Highly Enantiomerically Enriched Secondary Alcohols via Epoxide Hydrogenolysis

Abstract

In this article, we report the development of ruthenium-catalyzed hydrogenolysis of epoxides to selectively give the branched (Markovnikov) alcohol products. In contrast to previously reported catalysts, the use of Milstein's PNN-pincer-ruthenium complex at room temperature allows the conversion of enantiomerically enriched epoxides to secondary alcohols without racemization of the product. The catalyst is effective for a range of aryl epoxides, alkyl epoxides, and glycidyl ethers and is the first homogeneous system to selectively promote hydrogenolysis of glycidol to 1,2-propanediol, without loss of enantiomeric purity. A detailed mechanistic study was conducted, including experimental observations of catalyst speciation under catalytically relevant conditions, comprehensive kinetic characterization of the catalytic reaction, and computational analysis via density functional theory. Heterolytic hydrogen cleavage is mediated by the ruthenium center and exogenous alkoxide base. Epoxide ring opening occurs through an opposite-side attack of the ruthenium hydride on the less-hindered epoxide carbon, giving the branched alcohol product selectively.

Scheme 1. Catalytic Epoxide Hydrogenolysis

Chart 1. Previously Reported Catalysts for Branched-Selective Epoxide Hydrogenolysis

Scheme 2. Abbreviated Mechanism for Branched-Selective Epoxide Hydrogenolysis Catalyzed by Noyori-Type Ruthenium-Pincer Complexes

Scheme 3. Reversible Activation of Hydrogen by Ru-dearom

Scheme 4. Conversion of Precatalysts with Dearomatized Pincer Ligands to the Active, Noyori-Type Forms

Scheme 5. Equilibrium between RuOⁱPr and RuH

Figure 1

Mole fraction [RuH]/[Ru]_total vs [H₂], as determined by ¹H NMR spectroscopy. Blue points represent values measured in independent experiments. The orange curve represents the best fit of the data to determine the equilibrium constant K₁.

Scheme 6. Relative Standard-State Free Energies of Plausible Catalyst Resting States, Calculated by DFT at 298.15 K

Figure 2

Minimum energy pathway for epoxide hydrogenolysis beginning with RuOⁱPr-solv. Atoms in bold and blue represent the atoms primarily involved in bond-breaking and bond-forming in transition states. The energies reported are Gibbs free energies at 298.15 K, corrected to the 1.0 M standard state for all species except for the solvent isopropyl alcohol, whose standard state is 13.08 M, its neat molarity. Mass balance is ensured throughout, and energies are calculated relative to RuH-solv, the main catalyst resting state.

Scheme 7. Simplified Mechanism Determining the Kinetics for Epoxide Hydrogenolysis

Scheme 8. Standard Conditions for Kinetic Experiments

Figure 3

Plots of k_obs vs [Ru]_total (a), [epoxide]₀ (b), hydrogen pressure (c), and [KOⁱPr] (d). Blue points represent k_obs values from independent experiments. Orange lines represent the k_obs value predicted from a global fit of all 18 experiments.

Figure 4

Dependence of k_obs on the concentration of added [2.2.2]cryptand for epoxide hydrogenolysis with 18.75 mM KOⁱPr (blue circles) or NaOⁱPr (red triangles).

Figure 5

Comparison of (R)-styrene oxide hydrogenolysis catalyzed by RuCl vs RuPNN^HEt. The top panel shows the total yield of hydrogenolysis products, the middle panel shows the e.e. of the 1-phenylethanol product, and the bottom panel shows the branched:linear ratio.

Figure 6

MEP for the reversible dehydrogenation of 2-propanol to acetone, catalyzed by RuPNN^HEt. Free energies at 298.15 K are calculated relative to p, the calculated catalyst resting state.