PROCESS FOR THE SYNTHESIS OF NON-RACEMIC CYCLOHEXENES

Abstract

This invention relates to a process for the synthesis of a non-racemic cyclohexene compound of formula (I) by a Diels-Alder reaction of a compound of formula (II) with a compound of formula (III) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and Y have the meanings as defined in the description in the presence of a catalyst comprising at least one m-valent metal cation M.sup.m+ wherein the metal M is selected from Scandium (Sc), Yttrium (Y), Lanthanum (La), Cerium (Ce), Praseodymium (Pr), Neodymium (Nd), Promethium (Pm), Samarium (Sm), Europium (Eu), Gadolinium 15 (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho), Erbium (Er), Thulium (Tm), Ytterbium (Yb), Lutetium (Lu), Gallium (Ga) and Indium (In), and m is an integer of 1, 2 or 3, and a chiral ligand of the formula (IV) wherein R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10a′, R.sup.10b′, R.sup.10c′, R.sup.10d′, Z and Z′ have the meanings as defined in the description.

Claims

1. A process for the synthesis of a non-racemic cyclohexene compound of formula (I) ##STR00092## wherein R.sup.1 is selected from C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.12-cycloalkyl, unsubstituted or substituted C.sub.6-C.sub.20-aryl and unsubstituted or substituted C.sub.3-C.sub.20-heteroaryl, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each independently selected from hydrogen, C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.6-cycloalkyl, unsubstituted or substituted C.sub.6-C.sub.20-aryl and unsubstituted or substituted C.sub.3-C.sub.20-heteroaryl, or R.sup.5 and R.sup.8 together form a bridging moiety selected from —O—, —OH.sub.2—, and —CH.sub.2—CH.sub.2— between the carbon atoms to which they are connected; Y is OC(O)R.sub.A wherein R.sub.A is selected from C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.12-cycloalkyl, unsubstituted or substituted C.sub.6-C.sub.20-aryl, C.sub.6-C.sub.20-aryl-C.sub.1-C.sub.4-alkyl, di(C.sub.6-C.sub.20-aryl)-C.sub.1-C.sub.4-alkyl, unsubstituted or substituted C.sub.3-C.sub.20-heteroaryl, C.sub.1-C.sub.8-alkoxy, C.sub.3-C.sub.6-cycloalkyloxy, C.sub.6-C.sub.20-aryloxy, and NR.sub.BR.sub.B′, where R.sub.B and R.sub.B, are independently selected from hydrogen, C.sub.1-C.sub.8-alkyl, and C.sub.3-C.sub.12-cycloalkyl; which process comprises reacting a compound of formula (II) ##STR00093## wherein R.sup.1, R.sup.2, R.sup.3 and Y have the same meaning as in formula (I) with a compound of formula III, ##STR00094## wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 have the same meaning as in formula (I); in the presence of a catalyst comprising at least one m-valent metal cation M.sup.m+ wherein the metal M is selected from Scandium (Sc), Yttrium (Y), Lanthanum (La), Cerium (Ce), Praseodymium (Pr), Neodymium (Nd), Promethium (Pm), Samarium (Sm), Europium (Eu), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho), Erbium (Er), Thulium (Tm), Ytterbium (Yb), Lutetium (Lu), Gallium (Ga) and Indium (In), and m is an integer of 1, 2 or 3, and a chiral ligand of the formula (IV) ##STR00095## wherein R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10a′, R.sup.10b′, R.sup.10c′ and R.sup.10d′ are each independently selected from hydrogen, C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.6-cycloalkyl, unsubstituted or substituted C.sub.6-C.sub.20-aryl, C.sub.6-C.sub.20-aryl-C.sub.1-C.sub.4-alkyl and unsubstituted or substituted C.sub.3-C.sub.20-heteroaryl, or two or more of R.sup.10a, R.sup.10b, R.sup.10c and R.sup.10d and/or two or more of R.sup.10a′, R.sup.10b′, R.sup.10c′ and R.sup.10d′ together form an unsubstituted or substituted ring selected from C.sub.3-C.sub.6-cycloalkyl, C.sub.6-C.sub.20-aryl and C.sub.3-C.sub.20-heteroaryl; provided that at least one of R.sup.10a, R.sup.10b, R.sup.10c and R.sup.10d and at least one of R.sup.10a′, R.sup.10b′, R.sup.10c′ and R.sup.10d′ are not hydrogen; R.sup.11a, R.sup.11b and R.sup.11c are each independently selected from hydrogen, halogen, cyano, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-cycloalkyl, unsubstituted or substituted C.sub.6-C.sub.20-aryl, unsubstituted or substituted C.sub.3-C.sub.20-heteroaryl, C.sub.1-C.sub.5-alkoxy, C.sub.3-C.sub.6-cycloalkyloxy, C.sub.6-C.sub.2O-aryloxy, C(O)—O—C.sub.1-C.sub.6-alkyl and O—C(O)—C.sub.1-C.sub.6-alkyl, and Z and Z′ are the same or different and selected from —O—, —O—CH.sub.2—, ##STR00096## wherein R.sub.C is selected from C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.8-haloalkyl, and unsubstituted or substituted C.sub.6-C.sub.13 aryl.

2. The process according to claim 1 wherein, in the formulae (I) and (II), R.sup.1 is C.sub.1-C.sub.4-alkyl and R.sup.2 and R.sup.3 are both hydrogen.

3. The process according to claim 1 wherein, in the formulae (I) and (II), R.sup.1 is methyl and R.sup.2 and R.sup.3 are both hydrogen.

4. The process according to claim 1 wherein, in the formulae (I) and (III), R.sup.6 is C.sub.1-C.sub.4-alkyl and R.sup.4, R.sup.5, R.sup.7, R.sup.8 and R.sup.9 are each hydrogen.

5. The process according to claim 1 wherein, in the formulae (I) and (III), R.sup.6 is methyl and R.sup.4, R.sup.5, R.sup.7, R.sup.8 and R.sup.9 are each hydrogen.

6. The process according to claim 1 wherein, in the formulae (I) and (II), Y is OC(O)R.sub.A wherein R.sub.A is selected from C.sub.6-C.sub.20-aryl and di(C.sub.6-C.sub.20-aryl)-C.sub.1-C.sub.4-alkyl.

7. The process according to claim 1 wherein, in the formulae (I) and (II), Y is OC(O)R.sub.A wherein R.sub.A is selected from phenyl and diphenylmethyl.

8. The process according to claim 1 wherein the metal M is selected from Scandium (Sc), Yttrium (Y), Terbium (Tb) and Ytterbium (Yb).

9. The process according to claim 1 wherein the metal M is Yttrium (Y) or Ytterbium (Yb).

10. The process according to claim 1 wherein the metal M is Yttrium (Y).

11. The process according to claim 1 wherein the metal M is Ytterbium (Yb).

12. The process according to claim 1 wherein the catalyst additionally comprises at least one n-valent anion A.sup.n− wherein n is an integer of 1, 2 or 3.

13. The process according to claim 1 wherein the catalyst is obtained by reacting a metal salt of the formula [M.sup.m+].sub.n[A.sup.n−].sub.m (V) wherein M.sup.m+ is a m-valent metal cation M.sup.m+ wherein m is an integer of 1, 2 or 3 and the metal M has the same meaning as in any one of claims 1, 8 and 9 and A.sup.n− is a n-valent anion wherein n is an integer of 1, 2 or 3 with the chiral ligand of the formula (IV).

14. The process according to claim 12 wherein the n-valent anion A.sup.n− is independently selected from halide, tetrafluoroborate (BF.sub.4−), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate ([{3,5-(CF.sub.3).sub.2C.sub.6H.sub.3}.sub.4B].sup.−), perchlorate (ClO.sub.4.sup.−), hexafluorophosphate (PF.sub.6.sup.−), antimony hexafluoride (SbF.sub.6.sup.−), nitrate (NO.sub.3.sup.−), a sulfonate anion of the formula R.sup.12SO.sub.3 wherein R.sup.12 is selected from C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl and unsubstituted or substituted C.sub.6-C.sub.20-aryl, a carboxylate ion of the formula R.sup.13COO.sup.− wherein R.sup.13 is selected from hydrogen, C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.12-cycloalkyl, C.sub.1-C.sub.8-haloalkyl and unsubstituted or substituted C.sub.6-C.sub.20-aryl, sulfate (SO.sub.4.sup.2−), and a bis(sulfonyl)imide anion of the formula (R.sup.14SO.sub.2).sub.2N.sup.−, wherein R.sup.14 is selected from C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl and unsubstituted or substituted C.sub.6-C.sub.20-aryl.

