Chemoenzymatic Asymmetric Synthesis of Complex Heterocycles: Dihydrobenzoxazinones and Dihydroquinoxalinones

Faizan Bhat, Alejandro Prats Lujan, Mohammad Saifuddin, Gerrit Poelarends*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
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Chiral dihydrobenzoxazinones and dihydroquinoxalinones serve as essential building blocks for pharmaceuticals and agrochemicals. Here, we report short chemoenzymatic synthesis routes for the facile preparation of these complex heterocycles in an optically pure form. These synthetic routes involve a highly stereoselective hydroamination step catalyzed by ethylenediamine-N,N′-disuccinic acid lyase (EDDS lyase). This enzyme is capable of catalyzing the asymmetric addition of various substituted 2-aminophenols to fumarate to give a broad range of substituted N-(2-hydroxyphenyl)-l-aspartic acids with excellent enantiomeric excess (ee up to >99%). This biocatalytic hydroamination step was combined with an acid-catalyzed esterification–cyclization sequence to convert the enzymatically generated noncanonical amino acids into the desired dihydrobenzoxazinones in good overall yield (up to 63%) and high optical purity (ee up to >99%). By means of a similar one-pot, two-step chemoenzymatic approach, enantioenriched dihydroquinoxalinones (ee up to >99%) were prepared in good overall yield (up to 78%) using water as solvent for both steps. These chemoenzymatic methodologies offer attractive alternative routes to challenging dihydrobenzoxazinones and dihydroquinoxalinones, starting from simple and commercially available achiral building blocks.
Original languageEnglish
Pages (from-to)11421–11427
Number of pages7
JournalACS Catalysis
Publication statusPublished - 6-Sept-2022

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