Asymmetric Reduction Research Articles

Preparation of Chiral Allylic Alcohols by Asymmetric Reduction of Substituted Cycloalkenones

Preparation of Chiral Allylic Alcohols by Asymmetric Reduction of Substituted Cycloalkenones

Influence of Asymmetric Rolling Process and Thickness Reduction on the Microstructure and Mechanical Properties of the Al–Mg-Si Alloy

Influence of Asymmetric Rolling Process and Thickness Reduction on the Microstructure and Mechanical Properties of the Al–Mg-Si Alloy

Access to ports and the welfare gains from domestic transportation infrastructure

This paper quantifies the welfare gains from international and intranational trade cost reductions when inner regions of a country access international markets via coastal ports. Improvement in domestic transportation infrastructure reduces trade costs between inner regions and international markets while leaving coastal regions’ international trade costs unaffected. This asymmetric reduction in international trade costs improves inner regions’ global market access and amplifies their welfare gains from trade cost reductions. Our quantitative application to China shows that improved access to coastal ports amplifies the welfare gains for inner regions by 16%, and the effects are more significant for regions farther away from the ports.

Cobalt‐Catalyzed Asymmetric 1,4‐Reduction of β,β‐Dialkyl α,β‐Unsaturated Esters with PMHS

AbstractA cobalt‐catalyzed asymmetric reduction of β,β‐dialkyl α,β‐unsaturated esters with polymethylhydrosiloxane (PMHS) was reported to deliver the corresponding esters containing a chiral trialkyl carbon center at β‐position with up to 97 % yield and 98 % ee. The chiral tridentate ligand oxazoline iminopyridine (OIP) could perform well for the asymmetric reduction instead of chiral bidentate ligands. This operationally simple protocol shows a broad scope of substrates using one equivalent of readily available PMHS as a cheap and easy‐to‐handle reductive reagent.

Enantioselective Synthesis of Indanes with a Quaternary Stereocenter via Diastereoselective C(sp3)-H Functionalization.

A practical synthesis of enantioenriched indane derivatives with quaternary stereocenters was developed via sequential enantioselective reduction and C-H functionalization. Good to excellent enantioselectivity could be achieved by either the CuH-catalyzed asymmetric reduction or the Corey-Bakshi-Shibata (CBS) reduction of indanone derivatives. The subsequent diastereospecific and regioselective rhodium-catalyzed silylation of the methyl C-H bond led to indane derivatives with quaternary centers. This strategy was further applied in syntheses of (nor)illudalane and botryane sesquiterpenoids.

3D-Printed Aldo-keto reductase within biocompatible polymers as catalyst for chiral drug intermediate

Aldo-keto reductases (AKRs) are an important class of enzymes that can catalyze the asymmetric reduction of the first-line antidepressant duloxetine intermediate. Although the aldehyde ketone reductase has great application potential, the free state of the enzyme is unstable and difficult to recover, which greatly limits its practical applications in industry. In this work, we used 3D printing technology to immobilize the aldehyde ketone reductase AKR-IA to improve its reusability. After optimizing the preparation conditions of the 3D printing AKR-IA ink, it was determined that the concentrations of sodium alginate and CaCl2 were 1 wt% and 3.28 wt%, and the crosslinking time was 2 min. And the ink is determined to be printable. Scanning electron microscopy showed that the 3D printed AKR-IA was uniformly loaded in calcium alginate. Importantly, the reusability of 3D printed AKR-IA was also studied, the 3D printed AKR-IA still remains more than 57% enzyme activities after 6 repeated uses. Finally, we 3D printed the AKR-IA catalytic substrate DKTP, and the results showed that the conversion rate of the 3D printed AKR-IA catalytic product S-DHTP reached 70% with 96% optical purity. This study shows that 3D printing AKR-IA has certain application potential in the industrial production of the antidepressant duloxetine.

Biomimetic Asymmetric Reduction of Tetrasubstituted Olefin 2,3-Disubstituted Inden-1-ones with Chiral and Regenerable NAD(P)H Model CYNAM.

Because of the formidable development of the asymmetric reduction of tetrasubstituted olefins, an effective method is in urgent demand. Herein, through the biomimetic protocol of the coenzyme NAD(P)H, the reduction of tetrasubstituted olefin 2,3-substituted 1H-inden-1-ones has been successfully realized with the catalytic chiral NAD(P)H model CYNAM, which is hard to bring about via the common rhodium or iridium-based catalytic system, producing the corresponding products in good yield (up to 98%) with good enantioselectivity (up to 99% ee). Furthermore, the chiral bioactive molecule can be concisely synthesized from the reduced product.