15. The process according to claim 12 wherein the n-valent anion A.sup.n− is selected from halide and a sulfonate anion of the formula R.sup.12SO.sub.3.sup.− wherein R.sup.12 is selected from C.sub.1-C.sub.4-alkyl and C.sub.1-C.sub.4-haloalkyl.

16. The process according to claim 12 wherein the n-valent anion A.sup.n− is triflate (trifluoromethanesulfonate).

17. The process according to claim 1 wherein, in the formula (IV), R.sup.10a and R.sup.10a′ are independently selected from C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.6-cycloalkyl, unsubstituted or substituted C.sub.6-C.sub.20-aryl and unsubstituted or substituted C.sub.3-C.sub.20-heteroaryl, and R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10b′, R.sup.10c′ and R.sup.10d′ are each hydrogen.

18. The process according to claim 1 wherein, in the formula (IV), R.sup.10b and R.sup.10b′ are independently selected from C.sub.1-C.sub.8-alkyl, C.sub.3-C.sub.6-cycloalkyl, unsubstituted or substituted C.sub.6-C.sub.20-aryl and unsubstituted or substituted C.sub.3-C.sub.20-heteroaryl, and R.sup.10a, R.sup.10a, R.sup.10d, R.sup.10a′, R.sup.10c′ and R.sup.10d′ are each hydrogen.

19. The process according to claim 1 wherein, in the formula (IV), Z and Z′ are the same and selected ##STR00097## and R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10a′, R.sup.10b′, R.sup.10c′ and R.sup.10d′ are each independently selected from hydrogen or unsubstituted or substituted C.sub.6-C.sub.20-aryl.

20. The process according to claim 1 wherein, in the formula (IV), Z and Z′ are the same and selected from ##STR00098## and R.sup.10a, R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10a′, R.sup.10b′, R.sup.10c′ and R.sup.10d′ are each independently selected from hydrogen or phenyl.

21. The process according to claim 1 wherein, in the formula (IV), Z and Z′ are the same and selected from ##STR00099## and R.sub.C is selected from unsubstituted or substituted C.sub.6-C.sub.13 aryl.

22. The process according to claim 1 wherein, in the formula (IV), R.sup.11a, R.sup.11b and R.sup.11c are each hydrogen.

23. The process according to claim 1 wherein, in the formula (IV), R.sup.11a and R.sup.11c are both hydrogen, and R.sup.11b is halogen.

24. The process according to claim 1 wherein, in the formula (IV), R.sup.11a and R.sup.11c are both hydrogen, and R.sup.11b is chlorine.

25. The process according to claim 1 wherein, in the formula (IV), R.sup.10a and R.sup.10a′ are both phenyl and R.sup.10b, R.sup.10c, R.sup.10d, R.sup.10b′, R.sup.10c′, R.sup.10d′, R.sup.11a, R.sup.11b and R.sup.11c are each hydrogen.

26. The process according to claim 1 wherein the reaction is conducted in an organic solvent.

27. The process according to claim 26 wherein the organic solvent is selected from hydrocarbons, ethers, nitriles, esters, ketones and any combination thereof.

28. The process according to claim 26 wherein the organic solvent is selected from hydrocarbons.

29. The process according to claim 26 wherein the organic solvent is a hydrocarbon selected from aliphatic hydrocarbons, cycloaliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons and any combination thereof.

30. The process according to claim 29 wherein the organic solvent is a hydrocarbon selected from aromatic hydrocarbons, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons and any combination thereof.

31. The process according to claim 29 wherein the organic solvent is a hydrocarbon selected from halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons and any combination thereof.

32. The process according to claim 1 wherein the reaction is conducted at a temperature in the range from −20° C. to 50° C.

33. The process according to claim 1 wherein the non-racemic cyclohexene compound of formula (I) is further converted to a non-racemic cyclohexenol compound of formula (VI) ##STR00100## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 have the same meaning as in formula (I).

Description

EXAMPLES

[0327] Chemical terms and the definitions below have their usual meanings unless indicated otherwise. For example, “Yb(OTf.sub.3” refers to Ytterbium(III) triflate; “Y(OTf.sub.3” refers to Yttrium(III) triflate; “Sc(OTf).sub.2” refers to Scandium(II) triflate; “La(OTf).sub.3” refers to Lanthanum(II) triflate; “Ce(OTf).sub.3” refers to Cerium(III) triflate; “Pr(OTf).sub.3” refers to Praseodymium(II) triflate; “Nd(OTf).sub.3” refers to Neodymium(II) triflate; “Sm(OTf).sub.3” refers to Samarium(III) triflate; “Eu(OTf).sub.3” refers to Europium(III) triflate; “Gd(OTf).sub.3” refers to Gadolinium(II) triflate; “Tb(OTf).sub.3” refers to Terbium(III) triflate; “Dy(OTf).sub.3” refers to Dysprosium(III) triflate; “Ho(OTf).sub.3” refers to Holmium(III) triflate; “Er(OTf).sub.3” refers to Erbium(III) triflate; “Tm(OTf).sub.3” refers to Thulium(II) triflate; “Lu(OTf.sub.3” refers to Lutetium(III) triflate; “H.sub.2O” refers to water; “THF” refers to tetrahydrofurane; “MeCN” refers to acetonitrile; “Et.sub.2O” refers to diethyl ether; “EtOAc” refers to ethyl acetate; “MeOH” refers to methanol; “iPrOH” or “IPA” both refer to isopropanol; “CH.sub.2Cl.sub.2” or “DCM” both refer to dichloromethane; “PhH” refers to benzene; “PhMe” refers to toluene; “PhCl” refers to chlorobenzene; “DCE” refers to 1,2-dichloroethane; “Et.sub.3N” or “NEt.sub.3” both refer to triethylamine; “i-Pr.sub.2NH” refers to diisopropylamine, “DIPEA” refers to N,N-diisopropylethylamine; “Pyr” refers to pyridine; “Ph” refers to phenyl; “CH(Ph).sub.2” refers to diphenylmethyl; “Me” refers to methyl; “Et” refers to ethyl; “Ad” refers to 1-adamantyl; “Bz” refers to benzoyl; “BzCl” refers to benzoyl chloride; “Ph.sub.2CHCO.sub.2Cl” refers to diphenylacetyl chloride; “1-Nap” refers to “1-naphthyl”; “2-Nap” refers to “2-naphthyl”; “NaB.sub.ArF” refers to sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate; “N(n-Bu).sub.4Br” refers to tetra-n-butylammonium bromide; “.sup.tBu” refers to “tert-butyl”; “o-Br-Ph” refers to “2-bromophenyl”; “p-.sup.tBu-Ph” refers to “4-tert-butylphenyl”; “p-NO.sub.2-Ph” refers to “4-nitrophenyl”; “MS” refers to molecular sieve; “3 Å MS” refers to 3 Å molecular sieve; “equiv.” refers to equivalent; “mmol” refers to millimole or millimoles; “g” refers to gram or grams; “mg” refers to milligram or milligrams; “min” refers to minutes; “h” refers to hours; “I” or “L” refers to liters; “ml” or “mL” refers to milliliter or milliliters; “dr” refers to diasterometric ratio; “ee” refers to enantiomeric excess; “rr” refers to regiomeric ratio; “.sup.1H-NMR” refers to proton Nuclear Magnetic resonance; .sup.13C-NMR” refers to carbon-13 Nuclear Magnetic resonance; “SFC” refers to supercritical fluid chromatography, “HPLC” refers to high performance liquid chromatography; “HRMS” refers to high resolution mass spectrometry; and “TCL” refers to thin layer chromatography.

