Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas

Journal of the American Chemical Society
Noboru HayamaYoshiji Takemoto

Abstract

Carboxylic acids and their corresponding carboxylate anions are generally utilized as Brønsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH2 to α,β-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Brønsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also de...Continue Reading

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Citations

Feb 9, 2019·Organic & Biomolecular Chemistry·Kenichi MichigamiYoshiji Takemoto
Mar 23, 2019·Organic & Biomolecular Chemistry·Satoru KuwanoTakayoshi Arai
Apr 4, 2019·Organic & Biomolecular Chemistry·Joseph A IzzoMathew J Vetticatt
Aug 9, 2019·Chemistry : a European Journal·Satoru KuwanoTakayoshi Arai
Jan 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Franz SteppelerJacek Wojaczyński
May 16, 2019·Chemical Society Reviews·Dennis G Hall
Mar 3, 2020·Chemical Society Reviews·Congjun YuMónica H Pérez-Temprano
Mar 2, 2021·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Noboru Hayama
Jul 17, 2020·The Journal of Organic Chemistry·Keisuke YoshidaKen-Ichi Takao
Sep 3, 2021·Chemical & Pharmaceutical Bulletin·Yoshiji Takemoto
Dec 3, 2021·Organic & Biomolecular Chemistry·Rui NiuJun-Bing Lin
Nov 25, 2021·Chemistry, an Asian Journal·Shana SudhakaranBenudhar Punji
Dec 8, 2021·Chemical Communications : Chem Comm·Ryo TanakaShigeki Matsunaga

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