Reduction Of Ketones Research Articles

An approach for the diastereoselective synthesis of (R)‐(+)‐methyl pipecolate and (+)‐dextro‐erythrophacetoperane from (S)‐(−)‐methylbenzylamine

AbstractA diastereoselective synthesis for the preparation of (R)‐methyl pipecolate and dextro‐erythrophacetoperane, analogs of methylphenidate, drugs used to treat attention deficit hyperactivity disorder, is reported. The key steps involve a high diastereoselective ring‐closing reaction via enolate formation and a diastereoselective ketone reduction reaction. The total synthesis of these valuable drugs could be obtained in only 5 and 8 steps, respectively, starting from (S)‐(−)‐methyl benzylamine.

Modifying Proton Relay into Bioinspired Dye‐Based Coordination Polymer for Photocatalytic Proton‐Coupled Electron Transfer

AbstractProton‐coupled electron transfer (PCET) imparts an energetic advantage over single electron transfer in activating inert substances. Natural PCET enzyme catalysis generally requires tripartite preorganization of proton relay, substrate‐bound active center, and redox mediator, making the processes efficient and precluding side reactions. Inspired by this, a heterogeneous photocatalytic PCET system was established to achieve higher PCET driving forces by modifying proton relays into anthraquinone‐based anionic coordination polymers. The proximally separated proton relays and photoredox‐mediating anthraquinone moiety allowed pre‐assembly of inert substrate between them, merging proton and electron into unsaturated bonds by photoreductive PCET, which enhanced reaction kinetics compared with the counter catalyst without proton relay. This photocatalytic PCET method was applied to a broad‐scoped reduction of aryl ketones, unsaturated carbonyls, and aromatic compounds. The distinctive regioselectivities for the reduction of isoquinoline derivatives were found to occur on the carbon‐ring sides. PCET‐generated radical intermediate of quinoline could be trapped by alkene for proton relay‐assisted Minisci addition, forming the pharmaceutical aza‐acenaphthene scaffold within one step. When using heteroatom(X)−H/C−H compounds as proton‐electron donors, this protocol could activate these inert bonds through photooxidative PCET to afford radicals and trap them by electron‐deficient unsaturated compounds, furnishing the direct X−H/C−H functionalization.

Modifying Proton Relay into Bioinspired Dye-Based Coordination Polymer for Photocatalytic Proton-Coupled Electron Transfer.

Proton-coupled electron transfer (PCET) imparts an energetic advantage over single electron transfer in activating inert substances. Natural PCET enzyme catalysis generally requires tripartite preorganization of proton relay, substrate-bound active center, and redox mediator, making the processes efficient and precluding side reactions. Inspired by this, a heterogeneous photocatalytic PCET system was established to achieve higher PCET driving forces by modifying proton relays into anthraquinone-based anionic coordination polymers. The proximally separated proton relays and photoredox-mediating anthraquinone moiety allowed pre-assembly of inert substrate between them, merging proton and electron into unsaturated bonds by photoreductive PCET, which enhanced reaction kinetics compared with the counter catalyst without proton relay. This photocatalytic PCET method was applied to a broad-scoped reduction of aryl ketones, unsaturated carbonyls, and aromatic compounds. The distinctive regioselectivities for the reduction of isoquinoline derivatives were found to occur on the carbon-ring sides. PCET-generated radical intermediate of quinoline could be trapped by alkene for proton relay-assisted Minisci addition, forming the pharmaceutical aza-acenaphthene scaffold within one step. When using heteroatom(X)-H/C-H compounds as proton-electron donors, this protocol could activate these inert bonds through photooxidative PCET to afford radicals and trap them by electron-deficient unsaturated compounds, furnishing the direct X-H/C-H functionalization.

