Chemoenzymatic Synthesis Of O-Containing Heterocycles From Alpha-Diazo Esters

The synergy of biocatalysis and transition metal catalysis is rapidly moving forward, providing increasingly effective workflows in chemical synthesis. Here we present a facile way to prepare synthetically challenging O-containing heterocycles bearing disubstituted stereogenic centers via catalytic chemoenzymatic transformation of alpha-diazo carbonyl compounds. We demonstrate that keto-alpha-diazoesters can be enzymatically reduced to the corresponding alcohols with exquisite enantioselectivity and under retention of the diazo group using the ketoreductases LbADH and Gre2p. To further functionalize the resulting enantiopure (R)- and (S)-hydroxyl alpha-diazo esters, a variety of Cu and Rh catalysts were screened for intramolecular ring closure. Six- and seven-membered rings with both, aliphatic and ester substituents, were obtained with up to 93 : 7 diastereomeric ratio and 81 % yield. Up to 98 % enantiomeric excess was obtained for both diastereomers, yielding the thermodynamically less favored alpha,omega-trans-oxepanes as the main products.