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

no-3-chloro-4,5-dihydro-5-methyl-5-isoxazoleacetic acid (8), a ring-me thylated 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 es ter (1). The sterochemical course of the 1,3-dipolar cycloaddition is proven by means of a X-ray structure analysis of the major diastereois omer 7a formed in the chloronitrile oxide cycloaddition. The absolute configuration of the major (u) diastereomer 7a and the bromo derivativ e 7b is (alpha S,5R).