Reduction of antinutrients and off-flavour in kidney bean flour by acidic and alkaline reactive extrusion

The presence of antinutrients and undesirable flavours in kidney bean flour poses challenges to consumer acceptance. Although extrusion can mitigate antinutrients to some extent, its impact on reducing beany flavour in bean flour remains underexplored. This study investigated the effects of injecting acetic acid or sodium carbonate solutions at three concentration levels (0.05, 0.1, 0.15 mol/L), in conjunction with three temperature profiles (40/60/80/80/90, 40/60/80/90/110, 50/70/90/110/130 °C) and two feed moisture levels (25, 30 %), on the removal of antinutrients (condensed tannins, trypsin inhibitor activity, phytic acid, raffinose family oligosaccharides) and reduction of volatile compounds that contribute to beany flavour in whole kidney bean flour. The results showed that all concentrations of acetic acid and sodium carbonate solutions effectively reduced condensed tannins compared to water, especially at 130 °C extrusion temperature. Introducing acetic acid and sodium carbonate solutions at a concentration of 0.15 mol/L led to 72 and 90 % reduction of total raffinose family oligosaccharide content, respectively, in contrast to the 17 % reduction observed with water alone. The incorporation of sodium carbonate solution reduced the total volatile compounds by 45–58 % as compared with water (23–33 %) and acetic acid (11–27 %). This reduction was primarily due to the reduction of aldehydes, alcohols, and aromatic hydrocarbons. These results indicate that injecting sodium carbonate solution during extrusion can effectively reduce antinutrients and beany flavour compounds in kidney bean flour.

Aqueous organometallic synthesis: Ammonia borane (NH3.BH3) as a convenient metal-free reagent for the reduction of ferrocenyl and ferrocenium carbonyl derivatives in water

Herein, we present a green methodology for the reduction of ferrocene-derived aldehydes and ketones to their respective alcohols, employing ammonia borane as the reducing agent and neat water as the solvent. We also report the deoxygenation of the same precursors to the corresponding alkyl ferrocenes when reactions are performed under solvent-free conditions. Both methods, applicable to various carbonyl derivatives of ferrocene, give product yields in the range of 40–95 % and, in most cases, a product purification that does not require column chromatography. The investigation for the deoxygenation of alkyl derivatives was extended to the cobalt sandwich compound –[(COCH3)C5H4]Co(η4-C4Ph4) and ketone derivatives of ruthenocene as well. Ammonia borane has also been found to be useful as a convenient reducing reagent for the selective reduction of ferrocenium compounds to their respective ferrocene derivatives at room temperature in water medium. Control experiments have been carried out to explore the mechanistic details of these reactions.

Cobalt-Catalyzed Reduction of Aldehydes to Alcohols via the Hydroboration Reaction.

A method for the reduction of aldehydes with pinacolborane catalyzed by pincer cobalt complexes based on a triazine backbone is developed in this paper. The presented methodology allows for the transformation of several aldehydes bearing a wide range of electron-withdrawing and electron-donating groups under mild conditions. The presented procedure allows for the direct one-step hydrolysis of the obtained intermediates to the corresponding primary alcohols. A plausible reaction mechanism is proposed.

An evolved artificial radical cyclase enables the construction of bicyclic terpenoid scaffolds via an H-atom transfer pathway.

While natural terpenoid cyclases generate complex terpenoid structures via cationic mechanisms, alternative radical cyclization pathways are underexplored. The metal-catalysed H-atom transfer reaction (M-HAT) offers an attractive means for hydrofunctionalizing olefins, providing access to terpenoid-like structures. Artificial metalloenzymes offer a promising strategy for introducing M-HAT reactivity into a protein scaffold. Here we report our efforts towards engineering an artificial radical cyclase (ARCase), resulting from anchoring a biotinylated [Co(Schiff-base)] cofactor within an engineered chimeric streptavidin. After two rounds of directed evolution, a double mutant catalyses a radical cyclization to afford bicyclic products with a cis-5-6-fused ring structure and up to 97% enantiomeric excess. The involvement of a histidine ligation to the Co cofactor is confirmed by crystallography. A time course experiment reveals a cascade reaction catalysed by the ARCase, combining a radical cyclization with a conjugate reduction. The ARCase exhibits tolerance towards variations in the dienone substrate, highlighting its potential to access terpenoid scaffolds.