Materials and Methods:

[0328] Unless otherwise stated, reactions were performed with freshly dried solvents utilizing standard Schlenk techniques. Glassware was oven-dried at 120° C. for a minimum of four hours or flamedried utilizing a Bunsen burner under high vacuum. THF, DCM, MeCN, PhH, and PhMe were dried by passing through activated alumina columns. Pyridinebisimidazoline (PyBim) ligands were synthesized using the procedure reported by Bhor and coworkers (cf. Bhor, S. et al., Org. Lett. 2005, 7 (16), 3393-3396). MeOH (HPLC grade) was purchased from Fisher Scientific. 1,4-dioxane, anhydrous ≥99.9%, was purchased from Millipore Sigma. DCE, Et.sub.3N, i-Pr.sub.2NH, DIPEA, Pyr, and 2,6-lutidine were distilled from calcium hydride prior to use and stored under N.sub.2 or Ar. Commercial reagents were used directly as supplied from commercial sources and without further purification unless otherwise specified. All reactions were monitored by thin layer chromatography using EMD/Merck silica gel 60 F254 pre-coated plates (0.25 mm) and were visualized by UV (254 nm) and KMnO.sub.4, p-anisaldehyde, iodine, or CAM staining. Flash column chromatography was performed as described by Still and coauthors (cf. Still, W. C. et al. J. Org. Chem. 1978, 43 (14), 2923-2925) using silica gel (SiliaFlash® P60, particle size 40-63 microns [230 to 400 mesh]) purchased from Silicycle. .sup.1H and .sup.13C NMR spectra were recorded on a Bruker Advance III HD with Prodigy Cryoprobe (at 400 MHz and 101 MHz, respectively) or Varian Inova 500 (at 500 MHz and 126 MHz, respectively) and are reported relative to internal CDCl.sub.3 (.sup.1H, δ=7.26), CDCl.sub.3 (.sup.13C, δ=77.16). Data for .sup.1H NMR spectra are reported as follows: chemical shift (5 ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s=singlet, d=doublet, t=triplet, q=quartet, p=pentet, hept=heptet, m=multiplet. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm.sup.−1). Analytical chiral SFC was performed with a Mettler SFC supercritical CO.sub.2 analytical chromatography system (CO.sub.2=1450 psi, column temperature=40° C.) with a Chiralcel OD-H column (4.6 mm×25 cm). Preparative and analytical chiral HPLC was performed with an S3 Agilent 1100 Series HPLC with a Chiralpak IH column (4.6 mm×25 cm, Daicel Chemical Industries, Ltd.). HRMS were acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI) mode. Molecular formulas of the compounds [M] are given, with the observed ion fragment in brackets, e.g. [M+H]+. Benzoyl chloride, diphenylacetyl chloride, Ytterbium(III) triflate, 2,6-bis[(4S)-4-phenyl-2-oxazolinyl]pyridine of the formula (IV-1), and 2,6-Bis((S)-4,5-dihydro-4-phenethyloxazol-2-yl)pyridine of the formula (IV-10) were purchased from Sigma-Aldrich and used as received. Isoprene was purchased from Sigma-Aldrich and distilled prior to use. Diacetyl was purchased from TCI America and used as received. Yttrium(III) triflate, lanthanum(II) triflate, cerium(II) triflate, prasaeodymium(III) triflate, neodymium(III) triflate, europium(III) triflate, gadolinium(III) triflate, terbium(III) triflate, dysprosium(III) triflate, holmium(III) triflate, erbium(III) triflate, and lutetium(III) triflate were purchased from Strem Chemicals, Inc. and used as received. Scandium(II) triflate, samarium(II) triflate, and ytterbium(III) triflate were purchased from Sigma-Aldrich and used as received. Triethylamine was distilled over calcium hydride prior to use. Dichloromethane, toluene, tetrahydrofuran, methyl-tert-butyl ether, and diethyl ether were purchased from Fisher Scientific and dried by passing over an activated alumina column. 1,2-dichloroethane, tetrachloromethane, trichloroethylene, acetonitrile, 1,4-dioxane, 2,5-dimethyl tetrahydrofuran (mixture of cis and trans), cyclopentyl-methyl ether, and diisopropyl ether were purchased from Sigma-Aldrich. Deuteriochloroform was purchased from Cambridge Isotope Laboratories. The 3 Å molecular sieve was purchased from Sigma-Aldrich and activated by heating under a flame at reduced pressure (100 mTorr) for 20 minutes prior to use.

Preparation of the Compounds of Formula (II)

[0329] General Procedure A for compounds of formula II (see also Scheme A below): To a dry roundbottomed flask, equipped with a magnetic stir bar was charged diacetyl (IX) (1.0 equiv.), triethylamine (1.2 equiv.) and dry dichloromethane. To this solution was added electrophile (1.0 equiv.) at 0° C. under N.sub.2. The reaction was allowed to slowly warmed to 23° C. and monitored by TLC. Upon completion, hexanes (35 mL) was added, and the reaction mixture was filtered through a plug of sand. The resulting solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.

##STR00068##

Preparation of 3-oxobut-1-en-2-yl benzoate of the formula (II-1)

[0330] ##STR00069##

3-oxobut-1-en-2-yl benzoate of the formula (II-1) was prepared from diacetyl (IX) (2.62 mL, 30.0 mmol, 1.0 equiv.), triethylamine (5.02 mL, 36.0 mmol, 1.2 equiv.), benzoyl chloride (3.48 mL, 30.0 mmol, 1.0 equiv), and dry dichloromethane (35 mL) following General Procedure A. The resulting solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (1:20 EtOAc:hexanes.fwdarw.1:10 EtOAc:hexanes) to afford 3-oxobut-1-en-2-yl benzoate of the formula (II-1) (2.38 g, 12.5 mmol, 42%) as a yellow oil which solidifies upon storage at −20° C. Spectroscopic data matched previously reported values (cf. Tamariz, J.; Vogel, P. Helv. Chim. Acta 1981, 64 (1), 188-197).

[0331] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.12 (dt, J=7.0, 1.4 Hz, 2H), 7.74-7.56 (m, 1H), 7.56-7.40 (m, 2H), 6.04 (d, J=2.4 Hz, 1H), 5.74 (d, J=2.4 Hz, 1H), 2.42 (s, 3H).

Preparation of 3-oxobut-1-en-2-yl 2,2-diphenylacetate of the formula (II-2)

[0332] ##STR00070##

3-oxobut-1-en-2-yl 2,2-diphenylacetate of the formula (II-2) was prepared from diacetyl (IX) (2.19 mL, 25.0 mmol, 1.0 equiv.), triethylamine (4.18 mL, 30.0 mmol, 1.2 equiv.), diphenylacetyl chloride (2.90 mL, 25.0 mmol, 1.0 equiv), and dry dichloromethane (35 mL) following General Procedure A. The resulting solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (1:20 EtOAc:hexanes.fwdarw.1:10 EtOAc:hexanes) to afford 3-oxobut-1-en-2-yl 2,2-diphenylacetate of the formula (II-2) (3.1 g, 12.7 mmol, 74%) as a white solid. Spectroscopic data matched previously reported values (cf. Dominguez, D.; Cava, M. P. Tetrahedron Lett. 1982, 23 (52), 5513-5516)

[0333] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25-7.50 (m, 10H), 5.93 (d, J=2.5 Hz, 1H), 5.57 (d, J=2.5 Hz, 1H), 5.22 (s, 2H), 2.28 (s, 6H).

[0334] .sup.13C NMR (101 MHz, CDCl.sub.3) δ 191.54, 170.58, 151.67, 137.88, 128.78, 128.70, 127.53, 113.93, 56.60, 25.48.

