Design of Organocatalysts for Asymmetric Propargylations through Computational Screening

The development of
asymmetric catalysts is typically driven by
the experimental screening of potential catalyst designs. Herein,
we demonstrate the design of asymmetric propargylation catalysts through
computational screening. This was done using our computational toolkit
AARON (automated alkylation reaction optimizer for N-oxides), which automates the prediction of enantioselectivities
for bidentate Lewis base catalyzed alkylation reactions. A systematic
screening of 59 potential catalysts built on 6 bipyridine N,N′-dioxide-derived scaffolds results
in predicted ee values for the propargylation of benzaldehyde ranging
from 45% (S) to 99% (R), with 12
ee values exceeding 95%. These data provide a broad set of experimentally
testable predictions. Moreover, the associated data revealed key details
regarding the role of stabilizing electrostatic interactions in asymmetric
propargylations, which were harnessed in the design of a propargylation
catalyst for which the predicted ee exceeds 99%.