Off-campus UNL users: To download campus access dissertations, please use the following link to log into our proxy server with your NU ID and password. When you are done browsing please remember to return to this page and log out.

Non-UNL users: Please talk to your librarian about requesting this dissertation through interlibrary loan.

Studies in the synthesis of adriamycin

David Duran, University of Nebraska - Lincoln

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

Share

COinS