SYNTHESIS OF ALPHA-AMINO-3-CHLORO-4,5-DIHYDRO-5-METHYL-5 ISOXAZOLEACETIC ACID, A RING-METHYLATED ANALOG OF THE ANTITUMOR AGENT ACIVICIN (AT-125)

alpha-Amino-3-chloro-4,5-dihydro-5-methyl-5-isoxazoleacetic acid (8), a ring-methylated analogue of the potent antitumor agent acivicin (AT-125), is synthesized in a 6-step procedure in 63% overall yield from (S)-valine. Key step is the 1,3-dipolar addition of bromonitrile oxide to the N,C-protected (S)-isodehydrovaline (6) available from (S)-valine in four steps involving the photoisomerization of N-phthaloylvaline methyl ester (1). The sterochemical course of the 1,3-dipolar cycloaddition is proven by means of a X-ray structure analysis of the major diastereoisomer 7a formed in the chloronitrile oxide cycloaddition. The absolute configuration of the major (u) diastereomer 7a and the bromo derivative 7b is (alpha S,5R).