Stereocontrol in Diphenylprolinol Silyl Ether Catalyzed Michael Additions: Steric Shielding or Curtin–Hammett Scenario?

Abstract

The enantioselectivity of amine-catalyzed reactions of aldehydes with electrophiles is often explained by simple steric arguments emphasizing the role of the bulky group of the catalyst that prevents the approach of the electrophile from the more hindered side. This standard steric shielding model has recently been challenged by the discovery of stable downstream intermediates, which appear to be involved in the rate-determining step of the catalytic cycle. The alternative model, referred to as the Curtin-Hammett scenario of stereocontrol, assumes that the enantioselectivity is related to the stability and reactivity of downstream intermediates. In our present computational study, we examine the two key processes of the catalytic Michael reaction between propanal and β-nitrostyrene that are relevant to the proposed stereoselectivity models, namely the C-C bond formation and the protonation steps. The free energy profiles obtained for the pathways leading to the enantiomeric products suggest that the rate- and stereodetermining steps are not identical as implied by the previous models. The stereoselectivity can be primarily controlled by C-C bond formation even though the reaction rate is dictated by the protonation step. This kinetic scheme is consistent with all observations of experimental mechanistic studies including those of mass spectrometric back reaction screening experiments, which reveal a mismatch between the stereoselectivity of the back and the forward reactions.

Organocatalytic Access to a cis-Cyclopentyl-γ-amino Acid: An Intriguing Model of Selectivity and Formation of a Stable 10/12-Helix from the Corresponding γ/α-Peptide

“…53,54 The proposed catalytic cycle is depicted in Scheme 2. In a similar manner to the intermediates observed by Seebach and Hayashi, 55 Blackmond, [56][57][58][59] Wennemers, 60 Pihko and Papái 61,62 in studies performed with the Hayashi-Jørgensen catalyst, there are three intermediates the addition step can result in ( Figure 4). In a moderately polar solvent as DCE, the zwitterionic structure 10c is thermodynam- quickly results in formation of the product hemiaminal (10g in Scheme 2).…”

Mechanistic Studies on the Organocatalytic α‐Chlorination of Aldehydes: The Role and Nature of Off‐Cycle Intermediates

“…The stereoselectivity, however, was rationalized by the attack of the enamine (steric shielding model). The suggestion that the enantioselectivity is determined by the stability of rapidly interconverting intermediates was not supported …”

Organocatalytic Asymmetric Addition of Aldehyde to Nitroolefin by H-d-Pro-Pro-Glu-NH2: A Mechanistic Study

“…In the 1 -D hypothesis, conversion of dihydrooxazine into a cyclobutane adduct should also be considered because this species has been experimentally observed with diphenylprolinol trimethylsilyl ether as catalyst. 16…”