Asymmetric Reduction Research Articles

Enantioselective synthesis of triarylmethanes via organocatalytic transfer hydrogenation of para-quinone methides

An organocatalytic asymmetric reduction of in situ formed para-quinone methides has been developed for the synthesis of enantioenriched triarylmethanes.

An Efficient, Concise, and Scalable Synthesis of Izenamide a and B Via Asymmetric Reduction of Γ-Amino Β-Keto Ester Using 2-Methyl-Cbs-Oxazaborolidine Catalysts

An Efficient, Concise, and Scalable Synthesis of Izenamide a and B Via Asymmetric Reduction of Γ-Amino Β-Keto Ester Using 2-Methyl-Cbs-Oxazaborolidine Catalysts

Asymmetric Reduction of Conjugated C=C Bonds by Immobilized Fusion of Old Yellow Enzyme and Glucose Dehydrogenase

Asymmetric Reduction of Conjugated C=C Bonds by Immobilized Fusion of Old Yellow Enzyme and Glucose Dehydrogenase

Transfer-catalyst-free biomimetic asymmetric reduction of 3-sulfonyl coumarins with a regenerable NAD(P)H model.

A novel transfer-catalyst-free biomimetic reduction of the tetrasubstituted olefins 3-sulfonyl coumarins with the chiral and regenerable [2.2]paracyclophane-based NAD(P)H model CYNAM has been developed, affording chiral 3-sulfonyl dihydrocoumarins with excellent enantioselectivities.

Short electrochemical asymmetric synthesis of (+)-N-acetylcolchinol

A short synthesis of N-acetylcolchinol using a greener pathway is reported where all the redox steps, except for the asymmetric reduction, were carried out electrochemically, replacing protocols that employ stoichiometric hazardous reagents.

Recent advances in the asymmetric reduction of imines by recycled catalyst systems

Recent advances relating to the asymmetric reduction of imines to afford optically active amines via recyclable catalyst systems are reviewed.

Identification of a novel ene reductase from Pichia angusta with potential application in (R)-levodione production.

Asymmetric reduction of electronically activated alkenes by ene reductases (ERs) is an attractive approach for the production of enantiopure chiral products. Herein, a novel FMN-binding ene reductase (PaER) from Pichia angusta was heterologously expressed in Escherichia coli BL21(DE3), and the recombinant enzyme was characterized for its biocatalytic properties. PaER displayed optimal activity at 40 °C and pH 7.5, respectively. The purified enzyme was quite stable below 30 °C over a broad pH range of 5.0–10.0. PaER was identified to have a good ability to reduce the C Created by potrace 1.16, written by Peter Selinger 2001-2019 ]]> C bond of various α,β-unsaturated compounds in the presence of NADPH. In addition, PaER exhibited a high reduction rate (kcat = 3.57 s−1) and an excellent stereoselectivity (>99%) for ketoisophorone. Engineered E. coli cells harboring PaER and glucose dehydrogenase (for cofactor regeneration) were employed as biocatalysts for the asymmetric reduction of ketoisophorone. As a result, up to 1000 mM ketoisophorone was completely and enantioselectively converted to (R)-levodione with a >99% ee value in a space–time yield of 460.7 g L−1 d−1. This study provides a great potential biocatalyst for practical synthesis of (R)-levodione.

Synthesis of Chiral Amines via a Bi‐Enzymatic Cascade Using an Ene‐Reductase and Amine Dehydrogenase

AbstractAccess to chiral amines with more than one stereocentre remains challenging, although an increasing number of methods are emerging. Here we developed a proof‐of‐concept bi‐enzymatic cascade, consisting of an ene reductase and amine dehydrogenase (AmDH), to afford chiral diastereomerically enriched amines in one pot. The asymmetric reduction of unsaturated ketones and aldehydes by ene reductases from the Old Yellow Enzyme family (OYE) was adapted to reaction conditions for the reductive amination by amine dehydrogenases. By studying the substrate profiles of both reported biocatalysts, thirteen unsaturated carbonyl substrates were assayed against the best duo OYE/AmDH. Low (5 %) to high (97 %) conversion rates were obtained with enantiomeric and diastereomeric excess of up to 99 %. We expect our established bi‐enzymatic cascade to allow access to chiral amines with both high enantiomeric and diastereomeric excess from varying alkene substrates depending on the combination of enzymes.

Highly Efficient Kinetic Resolution of Aryl-Alkenyl Alcohols by Ru-Catalyzed Hydrogen Transfer.

No matter through asymmetric reduction of ketones or kinetic resolution of secondary alcohols, enantioselective synthesis of the corresponding secondary alcohols is challenging when the two groups attached to the prochiral or chiral centers are spatially or electronically similar. For examples, dialkyl (sp3 vs. sp3), diaryl (sp2 vs. sp2), and aryl-alkenyl (sp2 vs. sp2) alcohols are difficult to produce with high enantioselectivities. By exploiting our recently developed Ru-catalysts of minimal stereogenicity, we reported herein a highly efficient kinetic resolution of aryl-alkenyl alcohols through hydrogen transfer. This method enabled such versatile chiral building blocks for organic synthesis as allylic alcohols, to be readily accessed with excellent enantiomeric excesses at practically useful conversions.

Enantioselective Synthesis of 2-Functionalized Tetrahydroquinolines through Biomimetic Reduction.

Biomimetic asymmetric reduction of 2-functionalized quinolines has been successfully developed with the chiral and regenerable NAD(P)H model CYNAM in the presence of transfer catalyst simple achiral phosphoric acids, providing the chiral 2-functionalized tetrahydroquinolines with up to 99% ee. Using this methodology as a key step, a chiral and potent opioid analgesic containing a 1,2,3,4-tetrahydroquinoline motif was synthesized with high overall yield.

First asymmetric total synthesis of Millpuline B

Millpuline B (1), isolated from Millettia pulchra, is a naturally occurring bioactive compound with a chiral center. Herein, we report the first total syntheses of both (+/-)-Millpuline B from commercal available 6,7-dihydro-4(5H)-benzofuranone (4) using Grignard reaction and asymmetric CBS reduction as the key steps. Millpuline B (1) was synthesized with up to 94.3% enantiomeric excess and the Mosher’s methods were used to elucidate the absolute configuration of key intermediates 11 and 12. All of the synthetic steps could be carried out on gram-scale.

Geotrichum candidum acetophenone reductase immobilization on reduced graphene oxide: A promising biocatalyst for green asymmetric reduction of ketones

Highly functional carbon-based materials, such as graphene family nanomaterials (GFNs) like graphene oxide (GO) and reduced graphene oxide (rGO), have been synthesized through the years. In this research, GO and rGO were used as support to immobilize a novel alcohol dehydrogenase (ADH), acetophenone reductase from Geotrichum candidum (GcAPRD), via physical adsorption. The synthesized GO-GcAPRD and rGO-GcAPRD allowed GcAPRD recycling. Moreover, rGO-GcAPRD succeeded in reduction of a wide range of ketones to their corresponding (S)-alcohols with excellent enantioselectivity, including a ‘difficult to resolve’ aliphatic ketone, 3-hexanone, to achieve 99% yield and > 99% ee (S). We also synthesized a drug intermediate such as (S)−1-(3′,4′-dichlorophenyl)ethanol with 80% isolated yield and > 99% ee. To the best of our knowledge, this is the first time to present the versatility of immobilized ADH on the GFNs via direct and simple physical adsorption as a promising biocatalyst for asymmetric synthesis.

Does the Configuration at the Metal Matter in Noyori-Ikariya Type Asymmetric Transfer Hydrogenation Catalysts?

