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).

The combination of metal-, photo-, enzyme-, and/or organocatalysis provides multiple synthetic solutions, especially when the creation of chiral centers is involved. Historically, enzymes and transition metal species have been exploited simultaneously through dynamic kinetic resolutions of racemates. However, more recently, linear cascades have appeared as elegant solutions for the preparation of valuable organic molecules combining multiple bioprocesses and metal-catalyzed transformations. Many advantages are derived from this symbiosis, although there are still bottlenecks to be addressed including the successful coexistence of both catalyst types, the need for compatible reaction media and mild conditions, or the minimization of cross-reactivities. Therefore, solutions are here also provided by means of catalyst coimmobilization, compartmentalization strategies, flow chemistry, etc. A comprehensive review is presented focusing on the period 2015 to early 2022, which has been divided into two main sections that comprise first the use of metals and enzymes as independent catalysts but working in an orchestral or sequential manner, and later their application as bionanohybrid materials through their coimmobilization in adequate supports. Each part has been classified into different subheadings, the first part based on the reaction catalyzed by the metal catalyst, while the development of nonasymmetric or stereoselective processes was considered for the bionanohybrid section.

Dedicated to Professor Marko D. Mihovilovic on occasion of his 50 th birthday.

The combination of gold(I) and enzyme catalysis is used in at wo-step approach, including Meyer-Schuster rearrangement of as eries of readily available propargylic alcohols followed by stereoselective bioreduction of the corresponding allylic ketone intermediates,toprovide optically pure b,b-disubstituted allylic alcohols.T his cascade involves ag old N-heterocyclic carbene and an enzyme,d emonstrating the compatibility of both catalyst types in aqueous medium under mild reaction conditions.T he combination of [1,3bis(2,6-) and aselective alcohol dehydrogenase (ADH-A from Rhodococcus ruber,K RED-P1-A12 or KRED-P3-G09) led to the synthesis of as eries of optically active (E)-4-arylpent-3-en-2ols in good yields (65-86 %). The approach was also extended to various 2-hetarylpent-3-yn-2-ol, hexynol, and butynol derivatives.T he use of alcohol dehydrogenases of opposite selectivity led to the production of both allyl alcohol enantiomers (93-> 99 %ee) for ab road panel of substrates.

The combination of gold(I) and enzyme catalysis is used in at wo-step approach, including Meyer-Schuster rearrangement of as eries of readily available propargylic alcohols followed by stereoselective bioreduction of the corresponding allylic ketone intermediates,toprovide optically pure b,b-disubstituted allylic alcohols.T his cascade involves ag old N-heterocyclic carbene and an enzyme,d emonstrating the compatibility of both catalyst types in aqueous medium under mild reaction conditions.T he combination of [1,3bis(2,6-) and aselective alcohol dehydrogenase (ADH-A from Rhodococcus ruber,K RED-P1-A12 or KRED-P3-G09) led to the synthesis of as eries of optically active (E)-4-arylpent-3-en-2ols in good yields (65-86 %). The approach was also extended to various 2-hetarylpent-3-yn-2-ol, hexynol, and butynol derivatives.T he use of alcohol dehydrogenases of opposite selectivity led to the production of both allyl alcohol enantiomers (93-> 99 %ee) for ab road panel of substrates.