Total Synthesis and Anti-Cancer Activity of All Known Communesin Alkaloids and Related Derivatives
Name
jacs.9b07397.pdf
Description
Published version
Size
2.06 MB
Format
Adobe PDF
Checksum (MD5)
5a5562efd06c19e06762c75ef293947d
Author(s)
Pompeo, Matthew M
Cheah, Jaime H
Movassaghi, Mohammad
Date Issued
August 2019
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Pompeo, Matthew M. "Total Synthesis and Anti-Cancer Activity of All Known Communesin Alkaloids and Related Derivatives." Journal of the American Chemical Society 141, 36 (August 2019): 14411-14420 © 2019 American Chemical Society
Version
Final published version
Abstract
A unified enantioselective total synthesis and anticancer evaluation of all known epoxide-containing communesin alkaloids and related derivatives is described. Our synthesis is predicated on the convergent and modular diazene-directed assembly of two complex 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 application of a rationally designed sulfinamide chiral auxiliary, an efficient calcium trifluoromethanesulfonate promoted intramolecular amination, and a diastereoselective epoxidation that simultaneously converts the new chiral auxiliary to a versatile amine protective group. The modularity of our convergent approach enabled the rapid synthesis of all epoxide-containing members of the communesin family from a single heterodimeric intermediate, including the first total synthesis of communesins C-E, and G-I, and facilitated our stereochemical revision of (-)-communesin I, the most recently isolated communesin alkaloid. Furthermore, the generality of our biogenetically inspired heterodimer rearrangement was demonstrated in a guided synthesis of a communesin derivative with an unnatural topology. Finally, we report the first comparative analysis of the anticancer activities of all naturally occurring communesin alkaloids A-I and eight complex derivatives against five human cancer cell lines. From these data, we have identified (-)-communesin B as the most potent natural communesin and discovered that derivatives with N8'-sulfonamide substitution exhibit up to a 10-fold increase in potency over the natural alkaloids.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1021/jacs.9b07397
