X.sup.? are as defined above in formula (I), in order to obtain a compound having the formula (III): ##STR00060## R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and n are as defined above in formula (I), said compound of formula (III) being in the form of a racemic mixture, b) separating, by chiral HPLC, the compound of formula (III) in the form of a racemic mixture, for obtaining an optically pure (+) or (?) enantiomer compound having the formula (IV): ##STR00061## R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and n are as defined above in formula (I), said compound of formula (IV) being in the form of an optically pure (+) or (?) enantiomer, c) oxidizing the compound of formula (IV) for obtaining the compound of formula (I), and d) optionally a counteranion exchange step.

2. The process of claim 1, wherein the reducing step is carried out with a reduction agent selected from the group consisting of: LiAlH.sub.4, NaBH.sub.4, diisobutylaluminium hydride, lithium triethylborohydride, sodium bis(2-methoxyethoxy)aluminium hydride, and cyanoborohydrides.

3. The process of claim 1, wherein the oxidizing step is carried out with a oxidation agent selected from the group consisting of: Br.sub.2, N-bromosuccinimide, I.sub.2, N-iodosuccinimide, Cl.sub.2, a copper (II) compound, and a hypervalent iodine compound.

4. The process of claim 1, wherein R.sup.1 is a (C.sub.6-C.sub.10)aryl group substituted with at least one substituent selected from (C.sub.1-C.sub.6)alkyl groups, and/or wherein R.sup.2 is a (C.sub.1-C.sub.6)alkyl group.

5. The process of claim 1, wherein R.sup.2 and R.sup.3 are identical.

6. The process of claim 1, wherein R.sup.2 and R.sup.3 are different.

7. The process of claim 1, wherein R.sup.4 is H.

8. The process of claim 1, wherein R.sup.5 and R.sup.6 are different and selected from the following groups: a (C.sub.6-C.sub.10)aryl group, a (C.sub.1-C.sub.6)alkyl group, such as methyl, and a (C.sub.3-C.sub.6)cycloalkyl group, such as cyclohexyl, said aryl group being optionally substituted with two substituents selected from the (C.sub.1-C.sub.6)alkyl groups.

9. An optically pure (+) or (?) enantiomer of an iminium salt having the following formula (I): ##STR00062## wherein: R.sup.1 is a (C.sub.6-C.sub.14)aryl group, a (C.sub.1-C.sub.6)alkyl group or a (C.sub.8-C.sub.20)cycloalkyl group, said aryl group being optionally substituted with at least one substituent selected from the group consisting of: halogen, a (C.sub.6-C.sub.10)aryl group, and a (C.sub.1-C.sub.6)alkyl group, said alkyl group being optionally substituted with one or several phenyl group(s); or R.sup.1 is a NR.sub.aR.sub.b group, R.sub.a and R.sub.b being independently from each other selected from the group consisting of: H, (C.sub.1-C.sub.6)alkyl, and (C.sub.6-C.sub.10)aryl, or Ra and Rb form together with the nitrogen atom carrying them a N(CH.sub.2).sub.2+m heterocyclyl ring, m being 0 or an integer comprised from 1 to 6; R.sup.2 is H, a (C.sub.6-C.sub.10)aryl group or a (C.sub.1-C.sub.6)alkyl group; R.sup.3 is a (C.sub.1-C.sub.6)alkyl group; or R.sup.2 and R.sup.3 may together form, with the carbon atom carrying them, a (C.sub.3-C.sub.6)cycloalkyl; R.sup.5 is selected from the following groups: (C.sub.6-C.sub.20)aryl, (C.sub.1-C.sub.10)alkyl, and (C.sub.3-C.sub.12)cycloalkyl group, said alkyl group being optionally substituted with at least one substituent selected from the (C.sub.6-C.sub.10)aryl groups, and said aryl group being optionally substituted with at least one substituent selected from the group consisting of: (C.sub.1-C.sub.6)alkyl, optionally substituted with one or several phenyl group(s), (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, and (C.sub.6-C.sub.10)aryl, optionally substituted with one or several substituents selected from the group consisting of: (C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6) alkoxy, and (C.sub.1-C.sub.6)alkyl; R.sup.6 is selected from the following groups: (C.sub.6-C.sub.20)aryl, (C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.12)cycloalkyl, heteroaryl, (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, and heteroaryl(C.sub.1-C.sub.6)alkyl, said aryl group being optionally substituted with at least one substituent selected from the group consisting of: (C.sub.1-C.sub.6)alkyl, optionally substituted with one or several phenyl group(s), (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, and (C.sub.6-C.sub.10)aryl, optionally substituted with one or several substituents selected from the group consisting of: (C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6) alkoxy, and (C.sub.1-C.sub.6)alkyl; with the proviso that R.sup.6 is different from R.sup.5; or R.sup.5 and R.sup.6, taken together with the carbon atom to which they are attached, form a five-, six-, or ten-membered cycloalkyl or heterocyclyl ring; R.sup.4 is H or a (C.sub.1-C.sub.6)alkyl group; n is 0 or an integer comprised between 1 and 3; or R.sup.3 and R.sup.5, taken together with the carbon atom to which they are attached, form a six-, seven- or eight-membered cycloalkyl ring; and X.sup.? is a counteranion, said salt being in the form of an optically pure (+) or (?) enantiomer.

10. (canceled)

11. A combination comprising the compound of formula (I) as defined in claim 1, and a transition metal other than ruthenium.

12. A combination comprising the compound of formula (I) as defined in claim 1, and a transition metal selected from the group consisting of gold, copper, and rhodium.

13. A combination comprising the compound of formula (I) as defined in claim 1, a transition metal, and an organic light-emitting diode.

14. The combination of claim 13, wherein the transition metal is selected from the group consisting of gold, copper, and rhodium.

15. An organic light emitting device (OLED) comprising: an anode; a cathode; and an organic layer disposed between the anode and the cathode, wherein the organic layer comprises a compound of formula (I) according to claim 1, in combination with a transition metal selected from the group consisting of Ru, Os, Ir, Pd, Pt, Cu, Ag, and Au, and can be bonded to other ligands.

16. The process of claim 3, wherein the oxidation agent is selected from the group consisting of 2-iodoxybenzoic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetra-N-butylammonium iodide, and tert-butyl hydroperoxide.

17. The process of claim 1, wherein R.sup.1 is a (C.sub.6-C.sub.10)aryl group substituted with at least one substituent selected from a phenyl group substituted with two alkyl groups, optionally wherein the alkyl groups are methyl, isopropyl or ethyl groups, and R.sup.1 is a methyl group.

18. The process of claim 5, wherein R.sup.2 and R.sup.3 are a methyl group.

19. The process of claim 6, wherein R.sup.2 is a (C.sub.1-C.sub.6)alkyl group or a methyl group, and R.sup.3 is H, a (C.sub.6-C.sub.10)aryl group, or a phenyl group.

20. The process of claim 1, wherein R.sup.5 and R.sup.6 are different and selected from the following groups: a phenyl or naphthyl, a methyl, and a cyclohexyl.

21. The optically pure (+) or (?) enantiomer of an iminium salt according to claim 9, wherein n is 1.

Description

EXAMPLES

Preparation of the Compounds of the Invention

General Information

[0152] All reactions and subsequent manipulations were performed under an argon atmosphere in an MBraun glovebox or using standard Schlenk techniques, if not stated otherwise. .sup.1H and .sup.13C{.sup.1H} NMR spectra were recorded on a Varian 400 or Bruker Avance 400 at 25? C. .sup.1H NMR chemical shifts are reported relative to TMS (0 in ppm) and were referenced via residual proton resonances of the corresponding deuterated solvent (CHCl.sub.3: 7.26 ppm; C.sub.6D.sub.5H: 7.16 ppm) whereas .sup.13C{.sup.1H} NMR spectra are reported relative to TMS using the natural-abundance carbon resonances (CDCl.sub.3: 77.16 ppm; C.sub.6D.sub.6: 128.0 ppm). Coupling constants are given in Hertz.

CAAC Salt Reduction to Form H.SUB.2 .Adducts (Corresponding to Step a) of the Process According to the Invention for the Preparation of Compounds of Formula (III) According to the Invention)

[0153] General procedure: In a Schlenk tube under argon, lithium aluminum hydride (2 equiv) was slowly added to a solution of iminium salt (1.0 equiv) in a THF at 0? C. and received suspension was further stirred at room temperature overnight. Reaction mixture was then quenched with mixture of hydrated MgSO.sub.4 and silica and then passed through a short pad of silica which was further washed with Et.sub.2O. Evaporation of the combined organic fractions gives desired CAAC-H.sub.2 adducts as white sticky solids in typical yield of 90%.

Analytical Data:

[0154] ##STR00021##

[0155] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.41-7.31 (m, 4H), 7.28-7.20 (m, 2H), 7.16 (ddd, J=17.0, 7.5, 2.0 Hz, 2H), 4.01 (d, J=8.4 Hz, 1H), 3.91 (p, J=6.9 Hz, 1H), 3.50 (d, J=8.6 Hz, 1H), 3.37 (p, J=6.8 Hz, 1H), 2.54 (d, J=12.7 Hz, 1H), 2.30 (dd, J=12.7, 0.8 Hz, 1H), 1.63 (s, 3H), 1.30 (d, J=6.9 Hz, 3H), 1.26 (s, 3H), 1.16 (t, J=6.8 Hz, 6H), 1.08 (d, J=6.8 Hz, 3H), 1.05 (s, 3H).

