Prospects for the Computational Design of Bipyridine <i>N</i>,<i>N</i>′‑Dioxide Catalysts for
Asymmetric Propargylation Reactions
- Publication date
- 2015
- Publisher
Abstract
Stereoselectivities were predicted
for the allylation of benzaldehyde
using allyltrichlorosilanes catalyzed by 18 axially chiral bipyridine <i>N</i>,<i>N</i>′-dioxides. This was facilitated
by the computational toolkit AARON (Automated Alkylation Reaction
Optimizer for <i>N</i>-oxides), which automates the optimization
of all of the required transition-state structures for such reactions.
Overall, we were able to predict the sense of stereoinduction for
all 18 of the catalysts, with predicted ee’s in reasonable
agreement with experiment for 15 of the 18 catalysts. Curiously, we
find that ee’s predicted from relative energy barriers are
more reliable than those based on either relative enthalpy or free
energy barriers. The ability to correctly predict the stereoselectivities
for these allylation catalysts in an automated fashion portends the
computational screening of potential organocatalysts for this and
related reactions. By studying a large number of allylation catalysts,
we were also able to gain new insight into the origin of stereoselectivity
in these reactions, extending our previous model for bipyridine <i>N</i>-oxide-catalyzed alkylation reactions (<i>Organic
Letters</i> <b>2012</b>, <i>14</i>, 5310). Finally,
we assessed the potential performance of these bipyridine <i>N</i>,<i>N′</i>-dioxide catalysts for the propargylation
of benzaldehyde using allenyltrichlorosilanes, finding that
two of these catalysts should provide reasonable stereoselectivities
for this transformation. Most importantly, we show that bipyridine <i>N</i>,<i>N</i>′-dioxides constitute an ideal
scaffold for the development of asymmetric propargylation catalysts
and, along with AARON, should enable the rational design of such catalysts
purely through computation