Highly diastereoselective conjugate addition of lithium dialkylamides to alpha,beta-unsaturated esters having a chiral center at the gamma-position

The conjugate addition of lithium amides 2 to tert-butyl 4-(OR)-substituted-2-pentenoates 1 produced a mixture of the syn-and anti-amino esters (3 and 4) in high yields. Sterically bulky OR groups, such as trityloxy and tert-butyldiphenylsilyloxy, gave the syn diastereomer 3 either exclusively or predominantly. The syn-selectivity may be explained by a modified Felkin-Anh model. The use of tert-butyldimethylsilyloxy as an OR group afforded a nearly 1:1 mixture of diastereoisomers, and the use of the smallest MeO group produced a 63:37 mixture of the syn 3 and anti isomer 4. The presence of Me group at the alpha-position (C-2 position) of the enoate enhanced the syn diastereoselectivity up to 100%; the conjugate addition to tert-butyl 4-methoxy-2-methyl-2-pentenoate (17) gave the syn-isomer 18 exclusively. This enhancement may be explained by the combination of chelation and allylic strain model 19 in which the smallest H orients inside to avoid an allylic strain. A phenyl group at the gamma-position enhanced the anti selectivity in the case of gamma-alkoxy-alpha,beta-enoates such as isopropyl 4-[(tert-butyldimethylsilyl)oxy]-4-phenyl-2-buteonoate (20), and in the case of gamma-alkyl-alpha,beta-enoates such as tert-butyl 4-phenyl-2-pentenoate (27).