Mauro Marigo

Organocatalytic direct asymmetric α-heteroatom functionalization of aldehydes and ketones

The direct enantioselective introduction of a stereogenic carbon–heteroatom bond adjacent to a carbonyl functionality leads to optically active compounds of significant importance for e.g. the life-science industry. Organocatalytic enantioselective amination, oxygenation, fluorination, chlorination, bromination and sulfenylation of aldehydes and ketones, using chiral amines as the catalysts, are reviewed in this feature article. Furthermore, a few other transformations are also outlined. The scope, potential and application of these organocatalytic asymmetric reactions are presented and the mechanistic aspects discussed.

A simple asymmetric organocatalytic approach to optically active cyclohexenones

Optically active 2,5-disubstituted-cyclohexen-2-one derivatives have been prepared in a one-pot process consisting of five reaction steps: an organocatalytic asymmetric conjugated addition of beta-ketoesters to alpha,beta-unsaturated aldehydes that proceeds in aqueous solutions or under solvent-free conditions has been implemented in a multi-step process.

Organocatalytic asymmetric epoxidation reactions in water–alcohol solutions

The diastereo- and enantioselective organocatalytic epoxidation of alpha,beta-unsaturated aldehydes in aqueous solutions is presented. By the screening of the reaction conditions for the epoxidation of cinnamic aldehyde applying hydrogen peroxide as the oxidant and 2-[bis-(3,5-bis-trifluoromethyl-phenyl)-trimethylsilanyloxy-methyl]-pyrrolidine as the catalyst, a highly stereoselective reaction has been developed. The scope of the diastereo- and enantioselective organocatalytic epoxidation in aqueous solutions is documented by the asymmetric epoxidation of alpha,beta-unsaturated aldehydes with enantioselectivities up to 96% ee.

Organocatalytic asymmetric α-bromination of aldehydes and ketones

The first organocatalytic enantioselective α-bromination of aldehydes and ketones is presented; a C2-symmetric diphenylpyrrolidine catalyst afforded the α-brominated aldehydes in good yields and up to 96% ee, while ketones were α-brominated by a C2-symmetric imidazolidine in up to 94% ee; furthermore, the organocatalytic enantioselective α-iodination of aldehydes is also demonstrated to proceed with up to 89% ee.

Chemoselectivity in Asymmetric Aminocatalysis

Chemoselectivity is “the preferential reaction of a chemical reagent with one of two or more different functional groups”. It lies at the heart of modern organic chemistry. Generally, organic processes are mostly driven by the innate reactivity profiles of the reagents. Altering such an inherent behavior or discriminating between functional groups with similar reactivity requires a high degree of chemical innovation. In this Highlight article, we discuss recent efforts to discover new strategies and principles for controlling chemoselectivity, using case studies from the realm of asymmetric aminocatalysis. Traditionally, chemoselectivity is addressed by using electronic and steric factors as control elements to differentiate between functional groups with similar reactivity. MacMillan and co-workers successfully applied these basic principles to solving the formidable challenge of the cross-aldol coupling of non-equivalent aldehydes. 5] These reactions required that two enolizable aldehydes selectively partitioned into discrete components: the nucleophilic donor and the electrophilic acceptor. In 2002, Northrup and MacMillan reported that proline A selectively catalyzes the addition of 1 to a more encumbered aldehyde such as isovaleraldehyde 2 (Scheme 1). Although proline could condense with both aldehydes, the resulting enamines were formed at different extents and with distinct nucleophilic characters. The lower reactivity of the more sterically demanding intermediate prevented the self-condensation of 2, while the slow addition (syringe pump) of aldehyde donors suppressed the formation of byproducts arising from a self-aldolization of 1. These chemoselective profiles ensured the formation of cross-aldol adducts 3 in very high yield. In 2004, Northrup, MacMillan, and co-workers published another remarkable example of a cross-aldol reaction of enolizable aldehydes (Scheme 2). The protected hydroxyl group within the a-oxoaldehydes 4 enhanced the electrophilic nature of the carbonyl group and, at the same time, decreased the nucleophilic character of the corresponding enamine. As a result, although both reaction partners could efficiently undergo self-aldolization under the described reaction conditions, it was possible to selectively channel the reaction manifold toward the formation of only one of the four possible aldol products. In this particular reaction, the electronic properties of the aldehydes seemed to overrule the steric factors. Product 5 was also obtained in good yield when isovaleraldehyde 2 was designed to be the donor. Very recently, Fr chet and colleagues have chosen the field of aminocatalytic cascade reactions to introduce a completely novel approach to achieving chemoselectivity. They demonstrated how differences in the polarity of catalysts and reagents may be exploited to differentiate between aldehydic substrates with otherwise nearly identical reactivity profiles. In the reported polarity-directed three-component organocatalytic reaction, two aldehydes were reacted in a highly chemoselective manner by using a biphasic system based on an optiScheme 1. Chemoselective cross-aldol coupling: steric discrimination between aldehydes 1 and 2 ; donor 1 added slowly by syringe pump.

Diastereodivergent Access to Syn and Anti 3,4-Substituted β-Fluoropyrrolidines: Enhancing or Reversing Substrate Preference

A practical diastereodivergent access to β-fluoropyrrolidines with two adjacent stereocenters has been demonstrated, by either enhancing or completely reversing the substrate control, in the diastereoselective fluorination of a series of diverse pyrrolidinyl carbaldehydes using organocatalysis. Furthermore, enamine catalysis has been successfully utilized for kinetic resolution, obtaining a fluorinated β-prolinol analogue with two adjacent tetrasubstituted chiral centers in 95% ee from a racemic substrate.