Constituents of rhizoma Nupharis. XXVII. Synthesis and stereochemistry of 1- and 7-methyl-4-phenylquinolizidin-2-one.

Abstract

A stereoselective synthesis of 1-methyl (e)-4-phenyl (e)-trans-quinolizidin-2-one (16a) and 7-methyl (e)-4-phenyl (e)-trans-quinolizidin-2-one (23a) was accomplished during model studies for a stereoselective synthesis of quinolizidine-type Nuphar alkaloids. Condensation of ethylpyridine (11) with acetonitrile followed by ketalization gave the ketal (13), which was hydrogenated to afford two diastereoisomers (14a and 14b) in a 1 : 1 ratio. Deketalization of 14a or 14b afforded a diastereoisomeric mixture (1 : 1 ratio) of the aminoketone (15), which was condensed with benzaldehyde to give two quinolizidin-2-ones (16a and 16b) in 63 and 17% yields, respectively. The latter isomerized smoothly into the former on treatment with aqueous alkali in methanol. Similarly, the ketal (20) derived from 2, 5-lutidine (18) was hydrogenated to give the trans- and cis-piperidines (21a and 21b) in a 2 : 1 ratio. Treatment of both of them with hydrochloric acid effected deketalization and isomerization to yield a mixture of the trans- and cis-aminoketone (22a and 22b) in a 6 : 1 ratio, whereas deketalization with aqueous acetic acid or p-toluenesulfonic acid gave the mixture in a 1 : 3 ratio. Condensation of the mixture of 22a and 22b (6 : 1 ratio) with benzaldehyde gave two quinolizidin-2-ones (23a and 23b) in 65 and 10% yields, respectively. These were also obtained in 31 and 27% yields, respectively, from the mixture of 22a and 22b (1 : 3 ratio).