Aldol Reaction Research Articles

Development of the Synthesis of Desepoxy-Tedanolide C.

We are presenting the development of our route for the total synthesis of desepoxy-tedanolide C. Through the obtained analytical data, the proposed structure of tedanolide C is questioned and a different configuration for this natural product is proposed. Key steps of the synthesis are a Kiyooka aldol reaction that builds up the tertiary alcohol flanked by three oxygenated carbon atoms and two aldol reactions used for fragment couplings. A Julia-Kocienski olefination was used for installation of the side chain. Besides the successful synthesis, the development for the protecting group setup of the southwestern hemisphere is described in detail as well as another retrosynthetic attempt for building up the target molecule.

In Situ Assembly of a Metal‐Templated Catalyst for Asymmetric Aldol Reactions: From the Metal Complexes Equilibria to a Practical System

AbstractA zinc(II)‐templated catalyst assembling terpyridine and bipyridine organocatalytic ligands has been developed for the asymmetric aldol reaction. The system has been optimized to maximize the formation of the heteromeric bifunctional species through the determination of the equilibrium constants leading to the formation of all the species present. A practical, easy to synthesize catalytic system providing high stereoselectivity has been achieved in this way.

Decoding the impact of solvents in altering the conversion rates and stereoselectivity in proline-catalyzed asymmetric aldol reaction

Decoding the impact of solvents in altering the conversion rates and stereoselectivity in proline-catalyzed asymmetric aldol reaction

Reversibly photoswitchable catalysts for the aldol reaction based on azobenzene-bearing organocatalysts

Development of smart artificial switchable catalysis has aroused much research interest in wide fields. Herein, a series of azobenzene-bearing organocatalysts with L/D-proline units (Ⅰ-Ⅴ) were developed and evaluated in the catalytic efficiency for aldol reaction. The photoisomerization behavior of the azobenzene-bearing organocatalysts and the effect of light as external stimulus on the catalytic performance were investigated in depth. Worth to mention that the reaction rate of the aldol reaction can be regulated by light irradiation, detailly, the azobenzene-bearing organocatalysts displayed a substantial difference in photoswitchable “ONOFF” catalytic activity, which exhibited great potential for dynamic control in smart catalytic systems.

Engineering of Candida antarctica Lipase B for Enhanced Perhydrolysis Activity by Modulating the Potential Water Channel

AbstractAlthough Candida antarctica lipase B (CAL‐B) naturally hydrolyzes an ester compounds, it can catalyze a variety of promiscuous reactions, such as perhydrolysis, aldol reaction, and Michael‐type reactions. Perhydrolysis is similar to hydrolysis but uses hydrogen peroxide instead of water molecules. It was recently proposed that water molecules access the active site of CAL‐B through a water channel. We hypothesized that hydrogen peroxide may also use the channel to enter the active site, and that the access of hydrogen peroxide is one of the key factors for perhydrolysis activity. We investigated the effects of mutations at two residues in the water channel of CAL‐B on the perhydrolysis activity. The residues, Pro280 and Ala281, are located at the constricted area of the water channel. We found that the substitution of Ala281 to a small and polar amino acid, such as serine or threonine, resulted in a noticeable increase in hydrolysis and perhydrolysis activity. The activity of the variant enzymes was up to three times and twice higher for the activities of hydrolysis and perhydrolysis, respectively, than those of CAL‐B. In contrast, the substitution of the Pro280 residue with a small and polar amino acid decreased both hydrolysis and perhydrolysis activities.

Synthesis of Biomimetic Thioesters for Studies of Ketoreductase Domains from the Biosynthesis of Cytotoxic Polyketides

AbstractThe synthesis of biomimetic thioesters for enzymatic studies of ketoreductase (KR) domains from polyketide synthases is described. A TBS-protected dihydroxyalkene fragment was synthesised by a sequence involving a Nagao acetate aldol reaction, a Mukaiyama propionate aldol reaction, and a methylene Wittig olefination. Fragment coupling to N-acetylcysteamine (SNAC) (E)-3-hydroxyhex-4-enethioates by an olefin cross-metathesis (OCM) and subsequent deprotection gave the potential KR product stereoisomers. An analogous OCM with a SNAC (E)-3-ketohex-4-enethioate did not give the desired KR precursor, but the reaction could successfully be replaced by a Horner–Wadsworth–Emmons olefination between a SNAC 3-ketothioester phosphonate and a TBS-protected dihydroxy aldehyde. After deprotection, an intramolecular cyclisation was observed that needs to be considered as a spontaneous side reactivity in the enzymatic assays.

Enzymatic Synthesis of Noncanonical α‐Amino Acids Containing γ‐Tertiary Alcohols

AbstractNoncanonical amino acids (ncAAs) containing tertiary alcohols are valuable as precursors of natural products and active pharmaceutical ingredients. However, the assembly of such ncAA scaffolds from simple material by C−C bond formation remains a challenging task due to the presence of multiple stereocenters and large steric hindrance. In this study, we present a novel solution to this problem through highly selective enzymatic decarboxylative aldol addition. This method allows for the streamlined assembly of multifunctionalized ncAAs with γ‐tertiary alcohols from readily available materials, such as L‐aspartatic acid and isatins, vicinal diones and keto esters. The modularity of electrophiles furnished four classes of ncAAs with decent efficiency as well as excellent site and stereocontrol. Computational modeling was employed to gain detailed insight into the catalytic mechanism and to provide a rationale for the observed selectivities. The method offers a single‐step approach to producing multifunctionalized ncAAs, which can be directly utilized in peptide synthesis and bioactivity assessment.

