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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. . (Unpublished)

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(+)-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:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Kerkovius, Jeff K.0000-0001-5692-0285
Houk, Kendall N.0000-0002-8387-5261
Reisman, Sarah E.0000-0001-8244-9300
Additional Information:The content is available under CC BY NC ND 4.0 License. May 27, 2022. 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 NMR facility at Caltech and the X-ray Crystallography Facility in the Beckman Institute at Caltech. Mona Shahgholi at the Multi User Mass Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering is acknowledged for their help in acquisition of HRMS data with instrumentation purchased by funds from DOW Next Generation Instrumentation and the NSF CRIF program. Dr. M. Takase and L. Henling are acknowledged for acquiring the X-ray diffraction data. We thank Y. Tao for assistance in solving X-ray structures. Dr. David Miller of the Arnold lab 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., grant PGSD3-532535-2019), and the National Institutes of Health (NIH) (F32 to A. T.). S.E.R. acknowledges financial support from the NIH (R35GM118191), and K. N. H. acknowledges the National Science Foundation (CHE-1764328). Author contributions: Project conceptualization: J.K.K. Funding acquisition: J.K.K, S.E.R. Experimental design and investigation: J.K.K., A.S., P.H.L, S.E.R. Computational design and investigation: A.T., K.N.H. Supervision: S.E.R., K.N.H. Manuscript writing and editing: JKK, AS, AT, SER, KNH. Authors declare that they have no competing interests. Data materials availability: X-ray structural data are available free of charge from the Cambridge Structural Database under CCDC 2159764-2159768, 2159770-2159774, and 2163777. All other data are available in the main text or supplementary materials.
Funding AgencyGrant Number
Dow Next Generation Educator FundUNSPECIFIED
Natural Sciences and Engineering Research Council of Canada (NSERC)PGSD3-532535-2019
NIH Postdoctoral FellowshipF32GM134709
Subject Keywords:matrine; isomatrine; lupin alkaloids; pyridine; dearomative annulation
Record Number:CaltechAUTHORS:20220718-76928700
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115672
Deposited By: Tony Diaz
Deposited On:20 Jul 2022 17:24
Last Modified:20 Jul 2022 17:24

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