ASYMMETRIC SYNTHESES OF 3-SUBSTITUTED-CYCLOHEXANONE DERIVATIVES BY STEREOSELECTIVE CONJUGATE ADDITION TO CHIRAL 2-SUBSTITUTED-2-CYCLOHEXEN-1-ONES

Chiral 2-substituted-2-cyclohexen-1-one 2a is prepared from 1a by Birch reduction followed by acid-catalyzed hydrolysis-olefin migration. Conjugate additions of organometallic reagents to 2a occur with good to excellent diastereoselectivities (Table I). Enone 2b, which contains an additional potentially coordinating oxygen atom on the side chain of the chiral auxiliary, gave about the same stereoselectivity as 2a. The chiral auxiliary (S)-(+)-2-(methoxymethyl)pyrrolidine can be removed from the product of conjugate addition by treatment with hydroxylamine hydrochloride and sodium acetate in 95% ethanol at 60-degrees-C to give an oxime of a 3-substituted cyclohexanone (eg., 3a + 4a --> 6). The C2 carboxyl substituent is retained by treatment of the conjugate addition product with N-methylhydroxylamine hydrochloride and p-toluenesulfonic acid in benzene at reflux; 1-methyl-4,5,6,7-tetrahydro-4-substituted-2,1-benzisoxazolin-3-ones 10a-10d are obtained in 73-91% isolated yields. In the preparation of 10c it was demonstrated that thc chiral auxiliary could be easily recovered in 81% yield as the p-toluenesulfonic acid salt. Benzisoxazolin-3-one 10d (98.7% ee) gives (3R)-(+)-3-phenylcyclohexanone on treatment with lithium in NH3/THF solution.