Noyori–Ikariya type [(arene)RuCl(TsDPEN)] (TsDPEN, sulfonated diphenyl ethylenediamine) complexes are widely used C=O and C=N reduction catalysts that produce chiral alcohols and amines via a key ruthenium–hydride intermediate that determines the stereochemistry of the product. Whereas many details about the interactions of the pro-chiral substrate with the hydride complex and the nature of the hydrogen transfer from the latter to the former have been investigated over the past 25 years, the role of the stereochemical configuration at the stereogenic ruthenium center in the catalysis has not been elucidated so far. Using operando FlowNMR spectroscopy and nuclear Overhauser effect spectroscopy, we show the existence of two diastereomeric hydride complexes under reaction conditions, assign their absolute configurations in solution, and monitor their interconversion during transfer hydrogenation catalysis. Configurational analysis and multifunctional density functional theory (DFT) calculations show the λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to be both thermodynamically and kinetically favored over its λ-(R,R)RRu isomer with the opposite configuration at the metal. Computational analysis of both diastereomeric catalytic manifolds show the major λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to dominate asymmetric ketone reduction catalysis with the minor λ-(R,R)RRu [(mesitylene)RuH(TsDPEN)] stereoisomer being both less active and less enantioselective. These findings also hold true for a tethered catalyst derivative with a propyl linker between the arene and TsDPEN ligands and thus show enantioselective transfer hydrogenation catalysis with Noyori–Ikariya complexes to proceed via a lock-and-key mechanism.

Inverting the Stereoselectivity of an NADH-Dependent Imine-Reductase Variant.

Imine reductases (IREDs) offer biocatalytic routes to chiral amines and have a natural preference for the NADPH cofactor. In previous work, we reported enzyme engineering of the (R)‐selective IRED from Myxococcus stipitatus (NADH‐IRED‐Ms) yielding a NADH‐dependent variant with high catalytic efficiency. However, no IRED with NADH specificity and (S)‐selectivity in asymmetric reductions has yet been reported. Herein, we applied semi‐rational enzyme engineering to switch the selectivity of NADH‐IRED‐Ms. The quintuple variant A241V/H242Y/N243D/V244Y/A245L showed reverse stereopreference in the reduction of the cyclic imine 2‐methylpyrroline compared to the wild‐type and afforded the (S)‐amine product with >99 % conversion and 91 % enantiomeric excess. We also report the crystal‐structures of the NADPH‐dependent (R)‐IRED‐Ms wild‐type enzyme and the NADH‐dependent NADH‐IRED‐Ms variant and molecular dynamics (MD) simulations to rationalize the inverted stereoselectivity of the quintuple variant.

Dual-Purpose CuFe2O4-rGO-Based Nanocomposite for Asymmetric Flexible Supercapacitors and Catalytic Reduction of Nitroaromatic Derivatives.

Energy storage and environmental pollution are two major global concerns in today’s scenario. As a result of the momentous exhaustion of fossil fuels, the generation of energy from renewable sources is gaining immense importance. However, the irregular availability of energy from these renewable sources is the major encounter to achieve sustainable energy harvesting technology, yielding efficient but continuous and reliable energy supplies. Apart from the requirement of state-of-the-art heavy-duty technologies such as transportation, defense, etc., in the modern lifestyle to fulfill the demand for flexible electronic devices, the development of high-performance mechanically flexible all-solid-state supercapacitors is increasing massively. On the other hand, to cater to the need for accessibility of clean water for healthy lives, several technologies are evolving to treat wastewater and groundwater. Hence, the development of efficient catalysts for destroying water pollutants is an attractive approach. Considering these two crucial facets, in this paper, we have demonstrated the multifunctional features of a CuFe2O4-rGO nanocomposite, which was exploited to fabricate a high-performance mechanically flexible all-solid-state asymmetric supercapacitor and simultaneously used as an efficient but easily recoverable catalyst for the transformation of different nitroaromatic compounds. We have also demonstrated the conversion of trifluralin (a herbicide), which is present in the water body as a pollutant, to its corresponding amine derivatives, which can be utilized in the preparation of important pharmaceutical products.