Preparation of 3-oxobut-1-en-2-yl (3r,5r,7r)-adamantane-1-carboxylate of the formula (II-3)

[0335] ##STR00071##

3-oxobut-1-en-2-yl (3r,5r,7r)-adamantane-1-carboxylate of the formula (II-3) was prepared from diacetyl (IX) (1.32 mL, 15.0 mmol, 1.0 equiv.), triethylamine (2.51 mL, 18.0 mmol, 1.2 equiv.), 1-adamantanecarbonyl chloride (2.98 g, 15 mmol, 1.0 equiv), and dry dichloromethane (20 mL) following General Procedure A with 30 h at 23° C. The resulting solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (1:20 EtOAc:hexanes.fwdarw.1:10 EtOAc:hexanes) to afford 3-oxobut-1-en-2-yl (3r,5r,7r)-adamantane-1-carboxylate of the formula (II-3) (816 mg, 3.29 mmol, 22%).

[0336] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 5.90 (d, J=2.2 Hz, 1H), 5.54 (d, J=2.2 Hz, 1H), 2.34 (s, 3H), 2.06 (q, J=3.0 Hz, 3H), 2.01 (d, J=2.9 Hz, 6H), 1.75 (dt, J=4.5, 2.9 Hz, 6H).

Preparation of 3-oxobut-1-en-2-yl 1-naphthoate of the formula (II-4)

[0337] ##STR00072##

3-oxobut-1-en-2-yl 1-naphthoate of the formula (II-4) was prepared from diacetyl (IX) (1.32 mL, 15.0 mmol, 1.0 equiv.), triethylamine (2.51 mL, 18.0 mmol, 1.2 equiv.), 1-napthoyl chloride (2.26 mL, 15.0 mmol, 1.0 equiv), and dry dichloromethane (18 mL) following General Procedure A. The resulting solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (1:20 EtOAc:hexanes.fwdarw.1:10 EtOAc:hexanes) to afford 3-oxobut-1-en2-yl 1-naphthoate of the formula (II-4) (1.54 g, 6.4 mmol, 43%). Spectroscopic data matched previously reported values (cf. Tamariz, J.; Vogel, P. Helv. Chim. Acta 1981, 64 (1), 188-197).

[0338] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.94 (dq, J=8.7, 0.8 Hz, 1H), 8.39 (dd, J=7.3, 1.3 Hz, 1H), 8.09 (ddt, J=8.2, 1.3, 0.6 Hz, 1H), 7.91 (ddt, J=8.2, 1.3, 0.6 Hz, 1H), 7.64 (ddd, J=8.6, 6.8, 1.4 Hz, 1H), 7.60-7.51 (m, 2H), 6.09 (d, J=2.4 Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 2.47 (s, 3H).

Preparation of 3-oxobut-1-en-2-yl 2-naphthoate of the formula (II-5)

[0339] ##STR00073##

3-oxobut-1-en-2-yl 2-naphthoate of the formula (II-5) was prepared from diacetyl (IX) (1.32 mL, 15.0 mmol, 1.0 equiv.), triethylamine (2.51 mL, 18.0 mmol, 1.2 equiv.), 2-napthoyl chloride (2.26 mL, 15.0 mmol, 1.0 equiv), and dry dichloromethane (18 mL) following General Procedure A. The resulting solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (1:20 EtOAc:hexanes.fwdarw.1:10 EtOAc:hexanes) to afford 3-oxobut-1-en-2-yl 2-naphthoate of the formula (II-5) (1.54 g, 6.4 mmol, 43%). Spectroscopic data matched previously reported values (cf. Tamariz, J.; Vogel, P. Helv. Chim. Acta 1981, 64 (1), 188-197).

Preparation of 3-oxobut-1-en-2-yl 4-nitrobenzoate of the formula (II-10)

[0340] ##STR00074##

3-oxobut-1-en-2-yl 4-nitrobenzoate of the formula (II-10) was prepared from diacetyl (IX) (1.30 mL, 15.0 mmol, 1.0 equiv), triethylamine (2.5 mL, 18.0 mmol, 1.2 equiv), 4-nitrobenzoyl chloride (2.78 g, 15.0 mmol, 1.0 equiv), and dry dichloromethane (20 mL) following General Procedure A. The resulting solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (1:2 EtOAc/hexanes) to afford 3-oxobut-1-en-2-yl 4-nitrobenzoate of the formula (II-10) (2.16 g, 9.2 mmol, 61%) as a white solid.

[0341] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.35-8.32 (m, 2H), 8.31-8.27 (m, 2H), 6.10 (d, J=2.7 Hz, 1H), 5.85 (d, J=2.8 Hz, 1H), 2.45 (s, 3H).

Preparation of the chiral ligand of formula (IV)

Preparation of ((4S,4′S,5S,5′S)-pyridine-2,6-diylbis(4,5-diphenyl-4,5-dihydro-1H-imidazole-2,1-diyl))bis(naphthalen-1-ylmethanone) of the formula (IV-9)

[0342] The chiral ligand of the formula (IV-9) was prepared following the procedures of Bhor and coworkers (cf. Bhor, S. et al., Org. Lett. 2005, 7 (16), 3393-3396) as illustrated in the Scheme below and described in more detail hereinafter.

##STR00075##

Procedure: A 50 ml pressure tube was charged with dimethyl pyridine-2,6-dicarboximidate of formula (X-1) (483 mg, 2.50 mmol, 1.0 equiv), (S,S)-1,2-diphenylethane-1,2-diamine of the formula (XI) (1.11 g, 5.25 mmol, 2.1 equiv) and dry dichloromethane (50 ml). After the resulting mixture was stirred at refluxing temperature for two days, water (20 ml) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (20 ml×2). The combined organic layer was dried over MgSO.sub.4 and the solvent was removed in vacuo to give a light yellow solid, which was purified by crystallization (ethylacetate) to give 2-[(4S,5S)4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl]-6-[(4R,5R)-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl]pyridine of formula (XII-1) as a white solid (1.04 g, 2.00 mmol, 80%). Spectroscopic data matched previously reported values (cf. Bhor, S. et al., Org. Lett. 2005, 7 (16), 3393-3396).

[0343] To an oven-dried 250 mL round bottom flask, equipped with a stir bar, was charged 2-[(4S,5S)4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl]-6-[(4R,5R)-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl]pyridine of formula (XII-1) (1.58 g, 3.04 mmol, 1.0 equiv), 4-dimethylaminopyridine (1.11 g, 9.12 mmol, 3.0 equiv), and dry dichloromethane (63.1 mL). The resulting mixture was cooled to 0° C., and 1-naphthoyl chloride (1.01 mL, 6.69 mmol, 2.20 equiv) added neat via syringe. The ice bath was then removed and the reaction mixture was stirred at room temp for 5 hours. The solvent was removed in vacuo, the residue was partitioned between saturated NH.sub.4Cl (50 ml) and ethyl acetate (50 ml), and the aqueous phase was re-extracted with ethyl acetate (50 ml×2). The combined organic layer was dried (over MgSO.sub.4), and the solvent was removed in vacuo. The residue was crystallized (ethyl acetate/hexane) to give ((4S,4′S,5S,5′S)-pyridine-2,6-diylbis(4,5-diphenyl-4,5-dihydro-1H-imidazole-2,1-diyl))bis(naphthalen-1-ylmethanone) of the formula (IV-9) as a white solid (2.46 g, 2.97 mmol, 98%). Spectroscopic data matched previously reported values (cf. Bhor, S. et al., Org. Lett. 2005, 7 (16), 3393-3396).

Preparation of ((4S,4′S,5S,5′S)-(4-chloropyridine-2,6-diyl)bis(4,5-diphenyl-4,5-dihydro-1H-imidazole-2,1-diyl))bis(naphthalen-1-ylmethanone) of the formula (IV-12)

[0344] The synthesis of the chiral ligand of the formula (IV-12) was adapted from the procedures of Bhor and coworkers (cf. Bhor, S. et al., Org. Lett. 2005, 7 (16), 3393-3396) as illustrated in the Scheme below and described in more detail hereinafter.

