Design, development and mechanistic studies of hydrazide-catalyzed enantioselective cycloaddition reactions

Abstract

Novel cyclic hydrazides were designed and found to function as asymmetric organocatalysts in aqueous Diels-Alder reactions.1 The LUMO-lowering activation of alpha,beta-unsaturated aldehydes by the reversible formation of iminium ions from hydrazides was used as an efficient platform to achieve highly enantioselective Diels-Alder cycloadditions. The implementation of the hydrazide functionality promoted faster iminium formation relative to secondary amine catalysts via the alpha-heteroatom effect. The mechanism of the enantioselective hydrazide catalyzed Diels-Alder cycloaddition was investigated in detail.2 Both the formation of the reactive iminium species and the hydrolysis of the product iminium intermediates were found to be extremely rapid, leaving the cycloaddition as the kinetically significant step. Mechanistic studies using NMR showed that a retro Diels-Alder reaction occurred during the catalytic cycle suggesting a thermodynamic component to the reaction. Conformational control was utilized to design an improved hydrazide organocatalyst for asymmetric Diels-Alder reactions, thus introducing a new aspect to organocatalysis.3 Enhanced diastereoselectivities and enantioselectivities of up to 96% were achieved by the application of the rigidified catalyst. The first crystal structure of a key iminium intermediate in an organocatalyzed process was also achieved. The hydrazide-catalyzed protocol was expanded to the enantioselective [3+2] cycloadditions of nitrones with alpha,beta-unsaturated aldehydes to provide isoxazolidines in excellent optical purity. A synthetic approach to the alpha-oximation of carbonyls was investigated. 1-chloro-1-nitroso cyclohexane can be used in conjunction with cyclohexanone with catalytic L-proline to provide alpha-oximated product in 98% enantiomeric excess, in modest yield. 1 Lemay, M.; Ogilvie W.W. Org. Let. 2005, 7, 4141. 2 Lemay, M.; Ogilvie, W.W. J. Org. Chem. 2006, 71, 4663. 3 Lemay, M.; Aumand, L. Ogilvie, W. W. Adv. Synth. Catal. 2007, 349, 341.