Proline-catalysed Mannich reactions of acetaldehyde

Abstract

Small organic molecules recently emerged as a third class of broadly useful asymmetric catalysts that direct reactions to yield predominantly one chiral product, complementing enzymes and metal complexes. For instance, the amino acid proline and its derivatives are useful for the catalytic activation of carbonyl compounds via nucleophilic enamine intermediates. Several important carbon-carbon bond-forming reactions, including the Mannich reaction, have been developed using this approach, all of which are useful for making chiral, biologically relevant compounds. Remarkably, despite attempts, the simplest of all nucleophiles, acetaldehyde, could not be used in this way. Here we show that acetaldehyde is a powerful nucleophile in asymmetric, proline-catalysed Mannich reactions with N-tert-butoxycarbonyl (N-Boc)-imines, yielding beta-amino aldehydes with extremely high enantioselectivities-desirable products as drug intermediates and in the synthesis of other biologically active molecules. Although acetaldehyde has been used as a nucleophile in reactions with biological catalysts such as aldolases and thiamine-dependent enzymes, and has also been employed indirectly, its use as an inexpensive and versatile two-carbon nucleophile in asymmetric, small-molecule catalysis will find many practical applications.

Pyrrolidine-Mediated Direct Preparation of (E)-Monoarylidene Derivatives of Homo- and Heterocyclic Ketones with Various Aldehydes

“…Based on the results and previous reports [29,[34][35][36][37][38], two possible reaction mechanisms for the formation of (E)-monoarylidene derivatives of homo-and heterocyclic ketones with various aldehydes have been proposed. As depicted in Scheme 2, one route is the generation through an aldol reaction of product a, which then undergoes a dehydration process (Scheme 2, mechanism 1).…”

“…The use of such a ketone for the production of new α,β-unsaturated ketones of biological interest is not very extensive. Recently, chiral secondary amines were used as organocatalysts in the direct aldol reaction with great success [34][35][36][37]. The mechanism suggesting that ketones and amines facilicate the formation of the intermediate enamine, encouraged us to study the direct aldol-dehydration reaction for producing the title compounds.…”

Tandem Catalysis by Lipase in a Vinyl Acetate‐Mediated Cross‐Aldol Reaction

“…Since the report of its utilization in the Mannich reaction by List and co-workers, [9] acetaldehyde has also been effectively used in the cross-aldol, [10] self-aldol [11] and Michael reactions. [12] Hayashi et al [13] also employed it in the Mannich reaction with different catalysts to understand the mechanism.…”

The Asymmetric Catalytic Mannich Reaction Catalyzed by Organocatalyst ^|^mdash; A Personal Account ^|^mdash;

“…10). 27 At the same time, our group and the List group reported the asymmetric Michael reaction of acetaldehyde and nitroalkene (eq. 11).…”