4.8 Article

Total Synthesis of Aflastatin A

Journal

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c08244

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Funding

  1. National Institutes of Health [GM033327-19, GM081546-03]
  2. National Science Foundation
  3. Novartis
  4. Austrian Science Fund (FWF) [J2763-N17]
  5. NIH
  6. NSF
  7. German Academic Exchange Service (DAAD)
  8. Amgen
  9. Merck Research Laboratories

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The total syntheses of aflastatin A and its C3-C48 degradation fragment have been achieved, revealing a structural misassignment in the naturally derived degradation product. The revised absolute configurations of six stereogenic centers were also confirmed in this study.
The total syntheses of aflastatin A and its C3-C48 degradation fragment (6a, R = H) have been accomplished. The syntheses feature several complex diastereoselective fragment couplings, including a Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, a chelate-controlled aldol reaction involving soft enolization with magnesium, and an anti-Felkin-selective boron-mediated oxygenated aldol reaction. Careful comparison of the spectroscopic data for the synthetic C3-C48 degradation fragment to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. Ultimately, the data reported for the naturally derived aflastatin A C3-C48 degradation lactol (6a, R = H) were attributed to its derivative lactol trideuteriomethyl ether (6c, R = CD3). Additionally, the revised absolute configurations of six stereogenic centers (C8, C9, and C28-C31) were confirmed.

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