##STR00076##

[0345] Procedure: A 15 ml pressure tube was charged with dimethyl 4-chloropyridine-2,6-dicarboximidate of formula (X-2) (150 mg, 0.659 mmol, 1.0 equiv), (S,S)-1,2-diphenylethane-1,2-diamine of the formula (XI) (294 mg, 1.38 mmol, 2.1 equiv) and dry dichloromethane (4 ml). After the resulting mixture was stirred at refluxing temperature for two days, water (20 ml) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (20 ml×2). The combined organic layer was dried over MgSO.sub.4 and the solvent was removed in vacuo to give a light yellow solid, which was used directly in the next step without further purification. To an oven-dried 25 mL round bottom flask, equipped with a stir bar, was charged 4-chloro-2-[(4S,5S)-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl]-6-[(4R,5R)-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl]pyridine of formula (XII-2) (111 mg, 0.2 mmol, 1.0 equiv), 4-dimethylaminopyridine (73.3 mg, 0.6 mmol, 3.0 equiv), and dry dichloromethane (8 mL). The resulting mixture was cooled to 0° C., and 1-naphthoyl chloride (66.3 μL, 0.44 mmol, 2.20 equiv) added neat via microsyringe. The ice bath was then removed and the reaction mixture was stirred at room temp for 5 hours. The solvent was removed in vacuo, the residue was partitioned between saturated NH.sub.4Cl (50 ml) and ethyl acetate (50 ml), and the aqueous phase was re-extracted with ethyl acetate (50 ml×2). The combined organic layer was dried (over MgSO.sub.4), and the solvent was removed in vacuo. The residue was crystallized (ethyl acetate/hexane) to give ((4S,4′S,5S,5′S)-(4-chloropyridine-2,6-diyl)bis(4,5-diphenyl-4,5-dihydro-1H-imidazole-2,1-diyl))bis(naphthalen-1-ylmethanone) of the formula (IV-12) as a white solid (128 mg, 0.149 mmol, 74%).

[0346] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.84-6.92 (m, 36H), 5.49 (bs, 2H), 5.20 (bs, 2H).

Example 1: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1) and 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2) with a catalyst comprising Yb.SUP.3+ or Y.SUP.3+ and 2,6-Bis[(4S)-4-phenyl-2-oxazolinyl]pyridine of the formula (IV-1) or 2,6-Bis((S)-4,5-dihydro-4-phenethyloxazol-2-yl)pyridine of the formula (IV-10) as chiral ligand

Example 1.1: Preparation of 3-oxobut-1-en-2-yl benzoate of the Formula (II-1)

[0347] To a solution of diacetyl (2.19 mL, 25.0 mmol, 1.0 equiv.) and triethylamine (4.18 mL, 30.0 mmol, 1.2 equiv.) in dry dichloromethane (35 mL) was added benzoyl chloride at 0° C. under N.sub.2. The reaction was allowed to slowly warm to 23° C. After 14 h, hexanes (35 mL) was added, and the reaction mixture was filtered through a plug of sand. The resulting solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (1:20 EtOAc:hexanes.fwdarw.1:10 EtOAc:hexanes) to afford 3-oxobut-1-en-2-yl benzoate of the formula (II-1) (2.21 g, 11.6 mmol, 46%) as a yellow oil which solidifies upon storage at −20° C. Spectroscopic data matched previously reported values (cf. Tamariz, J.; Vogel, P. Helv. Chim. Acta 1981, 64 (1), 188-197).

Example 1.2: Preparation of 3-oxobut-1-en-2-yl 2,2-diphenylacetate of the formula (II-2)

[0348] To a solution of diacetyl (1.32 mL, 15.0 mmol, 1.0 equiv.) and triethylamine (2.51 mL, 18.0 mmol, 1.2 equiv.) in dry dichloromethane (20 mL) was added technical grade diphenylacetyl chloride (3.46 g, 15.0 mmol, 1.0 equiv.) at 23° C. under N.sub.2. After 24 h, hexanes (20 mL) was added, and the reaction mixture was filtered through a plug of sand, eluting with 1:1 dichloromethane:hexanes. The resulting solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (1:20 EtOAc:hexanes.fwdarw.1:10 EtOAc:hexanes.fwdarw.1:5 EtOAc:hexanes) to afford 3-oxobut-1-en-2-yl 2,2-diphenylacetate of the formula (II2) (3.55 g, 12.7 mmol, 85%) as a pale yellow solid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.33 (m, 10H), 5.92 (d, J=2.5 Hz, 1H), 5.58 (d, J=2.5 Hz, 1H), 5.22 (s, 1H), 5.28 (s, 3H).

Examples 1.3 to 1.7: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1) and 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2) by using varying of amounts of 2-methyl-1,3-butadiene of the formula (III-1) (hereinafter referred to as “isoprene”), Yb.SUP.3+ or Y.SUP.3+ as metal cation and 2,6-Bis[(4S)-4-phenyl-2-oxazolinyl]pyridine of the formula (IV-1) or 2,6-Bis((S)-4,5-dihydro-4-phenethyloxazol-2-yl)pyridine of the formula (IV-10) as chiral ligand

[0349] 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1) and 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2) were prepared as shown in Scheme 1 below and described in more detail in the general procedure below.

##STR00077##

[0350] General procedure for examples 1.3 to 1.7: Yttrium (III) triflate or ytterbium (III) triflate (0.05 mmol, 0.10 equiv.) was added to an oven-dried 1-dram vial in an N.sub.2-filled glovebox and capped with a Teflon-lined cap. The reaction vessel was then removed from the glovebox, and a stirbar, activated 3 Å molecular sieves (35 mg), and a solution of ligand in the organic solvent, i.e. dry dichloromethane (1.0 mL, 0.06 M), subsequently added. The mixture was stirred at 23° C. for 3 h, and then the diene, i.e. isoprene of the formula (III-1) (2.5 mmol or 5.0 mmol, 5.0 equiv. or 10.0 equiv.) was added, followed by the respective dienophile, i.e. 3-oxobut-1-en-2-yl benzoate of the formula (II-1) or 3-oxobut-1-en-2-yl 2,2-diphenylacetate of the formula (II-2) (0.50 mmol, 1.0 equiv.). The reaction mixture was then capped and sealed with electrical tape. After stirring at 23° C. for 42 h, the reaction mixture was filtered through a plug of silica gel, eluting with dichloromethane. The resulting solution was then concentrated, and dimethyl sulfone was added to the residue as an internal standard for .sup.1H NMR. The entire residue was taken up in CDCl.sub.3 and conversion/yield were determined by .sup.1H NMR spectroscopy. 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1): .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.02 (m, 2H), 7.58 (m, 1H), 7.46 (m, 2H), 5.34 (br s, 1H), 2.65 (m, 1H), 2.40 (m, 2H), 2.19 (s, 3H), 2.01 (m, 2H), 1.71 (s, 3H).

[0351] 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2): .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.32 (m, 10H), 5.23 (br s, 1H), 5.04 (s, 1H), 2.46 (m, 1H), 2.30 (m, 1H), 2.14 (m, 1H), 2.00 (s, 3H), 1.81 (m, 3H), 1.59 (br s, 3H).

[0352] The NMR sample was then loaded onto an EMD/Merck silica gel 60 F254 pre-coated plate (0.25 mm) and subjected to preparatory thin-layer chromatography, eluting with 1:5 EtOAc:hexanes. The isolated desired product was subjected to SFC analysis for determination of enantiomeric excess (ee).

[0353] SFC analysis was performed using a Mettler SFC supercritical CO.sub.2 analytical chromatography system (CO.sub.2=1450 psi, column temperature=40° C.) with Chiralcel AD-H or IC columns (4.6 mm×25 cm).

[0354] 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1): Chiralcel IC column, 2.5 mL/min, 7% iPrOH/CO.sub.2, t.sub.minor=11.3 min, t.sub.major=12.3 min.

[0355] 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2): Chiralcel AD-H column, 2.5 mL/min, 7% iPrOH/CO.sub.2, t.sub.major=11.2 min, t.sub.minor=13.3 min.

