Computational Prediction of Chiral Iron Complexes for Asymmetric Transfer Hydrogenation of Pyruvic Acid to Lactic Acid

Wan Wang,Xinzheng Yang

doi:10.3390/molecules25081892

Abstract

Density functional theory calculations reveal a formic acid-assisted proton transfer mechanism for asymmetric transfer hydrogenation of pyruvic acid catalyzed by a chiral Fe complex, FeH[(R,R)-BESNCH(Ph)CH(Ph)NH2](η6-p-cymene), with formic acid as the hydrogen provider. The rate-determining step is the hydride transfer from formate anion to Fe for the formation and dissociation of CO2 with a total free energy barrier of 28.0 kcal mol−1. A series of new bifunctional iron complexes with η6-p-cymene replaced by different arene and sulfonyl groups were built and computationally screened as potential catalysts. Among the proposed complexes, we found 1g with η6-p-cymene replaced by 4-isopropyl biphenyl had the lowest free energy barrier of 26.2 kcal mol−1 and excellent chiral selectivity of 98.5% ee.

Highlights

The asymmetric hydrogenation of prochiral unsaturated ketones is an important process for the synthesis of enantiopure alcohols for use in the pharmaceutical, agrochemical, fragrance, and flavor industries [1,2,3]
The catalytic cycle began with the approach of a pyruvic acid acid (PA) molecule to 1 from its Re-face for the formation of a 2.7 kcal mol−1 less-stable prochiral intermediate pro-2R
Our density functional functional theory theory (DFT) study of the asymmetric transfer hydrogenation of pyruvic acid to lactic acid enantiomers catalyzed by bifunctional Fe complex revealed a formic acid-assisted proton-coupled hydride transfer mechanism

Summary

Introduction

The asymmetric hydrogenation of prochiral unsaturated ketones is an important process for the synthesis of enantiopure alcohols for use in the pharmaceutical, agrochemical, fragrance, and flavor industries [1,2,3]. A series of efficient catalytic systems with high reactivity and enantioselectivity for ATH are Noyori and co-workers’ chiral bifunctional Ru and Ir complexes, which are stabilized by soft ligands (η6 -arene [9,10] or phosphine [11,12]) and contain at least one hard NH electron donor that activates or directs the ketone toward hydride attack. In 2015, Gao and co-workers [20] reviewed a series of iron, cobalt, and nickel catalysts containing novel chiral aminophosphine ligands for ATH or AH of ketones. Among those base metal catalysts, the P2 N4 macrocycles in connection with Fe(0) precursors exhibited high yield (up to 96%) with extraordinary enantioselectivities (up to 99% ee) at 65 ◦ C [20].

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Results

Conclusion