Synergistic Strategies in Aminocatalysis.

Synergistic catalysis offers the unique possibility of simultaneous activation of both the nucleophile and the electrophile in a reaction. A requirement for this strategy is the stability of the active species towards the reaction conditions and the two concerted catalytic cycles. Since the beginning of the century, aminocatalysis has been established as a platform for the stereoselective activation of carbonyl compounds through HOMO-raising or LUMO-lowering. The burgeoning era of aminocatalysis has been driven by a deep understanding of these activation and stereoinduction modes, thanks to the introduction of versatile and privileged chiral amines. The aim of this review is to cover recent developments in synergistic strategies involving aminocatalysis in combination with organo-, metal-, photo-, and electro-catalysis, focusing on the evolution of privileged aminocatalysts architectures.

DoE-Driven Development of an Organocatalytic Enantioselective Addition of Acetaldehyde to Nitrostyrenes in Water.

The development of an enantioselective enamine-catalysed addition of masked acetaldehyde to nitroalkenes via a rational approach helped to move away from the use of chloroform. The presented research allows the use of water as a reaction medium, therefore improving the industrial relevance of a protocol to access very important pharmaceutical intermediates. Critical to the success is the use of chemometrics-assisted 'Design of Experiments' (DoE) optimisation during the development of the presented new synthetic approach, which allows to investigate the chemical space in a rational way.

Palladium-catalyzed regio- and stereoselective synthesis of aryl and 3-indolyl-substituted 4-methylene-3,4-dihydroisoquinolin-1(2H)-ones.

Cascade cyclocarbopalladation of the readily available aryl/alkyl-substituted propargylic amides containing an aryl iodide moiety, followed by Suzuki-Miyaura coupling with arylboronic acids, allowed an efficient regio- and stereoselective synthesis of tetrasubstituted 4-methylene-3,4-dihydroisoquinolin-1(2H)-ones. Moreover, cascade cyclocarbopalladation, followed by the reaction with 2-alkynyltrifluoroacetanilides, accomplished a double cyclization to afford challenging 4-methylene-3,4-dihydroisoquinolin-1(2H)-ones bearing a 3-indolyl substituent through aminopalladation/reductive elimination.