Synthetic studies on the natural antitumor and antimicrobial agents: Fredericamycin A, cis- and trans-trikentrin A

Minsheng Zhang, Purdue University

Abstract

cis- and trans-Trikentrin A are highly substituted indoles isolated from the marine sponge Trikentrion flabelliforme, representative of a new class of alkaloids possessing antimicrobial activity. A five-step total synthesis of ($\pm$)-cis- and ($\pm$)-trans-trikentrin A was developed and is based on the implementation of two sequential heteroaromatic azadiene Diels-Alder reactions of 3,6-bis(methylthio)-1,2,4,5-tetrazine (10). It was found that the first Diels-Alder reaction of 10 with the pyrrolidine enamine of cis/trans-2,4-dimethyl cyclopentanone 26 proceeded in a diastereoselective manner to provide, after aromatization, pure 1,2-diazine 29 exclusively possessing the cis-dimethyl stereochemistry. Successful implementation of a second intramolecular Diels-Alder reaction of cis-dimethyl allene 1,2-diazine 34 obtained through oxidation of 29 to the bis-sulfone 33 followed by mono-selective nucleophilic displacement of a single sulfone in 33 by the $\alpha$-allene amine 32 afforded ($\pm$)-cis-trikentrin A. ($\pm$)-trans-trikentrin A was synthesized through a similar reaction sequence starting from the trans-dimethyl bis-sulfone 1,2-diazine ($\pm$)-39 which was obtained divergently from 33 by deliberate epimerization. Overall, this 1,2,4,5-tetrazine $\to$ allene 1,2-diazine $\to$ indole strategy constitutes a general approach to the preparation of substituted indoles. Fredericamycin A is a structurally unique, biologically potent antitumor agent isolated from Streptomyces griseus. Synthesis of a ($\pm$)-fredericamycin A full carbon precursor 99 has been achieved through an intermolecular alkyne-chromium carbene complex benzannulation reaction. It was found that the benzannulation reaction proceeded under exceptionally mild conditions with high chemo- and regioselectivity. It tolerated a variety of oxygen and nitrogen functionalities and possessed the full potential to be used as a strategic transformation for assemblage of complex chemical structures. The synthetic utility of this reaction in the present study rested on the successful preparation of the required alkyne 96 through implementation of an inverse electron demand Diels-Alder reaction of the N-sulfonyl-1-aza-1,3-butadiene 65 for introduction of the pyridone F ring and a Michael addition, Dieckmann condensation sequence for the E ring synthesis. The fully functionalized lower subunit of fredericamycin A 92 was also prepared from a synthetic intermediate and proved to be moderately active toward the L1210 leukemia cell line.

Degree

Ph.D.

Advisors

Boger, Purdue University.

Subject Area

Chemistry|Organic chemistry|Biochemistry

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