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Enantioselective, convergent synthesis of the ineleganolide core by a tandem annulation cascade

Craig, Robert A., II and Roizen, Jennifer L. and Smith, Russell C. and Jones, Amanda C. and Virgil, Scott C. and Stoltz, Brian M. (2017) Enantioselective, convergent synthesis of the ineleganolide core by a tandem annulation cascade. Chemical Science, 8 (1). pp. 507-514. ISSN 2041-6520. PMCID PMC5321630; PMC6349058. https://resolver.caltech.edu/CaltechAUTHORS:20160908-102036330

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Abstract

An enantioselective and diastereoselective approach toward the synthesis of the polycyclic norditerpenoid ineleganolide is disclosed. A palladium-catalyzed enantioselective allylic alkylation is employed to stereoselectively construct the requisite chiral tertiary ether and facilitate the synthesis of a 1,3-cis-cyclopentenediol building block. Careful substrate design enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold by a diastereoselective cyclopropanation–Cope rearrangement cascade under unusually mild conditions. Computational evaluation of ground state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures. This work represents the first successful synthesis of the core structure of any member of the furanobutenolide-derived polycyclic norcembranoid diterpene family of natural products. Advanced synthetic manipulations generated a series of natural product-like compounds that were shown to possess selective secretory antagonism of either interleukin-5 or interleukin-17. This bioactivity stands in contrast to the known antileukemic activity of ineleganolide and suggests the norcembranoid natural product core may serve as a useful scaffold for the development of diverse therapeutics.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1039/c6sc03347dDOIArticle
https://doi.org/10.1039/c8sc90236dDOICorrection
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321630PubMed CentralArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349058PubMed CentralCorrection
ORCID:
AuthorORCID
Roizen, Jennifer L.0000-0002-6053-5512
Jones, Amanda C.0000-0001-8426-8407
Stoltz, Brian M.0000-0001-9837-1528
Additional Information:© 2016 The Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Received 28 Jul 2016, Accepted 15 Aug 2016, First published online 17 Aug 2016. The authors wish to thank the NIH-NIGMS (R01GM080269), Amgen, the Gordon and Betty Moore Foundation, and Caltech for financial support and Eli Lilly & Co. for assistance with biological activity screening. Additionally, the authors gratefully acknowledge Larry Henling and Dr Michael Takase (Caltech) for X-ray crystallographic structural determination, Dr Mona Shahgholi and Naseem Torian (Caltech) for mass spectrometry assistance, and Dr David VanderVelde (Caltech) for NMR experimental assistance and helpful discussions. Additionally, Dr Jeffrey C. Holder, Dr Corey M. Reeves, Prof. Hosea M. Nelson, Dr Jonny R. Gordon, Dr Pamela M. Tadross, and Beau P. Pritchett (Caltech) and Dr Ryan Deluca and Dr Nick Cox (Stanford) are thanked for helpful discussions. R. A. C. gratefully acknowledges the support of this work provided by a fellowship from the National Cancer Institute of the National Institutes of Health (NIH) under Award Number F31A17435. J. L. R. thanks the California Tobacco-Related Disease Research Program of the University of California, Grant Number 14DT-0004 for a predoctoral fellowship. A. C. J. thanks the NIH for the support of this work provided by a postdoctoral fellowship (Award Number F32GM082000).
Errata:Since publication of the original manuscript, the authors have carried out some additional research and can now unambiguously confirm the reassignment of a few late-stage, intermediate compounds that were incorrectly assigned in the original manuscript. Specifically, they have obtained an X-ray structure of the product of Amberlyst® treatment of the mixture of compounds 32 and S2 and the product obtained is epimeric at C7. To avoid confusion, this new product is called product ent-12A. An updated and corrected Scheme 5 is provided below. Scheme 1 Synthesis of ent-isoineleganolide A (29) and X-ray crystal structure of ent-epi-isoineleganolide B (ent-12A). Additional Supplementary Information is provided, containing details of the newly solved X-ray crystal structure. For a complete discussion, please see the authors’ recently published account of their research program toward the enantioselective synthesis of ineleganolide.
Funders:
Funding AgencyGrant Number
NIHR01GM080269-01
AmgenUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
CaltechUNSPECIFIED
NIH Predoctoral FellowshipF31A174359
California Tobacco-Related Disease Research Program14DT-0004
NIH Postdoctoral FellowshipF32GM082000
Issue or Number:1
PubMed Central ID:PMC5321630; PMC6349058
Record Number:CaltechAUTHORS:20160908-102036330
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160908-102036330
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:70204
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:08 Sep 2016 18:13
Last Modified:03 Oct 2019 10:28

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