Aldol Reaction Research Articles

Copper-Catalyzed Direct Asymmetric Aldol Reaction of Glycine Schiff Bases to Access syn-β-Hydroxy-α-amino Esters.

This study reported a copper-catalyzed direct asymmetric aldol reaction between aldehydes and glycine Schiff bases with methyl, allyl, and tert-butyl esters. Additionally, this reaction afforded high yields of syn-β-hydroxy-α-amino esters with excellent enantio- and diastereoselectivities (93-99% ee, up to >99:1 dr). The aldol reaction accepted aromatic, linear aliphatic, and α-substituted aliphatic aldehydes.

Synthesis and application of triptycene based oligomers for the stereoselective aldol reaction of isatin and ketones

Novel triptycene derived oligomers (TOL1, TOL2 and TOL3) with multiple metal-coordinating sites have been synthesized in high yields using a three-component one-pot synthetic protocol and were characterized by various analytical tools such as FT-IR, solid state 13C NMR, GPC and FESEM. The GPC analysis revealed TOLs as oligomers with 8-10 repeating units. The catalytic applications of these oligomers were investigated for the stereoselective synthesis of 3-hydroxy-2-oxindoles via aldol reaction of isatin with ketones by the in-situ complexation of the oligomers with Cobalt metal. All the tested reactions worked well to generate the corresponding products in excellent yields with good diastereo-selectivities.

Synthesis of Chiral Substituted meta‐Bromoanilines as Ligands for Copper-Catalyzed Asymmetric Aldol Addition Reactions

Synthesis of Chiral Substituted meta‐Bromoanilines as Ligands for Copper-Catalyzed Asymmetric Aldol Addition Reactions

C2-Symmetric Amino Acid Amide-Derived Organocatalysts

N-alkylated C2-symmetric amino acid amide derivatives were shown to catalyse the Michael addition of 2-hydroxy-1,4-napthoquinone to β-nitrostyrene, achieving a maximum ee of 44%. The corresponding trifluoroacetic acid salts also catalysed the aldol reaction between 4-nitrobenzaldehyde and hydroxyacetone, leading to the formation of predominantly syn-aldol products in up to 55% ee. Aspects of the solvent dependence of the aldol reaction and the H-bonding of the catalyst were investigated.

Instant Synthesis of 2,5‐Diformylfuran from Concentrated 5‐Hydroxymethylfurfural without Catalyst and Organic Solvent

Abstract5‐Hydroxymethylfurfural (HMF) was transformed into 2,5‐diformylfuran (DFF) with nitric acid as the oxidant. The initial HMF content was as high as 12.5 wt %, and water was the sole solvent. This is an intensely exothermic reaction along with the emission of NO2 gas. A high DFF yield of 83.2 % was achieved if the oxidation ability of nitric acid matched with the requirement of target oxidation reaction while mismatched those of side reactions by regulating the initial concentration of nitric acid (59.5 wt %) and reaction temperature (50–60 °C). The oxidation reaction of HMF, overoxidation of HMF, and skeleton‐cracking reaction of FDCA preferred concentrated HNO3, hot HNO3, and concentrated or hot HNO3, respectively. After liquid‐liquid extraction, filtration, and column chromatography, light‐yellow DFF powders with purity of 92.1 wt % and isolated yield of 40.2 % were obtained and confirmed by NMR, FTIR, UV‐Vis, and elemental analysis. HMF was the dominant impurity due to its affinity to DFF. In addition, chromogenic substances were obtained as a byproduct, and they were potential pH indicators. These chromogenic substances had highly conjugated molecular structures, and they were generated via successive β‐protonation‐based ring‐opening reaction of HMF, aldol reaction, and dehydration reaction.

Broadening The Substrate Scope of Aldolases Through Metagenomic Enzyme Discovery.

Bio-processes based on enzymatic catalysis play a major role in the development of green, sustainable processes, and the discovery of new enzymes is key to this approach. In this work, we analysed ten metagenomes and retrieved 48 genes coding for deoxyribose-5-phosphate aldolases (DERAs, EC 4.1.2.4) using a sequence-based approach. These sequences were recombinantly expressed in Escherichia coli and screened for activity towards a range of aldol additions. Among these, one enzyme, DERA-61, proved to be particularly interesting and catalysed the aldol addition of furfural or benzaldehyde with acetone, butanone and cyclobutanone with unprecedented activity. The product of these reactions, aldols, can find applications as building blocks in the synthesis of biologically active compounds. Screening was carried out to identify optimized reaction conditions targeting temperature, pH, and salt concentrations. Lastly, the kinetics and the stereochemistry of the products were investigated, revealing that DERA-61 and other metagenomic DERAs have superior activity and stereoselectivity when they are provided with non-natural substrates, compared to well-known DERAs.