Chiral Phosphoric Acids as Versatile Tools for Organocatalytic Asymmetric Transfer Hydrogenations.

Herein, recent developments in the field of organocatalytic asymmetric transfer hydrogenation (ATH) of C=N, C=O and C=C double bonds using chiral phosphoric acid catalysis are reviewed. This still rapidly growing area of asymmetric catalysis relies on metal‐free catalysts in combination with biomimetic hydrogen sources. Chiral phosphoric acids have proven to be extremely versatile tools in this area, providing highly active and enantioselective alternatives for the asymmetric reduction of α,β‐unsaturated carbonyl compounds, imines and various heterocycles. Eventually, such transformations are more and more often used in multicomponent/cascade reactions, which undoubtedly shows their great synthetic potential and the bright future of organocatalytic asymmetric transfer hydrogenations.

"A Study in Yellow": Investigations in the Stereoselectivity of Ene-Reductases.

Ene‐reductases from the Old Yellow Enzyme (OYE) superfamily are a well‐known and efficient biocatalytic alternative for the asymmetric reduction of C=C bonds. Considering the broad variety of substituents that can be tolerated, and the excellent stereoselectivities achieved, it is apparent why these enzymes are so appealing for preparative and industrial applications. Different classes of C=C bonds activated by at least one electron‐withdrawing group have been shown to be accepted by these versatile biocatalysts in the last decades, affording a vast range of chiral intermediates employed in the synthesis of pharmaceuticals, agrochemicals, flavours, fragrances and fine chemicals. In order to access both enantiomers of reduced products, stereodivergent pairs of OYEs are desirable, but their natural occurrence is limited. The detailed knowledge of the stereochemical course of the reaction can uncover alternative strategies to orient the selectivity via mutagenesis, evolution, and substrate engineering. An overview of the ongoing studies on OYE‐mediated bioreductions will be provided, with particular focus on stereochemical investigations by deuterium labelling.

Investigating the Structure‐Reactivity Relationships Between Nicotinamide Coenzyme Biomimetics and Pentaerythritol Tetranitrate Reductase

AbstractEne reductases (ERs) are attractive biocatalysts in terms of their high enantioselectivity and expanded substrate scope. Recent works have proved that synthetic nicotinamide coenzyme biomimetics (NCBs) can be used as easily accessible alternatives to natural cofactors in ER‐catalyzed reactions. However, the structure‐reactivity relationships between NCBs and ERs and influence factors are still poorly understood. In this study, a series of C‐5 methyl modified NCBs were synthesized and tested in the PETNR‐catalyzed asymmetric reductions. The physicochemical properties of these NCBs including electrochemical properties, stability, and kinetic behavior were studied in detail. The results showed that hydrophobic interaction caused by the introduced methyl group contributed to the stabilization of binding conformation in enzyme active site, resulting in comparable catalytic activity with that of NADPH. Molecular dynamics and steered molecular dynamics simulations were further performed to explain the binding mechanism between PETNR and NCBs, which revealed that stable catalytic conformation, appropriate donor‐acceptor distance and angle, as well as free dissociation energy are important factors affecting the activity of NCBs.magnified image

Stereoselective Synthesis of the C19–C39 Fragment of Bastimolide A

AbstractThis paper describes the synthesis of the C19–C39 fragment of the antimalarial natural product bastimolide A via addition of a functionalized C19–C26 alkyne fragment to a C27–C39 aldehyde fragment. Opening of a terminal epoxide and Noyori asymmetric reduction were used as key steps in the synthesis.

Reduction of Oximes and Hydrazones: Asymmetric and Diastereoselective Approaches

: The asymmetric reduction of oximes and hydrazones is an attractive and versatile strategy for the synthesis of chiral amines, which are valuable building blocks in organic synthesis. This review summarizes the relevant developments made in the last decade on the enantioselective and diastereoselective reduction of oximes and hydrazones involving metalcatalyzed hydrogenation/hydrogenolysis reactions, hydride donor reactions, and electrochemical reactions.