[0156] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=152.3, 152.3, 150.7, 138.4, 128.2, 126.5, 126.0, 125.6, 124.1, 123.8, 65.8, 62.7, 54.4, 45.1, 32.2, 29.7, 29.4, 28.4, 28.2, 26.7, 26.6, 23.1, 22.8.

##STR00022##

[0157] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.91-7.82 (m, 3H), 7.80 (d, J=1.9 Hz, 1H), 7.56-7.44 (m, 3H), 7.30-7.23 (m, 1H), 7.22 (dd, J=7.7, 2.1 Hz, 1H), 7.17 (dd, J=7.3, 2.1 Hz, 1H), 4.14 (d, J=8.4 Hz, 1H), 3.94 (hept, J=6.9 Hz, 1H), 3.63 (d, J=8.4 Hz, 1H), 3.42 (hept, J=6.8 Hz, 1H), 2.71 (d, J=12.7 Hz, 1H), 2.40 (d, J=12.7 Hz, 1H), 1.73 (s, 3H), 1.35 (d, J=6.9 Hz, 3H), 1.31 (s, 3H), 1.21 (d, J=6.9 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.08 (s, 3H).

[0158] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=152.3, 152.3, 147.9, 138.5, 133.4, 131.8, 127.9, 127.9, 127.5, 126.6, 125.9, 125.5, 125.3, 124.1, 123.8, 123.6, 65.9, 62.9, 54.6, 45.3, 32.0, 29.7, 29.5, 28.4, 28.3, 26.8, 26.7, 23.2, 22.9.

##STR00023##

[0159] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=8.27-8.18 (m, 1H), 7.96-7.87 (m, 1H), 7.82-7.72 (m, 1H), 7.53-7.42 (m, 4H), 7.29-7.19 (m, 2H), 7.15 (dd, J=7.0, 2.5 Hz, 1H), 4.34 (d, J=8.6 Hz, 1H), 4.06 (hept, J=6.9 Hz, 1H), 3.85 (d, J=8.6 Hz, 1H), 3.34 (hept, J=6.9 Hz, 1H), 2.84 (d, J=12.6 Hz, 1H), 2.67 (d, J=12.5 Hz, 1H), 1.94 (s, 3H), 1.39-1.32 (m, 6H), 1.23 (d, J=6.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.08 (s, 3H), 1.00 (d, J=6.8 Hz, 3H).

[0160] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=0.2, 152.1, 146.6, 138.7, 134.9, 131.5, 129.5, 127.2, 126.6, 126.2, 125.2, 125.0, 124.9, 124.2, 123.8, 123.6, 67.2, 62.4, 56.1, 46.0, 31.2, 29.7, 28.8, 28.6, 28.2, 26.7, 26.3, 23.3, 22.9.

##STR00024##

[0161] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.28-7.14 (m, 3H), 6.99-6.94 (m, 2H), 6.91 (qd, J=1.6, 0.9 Hz, 1H), 4.01 (d, J=8.3 Hz, 1H), 3.99-3.91 (m, 1H), 3.49 (d, J=8.3 Hz, 1H), 3.40 (hept, J=6.8 Hz, 1H), 2.55 (d, J=12.7 Hz, 1H), 2.37 (s, 6H), 2.30 (d, J=12.6 Hz, 1H), 1.64 (s, 3H), 1.32 (d, J=6.9 Hz, 3H), 1.28 (s, 3H), 1.19 (dd, J=12.0, 6.8 Hz, 6H), 1.12 (d, J=6.8 Hz, 3H), 1.08 (s, 3H).

[0162] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=152.3, 152.3, 150.9, 138.5, 137.6, 127.3, 126.5, 124.1, 123.8, 123.7, 65.9, 62.7, 54.3, 44.9, 32.3, 29.8, 29.5, 28.5, 28.1, 26.8, 26.6, 23.2, 22.8, 21.6.

##STR00025##

[0163] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.25-7.18 (m, 1H), 7.18-7.12 (m, 2H), 3.88 (hept, J=6.9 Hz, 1H), 3.56-3.41 (m, 2H), 3.01 (d, J=8.3 Hz, 1H), 1.91 (d, J=12.7 Hz, 1H), 1.86-1.67 (m, 5H), 1.54-1.46 (m, 1H), 1.36-1.25 (m, 10H), 1.22 (s, 4H), 1.20 (s, 4H), 1.17 (d, J=6.8 Hz, 4H), 1.09 (d, J=6.7 Hz, 7H).

[0164] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=? 152.4, 152.1, 138.9, 126.3, 123.9, 123.7, 66.6, 62.6, 55.2, 49.9, 43.5, 29.7, 29.2, 28.8, 28.7, 28.5, 27.9, 27.2, 27.1, 26.9, 26.6, 26.6, 23.2, 22.9, 22.1.

##STR00026##

[0165] Diastereoisomeric ratio of starting iminium salt range between 90/10 to 75/25 and are the same in the product.

Analytical Data are Given for a Major Dia

[0166] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.25-7.19 (m, 2H), 7.18-7.12 (m, 2H), 7.09 (m, 3H), 7.00 (dd, J=7.5, 2.0 Hz, 1H), 3.67 (hept, J=6.9 Hz, 1H), 3.21 (dd, J=8.8, 2.8 Hz, 1H), 2.99 (hept, J=6.8 Hz, 1H), 2.79 (q, J=7.3 Hz, 1H), 2.50 (dd, J=8.7, 1.7 Hz, 1H), 2.30-2.15 (m, 1H), 2.05 (dd, J=12.6, 10.9 Hz, 1H), 1.92-1.83 (m, 2H), 1.81-1.71 (m, 2H), 1.75-1.56 (m, 1H), 1.30 (d, J=7.2 Hz, 3H), 1.28-1.21 (m, 6H, overlapping signals), 1.09 (d, J=6.9 Hz, 3H), 0.64 (s, 3H), 0.63 (d, J=6.8 Hz, 3H).

[0167] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=151.8, 151.5, 143.9, 143.0, 129.4, 127.6, 126.2, 126.1, 124.1, 123.5, 55.7, 51.3, 47.9, 42.5, 38.7, 35.5, 31.2, 28.5, 27.6, 26.4, 25.7, 24.8, 24.6, 24.5, 23.6, 17.3, 14.1.

##STR00027##

[0168] Diastereoisomeric ratio: 75/25

[0169] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.54-7.47 (m, 2H), 7.47-7.35 (m, 3H), 7.33-7.24 (m, 2H), 7.24-7.07 (m, 7H), 6.99-6.87 (m, 2H), 4.23 (p, J=6.9 Hz, OH), 4.14 (d, J=9.2 Hz, 1H), 4.10 (d, J=8.6 Hz, OH), 3.67-3.42 (m, 2H), 3.15 (d, J=12.8 Hz, 1H), 2.82 (td, J=13.2, 6.2 Hz, 2H), 2.47 (dd, J=13.1, 0.8 Hz, OH), 2.16 (p, J=6.8 Hz, OH), 1.80 (s, 1H), 1.73 (s, 1H), 1.56 (s, 2H), 1.44 (d, J=7.0 Hz, 1H), 1.32-1.24 (m, 5H), 1.24-1.18 (m, 1H), 1.14 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 2H), 0.85 (d, J=6.7 Hz, 1H), 0.30 (d, J=6.8 Hz, 2H), 0.16 (d, J=6.7 Hz, 1H).

[0170] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=152.3, 151.9, 151.2, 150.8, 150.1, 146.2, 146.0, 140.1, 138.8, 128.5, 128.3, 127.8, 127.6, 126.7, 126.7, 126.6, 126.1, 126.0, 125.9, 125.8, 125.7, 124.2, 123.9, 123.7, 123.6, 68.0, 67.9, 65.9, 52.0, 45.3, 33.8, 32.9, 30.6, 29.2, 28.8, 28.2, 28.0, 26.8, 26.8, 26.7, 26.2, 25.6, 23.7, 23.0, 21.5, 21.1.

##STR00028##

[0171] Diastereoisomeric ratio: 55/45

[0172] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.42-7.30 (m, 4H), 7.30-7.20 (m, 2H), 7.20-7.07 (m, 2H), 4.10-3.93 (m, 1H), 3.85 (d, J=8.1 Hz, 1H), 3.83-3.74 (m, 1H), 3.71 (d, J=8.4 Hz, OH), 3.64 (p, J=6.9 Hz, 1H), 3.46 (dd, J=8.3, 0.9 Hz, 1H), 3.44-3.37 (m, 1H), 2.99 (p, J=6.8 Hz, OH), 2.75 (dd, J=12.7, 8.7 Hz, OH), 2.34 (dd, J=11.7, 5.4 Hz, 1H), 2.10 (dd, J=11.7, 9.0 Hz, 1H), 1.95 (ddd, J=12.7, 5.0, 0.9 Hz, OH), 1.67 (s, 1H), 1.58 (s, 2H), 1.32-1.27 (m, 4H), 1.27-1.22 (m, 2H), 1.21-1.14 (m, 5H), 1.12 (t, J=6.6 Hz, 3H), 0.97 (d, J=6.0 Hz, 2H).

[0173] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=. 2, 151.0, 150.5, 150.2, 150.2, 149.9, 140.6, 139.7, 128.3, 128.2, 126.5, 126.4, 126.0, 125.9, 125.7, 125.7, 124.6, 124.0, 123.7, 123.5, 66.9, 66.8, 58.1, 57.0, 49.1, 46.8, 45.9, 45.3, 31.8, 30.5, 27.9, 27.8, 27.5, 27.4, 25.6, 25.5, 24.8, 24.7, 24.2, 24.2, 23.9, 23.6, 22.3, 20.5.

##STR00029##

[0174] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.41-7.31 (m, 4H), 7.26-7.21 (m, 1H), 7.17 (d, J=5.3 Hz, 2H), 7.12 (dd, J=5.5, 4.0 Hz, 1H), 3.98 (d, J=8.4 Hz, 1H), 3.49 (d, J=8.3 Hz, 1H), 3.17 (dq, J=15.0, 7.5 Hz, 1H), 2.86-2.65 (m, 2H), 2.60-2.47 (m, 2H), 2.27 (dd, J=12.7, 0.9 Hz, 1H), 1.64 (s, 3H), 1.27-1.20 (m, 6H), 1.19-1.11 (m, 3H), 1.02 (s, 3H).

[0175] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=150.7, 147.6, 147.5, 140.3, 128.2, 127.1, 126.6, 126.0, 125.9, 125.6, 65.3, 63.4, 54.5, 45.2, 32.2, 29.9, 29.2, 25.5, 25.4, 16.3, 16.2.

##STR00030##

[0176] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.88-7.81 (m, 3H), 7.78 (d, J=2.1 Hz, 1H), 7.54-7.41 (m, 3H), 7.18-7.16 (m, 2H), 7.14-7.10 (m, 1H), 4.09 (d, J=8.6 Hz, 1H), 3.60 (d, J=8.6 Hz, 1H), 3.25-3.12 (m, 1H), 2.89-2.68 (m, 2H), 2.64 (d, J=12.7 Hz, 1H), 2.59-2.45 (m, 1H), 2.36 (d, J=12.7 Hz, 1H), 1.71 (s, 3H), 1.27 (t, J=7.6 Hz, 3H, overlapping) 1.27 (s, 3H, overlapping). 1.14 (t, J=7.5 Hz, 3H), 1.02 (s, 3H).

[0177] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=148.0, 147.7, 147.6, 140.5, 133.5, 131.9, 128.0, 128.0, 127.6, 127.2, 126.8, 126.2, 126.1, 125.6, 125.5, 123.8, 65.5, 63.6, 54.8, 45.5, 32.1, 29.9, 29.4, 25.7, 16.5.

##STR00031##

[0178] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=8.24-8.18 (m, 1H), 7.92-7.87 (m, 1H), 7.75 (dd, J=6.7, 2.8 Hz, 1H), 7.49-7.42 (m, 4H), 7.21-7.15 (m, 2H), 7.11 (dd, J=6.7, 2.8 Hz, 1H), 4.27 (d, J=8.6 Hz, 1H), 3.85 (d, J=8.6 Hz, 1H), 3.33-3.20 (m, 1H), 2.83-2.70 (m, 2H, overlapping), 2.79 (d, J=12.7 Hz, 1H, overlapping), 2.63 (d, J=12.6 Hz, 1H), 2.53 (dq, J=15.0, 7.6 Hz, 1H), 1.35 (s, 3H), 1.29 (t, J=7.6 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H), 1.04 (s, 3H).

[0179] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=147.7, 147.4, 146.9, 140.6, 135.0, 131.6, 129.6, 127.4, 127.3, 126.8, 126.4, 126.2, 125.4, 125.2, 125.0, 123.8, 66.8, 63.0, 56.2, 46.2, 31.3, 30.0, 28.8, 25.7, 25.6, 16.4, 16.3.

##STR00032##

[0180] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): 7.16-7.08 (m, 3H), 3.40 (d, J=8.3 Hz, 1H), 3.14-3.05 (m, 1H), 2.98 (d, J=8.3 Hz, 1H), 2.91-2.81 (m, 1H), 2.69-2.58 (m, J=2H), 1.88-1.73 (m, 4H), 1.69 (m, 2H), 1.54-1.46 (m, 1H), 1.30-1.10 (m, 9H, overlapping) 1.21 (s, 3H, overlapping), 1.21 (t, 3H, J=7.6 Hz overlapping), 1.18 (s, 3H, overlapping), 1.17 (t, J=7.5 Hz, 3H, overlapping) 1.04 (s, 3H).

[0181] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=147.9, 147.5, 140.9, 127.1, 126.6, 125.9, 66.3, 63.4, 55.3, 50.1, 43.7, 30.3, 29.1, 28.8, 28.6, 27.3, 27.2, 27.0, 25.8, 25.3, 22.3, 16.4, 16.3.

##STR00033##

[0182] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.18-7.10 (m, 7H), 3.51 (d, J=8.5 Hz, 1H), 3.10 (d, J=8.5 Hz, 1H), 3.07-2.95 (m, 2H), 2.96-2.88 (m, 1H), 2.87-2.78 (m, 2H), 2.73-2.56 (m, 2H), 2.08 (d, J=12.8 Hz, 1H), 1.76 (d, J=12.7 Hz, 1H), 1.29-1.23 (m, 12H), 1.17 (t, J=7.6 Hz, 2H, overlapping), 1.16 (s, 3H, overlapping), 1.13 (s, 3H).

[0183] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=147.7, 147.4, 146.5, 140.7, 137.2, 130.4, 126.9, 126.8, 126.0, 65.6, 63.6, 54.8, 48.2, 41.7, 33.8, 29.6, 29.3, 27.5, 25.6, 25.5, 24.2, 16.4, 16.4.

##STR00034##

[0184] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.42-7.30 (m, 4H), 7.28-7.19 (m, 1H), 6.95 (s, 1H), 6.89 (s, 1H), 4.01 (d, J=8.3 Hz, 1H), 3.41 (d, J=8.3 Hz, 1H), 2.48 (d, 1H, J=11.6 Hz, overlapping), 2.47 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H), 2.25 (d, J=11.6 Hz, 1H), 1.66 (s, 3H), 1.31 (s, 3H), 1.11 (s, 3H).

[0185] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=150.9, 141.3, 140.9, 139.6, 135.0, 130.2, 129.7, 128.3, 126.1, 125.7, 64.1, 63.9, 54.6, 45.0, 32.3, 30.1, 29.5, 21.1, 20.9, 20.9.

##STR00035##

[0186] Diastereoisomeric ratio of starting iminium salt is 1/1 but product is received in 4/1 mixture.

[0187] Analytical data are given for a Major Dia

[0188] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=7.48-7.41 (m, 2H), 7.40-7.33 (m, 3H), 7.32-7.26 (m, 2H), 7.26-7.20 (m, 3H), 7.04 (s, 1H), 7.02 (s, 1H), 4.25 (d, J=8.3 Hz, 1H), 3.55 (d, J=8.3 Hz, 1H), 2.37 (s, 3H), 2.35 (s, 3H), 2.30 (d, J=12.6 Hz, 1H), 1.97 (d, J=12.6 Hz, 1H), 1.45 (s, 3H), 1.00 (s, 3H), 0.60 (s, 3H).

[0189] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=151.5, 146.2, 144.1, 140.9, 138.5, 135.0, 132.2, 130.4, 130.3, 128.4, 127.5, 126.3, 125.9, 125.7, 65.1, 64.4, 54.1, 45.09, 32.4, 30.5, 28.5, 21.7, 20.9.

Chiral Resolution: Analytical Chiral HPLC Separation Data (Corresponding to Step b) of the Process According to the Invention for the Preparation of Compounds of Formula (IV) According to the Invention)

Analytical Chiral HPLC Separation for Compound 1

[0190] ##STR00036##

[0191] The sample is dissolved in hexane, injected on the chiral column, and detected with an UV detector at 220 nm and a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min.

TABLE-US-00001 Mobile Column Phase t1 k1 t2 k2 ? Rs Lux-Cellulose-4 Heptane 4.57 0.55 5.54 0.88 1.60 3.15 (+) (?)

TABLE-US-00002 RT Area Capacity Resolution [min] Area % Factor Enantioselectivity (USP) 4.57 6687 49.83 0.55 5.54 6731 50.17 0.88 1.60 3.15 Sum 13418 100.00

Semi-Preparative Separation for Compound 1:

[0192] Sample preparation: About 160 mg of compound 1 are dissolved in 1.8 mL of hexane. [0193] Chromatographic conditions: Lux-Cellulose-4 (250?10 mm), hexane as mobile phase, flow-rate=5 mL/min, UV detection at 254 nm. [0194] Injections (stacked): 45 times 40 ?L, every 2.8 minutes. [0195] First fraction: 72 mg of the first eluted enantiomer with ee>99.5% (45% yield).

TABLE-US-00003 RT [min] Area Area % 4.27 9480 100.00 Sum 9480 100.00 [0196] Second fraction: 72 mg of the second eluted enantiomer with ee>96% (45% yield).

