A chiral Brønsted acid-catalyzed highly enantioselective Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines

Abstract

A chiral phosphoric acid-catalyzed asymmetric Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines, derived from 3-hydroxyisoindolinones has been demonstrated in this communication. A variety of isoindolinone-based α-amino diazo esters bearing a quaternary stereogenic center were afforded in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the products has been depicted by the hydrogenation of the diazo moiety of adducts.

Enantioselective Addition of Enamides to Cyclic Ketimines: Access to Chiral 3,3‐Disubstituted Isoindolin‐1‐Ones

“…Hayashi and co‐workers developed a rhodium‐catalyzed asymmetric arylation of 3‐hydroxyisoindolinones by employing arylboroxines as nucleophiles. Both research groups of Hu and Singh described the asymmetric alkylation of 3‐hydroxyisoindolinones with oxonium ylides or α‐diazo esters. Considering the limited availability of successful carbon nucleophiles, it remains highly demanded to explore enantioselective addition of 3‐hydroxyisoindolinone‐derived cyclic N ‐carbonyl ketimines with other types of carbon nucleophile.…”

“…[2] As a result, their asymmetric synthesis has attracted increasing attention in recent years. Among the established methods for the synthesis of chiral 3,3-disubstituted isoindolinones, [3][4][5][6][7][8][9] a particularly straightforward approach is the catalytic enantioselective addition of nucleophilic partners to cyclic Ncarbonyl ketimines, which were generated in situ by dehydration of 3-hydroxyisoindolinones (Scheme 1b). Followed this concept, the research groups of Zhou [4a] and Gredičak [4b] reported the asymmetric addition of indoles to 3-hydroxyisoindolinone-derived cyclic Ncarbonyl ketimines.…”

Catalytic Asymmetric Synthesis of Isoindolinones

“…α‐Diazocarbonyl compounds are important structural motifs in synthetic organic chemistry . In 2018, Singh and co‐workers established an asymmetric Mannich‐type process employing α‐diazo esters as the nucleophiles under ambient conditions (Scheme ). It is noteworthy that 4 Å molecular sieves were essential to improve the efficiency of the reaction.…”

Organocatalytic Asymmetric Transformations Involving the Cyclic Imine Moiety in Indole and Isoindole Related Heterocycles

“…elegantly achieved the asymmetric synthesis of chiral isoindolinone‐based α‐amino diazo esters 127 via a Mannich‐type reaction of 2f with α‐diazo esters 128 that was driven by the ( S )‐BINOL‐derived phosphoric acid Cat. 10 . Under the optimized conditions, a variety of 3‐aryl‐3‐hydroxyisoindolinones smoothly reacted with 128 , yielding the corresponding products 127 in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee ) (Scheme ).…”