Patent TW-432028-B (TW)
Title: Asymmetric conjugate addition reaction using a chiral additive
Inventor: TILLYER RICHARD D
IPC: C07D263/06
Filed: 1998-01-05
Granted: 2001-05-01
Abstract: This invention relates to a process for the preparation of a key intermediate using an chiral additive to effect an asymmetric conjugate addition. A process for the preparation of a compound of formula I: wherein represents: (a) 5- or 6-membered heterocyclyl containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, (b) 5- or 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, (c) aryl, wherein aryl is as defined below, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, R1 is: (a) C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, (b) aryl, or (c) heteroaryl; heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, R2 is OR4 or N(R5)2; R3 is (a) H, (b) C1-C8 alkyl, (c) C1-C8 alkenyl, (d) C1-C8 alkynyl, (e) C1-C8 alkoxyl, (f) C3-C7 cycloalkyl, (g) S(O)tR5, (h) Br, Cl, F, I, (i) aryl, (j) heteroaryl, (k) N(R5)2, (l) NH2, (m) CHO, (n) -CO-C1-C8 alkyl, (o) -CO-aryl, (p) -CO-heteroaryl, (q) -CO2R4, or (r) protected aldehyde; X and Y are independently: O, S, or NR5; n is: 0 to 5; t is: 0, 1 or 2; R4 is C1-C8 alkyl; R5 is: C1-C8 alkyl, or aryl; and R6 is: H, C1-C8 alkyl, and aryl; and R7 are independently: H, C1-C8 alkyl, and aryl, when there are two R7 substituents on a nitrogen they can join to form a 3-through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)2; comprising reacting a Α,β-unsaturated ester or amide with an organolithium compound, R1Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of -78 DEG C to 0 DEG C, wherein the chiral additive is selected from the group consisting of: (a) (-)-sparteine, (b) N, N, N', N' -tetra(C1C6)-alkyltrans-1,2-diamino-cyclohexane, or (c) wherein R8 and R9 are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or phenyl, except that R8 and R9 cannot simultaneously be H; and R10 is H, C1-C6 alkyl or phenyl.