Acetoacetyl-CoA reductase PhaB as an excellent anti-Prelog biocatalyst for the synthesis of chiral β-hydroxyl ester and the molecular basis of its catalytic performance

• PhaB was an excellent tool for the preparation of anti-Prelog β-hydroxyl esters. • Halogen bond was a main force of PhaB specificity toward chlorinated β-ketoesters. • Distribution of enzyme-substrate interactions was connected to enzyme activity. • Configurations of substrate and active pocket determined enzyme stereoselectivity. Acetoacetyl-CoA reductase PhaB turned out to be capable of catalyzing the anti-Prelog asymmetric reduction of various β-ketoesters ( 1a - 12a ) and aromatic ketones ( 13a - 29a ). Particularly, PhaB showed high specific activity and excellent stereoselectivity (93.0%-99.8% ee p ) toward β-ketoesters. The specific activity of PhaB toward ethyl 4-chloroacetoacetate 11a was up to 1302.2 mU/mg. The molecular basis analysis showed the rotatable single bonds in β-ketoesters endow them with a high degree of structural flexibility and adaptability. Thus, β-ketoesters could quickly adjust their conformation and further form a productive conformation in the narrow substrate-binding pocket of the enzyme. In contrast, PhaB exhibited low specific activity and stereoselectivity toward the majority of aromatic ketones. The large steric hindrance and rigid structure resulted from aromatic rings made the aromatic ketones impossible to adjust their conformation as conveniently as β-ketoesters. Furthermore, it was found the halogen bond was the major driven force of the high specific activity of PhaB toward chlorinated β-ketoesters ( 10a and 11a ), while the distribution of enzyme-substrate interactions was an important factor determining the enzyme activity besides the steric hindrance. Moreover, the geometric configuration of the substrate and the enzyme substrate-binding pocket played critical roles in determining the substrate binding mode and the enzyme stereoselectivity.

Evaluation of 3,3'-Triazolyl Biisoquinoline N,N'-Dioxide Catalysts for Asymmetric Hydrosilylation of Hydrazones with Trichlorosilane.

A new class of axial-chiral biisoquinoline N,N′-dioxides was evaluated as catalysts for the enantioselective hydrosilylation of acyl hydrazones with trichlorosilane. While these catalysts provided poor to moderate reactivity and enantioselectivity, this study represents the first example of the organocatalytic asymmetric reduction of acyl hydrazones. In addition, the structures and energies of two possible diastereomeric catalyst–trichlorosilane complexes (2a–HSiCl3) were analyzed using density functional theory calculations.

Chemoenzymatic access to enantiopure N-containing furfuryl alcohol from chitin-derived N-acetyl-D-glucosamine

BackgroundChiral furfuryl alcohols are important precursors for the synthesis of valuable functionalized pyranones such as the rare sugar L-rednose. However, the synthesis of enantiopure chiral biobased furfuryl alcohols remains scarce. In this work, we present a chemoenzymatic route toward enantiopure nitrogen-containing (R)- and (S)-3-acetamido-5-(1-hydroxylethyl)furan (3A5HEF) from chitin-derived N-acetyl-D-glucosamine (NAG).Findings3-Acetamido-5-acetylfuran (3A5AF) was obtained from NAG via ionic liquid/boric acid-catalyzed dehydration, in an isolated yield of approximately 31%. Carbonyl reductases from Streptomyces coelicolor (ScCR) and Bacillus sp. ECU0013 (YueD) were found to be good catalysts for asymmetric reduction of 3A5AF. Enantiocomplementary synthesis of (R)- and (S)-3A5HEF was implemented with the yields of up to > 99% and the enantiomeric excess (ee) values of > 99%. Besides, biocatalytic synthesis of (R)-3A5HEF was demonstrated on a preparative scale, with an isolated yield of 65%.ConclusionsA two-step process toward the chiral furfuryl alcohol was successfully developed by integrating chemical catalysis with enzyme catalysis, with excellent enantioselectivities. This work demonstrates the power of the combination of chemo- and biocatalysis for selective valorization of biobased furans.Graphic abstract

Engineering of Yeast Old Yellow Enzyme OYE3 Enables Its Capability Discriminating of (E)-Citral and (Z)-Citral.

