Total Synthesis of Matrine Alkaloids

Abstract

The total synthesis of three diastereomeric matrine natural products is reported. The 8-step synthesis commences with simple acyclic precursors, forms all 4 rings of the tetracyclic natural product framework, and forges 10 of the 20 covalent bonds of the target structure. A cross-conjugated triene is positioned at the core of an acyclic branched structure. This precursor collapses to the tetracyclic natural product framework through an orchestrated sequence of two separate intramolecular cycloadditions. A subsequent, late-stage hydrogenation is accompanied by strain-release redox epimerizations to deliver the three natural products. An unprecedented carba-analogue is prepared in the same way. Semisynthetic manipulations of matrine provide access to 10 additional natural products.

Sustained release of matrine via salt formation with hesperetin

“…MAT is an enantiomerically pure chiral compound. 33,34 Thus, it is a normal result for MAT-HES to crystallize in the chiral space group. An immediate expectation for this result is that one specific enantiomer of racemic HES has been selectively crystallized in the salt.…”

A Rapid Aza-Bicycle Synthesis from Dendralenes and Imines

“…The synthetic application of aza-dienophiles in intramolecular diene-transmissive sequences was recently demonstrated. 9 The present work sets the scene for total synthesis applications involving the corresponding intermolecular process.…”

“…A recent example of this sequence in total synthesis 4−8 is depicted in Scheme 1a, which summarizes the preparation of the tetracyclic framework of the alkaloid matrine. 9 The key steps (1 → 2, 3 → 4) involve intramolecular aza-Diels−Alder reactions of a substituted [3]dendralene. 10,11 Such conversions, called diene-transmissive Diels−Alder (DTDA) sequences, 12,13 have been studied extensively with carbo-dienophiles 14−18 but rarely with hetero-dienophiles.…”

“…[3]­Dendralenes undergo a sequence of two Diels–Alder reactions with dienophiles, hence generating a new bicyclic system and four covalent bonds. A recent example of this sequence in total synthesis − is depicted in Scheme a, which summarizes the preparation of the tetracyclic framework of the alkaloid matrine . The key steps ( 1 → 2 , 3 → 4 ) involve intramolecular aza-Diels–Alder reactions of a substituted [3]­dendralene. , Such conversions, called diene-transmissive Diels–Alder (DTDA) sequences, , have been studied extensively with carbo-dienophiles − but rarely with hetero-dienophiles. − In fact, the two intramolecular aza-Diels–Alder reactions in Scheme a are, to our knowledge, the only examples involving dendralenes in the literature.…”

“…This process permits rapid access to various octahydroisoquinoline ring systems through diene-transmissive Diels–Alder sequences that are both regioselective and diastereoselective and both step and atom economic. The synthetic application of aza-dienophiles in intra molecular diene-transmissive sequences was recently demonstrated . The present work sets the scene for total synthesis applications involving the corresponding intermolecular process.…”