Unmasking the Hidden Carbonyl Group Using Gold(I) Catalysts and Alcohol Dehydrogenases: Design of a Thermodynamically-Driven Cascade toward Optically Active Halohydrins

A concurrent cascade combining the use of a gold(I) N-heterocyclic carbene (NHC) and an alcohol dehydrogenase (ADH) is disclosed for the synthesis of highly valuable enantiopure halohydrins in an aqueous medium and under mild reaction conditions. The methodology consists of the goldcatalyzed regioselective hydration of easily accessible haloalkynes, followed by the stereoselective bioreduction of the corresponding alpha-halomethyl ketone intermediates. Thus, a series of alkyl- and aryl-substituted haloalkynes have been selectively converted into chloro- and bromohydrins, which were obtained in good to high yields (65-86%). Remarkably, the use of stereocomplementary commercial or made-in-house overexpressed alcohol dehydrogenases in Escherichia coli has allowed the synthesis of both halohydrin enantiomers with remarkable selectivities (98 -> 99% ee). The outcome success of this method was due to the thermodynamically driven reduction of the ketone intermediates, as just a small excess of the hydrogen donor (2-propanol, 2-PrOH) was necessary. In the cases that larger quantities of 2-PrOH were applied, higher amounts of other by-products (e.g., a vinyl ether derivative) were detected. Finally, as an extension of this cascade transformation and exploration of the synthetic potential of chiral halohydrins, the synthesis of both enantiomers of styrene oxide has been developed in a one-pot sequential manner in very high yields (88-92%) and optical purities (97 -> 99% ee).

Automated summary

A concurrent cascade reaction using a gold(I) N-heterocyclic carbene and an alcohol dehydrogenase was developed for the synthesis of enantiopure halohydrins. The reaction proceeds through regioselective hydration of haloalkynes followed by stereoselective bioreduction of alpha-halomethyl ketone intermediates. The method demonstrates high selectivity and good yields of chloro- and bromohydrins. Additionally, the synthesis of enantiomers of styrene oxide in high yields and optical purities was achieved.