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Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade

Craig, Robert A., II and Smith, Russell C. and Roizen, Jennifer L. and Jones, Amanda C. and Virgil, Scott C. and Stoltz, Brian M. (2018) Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade. Journal of Organic Chemistry, 83 (7). pp. 3467-3485. ISSN 0022-3263. PMCID PMC5889334. https://resolver.caltech.edu/CaltechAUTHORS:20180327-133635374

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Abstract

An enantioselective and diastereoselective approach toward the synthesis of the tetracyclic scaffold of the furanobutenolide-derived polycyclic norditerpenoids is described. Focusing on synthetic efforts toward ineleganolide, the synthetic approach utilizes a palladium-catalyzed enantioselective allylic alkylation for the construction of the requisite chiral tertiary ether. A diastereoselective cyclopropanation–Cope rearrangement cascade enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold. Investigation of substrates for this critical tandem annulation process is discussed along with synthetic manipulations of the [6,7,5,5]-tetracyclic scaffold and the attempted interconversion of the [6,7,5,5]-tetracyclic scaffold of ineleganolide to the isomeric [7,6,5,5]-core of scabrolide A and its naturally occurring isomers. 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acs.joc.7b02825DOIArticle
https://pubs.acs.org/doi/suppl/10.1021/acs.joc.7b02825PublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889334PubMed CentralArticle
ORCID:
AuthorORCID
Craig, Robert A., II0000-0002-2435-1564
Roizen, Jennifer L.0000-0002-6053-5512
Jones, Amanda C.0000-0001-8426-8407
Virgil, Scott C.0000-0001-8586-5641
Stoltz, Brian M.0000-0001-9837-1528
Additional Information:© 2018 American Chemical Society. Received: December 4, 2017; Published: February 21, 2018. We 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, we 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, Prof. Sarah Reisman, 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) 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 No. F31A17435. J.L.R. thanks the California Tobacco-Related Disease Research Program of the University of California, Grant No. 14DT-0004 for a predoctoral fellowship. A.C.J. thanks the NIH for the support of this work provided by a postdoctoral fellowship (Award No. F32GM082000).
Funders:
Funding AgencyGrant Number
NIHR01GM080269
AmgenUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
CaltechUNSPECIFIED
Eli Lilly and Co.UNSPECIFIED
NIH Predoctoral FellowshipF31A17435
California Tobacco-Related Disease Research Program14DT-0004
NIH Postdoctoral FellowshipF32GM082000
Issue or Number:7
PubMed Central ID:PMC5889334
Record Number:CaltechAUTHORS:20180327-133635374
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180327-133635374
Official Citation:Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade. Robert A. Craig, II, Russell C. Smith, Jennifer L. Roizen, Amanda C. Jones, Scott C. Virgil, and Brian M. Stoltz. The Journal of Organic Chemistry 2018 83 (7), 3467-3485. DOI: 10.1021/acs.joc.7b02825
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85462
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:27 Mar 2018 21:01
Last Modified:14 Apr 2020 15:52

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