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Progress toward the total synthesis of citrinadins A and B




Smith, Genessa M., author
Wood, John L., advisor
Williams, Robert M., committee member
Ferreira, Eric M., committee member
Chen, Eugene Y., committee member
O'Keefe, Garrett J., committee member

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In 2005 Kobayashi reported the isolation and absolute stereochemistry of Citrinadin A (1) and Citrinadin B (2), novel secondary metabolites of the marine fungus Penicillium citrinum. In addition to their interesting molecular architecture, the citrinadins are biologically active. Both exhibit cytotoxicity against murine leukemia L1210 (IC50 6.2 and 10 μg/mL respectively), and 1 has shown activity against human epidermoid carcinoma KB cells (IC50 6.2 μg/mL). Synthesis of 1 and 2 would allow for further testing of their biological activity and remains the best way to confirm their assigned structures. While, no total synthesis of either natural product has been reported to date, two synthetic approaches toward the citrinadins have been disclosed by Martin and Sorensen. Efforts to synthesize 1 and 2 in the Wood laboratory are based upon a convergent (3+2) dipolar cycloaddition reaction between a spiro-oxindole dipolarophile and a nitrone, where two diastereomeric isoxazolidine cycloadducts are formed. Using the undesired cycloadduct, exploratory studies toward a synthesis of 2 were conducted, resulting in the synthesis of the C3-epi-Citrinadin Core (±)-96. Elaboration of the desired cycloadduct then led to a synthesis of the ent-Citrinadin Core (+)-100. In order gain to access 2, a C7-functionalized spiro-oxindole dipolarophile was employed in the cycloaddition; however, elaboration of the desired C7-functionalized cycloadduct to ent-2 may result in a structural reassignment of 2. Preliminary results suggest that spectral data for the C21-epi-ent diastereomer of 2 (175) match the data reported by Kobayashi for Citrinadin B (2) itself. In an effort to gain access to 1, a (3+2) cycloaddition strategy utilizing a C14-functionalized nitrone was explored. Following the synthesis of three nitrone precursors, a one-pot nitrone formation / (3+2) cycloaddition reaction was developed and one of the cycloadducts was successfully advanced to a key ring-fusion epoxide. Elaboration of this advanced intermediate is expected to eventually provide a total synthesis of Citrinadin A (1).


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(3+2) dipolar cycloaddition
Citrinadin B
Citrinadin A


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