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. 2022 Sep 7;144(35):15938-15943.
doi: 10.1021/jacs.2c06584. Epub 2022 Aug 25.

A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids

Jeff K Kerkovius  1 , Andrea Stegner  1 , Aneta Turlik  2 , Pik Hoi Lam  1 , Kendall N Houk  2 , Sarah E Reisman  1
Affiliations

A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids

Jeff K Kerkovius et al. J Am Chem Soc. .

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.

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Figures

Figure 1.
Figure 1.
(A) Chemical structures of matrine-type lupin alkaloids. (B) Proposed biosynthesis of matrine. (C) Retrosynthetic analysis of isomatrine.
Figure 2.
Figure 2.
(A) Diastereoselective cyclization of pyridine and glutaryl chloride. (B) Diastereoselective cyclization of (R)-2-methylpentandioyl chloride. (C) Proposed mechanism for the diastereoselective cyclization. (D) Reaction coordinate diagram – performed with Gaussian using ωB97XD/def2-TZVP/SMD(DCM).
Figure 3.
Figure 3.
(A) Complete total synthesis of isomatrine. (B) Attempted oxidation reactions.
Figure 4.
Figure 4.
Isomerization of (+)-isomatrine to additional matrine-type lupin alkaloids. Highlighted values are the isolated yields of the indicated products.
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References

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    1. No vendors were found to stock either (+)-isomatrine or (+)-isosophoridine as found by a CAS SciFinder supplier search (06/14/2022) and an eMolecule supplier search (06/14/2022).

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