[0356] The results are summarized in the following Table I:

TABLE-US-00001 TABLE I Amount isoprene of Final Ex. (equiv.) product R.sub.A M.sup.m+ Chiral ligand Conversion (%) Yield (%) ee (%) 1.3 5.0 (I-1) Ph Yb.sup.3+ (IV-1) 30 29 67 1.4 5.0 (I-1) Ph Y.sup.3+ (IV-1) 23 23 70 1.5 5.0 (I-1) Ph Yb.sup.3+  (IV-10) 25 23 43 1.6 5.0 (I-2) CH(Ph).sub.2 Yb.sup.3+ (IV-1) 36 36 68 1.7 10.0  (I-1) Ph Yb.sup.3+ (IV-1) 48 46 68

Example 2: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1) by using varying organic solvents

[0357] 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1) was prepared as shown in Scheme 2 below. The general procedure for Examples 1.3 to 1.7 was used, except that ytterbium (III) triflate was used in all cases, the temperature was 35° C. and varying organic solvents listed in Table II were used (i.e. dichloromethane and further organic solvents).

##STR00078##

[0358] The results are summarized in the following Table II:

TABLE-US-00002 TABLE II Ex. Organic solvent Conversion (%) ee (%) 2.1 dichloromethane 65 63 2.2 1,2-dichloroethane 50 50 2.3 deuteriochloroform (CDCl.sub.3) 46 66 2.4 tetrachloromethane 22 27 2.5 trichloroethylene 33 40 2.6 acetonitrile — −5 2.7 toluene — 25 2.8 tetrahydrofuran — 29 2.9 Methyl-tert-butyl ether 54 58 2.10 Diethylether 46 53 2.11 1,4-dioxane 34 58 2.12 2,5-dimethyl tetrahydrofuran 29 49 (mixture of cis and trans) 2.13 Cyclopentyl-methylether 48 50 2.14 diisopropylether 10 35

Example 3: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the Formula (I-1) by Using Varying Metal Salts

[0359] 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1) was prepared as shown in Scheme 3 below. The general procedure for Examples 1.3 to 1.7 was used, except that the temperature was 35° C. and varying metal salts listed in Table III were used (i.e. ytterbium (III) triflate and further metal salts).

##STR00079##

[0360] The results are summarized in the following Table III:

TABLE-US-00003 TABLE III Ex. Metal salt Conversion (%) ee (%) 3.1 Sc(OTf).sub.3 17 <2 3.2 La(OTf).sub.3  9 11 3.3 Ce(OTf).sub.3 18 19 3.4 Pr(OTf).sub.3 29 43 3.5 Nd(OTf).sub.3 22 39 3.6 Sm(OTf).sub.3 35 46 3.7 Eu(OTf).sub.3 24 36 3.8 Gd(OTf).sub.3 40 58 3.9 Tb(OTf).sub.3 49 62 3.10 Dy(OTf).sub.3 35 41 3.11 Ho(OTf).sub.3 39 56 3.12 Er(OTf).sub.3 21 28 3.13 Yb(OTf).sub.3 65 63 3.14 Lu(OTf).sub.3 47 47

Example 4: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1), 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2) and 1-acetyl-4-methylcyclohex-3-en-1-yl adamantane-2-carboxylate of the formula (I-3) by using varying chiral ligands

[0361] 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1), 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2) and 1-acetyl-4-methylcyclohex-3-en-1-yl adamantane-2-carboxylate of the formula (I-3) were prepared as shown in Scheme 4 below. The general procedure for Examples 1.3 to 1.7 was used, except that varying chiral ligands, namely 2,6-bis((S)-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine of the formula (IV-1), 2,6-bis((S)-4-(4-bromophenyl)-4,5-dihydrooxazol-2-yl)pyridine of the formula (IV-2) and ((4S,4′S,5S,5′S)-pyridine2,6-diylbis(4,5-diphenyl-4,5-dihydro-1H-imidazole-2,1-diyl))bis(naphthalen-1-ylmethanone) of the formula (IV-9), were used as shown in Table IV below. Further, oxobut-1-en-2-yl adamantane-2-carboxylate of the formula (II-3) was used as an additional dienophile of formula (II).

##STR00080##

[0362] The results are summarized in the following Table IV:

TABLE-US-00004 TABLE IV Chiral Metal Dienophile Final Conversion ee Ex. ligand salt (II) compound (I) (%) (%) 4.1 (IV-1) Yb(OTf).sub.3 (II-2) (I-2) >98  74 4.2 (IV-2) Yb(OTf).sub.3 (II-2) (I-2) 25 60 4.3 (IV-9) Yb(OTf).sub.3 (II-2) (I-2) 83 77 4.4 (IV-1) Yb(OTf).sub.3 (II-3) (I-3) 81 86 4.5 (IV-9) Y(OTf).sub.3 (II-1) (I-1) >98  86

Example 5: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1) by using varying temperatures

[0363] 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1) was prepared as shown in Scheme 5 below. The general procedure for Examples 1.3 to 1.7 was used, except that the temperature was varied, as shown in Table V below.

##STR00081##

[0364] The results are summarized in the following Table V:

TABLE-US-00005 TABLE V Temperature Ex. T (° C.) Conversion (%) ee (%) 5.1 23 30 67 5.2 35 65 63

Example 6: Preparation of 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl benzoate of the formula (I-6) and 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-7) by using 2,3-dimethyl-1,3-butadiene of the formula (III-2) as the diene

[0365] 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl benzoate of the formula (I-6) and 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-7) were prepared as shown in Scheme 6 below. The general procedure for Examples 1.3 to 1.7 was used, except that 2,3-dimethyl-1,3-butadiene of the formula (III-2) was used as the diene (see also Table VI below).

##STR00082##

[0366] The results are summarized in the following Table VI:

TABLE-US-00006 TABLE VI Final Con- Dienophile Diene compound version Ee Ex. (II) (III) (I) (%) (%) 6.1 (II-1) (III-2) (I-6) 52 68 6.2 (II-2) (III-2) (I-7) 60 67

Example 7: Preparation of 2-acetylbicyclo[2.2.2]oct-5-en-2-yl benzoate of the formula (I-8), 2-acetylbicyclo[2.2.2]oct-5-en-2-yl 2,2-diphenylacetate of the formula (I-9) and 2-acetylbicyclo[2.2.2]oct-5-en-2-yl adamantane-2-carboxylate of the formula (I-10) by using 1,3-cyclohexadiene of the formula (III-3) as the diene

[0367] 2-acetylbicyclo[2.2.2]oct-5-en-2-yl benzoate of the formula (I-8), 2-acetylbicyclo[2.2.2]oct-5-en2-yl 2,2-diphenylacetate of the formula (I-9) and 2-acetylbicyclo[2.2.2]oct-5-en-2-yl adamantane2-carboxylate of the formula (I-10) were prepared as shown in Scheme 7 below. The general procedure for Examples 1.3 to 1.7 was used, except that 1,3-cyclohexadiene of the formula (III3) was used as the diene. Further, oxobut-1-en-2-yl adamantane-2-carboxylate of the formula (II-3) was used as an additional dienophile of formula (II).