The importance of yeast old yellow enzymes is increasingly recognized for direct asymmetric reduction of (E/Z)-citral to (R)-citronellal. As one of the most performing old yellow enzymes, the enzyme OYE3 from Saccharomyces cerevisiae S288C exhibited complementary enantioselectivity for the reduction of (E)-citral and (Z)-citral, resulting in lower e.e. value of (R)-citronellal in the reduction of (E/Z)-citral. To develop a novel approach for the direct synthesis of enantio-pure (R)-citronellal from the reduction of (E/Z)-citral, the enzyme OYE3 was firstly modified by semi-rational design to improve its (R)-enantioselectivity. The OYE3 variants W116A and S296F showed strict (R)-enantioselectivity in the reduction of (E)-citral, and significantly reversed the (S)-enantioselectivity in the reduction of (Z)-citral. Next, the double substitution of OYE3 led to the unique variant S296F/W116G, which exhibited strict (R)-enantioselectivity in the reduction of (E)-citral and (E/Z)-citral, but was not active on (Z)-citral. Relying on its capability discriminating (E)-citral and (Z)-citral, a new cascade reaction catalyzed by the OYE3 variant S296F/W116G and glucose dehydrogenase was developed, providing the enantio-pure (R)-citronellal and the retained (Z)-citral after complete reduction of (E)-citral.

An industrial perspective fermentative bioreduction of aromatic ketones by Penicillium rubens VIT SS1 and Penicillium citrinum VIT SS2

Microbial mediated, especially the fungi mediated asymmetric reduction of the ketone is one of the most promising tools for the synthesis of chiral alcohols. Many fungal cultures were isolated from soil and screened for the stereo selective bioreduction of acetophenone. The potential isolates are characterised using molecular techniques and found to be Penicillium rubens VIT SS1 (Genbank ID: MK063869) and Penicillium citrinum VIT SS2 (Genbank ID: MW960208). Both the isolates were tested for the bioreduction of few aromatic ketones such as 4-fluoro acetophenone, 3-hydroxy acetophenone, and oxcarbazepine, which are the key chiral intermediates of various pharmaceutical drugs. The P. rubens VIT SS1 produced (S)-alcohol obeying Prelog’s rule, and P. citrinum was anti-Prelog configuration in nature. Preparatory scale reactions were conducted using the optimised bioreduction process, and the keto loading was significantly increased by 12-fold (from 0.5 to 6 g/L) with >99% conversion and >98% enantiomeric excess. The study discloses the vast prospective approach of exploring filamentous fungi for sustainable synthesis of chiral alcohols in an environment-friendly, novel, and cost competent way.

Synthesis of ursodeoxycholic acid by electrochemical stereoselective reduction of 7-ketolithocholic acid in aprotic solvents

A novel method of producing ursodeoxycholic acid was developed through electrochemical stereoselective reduction of 7-ketolithocholic acid (7K-LCA) in a undivided electrolytic cell and aprotic solvents as electrolyte. Five aprotic solvents were investigated as electrolytes, the simple structure of dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF) were easily attacked by chloride ions and undergo nucleophilic reactions, resulting in no target reactions. The structure of hexamethylphosphoric triamide (HMPA) and 1,3-methyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU) is relatively complex, but chloride ions can still attack them, and it was easier for 7K-LCA to directly undergo a reduction reaction under the action of electric current, because of the small steric hindrance of chenodeoxycholic acid (CDCA), 7K-LCA was stereoselectively reduced to CDCA. Due to the stable structure of the five-membered imidazole ring of 1,3-dimethyl-2-imidazolidinone (DMI), 7K-LCA undergoes two nucleophilic and a "Walden inversion", thereby stereoselective reduction of 7K-LCA to UDCA. In DMI, the highest conversion rate of 7K-LCA was 58.3%, the yield of UDCA was 34.9%, ee value was 100%. Linear sweep voltammetry was used to explore the electrochemical behavior of the reaction, and the electrolysis results were consistent with the linear sweep voltammetry. The product was characterized by using IR, 1H NMR and 13C NMR, it confirm the product was UDCA. The method developed in this paper provides a relatively environmentally friendly and low-consumption method for large-scale production of ursodeoxycholic acid, and provides a valuable reference for the asymmetric electrochemical reduction of ketone groups.

