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<p>The hetero-Diels–Alder (HDA) reaction is a key method for synthesizing six-membered heterocyclic rings in natural products and bioactive compounds. Despite its importance in synthetic chemistry, naturally occurring enzymatic HDA reactions are rare and limited to a single heteroatom. Here we report Abx<sub>(−)</sub>F, a bifunctional vicinal oxygen chelate (VOC)-like protein that catalyses dehydration and dual-oxa Diels–Alder reactions to stereoselectively form the oxygen-bridged tricyclic acetal of (–)-anthrabenzoxocinone ((−)-ABX). Isotope assays and density functional theory calculations reveal a dehydration-coordinated, concerted HDA mechanism. The crystal structure of Abx<sub>(−)</sub>F and NMR complex structures of Abx<sub>(−)</sub>F with its substrate analogue and (−)-ABX define the reaction’s structural basis. Mutational analysis identifies Asp17 as a general base that mediates dehydration, forming an <i>o</i>-quinone methide intermediate for stereoselective dual-oxa HDA. This work establishes the molecular and structural basis of a polyheteroatomic Diels–Alderase, paving the way for designing polyheteroatomic DA enzymatic tools.</p><p></p>

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An enzymatic dual-oxa Diels–Alder reaction constructs the oxygen-bridged tricyclic acetal unit of (–)-anthrabenzoxocinone

  • 期刊论文

  • 发表日期：

    2025年4月22日

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  • Xiaoli Yan,
  • Xinying Jia,
  • Zhenyao Luo,
  • Shunjia Ji,
  • Meng-Jie Zhang,
  • Hui Zhang,
  • Mingjia Yu,
  • Julien Orts,
  • Kai Jiang,
  • Zhi Lin,
  • Zixin Deng,
  • Xu-Dong Kong,
  • Bostjan Kobe,
  • Yi-Lei Zhao,
  • Mehdi Mobli,
  • Xudong Qu

摘要

The hetero-Diels–Alder (HDA) reaction is a key method for synthesizing six-membered heterocyclic rings in natural products and bioactive compounds. Despite its importance in synthetic chemistry, naturally occurring enzymatic HDA reactions are rare and limited to a single heteroatom. Here we report Abx(−)F, a bifunctional vicinal oxygen chelate (VOC)-like protein that catalyses dehydration and dual-oxa Diels–Alder reactions to stereoselectively form the oxygen-bridged tricyclic acetal of (–)-anthrabenzoxocinone ((−)-ABX). Isotope assays and density functional theory calculations reveal a dehydration-coordinated, concerted HDA mechanism. The crystal structure of Abx(−)F and NMR complex structures of Abx(−)F with its substrate analogue and (−)-ABX define the reaction’s structural basis. Mutational analysis identifies Asp17 as a general base that mediates dehydration, forming an o-quinone methide intermediate for stereoselective dual-oxa HDA. This work establishes the molecular and structural basis of a polyheteroatomic Diels–Alderase, paving the way for designing polyheteroatomic DA enzymatic tools.