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A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids

Kerkovius, Jeff K. and Stegner, Andrea and Turlik, Aneta and Lam, Pik Hoi and Houk, Kendall N. and Reisman, Sarah E. (2022) A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids. Journal of the American Chemical Society, 144 (35). pp. 15938-15943. ISSN 0002-7863. doi:10.1021/jacs.2c06584. https://resolver.caltech.edu/CaltechAUTHORS:20220909-232904000

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Abstract

(+)-Matrine and (+)-isomatrine are tetracyclic alkaloids isolated from the plant Sophora flavescens, the roots of which are used in traditional Chinese medicine. Biosynthetically, these alkaloids are proposed to derive from three molecules of (−)-lysine via the intermediacy of the unstable cyclic imine Δ1-piperidine. Inspired by the biosynthesis, a new dearomative annulation reaction has been developed that leverages pyridine as a stable surrogate for Δ1-piperidine. In this key transformation, two molecules of pyridine are joined with a molecule of glutaryl chloride to give the complete tetracyclic framework of the matrine alkaloids in a single step. Using this dearomative annulation, isomatrine is synthesized in four steps from inexpensive commercially available chemicals. Isomatrine then serves as the precursor to additional lupin alkaloids, including matrine, allomatrine, isosophoridine, and sophoridine.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.2c06584DOIArticle
https://resolver.caltech.edu/CaltechAUTHORS:20220718-76928700Related ItemDiscussion Paper
ORCID:
AuthorORCID
Kerkovius, Jeff K.0000-0001-5692-0285
Stegner, Andrea0000-0001-9408-3967
Turlik, Aneta0000-0002-0907-8969
Houk, Kendall N.0000-0002-8387-5261
Reisman, Sarah E.0000-0001-8244-9300
Additional Information:The California Institute of Technology Center for Catalysis and Chemical Synthesis is gratefully acknowledged for access to analytical equipment. We thank the Dow Next Generation Educator Funds and Instrumentation Grants for their support of the Beckman Institute X-ray Crystallography Facility at Caltech, as well as the Caltech CCE NMR facility and Multiuser Mass Spectrometry Laboratory, which is also supported by the NSF CRIF program (No. CHE-0541745). Dr. M. Shahgholi is acknowledged for acquisition of HRMS data. Dr. Michael Takase and Larry Henling are acknowledged for acquiring the X-ray diffraction data, and Yujia Tao is thanked for assistance in solving X-ray structures. Dr. David Miller of the Arnold Laboratory at Caltech is acknowledged for his help in running the P450 enzyme oxidation screen. Fellowship support was provided by the Natural Sciences and Engineering Research Council (NSERC) of Canada (PGS-D fellowship to J.K.K. (under Grant No. PGSD3-532535-2019), and the National Institutes of Health (NIH) (No. F32GM134709 to A.T.). S.E.R. acknowledges financial support from the NIH (No. R35GM118191), and K.N.H. acknowledges the National Science Foundation (No. CHE-1764328).
Funders:
Funding AgencyGrant Number
Dow Next Generation Educator FundUNSPECIFIED
NSFCHE-0541745
Natural Sciences and Engineering Research Council of Canada (NSERC)PGSD3-532535-2019
NIH Postdoctoral FellowshipF32GM134709
NIHR35GM118191
NSFCHE-1764328
Issue or Number:35
DOI:10.1021/jacs.2c06584
Record Number:CaltechAUTHORS:20220909-232904000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220909-232904000
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:116884
Collection:CaltechAUTHORS
Deposited By: Olivia Warschaw
Deposited On:29 Oct 2022 21:12
Last Modified:29 Oct 2022 21:12

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