The Catalytic Asymmetric Intramolecular Stetter Reaction

Abstract

This account chronicles our efforts at the development of a catalytic asymmetric Stetter reaction using chiral triazolium salts as small molecule organic catalysts. Advances in the mechanistically related azolium-catalyzed asymmetric benzoin reaction are discussed, particularly as they apply to catalyst design. A chronological treatise of reaction discovery, catalyst optimization and reactivity extension follows.

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes

“…The enantioselective intramolecular Stetter reaction, first reported by Enders, 12 has been the object of much research in recent years and progress in this field has been prevsiouly reviewed (Scheme 32). 85 …”

Understanding the Mechanism of the Intramolecular Stetter Reaction. A DFT Study

“…The umpolung reactivity of aldehydes promoted by N -heterocyclic carbenes (NHCs) constitutes an important class of organocatalysis and has found a broad range of applications in synthetic organic chemistry [ 1 , 2 , 3 , 4 , 5 , 6 ]. The corresponding acyl anions or equivalent homoenolate intermediates are able to attack nucleophilically various electrophiles, such as aldehydes [ 7 , 8 , 9 ], ketones [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], imines [ 19 , 20 , 21 , 22 ], and even activated polarized C=C double bonds [ 23 , 24 ].…”

Rate and Equilibrium Constants for the Addition of N‐Heterocyclic Carbenes into Benzaldehydes: A Remarkable 2‐Substituent Effect

“…[1] In this regard, NHC-catalyzed benzoin and Stetter reactions have been widely studied, with a number of efficient catalytic asymmetric methods available for both intra- and intermolecular reactions. [1,2] However, the development of cross-benzoin reactions has proven difficult in terms of the chemoselective formation of a single reaction product. [3] While efficient chemoselective NHC-catalyzed protocols for both intra- and intermolecular cross-benzoin reactions between aldehydes and ketones have been reported,[4] the reaction between two distinct aldehydes remains a significant synthetic challenge.…”