Organocatalytic Regioselective Aldol Reaction of Hydroxyacetone with Aliphatic Aldehydes for the Synthesis of Linear Products

Organocatalytic Regioselective Aldol Reaction of Hydroxyacetone with Aliphatic Aldehydes for the Synthesis of Linear Products

Et3Al/Light-Promoted Radical-Polar Crossover Reactions of α-Alkoxyacyl Tellurides.

Here, we report new radical-polar crossover reactions of α-alkoxy carbon radicals for constructing highly oxygenated molecules with contiguous stereocenters. The method employs a 370 nm UV light-emitting diode (LED) for the photoexcitation of α-alkoxyacyl telluride, and Et3Al as the radical initiator and terminator. First, Et3Al and UV LED promoted radical coupling between the α-alkoxyacyl telluride and cyclopentenone via C-Te bond homolysis, CO expulsion, and C-C bond formation. Second, Et3Al converted the radical species to the corresponding aluminum enolate. Third, the second C-C bond formation occurred via a polar mechanism: intermolecularly with aldehydes/ketones and intramolecularly with epoxide, producing aldol and SN2 adducts, respectively. The present coupling reactions increase the molecular complexity in a single step by stereoselective formation of the two hindered C-C bonds. The devised method is expected to be useful for the expeditious assembly of densely oxygenated natural products.

Total Synthesis of Ganoapplanin Enabled by a Radical Addition/Aldol Reaction Cascade.

The total synthesis of the Ganoderma meroterpenoid ganoapplanin, an inhibitor of T-type voltage-gated calcium channels, is reported. Our synthetic approach is based on the convergent coupling of a readily available aromatic polyketide scaffold with a bicyclic terpenoid fragment. The three contiguous stereocenters of the terpenoid fragment, two of which are quaternary, were constructed by a diastereoselective, titanium-mediated iodolactonization. For the fusion of the two fragments and to simultaneously install the crucial biaryl bond, we devised a highly effective two-component coupling strategy. This event involves an intramolecular 6-exo-trig radical addition of a quinone monoacetal followed by an intermolecular aldol reaction. A strategic late-stage oxidation sequence allowed the selective installation of the remaining oxygen functionalities and the introduction of the characteristic spiro bisacetal structure of ganoapplanin.

Mn(I)-Catalyzed Carbon-Skeleton Rearrangement of Tertiary Alcohol-Based Aldol Reaction with Aldehydes.

A Mn-catalyzed ligand-directed Csp3-Csp2 coupling of tertiary allylic alcohols with arylaldehydes has been developed. The method provides an efficient approach to access 1,5-diarylpent-1-en-3-ones via carbon-skeleton rearrangement-based aldol reaction.

Recent Progress in Synthesis of Alkyl Fluorinated Compounds with Multiple Contiguous Stereogenic Centers.

Organic fluorides are widely used in pharmaceuticals, agrochemicals, material sciences, and other fields due to the special physical and chemical properties of fluorine atoms. The synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers is the most challenging research area in synthetic chemistry and has received extensive attention from chemists. This review summarized the important research progress in the field over the past decade, including asymmetric electrophilic fluorination and the asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions), with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms.

From Coordination to Noncoordination: Syntheses and Substitution Lability Studies of Titanium Triflato Complexes.

A new concept for obtaining cationic complexes with triflate counteranions from coordinating triflato ligands was developed. Various routes are leading to titanium(IV) and titanium(III) triflato complexes efficiently. The reactions of pentafulvene titanium complexes with either triflic acid or silver triflate give the corresponding titanium(IV) triflato complexes in excellent yields. Hydrolysis of the titanium(IV) bistriflato complexes leads to cationic aqua complexes via displacement of the triflato ligand, which consequently acts as a noncoordinating anion. A functionalized titanium(IV) monotriflato complex was synthesized by insertion of a nitrile into the Ti-C bond and the triflato ligand was displaced by an NHC. While the titanium(IV) complexes are mostly inert toward substrates, the donor-free titanium(III) triflato complex is a strong Lewis acid and forms various adducts with monodentate Lewis bases. The titanium(III) complex was oxidized by reaction with TEMPO, resulting in a diamagnetic titanium(IV) complex. The reaction with bidentate ligands results in cationic titanium(III) complexes due to displacement of the triflato ligand by the bidentate ligands. Treatment with acetone leads to an aldol reaction of two acetone molecules and the formation of a cationic diacetone alcohol complex.

