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

Sergio González-Granda,Iván Lavandera,Vicente Gotor-Fernández,Lorena Escot

doi:10.1021/acscatal.1c05216

Abstract

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 gold-catalyzed regioselective hydration of easily accessible haloalkynes, followed by the stereoselective bioreduction of the corresponding α-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).

Highlights

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
Being aware of the difficulties to develop multicatalytic transformations when considering an alkyne hydration and biotransformation sequences in a concurrent cascade mode,[50−52] we have focused on the exploitation of the compatibility of an N-heterocyclic carbene (NHC)− gold(I) complex, namely, [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene] [bis(trifluoromethanesulfonyl)imide]gold(I) (IPrAuNTf2) with ADHs, recently reported as the first example of a concurrent cascade involving a gold species and these oxidoreductases.[53]
The most representative results are presented: (i) the gold(I)-catalyzed hydration process ofbenzene (1a) and the scope of the reaction using other haloalkynes 1b1l; (ii) the bioreduction of 2-chloro-1-phenylethan-1-one (2a) using different ADHs; (iii) the development and scope of the stereodivergent concurrent cascade consisting in the alkyne-hydration sequence; (iv) and an application of this methodology for creating new molecular diversity in a onepot sequential transformation toward an optically active epoxide

Summary

Introduction

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. Α-Halomethyl ketones constitute one of the most important classes of organic intermediates based on their multiple synthetic possibilities due to the susceptibility of the carbonyl group to be reduced with reducing agents, react with different nucleophile classes,[1−3] and their ability to become carboxylic acid precursors through the Favorskii rearrangement.[4] Two traditional approaches have been described for their synthesis, consisting of the development of α-halogenation of the corresponding ketones[1] or alternatively the chemical modification of olefins and alkynes.[5] the halogenation of ketones with molecular halogens, metal halides, or N-halosuccinimides usually suffers from serious drawbacks due to the occurrence of low regiospecificity or polyhalogenation transformations, and special efforts have been made in recent years toward the selective modification of C−C multiple bonds under mild reaction conditions. Liu and co-workers have demonstrated the potential of this methodology combining the gold(I)-mediated hydration of haloalkynes with a Ru-catalyzed hydrogen transfer reaction to obtain enantioenriched halohydrins in 1,2-dichloroethane at 20 °C.25,26

Methods

Results

Conclusion