A NEW APPROACH TO THE SYNTHESIS OF ETOPOSIDE (VP16)

The synthesis of the glycosyl donors 2,3-di-O-acetyl- and 2,3-di-O-chloroacetyl-4,6-O-ethylidene-B-D-glucopyranose (10β) and (11β) and their use for the glycosidation of 4’-O-benzyloxy carbonyl- and 4,-O-chloroacetyl-4’-O-demethyl-4-epi-podophyllotoxins (12) and (13) is described. Starting from benzyl β-D-glucopyranoside (6), benzyl 2,3-di-O-acetyl-and 2,3-di-O-chloroacetyl-4,6-O-ethylidene-β-D-glucopyranoside (8) and (9) were prepared. Hydrogenolysis of the benzyl group in 8 or 9 afforded the β-hydroxy glucopyranose donors 10β and liβ. Condensation of 10β or lip with 4’-O-Z-epi-podophyl-lotoxin 12 in the presence of BF3-etherate gave selectively the 4-O-(2,3-di-0-acetyl- or -2,3-di-O-chloroacetyl-4,6-(O-ethylidene-β-D-glucopyranosyl)-epi-podophyllotoxins 14β and 15β, respectively. The β-glycoside 16 was prepared in the same manner starting from liβ and 4,-O-chloroacetyl-epi-podophyllotoxin 13. By deblocking (Dowex 1X8, 3:2 methanol-chloroform) of the chloroacetyl groups in 15β and the following hydrogenolysis of the benzyloxycarbonyl group in 17 etoposide 1 was obtained. The deacylation of 16 afforded 1 in a one step procedure. © 1990, Taylor & Francis Group, LLC. All rights reserved.