Mukaiyama–Michael Reactions with trans‐2,5‐Diarylpyrrolidine Catalysts: Enantioselectivity Arises from Attractive Noncovalent Interactions, Not from Steric Hindrance

Abstract

The scope of the enantioselective Mukaiyama-Michael reactions catalyzed by trans-2,5-diphenylpyrrolidine has been expanded to include both α- and β-substituted enals. However, the rationalization of the observed enantioselectivity is far from obvious since the catalyst is not very sterically hindered. DFT calculations were carried out to rationalize the observed stereoselectivities. Transition states of the C-C bond formation between iminium intermediates and silyloxyfurans were located and their relative energies were used to estimate the stereoselectivity data. We find excellent agreement between the predicted and observed stereoselectivities. The analysis of intermolecular forces reveals that the enantioselectivity is mostly due to stabilizing noncovalent interactions between the reacting partners, not due to steric hindrance. The role of attractive noncovalent interactions in enantioselective catalysis may be underappreciated.

Organocatalytic Asymmetric Vinylogous Michael Reactions

“…Pápai, Pihko and co‐workers were focused on the total synthesis of pectenotoxin‐2 8 , and the development of a simple method for accessing chiral motifs 9 and 10 featuring a tertiary stereocenter at C25 and a methyl group at C27 became their desired task (Scheme a). To address this challenge and depending on the reasonable retrosynthetic analysis, in 2014, they described an AVMM reaction of 4‐substituted 2‐silyloxy furans 11 with methacrolein and analogues 12 (Scheme b).…”

A Theoretical and Experimental Study of the Effects of Silyl Substituents in Enantioselective Reactions Catalyzed by Diphenylprolinol Silyl Ether

“…After taking the entropic and sol- vation contributions into account, however, the relative energies of the isomers of iminium ions 3, as well as those of enamine 5, did not alter significantly compared with those obtained from the gas-phase electronic energies, and the error bar on the Gibbs free energy predictions is expected to be significantly larger than that of the electronic energies. [13] Accordingly, the relative energies (including the zero-point energies) reported herein are those obtained from gas-phase electronic energies at the B3LYP/6-31G(d) and M06-2X/6-311 + G(2df,2p) levels. The DFT calculations were carried out by using the Gaussian 09 program package.…”

Catalytic Enantioselective [10+4] Cycloadditions

“…The products 4 are formed with anti configuration, in agreement with the reaction proceeding through an exo transition state. Unfortunately,w eh ave not been able to observe the intermediates by NMR analysis.I nstead, the hypothesis was probed indirectly by employment of the C 2 -symmetric catalyst 3c, [12] forw hich INT-I A and INT-I B are equivalent as ar esult of the rotational symmetry axis of the catalyst (Scheme 5). [10] However,a pplication of symmetry rules and FMO analysis in large polyene systems is complicated.…”