Organocatalytic enantioselective α-hydroxymethylation of aldehydes: mechanistic aspects and optimization

The Journal of Organic Chemistry
Robert K BoeckmanJohn R Miller

Abstract

Further studies of the direct enantioselective α-hydroxymethylation of aldehydes employing the α,α-diarylprolinol trimethylsilyl ether class of organocatalysts are described. This process has proven efficient for access to β-hydroxycarboxylic acids and δ-hydroxy-α,β-unsaturated esters from aldehydes in generally good yields, excellent enantioselectivity, and compatibility with a broad range of functional groups in the aldehyde. The goal of these studies was to identify the critical reaction variables that influence the yield and enantioselectivity of the α-hydroxymethylation process such as catalyst structure, pH of the medium, purity of the reactants and reagents particularly with respect to the presence of acidic impurities, and the nature of the buffer, along with the standard variables including solvent, time, temperature and mixing efficiency. The previously identified intermediate lactol has been further characterized and its reactivity examined. These studies have led to identification of the most critical variables translating directly into improved substrate scope, reproducibility, enantioselectivity, and yields.

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Citations

Aug 19, 2020·Natural Product Reports·Sarah J HillRyan A Shenvi
Oct 2, 2015·Angewandte Chemie·Bjarke S DonslundKarl Anker Jørgensen
Jun 23, 2016·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Sara Meninno, Alessandra Lattanzi
Sep 10, 2020·Angewandte Chemie·Hong-Xiu HuangYong Qin
Sep 24, 2019·Journal of the American Chemical Society·Long MinChuang-Chuang Li
Dec 23, 2020·Accounts of Chemical Research·Xiao-Yu LiuYong Qin
Sep 15, 2017·Organic Letters·Alexander M SherwoodThomas E Prisinzano
Jul 4, 2020·Organic Letters·Jun HirabayashiSatoshi Ichikawa
Sep 3, 2021·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Li ZhaiRan Hong

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