Armando Carlone

Aminocatalytic Enantioselective anti‐Mannich Reaction of Aldehydes with In Situ Generated N‐Cbz and N‐Boc Imines

The catalytic asymmetric Mannich reaction constitutes one of the most powerful routes for accessing chiral b-amino carbonyl compounds, and much effort has been devoted toward the development of new and effective methodologies. In this context, the discovery that chiral secondary amines, such as proline and its derivatives, are able to catalyze the direct, highly enantioselective addition of unmodified carbonyl compounds to N-PMP (p-methoxyphenyl) imines has represented an important achievement from an atomeconomy standpoint. Accordingly, an impressive scientific competition toward the identification of more efficient aminocatalytic tactics started, and the Mannich reaction has represented a benchmark for measuring the progress of asymmetric aminocatalysis. Although proline-catalyzed addition of aldehydes to N-PMP imines affords syn-b-amino aldehydes with high diastereoand enantiocontrol, the development of an effective anti-Mannich protocol has represented a challenging synthetic problem that was solved by the rational design of new chiral amine catalysts. Recently, an important breakthrough was advanced by List and co-workers, who identified suitable reaction conditions that account for the use of preformed aromatic N-Boc imine (Boc= tert-butyloxycarbonyl) in proline-catalyzed syn-Mannich reactions of aldehydes. This study introduced important synthetic advances owing to the easy removal of the Nprotecting group, which allows access to unfunctionalized chiral amines. Herein, we describe our contribution to the progress of the aminocatalytic Mannich reaction and report the first antiselective addition of aldehydes to N-Cbzand N-Bocprotected imines (Cbz= benzyloxycarbonyl) catalyzed by the commercially available chiral secondary amine 1. Besides the high stereocontrol achieved, the main feature of this research lies in the identification of a suitable procedure that allows the in situ generation of carbamate-protected imines from stable a-amido sulfones 2 (Scheme 1). We felt that our approach provides a simple and convenient protocol that significantly expands the synthetic potential and the scope of the asymmetric aminocatalytic Mannich reaction of aldehydes. Because of their inherent high reactivity, the N-carbamoyl imines are rather sensitive to moisture, and their employment introduces practical complications. Recently, the benefit of using stable a-amido sulfones 2 as an imine surrogate has been exploited in phase-transfer-catalyzed Mannich-type reactions and, later, extended to chiral base catalysis, with important procedural simplification. Inspired by these studies, and convinced of the compatibility between a chiral secondary amine such as 1 and an inorganic base, necessary for the in situ generation of N-carbamoyl imines from 2, we sought to develop a simple protocol for the aminocatalytic anti-Mannich reaction of aldehydes. For the exploratory studies, we selected the reaction between hydrocinnamaldehyde and the bench-stable a-amido sulfone 2a catalyzed by 1 (Table 1). The choice of the chiral amine 1 was triggered by its known ability to impart high anti selectivity in the direct addition of aldehydes to preformed N-PMP imines, Scheme 1. In situ generation of N-carbamoyl imines. TMS= trimethylsilyl.

Organocatalytic asymmetric hydrophosphination of nitroalkenes

The use of a bifunctional Cinchona alkaloid catalyst has provided a new organocatalytic strategy for the enantioselective addition of diphenylphosphine to a range of nitroalkenes, affording optically active beta-nitrophosphines (up to 99% ee after crystallization); this organocatalytic approach, providing a direct route to a new class of potentially useful enantiopure P,N-ligands, constitutes a bridge between the two complementary areas of asymmetric catalysis: organo- and metal-catalyzed transformations.