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Synthesis of Azabicyclo[3.1.1]heptenes Enabled by Catalyst-Controlled Annulations of Bicyclo[1.1.0]butanes with Vinyl Azides.
Lin, Zhongren; Ren, Haosong; Lin, Xinbo; Yu, Xinhong; Zheng, Jun.
Afiliação
  • Lin Z; Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China.
  • Ren H; Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China.
  • Lin X; Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China.
  • Yu X; Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China.
  • Zheng J; Engineering Research Center of Pharmaceutical Process Chemistry, Ministry of Education; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China.
J Am Chem Soc ; 146(27): 18565-18575, 2024 Jul 10.
Article em En | MEDLINE | ID: mdl-38935924
ABSTRACT
Bridged bicyclic scaffolds are emerging bioisosteres of planar aromatic rings under the concept of "escape from flatland". However, adopting this concept into the exploration of bioisosteres of pyridines remains elusive due to the challenge of incorporating a N atom into such bridged bicyclic structures. Herein, we report practical routes for the divergent synthesis of 2- and 3-azabicyclo[3.1.1]heptenes (aza-BCHepes) as potential bioisosteres of pyridines from the readily accessible vinyl azides and bicyclo[1.1.0]butanes (BCBs) via two distinct catalytic annulations. The reactivity of vinyl azides tailored with BCBs is the key to achieving divergent transformations. TiIII-catalyzed single-electron reductive generation of C-radicals from BCBs allows a concise (3 + 3) annulation with vinyl azides, affording novel 2-aza-BCHepe scaffolds. In contrast, scandium catalysis enables an efficient dipolar (3 + 2) annulation with vinyl azides to generate 2-azidobicyclo[2.1.1]hexanes, which subsequently undergo a chemoselective rearrangement to construct 3-aza-BCHepes. Both approaches efficiently deliver unique azabicyclo[3.1.1]heptene scaffolds with a high functional group tolerance. The synthetic utility has been further demonstrated by scale-up reactions and diverse postcatalytic transformations, providing valuable azabicyclics including 2- and 3-azabicyclo[3.1.1]heptanes and rigid bicyclic amino esters. In addition, the related sp2-hybridized nitrogen atom and the similar geometric property between pyridines and corresponding aza-BCHepes indicate that they are promising bioisosteres of pyridines.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article