Enantioselectivity in the Noyori–Ikariya Asymmetric Transfer Hydrogenation of Ketones

Abstract

Asymmetric transfer hydrogenation (ATH) is an important catalytic process in the fragrance and pharmaceutical industries. The Noyori–Ikariya chiral molecular ruthenium complex has been the catalyst of choice for this reaction for over 25 years. The mechanism and origin of enantioselectivity have irked chemists ever since the catalyst conception. This work addresses important shortcomings in understanding the origin of enantioselectivity with the Noyori–Ikariya catalysts, traditionally associated with the CH−π interaction [Angew. Chem., Int. Ed.2001402818 Here, we show that there are two spatial regions of the catalyst that simultaneously control the enantioselectivity for any arbitrary substrate: the region of the (tethered) η6-arene ligand and the region of the SO2 moiety. Dynamic equilibrium and interplay of attraction and repulsion via CH−π, C–H···H–C, lone pair−π, lone pair···H–C, and other noncovalent interactions in each region lead to stabilization/destabilization of the corresponding diastereomeric transition state and, as such, determine the final percent enantiomeric excess (% ee).

Does the Configuration at the Metal Matter in Noyori–Ikariya Type Asymmetric Transfer Hydrogenation Catalysts?

“…Numerous experimental and computational studies of ( R , R )- 3 and its derivatives have indicated that the stereochemistry of the product is driven by a C–H···π interaction between mesitylene and the acetophenone phenyl ring, which helps to stabilize the transition state for the formation of R -1-phenylethanol (Scheme a). ,,,,− Reverse binding to give the S -1-phenylethanol product was found to be disfavored by a repulsive interaction between the lone pair on the sulfone and the substrate arene ring, further reinforcing the product enantioselectivity (Scheme b).…”

Engineered non-covalent π interactions as key elements for chiral recognition

“…Thus, further investigation into such a catalytic system would not only help shed light on the intricate origin of enantioselectivity in this important catalytic reaction, but also stimulate understanding on the underlying principles of π interactions as well as developing catalysts with assembling properties based on these non-covalent forces. To the best of our knowledge, very few examples exist that use such weak yet essential non-covalent π interactions as the control elements in asymmetric catalytic reactions 45 , 46 .…”

Aluminum‐Ligand Cooperative O−H Bond Activation Initiates Catalytic Transfer Hydrogenation

“…After more than two decades since the Nobel‐Prize‐winning developments in asymmetric TH (ATH) by Noyori, [4] molecular catalysts centered on Ru have remained of great interest to the chemical community. The origin of enantioselectivity is a result of a dynamic interplay of non‐covalent interactions within the transition state that ultimately determines enantiomeric excess [5] . Ligand design has played an important role in Ru‐catalyzed ATH and has led to the gram‐scale synthesis of chiral exocyclic allylic alcohols and cis ‐β‐substituted α‐hydroxybutyrolactone, which have otherwise been difficult to isolate [6]…”