Pernille H. Poulsen

The Diarylprolinol Silyl Ethers: Ten Years After

Asymmetric organocatalysis has experienced an incredible development since the beginning of this century. The expansion of the field has led to a large number of efficient types of catalysts. One group, the diarylprolinol silyl ethers, was introduced in 2005 and has been established as one of the most frequently used in aminocatalysis. In this Minireview, we will take a look in the rear-view mirror, ten years after the introduction of the diarylprolinol silyl ethers. We will focus on the perspectives of the different activation modes made available by this catalytic system. Starting with a short introduction to aminocatalysis, we will outline the properties that have made the diarylprolinol silyl ethers a common choice of catalyst. Furthermore, we will describe the major tendencies in the activation and reaction concepts developed with regard to reactivity patterns and combinations with other activation concepts.

A New Organocatalytic Concept for Asymmetric α-Alkylation of Aldehydes

The organocatalytic asymmetric α-alkylation of aldehydes by 1,6-conjugated addition of enamines to p-quinone methides is described. Employing a newly developed class of chiral secondary amine catalysts, α-diarylmethine-substituted aldehydes with two contiguous stereocenters have been synthesized in a simple manner with good diastereocontrol and excellent enantioselectivity.

Beyond classical reactivity patterns: shifting from 1,4- to 1,6-additions in regio- and enantioselective organocatalyzed vinylogous reactions of olefinic lactones with enals and 2,4-dienals.

Organocatalysis is shown to expand the classical reactivity pattern for conjugate addition reactions. It is demonstrated that the site selectivity can be extended from 1,4- to 1,6-additions for the enantioselective vinylogous additions of methyl-substituted vinylogous lactones to enals and 2,4-dienals. This novel reactivity is demonstrated for methyl-substituted olefinic azlactones and butyrolactones. Their synthetic potential is first highlighted by the development of the organocatalytic regioselective vinylogous 1,4-addition to enals which proceeds with a very high level of double-bond geometry control and excellent enantioselectivity. The concept is developed further for the unprecedented intermolecular enantioselective organocatalyzed vinylogous 1,6-addition to linear 2,4-dienals, by which the site selectivity of the process is extended from the β-position to the remote δ-position of the 2,4-dienal. The organocatalyst controls the newly generated stereocenter six bonds away from the stereocenter of the catalyst with a high level of enantiocontrol, and the products are obtained with full control of double-bonds configuration. The scope of these new reaction concepts is demonstrated for a series of aliphatic and aryl-substituted enals and 2,4-dienals undergoing enantioselective vinylogous reactions with methyl-substituted olefinic azlactones and butyrolactones. Furthermore, mechanistic considerations are presented which can account for the change from 1,4- to 1,6-selectivity. Finally, a number of different transformations of the optically active 1,4- and 1,6-addition products are demonstrated.

Organocatalytic Asymmetric 1,6‐Addition/1,4‐Addition Sequence to 2,4‐Dienals for the Synthesis of Chiral Chromans

A novel asymmetric organocatalytic 1,6-addition/1,4-addition sequence to 2,4-dienals is described. Based on a 1,6-Friedel-Crafts/1,4-oxa-Michael cascade, the organocatalyst directs the reaction of hydroxyarenes with a vinylogous iminium-ion intermediate to give only one out of four possible regioisomers, thus providing optically active chromans in high yields and 94-99 % ee. Furthermore, several transformations are presented, including the formation of an optically active macrocyclic lactam. Finally, the mechanism for the novel reaction is discussed based on computational studies.

Asymmetric synthesis of γ-nitroesters by an organocatalytic one-pot strategy.

An enantioselective synthesis of γ-nitroesters by a one-pot asymmetric Michael addition/oxidative esterification of α,β-unsaturated aldehydes is presented. The procedure is based on merging the enantioselective organocatalytic nitroalkane addition with an N-bromosuccinimide-based oxidation. The γ-nitroesters are obtained in good yields and enantioselectivities, and the method provides an attractive entry to optically active γ-aminoesters, 2-piperidones, and 2-pyrrolidones.

Organocatalytic [4+2] addition reactions via tetraenamine intermediate

The [4+2]-cycloaddition reaction of 3-olefinic oxindoles with a tetraenamine intermediate is presented. In the reaction, a novel class of highly functionalized spirocyclic cyclohexanes with four stereocenters is formed in high yield and excellent stereoselectivity. Mechanistic investigations and calculations point to a stepwise mechanism involving tetraenamine intermediates. Furthermore, several transformations are presented.

Controlling Asymmetric Remote and Cascade 1,3-Dipolar Cycloaddition Reactions by Organocatalysis

The regio- and stereoselective control of cycloaddition reactions to polyconjugated systems has been demonstrated by applying asymmetric organocatalysis. Reaction of 2,4-dienals with nitrones allows for a highly regio- and stereoselective 1,3-dipolar cycloaddition in the presence of an aminocatalyst. The first cycloaddition on the remote olefin can be followed either by a cascade reaction or by other selective reactions of the remaining olefin. The chiral products are obtained in good to high yields and excellent diastereo- and enantioselectivities. The remote selective concept has been extended to 2,4,6-trienals by means of a novel enantioselective triple cascade 1,3-dipolar cycloaddition reaction. The formation of chiral poly 1,3-amino alcohols is also demonstrated.

Asymmetric Organocatalytic Synthesis of Complex Cyclopenta[b]quinoline Derivatives

An efficient one-pot procedure that provides a direct access to polycyclic hexahydrocyclopenta[b]quinoline derivatives having five stereogenic centers has been developed. The system displays great tolerance toward different aldehydes, anilines, and nitroalkenes. The products are obtained in high yields and excellent enantio- and diastereoselectivities.

Catalytic Asymmetric Oxidative γ-Coupling of α,β-Unsaturated Aldehydes with Air as the Terminal Oxidant

A novel concept for catalytic asymmetric coupling reactions is presented. Merging organocatalysis with single-electron oxidation by using a catalytic amount of a copper(II) salt and air as the terminal oxidant, we have developed a highly stereoselective carbon-carbon oxidative coupling reaction of α,β-unsaturated aldehydes. The concept relies on the generation of a dienamine intermediate, which is oxidized to an open-shell activated species that undergoes highly selective γ-homo- and γ-heterocoupling reactions. In the majority of examples presented, only a single stereoisomer was formed.

Enantioselective Organocatalytic α‐Arylation of Aldehydes

This article describes an organocatalytic, enantioselective α- arylation of aldehydes, in which quinones are applied as the aromatic partner, to afford optically active α-arylated aldehydes. Following the addition/aromatization sequence, subsequent hemiacetal formation affords the 2,3-dihydrobenzofuran products. The direct α-arylation consists of two catalytic cycles. The stereogenic center is formed in the first cycle - the reaction of the enamine intermediate with the quinone. In the second cycle a series of proton-transfer reactions leads to the optically active α-arylated aldehyde.