Anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients

Tomoya Karasawa, Raphaël Oriez, Naoya Kumagai, Masakatsu Shibasaki

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.

Original languageEnglish
Pages (from-to)12290-12295
Number of pages6
JournalJournal of the American Chemical Society
Volume140
Issue number38
DOIs
Publication statusPublished - 2018 Sep 26
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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