TABLE-US-00004 RT [min] Area Area % 4.29 368 1.97 4.78 18352 98.03 Sum 18720 100.00 [0197] Intermediate: 12 mg

Optical Rotations

[0198] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578 and 546 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

TABLE-US-00005 (+)-Compound 1 (?)-Compound 1 First eluted enantiomer Second eluted enantiomer on Lux-Cellulose-4 on Lux-Cellulose-4 ? (nm) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.62) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.53) 589 +61 ?59 578 +64 ?62 546 +76 ?74 436 +152 ?146 405 +209 ?201 365 +360 ?348

Preparative Separation for Compound 1:

[0199] Sample preparation: about 2.54 g of compound 2 are dissolved in 30 ml of hexane. [0200] Chromatographic conditions: Lux-Cellulose-2 (250?10 mm), thermostated at 30? C. in an oven, hexane/2-PrOH (99.9/0.1) as mobile phase, flow-rate=5 mL/min, UV detection at 254 nm [0201] Injections (stacked): 600 times 50 mL, every 1.5 minutes, collection of two fractions. [0202] The first fraction (er 98/2) is dissolved in 16 mL of hexane and was purified again. Injections (stacked): 64 times 250 mL, every 2.5 minutes, to obtain 1.09 g of the first eluted enantiomer ((+)-(R)-Compound 1) with ee>99.5%

TABLE-US-00006 RT [min] Area Area % 4.67 15411 100.00 Sum 15411 100.00 [0203] The second fraction (er 7/93) is dissolved in 14 mL of hexane and was purified again. Injections (stacked): 700 times 20 mL, every 1.5 minutes, to obtain 1.22 g of the second eluted enantiomer ((?)-(S)-Compound 1) with ee>98.5%

TABLE-US-00007 RT [min] Area Area % 4.78 159 0.61 5.58 26164 99.39 Sum 26323 100.00

Optical Rotations

[0204] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

[0205] Structures of (+)-(R)-Compound 1 (from first fraction) and (?)-(S)-Compound 1 (from second fraction) were determined by single crystal X-ray diffraction.

Analytical Chiral HPLC Separation for Compound 2

[0206] ##STR00037##

[0207] The sample is dissolved in ethanol, injected on the chiral column, and detected with an UV detector at 254 nm. The flow-rate is 0.5 mL/min.

TABLE-US-00008 Mobile Column Phase t1 k1 t2 k2 ? Rs Lux-Cellulose-3 Ethanol 8.14 0.3 10.95 0.75 2.49 2.87

TABLE-US-00009 RT Area Capacity Resolution [min] Area % Factor Enantioselectivity (USP) 8.14 4031 50.50 0.30 10.95 3951 49.50 0.75 2.49 2.87 Sum 7982 100.00

Preparative Separation for Compound 2

[0208] Sample preparation: about 360 mg of compound 2 are dissolved in 150 ml of ethanol. [0209] Chromatographic conditions: Lux-Cellulose-3 (250?10 mm), ethanol as mobile phase, flow-rate=2 mL/min, UV detection at 310 nm. [0210] Injections (stacked): 185 times 800 ?L, every 8 minutes. [0211] First fraction: 160 mg of the first eluted enantiomer ((+)R-compound 2) with ee>99%, 44% yield

TABLE-US-00010 RT [min] Area Area % 8.20 1735 100.00 Sum 1735 100.00 [0212] Second fraction: 160 mg of the second eluted enantiomer ((?)S-compound 2) with ee>99%, 44% yield

TABLE-US-00011 RT [min] Area Area % 11.08 946 100.00 Sum 946 100.00

[0213] Impurity: 12 mg

Optical Rotations

[0214] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

TABLE-US-00012 (+)-Compound 2 (?)-Compound 2 First eluted enantiomer Second eluted enantiomer on Lux-Cellulose-3 on Lux-Cellulose-3 ? (nm) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 1.25) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.98) 589 +51 ?51 578 +54 ?54 546 +64 ?64 436 +128 ?128 405 +176 ?176 365 +300 ?300

Analytical Chiral HPLC Separation for Compound 3

[0215] ##STR00038##

[0216] The sample is dissolved in ethanol, injected on the chiral column, and detected with an UV detector at 254 nm. The flow-rate is 0.5 mL/min.

TABLE-US-00013 Mobile Column Phase t1 k1 t2 k2 ? Rs Lux-Cellulose-3 Ethanol 7.76 0.24 9.62 0.54 2.23 1.41

TABLE-US-00014 RT Area Capacity Resolution [min] Area % Factor Enantioselectivity (USP) 7.76 5304 50.94 0.24 9.62 5109 49.06 0.54 2.23 1.41 Sum 10412 100.00

Preparative Separation for Compound 3

[0217] Sample preparation: About 320 mg of compound 3 are dissolved in 15 mL of ethanol. [0218] Chromatographic conditions: Lux-Cellulose-3 (250?10 mm), ethanol as mobile phase, flow-rate=2 mL/min, UV detection at 310 nm. [0219] Injections (stacked): 60 times 250 ?L, every 6 minutes.

[0220] After collection and evaporation of the first intermediate fraction: 28 times 250 UL, every 5 minutes.

[0221] After evaporation of the second intermediate fraction: 20 times 250 ?L, every 5 minutes [0222] First fraction: 152 mg of the first eluted enantiomer ((?)S-compound 3) with ee>99%, 48% yield

TABLE-US-00015 RT [min] Area Area % 7.81 4433 100.00 Sum 4433 100.00 [0223] Second fraction: 152 mg of the second eluted enantiomer ((+)R-compound 3) with ee>98.5%, 48% yield

TABLE-US-00016 RT [min] Area Area % 7.77 42 0.54 9.71 7754 99.46 Sum 7796 100.00

[0224] Impurity: 15 mg

Optical Rotations

[0225] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

TABLE-US-00017 (?)-Compound 3 (+)-Compound 3 First eluted enantiomer Second eluted enantiomer on Lux-Cellulose-3 on Lux-Cellulose-3 ? (nm) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.77) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.95) 589 ?44 44 578 ?46 46 546 ?56 56 436 ?118 118 405 ?170 170 365 ?320 320

Analytical Chiral HPLC Separation for Compound 4

[0226] ##STR00039##

[0227] The sample is dissolved in ethanol, injected on the chiral column, and detected with an UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min.

TABLE-US-00018 Mobile Column Phase t1 k1 t2 k2 ? Rs Lux-Cellulose-2 Heptane/ 8.75 0.40 9.70 0.55 1.38 1.72 2-PrOH (+) (?)

TABLE-US-00019 RT Area Capacity Resolution [min] Area % Factor Enantioselectivity (USP) 4.26 614 53.95 0.45 5.02 524 46.05 0.70 1.57 2.17 Sum 1137 100.00

Semi-Preparative Separation for Compound

[0228] Sample preparation: About 234 mg of compound 4 are dissolved in 3.6 mL of hexane. [0229] Chromatographic Lux-Cellulose-2 (250?10 mm), hexane/2-PrOH 99.9/0.1 as mobile phase, flow-rate=5 mL/min, 30? C., UV detection at 290 nm. [0230] Injections (stacked): 90 times 40 ?L, every 2.4 minutes. [0231] First fraction: 108 mg of the first eluted enantiomer ((+)-(R)-compound 4) with ee>99.5%

TABLE-US-00020 RT [min] Area Area % 4.27 1645 100.00 Sum 1645 100.00 [0232] Second fraction: (127 mg, er 7/93) is dissolved in 2 mL of hexane and was purified again. Injections (stacked): 50 times 40 ?L, every 2.4 minutes, to obtain 106 mg of the second eluted enantiomer ((?)-(S)-compound 4) with ee>98%

TABLE-US-00021 RT [min] Area Area % 4.31 20 0.94 5.01 2090 99.06 Sum 2110 100.00

Optical Rotations

[0233] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

TABLE-US-00022 (+)-Compound 4 (+)-Compound 4 First eluted enantiomer Second eluted enantiomer on Lux-Cellulose-2 on Lux-Cellulose-2 ? (nm) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.19) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.18) 589 +51 ?50 578 +54 ?53 546 +64 ?63 436 +127 ?125 405 +177 ?174 365 +308 ?302 325 +580 ?570

Analytical Chiral HPLC Separation for Compound 6

[0234] ##STR00040##

Analytical Chiral HPLC Separation for Compound 6

[0235] The sample is dissolved in heptane/2-PrOH, injected on the chiral column, Lux-Cellulose-2 and detected with an UV detector at 230 nm, a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min.

