Enantioselective Total Synthesis of Tricyclic Myrmicarin Alkaloids

Abstract

An enantioselective gram-scale synthesis of a key dihydroindolizine intermediate for the preparation of myrmicarin alkaloids is described. Key transformations in this convergent approach include a stereospecific palladium-catalyzed N-vinylation of a pyrrole with a vinyl triflate, a copper-catalyzed enantioselective conjugate reduction of a β-pyrrolyl enoate, and a regioselective Friedel-Crafts reaction. The synthesis of optically active and isomerically pure samples of (4aR)-myrmicarins 215A, 215B, and 217 in addition to their respective C4a-epimers is presented. The myrmicarins are a family of structurally fascinating alkaloids isolated from the poison gland secretions of the African ant species Myrmicaria opaciventris (Figure 1). 1 Despite significant isolation and purification challenges due to air and temperature sensitivity, elegant spectroscopic studies have revealed their molecular structures. 2 The pyrroloindolizine core of myrmicarins 215A (1), 215B (2), and 217 (3) is a common structural motif within many of these alkaloids. Within the family, only the absolute stereochemistry of myrmicarin 237A (4) has been secured through an enantioselective synthesis. 1a,3 Interestingly, the conversion of an unsaturated derivative of 4 to myrmicarin 217 (3) suggests the possible biogenesis of other myrmicarins from simpler indolizine derivatives. 1b,4 The synthesis of (R)-myrmicarin 217 (3) and (R)-myrmicarin 215 as a mixture of olefin isomers has been reported starting with D-glutamic acid. 5 The intriguing molecular structures of these poisonous alkaloids combined with challenges associated with their sensitivity provide an exciting arena to test and discover new methodologies for organic synthesis. Herein we describe a convergent synthesis of all naturally occurring tricyclic myrmicarin alkaloids employing an efficient approach to a pivotal optically active dihydroindolizine intermediate. The first preparation of isomerically pure samples of myrmicarins 215A and 215B is discussed. Key steps of the synthesis include an efficient palladium-catalyzed fragment coupling reaction, a copper catalyzed asymmetric conjugate reduction and a regioselective Friedel-Crafts reaction. We envisioned utilization of the optically active dihydroindolizine 7 as a key intermediate for the preparation of myrmicarin alkaloids (Scheme 1). A regioselective Friedel-Crafts reaction of the pyrrole ring (C7a-alkylation) upon Brönsted-acid activation of the dimethoxyacetal 8 and elimination of methanol was expected to afford the bicyclic vinyl pyrrole 7. We planned to use a metal-catalyzed enantioselective conjugate reduction of the β-pyrrolyl enoate 9 to introduce the C4a-stereochemistry. 6,7 A convergent synthesis of the pyrrolylenoate 9 was envisioned via a metal-catalyzed union of pyrrole 11 and readily available Z-vinyl triflate 10 (Scheme 1). The synthesis of the required β-pyrrolylenoate 9 began with the Claisen condensation of the lithium enolate 12 and methyl 4-(dimethoxy)-butyrate (13) 8 to give the β-ketoester 14 (Scheme 2). The lit...

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…It was noted that attempts to perform a copper-based coupling on these substrates were unsuccessful. [205] Kerr [206] carried out an intramolecular amination of aryl triflate 112 with a Pd 2 dba 3 / JohnPhos catalyst combination to form a dihydropyrrolo[3,2-e]indole as part of a synthetic studies on the synthesis of the CC-1065 CPI subunit, such natural products have been studied intensively for their antitumor properties (Scheme 47).…”

Dimerization of (+)-myrmicarin 215B. A potential biomimetic approach to complex myrmicarin alkaloids

“…We have recently reported a concise, enantioselective synthesis of all tricyclic myrmicarins (Scheme 4). 5,6 The key steps involve palladium-catalyzed coupling between triflate 19 and pyrrole 18 ,7,8 copper-catalyzed enantioselective conjugate reduction of the resulting N-vinyl pyrrole 17 ,9,10 and a regioselective acid catalyzed Friedel-Crafts cyclization to provide the dihydroindolizine 15 (Scheme 4). 5 Hydrogenation of the C6-C7 alkene in 15 (Scheme 4) and selective conversion of the tert-butyl ester to the corresponding primary iodide followed by a silver tetrafluoroborate promoted cyclization provides the tricyclic ketone 20 (Scheme 5).…”

“…5,6 The key steps involve palladium-catalyzed coupling between triflate 19 and pyrrole 18 ,7,8 copper-catalyzed enantioselective conjugate reduction of the resulting N-vinyl pyrrole 17 ,9,10 and a regioselective acid catalyzed Friedel-Crafts cyclization to provide the dihydroindolizine 15 (Scheme 4). 5 Hydrogenation of the C6-C7 alkene in 15 (Scheme 4) and selective conversion of the tert-butyl ester to the corresponding primary iodide followed by a silver tetrafluoroborate promoted cyclization provides the tricyclic ketone 20 (Scheme 5). 5 The final stages of the synthesis of myrmicarin 215B (4) involved reduction of the ketone 20 with lithium aluminum hydride at 0°C to afford the acid sensitive tricyclic alcohol 21 as an equal mixture of C8-epimers (Scheme 5).…”

“…5 Hydrogenation of the C6-C7 alkene in 15 (Scheme 4) and selective conversion of the tert-butyl ester to the corresponding primary iodide followed by a silver tetrafluoroborate promoted cyclization provides the tricyclic ketone 20 (Scheme 5). 5 The final stages of the synthesis of myrmicarin 215B (4) involved reduction of the ketone 20 with lithium aluminum hydride at 0°C to afford the acid sensitive tricyclic alcohol 21 as an equal mixture of C8-epimers (Scheme 5). Acid catalyzed dehydration of alcohol 21 gave exclusively myrmicarin 215B (4).…”

“…5 The synthesis of the acid sensitive C8-C9 Z-alkene of myrmicarin 215A (3) was possible by an initial dehydration of ketone 20, using 2-chloro-3-ethylbenzoxazolium tetrafluoroborate, 11 followed by partial hydrogenation with Lindlar catalyst. 5 These stereoselective routes to the vinyl pyrroloindolizine structure provided access to the first pure samples of myrmicarins 215A (3) and 215B (4). Complete reduction of the C3-carbonyl of 20 using lithium aluminum hydride at high temperature provided myrmicarin 217 (6).…”