Diastereo- and Enantioselective Construction of Stereochemical Arrays Exploiting Non-Classical Hydrogen Bonding in Enolborates.

We report a copper-catalyzed reductive aldol addition to aldehydes and ketones, with pinacolborane as stoichiometric reductant, that results in the generation of stereodefined syn-aldol products. Cyclic, acyclic, fused and spirocyclic aldols bearing contiguous stereocenters are obtained with excellent yields and diastereoselectivities. Moreover, enantioselective reactions could be carried out with cycloalkenones to deliver aldols bearing three contiguous stereocenters and with up to 98 % ee. Computations reveal that the enolborate intermediate undergoes the syn-aldol reaction via a twist-boat transition state that is stabilized by non-classical hydrogen bonding interactions.

Structure of the iminium reaction intermediate in an engineered aldolase explains the carboligation activity toward arylated ketones and aldehydes

Two structures of fructose 6-phosphate aldolase, the wild-type and an engineered variant containing five active-site mutations, have been solved by cryoelectron microscopy (cryo-EM). The engineered variant affords production of aldols from aryl substituted ketones and aldehydes. This structure was solved to a resolution of 3.1Å and contains the critical iminium reaction intermediate trapped in the active site. This provides new information that rationalizes the acquired substrate scope and aids in formulating hypotheses of the chemical mechanism. A Tyr residue (Y131) is positioned for a role as catalytic acid/base during the aldol reaction and the different structures demonstrate mobility of this amino acid residue. Further engineering of this fructose 6-phosphate aldolase (FSA) variant, guided by this new structure, identified additional FSA variants that display improved carboligation activities with 2-hydroxyacetophenone and phenylacetaldehyde.

New Polymeric Disulfonimide for Heterogeneous Silicon Lewis Acid Catalysis

AbstractA new heterogeneous polymeric disulfonimide was very easily synthesized from simple commercially available reagents. The new cost-effective catalytic material exhibited a tremendously enhanced reactivity in a benchmark Mukaiyama aldol reaction via silicon Lewis acid activation when compared with common acidic resins. Moreover, the reported polymeric disulfonimide exhibits outstanding robustness, as confirmed by its good thermal stability and excellent recyclability.

Computational Design of an Electro-Organocatalyst for Conversion of CO2 into Long Chain Aldehydes.

Density functional theory calculations employing a hybrid implicit/explicit solvation method were used to demonstrate that an electro-organocatalyst designed in our previous work for reducing CO2 to formaldehyde could also be capable of coupling formaldehyde to form long chain aldehydes. The catalytic activity is enabled by an electron-rich vicinal enediamine (>N-C═C-N<) backbone that activates formaldehyde by reversing the polarity on the carbon atom, enabling it to act as a nucleophile in the subsequent aldol addition step. The catalyst then enables reductive dehydroxylation of the aldol addition product by facilitating outer-sphere electron transfer. The optimal pH as well as the limiting potential and formaldehyde concentration are identified and related to the kinetic balance between several rate limiting steps. Finally, the optimal conditions for coupling with the CO2 reduction cycle are discussed, demonstrating that the electro-organocatalyst is capable of efficiently converting CO2 into aldehyde products with a turnover frequency (per carbon atom) on the order of 0.1-1 s-1.

