Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 58, Issue 42, Pages 15111-15119Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201908627
Keywords
enantioselective Michael addition; inverse secondary kinetic isotope effect; isothiourea catalysis; mechanistic analysis; VTNA
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Funding
- European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) ERC grant [279850]
- EPSRC [EP/M508214/1]
- Royal Society
- EPSRC [1792153] Funding Source: UKRI
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An isothiourea-catalyzed enantioselective Michael addition of aryl ester pronucleophiles to vinyl bis-sulfones via C(1)-ammonium enolate intermediates has been developed. This operationally simple method allows the base-free functionalization of aryl esters to form alpha-functionalized products containing two contiguous tertiary stereogenic centres in excellent yield and stereoselectivity (all >= 99:1 er). Key to the success of this methodology is the multifunctional role of the aryloxide, which operates as a leaving group, Bronsted base, Bronsted acid and Lewis base within the catalytic cycle. Comprehensive mechanistic studies, including variable time normalization analysis (VTNA) and isotopologue competition experiments, have been carried out. These studies have identified (i) orders of all reactants; (ii) a turnover-limiting Michael addition step, (iii) product inhibition, (iv) the catalyst resting state and (v) catalyst deactivation through protonation.
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