ABSTRACT
Synthesis of 7-O-(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)-epsilon-(i so)rhodomycinones 16 and 17, and their 3'-morpholino derivatives are described. Glycosylation (trimethylsilyl triflate, 10:1 dichloro-methane-acetone, -35 degrees) of 1-O-tert-butyldimethylsilyl-2,3-6-trideoxy-4-O-p-nitrobenzoyl-3-trifl uoroacetamido-beta-L-lyxo-hexopyranose (4) with epsilon-rhodomycinone (epsilon-RMN, 5) or epsilon-isorhodomycinone (epsilon-isoRMN, 6) afforded 7-O-alpha-glycosyl-epsilon-RMN (9) and -epsilon-isoRMN (12) in high yield. The glycosyl donors 2,3,6-trideoxy-4-O-p-nitrobenzoyl-3-trifluoroacetamido-L-lyxo++ +-hexopyrano se (2) or its 1-O-trimethylsilylated alpha-anomer 3 were less suitable for the glycosylation of these aglycons. Sapinification of 9 and 12 provided 16 and 17, respectively, which reacted with various 2,2'-oxydiacetaldehydes under conditions of reductive alkylation to give 3'-morpholinyl-epsilon-(iso)rhodomycins.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Anthracyclines , Antibiotics, Antineoplastic/chemistry , Carbohydrate Conformation , Carbohydrate Sequence , Glycosylation , Molecular Sequence Data , Molecular StructureABSTRACT
Synthesis of 3-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6-O-ethylidene- alpha-(7 alpha) and-beta-D-glucopyranose (7 beta) and their 3-O-chloroacetyl analogues (11 alpha and 11 beta) are described. Condensation (BF3-etherate, ethyl acetate, -20 degrees) of 7 alpha with 4'-O-benzyloxycarbonyl-4'-O-demethyl-4-epipodophyllotoxin (8) afforded mainly the beta-glycoside 9 beta (alpha, beta-ratio 1:9). Condensation of 11 alpha beta with 8 or the 4'-O-chloroacetyl analogue 13 gave mainly the 4-O-(2-benzyloxycarbonylamino-3-O-chloroacetyl-2-deoxy-4,6-O-ethyl idene-beta-D- glucopyranosyl)-epipodophyllotoxin 12 beta or 15 beta. Glycosidation of podophyllotoxin (14) with 11 alpha beta (during which the aglycon epimerized at C-4 under the action of BF3-etherate) afforded alpha- (16 alpha) and beta-glycoside (16 beta) in the ratio 1:5. Removal of the chloroacetyl groups from 12 beta, its alpha analogue 12 alpha, and 15 beta gave the 4-O-(2-benzyloxycarbonylamino-2-deoxy-4,6-O-ethylidene-alpha-(17 alpha) and -beta-D-glucopyranosyl)-4'-O-demethyl-epipodophyllotoxins (17 beta and 20 beta), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4-O-(2-amino-2-deoxy-4,6-O-ethylidene-alpha- (18 alpha) and -beta-D-glucopyranosyl)-4'-O-demethyl-4-epipodophyllotoxin (18 beta). Reductive alkylation of 18 beta and 18 alpha afforded the 2"-deoxy-2"-dimethylamino-etoposide 3 and its alpha analogue 19 alpha.
Subject(s)
Etoposide/chemical synthesis , Carbohydrate Conformation , Etoposide/chemistry , Magnetic Resonance Spectroscopy , Methods , Molecular Structure , Optical RotationABSTRACT
Syntheses and structure-activity relationships of 7-O-(3-amino-2,3,6-trideoxy-a-L-lyxo- (18), -L-arabino- (20) and -L-ribo- hexopyranosyl)-epsilon-isorhodomycins (25) and their 3'-dimethylamino derivatives 22, 23 and 26 are described. Condensation (trimethylsilyl triflate, molecular sieves 4 A, 10:1 dichloromethane-acetone, -15 degrees) of epsilon-isorhodomycinone (epsilon-isoRMN, 6) with 1,5-anhydro-4-O-p-nitrobenzoyl-3-trifluoroacetamido-L-lyxo- (5) -L-arabino- (9) or -L-ribo-hex-l-enitols (10) afforded mainly the 7-O-a-glycosyl-epsilon-isoRMNs 7, 11, and 12. Similar glycosylation of 6 with 1,5-anhydro-3-azido-4-O-p-nitrobenzoyl-2,3,6-trideoxy-L-arabino-hex-1-++ +enitol (15) yielded a-glycoside 16. Removal (M NaOH) of the p-nitrobenzoyl and trifluoroacetyl groups from 7, 11, and 12 gave the 7-O-(3-amino-2,3,6-trideoxy-a-L-hexopyranosyl)-epsilon-isoRMNs 18, 20, and 25. Reductive alkylation (CH2O, NaCNBH3) of these products afforded the 3'-N,N-dimethyl analogues 22, 23, and 26. The cytotoxic effect (IC50) of the semisynthetic epsilon-isorhodomycins was tested in vitro in leukemia cell line L1210.
