Hexafluoroisobutylation of Enolates Through a Tandem Elimination/allylic Shift/hydrofluorination Reaction

Overview

Journal Chem Sci

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 Sep 12

PMID 36091907

Authors

Aline Delamare

Guillaume Naulet

Brice Kauffmann

Gilles Guichard

Guillaume Compain

Affiliations

Soon will be listed here.

Abstract

The isobutyl side chain is a highly prevalent hydrophobic group in drugs, and it notably constitutes the side chain of leucine. Its replacement by a hexafluorinated version containing two CF groups may endow the target compound with new and advantageous properties, yet this modification remains overlooked due to the absence of a general and practical synthetic methodology. Herein, we report the first general method to introduce the hexafluoroisobutyl group into ketoesters, malonates, 1,3-diketones, Schiff base esters and malononitrile. We demonstrated that the reaction occurs through an elimination/allylic shift/hydrofluorination cascade process which efficiently overcomes the usual fluoride β-elimination observed with α-CF-vinyl groups. We showed that with alkali metal bases, a pentafluorinated alkene is obtained predominantly, whereas the use of tetrabutylammonium fluoride (TBAF) allows hydrofluorination to occur. This tandem process represents a conceptually new pathway to synthesize bis-trifluoromethylated compounds. This methodology was applied to the multigram-scale synthesis of enantiopure ()-5,5,5,5',5',5'-hexafluoroleucine.

Citing Articles

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Lends A, Daskalov A, Maleckis A, Delamare A, Berbon M, Grelard A Commun Biol. 2022; 5(1):1202.

PMID: 36352173 PMC: 9646696. DOI: 10.1038/s42003-022-04175-1.

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