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

• 小林, 祐輔

  Graduate School of Pharmaceutical Sciences, Kyoto University

• 竹本, 佳司

  Graduate School of Pharmaceutical Sciences, Kyoto University

• Földes, Tamás

  Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences

• Nishibayashi, Kazuya

  Graduate School of Pharmaceutical Sciences, Kyoto University

• Kobayashi, Yusuke

  Graduate School of Pharmaceutical Sciences, Kyoto University

• Pápai, Imre

  Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences

• Takemoto, Yoshiji

  Graduate School of Pharmaceutical Sciences, Kyoto University

抄録

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 designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.

収録刊行物

• Journal of the American Chemical Society

  Journal of the American Chemical Society 140 (38), 12216-12225, 2018-09-26

  American Chemical Society (ACS)

キーワード

• Colloid and Surface Chemistry
• Biochemistry
• General Chemistry
• Catalysis

詳細情報

• CRID: 1050003824826396032
• NII論文ID: 120006865702
• ISSN: 00027863
• ISSN: 15205126
• DOI: 10.1021/jacs.8b07511
• HANDLE: 2433/252370
• Web Site: https://pubs.acs.org/doi/pdf/10.1021/jacs.8b07511
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN