Highly Efficient Formal [2+2+2] Strategy for the Rapid Construction of Polycyclic Spiroindolines: A Concise Synthesis of 11‐Demethoxy‐16‐epi‐myrtoidine

Abstract

A novel formal [2+2+2] strategy for the stereoselective elaboration of polycyclic indole alkaloids is described. Upon treatment with the catalyst InCl3 (5 mol %), tryptamine-derived enamides reacted readily with methylene malonate, thus enabling rapid and gram-scale access to versatile tetracyclic spiroindolines with excellent diastereoselectivity (21 examples, up to 95 % yield, up to d.r.>95:5). This strategy provides a concise approach to alkaloids isolated from Strychnos myrtoides, as demonstrated by a short synthesis of 11-demethoxy-16-epi-myrtoidine.

Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization

“…Prior to their endeavor in the donor–acceptor cyclobutane strategy, Tang and co‐workers have described a formal [2+2+2]‐cycloaddition approach towards tetracyclic indolines 140 . Starting from tosyl enamines 137 , an intermolecular conjugate addition to methylene malonate 138 occurs.…”

Selectivity Switch in a Rhodium(II) Carbene Triggered Cyclopentannulation: Divergent Access to Three Polycyclic Indolines

“…Consistent with the better thermal stability of 4 a (Scheme b), reactions heated in either DCM or DCE delivered 4 a (entries 7–9). A higher yield of 4 a was obtained by lowering the InCl 3 loading (entry 10), probably because of the suppression of the Pictet–Spengler reaction of 1 a and the formation of 6 a . Moreover, reactions performed at −15 °C in DCM gave the 5 a in 78 % yield with 97:3 r.r.…”

Tandem Cross‐Coupling/Spirocyclization/Mannich‐Type Reactions of 3‐(2‐Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines

“…However, most strategies rely on the design of intramolecular reactions, and the intermolecular version is less studied possibly due to the unfavorable entropic factors and stereochemical control. To our knowledge, only a few intermolecular approaches have so far been reported (Scheme b), such as formal [2+2+2]‐cycloaddition reaction between tosyl enamines with methylene malonate; [4+2] annulation/Mitsunobu cascade reaction of tryptamine derivative and donor‐acceptor cyclobutene; [4+2] cycloaddition‐conjugate addition cascade reaction of 2‐vinyltryptamine with propynal;– lactam opening‐double aza‐Michael addition cascade reaction of spirodienone with primary amines,– and Pictet‐Spengler/[3,3]‐sigmatropic rearrangement/Pictet‐Spengler cascade reaction of tryptamine derivative with α,β‐unsaturated aldehyde –. Despite these significant achievements, the preparation of substrates often needs tedious steps, and the structure diversity of the current synthetic methods is still limited.…”

“…Despite these significant achievements, the preparation of substrates often needs tedious steps, and the structure diversity of the current synthetic methods is still limited. In particular, strategies that are capable of constructing tetracyclic spiroindolines with trans ‐fused C/D ring systems have only rarely been reported . As a result, seeking alternative protocols for the rapid (one‐step or two‐step) and highly stereoselective construction of [6,5,5,6] ABCD tetracyclic skeleton with diverse substitution and fusion patterns from readily available starting materials is highly desirable.…”

“…Some indole alkaloids exhibited highprofile biological activities and have been developed as clinically useful antitumor drugs for chemotherapy (for example, vinblastine and vincristine). [2] Given the unique structures and potential great value of such indole alkaloids as well as their analogues in drug discovery, the development of efficient and practical methods to access their common [6,5,5,6] ABCD ring system has attracted enormous research attention from the synthetic community. Therefore, not surprisingly, a variety of strategies have been established.…”