TABLE-US-00023 RT [min] Area Area % Capacity Factor 4.44 3679 39.28 0.50 ?Main? 1 4.81 1879 20.06 0.63 ?Mino? 5.24 3807 40.65 0.78 ?Main 2? Sum 9364 100.00

Preparative Separation for Compound 6

[0236] Sample preparation: About 100 mg of compound 6 are dissolved in 10 ml of hexane. [0237] Chromatographic conditions: Lux-Cellulose-2 (250?10 mm), hexane/2-PrOH (99.9/0.1) as mobile phase, flow-rate=5 mL/min, UV detection at 290 nm. [0238] Injections (stacked): 200 times 50 ?L, every 5 minutes. [0239] First fraction: 25 mg with ee>99.5% (Main 1)

TABLE-US-00024 RT [min] Area Area % 4.45 1423 100.00 Sum 1423 100.00 [0240] Second fraction: 14 mg mino)

TABLE-US-00025 RT [min] Area Area % 4.47 49 8.20 4.83 546 91.80 Sum 595 100.00 [0241] Third fraction: 28 mq with ee>99.5% (Main 2)

TABLE-US-00026 RT [min] Area Area % 5.32 486 100.00 Sum 486 100.00 [0242] Intermediate: 17 mg

Optical Rotations

[0243] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

TABLE-US-00027 (?)-Compound 6 (+)-Compound 6 First eluted enantiomer Second eluted enantiomer on Lux-Cellulose-2 on Lux-Cellulose-2 ? (nm) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.19) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.18) 589 ?32 +32 578 ?33 +33 546 ?42 +42 436 ?96 +96 405 ?145 +145 365 ?290 +290

Analytical Chiral HPLC Separation for Compound 9

[0244] ##STR00041##

[0245] The sample is dissolved in ethanol, injected on the chiral column, and detected with an UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow-rate is 0.5 mL/min.

TABLE-US-00028 Mobile Column Phase t1 k1 t2 k2 ? Rs Lux-Cellulose-3 Ethanol 8.75 0.40 9.70 0.55 1.38 1.72 (+) (?)

TABLE-US-00029 RT Area Capacity Resolution [min] Area % Factor Enantioselectivity (USP) 8.75 4714 49.91 0.40 9.70 4731 50.09 0.55 1.38 1.72 Sum 9444 100.00

Semi-Preparative Separation for Compound 9:

[0246] Sample preparation: About 160 mg of compound 9 are dissolved in 2 mL of ethanol. [0247] Chromatographic conditions: Lux-Cellulose-3 (250?10 mm), ethanol as mobile phase, flow-rate=2 mL/min, UV detection at 254 nm. [0248] Injections (stacked): 25 times 80 ?L, every 4 minutes. [0249] First fraction: 69 mg of the first eluted enantiomer ((+)-(R)-compound 9) with ee>99.5% (43% yield)

TABLE-US-00030 RT [min] Area Area % 8.81 18659 100.00 Sum 18659 100.00 [0250] Second fraction: 76 mg of the second eluted enantiomer ((?)-(S)-compound 9) with ee>97% (48% yield)

TABLE-US-00031 RT [min] Area Area % 8.83 299 1.46 9.70 20140 98.54 Sum 20439 100.00 [0251] Intermediate: 14 mg

Optical Rotations

[0252] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

TABLE-US-00032 (+)-Compound 9 (?)-Compound 9 First eluted enantiomer Second eluted enantiomer on Lux-Cellulose-3 on Lux-Cellulose-3 ? (nm) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.19) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.18) 589 +64 ?62 578 +67 ?65 546 +79 ?77 436 +157 ?153 405 +215 ?209 365 +368 ?359

Analytical Chiral HPLC Separation for Compound 13

[0253] ##STR00042## [0254] The sample is dissolved in ethanol, injected on the chiral column Lux-Cellulose-3, and detected with an UV detector at 254 nm. The flow-rate is 0.5 mL/min.

TABLE-US-00033 RT Area Capacity Resolution [min] Area % Factor Enantioselectivity (USP) 8.06 3969 50.60 1.73 8.95 3876 49.40 2.04 1.17 1.63 Sum 7845 100.00

Preparative Separation for Compound 13:

[0255] Sample preparation: About 182 mg of compound 13 are dissolved in 7 mL of ethanol. [0256] Chromatographic conditions: Lux-Cellulose-3 (250?10 mm), methanol as mobile phase, flow-rate=3 mL/min, UV detection at 254 nm. [0257] Injections (stacked): 35 times 200 ?L, every 8 minutes. [0258] First fraction: 83 mg of the first eluted enantiomer with ee>99.5%

TABLE-US-00034 RT [min] Area Area % 8.07 2593 100.00 Sum 2593 100.00 [0259] Second fraction: 81 mg of the second eluted enantiomer with ee>99.5%

TABLE-US-00035 RT [min] Area Area % 7.93 6 0.25 8.96 2519 99.75 Sum 2526 100.00

[0260] Intermediate: 11 mg

Optical Rotations

[0261] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

TABLE-US-00036 (?)-Compound 13 (+)-Compound 13 First eluted enantiomer Second eluted enantiomer on Lux-Cellulose-3 on Lux-Cellulose-3 ? (nm) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.19) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.18) 589 +4 ?4 578 +4 ?4 546 +3 ?3 436 ?3 +4 405 ?13 +13 365 ?45 +45 325 ?135 +135

Analytical Chiral HPLC Separation for Compound 14

[0262] ##STR00043## [0263] The sample is dissolved in heptane/2-PrOH, injected on the chiral column Lux-Cellulose-2, and detected with an UV detector at 230 nm and a polarimetric detector. The flow-rate is 1 mL/min.

TABLE-US-00037 RT Area Capacity Resolution [min] Area % Factor Enantioselectivity (USP) 5.43 9568 49.06 0.84 7.20 9936 50.94 1.44 1.72 4.10 Sum 19504 100.00

Preparative Separation for Compound 14:

[0264] Sample preparation: About 127 mg of compound 14 are dissolved in 8 mL hexane [0265] Chromatographic conditions: Lux-Cellulose-2 (250?10 mm), hexane/2-PrOH (99.9/0.1) as mobile phase, flow-rate=5 mL/min, UV detection at 290 nm. [0266] Injections (stacked): 45 times 180 ?L, every 5.25 minutes. [0267] First fraction: 54 mg with ee>99.5%

TABLE-US-00038 RT [min] Area Area % 5.44 6293 100.00 Sum 6293 100.00 [0268] Second fraction: 53 mg with ee>99.5%

TABLE-US-00039 RT [min] Area Area % 5.56 13 0.14 7.20 9150 99.86 Sum 9163 100.00

Optical Rotations

[0269] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

TABLE-US-00040 (?)-Compound 14 (+)-Compound 14 First eluted enantiomer Second eluted enantiomer on Lux-Cellulose-2 on Lux-Cellulose-2 ? (nm) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.15) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.16) 578 ?84 +84 546 ?99 +99 436 ?192 +192 405 ?260 +260 365 ?430 +430 325 ?135 +135

Analytical Chiral HPLC Separation for Compound 15

[0270] ##STR00044## [0271] The sample is dissolved in heptane/2-PrOH, injected on the chiral column, Lux-Cellulose-2 and detected with an UV detector at 230 nm and a polarimetric detector. The flow-rate is 1 mL/min.

TABLE-US-00041 RT Area Capacity Resolution [min] Area % Factor Enantioselectivity (USP) 8.78 26945 50.19 1.98 11.78 26742 49.81 2.99 1.51 3.21 Sum 53687 100.00

Preparative Separation for Compound 15:

[0272] Sample preparation: About 80 mg of compound 15 are dissolved in 10 mL of hexane. [0273] Chromatographic conditions: Lux-Cellulose-2 (250?10 mm), hexane/2-PrOH (99.9/0.1) as mobile phase, flow-rate=5 mL/min, UV detection at 290 nm. [0274] Injections (stacked): 67 times 150 ?L, every 9 minutes. [0275] First fraction: 38 mg with ee>99.5%

TABLE-US-00042 RT [min] Area Area % 8.73 27988 100.00 Sum 27988 100.00 [0276] Second fraction: 41 mg with ee>99.5%

TABLE-US-00043 RT [min] Area Area % 9.09 18 0.14 11.93 13268 99.86 Sum 13286 100.00

Optical Rotations

[0277] Optical rotations were measured on a Jasco P-2000 polarimeter with a halogen lamp (589, 578, 546, 436, 405 and 365 nm), in a 10 cm cell, thermostated at 25? C. with a Peltier controlled cell holder.

TABLE-US-00044 (?)-Compound 15 (+)-Compound 15 First eluted enantiomer Second eluted enantiomer on Lux-Cellulose-2 on Lux-Cellulose-2 ? (nm) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.16) ?.sub.D.sup.25 (CH.sub.2Cl.sub.2, c = 0.21) 589 ?76 +76 578 ?80 +80 546 ?95 +95 436 ?190 +190 405 ?262 +262 365 ?410 +410
CAAC-H.sub.2 Adduct Oxidation to Obtain the CAAC.Math.BF.sub.4 Iminium Salt (Corresponding to Step c) of the Process According to the Invention for the Preparation of Compounds of Formula (I) According to the Invention)

[0278] General procedure: In a Schlenk tube under argon enantiopure CAAC-H.sub.2 adducts were dissolved in dry DCM. Received solution was then cooled down in an ice bath to 0? C. and bromine (3 equiv) was added dropwise. Reaction mixture was then brought to RT and stirred overnight. Then water solution of KBF.sub.4 (6 equiv) and Na.sub.2S.sub.2O.sub.3 (3 equiv) was then added and resulting biphasic mixture was stirred for an hour. Phases were then separated and water phase was additionally washed with extra DCM. Combined organic phases were dried over anhydrous MgSO.sub.4 and filtered. Remaining solution was then reduced to ca. 5 ml and an excess of Et.sub.2O was added causing precipitation of white solid. Filtration and copious washing of the precipitate with Et.sub.2O and pentane afforded cyclic iminium salt BF 4 in typical yield of 85% as white solids.

