Stereoselective Total Synthesis of Eburnane‐Type Alkaloids Enabled by Conformation‐Directed Cyclization and Rearrangement

Abstract

Controlling the cis C20/C21 relative stereochemistry remains an unsolved issue in the synthesis of eburnane‐type indole alkaloids. Provided herein is a simple solution to this problem by developing a unified and diastereoselective synthesis of four representative members of this class of natural products, namely, eburnamonine, larutensine, terengganensine B, and melokhanine E. The synthesis features the following key steps: a) an α‐iminol rearrangement transforming the 3‐hydroxyindolenine into spiroindolin‐3‐one, b) a highly diastereoselective conformation‐directed cyclization leading to the melokhanine skeleton with the desired C20/C21 cis stereochemistry, and c) either an aza‐pinacol or an unprecedented α‐aminoketone rearrangement converting spiroindolinone back into the indole skeleton.

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′‐epi‐Leucophyllidine

“…[7] Dimeric alkaloids generally exhibit stronger biological activities than their component monomers, [8] and though the mechanisms of action are poorly understood, they are hypothesized to promote higher target affinity or greater stabilization of protein-protein interactions. [9] Despite successful synthesis of both eucophylline (5) [10,11] and eburnamine (6) [12,13] no successful synthesis of leucophyllidine (1) has been completed to date. A report from Pandey and coworkers details an assumed "biomimetic" Friedel-Crafts alkylation that generated isoleucophyllidine 7 as the exclusive product (Scheme 1 b, right).…”

Catalytic Enantioselective Aminopalladation–Heck Cascade

“…Compound 9 , unstable in solution, was readily converted to the hemiacetal 10 via presumably its epimeric aminal 9′ . The structures of 9 and 10 are reminiscent of the rearranged eburnane alkaloids [29] …”

Recent development and applications of semipinacol rearrangement reactions

“…Next, an oxidative rearrangement of 92 was designed and realized to transform the fused tetrahydro-pyrido indole ring system into a spirooxindole compound 96. From precedent studies, [71][72][73] this cascade reaction may involve the initial formation of b-chlorinated hemiaminal 94 from indole chlorination product 93. Then, an intermediate benzylic carbocation 95 would presumably be formed from 94 and trigger the following ring-contraction semipinacol rearrangement to afford 96 in 75% yield.…”