Total synthesis and anticancer evaluation of all known communesin alkaloids and related complex derivatives
Author(s)Pompeo, Matthew M.
Massachusetts Institute of Technology. Department of Chemistry.
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I. Convergent and Biomimetic Enantioselective Total Synthesis of (-)-Communesin F Enabled by Diazene-Directed Fragment Assembly. The first biomimetic enantioselective total synthesis of (-)-communesin F based on a late-stage heterodimerization and aminal exchange is described. Our synthesis features the expedient diazene-directed assembly of two advanced fragments to secure the congested C3a-C3a' linkage in three steps, followed by a highly efficient biogenetically inspired aminal reorganization to access the heptacyclic communesin core in only two additional steps. Enantioselective syntheses of the two fragments were developed, with highlights including the catalytic asymmetric halocyclization of tryptamine derivatives, a stereoselective sulfinimine allylation, and an efficient cyclotryptamine-C3a-sulfamate synthesis by either a new silver-promoted nucleophilic amination or a rhodium-catalyzed C-H amination protocol.The versatile synthesis of the fragments, their stereocontrolled assembly, and the efficient aminal-exchange as supported by in situ monitoring experiments, in addition to the final stage Nl'-acylation of the communesin core provide a highly convergent synthesis of (-)-communesin F. II. Enantioselective Total Synthesis and Anticancer Activity of All Known Communesin Alkaloids and Related Complex Derivatives. A unified enantioselective total synthesis and side-by-side anticancer evaluation of all known epoxide-containing communesin alkaloids and related complex derivatives is described. Our synthesis is predicated on the convergent and modular diazene-directed assembly of two advanced fragments to secure the critical C3a-C3a' linkage followed by a guided biomimetic aminal reorganization to deliver the heptacyclic core of these alkaloids.Concise enantioselective syntheses of the fragments were devised, with highlights including the use of a new, rationallydesigned sulfinamide chiral auxiliary and a highly efficient 1,1,1 -trifluoroacetone-mediated epoxidation. The modularity of our convergent approach enables the rapid synthesis of all epoxidecontaining members of the communesin family from a common synthetic intermediate, which prompted the stereochemical revision of (-)-communesin I, the most recently isolated communesin analogue. Furthermore, the generality of our biomimetic reorganization was conclusively demonstrated in the first total synthesis of an iso-communesin derivative, an unnatural constitutional isomer of the communesin skeleton. Finally, we report the first comparative analysis of the anticancer activities of all naturally occurring communesin alkaloids and nine complex derivatives against five human cancer cell lines.From these data, we have identified (-)- communesin B as the most potent natural isolate and discovered that derivatives with N8'- sulfonamide substitution exhibit up to a ten-fold increase in potency over the natural products.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2019Vita. Cataloged from PDF version of thesis.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology