Studies of the total synthesis of Fredericamycin A. Development of an intermolecular alkyne-chromium carbene benzannulation approach to the ABCD(E) ring system: Preparation of ABCD, ABCDE and fully functionalized ABCDE structural analogs
Abstract
Fredericamycin A (1), an antitumor antibiotic with a highly unusual structure, isolated from Streptomyces griseus, exhibits very good in vitro cytotoxic activity and confirmed antibacterial and antifungal activity. In vivo, it exhibits significant antitumor activity. The syntheses of ABCD (77), ABCDE (80) and fully functionalized ABCDE (78) structural analogs of Fredericamycin A are described. The highly convergent approach to the synthesis of Fredericamycin A is based on implementation of the two key carbon-carbon bond forming steps with the rest being functional group interconversions and/or protection/deprotection. The first key carbon-carbon bond forming step is the regiospecific alkyne-chromium carbene benzannulation reaction that introduces the fully functionalized AB ring framework of Fredericamycin A. The second carbon-carbon bond forming step is intramolecular aldol condensation that introduces the spiro(4.4) CD ring system. The study of the electronic and steric features of the alkyne that control the chromium carbene benzannulation reaction mode and regioselectivity revealed that optimal benzannulation conversions were observed with electron-neutral alkynes (neutral alkynes $>$ electron-deficient alkynes) and that modest steric differences in the substitution pattern at the alkyne $\alpha$-carbons are sufficient for observation of full regiocontrol in the benzannulation reaction. Preparation of a fully oxygenated arylchromium carbene complex (121) and its utilization in benzannulation reaction is detailed. Comparative in vitro cytotoxic activity, enzyme (Topoisomerase I and Topoisomerase II) inhibition studies and comparative spectroscopic properties between Fredericamycin A and fully functionalized ABCDE structural analog (78) are presented.
Degree
Ph.D.
Advisors
Boger, Purdue University.
Subject Area
Organic chemistry
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