Total Synthesis of Matrine Alkaloids

Abstract

The total synthesis of three diastereomeric matrine natural products is reported. The eight-step synthesis commences with simple acyclic precursors, forms all four rings of the tetracyclic natural product framework and forges ten of the twenty covalent bonds of the target structure. The chemical synthesis adopts an unprecedented strategy that encompasses both transform and stereochemical attributes. A cross-conjugated triene is positioned at the core of an acyclic branched structure, which collapses to the tetracyclic natural product framework through an orchestrated sequence of two intramolecular cycloadditions. A subsequent, late-stage hydrogenation is accompanied by strain-release redox epimerizations to deliver the three natural products. Semisynthetic manipulations of matrine provide access to ten additional natural products.

A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids

“…Therefore, we anticipated that access to 1 could enable the synthesis of additional lupin alkaloids . This type of late-stage isomerization strategy was also deployed in the 2022 Sherburn synthesis of several matrine alkaloids …”

“…Synthetically, most of the work prior to 2022 had focused on matrine ( 2 ), with four reported total syntheses. − Synthetic access to the minor congeners is far more limited: until a recent report by Sherburn and co-workers, there was a single total synthesis each of allomatrine ( 3 ) and isosophoridine ( 5 ), and no reported total syntheses of isomatrine or sophoridine ( 4 ). , We sought to devise a unified synthesis that could provide access to the series of matrine-type alkaloids shown in Figure A. Inspired by the proposed biosynthesis, it was envisioned that pyridine ( 14 ) could serve as a stable, inexpensive synthon for Δ 1 -piperidine ( 7 ), and the remaining five carbons of the tetracyclic matrine framework could derive from glutaryl chloride ( 15 , Figure C).…”