jo3023654_si_001.pdf (6.95 MB)
Refined Transition-State Models for Proline-Catalyzed Asymmetric Michael Reactions under Basic and Base-Free Conditions
journal contribution
posted on 2016-02-20, 04:27 authored by Akhilesh
K. Sharma, Raghavan B. SunojThe stereocontrolling transition state (TS) models for
C–C
bond formation relying on hydrogen bonding have generally been successful
in proline-catalyzed aldol, Mannich, α-amination, and α-aminoxylation
reactions. However, the suitability of the hydrogen-bonding model
in protic and aprotic conditions as well as under basic and base-free
conditions has not been well established for Michael reactions. Through
a comprehensive density functional theory investigation, we herein
analyze different TS models for the stereocontrolling C–C bond
formation, both in the presence and absence of a base in an aprotic
solvent (THF). A refined stereocontrolling TS for the Michael reaction
between cyclohexanone and nitrostyrene is proposed. The new TS devoid
of hydrogen bonding between the nitro group of nitrostyrene and carboxylic
acid of proline, under base-free conditions, is found to be more preferred
over the conventional hydrogen-bonding model besides being able to
reproduce the experimentally observed stereochemical outcome. A DBU-bound
TS is identified as more suitable for rationalizing the origin of
asymmetric induction under basic reaction conditions. In both cases,
the most preferred approach of nitrostyrene is identified as occurring
from the face anti to the carboxylic acid of proline–enamine.
The predicted enantio- and diastereoselectivities are in very good
agreement with the experimental observations.