Organocatalytic Enantioselective Synthesis of Tetrasubstituted α‐Amino Allenoates by Dearomative γ‐Addition of 2,3‐Disubstituted Indoles to β,γ‐Alkynyl‐α‐imino Esters

Abstract

The first asymmetric synthesis of tetrasubstituted α‐amino allenoates by a chiral phosphoric acid catalyzed dearomative γ‐addition reaction of 2,3‐disubstituted indoles to β,γ‐alkynyl‐α‐imino esters is reported. This method provides access to a series of highly functionalized tetrasubstituted allenes featuring quaternary stereocenters in high yields, and with excellent regio‐, diastereo‐, and enantioselectivities under mild conditions without by‐product formation. Representative large‐scale reactions and diverse transformations of the products into various scaffolds with potential biological activities render are also disclosed. The mechanism of the reaction was elucidated by control reactions and DFT calculations.

Progresses in organocatalytic asymmetric dearomatization reactions of indole derivatives

“…Recently, Wang, Sun and coworkers employed β,γ-alkynylα-imino esters 162 as electrophiles to react with C3,C2-substituted indoles 129 in the presence of CPA (S)-C30, thus realizing an organo-CADA addition of C3,C2-substituted indoles (Scheme 36). 67 More importantly, this dearomative reaction occurred with a selectivity of γ-addition, thus generating products 163 bearing a quaternary stereogenic center with central chirality and a moiety of tetrasubstituted α-aminoallenoate with axial chirality. In fact, the simultaneous construction of two elements of chirality has become a hot topic in catalytic asymmetric synthesis.…”

“…Scheme 36 Organo-CADA addition of C3,C2-substituted indoles with β,γ-alkynyl-α-imino esters by Wang, Sun and coworkers. 67 Scheme 37 Organo-CADA reduction of C3,C2-substituted indoles by Chen, Sun, Wang and coworkers. 70,71 by L-B*, which was followed by a hydrogen transfer to give final products 165.…”

Chiral phosphoric acid-catalyzed regio- and enantioselective reactions of functionalized propargylic alcohols

“…14b Recently, Sun and Wang et al realized a CPAcatalyzed γ-addition of 2,3-disubstituted indoles to β,γ-alkynylα-imino esters. 15 With the aid of CPA, we also established an enantioselective γ-addition of isoxazol-5(4H)-ones to β,γ-alkynyl-α-imino esters. 16 Based on these results and in continuation of our efforts on the organocatalytic reactions of propargylic alcohols, we became highly interested in developing organocatalytic regio-and enantioselective reactions of α- (3isoindolinonyl) propargylic alcohols (Scheme 1E).…”

Brønsted acid–catalyzed asymmetric dearomatization for synthesis of chiral fused polycyclic enone and indoline scaffolds

“…However, these reactions generally depend on the transition metals (Fig. 2B, left), except those based on electron-deficient alkynes involving Michael-type addition (40)(41)(42), in which chiral BAs did not directly activate the carbon-carbon triple bonds (Fig. 2B, middle).…”