Undescribed polyketides from endophytes associated with the critically endangered conifer Abies beshanzuensis

Four undescribed polyketides, beshanzones A (1) and B (2) as well as beshanhexanols A (3) and B (4), along with three known ones (5–7) were isolated from the rice fermentation of two endophytic fungi associated with the critically endangered Chinese endemic conifer Abies beshanzuensis. γ-Butyrolactone derivatives 1, 2, and 5 were isolated from Phomopsis sp. BSZ-AZ-2, an interesting strain that drawn our attention this time. The cyclohexanol derivatives 3, 4, 6, and 7 were obtained during a follow-up investigation on Penicillium commune BSZ-P-4-1. The chemical structures including absolute configurations of compounds 1–4 were determined by spectroscopic methods, Mo2(OAc)4 induced electronic circular dichroism (IECD), GIAO NMR calculations and DP4+ probability analyses. In particular, compound 2 contains a novel 5/5 bicyclic ring system, which might be biogenetically derived from the known compound 5 through hydrolysis followed by an Aldol reaction. All isolates were evaluated for their antimicrobial activities against a small panel of bacterial and fungal pathogens. Compounds 6 and 7 showed moderate inhibitory activities against Candida albicans, with MIC values of 16 and 32 μg/mL, respectively.

Diastereoselective Synthesis of the HIV Protease Inhibitor Darunavir and Related Derivatives via a Titanium Tetrachloride-Mediated Asymmetric Glycolate Aldol Addition Reaction.

Darunavir is a potent HIV protease inhibitor that has been established as an effective tool in the fight against the progression of HIV/AIDS in the global community. The successful application of this drug has spurred the development of derivatives wherein strategic regions (e.g., P1, P1', P2, and P2') of the darunavir framework have been structurally modified. An alternate route for the synthesis of darunavir and three related P1 and P1' derivatives has been developed. This synthetic pathway involves the use of a Crimmins titanium tetrachloride-mediated oxazolidine-2-thione-guided asymmetric glycolate aldol addition reaction. The resultant aldol adduct introduces the P1 fragment of darunavir via an aldehyde. Transamidation with a selected amine (isobutylamine or 2-ethyl-1-butylamine) to cleave the auxiliary yields an amide wherein the P1' component is introduced. From this stage, the amide is reduced to the corresponding β-amino alcohol and the substrate is then bis-nosylated to introduce the requisite p-nitrobenzenesulfonamide component and activate the secondary alcohol for nucleophilic substitution. Treatment with sodium azide yielded the desired azides, and the deprotection of the p-methoxyphenoxy group is achieved with the use of ceric ammonium nitrate. Finally, hydrogenation to reduce both the aniline and azide functionalities with concurrent acylation yields darunavir and its derivatives.

Controlled synthesis of chiral carbon dots with high asymmetric catalytic properties and reproducibility for direct aldol reactions: The impact of functional groups of carbon sources

The controlled synthesis of carbon dots (CDs) has been a key scientific problem in the field of catalysis. In this study, chiral CDs from different carbon sources were prepared using the hydrothermal method with d-proline as the chiral source. The effects of the carbon source skeleton (conjugated and unconjugated) and functional groups (hydroxyl, carboxyl, and amino) on its structure, reproducibility, and asymmetric catalytic performance in Aldol condensation were investigated. It was observed that hydroxyl groups in the carbon source are more favorable for enhancing the asymmetric catalytic activity and reproducibility of CDs compared to amino and carboxyl groups. The mechanism for the difference in reproducibility and asymmetric catalytic properties is investigated, which is ascribed to the effect of bonding (Directional factor or Random factor) between active sites and carbon cores, as well as the effect of carbonization (Random factor). The directional factor contributes to high reproducibility and asymmetric catalytic activity.

Synthesis of Chiral Acyclic Pyrimidine Nucleoside Analogues from DHAP-Dependent Aldolases.

Dihydroxyacetone phosphate (DHAP)-dependent aldolases catalyze the aldol addition of DHAP to a variety of aldehydes and generate compounds with two stereocenters. This reaction is useful to synthesize chiral acyclic nucleosides, which constitute a well-known class of antiviral drugs currently used. In such compounds, the chirality of the aliphatic chain, which mimics the open pentose residue, is crucial for activity. In this work, three DHAP-dependent aldolases: fructose-1,6-biphosphate aldolase from rabbit muscle, rhanmulose-1-phosphate aldolase from Thermotoga maritima, and fuculose-1-phosphate aldolase from Escherichia coli, were used as biocatalysts. Aldehyde derivatives of thymine and cytosine were used as acceptor substrates, generating new acyclic nucleoside analogues containing two new stereocenters with conversion yields between 70% and 90%. Moreover, structural analyses by molecular docking were carried out to gain insights into the diasteromeric excess observed.