Co2(CO)8 as a CO-source for Pd-catalyzed Carbonylations: An Update

Abstract: Palladium-catalyzed carbonylative cross-coupling reactions with various carbon monoxide (CO) sources cultivate competent routes for the synthesis of bulk and value-added chemicals. However, the practical use of this odorless, inflammable, lethal gas has always raised a concern for chemists. The attention and advancement of various CO-surrogates is surely wel-comed as a green alternative to CO-gas. However, the main concern lies in the suitability and scalability of these CO-surrogate-driven reactions. Literature showed the progress of various ways to make in-situ CO from these CO surrogates. One of the most convenient sources is using metal carbonyls which are already known to lose CO easily. Among all the kinds, Mo(CO)6 gained much popularity but its toxic nature and demand for high temperatures restricted its use. However, Co2(CO)8 is popular as a catalyst but as an in-situ CO-source reports are scarce. This low-melting CO-releaser was found effective in flourishing aminocarbonylation, alkoxycar-bonylation, and reductive carbonylation under mild conditions. This mini-review portrays the recent developments of palladium-catalyzed carbonylation reactions using Co2(CO)8 as a CO source.

Synthesis of Substituted Benzimidazoles and Benzoxazoles by Iron‐catalysed Reductive Carbonylation of Aryl Iodides

AbstractThis work describes a novel iron‐catalysed approach for the synthesis of aryl‐substituted benzimidazoles and benzoxazoles. The methodology employs reductive carbonylation using readily available aryl iodides and aryl amines as precursors, with carbon monoxide serving as the efficient carbonyl source. The reaction proceeds under mild conditions with the addition of hydrosilanes and bases. Notably, aryl aldehydes are generated in situ from the aryl iodides, which subsequently react with o‐phenylenediamine or 2‐aminophenol to afford the desired products in high yields. The structures of the synthesized benzimidazoles and benzoxazoles were confirmed using 1H and 13C NMR spectroscopy and mass spectrometry.

Efficient Stereoselective Biotransformation of Prochiral Carbonyls by Endophytic Fungi from Handroanthus impetiginosus

Endophytic microorganisms are promising sources for new biocatalysts as they must deal with their host plants’ chemicals by developing adaptative strategies, such as enzymatic pathways. As part of our efforts in selecting endophytic strains as biocatalysts, this study describes the screening of endophytic fungi isolated from Handroanthus impetiginosus leaves for selective bioreduction of Acetophenone. The bioreductions were monitored by chiral gas chromatography and conducted to the selection of the endophyte Talaromyces sp. H4 as capable of reducing acetophenone to (S)-1-phenylethanol in excellent conversion and enantiomeric excess rates. The influence of seven parameters on the stereoselective bioreduction of acetophenone by Talaromyces sp. H4 was studied: reaction time, inoculum charge, shaking, pH, temperature, substrate concentration, and co-solvent. The optimal conditions were then used to reduce substituted acetophenones and Acetophenone scale-up, which furnished (S)-1-Phenylethanol in 73% yield and 96% ee. The results highlight the endophytic fungus Talaromyces sp. H4 as an excellent biocatalyst for stereoselective reduction of prochiral carbonyls.

Reduction of Ketones and Coupling of Ketyls by a Zn-Zn-Bonded Compound.

The α-diimine-ligated Zn-Zn-bonded compound [K(THF)2]2[LZn-ZnL] (1, L = [(2,6-iPr2C6H3)NC(Me)]22-) displays diverse reactivities toward a variety of ketones. In the reaction of 1 with benzophenone or 4,4'-di-tert-butylbenzophenone, a multielectron transfer process was observed to give bimetallic (Zn/K) complexes with both ketyl radical fragments and C-C coupled pinacolate moieties (products 2 and 3). In contrast, treating 1 with 9-fluorenone only afforded pinacolate complex 5. Moreover, the reactions of 1 with N- or O-heterocycle-functionalized ketones, i.e., di(2-pyridyl)ketone, 2,2-pyrrolidinone, 9-xanthenone, or 10-methyl-9(10H)-acridone, were also carried out. Besides different transformations of the ketone moiety, the heteroatoms (nitrogen or oxygen) are also involved in coordination with zinc or potassium ions, yielding discrete aggregates or polymeric structures of products 6-9.

Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity.

Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules-water and carbon dioxide-to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double mutant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site-selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to variants of hCAII containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate.

Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity

Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules – water and carbon dioxide – to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double variant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site‐selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to the double variant containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate

Transition-Metal-Free Hydrodefluoroamination of Trifluoromethyl Enones for the Synthesis of α-Fluoroenamides.

A three-component strategy was developed to enable hydrodefluoroamination of β-trifluoromethyl enones by selectively activating two C(sp3)-F bonds in the trifluoromethyl group. The method involved a sequence of carbonyl reduction, hydrodefluorination, and defluoroamination under transition-metal-free conditions. Synthetically useful (E)-stereospecific α-fluoroenamides were obtained in good yields with diverse functional group tolerance, which could be easily transformed into valuable organofluorides and heterocycles. The carbonyl auxiliary exerts both electronic and steric impacts on the CF3-alkenes, allowing for controllable and selective defluorination.

Reduction of toxic aldehydes in heated flaxseed oil using sesame and perilla protein enzymatic hydrolysates.

Reducing ability of sesame meal protein enzymatic hydrolysates (SMH) and perilla protein enzymatic hydrolysates (PMH) on the content of toxic aldehydes including acetaldehyde, formaldehyde, 2-hydroxylhexenal (HHE), and 2-hydroxyl nonenal (HNE), were evaluated in heated flaxseed oil at concentrations ranging from 0.01 to 1.0g. Adding SMH and PMH decreased the formation of secondary oxidation products and toxic aldehydes during heating. In particular, HHE and HNE were not detected, even at 0.01g of protein concentration. Free radical scavenging activities in heated flaxseed oil significantly increased when 1.0g of SMH and PMH were added (p < 0.05). Some volatiles including 2-ethylpyridine, pyrazines, and trimethylamine were formed or increased substantially in flaxseed oils with higher concentrations of SMH and PMH. In general, SMH showed higher antioxidative activity and reducing ability on the toxic aldehydes than PMH. Plant protein enzymatic hydrolysate could control the formation of toxic aldehydes during oxidation of ω-3 edible oil.

Volatile Organic Compounds (VOCs) in Mediterranean Oak Forests of Hungarian Oak (Quercus frainetto Ten) Affected by Dieback Phenomena

In recent years, long periods of drought and heat waves have become increasingly frequent, causing forest dieback phenomena that make stands more sensitive to biotic stressors. How trees may respond to extreme climatic events and which metabolites are involved under stress conditions is still not clear. In this study, using Solid Phase Micro-Extraction (SPME)-GC/MS, we analysed how dieback (D) and non-dieback (ND) Hungarian oak trees from the San Paolo Albanese site respond to these climatic dynamics, focusing on volatile organic compounds (VOCs). For each group of trees, three wood samples were taken, and each was divided into four sub-samples with five growth rings and subjected to SPME and increase in basal area (BAI) analysis of the last 20 years. Dieback trees had a lower number of leaves, and this condition may translate into less photosynthesis, less organic matter production, and lower reserves of carbohydrates being available for growth. Indeed, D trees showed lower radial increases and a lower content of aldehydes, terpenes, and fatty acids than ND trees, indicating a better health of ND trees compared to D trees. Meanwhile, D trees showed a reduction in terpenes, such as α-pinene, γ-eudesmol, and cyperene (with significant insecticidal activity), a reduction in aromatic aldehydes, such as furfural and 5-methylfurfural, and an increase in silanols (with antimicrobial function). Considering the different compounds’ contents between D and ND trees, our study could be useful for detecting bio-indicators to identify an early warning signal of dieback phenomena.

