The ruthenium-catalyzed redox isomerization of allylic alcohols was successfully coupled with the enantioselective enzymatic ketone reduction (mediated by KREDs) in a concurrent process in aqueous medium. The overall transformation, formally the asymmetric reduction of allylic alcohols, took place with excellent conversions and enantioselectivities, under mild reaction conditions, employing commercially and readily available catalytic systems, and without external coenzymes or cofactors. Optimization resulted in a multistep approach and a genuine cascade reaction where the metal catalyst and biocatalyst coexist from the beginning.
A hybrid organo-and biocatalytic system for the asymmetric conversion of racemic alcohols into amines was developed. Combining an organocatalyst, AZADO, an oxidant, NaOCl, and an enzyme, transaminase, we implemented a one-pot oxidation-transamination sequential process in aqueous medium.The method showed broad substrate scope and was successfully applied to conventional secondary alcohols and sterically hindered -substituted cycloalkanols, where a highly stereoselective dynamic asymmetric bioamination enabled to set up both contiguous stereocenters with very high enantio-and diastereomeric ratio (>90% yield, >99% ee and up to 49:1 dr). KEYWORDS: One-pot reaction, organocatalysis, biocatalysis, asymmetric synthesis, amino alcohols, transaminase, AZADO. yield. On the other hand, treatment of 3a,b with di-tert-butyl dicarbonate led to the orthogonally protected derivatives (1R,2R)-5a,b. Actually, orthogonally protected amino alcohols are highly valuable molecules in both asymmetric catalysis and medicinal chemistry. 17 Debenzylation of 5a,b gives entry to N-protected amino alcohols (1R,2R)-6a,b, thus completing the practical syntheses of an interesting set of derivatives by means of quantitative and simple processes. Scheme 2. Organo-enzymatic platform towards valuable optically active -aminocycloalkanol derivatives. i) H2, Pd-C 10%, MeOH; ii) (Boc)2O, CH2Cl2, iii) CF3CO2H, CH2Cl2; iv) H2, Pd-C 10%, (Boc)2O, MeOH. CONCLUSIONSIn conclusion, we disclosed an expedient, stereoselective and operationally simple protocol for the synthesis of a variety of optically active amines, through the unprecedented one-pot combination of: i) organocatalyzed oxidation of secondary alcohols; ii) subsequent enantioselective bioamination of the transiently formed ketones. In all cases, the desired final amines were isolated in high yields and with excellent diastereo-and enantiomeric excesses. Likewise, it is worth noting the use of a one-pot methodology, in which the aqueous reaction medium from the organocatalyzed reaction feeds the 15 enzymatic amination. This methodology, which exploits the advantages of merging two catalytic worlds such as organo-and enzymatic catalysis, represents one of the few contributions of this kind of combination in water. Moreover, it is a robust alternative to the existing methodologies, with proven efficacy for a broad variety of secondary alcohols.
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.
A stereoselective bioreduction of 2-oxocycloalkanecarbonitriles was concurrently coupled to a whole cell-catalyzed nitrile hydrolysis in one-pot. The first step, mediated by ketoreductases, involved a dynamic reductive kinetic resolution which led to 2-hydroxycycloalkanenitriles in very high enantio-and diastereomeric ratios. Then, the simultaneous exposure to Nitrile hydratase and amidase from whole cells of Rhodococcus rhodochrous provided the corresponding 2-hydroxycycloalkanecarboxylic acids with excellent overall yield and optical purity for the all-enzymatic cascade.Oxidative-reductive transformations belong to the most important reactions in organic synthesis. Redoxactive enzymes such as oxygenases, alcohol dehydrogenases, amine dehydrogenases, and enereductases, selectively catalyse the introduction and modification of functional groups under mild reaction conditions and can create chiral centers with excellent stereoselectivity. Although some critical issues such as cofactor-dependency, regeneration systems, or unfavourable reaction equilibria are associated to these processes, different approaches such as the use of biomimetic cofactors 1 or the coupling of several enzymatic steps have been developed. 2 † Universidad de Oviedo; ‡ EntreChem SL.(1) (a) Knaus, T; Paul, C. On the other hand, the possibility of performing multistep enzymatic synthesis in a concurrent fashion is particularly appealing since this strategy can reduce costs
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