Strengthening the Combination between Enzymes and Metals in Aqueous Medium: Concurrent Ruthenium‐Catalyzed Nitrile Hydration ‐ Asymmetric Ketone Bioreduction

Abstract

A dual ruthenium/ketoreductase catalytic system has been developed for the conversion of β‐ketonitriles into optically active β‐hydroxyamides through an unprecedented hydration/bioreduction cascade process in aqueous medium working in concurrent mode. The ketoreductase‐mediated ketone reduction took place with exquisite stereoselectivity and it was simultaneous to the nitrile hydration promoted by the ruthenium catalyst. The overall transformation occurred: (i) employing commercially and readily available catalytic systems (ii) under mild reaction conditions, (iii) with high degree of conversion and excellent stereoselectivity, and (iv) without the need to isolate intermediates and with high final product yields. This genuine process demonstrates the benefits of combining metal and enzymatic catalysis to tackle the limitations arising from each field.

Access to α‐ and β‐Hydroxyamides and Ureas Through Metal‐Catalyzed C≡N Bond Hydration and Transfer Hydration Reactions

“…[50b] In a subsequent study, we also succeeded in the one-pot conversion of β-ketonitriles into optically pure β-hydroxyamides, through a bioreduction/hydration cascade process, by sequential combination of commercial engineered ketoreductases (included in the Codex® KRED Screening Kit from Codexis) with the bis(allyl)-ruthenium(IV) derivative [RuCl 2 (η 3 :η 3 -C 10 H 16 )(PMe 2 OH)] (4; see Scheme 9). [51] Unlike [RuCl 2 (η 6 -pcymene){P(4-C 6 H 4 F) 2 Cl}] (11), complex 4 was found to be fully compatible with the KREDs and the reaction conditions required for the enzymatic reduction of the substrates to proceed, thus allowing to catenate a ruthenium-catalyzed hydration of the resulting β-hydroxynitriles without the requirement of purification steps. The results obtained employing a family of aromatic and heteroaromatic α-unsubstituted βketonitriles are shown in Scheme 20.…”

“…[53] As shown in Figure 5, the resulting β-hydroxyamide products were produced with high diastereo-and enantioselectivity levels, not observing the racemization of any stereogenic center of the chiral β-hydroxynitrile intermediates during the Ru-catalyzed hydration step. [51] Moreover, we demonstrated the usefulness of this sequential chemoenzymatic protocol with the total synthesis of the naturally occurring alkaloids (S)-( + )-tembamide (active against HIV) and (R)-(À )-aegeline (hypoglycemic activity) using the single enantiomers of the β-hydroxyamide 19, generated as depicted in Scheme 20, as starting materials (Scheme 21). [51] The synthetic routes involved the initial Hoffman rearrangement of 19 promoted by iodobenzene diacetate, followed by basic hydrolysis of the resulting oxazolidinones 20, and final acylation of the β-amino alcohols 21 with the appropriate acid chloride.…”

The various levels of integration of chemo- and bio-catalysis towards hybrid catalysis

“…94,116,117 Metals can catalyze many types of reactions and are active in aqueous medium, making them good candidates for the implementation of hybrid processes with a wide variety of enzymes. 106,[118][119][120][121] Finally, the material on which to immobilize the catalysts must be considered. Various solid particles can be used to manufacture biohybrid catalysts, ranging from silica to reduced graphene oxide to a polymer matrix composite.…”

Synthesis of α‐Alkyl‐β‐Hydroxy Amides through Biocatalytic Dynamic Kinetic Resolution Employing Alcohol Dehydrogenases

“…From an enzymatic point of view (Figure B), the kinetic resolution of racemic β‐hydroxy esters through lipase‐catalysed aminolysis, or β‐ O ‐protected nitriles with Rhodococcus erythropolis whole cells and the reduction of β‐keto amides using yeasts or fungi, have provided the chiral alcohols but with low yields and/or selectivities. Very recently, the combination of Rhodococcus rhodochrous whole cells or a ruthenium catalyst with alcohol dehydrogenases (ADHs) delivered different cyclic β‐hydroxy amides starting from the corresponding racemic β‐keto nitriles through a DKR process with excellent de and ee .…”