New Strategies for Organic Catalysis:  The First Highly Enantioselective Organocatalytic Diels−Alder Reaction

Abstract

Over the past 30 years, enantioselective catalysis has become one of the most important frontiers in exploratory organic synthetic research. During this time, remarkable advances have been made in the development of organometallic asymmetric catalysts that in turn have provided a wealth of enantioselective oxidation, reduction, π-bond activation, and Lewis acid-catalyzed processes. 1 Surprisingly, however, relatively few asymmetric transformations have been reported which employ organic molecules as reaction catalysts, 2 despite the widespread availability of organic chemicals in enantiopure form and the accordant potential for academic, industrial, and economic benefit. Herein, we introduce a new strategy for organocatalysis that we expect will be amenable to a range of asymmetric transformations. In this context, we document the first highly enantioselective organocatalytic Diels-Alder reaction. 3 We recently embarked upon the development of a general strategy for organocatalytic reactions based upon design features derived from the arena of Lewis acid catalysis. Specifically, we reasoned that (i) LUMO-lowering activation and (ii) the kinetic lability toward ligand substitution that enables Lewis acid-catalyst turnover (eq 1) might also be available with a carbogenic system that exists as a rapid equilibrium between an electron-deficient and a relatively electron-rich state. With this in mind, we hypothesized that the reversible formation of iminium ions from R,β-unsaturated aldehydes and amines (eq 2) might emulate the equilibrium dynamics and π-orbital electronics that are inherent to Lewis acid catalysis, thereby providing a new platform for the design of organocatalytic processes. Significantly, this analysis reveals the attractive prospect that chiral amines might function as enantioselective catalysts for a range of transformations that traditionally utilize metal salts.

Origins of Stereoselectivity in Diels−Alder Cycloadditions Catalyzed by Chiral Imidazolidinones

“…2,16 The small energy differences found between the endo and exo orientations of each conformer demonstrated that a distinct preference for one over the other does not occur. This fact is in agreement with the experimentally observed 1:1 endo:exo ratio (predicted endo:exo ratio is 1:1.5 for catalyst 1 and 1.3:1 for catalyst 2 in the gas phase at 25 °C in the case of the alkylation reaction of Nmethyl pyrrole with (E)-crotonaldehyde).…”

“…This results are also in agreement with the higher enantioselectivity experimentally observed for the endo product (endo 90% ee, exo 86% ee). 2 In 2002 Zora reported the AM1 theoretical study of the cycloaddition reaction of cyclopentadiene with allylidenammonium cation. 38 A stepwise pathway was found, and the activation barrier for the cycloaddition to the C=C bond was 4.2 kcal/mol lower than that to the C=N bond.…”

“…The authors demonstrated that the reaction of a variety of aldehydes (R = Me, Pr, i-Pr, Ph, furyl) occurs with good yield and enantioselectivity (>75% yield, endo>90% ee, exo>84% ee). 2 For asymmetric alkylations of indoles, enantioselectivities were improved by using the 2-tbutyl imidazolidinone 2. 6 Compound 2 gave also excellent results as enantioselective organocatalyst in 1,4-addition reactions of electron-rich benzenes to α,β-unsaturated aldehydes, 7 in the synthesis of butenolides by Mukaiyama-Michael with silyloxyfurans.…”

Asymmetric organocatalytic reductions mediated by dihydropyridines

“…In 2000, MacMillan et al 30 demonstrated that a,b-unsaturated aldehydes could be activated in a face-selective fashion by exposure to the conjugate acids of chiral cyclic secondary amines such as 11 via the formation of an iminium ion 12. Since the condensation is reversible in the presence of trace amounts of water the amine salt could be used in substoichiometric amounts, which quickly led to a new field commonly called 'iminium ion catalysis' (Fig.…”

Improving catalyst activity in secondary amine catalysed transformations

“…6 Within the field of LUMO catalysis using secondary amines a consistent mechanism has been accepted, the fundamental steps of which are outlined in Figure 1. 7,8,9 In Step 1 the secondary amine salt 1 condenses with the , -unsaturated carbonyl compound 2 to form the reactive iminium ion 3. In…”