A Pyridine Dearomatization Approach to the Matrine-type Lupin Alkaloids

Kerkovius, Jeff K.; Stegner, Andrea; Turlik, Aneta; Lam, Pik Hoi; Houk, Kendall N.; Reisman, Sarah E.

doi:10.26434/chemrxiv-2022-0v94t

Published May 27, 2022 | Version Supplemental Material + Submitted

Discussion Paper Open

A Pyridine Dearomatization Approach to the Matrine-type Lupin Alkaloids

1. California Institute of Technology
2. University of California, Los Angeles

(+)-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.

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.

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Submitted - a-pyridine-dearomatization-approach-to-the-matrine-type-lupin-alkaloids.pdf

Supplemental Material - supplementary-materials-experimental-procedures.pdf

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