Structures of Compounds Isolated and Analysed by NMR for which Study of Single Crystals by Means of X-Ray Diffractometry Allowed for Determination of Absolute Configuration.

##STR00045##

[0279] (?)-(R)-Compound-16 (received from (+)-(R)-Compound 1) and its enantiomer (+)-(S)-Compound-16 (received from (?)-(S)-Compound 1) have identical spectra

[0280] .sup.1H NMR (500 MHZ, 25? C., CD.sub.3CN): ?: 9.26 (s, 1H), 7.64 (t, J=7.5 Hz 1H), 7.55 (t, J=7.5 Hz, 2H), 7.52 (d, J=7.5 Hz, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 3.10 (d, J=14.0 Hz, 1H), 2.82 (d, J=14.0 Hz, 1H), 2.79 (sept, J=7.0 Hz, 1H), 2.55 (sept, J=7.0 Hz, 1H), 1.93 (s, 3H), 1.58 (s, 3H), 1.40 (s, 3H), 1.39 (d, J=7.0 Hz, 3H), 1.25 (d, J=7.0 Hz, 3H), 1.15 (d, J=7.0 Hz, 3H), 1.08 (d, J=7.0 Hz, 3H).

[0281] .sup.13C NMR (125 MHZ, CD.sub.3CN): ?: 189.8, 145.7, 145.4, 142.0, 133.2, 130.8, 130.0, 129.6, 126.7, 126.6, 126.6, 85.3, 55.7, 48.6, 29.9, 29.7, 27.2, 26.8, 26.8, 25.6, 25.5, 21.5, 21.4.

[0282] .sup.11B NMR (128 MHZ, CDCl.sub.3): ?: ?0.98.

[0283] .sup.19F NMR (376 MHZ, CDCl.sub.3): ?: ?151.0 (small), 151.1

[0284] Compounds have opposite [?].sub.D= [0285] (?)-(R)-Compound-16 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=?22.0 [0286] (+)-(S)-Compound-16 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=+22.1

##STR00046##

[0287] (?)-(R)-Compound-17 (received from (+)-(R)-Compound 2) and its enantiomer (+)-(S)-Compound-17 (received from (?)-(S)-Compound 2) have identical spectra.

[0288] .sup.1H NMR (300 MHZ, CD.sub.3CN) ?: ppm) 9.72 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.89-7.97 (m, 3H), 7.58-7.66 (m, 4H), 7.51 (d, J=8.1 Hz, 1HHz), 7.47 (d, J=8.1 Hz, 1H), 3.22 (d, J=14.1 Hz, 1H), 2.88 (d, J=14.1 Hz, 1H), 2.83 (sept, J=6.6 Hz, 1H), 2.60 (sept, J=6.6 Hz, 1H), 2.01 (s, 3H), 1.60 (s, 3H), 1.41 (d, J=6.6 Hz, 3H), 1.40 (s, 3H), 1.21 (d, J=6.6 Hz, 3H), 1.19 (d, J=6.6 Hz, 3H), 1.15 (d, J=6.6 Hz, 3H)

[0289] .sup.13C NMR (125 MHz, CD.sub.3CN) ?: 190.4, 145.7, 145.4, 139.7, 134.2, 133.7, 133.1, 130.8, 130.1, 128.9, 128.7, 128.2, 128.1, 126.7, 126.5, 125.6, 124.4, 85.3, 55.9, 48.5, 29.9, 29.7, 27.4, 26.9, 26.9, 25.7, 25.6, 21.6, 21.5.

[0290] .sup.11B NMR (128 MHZ, CDCl.sub.3) ?: ?0.91.

[0291] .sup.19F NMR (376 MHZ, CDCl.sub.3): ?: ?150.9 (small), ?151.0.

[0292] Compounds have opposite [?].sub.D= [0293] (?)-(S)-Compound-16 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=?239.2 [0294] (+)-(R)-Compound-16 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=+241.8

##STR00047##

[0295] (+)-(R)-Compound-18 (received from (+)-(R)-Compound 3) and its enantiomer

[0296] (?)-(S)-Compound-18 (received from (?)-(S)-Compound 3) have identical spectra:

[0297] .sup.1H NMR (400 MHZ, CDCl.sub.3) ?: 9.89 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.52-7.55 (m, 2H), 7.33-7.38 (m, 4H), 3.30 (d, J=14.0 Hz, 1H), 3.19 (d, J=14.0 Hz, 1H), 2.70 (sept, J=6.5 Hz, 1H), 2.69 (sept, J=6.5 Hz, 1H), 2.15 (s, 3H), 1.54 (s, 3H), 1.37 (d, J=6.5 Hz, 3H), 1.31 (d, J=6.5 Hz, 3H), 1.25 (s, 3H), 1.23 (d, J=6.5 Hz, 3H), 1.20 (d, J=6.5 Hz, 3H).

[0298] .sup.13C NMR (125 MHZ, CDCl.sub.3) ?: 191.6, 145.3, 144.3, 138.3, 135.8, 132.6, 130.5, 130.1, 129.3, 129.3, 127.2, 126.6, 126.0, 126.0, 125.6, 124.8, 123.5, 84.0, 55.8, 50.0, 30.0, 29.4, 28.1, 26.9, 26.9, 25.9, 25.6, 22.3, 22.0.

[0299] .sup.11B NMR (128 MHZ, CDCl.sub.3) ?: ?0.91.

[0300] .sup.19F NMR (376 MHZ, CDCl.sub.3) ?: ppm) ?150.9 (small), ?151.0.

[0301] Compounds have opposite [?].sub.D= [0302] (?)-(S)-Compound-18 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=?21.3 [0303] (+)-(R)-Compound-18 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=+22.2

##STR00048##

[0304] (?)-(R)-Compound-19 (received from (+)-(R)-Compound 4) and its enantiomer (+)-(S)-Compound-19 (received from (?)-(S)-Compound 4) have identical spectra:

[0305] .sup.1H NMR (500 MHZ, CDCl.sub.3) ?: 9.59 (s, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 7.06 (s, 2H), 6.97 (s, 1H), 3.16 (d, J=14.0 Hz, 1H), 2.67 (sept, J=6.5 Hz, 1H), 2.66 (d, J=14.0 Hz, 1H), 2.39 (sept, J=6.5 Hz, 1H), 2.31 (s, 6H), 1.87 (s, 3H), 1.52 (s, 3H), 1.35 (d, J=6.5 Hz, 3H), 1.31 (s, 3H), 1.18 (d, J=6.5 Hz, 3H), 1.16 (d, J=6.5 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H).

[0306] .sup.13C NMR (125 MHZ, CDCl.sub.3) ?: 191.0, 145.2, 144.6, 141.2, 140.1, 132.4, 130.5, 129.3, 125.8, 123.6, 83.6, 55.3, 48.5, 30.0, 29.1, 28.7, 27.0, 26.4, 25.9, 25.7, 22.2, 21.9, 21.2.

[0307] .sup.11B NMR (128 MHz, CDCl.sub.3) ?: ?0.99.

[0308] .sup.19F NMR (376 MHZ, CDCl.sub.3): ?: (ppm) ?151.2 (small), ?151.3.

[0309] Compounds have opposite [?].sub.D= [0310] (?)-(S)-Compound-19 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=?71.4 [0311] (+)-(R)-Compound-19 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=+71.5

##STR00049##

[0312] (?)-(R)-Compound-20 (received from (+)-(R)-Compound 9) and its enantiomer (+)-(S)-Compound-20 (received from (?)-(S)-Compound 9) have identical spectra:

[0313] .sup.1H NMR (500 MHZ, CDCl.sub.3) ?: 9.55 (s, 1H), 7.47 (t, J=7.5 Hz, 2H), 7.44 (d, J=7.5 Hz, 2H), 7.42 (d, J=7.5 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 3.16 (d, J=14.0 Hz, 1H), 2.67 (d, J=14.0 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 2.33 (dt, J=7.5 Hz, 1H), 2.16 (dt, J=7.5 Hz, 1H), 1.91 (s, 3H), 1.52 (s, 3H), 1.31 (s, 3H), 1.26 (t, J=7.5 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H).

[0314] .sup.13C NMR (125 MHZ, CDCl.sub.3) ?: 190.5, 141.0, 140.2, 139.7, 131.8, 131.0, 130.3, 128.9, 128.3, 128.1, 126.0, 83.8, 55.5, 48.3, 28.9, 26.9, 26.6, 24.8, 24.6, 15.3, 14.5.

[0315] .sup.11B NMR (128 MHZ, CDCl.sub.3) ?: ?0.98.

[0316] .sup.19F NMR (376 MHZ, CDCl.sub.3): ?: ?151.0 (small), ?151.1

[0317] Compounds have opposite [?].sub.D= [0318] (?)-(S)-Compound-20 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=?59.7 [0319] (+)-(R)-Compound-20 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=+60.3

[0320] Structures of (+)-(R)-Compound 16, (+)S-Compund-16, (?)-(R)-Compound 17, (+)S-Compound 18, (?)R-Compound 18, (?)-(R)-Compound 19 and (?)-(R)-Compound 20 were determined by single crystal X-ray diffraction.

