May 23, 2020

Stereoselective Reductions of 3-Substituted Cyclobutanones: a Comparison Between Experiment and Theory

The Journal of Organic Chemistry
Xavier DeraetMercedes Alonso

Abstract

The stereoselective reduction of carbonyls is of key importance in the total synthesis of natural products and in medicinal chemistry. Nevertheless, models for rationalizing the stereoselectivity of the hydride reductions of cyclobutanones towards cyclobutanols are largely lacking, unlike cyclohexanone reductions. In order to elucidate the factors that control the stereoselectivity of these reductions, we have investigated the effect of the reaction temperature, solvent, substituent and type of reducing agent using a synergistic experimental-computational approach. On the experimental side, the hydride reduction of 3-substituted cyclobutanones was proven to be highly selective for the formation of the cis alcohol (> 90%) irrespective of the size of the hydride reagent. The pronounced selectivity can be further enhanced by lowering the reaction temperature or decreasing solvent polarity. On the computational side, DFT and noncovalent interaction analysis reveal that torsional strain plays a major role in the preference for the anti-facial hydride approach, consistent with the Felkin-Anh model. In the presence of the benzyloxy substituent, the high selectivity for the cis isomer is also driven by repulsive electrostatic interacti...Continue Reading

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Mentioned in this Paper

Research Study
Tenofovir
Synucleins
Cell Polarity
Chemistry, Pharmaceutical
Benzylhemiformal
Side
2-dodecylcyclobutanone
Cyclohexanone
Size

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