##STR00083##

[0368] The results are summarized as follows:

##STR00084##

Example 8: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1) and 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2)

[0369] General procedure for examples 8.1 to 8.8: metal salt (0.05 mmol, 0.10 equiv.) was added to an oven-dried 1-dram vial in an N.sub.2-filled glovebox and capped with a Teflon-lined cap. The reaction vessel was then removed from the glovebox, and a stirbar, and a solution of the chiral ligand (IV) in the dry organic solvent (1.0 mL, 0.06 M), was subsequently added. The mixture was stirred at 23° C. for 3 h, and then the diene, i.e. isoprene of the formula (III-1) (2.5 mmol or 5.0 mmol, 5.0 equiv. or 10.0 equiv.) was added, followed by the respective dienophile, i.e. 3-oxobut-1-en-2-yl benzoate of the formula (II-1) or 3-oxobut-1-en-2-yl 2,2-diphenylacetate of the formula (II-2) (0.50 mmol, 1.0 equiv.). The reaction mixture was then capped and sealed with electrical tape. After stirring at 23° C. for 42 h, the reaction mixture was filtered through a plug of silica gel, eluting with dichloromethane. The resulting solution was then concentrated, and dimethyl sulfone was added to the residue as an internal standard for .sup.1H NMR. The entire residue was taken up in CDCl.sub.3 and conversion/yield were determined by .sup.1H NMR spectroscopy. The NMR sample was then loaded onto an EMD/Merck silica gel 60 F254 pre-coated plate 10 (0.25 mm) and subjected to preparatory thin-layer chromatography, eluting with 1:5 EtOAc:hexanes. The isolated desired product was subjected to SFC analysis for determination of enantiomeric excess (ee). SFC analysis was performed using a Mettler SFC supercritical CO.sub.2 analytical chromatography 15 system (CO.sub.2=1450 psi, column temperature=40° C.) with Chiralcel AD-H or IC columns (4.6 mm×25 cm). 1-acetyl-4-methylcyclohex-3-en-1-yl benzoate of the formula (I-1): Chiralcel IC column, 2.5 mL/min, 7% iPrOH/CO.sub.2, t.sub.minor=11.3 min, t.sub.major=12.3 min. 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2): Chiralcel AD-H column, 2.5 mL/min, 7% iPrOH/CO.sub.2, t.sub.minor=11.2 min, t.sub.major=13.3 min.

##STR00085##

[0370] The results are summarized in the following Table VII:

TABLE-US-00007 TABLE VII Chiral Organic Solvent Ex. Metal salt Dienophile (II) ligand (IV) solvent amount Conversion (%) Ee (%) 8.1 Y(OTf).sub.3 (II-1) IV-9 DCM 0.25 mL 94 89 8.2 Y(OTf).sub.3 (II-1) (IV-9) PhCl 0.25 mL >98  91 8.3 Sc(OTf).sub.3 (II-1) (IV-9) DCM   1 mL 24 40 8.4 Y(OTf).sub.3 (II-1) (IV-9) DCM   1 mL 45 84 8.5 Yb(OTf).sub.3 (II-1) (IV-9) DCM   1 mL 18 65 8.6 Y(OTf).sub.3 (II-1) (IV-1) DCM   1 mL 37 67 8.7 Yb(OTf).sub.3 (II-1) (IV-1) DCM   1 mL 13 63 8.8 Y(OTf).sub.3 (II-2) (IV-9) PhCl 0.25 mL >98  86

Example 9: Preparation of 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-7), 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 1-napthoate of the formula (I-11), and 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 2-napthoate of the formula (I12) by using 2,3-dimethyl-1,3-butadiene of the formula (III-2) as the diene

[0371] 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-7), 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 1-napthoate of the formula (I-11), and 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 2-napthoate of the formula (I-12) were prepared as shown in Scheme 9 below. The general procedure for Examples 8.1 to 8.8 was used, except that 2,3-dimethyl-1,3-butadiene of the formula (III-2) was used as the diene (see also Table VIII below).

##STR00086##

[0372] The results are summarized in the following Table VIII:

TABLE-US-00008 TABLE VIII Dienophile Diene Solvent Conversion Ee Ex. (II) equiv amount (%) (%) 9.1 (II-4) 5.0 0.25 mL 89 95 9.2 (II-5) 5.0 0.25 mL 88 95 9.3 (II-2) 2 0.25 mL >98 95.5 9.4 (II-2) 3 0.25 mL >98 95.5 9.5 (II-2) 5 0.25 mL >98 96 9.6 (II-2) 2  0.4 mL >98 95.5 9.7 (II-2) 3  0.4 mL >98 95.5 9.8 (II-2) 5  0.4 mL >98 96 9.9 (II-2) 2  0.6 mL >98 95.5 9.10 (II-2) 3  0.6 mL >98 96 9.11 (II-2) 5  0.6 mL >98 96
SFC analysis was performed using a Mettler SFC supercritical CO.sub.2 analytical chromatography 15 system (CO.sub.2=1450 psi, column temperature=40° C.) with Chiralcel AD-H or IC columns (4.6 mm×25 cm).

[0373] 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 1-napthoate of the formula (I-11): Chiralcel IC column, 2.5 mL/min, 15% iPrOH/CO.sub.2, t.sub.minor=9.8 min, t.sub.major=10.5 min. 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 2-napthoate of the formula (I-12): Chiralcel IC column, 2.5 mL/min, 15% iPrOH/CO.sub.2, t.sub.minor=10.4 min, t.sub.major=12.0 min.

[0374] 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 1-naphthoate (I-11):

[0375] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.94-8.70 (m, 1H), 8.16 (dd, J=7.3, 1.3 Hz, 1H), 8.05 (dt, J=8.2, 1.1 Hz, 1H), 7.95-7.83 (m, 1H), 7.67-7.43 (m, 3H), 2.72 (d, J=17.9 Hz, 1H), 2.50-2.33 (m, 2H), 2.27 (d, J=0.4 Hz, 3H), 2.25-2.15 (m, 1H), 2.13-1.89 (m, 2H), 1.74-1.68 (m, 6H).

[0376] 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl 2-naphthoate (1-12):

[0377] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.65-8.52 (m, 1H), 8.08-7.94 (m, 2H), 7.91-7.84 (m, 2H), 7.69-7.44 (m, 2H), 2.70 (d, J=17.9 Hz, 1H), 2.49-2.29 (m, 2H), 2.23 (s, 3H), 2.29-2.14 (m, 1H), 2.09-1.81 (m, 2H), 1.68 (s, 6H).

Example 10: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2)

[0378] 1-acetyl-4-methylcyclohex-3-en-1-yl 2,2-diphenylacetate of the formula (I-2) was prepared as shown in Scheme 10 below. The general procedure for Examples 8.1 to 8.8 was used except that, in certain examples, an additive was added following addition of the dienophile (see also Table IX below).

##STR00087##

[0379] The results are summarized in the following Table IX:

TABLE-US-00009 TABLE IX Metal Organic Conversion ee Ex. salt additive solvent (%) (%) 10.1 Y(OTf).sub.3 — PhCl 93 87 10.2 Y(OTf).sub.3 — DCM 56 72 10.3 YCl.sub.3 — DCM 6 11 10.4 YCl.sub.3 NaB.sub.ArF (10 mol %) DCM 16 0 10.5 YCl.sub.3 NaB.sub.ArF (30 mol %) DCM Nd Nd 10.6 Y(OTf).sub.3 N(n-Bu).sub.4Br (20 mol %) DCM >98 54 10.7 Y(OTf).sub.3 N(n-Bu).sub.4Br (10 mol %) DCM 91 65

Example 11: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl 1-napthoate of the formula (I13) and 1-acetyl-4-methylcyclohex-3-en-1-yl 2-napthoate of the formula (I-14)

[0380] 1-acetyl-4-methylcyclohex-3-en-1-yl 1-napthoate of the formula (I-13) and 1-acetyl-4-methylcyclohex-3-en-1-yl 2-napthoate of the formula (I-14) were prepared as shown in Scheme 11 below. The general procedure for Examples 8.1 to 8.8 was used, except that activated 3 Å molecular sieves (35 mg) were added before the ligand (see also Table X below).

##STR00088##

[0381] The results are summarized in the following Table X:

TABLE-US-00010 TABLE X Final Con- Dienophile product version Ee Ex. (II) (I) (%) (%) 11.1 (II-4) (I-13) >98 81 11.2 (II-5) (I-14) >98 87

[0382] SFC analysis was performed using a Mettler SFC supercritical CO.sub.2 analytical chromatography 15 system (CO.sub.2=1450 psi, column temperature=40° C.) with Chiralcel AD-H or IC columns (4.6 mm×25 cm).

[0383] 1-acetyl-4-methylcyclohex-3-en-1-yl 1-napthoate of the formula (I-13): Chiralcel IC column, 2.5 mL/min, 20% iPrOH/CO.sub.2, t.sub.minor=6.7 min, t.sub.major=7.2 min. 1-acetyl-4-methylcyclohex-3-en-1-yl 2-napthoate of the formula (I-14): Chiralcel IC column, 3.0 mL/min, 15% iPrOH/CO.sub.2.

