TOTAL SYNTHESES OF (+)-CASTANOSPERMINE AND (+)-1-EPICASTANOSPERMINE AND THEIR 1-O-ACYL DERIVATIVES FROM A COMMON CHIRAL BUILDING BLOCK

Stereoselective total syntheses of (+)-castanospermine (1) and (+)-1-epicastanospermine (2) and their 1-O-acyl derivatives 3-5 have been achieved via a noncarbohydrate-based approach utilizing allylic alcohol 9 as a common chiral building block. Epoxide 10, prepared from 9, underwent regioand stereoselective ring opening with Et2AlN(CH2Ph)2 to give amino alcohol 11, which was converted to aldehyde 15 in four steps. The aldol reaction of 15 with lithio ethyl acetate was predominantly anti selective and generated alpha-hydroxy ester 16 by a nonchelate Felkin-Anh pathway. Compound 16 was transformed into (+)-1-epicastanospermine (2) and its 1-O-acetyl and 1-O-butyryl derivatives (4 and 5) via the lactam intermediate 21. Alternatively, alpha-hydroxy ester 16 was converted to (+)-castanospermine (1) and its 1-O-acetyl derivative (3); these syntheses were achieved via reaction sequences involving the inversion of the C-3 configuration by the Mitsunobu process and 2-fold tandem cyclizations to form the indolizidine skeleton. The results of preliminary biological testing of compounds 2-5 for anti-HIV-1 activity in whole cells are presented.