Prospects for the Computational Design of Bipyridine N,N′-Dioxide Catalysts for Asymmetric Propargylation Reactions

Abstract

Stereoselectivities were predicted for the allylation of benzaldehyde using allyltrichlorosilanes catalyzed by 18 axially chiral bipyridine N,N′-dioxides. This was facilitated by the computational toolkit AARON (Automated Alkylation Reaction Optimizer for N-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 N-oxide-catalyzed alkylation reactions (Organic Letters 2012, 14, 5310). Finally, we assessed the potential performance of these bipyridine N,N′-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 N,N′-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.

Transition state geometry prediction using molecular group contributions

“…23 A catalyst structure is provided by the user and mapped onto a parent catalyst structure for which the transition state geometry is already known, then a series of partially constrained semiempirical and DFT optimizations allow the new transition state to be found. 23 A catalyst structure is provided by the user and mapped onto a parent catalyst structure for which the transition state geometry is already known, then a series of partially constrained semiempirical and DFT optimizations allow the new transition state to be found.…”

Automated Quantum Mechanical Predictions of Enantioselectivity in a Rhodium‐Catalyzed Asymmetric Hydrogenation

“…AARON automates the optimization of all relevant structures by starting with a library of TS structures for a representative model ligand . AARON then maps key atoms of the new ligand onto the corresponding atoms from structures in the TS library (in this case, the two phosphorus atoms) and then performs a prescribed series of constrained and unconstrained geometry optimizations, as described previously ,. For each structure, the conformations of simple rotatable groups (for example OMe) are systematically scanned automatically.…”

Quantum chemical studies of asymmetric reactions: Historical aspects and recent examples

“…Semiautomated approaches for TS searches have also been reported, as for example, illustrated by the recently reported Automated Alkylation Reaction Optimizer for N‐oxides (AARON) by Wheeler and coworkers . To investigate the stereoselectivity of 18 chiral bipyridine N,N'‐dioxide catalysts for allylation of benzaldehyde, a text‐based interface with GAUSSIAN09 was written that automatically located the relevant 820 TS structures.…”

“…To investigate the stereoselectivity of 18 chiral bipyridine N,N'‐dioxide catalysts for allylation of benzaldehyde, a text‐based interface with GAUSSIAN09 was written that automatically located the relevant 820 TS structures. However, note that this approach was based on detailed preknowledge about the reaction pathway and expected transition states, as the initial TS structures were constructed by mapping the 18 catalysts onto the already known TS structures for a related catalyst …”