Highly Diastereo- and Enantioselective Synthesis of Monodifferentiated syn-1,2-Diol Derivatives through Asymmetric Transfer Hydrogenation via Dynamic Kinetic Resolution

Abstract

The first enantio- and diastereoselective approach to alpha-alkoxy-substituted syn-beta-hydroxyesters through highly efficient catalytic asymmetric transfer hydrogenation via dynamic kinetic resolution reactions from the corresponding racemic beta-ketoesters is described. In this atom-economical process, two contiguous stereogenic centers are generated simultaneously with an excellent diastereoselectivity (up to 99/1) and enantioselectivity (up to 99%), allowing a rapid access to a wide variety of aromatic and heteroaromatic monodifferentiated syn-1,2-diols.

Transition‐Metal‐Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation: Sustainable Chemistry to Access Bioactive Molecules

“…However, most of the reported synthetic approaches to such units suffered from no differentiation of the two hydroxyl groups. In this context, we envisaged, in collaboration with Hoffmann‐La Roche, that the combination of DKR process with the ATH of racemic α‐alkoxy‐substituted β‐keto esters could provide a novel route to access stereodefined monodifferentiated 1,2‐diols units 60…”

Recent advances in enzymatic and chemical deracemisation of racemic compounds

“…In the same year Ratovelomanana-Vidal et al reported a DKR of related a-alkoxy-b-ketoesters based on Noyori's catalyst. 11 A number of ruthenium complexes were screened at 30 1C using 1.4 equiv. of a 5 : 2 formic acid-triethylamine mixture as a hydrogen source.…”

Efficient Synthesis of Differentiated syn‐1,2‐Diol Derivatives by Asymmetric Transfer Hydrogenation–Dynamic Kinetic Resolution of α‐Alkoxy‐Substituted β‐Ketoesters

“…Continuing our ongoing research toward the synthesis of relevant biologically active compounds by transition‐metal‐catalyzed asymmetric reduction,7 in a preliminary communication,8 we described a highly efficient procedure for ATH of prochiral α‐alkoxy‐β‐ketoesters coupled with a DKR process under mild reaction conditions with HCO 2 H/NEt 3 as the hydrogen source and well‐defined, commercially available chiral catalyst Ru II –TsDPEN. In this earlier effort, we demonstrated that easily accessible racemic aryl α‐alkoxy‐β‐ketoesters could be efficiently transformed to the corresponding monodifferentiated 1,2‐diols with almost perfect enantioselectivity (enantiomeric excess ( ee ) up to 99 %) and excellent diastereoselectivity (diastereomeric ratio (d.r.)…”