Highly Enantioselective Synthesis of syn-β-Hydroxy α-Dibenzylamino Esters via DKR Asymmetric Transfer Hydrogenation and Gram-Scale Preparation of Droxidopa

Abstract

A highly efficient preparation of enantiomerically pure syn aryl β-hydroxy α-dibenzylamino esters is reported. The outcome was achieved via dynamic kinetic resolution and asymmetric transfer hydrogenation of aryl α-dibenzylamino β-keto esters. The desired products were obtained in high yields (up to 98%) with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (up to >99% ee). Furthermore, this method was applied for the gram-scale preparation of droxidopa.

Asymmetric Transfer Hydrogenation of α-Substituted-β-Keto Carbonitriles via Dynamic Kinetic Resolution

“…Asymmetric transformations comprising DKR processes are very attractive since racemic substrates converge ideally to a diastereo- and enantiomerically pure product in this transformation. − In particular, the DKR encountered in asymmetric transfer hydrogenation (ATH) of ketones is a powerful protocol for “deracemization” of substrates, which possess a stereolabile α-carbon by converting them into alcohols with two contiguous stereogenic centers. − In 1989, Noyori and co-workers reported trailblazing work on the asymmetric hydrogenation of β-keto esters using Ru–BINAP catalysts . Since then, the utility of reductive DKR processes has been further accentuated by taking advantage of asymmetric transfer hydrogenation (ATH) with bifunctional Ru, Rh, and Ir catalysts containing chiral N -sulfonyl-1,2-diamine scaffolds. − …”

Bifunctional Homogeneous Catalysts Based on Ruthenium, Rhodium and Iridium in Asymmetric Hydrogenation

“…By following a similar approach, Wang and co-workers reported on the application of DKR/ATH for the gram scale production of syn--hydroxy -dibenzylamino esters intermediate in the synthesis of Doxidopa. 128 Other tethered ruthenium catalysts were developed by Mohar and co-workers on the basis of an enantiopure N,C-(N-ethylene-N-methyl-sulfamoyl)-tethered DPEN-toluene hybrid ligand. 129 This new catalyst was rather efficient for the ATH of challenging 1-naphthyl ketones, a large array of substrates being reduced in the presence of HCO2H/NEt3 (Scheme 23).…”

Enantio‐ and Diastereoselective Synthesis of Chiral Syn‐Aryl β‐Hydroxy α‐Amino Esters via Biocatalytic Dynamic Reductive Kinetic Resolution

“…Among others, dynamic reductive kinetic resolution (DYRKR) of racemic aryl α‐amino β‐keto esters represents a step‐ and atom‐economic approach to synthesize chiral aryl β‐hydroxy α‐amino esters, as the α‐protons of these substrates are acidic. In this regard, transition metals such as ruthenium and rhodium, derived chiral catalysts have been widely utilized for this specific DYRKR reaction, both in asymmetric hydrogenation and asymmetric transfer hydrogenation modes [3b,4d,6] . Depending on the conditions employed, syn ‐ and anti ‐aryl β‐hydroxy α‐amino esters could be accessed in a controllable manner with good‐to‐excellent diastereo‐ and enantioselectivity.…”