Does the orientation of syndesmosis fixative device affect the immediate reduction of the distal tibiofibular joint?

IntroductionIncongruent stabilization of the distal tibiofibular joint (syndesmosis) results in poorer long-term outcome in malleolar fractures. The aim was to analyze whether the orientation of the syndesmotic stabilization would affect the immediate reduction imaged in computed tomography (CT).Materials and methodsThe syndesmotic congruity in 114 ankle fractures with stabilization of the syndesmosis were retrospectively analyzed in the post-operative bilateral CT scans. The incisura device angle (IDA) was defined and correlated with the side-to-side difference of Leporjärvi clear-space (ΔLCS), anterior tibiofibular distance (ΔantTFD) and Nault talar dome angle (ΔNTDA) regardless of the stabilization technique and separately for suture button system and syndesmotic screw. Asymmetric reduction was defined as ΔLCS > 2 mm and |ΔantTFD|> 2 mm.ResultsRegardless of the stabilization technique, no correlation between the IDA and the ΔLCS (r = 0.069), the ΔantTFD (r = 0.019) nor the ΔNTDA (r = 0.177) could be observed. There were no differences between suture button system and syndesmotic screw. Asymmetrical reduction was detected in 46% of the cases, while sagittal asymmetry was most common. No association was found between the orientation of stabilization device and occurrence of asymmetrical reduction (p > 0.05). The results of suture button system and syndesmotic screw were comparable in this respect (p > 0.05).ConclusionPoor correlation between the orientation of the stabilization device and the immediate post-operative congruity of the syndesmosis could be shown. In contrast to current literature, this study did not show difference of suture button system over syndesmotic screw in this regard. Careful adjustment of the fibula in anteroposterior orientation should be given special attention.

Boosting the Productivity of H2-Driven Biocatalysis in a Commercial Hydrogenation Flow Reactor Using H2 From Water Electrolysis

Translation of redox biocatalysis into a commercial hydrogenation flow reactor, with in-built electrolytic H2 generation, was achieved using immobilized enzyme systems. Carbon-supported biocatalysts were first tested in batch mode, and were then transferred into continuous flow columns for H2-driven, NADH-dependent asymmetric ketone reductions. The biocatalysts were thus handled comparably to heterogeneous metal catalysts, but operated at room temperature and 1–50 bar H2, highlighting that biocatalytic strategies enable implementation of hydrogenation reactions under mild–moderate conditions. Continuous flow reactions were demonstrated as a strategy for process intensification; high conversions were achieved in short residence times, with a high biocatalyst turnover frequency and productivity. These results show the prospect of using enzymes in reactor infrastructure designed for conventional heterogeneous hydrogenations.

Low-carbon consumption with government subsidy under asymmetric carbon emission information

The government subsidy for low-carbon consumption can stimulate demands and thus help increase enterprises' profits on sales. Unfortunately, not all manufacturers report their carbon emission reduction truthfully to the government. In the presence of information asymmetry, the manufacturer who produces low-carbon products has an incentive to get a higher subsidy, thereby dishonestly signaling a higher carbon reduction level to the government. This paper analytically investigates the impacts of government subsidy on participants' performances under asymmetric carbon reduction information. A classical signaling game arises between the manufacturer and government and at equilibrium. We show that the manufacturer with high emission reduction level distorts the price upwards in order to separate from the manufacturer with a low reduction level. From the comprehensive analysis, a few important findings are obtained. Firstly, this paper shows that the subsidy can benefit both the government and manufacturer when consumers are moderately sensitive to subsidy policy under complete information. Secondly, as a result of information asymmetry, the government is willing to subsidize only when consumers' sensitivity to government subsidy is relatively low or sufficiently high within a certain range. Interestingly, it is further found that if subsidy policy is more effective in stimulating demand, the subsidy can encourage the manufacturer to share information with the government in order to avoid the losses caused by the upward price distortion under asymmetric information. Consequently, they reach a consensus on both government subsidy and manufacturer information sharing only when consumers are rather sensitive to subsidies.

