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.

Organocatalytic Asymmetric C(sp2)−H Allylic Alkylation: Enantioselective Synthesis of Tetrasubstituted Allenoates

“…While metal‐catalyzed asymmetric reactions showed great ability in synthesis of chiral allenes, [6] organocatalytic asymmetric tools also demonstrated their practicability, but these organocatalytic methods still remain limited [7, 8] . Most organocatalytic processes handled synthesis of di‐ or trisubstituted allenes, [7a–g] and those synthetic accesses to chiral tetrasubstituted allenes are rare [7h–n, 8] . Among various approaches for chiral allenes, enantioselective functionalization of racemic allenes is an attractive and challenging one.…”

Recent Advances in Metal‐Catalyzed Functionalization of Indoles

“…In 2020, the Wang group reported enantioselective dearomatization of indoles via γ ‐addition to β,γ‐alkynyl‐α‐imino esters under mild conditions (Scheme 13). [28] The reaction generates a tetrasubstituted allene moiety at the C3 position and proceeds with impressive levels of regio‐, enantio‐ and diastereocontrol. The method works well for 2,3‐disubstituted indoles and β,γ‐alkynyl‐α‐imino esters in the presence of a chiral phosphoric acid catalyst (10 mol%) in DCE at 0 °C.…”

“… Enantioselective C3−H dearomatization of indoles with α‐amino allenoates by Wang [28] …”

Chiral Spirocyclic Phosphoric Acids and Their Growing Applications

“…Sun and Wang developed the first enantioselective synthesis of tetrasubstituted α‐amino allenoates through (S)‐ SPA 5 catalyzed dearomative γ‐addition reaction of 2,3‐disubstituted indoles to β,γ‐alkynyl‐α‐imino esters (Scheme 65). [ 69 ] A variety of highly functionalized tetrasubstituted allenes featuring quaternary stereocenters were provided in high yields (up to 99%), with generally excellent diastereo‐, and enantioselectivities (>20 : 1 dr, up to 99% ee) without by‐product formation. The consequent amino allenoates could be easily converted into other important building blocks as the synthesis of cyclopenta‐[ b ]indolines and a 4 H ‐1,4‐ methanoquinoline.…”