Chiral phosphoric acid (PA) catalysts are powerful tools for asymmetric organic synthesis. Their bifunctional mode of substrate activation allows for a wide variety of applications, which are mostly focused on additions of nucleophiles to sp2-hybridized electrophiles such as imines and other carbonyl derivatives. Enantioselective nucleophilic openings of small saturated heterocycles (oxiranes, oxetanes, aziridines and azetidines), which are sp3-hybridized electrophiles, are also known using chiral PAs. Although models of selectivity for imine additions were already well-established, there were no similar models for sp3 electrophiles at the start of this project. We have studied a wide variety of chiral PA-catalyzed reactions of sp3 electrophiles using density functional theory (DFT) calculations. Our results indicate that transition states (TS) computed with a model (achiral) catalyst correlate with the arrangements found within the active site (pocket) of BINOL- or SPINOL-derived PA catalysts. This discovery allowed us to put forward a general model to predict and understand the sense of stereoselectivity in these reactions, without requiring optimization of all conformations of the complex systems. Using available visualization tools, we have produced steric maps of the TS and catalyst structures, which highlight how this qualitative analysis leads to a quick identification of the catalysts that will be the most selective in each transformation. Application of the model will be demonstrated using various published examples.

Rationalization of enantioselectivity in chiral phosphoric acid-catalyzed reactions of sp3 electrophiles using DFT calculations

253rd National Meeting (2017)

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