Synergistic Catalysis for Asymmetric [3 + 2] Cycloadditions of 2-Indolylmethanols with α,β-Unsaturated Aldehydes

Abstract

A catalytic asymmetric [3 + 2] cycloaddition of 2-indolylmethanols with α,β-unsaturated aldehydes was developed for the first time. This transformation was achieved by a synergistic catalytic system consisting of a palladium complex, a Brønsted acid, and a chiral secondary amine to synthesize biologically active cyclopenta­[b]­indole derivatives with excellent diastereo- and enantioselectivities (up to >20:1 dr, up to 99% ee).

New Perspectives in the Indole Ring Functionalization using 2‐Indolylmethanols

“…This process has been recently implemented using enals as reagents in the reaction with indolylmethanols 33 jointly catalyzed by chiral pyrrolidine 43 and Pd 2 (dba) 3 (Scheme ) . The target hydroxyethylcyclopenta[ b ]indoles 44 are obtained in high anti diastereoselectivity and excellent enantioselectivity in a two‐step process involving a final reduction of the intermediate aldehyde with sodium borohydride.…”

Synthesis of C3-functionalized indole derivatives via Brønsted acid-catalyzed regioselective arylation of 2-indolylmethanols with guaiazulene

“…Recently, 2-indolylmethanols have been demonstrated as versatile platform molecules for the synthesis of indole-based heterocycles, through substitution reactions and cycloadditions. 11–22 It is universally acknowledged that 2-indolylmethanols can easily be converted into delocalized cation intermediates with carbocation resonance structures by the use of Brønsted or Lewis acids that act as a catalyst. For this reason, the regioselective substitution reactions of 2-indolylmethanols could lead to benzylic site functionalized 12,19 a ,20,21 or C3-functionalized indole derivatives.…”

“…For this reason, the regioselective substitution reactions of 2-indolylmethanols could lead to benzylic site functionalized 12,19 a ,20,21 or C3-functionalized indole derivatives. 16–22 Moreover, 2-indolylmethanols are also involved in cycloadditions, including [3 + 2], 13 [3 + 3], 14 and [4 + 3] 15 cyclizations, which are efficient methods to synthesize indole-fused cyclic derivatives.…”

Regio‐ and Enantioselective (3+3) Cycloaddition of Nitrones with 2‐Indolylmethanols Enabled by Cooperative Organocatalysis

“…In this context, we wondered whether 2-indolylmethanols could serve as suitable three-atom reaction partners to undergo organocatalytic asymmetric (3+ +3) cycloaddition with nitrones.T his consideration is based on our understanding of the chemistry of 2-indolylmethanols (Scheme 2). [11][12][13] In recent years,2 -indolylmethanols have proven to be versatile reactants in organocatalytic asymmetric reactions due to their unique property of C3 electrophilicity, [11] and they have been widely used in catalytic asymmetric C3-electrophilic substitutions [14] and cycloadditions [15] (Scheme 2a). However,i ns harp contrast, the C3 nucleophilicity of 2indolylmethanols has scarcely been reported, and the catalytic asymmetric C3-nucleophilic reactions of 2-indolylmethanols are rather underdeveloped (Scheme 2b).…”