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Studies in the synthesis of adriamycin
Abstract
Adriamycin and daunomycin are two important anticancer drugs. Their toxicity and cost have led to a search for other anthracycline anticancer compounds. This thesis, which is part of a general effort to develop a total synthesis of the aglycones of adriamycin and its analogs, describes a regiospecific synthesis of the tetracyclic nucleus of adriamycin and its 6-deoxy analog. The synthesis was effected by a tandem Michael-addition/Dieckmann cyclization using juglone methyl ether monoacetal 1 as the CD precursor and methyl 2-nitromethyl-5-oxocyclohexanecarboxylate 2, as the A ring precursor. A new method of preparing 1 was developed from 1,5-dihydroxynaphthalene, and improves the yield from 8% to 52%. Compound 2 was synthesized by a three step process from m-anisic acid in 70% yield. Methyl 2-nitromethyl-5-oxocyclohexanecarboxylate 2 was condensed with juglone methyl ether monoacetal in acetonitrile, using DBU as base. The resulting adduct (obtained in 66% yield) was cyclized to afford the planar backbone of the anthracyclines 3a or denitrated with tributyltin hydride and then cyclized to afford the backbone of the 6-deoxyanthracyclines 3b. Additional transformations on these cyclized products are described. This approach provides a model study which others are using to synthesize compounds with a A ring precursor containing a 7,9-cis diol function and C$\bf \sb{13}$-C$\bf \sb{14}$ acetylenic side chain.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)
Subject Area
Organic chemistry|Oncology|Pharmacology
Recommended Citation
Duran, David, "Studies in the synthesis of adriamycin" (1989). ETD collection for University of Nebraska-Lincoln. AAI9118449.
https://digitalcommons.unl.edu/dissertations/AAI9118449