ETOPOSIDE - A NEW APPROACH TO THE SYNTHESIS OF 4-O-(2-AMINO-2-DEOXY-4,6-O-ETHYLIDENE-BETA-D-GLUCOPYRANOSYL)-4'-O-DEMETHYL-4-EPIPODOPHYLLOTOXIN

Synthesis of 3-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6-O-ethylidene-α-(7α) and -β-d-glucopyranose (7β) and their 3-O-chloroacetyl analogues (11α and 11β) are described. Condensation (BF3-etherate, ethyl acetate, -20°) of 7α with 4′-O-benzyloxycarbonyl-4′-O-demethyl-4-epipodophyllotoxin (8) afforded mainly the β-glycoside 9β (α,β-ratio 1:9). Condensation of 11αβ with 8 or the 4′-O-chloroacetyl analogue 13 gave mainly the 4-O-(2-benzyloxycarbonylamino-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-β-d-glucopyranosyl)- epipodophyllotoxin 12β or 15β. Glycosidation of podophyllotoxin (14) with 11αβ (during which the aglycon epimerized at C-4 under the action of BF3-etherate) afforded α- (16α) and β-glycoside (16β) in the ratio 1:5. Removal of the chloroacetyl groups from 12β, its α analogue 12α, and 15β gave the 4-O-(2-benzyloxycarbonylamino-2-deoxy-4,6-O-ethylidene-α- (17α) and -β-d-glucopyranosyl)-4′-O-demethyl-epipodophyllotoxins (17β and 20β), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4-O-(2-amino-2-deoxy-4,6-O-ethylidene-α- (18α) and -β-d-glucopyranosyl)-4′-O-demethyl-4-epipodophyllotoxin (18β). Reductive alkylation of 18β and 18α afforded the 2″-deoxy-2″-dimethylamino-etoposide 3 and its α analogue 19α. © 1990.