Example 12: Preparation of 1-acetyl-4-methylcyclohex-3-en-1-yl pivalate of the formula (I-5), 1-acetyl-4-methylcyclohex-3-en-1-yl 2-bromobenzoate of the formula (I-15), 1-acetyl-4-methylcyclohex-3-en-1-yl 4-(tert-butyl)benzoate of the formula (I-16), 1-acetyl-4-methylcyclohex-3-en-1-yl 4-nitrobenzoate of the formula (I-17), 1-acetyl-4-methylcyclohex-3-en-1-yl 1-naphthoate of the formula (I-13) and 1-acetyl-4-methylcyclohex-3-en-1-yl 2-naphthoate of the formula (I-14)

[0384] 1-acetyl-4-methylcyclohex-3-en-1-yl pivalate of the formula (I-5), 1-acetyl-4-methylcyclohex-3-en-1-yl 2-bromobenzoate of the formula (I-15), 1-acetyl-4-methylcyclohex-3-en-1-yl 4-(tert-butyl)benzoate of the formula (I-16), 1-acetyl-4-methylcyclohex-3-en-1-yl 4-nitrobenzoate of the formula (I-17), 1-acetyl-4-methylcyclohex-3-en-1-yl 1-naphthoate of the formula (I-13) and 1-acetyl-4-methylcyclohex-3-en-1-yl 2-naphthoate of the formula (I-14) were prepared as shown in Scheme 12 below. The general procedure for Examples 8.1 to 8.8 was used.

##STR00089##

[0385] Results are as summarized below:

##STR00090##

[0386] SFC analysis was performed using a Mettler SFC supercritical CO.sub.2 analytical chromatography 15 system (CO.sub.2=1450 psi, column temperature=40° C.) with Chiralcel AD-H or IC columns (4.6 mm×25 cm).

[0387] 1-acetyl-4-methylcyclohex-3-en-1-yl pivalate of the formula (I-5): Chiralcel AD-H column, 2.5 mL/min, 4% iPrOH/CO.sub.2, t.sub.minor=3.0 min, t.sub.major=3.4 min, 1-acetyl-4-methylcyclohex-3-en-1-yl 2-bromobenzoate of the formula (I-15): Chiralcel IC column, 3.0 mL/min, 15% iPrOH/CO.sub.2, 1-acetyl-4-methylcyclohex-3-en-1-yl 4-(tert-butyl)benzoate of the formula (I-16): Chiralcel IC column, 2.5 mL/min, 10% iPrOH/CO.sub.2, t.sub.minor=9.4 min, t.sub.major=10.7 min, 1-acetyl-4-methylcyclohex-3-en1-yl 4-nitrobenzoate of the formula (I-17): Chiralcel IC column, 3.0 mL/min, 15% iPrOH/CO.sub.2, t.sub.minor=9.3 min, t.sub.major=10.1 min.

[0388] 1-acetyl-4-methylcyclohex-3-en-1-yl pivalate (1-5):

[0389] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 5.47 (s, 1H), 2.51 (d, J=18.2 Hz, 1H), 2.40 (s, 1H), 2.28 (d, J=18.1 Hz, 1H), 2.24-2.16 (m, 1H), 2.13 (s, 3H), 2.04 (d, J=11.0 Hz, 1H), 2.01-1.90 (m, 1H), 1.68 (s, 3H), 1.21 (s, 9H).

[0390] 1-acetyl-4-methylcyclohex-3-en-1-yl 2-bromobenzoate (1-15):

[0391] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.80-7.72 (m, 1H), 7.72-7.63 (m, 1H), 7.42-7.30 (m, 2H), 5.35 (dp, J=4.7, 1.5 Hz, 1H), 2.73-2.63 (m, 1H), 2.48 (d, J=18.4 Hz, 1H), 2.44-2.35 (m, 1H), 2.26 (s, 3H), 2.23-2.14 (m, 1H), 2.07-1.93 (m, 2H), 1.74-1.69 (m, 3H).

[0392] 1-acetyl-4-methylcyclohex-3-en-1-yl 4-(tert-butyl)benzoate (1-16):

[0393] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.05 (s, 2H), 7.94 (d, J=8.1 Hz, 2H), 5.59 (d, J=1.5 Hz, 1H), 2.62 (d, J=18.4 Hz, 1H), 2.30 (t, J=16.0 Hz, 1H), 2.18 (s, 3H), 2.16-1.90 (m, 4H), 1.69 (s, 3H), 1.34 (dd, J=3.9, 1.5 Hz, 9H).

[0394] 1-acetyl-4-methylcyclohex-3-en-1-yl 4-nitrobenzoate (1-17):

[0395] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.31-8.26 (m, 2H), 8.21-8.15 (m, 2H), 5.47 (s, 1H), 2.67 (d, J=18.1 Hz, 1H), 2.50 (s, 1H), 2.43-2.36 (m, 1H), 2.22 (s, 3H), 2.16-1.92 (m, 3H), 1.71 (d, J=1.6 Hz, 3H).

[0396] 1-acetyl-4-methylcyclohex-3-en-1-yl 1-naphthoate (1-13):

[0397] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.85 (d, J=8.6 Hz, 1H), 8.17 (dd, J=7.3, 1.3 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.90 (dt, J=8.0, 1.0 Hz, 1H), 7.57-7.46 (m, 3H), 5.42 (d, J=4.0 Hz, 1H), 2.70 (d, J=18.2 Hz, 1H), 2.55 (d, J=18.3 Hz, 1H), 2.43 (ddd, J=13.5, 5.3, 2.5 Hz, 1H), 2.27 (s, 3H), 2.21 (d, J=14.2 Hz, 1H), 2.12-1.95 (m, 2H), 1.76 (s, 3H).

[0398] 1-acetyl-4-methylcyclohex-3-en-1-yl 2-naphthoate (1-14):

[0399] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.61-8.55 (m, 1H), 8.02 (dd, J=8.6, 1.7 Hz, 1H), 8.00-7.95 (m, 1H), 7.94-7.86 (m, 2H), 7.59 (dddd, J=25.8, 8.1, 6.9, 1.3 Hz, 2H), 5.39 (tt, J=3.6, 1.6 Hz, 1H), 2.73-2.65 (m, 1H), 2.53 (d, J=17.9 Hz, 1H), 2.42 (ddt, J=10.4, 5.1, 2.6 Hz, 1H), 2.23 (s, 3H), 2.17 (s, 1H), 2.09-1.99 (m, 2H), 1.73 (t, J=1.7 Hz, 3H).

Example 13: Preparation of 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl benzoate (1-1) and 1-ace-tyl-3,4-dimethylcyclohex-3-en-1-yl 2,2-diphenylacetane of the formula (I-2)

[0400] 1-acetyl-3,4-dimethylcyclohex-3-en-1-yl benzoate (1-1) and 1-acetyl-3,4-dimethylcyclohex-3-en1-yl 2,2-diphenylacetane of the formula (I-2) were prepared as shown in Scheme 13 below. The general procedure for Examples 8.1 to 8.8 was used except that the amount of diene was varied (see Table XI below).

##STR00091##

TABLE-US-00011 TABLE XI Ex. Dienophile (II) Diene equiv Metal salt Chiral ligand organic solvent Conversion (%) ee (%) 13.1 (II-2) 20  Yb(OTf).sub.3 (IV-8) DCM 79 65 (0.25 mmol) 13.2 (II-1) 5 Y(OTf).sub.3 (IV-12) PhCl 38 65 (0.25 mmol) 13.3 (II-1) 5 Yb(OTf).sub.3 (IV-13) DCM 29 26  (0.5 mmol) 13.4 (II-1) 5 Yb(OTf).sub.3 (IV-14) DCM 38 12  (0.5 mmol) 13.5 (II-1) 5 Yb(OTf).sub.3 (IV-10) DCM 25 30  (0.5 mmol) 13.6 (II-1) 5 Y(OTf).sub.3 (IV-15) DCM 16 38  (0.2 mmol)