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

Abstract

Noyori-Ikariya type [(arene)RuCl(TsDPEN)] (TsDPEN, sulfonated diphenyl ethylenediamine) complexes are widely used C=O and C=N reduction catalysts that produce chiral alcohols and amines via a key ruthenium-hydride intermediate that determines the stereochemistry of the product. Whereas many details about the interactions of the pro-chiral substrate with the hydride complex and the nature of the hydrogen transfer from the latter to the former have been investigated over the past 25 years, the role of the stereochemical configuration at the stereogenic ruthenium center in the catalysis has not been elucidated so far. Using operando FlowNMR spectroscopy and nuclear Overhauser effect spectroscopy, we show the existence of two diastereomeric hydride complexes under reaction conditions, assign their absolute configurations in solution, and monitor their interconversion during transfer hydrogenation catalysis. Configurational analysis and multifunctional density functional theory (DFT) calculations show the λ-(R,R)S ^Ru configured [(mesitylene)RuH(TsDPEN)] complex to be both thermodynamically and kinetically favored over its λ-(R,R)R ^Ru isomer with the opposite configuration at the metal. Computational analysis of both diastereomeric catalytic manifolds show the major λ-(R,R)S ^Ru configured [(mesitylene)RuH(TsDPEN)] complex to dominate asymmetric ketone reduction catalysis with the minor λ-(R,R)R ^Ru [(mesitylene)RuH(TsDPEN)] stereoisomer being both less active and less enantioselective. These findings also hold true for a tethered catalyst derivative with a propyl linker between the arene and TsDPEN ligands and thus show enantioselective transfer hydrogenation catalysis with Noyori-Ikariya complexes to proceed via a lock-and-key mechanism.

Scheme 1. Simplified Schematic of the Noyori–Ikariya Asymmetric Transfer Hydrogenation Reaction Showing Catalyst Precursor 1 and Major in-Cycle Intermediates 2 and 3

Typically R³=R⁴=CH₃.

Scheme 2. Structures and Relationships between Possible Stereoisomers of [(Mesitylene)RuH(TsDPEN)] Transfer Hydrogenation Catalysts

Scheme 3. Simplified Depiction of the Interconversion of Diastereomeric Hydride Complexes (R,R)S^Ru-3 and (R,R)R^Ru-3 via the Achiral-at-Metal Amido Intermediate (R,R)-2

Scheme 4. Expected Geometries for the Two Possible Diastereomers of [(Mesitylene)RuH(TsDPEN)] Resulting from the Inversion of Chirality at Ruthenium

Scheme 5. Standard Conditions Used for the Catalytic Asymmetric Transfer Hydrogenation of Acetophenone to (R)-1-Phenylethanol with [(Mesitylene)RuCl((R,R)-TsDPEN)] 1

Unless otherwise specified, catalysts with the (R,R)-TsDPEN ligand configuration were used in all experiments.

Figure 1

(a) ¹H NMR spectrum of hydrides 3a (−5.26 ppm) and 3b (−6.54 ppm) and (b) product conversion and concentration profiles of hydrides 3a and 3b during the course of catalytic transfer hydrogenation of acetophenone to R-1-phenylethanol in flow at 4 mL/min (400 mM acetophenone, 10 mM KOH, 2 mM complex 1, 9.5 mL of dry isopropanol, 20 °C). Selective excitation using a gradient spin echo pulse sequence with a shaped 180° pulse centered at −5.5 ppm (8 scans, 2 s acquisition time, 1 s delay time, 1600 μs Gaussian shaped pulse).

Figure 2

Concentration profiles of hydride peaks 3a (−5.26 ppm) and 3b (−6.54 ppm) in flow at 4 mL/min (40 mM acetophenone, 360 mM rac-1-phenylethanol, 360 mM acetone, 10 mM KOH, 4 mM (1), 9.5 mL of dry isopropanol, 20 °C). Selective excitation using a gradient spin echo pulse sequence with a shaped 180° pulse centered at −5.5 ppm (8 scans, 2 s acquisition time, 1 s delay time, 1600 μs Gaussian shaped pulse).

Scheme 6. DFT Optimized Solution Structures and Experimental ¹H NMR Chemical Shifts (C₆D₆) of Hydride Complexes (R,R)S^Ru-3a and (R,R)R^Ru-3b Showing Observed NOE Interactions and Contact Distances

rωB97X-D(SMD:iPrOH)/SDD (Ru)/6-31+G(d) (Ph and Ts C,H)/6-311++G(d,p) (all other atoms).

Scheme 7. Proposed Mechanism and Calculated Ground and Transition State Energies (kcal/mol) for the Formation of R-1-Phenylethanol and S-1-Phenylethanol via Either the (R,R)S^Ru or (R,R)R^Ru Configured Catalyst

See the Supporting Information for the details of the calculations. IPA = 2-propanol; Ac. = acetone; Acp. = acetophenone; 1-PE = 1-phenylethanol.

Figure 3

¹H NMR spectra of (a) hydride complexes 3a and 3b and (b) hydride complexes 3a and 3b after pressurizing with 5 bar CO₂ (THF-h₈, 20 °C). Selective excitation using a gradient spin echo pulse sequence with a shaped 180° pulse centered at −9 ppm (12 scans, 1.33 s acquisition time, 1 s delay time, 1000 μs Gaussian shaped pulse).

Scheme 8. Schematic of (a) Favorable C–H···π Attractions between the Mesitylene and Acetophenone Arene Rings and (b) Unfavorable Oxygen Lone Pair-π Repulsion between the SO₂ Group and Acetophenone in the Transition State of (R,R)S^Ru-3a Reducing Acetophenone

Scheme 9. Structure of Wills’ C3-Tethered Complex 4

Scheme 10. Interconversion of Hydride Complexes (R,R)S^Ru-6a and (R,R)R^Ru-6b via the Achiral-at-Metal Intermediate (R,R)-5

Figure 4

Concentration of hydride complexes (R,R)S^Ru-6a (−5.26 ppm) and (R,R)R^Ru-6b (−5.51 ppm), conversion, and product enantioselectivity data for the asymmetric transfer hydrogenation of acetophenone to (S)-1-phenylethanol (4 mM (R,R)-4, 20 mM KOH, 400 mM acetophenone (additional 400 mM acetophenone added after 14.5 h), 38 mL of isopropanol, 20 °C). Selective excitation using a gradient spin echo pulse sequence with a shaped 180° pulse centered at −5.5 ppm (96 scans, 2 s acquisition time, 1 s delay time, 1600 μs Gaussian shaped pulse). Note: The minor increase in conversion after 20 h is due to evaporation of acetone (formed as a byproduct of the reaction), leading to a shift in the equilibrium position.