[0321] Structures of compounds isolated and analysed by NMR for which enantiomers were assigned as (+) or (?) based on sign of their optical rotation.

##STR00050##

[0322] (+)-Compound 21 and (?)-Compound 21 were received from (+) or (?)-Compound 6

[0323] .sup.1H NMR (400 MHZ, 25? C., acetone-d.sub.6): ?=8.82 (s, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.42-7.29 (m, 5H), 7.27-7.22 (m, 1H), 7.18 (dd, J=7.8, 1.5 Hz, 1H), 3.77 (q, J=7.2 Hz, 1H), 3.47 (q, J=7.0 Hz, 1H), 2.93-2.79 (m, 2H), 2.72 (m, 1H), 2.67-2.60 (m, 1H), 2.51-2.40 (m, 1H), 1.76-1.58 (m, 5H), 1.47 (d, J=7.2 Hz, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.24 (d, J=6.7 Hz, 3H), 1.22-1.18 (m, 7H), 0.34 (d, J=6.8 Hz, 3H).

[0324] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., acetone-d.sub.6): ?=190.6, 143.7, 143.5, 141.0, 135.7, 132.1, 129.7, 129.3, 128.0, 125.7, 125.7, 70.5, 66.0, 51.9, 44.0, 39.0, 35.9, 33.0, 30.2, 28.9, 25.6, 25.4, 24.1, 23.4, 22.6, 21.7, 20.5, 15.4, 13.5.

[0325] .sup.11B NMR (128 MHZ, CDCl.sub.3) ?: ?0.90.

[0326] .sup.19F NMR (376 MHZ, CDCl.sub.3): ?: ?152.7 (small), ?152.8

[0327] (?)-Compound-21 (T=25? C., c=0.101 g/mL, L=10 cm, acetonitrile)=?87.4

[0328] (+)-Compound-21 (T=25? C., c=0.103 g/mL, L=10 cm, acetonitrile)=+87.1

##STR00051##

[0329] (+)-Compound 22 and (?)-Compound 22 were received from (+) or (?)-Compound 13.

[0330] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=9.38 (s, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.35-7.29 (m, 3H), 7.27-7.21 (m, 3H), 3.75 (d, J=14.0 Hz, 1H), 2.93 (sept, J=6.9 Hz, 1H), 2.86 (d, J=14.0 Hz, 1H), 2.72 (d, J=13.7 Hz, 1H), 2.51 (q, J=7.5 Hz, 2H), 2.27 (d, J=13.7 Hz, 1H), 1.89-1.78 (m, 5H), 1.45 (s, 3H), 1.32 (d, J=7.4 Hz, 3H), 1.26 (dd, J=6.9, 1.8 Hz, 6H), 1.11 (t, J=7.5 Hz, 3H), 0.98 (s, 3H).

[0331] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., CDCl.sub.3): ?=192.5, 148.4, 139.8, 139.4, 133.4, 131.2, 130.5, 130.4 (2C), 127.6 (2C), 127.2 (2C), 83.0, 54.5, 44.4, 43.6, 33.8, 28.1, 27.9, 27.4, 24.7, 24.4, 24.0, 24.0, 15.3, 14.9.

[0332] .sup.11B NMR (128 MHZ, CDCl.sub.3) ?: ?0.89.

[0333] .sup.19F NMR (376 MHZ, CDCl.sub.3): ?: ?151.1 (small), 151.2.

[0334] (?)-Compound-22 (T=25? C., c=0.120 g/mL, L=10 cm, CHCl.sub.3)=?65.7

[0335] (+)-Compound-22 (T=25? C., c=0.110 g/mL, L=10 cm, CHCl.sub.3)=+64.8

##STR00052##

[0336] (+)-Compound 23 and (?)-Compound 23 were received from (+) or (?)-Compound 14.

[0337] .sup.1H NMR (400 MHZ, 25? C., acetone-d.sub.6): ?=9.71 (s, 1H), 7.65 (m, 2H), 7.50 (m, 2H), 7.44-7.35 (m, 1H), 7.18 (s, 1H), 7.14 (s, 1H), 3.23 (d, J=13.9 Hz, 1H), 2.94 (d, J=14.1 Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H), 2.01 (s, 3H, overlapping with acetone), 1.70 (s, 3H), 1.52 (s, 3H).

[0338] .sup.13C{.sup.1H} NMR (100 MHZ, 25? C., acetone-d.sub.6): ?=190.8, 142.4, 134.8, 134.4, 131.2, 131.1, 130.5, 129.1, 126.7, 85.6, 56.1, 49.1, 28.6, 27.7, 27.4, 20.7, 19.4.

[0339] .sup.11B NMR (128 MHz, acetone-d.sub.6) ?: ?0.93.

[0340] .sup.19F NMR (376 MHZ, acetone-d.sub.6 ?: ?151.2 (small), ?151.3

[0341] (?)-Compound-23 (T=25? C., c=0.120 g/mL, L=10 cm, acetonitrile)=?67.5

[0342] (+)-Compound-23 (T=25? C., c=0.122 g/mL, L=10 cm, acetonitrile)=+68.3

##STR00053##

[0343] (+)-Compound 24 and (?)-Compound 24 were received from (+) or (?)-Compound 15.

[0344] Diastereoisomeric ratio of starting amine is 4/1 and iminium salt is received in same ratio

[0345] .sup.1H NMR (400 MHZ, 25? C., CDCl.sub.3): ?=9.85 (s, 1H), 7.53 (m, 2H), 7.47-7.28 (m, 7H), 7.20-6.95 (m, 3H), 2.96 (d, J=13.9 Hz, 1H), 2.36 (s, 3H), 2.09 (s, 3H), 2.06 (d, J=13.9 Hz, 1H), 1.76 (s, 3H), 1.23 (s, 3H), 0.81 (s, 3H). (analytical data given for major isomer, aromatic region is hard to define as signals for two diastereomers overlap).

[0346] .sup.13C{.sup.1H} NMR (100 MHz, 25? C., acetone-d.sub.6): ?=191.5, 191.4, 142, 7, 142.6, 141.9, 141.2, 139.4, 139.3, 139.1, 138.7, 135.7, 135.5, 132.9, 132.9, 131.9, 131.8, 131.1, 130.7, 130.7, 130.6, 130.1, 129.7, 129.4, 129.4, 127.3, 126.9, 85.9, 85.7, 56.3, 56.1, 49.3, 48.8, 29.0, 28.7, 27.9, 27.6, 27.3, 27.1, 21.0, 19.5, 19.5. (analytical data given for mixture of diasteroisomers)

[0347] .sup.11B NMR (128 MHZ, acetone-d.sub.6) ?: ?0.89

[0348] .sup.19F NMR (376 MHZ, acetone-d.sub.6): ?: ?151.2 (small), ?151.3

[0349] (?)-Compound-24 (T=25? C., c=0.141 g/mL, L=10 cm, acetonitrile)=?40.1

[0350] (+)-Compound-24 (T=25? C., c=0.136 g/mL, L=10 cm, acetonitrile)=+39.3

Complexation of CAAC Iminium Salt to Prove the Ee Conservation

[0351] ##STR00054##

[0352] Procedure for the (?)-(S)Ru complex: In a glove box, (+)-(S)-compound 19 (2.5 equiv) was dissolved in dry and degassed Toluene (0.5 mL). KHMDS (0.5 M in Toluene, 2.5 equiv) was added. The mixture was allowed to stirred 1 min at 40? C. Then, M10 catalyst (1 equiv) and toluene (0.5 mL) were then added. The mixture was stirred 5 min at 40? C. CuCl (4.5 equiv), Styrenyl ether (1.6 equiv) and Toluene (0.5 mL) were added. The mixture was stirred at 80? C. for 30 min out of the box. Volatiles were removed under vacuum and the product was purified by column chromatography (eluent: toluene). Green fraction was washed with pentane.

[0353] The desired complex is obtained as a green solid (61% yield) as a mixture of rotamers (ratio determined by .sup.1H NMR in CDCl.sub.3: 76:24).

##STR00055##

[0354] .sup.1H NMR (400 MHz, CDCl.sub.3): ? 17.78 (s, 0.23H), 16.45 (s, 0.77H), 8.45 (d, J=9.1 Hz, 1H), 8.23 (s, 1H), 7.75-7.38 (m, 8H), 6.98 (d, J=9.0 Hz, 1H), 5.15-4.97 (m, 1H), 3.30-3.07 (m, 1H), 2.86-2.64 (m, 2H), 2.63-2.48 (m, 2H), 2.48-2.24 (m, 4H), 1.69-1.50 (m, 6H), 1.50-1.28 (m, 8H), 1.19-1.01 (m, 3H), 0.98-0.74 (m, 3H).

[0355] .sup.13C NMR (101 MHZ, CDCl.sub.3): ?: 295.1, 260.6, 156.5, 143.5, 143.2, 142.6, 138.2, 132.1, 129.5, 129.4, 128.7, 128.6, 127.6, 127.4, 127.1, 125.4, 118.2, 113.2, 78.4, 63.2, 48.4, 31.1, 29.7, 27.6, 25.6, 24.2, 22.2, 14.8, 14.3.

