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A Customizable Approach for the Enzymatic Production and Purification of Diterpenoid Natural Products
Published on: October 4, 2019
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Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis
Sara E Dibrell1, Yujia Tao1, Sarah E Reisman1
1The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
Accounts of Chemical Research
|February 23, 2021
Summary
This study demonstrates how analyzing oxidation patterns and functional group relationships simplifies complex diterpene natural product synthesis. Reductive cyclizations and strategic oxidation analyses streamline the creation of molecules like ryanodol and pleuromutilin.
Area of Science:
- Organic Chemistry
- Natural Product Synthesis
- Medicinal Chemistry
Background:
- Diterpene natural products possess complex molecular architectures, unique oxidation patterns, and diverse biological activities, making them significant targets in organic chemistry and drug discovery.
- Previous research has focused on the total synthesis of various diterpenes, but simplifying strategies for highly oxidized polycyclic structures remains a challenge.
Purpose of the Study:
- To present a conceptual framework for the total synthesis of complex diterpene natural products by analyzing oxidation patterns and functional group relationships.
- To showcase the application of reductive cyclizations and strategic oxidation analyses in streamlining synthetic routes to highly oxidized diterpenes.
Main Methods:
- Utilized reductive cyclizations, specifically samarium (Sm)-ketyl radical cyclizations and SmI2-mediated reactions, to construct polycyclic systems with γ-hydroxyketone motifs.
- Employed oxidation pattern analysis to guide synthetic design, including dihydroxylation and selenium dioxide (SeO2)-mediated trioxidation for installing multiple oxygen atoms efficiently.
- Applied fragment coupling strategies and palladium (Pd)-mediated carbopalladation/carbonylation cascades for assembling complex molecular frameworks.
Main Results:
- Successfully synthesized highly oxidized diterpenes including ent-kauranoids (maoecrystal Z, trichorabdal A, longikaurin E), pleuromutilin, ryanodol, ryanodine, and perseanol.
- Demonstrated that reductive cyclizations are effective umpolung tactics for simultaneous ring formation and 1,4-dioxygenation.
- Showcased strategic oxidation analyses that enabled the installation of multiple hydroxyl groups in few steps, significantly simplifying synthetic pathways.
Conclusions:
- Analysis of oxidation patterns and functional group relationships provides a powerful strategy for simplifying complex polycyclic diterpene synthesis.
- Reductive cyclizations and targeted oxidation strategies offer efficient routes to highly oxygenated natural products, advancing synthetic methodology.
- The presented conceptual framework and synthetic approaches inspire future innovations in natural product synthesis and drug discovery.
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