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H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Enantioenriched Secondary Alcohols by N-, O-, and S-Centered Nucleophiles to Generate Heterocycles
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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Number of Authors: 82020 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 10, no 2, p. 1344-1352Article in journal (Refereed) Published
Abstract [en]

The direct intramolecular stereospecific substitution of the hydroxyl group in enantiomerically enriched secondary benzylic, allylic, propargylic, and alkyl alcohols was successfully accomplished by phosphinic acid catalysis. The hydroxyl group was displaced by O-, S-, and N-centered nucleophiles to provide enantioenriched five-membered tetrahydrofuran, pyrrolidine, and tetrahydrothiophene as well as six-membered tetrahydroquinolines and chromanes in up to a 99% yield and 100% enantiospecificity with water as the only byproduct. Mechanistic studies using both experiments and calculations have been performed for substrates generating 5-membered heterocycles. Rate studies show dependences in a catalyst, an internal nucleophile, and an electrophile, however, independence in an external nucleophile, an electrophile, or water. Kinetic isotope effect studies show an inverse KIE of k(H)/k(D) = 0.79. Furthermore, phosphinic acid does not promote S(N)1 reactivity. Computational studies support a bifunctional role of the phosphinic acid in which activation of both nucleofuge and nucleophile occurs in a bridging S(N)2-type transition state. In this transition state, the acidic hydrogen of phosphinic acid protonates the leaving hydroxyl group simultaneously as the oxo group partially deprotonates the nucleophile. Thereby, phosphinic acid promotes the substitution of the nonderivatized hydroxyl group in enantioenriched secondary alcohols by uncharged nucleophiles with conservation of the chirality from the alcohol to the heterocycle.

Place, publisher, year, edition, pages
2020. Vol. 10, no 2, p. 1344-1352
Keywords [en]
stereospecific substitution, alcohols, phosphinic acid catalysis, heterocyclic compounds, atom economy
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-179626DOI: 10.1021/acscatal.9b03458ISI: 000508466700038OAI: oai:DiVA.org:su-179626DiVA, id: diva2:1414762
Available from: 2020-03-16 Created: 2020-03-16 Last updated: 2020-03-16Bibliographically approved

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Srifa, PemikarRukkijakan, ThanyaHuang, GenpingWatile, Rahul A.Samec, Joseph S. M.
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