A Telescoped Continuous Flow Enantioselective Process for Accessing Intermediates of 1-Aryl-1,3-diols as Chiral Building Blocks

Aitor Maestro; Bence S Nagy; Sándor B Ötvös; C Oliver Kappe

doi:10.1021/acs.joc.3c02040

A Telescoped Continuous Flow Enantioselective Process for Accessing Intermediates of 1-Aryl-1,3-diols as Chiral Building Blocks

J Org Chem. 2023 Nov 3;88(21):15523-15529. doi: 10.1021/acs.joc.3c02040. Epub 2023 Oct 16.

Authors

Aitor Maestro^{1

2}, Bence S Nagy², Sándor B Ötvös^{2

3}, C Oliver Kappe^{2

3}

Affiliations

¹ Department of Organic Chemistry I, University of the Basque Country, UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
² Institute of Chemistry, University of Graz, NAWI Graz, A-8010 Graz, Austria.
³ Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), A-8010 Graz, Austria.

Abstract

A telescoped continuous flow process is reported for the enantioselective synthesis of chiral precursors of 1-aryl-1,3-diols, intermediates in the synthesis of ezetimibe, dapoxetine, duloxetine, and atomoxetine. The two-step sequence consists of an asymmetric allylboration of readily available aldehydes using a polymer-supported chiral phosphoric acid catalyst to introduce asymmetry, followed by selective epoxidation of the resulting alkene. The process is highly stable for at least 7 h and represents a transition-metal free enantioselective approach to valuable 1-aryl-1,3-diols.