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Computationally Augmented Retrosynthesis: Total Synthesis of Paspaline A and Emindole PB

preprint
submitted on 09.11.2018, 17:30 and posted on 13.11.2018, 15:00 by Timothy Newhouse, Daria E. Kim, Joshua E. Zweig
The diverse molecular architectures of terpene natural products are assembled by exquisite enzyme-catalyzed reactions. Successful recapitulation of these transformations using chemical synthesis is hard to predict from first principles and therefore challenging to execute. A means of evaluating the feasibility of such chemical reactions would greatly enable the development of concise syntheses of complex small molecules. Herein, we report the computational analysis of the energetic favorability of a key bio-inspired transformation, which we use to inform our synthetic strategy. This approach was applied to synthesize two constituents of the historically challenging indole diterpenoid class, resulting in a concise route to (–)-paspaline A in 9 steps from commercially available materials and the first pathway to and structural confirmation of emindole PB in 13 steps. This work highlights how traditional retrosynthetic design can be augmented with quantum chemical calculations to reveal energetically feasible synthetic disconnections, minimizing time-consuming and expensive empirical evaluation.

Funding

NSF GRFP to J.E.Z.

History

Email Address of Submitting Author

timothy.newhouse@yale.edu

Institution

Yale University

Country

United States

ORCID For Submitting Author

0000-0001-8741-7236

Declaration of Conflict of Interest

No conflict of interest

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