Enantioselective Conjugate Addition of Nitro Compounds to α,β‐Unsaturated Ketones: An Experimental and Computational Study

Abstract

A series of chiral thioureas derived from easily available diamines, prepared from α-amino acids, have been tested as catalysts in the enantioselective Michael additions of nitroalkanes to α,β-unsaturated ketones. The best results are obtained with the bifunctional catalyst prepared from L-valine. This thiourea promotes the reaction with high enantioselectivities and chemical yields for aryl/vinyl ketones, but the enantiomeric ratio for alkyl/vinyl derivatives is very modest. The addition of substituted nitromethanes led to the corresponding adducts with excellent enantioselectivity but very poor diastereoselectivity. Evidence for the isomerization of the addition products has been obtained from the reaction of chalcone with [D(3)]nitromethane, which shows that the final addition products epimerize under the reaction conditions. The epimerization explains the low diastereoselectivity observed in the formation of adducts with two adjacent tertiary stereocenters. Density functional studies of the transition structures corresponding to two alternative activation modes of the nitroalkanes and α,β-unsaturated ketones by the bifunctional organocatalyst have been carried out at the B3LYP/3-21G* level. The computations are consistent with a reaction model involving the Michael addition of the thiourea-activated nitronate to the ketone activated by the protonated amine of the organocatalyst. The enantioselectivities predicted by the computations are consistent with the experimental values obtained for aryl- and alkyl-substituted α,β-unsaturated ketones.

Chalcone: A Privileged Structure in Medicinal Chemistry

“…For example, in 2005, a cinchona alkaloid derived chiral bifunctional thiourea organocatalyst ( 12 , Scheme 14) was used in the Michael addition of nitroalkanes to chalcones, and R - 22 was obtained, 194 while catalyst 23 was used to give S - 22 . 195 In 2010, Du and co-workers reported a class of squaramide-based organocatalysts, among which squaramides 24 and 25 showed excellent catalytic activity to obtain the desired R or S enantiomers, respectively, with high yields and excellent enantioselectivities (94–95% ee). 196 The above conditions could achieve high ee and yields, although the reaction time was long.…”

Highly Diastereo‐ and Enantioselective Michael Addition of Nitroalkanes to 2‐Enoyl‐Pyridine N‐Oxides Catalyzed by Scandium(III)/Copper(II) Complexes

“…Although impressive progress in the transition‐metal‐catalyzed asymmetric Michael additions has been made in the past decades, there remains a great challenge in the diastereoselectivity issue of Michael additions 2. It is noteworthy that a satisfactory diastereoselectivity in the Michael addition of nitroalkanes to α,β‐unsaturated ketones still was a challenging problem despite the immense developments in the enantioselective version of this reaction (Scheme ) 2g–n. Meanwhile, 2‐enoyl‐pyridine N ‐oxides have been extensively explored in asymmetric transformations as a popular Michael acceptor since the pioneering work of Jørgensen, Pedro, and Singh 3.…”

Acyclic Amino Acid Based Bifunctional Chiral Tertiary Amines, Quaternary Ammoniums and Iminophosphoranes as Organo­catalysts

“…In 2009, Zhu, Zhao and co-workers 12a described a highly enantio-and diastereoselective synthesis of α-trifluoromethyldihydropyrans, through the development of an asymmetric reaction of α-cyanoketones (14) with α,β-unsaturated trifluoromethyl ketones (13), utilizing L-phenylglycine-derived thiourea-cyclic tertiary amine 11 as the catalyst (Scheme 4a). After five hours, the reactions provided the desired α-trifluoromethyldihydropyrans 15 with 87-95% ee and diastereomeric ratios (dr) of 6:1 to >19:1.…”