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

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 goldcatalyzed 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).

TiCl4-Catalyzed Hydroboration of Ketones with Ammonia Borane

“…13 C­{1H} NMR (101 MHz, CDCl 3 ): δ 140.2, 128.6, 128.4, 125.9, 73.7, 40.1. Compound characterization is in accordance with previous reports …”

The Ir-Catalyzed Asymmetric Hydrogenation of α-Halogenated Ketones Utilizing Cinchona-Alkaloid-Derived NNP Ligand to Produce (R)- and (S)-Halohydrins

“…Known compound, colorless oil, 65.6 mg, 97.0% yield, 89.7% ee, R isomer, [α] D 25 = −18.3 ( c = 1.00 in CHCl 3 ), (lit . [α] D 25 = −13.3 ( c = 0.5, CHCl 3 )).…”

“…The product was purified by silica gel chromatography using petroleum ether/ethyl acetate ( 10 (R)-2-Chloro-1-(2-chlorophenyl)ethan-1-ol (P3). Known compound, 45 colorless oil; 25.1 mg, 87.6% yield, 99.0% ee, R isomer, [α] D 25 = −60.9 (c = 1.00 in CHCl 3 ), (lit. 27 [α] D 25 = +54.0 (c = 1.0, CHCl 3 )).…”

Application of Biobased Solvents in Asymmetric Catalysis

“…Recently, the group of Lavandera and Gotor-Fernández have reported a concurrent chemoenzymatic cascade to convert different haloalkynes ( 59 ) into enantiopure halohydrins ( 61 ) in an aqueous/2-MeTHF medium by combining a gold(I) N -heterocyclic carbene (NHC) and stereo-complementary KREDs, as shown in Figure 31 [ 135 ].…”