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Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis

Dibrell, Sara E. and Tao, Yujia and Reisman, Sarah E. (2021) Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis. Accounts of Chemical Research, 54 (6). pp. 1360-1373. ISSN 0001-4842. PMCID PMC9169581. doi:10.1021/acs.accounts.0c00858.

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Conspectus: With complex molecular architectures, intriguing oxidation patterns, and wide-ranging biological activities, diterpene natural products have greatly impacted research in organic chemistry and drug discovery. Our laboratory has completed total syntheses of several highly oxidized diterpenes, including the ent-kauranoids maoecrystal Z, trichorabdal A, and longikaurin E; the antibiotic pleuromutilin; and the insecticides ryanodol, ryanodine, and perseanol. In this Account, we show how analysis of oxidation patterns and inherent functional group relationships can inform key C–C bond disconnections that greatly simplify the complexity of polycyclic structures and streamline their total syntheses. In articulating these concepts, we draw heavily from the approaches to synthetic strategy that were codified by Evans, Corey, Seebach, and others, based on the formalism that heteroatoms impose an alternating acceptor and donor reactivity pattern upon a carbon skeleton. We find these ideas particularly useful when considering oxidized diterpenes as synthetic targets. In the first part of the Account, we describe the use of reductive cyclizations as strategic tactics for building polycyclic systems with γ-hydroxyketone motifs. We have leveraged Sm-ketyl radical cyclizations as “reactivity umpolungs” to generate γ-hydroxyketones in our total syntheses of the Isodonent-kauranoid diterpenes (−)-maoecrystal Z, (−)-longikaurin E, and (−)-trichorabdal A. Following this work, we identified the same γ-hydroxyketone pattern in the diterpene antibiotic (+)-pleuromutilin, which again inspired the use of a SmI₂-mediated reductive cyclization, this time to construct a bridging eight-membered ring. This collection of four total syntheses highlights how reductive cyclizations are particularly effective umpolung tactics when used to simultaneously form rings and introduce 1,4-dioxygenation patterns. In the second part of the Account, we detail the syntheses of the complex and highly oxidized ryanodane and isoryanodane diterpenes and present the oxidation pattern analysis that guided our synthetic designs. We first discuss our 15-step total synthesis of (+)-ryanodol, which incorporated five of the eight oxygen atoms in just two transformations: a dihydroxylation of (S)-pulegone and a SeO₂-mediated trioxidation of the A-ring cyclopentenone. This latter transformation gave rise to an independent investigation of SeO₂-mediated peroxidations of simple bicyclic cyclopent-2-en-1-ones. The syntheses of (+)-ryanodine and (+)-20-deoxyspiganthine are also presented, which required modified end-game strategies to selectively incorporate the key pyrrole-2-carboxylate ester. Finally, we describe our fragment coupling approach to prepare the isoryanodane diterpene (+)-perseanol. Using a similar oxidation pattern analysis to that developed in the synthesis of ryanodol, we again identified a two-stage strategy to install the five hydroxyl groups. This strategy was enabled by a Pd-mediated carbopalladation/carbonylation cascade and leveraged unexpected, emergent reactivity to sequence a series of late-stage oxidations. While each of the diterpene natural products discussed in this Account present unique synthetic questions, we hope that through their collective discussion, we provide a conceptual framework that condenses and summarizes the chemical knowledge we have learned and inspires future discourse and innovations in strategy design and methodology development.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Dibrell, Sara E.0000-0003-0332-1101
Tao, Yujia0000-0003-4615-6409
Reisman, Sarah E.0000-0001-8244-9300
Additional Information:© 2021 American Chemical Society. Received: December 17, 2020; Publication Date: February 23, 2021. Published as part of the Accounts of Chemical Research special issue “Total Synthesis of Natural Products”. We would like to gratefully acknowledge the past and present members of the Reisman laboratory who have contributed to the science that is captured in this Account. Fellowship support was provided by the NSF (S.E.D., Grant No. DGE-1144469). S.E.R. is a Heritage Medical Research Institute Investigator. Financial support from the NIH (R35GM118191) is acknowledged. The authors declare no competing financial interest.
Group:Heritage Medical Research Institute
Funding AgencyGrant Number
NSF Graduate Research FellowshipDGE-1144469
Heritage Medical Research InstituteUNSPECIFIED
Subject Keywords:Redox reactions, Hydrocarbons, Alcohols, Oxidation, Cyclization
Issue or Number:6
PubMed Central ID:PMC9169581
Record Number:CaltechAUTHORS:20210224-121416493
Persistent URL:
Official Citation:Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis. Sara E. Dibrell, Yujia Tao, and Sarah E. Reisman. Accounts of Chemical Research 2021 54 (6), 1360-1373; DOI: 10.1021/acs.accounts.0c00858
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108172
Deposited By: Tony Diaz
Deposited On:24 Feb 2021 20:38
Last Modified:17 Aug 2022 16:36

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