Phosphine‐substituted N‐coordinated Stannylene: Efficient Catalyst in Ketone Hydroboration

AbstractP‐substituted stannylene (Ph2PCH2)(L)Sn containing N,C,N‐pincer ligand (L=[2,6‐(Me2NCH2)2C6H3]) was prepared. The complex was further oxidised to prepare P‐substituted organotin (IV) compounds (Ph2PCH2)(L)SnX2. Finally, P(S)‐substituted N‐coordinated stannylene [(Ph2P(S)CH2](L)Sn containing P atom in the oxidation state +V was also prepared. All these P‐substituted organotins were tested as catalysts for the hydroboration of ketones to see the effect of oxidation numbers of Sn/P atoms. Stannylene (Ph2PCH2)(L)Sn showed remarkable conversions with TOF about 1800 h−1 and is suitable for the reduction of several ketones. The mechanistic studies are also discussed.

Counterintuitive chemoselectivity in the reduction of carbonyl compounds.

The reactivity of carbonyl functional groups largely depends on the substituents on the carbon atom. Reversal of the commonly accepted order of reactivity of different carbonyl compounds requires novel synthetic approaches. Achieving selective reduction will enable the transformation of carbon resources such as plastic waste, carbon dioxide and biomass into valuable chemicals. In this Review, we explore the reduction of less reactive carbonyl groups in the presence of those typically considered more reactive. We discuss reductions, including the controlled reduction of ureas, amides and esters to aldehydes, as well as chemoselective reductions of carbonyl groups, including the reduction of ureas over carbamates, amides and esters; the reduction of amides over esters, ketones and aldehydes; and the reduction of ketones over aldehydes.

Al(OiPr)3 as an effective catalyst for the enhancement of Meerwein−Ponndorf−Verley (MPV) reductions of Morita-Baylis-Hillman (MBH) cyclic alcohols

Carbonyl reductions using NaBH4 are generally high-yielding and highly selective processes commonly used in organic synthesis and the pharmaceutical industry. However, the reaction is exothermic, and the stability of the NaBH4 solution is limited, resulting in long reaction times. In this work, efficient reductions of MBH alcohols with CeCl3/NaBH4 in MeOH are reported . Furthemore in this method, aluminum isopropoxide and isobutanol are employed as proton sources in a transfer process. This approach exhibits impressive selectivity and high yields, resulting in the desired formation of bidentate allylic alcohol.

A novel alcohol dehydrogenase in the hyperthermophilic crenarchaeon Hyperthermus butylicus.

Hyperthermus butylicus is a hyperthermophilic crenarchaeon that produces 1-butanol as an end product. A thermostable alcohol dehydrogenase (ADH) must be present in H. butylicus to act as the key enzyme responsible for this production; however, the gene that encodes the ADH has not yet been identified. A novel ADH, HbADH2, was purified from a cell-free extract of H. butylicus, and its characteristics were determined. The gene that encodes HbADH2 was demonstrated to be HBUT_RS04850 and annotated as a hypothetical protein in H. butylicus. HbADH2 was found to be a primary-secondary ADH capable of using a wide range of substrates, including butyraldehyde and butanol. Butyraldehyde had the highest specificity constant, calculated as k c at/K m, with k cat and apparent K m values of 8.00 ± 0.22 s-1 and 0.59 ± 0.07 mM, respectively. The apparent K m values for other substrates, including ethanol, 1-propanol, 2-propanol, butanol, acetaldehyde, propanal, and acetone, were 4.36 ± 0.42, 4.69 ± 0.41, 3.74 ± 0.46, 2.44 ± 0.30, 1.27 ± 0.18, 1.55 ± 0.20, and 0.68 ± 0.04 mM, respectively. The optimal pH values for catalyzing aldehyde reduction and alcohol oxidation were 6.0 and 9.0, respectively, while the optimal temperature was higher than 90°C due to the increase in enzymatic activity from 60°C to 90°C. Based on its substrate specificity, enzyme kinetics, and thermostability, HbADH2 may be the ADH that catalyzes the production of 1-butanol in H. butylicus. The putative conserved motif sites for NAD(P)+ and iron binding were identified by aligning HbADH2 with previously characterized Fe-containing ADHs.