TOTAL SYNTHESES OF (-)-NOCARDICINS A-G - A BIOGENETIC APPROACH

The known nocardicins A-G have been synthesized, several for the first time, having geometric and stereoisomeric purities of a high order. The syntheses proceed through the central intermediacy of ierr-butyl (-)-3-aminocardicinate (14), which has been prepared in a biogenetically patterned, modified Mitsunobu cyclodehydration reaction of a protected L-seryl-o-(p-hydroxyphenyl)glycine dipeptide 12. An overall 54% yield from the precursor amino acids was achieved with complete stereochemical control at the labile C-5 position of 14. Mixed anhydride coupling of 14 to Ar-(Zerf-butoxycarbonyl)-D-(phydroxyphenyl) glycine (15) and deprotection afforded nocardicin G (7), which was selectively converted to nocardicin F (6, anti-oxime 15:1) through the action of 30% hydrogen peroxide in the presence of a catalytic amount of sodium tungstate, or to nocardicin E (5, syn-oxime 20:1) in a transamination protocol and reaction with hydroxylamine. Methods were developed to prepare the aryl alkyl ether side-chain components 29-31 in high yield to enable the efficient synthesis of nocardicins A-D. Nocardicin A, for example, was prepared in an overall 22% yield from L-serine and D-(p-hydroxyphenyl)glycine. © 1990, American Chemical Society. All rights reserved.