A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids

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 Δ 1 -piperidine. Inspired by the biosynthesis, a new dearomative annulation reaction has been developed that leverages pyridine as a stable surrogate for Δ 1 -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. Main text:The lupin alkaloids are a structurally diverse class of quinolizidine-containing natural products isolated from plants in the Lupinus genus (Fig. 1A). 1 (+)-Matrine (2), the primary component of Chinese Kushen injection, inhibits proliferation in metastatic cancer cell lines and has also been investigated as a therapeutic agent against encephalomyelitis, asthma, arthritis, and osteoporosis. 2,3 (-)-Sophoridine ( 4) is an approved chemotherapeutic in China, which has also demonstrated antibiotic activity. 4 Little is known about the pharmacological properties of (+)-isomatrine (1) and (+)-isosophoridine (5), which likely reflects their limited accessibility from commercial vendors. 5Although the detailed enzymatic pathway has not been fully annotated, the biosynthesis of matrine is proposed to initiate with the enzymatic conversion of (-)-lysine (6) to Δ 1 -piperidine (7) (Fig. 1B). 6,7 Subsequent dimerization of 7 followed by oxidation and isomerization is proposed to yield quinolizidine 8, a shared biosynthetic precursor to several lupin alkaloids. 8,9 Mannich addition of 8 to a third equivalent of 7 and cyclization

Total Synthesis of Matrine Alkaloids

“…Until very recently, there were three reported total syntheses of (±)-matrine ( 2 ), one synthesis of (+)-allomatrine ( 3 ), and several other syntheses and semisyntheses of related molecules bearing the matrine tetracyclic core . A short time ago, the Reisman group described an elegant synthesis of the matrine framework in racemic form using pyridine as a building block for the B and D rings . This recent publication, which also demonstrates the feasibility of classical resolution, prompts the disclosure of our own approach, which leverages (a) the ability of dendralenes to rapidly generate target-relevant structural complexity (Figure B) and (b) the redox isomerization of amides and amines to drive successive strain-release epimerizations in a tetracyclic framework (Figure C).…”

Bioinspired Formal Synthesis of Pancracine via Selective Hydro­genation of an Indole Derivative

“…8 For example, the ruthenium catalysts (Figure 1a, left) with a chiral diamine ligand promote the highly stereoselective reduction of quinolines, [9][10][11][12] isoquinolines, 13 quinolizidines, 14 benzoxazines, 15 and indoles. 16,17 Hydrogenation of arenes has also been broadly utilized in the total synthesis of natural products, [18][19][20][21] further demonstrating the power of this strategy. Although more and more researchers are devoted to designing homogenous and heterogenous catalysts to achieve the chemo-and stereoselective hydrogenation of aromatic rings, [22][23][24][25][26][27][28][29][30][31][32][33][34][35] the stereoselective perhydrogenation of indole to saturated [6,5]-fused ring system is less explored due to the Synlett Letter / Cluster / New Tools Template for SYNLETT Thieme high energy necessary to break the aromaticity of both pyrrole and benzene ring.…”

“…8 For example, ruthenium catalysts with a chiral diamine ligand (Figure 1a, left) promote the highly stereoselective reduction of quinolines, [9][10][11][12] isoquinolines, 13 quinolizidines, 14 benzoxazines, 15 and indoles. 16,17 The hydrogenation of arenes has also been broadly utilized in total syntheses of natural products, [18][19][20][21] further demonstrating the power of this strategy.…”

A Pyridine Dearomatization Approach for the Gram Scale Synthesis of (±)-Sparteine

“…We recently reported the synthesis of isomatrine, matrine, and additional matrine alkaloids using a dearomative annulation reaction of pyridine (10). Mechanistic studies revealed that the cascade cyclization between 10 and glutaryl chloride (8) occurs via a stepwise pathway that could be interrupted by addition of methanol (Scheme 2a).…”

“…We recently reported the synthesis of isomatrine, matrine, and additional matrine alkaloids using a dearomative annulation reaction of pyridine ( 10 ). Mechanistic studies revealed that the cascade cyclization between 10 and glutaryl chloride ( 8 ) occurs via a stepwise pathway that could be interrupted by addition of methanol (Scheme a). , We hypothesized that if instead of methanol, intermediate 11 could be trapped with 4-pyridone ( 12 ), subsequent enolization and conjugate addition could form the sparteine tetracycle (Scheme b). Unfortunately, initial attempts to trap acid chloride 11 (formed in situ by the reaction of 8 with 10 ) with 2- or 4-pyridone led predominately to O -acylation.…”