Organosilanes in Metal-Catalyzed, Enantioselective Reductions

The growth and development of an extensive range of metals complexed with chiral ligands for the purpose of catalyzing a variety of reactions in an enantioselective manner has been impressive for its scope, chemical yields and high ee values. Chief among the classes of synthetic transformations has been that of the asymmetric reduction of prochiral substrates. These include the asymmetric reduction of prochiral ketones, imines, unsaturated aldehydes, ketones, esters, nitriles and olefins, as well as a number of asymmetric coupling reactions. In concert with these efficient catalyst systems, organosilanes have the ability to carry out any number of organic reductions under a variety of conditions. In these reactions, which in reality are hydrosilylations (hydrosilylation and reduction are considered interchangeable herein) in which the initially resulting silylated product is hydrolyzed to the ultimate desired functionality, the ability to sterically and electronically alter the organosilane reductant can contribute to the overall success of the transformation. In this review, we present a thorough compilation of the literature covering the use of organosilanes in metal-catalyzed asymmetric reductions (hydrosilylations) and coupling reactions.

Enzymatic Asymmetric Reduction of Unfunctionalized C=C Bonds with Archaeal Geranylgeranyl Reductases.

The asymmetric reduction of activated C=C bonds such as enones is well established for non‐enzymatic methods as well as in biocatalysis. However, the asymmetric reduction of unfunctionalized C=C bonds is mainly performed with transition metal catalysts whereas biocatalytic approaches are lacking. We have tested two FAD‐dependent archaeal geranylgeranyl reductases (GGR) for the asymmetric reduction of isolated C=C bonds. The reduction of up to four double bonds in terpene chains with different chain lengths and head groups was confirmed. Methyl‐branched E‐alkenes were chemoselectively reduced in the presence of cyclic, terminal or activated alkenes. Using a removable succinate “spacer”, farnesol and geraniol could be quantitatively reduced (>99 %). The reduction is strictly (R)‐selective (enantiomeric excess >99 %). Hence, GGRs are promising biocatalysts for the asymmetric reduction of unactivated isolated C=C bonds, opening new opportunities for the synthesis of enantiopure branched alkyl chains.

Regioselective asymmetric bioreduction of trans-4-phenylbut-3-en-2-one by whole-cell of Weissella cibaria N9 biocatalyst.

There is a considerable interest in the asymmetric production of chiral allylic alcohols, the main building blocks of many functional molecules. The asymmetric reduction of α,β-unsaturated ketones is difficult with traditional chemical protocols in a regioselective and stereoselective manner. In this study, the reductive capacity of whole cell of Leuconostoc mesenteroides N6, Weissella paramesenteroides N7, Weissella cibaria N9, and Leuconostoc pseudomesenteroides N13 was investigated as whole-cell biocatalysts in the enantioselective reduction of (E)-4-phenylbut-3-en-2-one (1). The biocatalytic reduction of 1 to (S,E)-4-phenylbut-3-en-2-ol ((S,E)-2) using the whole cell of W.cibaria N9 isolated from Turkish sourdough was developed in a regioselective fashion, occurring with excellent conversion and recovering the product in good yield. In biocatalytic reduction reactions, the conversion of the substrate and the enantiomeric excess (ee) of the product are significantly affected by optimization parameters such as temperature, agitation rate, pH, and incubation time. Effects of these parameters on ee and conversion were investigated comprehensively. In addition, to our knowledge, this is the first report on production of (S,E)-2 using whole-cell biocatalyst in excellent yield, conversion with enantiopure form and at gram scale. These findings pave the way for the use of whole cell of W.cibaria N9 for challenging higher substrate concentrations of different α,β-unsaturated ketones for regioselective reduction at industrial scale.

Effect of organic solvents on asymmetric reduction of β-keto esters using cyanobacterium Synechocystis sp. PCC 6803

The asymmetric reduction of tert-butyl 3-oxobutanoate by cyanobacterium Synechocystis sp. PCC 6803 under illumination with red LED light at 25 °C for 24 h afforded the corresponding (R)-β-hydroxy ester in 79% enantiomeric excess (ee) (81% yield), while the addition of toluene (1% (v/v)) to the system gave the corresponding (S)-β-hydroxy ester in >99% ee (87% yield). Organic solvents such as chloroform, benzene, ethylbenzene, cyclohexane, and methylcyclohexane showed similar effects and afforded the corresponding (S)-β-hydroxy ester in >99% ee. However, polar organic solvents, such as DMSO, THF, and ethanol, as well as dodecane—a hydrophobic solvent with a straight long-chain—did not exhibit such effects.