Total and stereospecific synthesis of cadeguomycin, 2′deoxycadeguomycin, ara-cadeguomycin, and certain related nucleosides

Abstract

A total and stereospecific synthesis of cadeguomycin (1), ara-cadeguomycin (2), and 2′-deoxycadeguomycin (3) has been accomplished from the novel aglycones 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (11) or methyl 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (13). Ring annulation of 2,6-diaminopyrimidin-4(3H)-one (6) with methyl chloro(formyl)acetate (7) in the presence of NaOAc provided a mixture of two products (8) and (9), from which the desired methyl 2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (9) was separated and converted into the key intermediates (11) and (13). Reaction of the sodium salt of (11) with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride (14) gave the corresponding protected nucleoside (15). Deprotection of (15) provided (16), which on treatment with NH₄OH–H₂O₂, followed by saponification, gave the target nucleoside (3) in good yield. Compound (3) was also prepared from compounds (13) and (14) by a similar sequence of reactions. Glycosylation of the sodium salt of (11) with 5-O-t-butyldimethylsilyl-2,3-O-isopropylidene-α-D-ribofuranosyl chloride (22) gave protected nucleoside (23), which on treatment with 4M-KOH followed by deisopropylidenation afforded cadeguomycin (1). Similarly, glycosylation of the sodium salt of (11) with 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride (27) furnished the corresponding glycosylated product (28), which on debenzylation and hydrolysis produced ara-cadeguomycin (2). Selective functional-group transformations of compound (16), (21), and (24) furnished several 2-amino-4,5-disubstituted pyrrolo[2,3-d]pyrimidine nucleosides.