[0356] [?].sub.D=(?)-(S)-ruthenium complex (T=25? C., c=0.110 g/mL, L=10 cm, CH.sub.2Cl.sub.2)=?565.

[0357] Analytical data for this compound were consistent with the previously reported data.

Analytical Chiral HPLC for (?)-(S)Ru Complex

[0358] The sample is dissolved in dichloromethane, injected on the chiral column Chiralpak IE, and detected with an UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min, Heptane/Ethanol/dichloromethane (60/20/20)

[0359] ee determination: 98%

TABLE-US-00045 RT [min] Area Area % 4.98 13 1.02 5.87 1294 98.98 Sum 1308 100.00

##STR00056##

Procedure for the Au and Cu Complexes Preparation:

[0360] In a glovebox, a 100 mL Schlenk flask equipped with a magnetic stirring bar and a septum was charged with (+)-(R)-Compound-14 (100.0 mg, 0.23 mmol, 1.0 eq), copper (I) chloride (25.0 mg, 0.25 mmol, 1.1 eq) and sodium acetate (56.5 mg, 0.69 mmol, 3.0 eq). Toluene (11 mL) was added, and the reaction vessel was brought outside of a glovebox. Septum was then change for a glass stopcock with a metal clipper and the reaction mixture was stirred overnight at 110? C. in a close system. After cooling down to RT, the suspension was opened to air, filtered through a silica gel column, and washed with dichloromethane. The pure (+)-(R)-copper complex (86.7 mg, 0.2 mmol) was obtained as a white powder (Isolated mass=86.7 mg, Yield=87%)

[0361] .sup.1H NMR (400 MHZ, CDCl.sub.3) ?: 7.57-7.46 (m, 2H), 7.46-7.31 (m, 3H), 7.31-7.19 (m, 3H), 2.86 (m 2H), 2.58 (d, J=13.4 Hz, 1H), 2.32 (d, J=13.4 Hz, 1H), 1.82 (s, 3H), 1.38-1.30 (m, 12H), 1.26 (d, J=6.7 Hz, 3H), 1.21 (s, 3H).

[0362] .sup.13C NMR (101 MHZ, CDCl.sub.3): ?: .sup.13C NMR (101 MHZ, CDCl.sub.3) ? 246.8, 145.9, 145.1, 144.8, 134.5, 129.9, 129.0, 127.2, 126.3, 124.9, 124.9, 81.2, 60.9, 51.4, 29.2, 29.2, 28.2, 28.1, 27.2, 27.2, 22.5, 22.4.

[0363] [?].sub.D=(+)-(R)-copper complex (T=25? C., c=0.110 g/mL, L=10 cm, CH.sub.2Cl.sub.2)=+20

Analytical Chiral HPLC for Cu Complex

[0364] ee determination: The sample is dissolved in dichloromethane, injected on the chiral column Chiralpak IG, and detected with an UV detector at 254 nm and a circular dichroism detector mL/min at 254 nm. The flow-rate is 1 mL/min Heptane/Isopropanol/dichloromethane (80/10/10), 1 mL/min. ee>99.5%

TABLE-US-00046 RT [min] Area Area % 10.88 7752 100.00 Sum 7752 100.00

[0365] In a glovebox, a Schenck was charged with the (R)-copper complex (23.6 mg, 0.055 mmol, 1.0 eq), [(SMe2)AuCl] (24.2 mg, 0.082 mmol, 1.5 eq), and THF (0.5 mL). The mixture was then heated at 40 degrees for 4 hours. Solvent was removed under reduced pressure and the crude was purified by column chromatography (dichloromethane). The received solid was filtered over packed celite to remove any nanoparticles. (R)-gold complex (19.9 mg, 0.035 mmol) was obtained as a white solid (19.9 mg, 64% yield).

[0366] .sup.1H NMR (400 MHZ, CD.sub.2Cl.sub.2): ?: 7.59-7.53 (m, 2H), 7.51 (d, J=7.7 Hz, 1H), 7.48-7.39 (m, 2H), 7.39-7.29 (m, 3H), 2.96 (hept, J=6.8 Hz, 1H), 2.84 (hept, J=6.7 Hz, 1H), 2.65 (d, J=13.4 Hz, 1H), 2.45 (d, J=13.4 Hz, 1H), 1.92 (s, 3H), 1.46 (d, J=2.4 Hz, 3H), 1.45 (d, J=2.4 Hz, 3H), 1.42 (s, 3H), 1.36 (d, J=6.7 Hz, 3H), 1.33 (d, J=6.8 Hz, 3H), 1.29 (s, 3H).

[0367] .sup.13C NMR (101 MHZ, CD.sub.2Cl.sub.2) ?: 234.6, 145.8, 145.6, 145.3, 134.7, 130.5, 129.3, 127.7, 126.9, 125.6, 125.4, 81.1, 61.4, 52.4, 29.8, 29.6, 28.9, 28.6, 28.5, 27.1, 26.9, 23.1, 22.8.

[0368] [?].sub.D=(+)-(R)-gold complex (T=25? C., c=0.153 g/mL, L=10 cm, acetonitrile)=+24

[0369] As preliminary photophysical and chiroptical characterizations, the unpolarized (black solid line) and circularly polarized luminescence (CPL) of the enantiopure copper complexes ((R) and(S), blue and red solid lines, respectively, with an average gium value of 10.sup.?3) were measured using a CPL spectrofluoropolarimeter. The samples were excited using a 90? geometry with a Xenon ozone-free lamp 150 W LS. The following parameters were used: emission slit width?2 mm, integration time=4 sec, scan speed=50 nm/min, accumulations=5. The concentration of all the samples was ?10.sup.?5 M. Excitation of the samples were performed at 320 nm. The corresponding results are shown in FIGS. 1 and 2.

Analytical Chiral HPLC for Au Complex

[0370] ee determination: The sample is dissolved in dichloromethane, injected on the chiral column Chiralpak IG, and detected with an UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min Heptane/Isopropanol/dichloromethane (80/10/10), 1 mL/min. ee>98%

TABLE-US-00047 RT [min] Area Area % 10.33 7583 99.21 19.46 60 0.79 Sum 7643 100.00

##STR00057##

Procedure for the (+)-(S)Rh Complex:

[0371] [Rh(COD)Cl].sub.2 (36.3 mg, 0.074 mmol, 0.5 equiv.), (?)-(S)-Compound-14 (75 mg, 0.172 mmol, 1.2 equiv.) and KHMDS (39.2 mg, 0.197 mmol, 1.3 equiv.) were added to a Schlenk tube in the glovebox. Out of the box under Ar atmosphere, dry and degassed THF (3 mL) was added dropwise over 10 min to the solids at ?78? C. The suspension was stirred for 10 min at ?78? C., after which the cooling bath was removed, and the reaction mixture was allowed to warm up to rt. After stirring for 16 h at room temperature, volatiles were removed under vacuum. The product was purified by column chromatography (pentane/diethyl ether=9:1) to received yellow-orange solid of (+)-(S)Rh complex (44.9 mg 51% yield)

[0372] .sup.1H NMR (400 MHZ, CDCl.sub.3): 7.99 (d, J=7.3 Hz, 2H), 7.41 (dt, J=17.2, 7.6 Hz, 4H), 7.29 (d, J=7.2 Hz, 1H), 7.11 (dd, J=7.5, 1.8 Hz, 1H), 5.32 (m, 1H), 4.52 (m, 1H), 3.87 (m, 1H), 2.86 (d, J=13.3 Hz, 1H), 2.65 (m, 2H), 2.51-2.40 (m, 1H), 2.38 (s, 3H), 2.07 (d, J=13.2 Hz, 1H), 1.91 (m, 1H), 1.75 (d, J=6.4 Hz, 3H), 1.66 (s, 3H), 1.66-1.49 (m, 3H), 1.48-1.38 (m, 2H), 1.35 (s, 3H), 1.29 (two pairs of d overlapping, 6H), 1.24-1.07 (m, 2H), 0.72 (d, J=6.7 Hz, 3H).

[0373] .sup.13C NMR (101 MHZ, CDCl.sub.3): 269.23 (d, J=46.7 Hz), 147.98, 146.11, 145.89, 136.57, 129.00, 128.50, 128.11, 126.59, 126.53, 124.15, 101.81 (d, J=5.8 Hz), 98.00 (d, J=6.4 Hz), 78.67, 78.65, 72.11 (d, J=14.6 Hz), 66.37 (d, J=14.0 Hz), 49.03, 35.16, 33.29, 31.28, 30.16, 28.84, 28.58, 28.56, 26.27, 25.52, 25.28, 24.58.

[0374] [?].sub.D=(+)-(S)-Rhodium complex (T=25? C., c=0.110 g/mL, L=10 cm, CH.sub.2Cl.sub.2)=+5

Analytical Chiral HPLC for Rh Complex

[0375] ee determination: The sample is dissolved in dichloromethane, injected on the chiral column Chiralpak IB N-5, and detected with an UV detector at 254 nm and a circular dichroism detector at 254 nm. The flow-rate is 1 mL/min. ee>99%

TABLE-US-00048 RT [min] Area Area % 6.80 1386 100.00 Sum 1386 100.00