Enzymatic Synthesis of Noncanonical α-Amino Acids Containing γ-Tertiary Alcohols.

Noncanonical amino acids (ncAAs) containing tertiary alcohols are valuable as precursors of natural products and active pharmaceutical ingredients. However, the assembly of such ncAA scaffolds from simple material by C-C bond formation remains a challenging task due to the presence of multiple stereocenters and large steric hindrance. In this study, we present a novel solution to this problem through highly selective enzymatic decarboxylative aldol addition. This method allows for the streamlined assembly of multifunctionalized ncAAs with γ-tertiary alcohols from readily available materials, such as L -aspartatic acid and isatins, vicinal diones and keto esters. The modularity of electrophiles furnished four classes of ncAAs with decent efficiency as well as excellent site and stereocontrol. Computational modeling was employed to gain detailed insight into the catalytic mechanism and to provide a rationale for the observed selectivities. The method offers a single-step approach to producing multifunctionalized ncAAs, which can be directly utilized in peptide synthesis and bioactivity assessment.

L-proline-based deep eutectic solvents as green and enantioselective organocatalyst/media for aldol reaction

The use of chiral deep eutectic solvents (DESs) based on the natural amino acid L-proline and various glycols presents an environmentally friendly approach for important CC bond formation reactions. These DESs serve as both organocatalysts and reaction media in the aldol reaction, reducing the need for additional toxic or hazardous chemicals. By employing these DESs, we were able to activate the desired reaction through the condensation of ketones and L-proline via enamine activation. This approach eliminates the requirement for traditional, often environmentally harmful, organic solvents. Notably, diethylene glycol played a crucial role in modulating the reaction performance, including conversion and enantioselectivity. Diethylene glycol is a relatively safer alternative compared to other commonly used solvents or additives with potential environmental and health risks. Moreover, reducing the L-proline content in the DESs led to a slight increase in the enantiomeric excess of the predominant diastereomeric product. This finding suggests the possibility of minimizing the use of L-proline, which can be advantageous from both cost and environmental perspectives.The results of these reactions demonstrate promising green outcomes, with a diastereomeric ratio up to 25:1 for the major anti-isomer, showcasing excellent selectivity (>90 % ee). In addition to these high enantiomeric excess values, quantitative yields in the aldol reaction highlight the potential for high efficiency and reduced waste production.Overall, the utilization of chiral DESs based on L-proline and glycols offers a greener alternative for enantioselective organocatalytic reactions. This approach minimizes the use of hazardous catalysts, reduces waste generation, and demonstrates impressive selectivity, paving the way for more sustainable synthetic methodologies.

Stereo flexible synthesis of the C8-C23 fragment of antarlides, androgen receptor antagonists.

A practical and efficient synthesis of the C8-C23 fragment of antarlides A-H, incorporating six stereocenters and a conjugated diene, is reported. A strategic combination of synthetic methods, including CBS reduction, Evans' aldol reaction, Keck-Maruoka allylation, and enzymatic resolution, enabled the selective introduction of these stereocenters. Furthermore, the pivotal coupling of key fragments is successfully executed through a Julia-Kocienski olefination reaction, connecting the C8-C14 and C15-C23 subunits.

Three-dimensional structural alignment based discovery and molecular basis of AtoB, catalyzing linear tetracyclic formation.

Enzymes from the nuclear transport factor 2-like (NTF2-like) superfamily represent a rare group of biocatalysts with diverse catalytic functions facilitating intriguing skeleton formations. However, most proteins of this family remain enigmatic and await further elucidation. In this study, a combination of protein structural alignment with clustering analysis uncovers a new aldolase, AtoB, belonging to the NTF2-like superfamily. AtoB catalyzes the key intramolecular aldol reaction in linear tetracyclic meroterpenoid biosynthesis. The X-ray crystal structures of AtoB and AtoB-ligand complex are established at 1.9 Å and 1.6 Å resolution, respectively, revealing the rotation of the α4 helix and key residues in the active site for substrate binding. Molecular docking and site-directed mutagenesis demonstrate an acid-base pair involved in the AtoB-catalyzed aldol reaction, of which Arg59 is responsible for stereocontrol of hydroxylated C-10a during condensation. These findings provide valuable information for understanding the catalytic mechanisms of the AtoB-catalyzed aldol reaction. Additionally, a branching biosynthetic pathway of aspertetranones is elucidated during the exploration of the natural substrate of AtoB.

Organocatalytic enantioselective desymmetrization of enal-tethered cyclohexane-1,3-diones.

Organocatalytic asymmetric desymmetrization of prochiral cyclohexane-1,3-diones has been demonstrated through the merging of iminium and enamine activation. The tandem annulation reaction proceeds through a sequential oxa-Michael addition/intramolecular aldol reaction/[1,3]-amino oxetane rearrangement pathway. Mechanistic study using an 18O-water experiment suggests oxetane rearrangement instead of direct dehydration. The formation of other competing Rauhut-Currier products via alkoxy-elimination was not observed.

Intrinsic and environmental modulation of stereoselective aldol organocatalyzed reactions by proline-containing lipopeptides.

Proline, along with its derivatives, has been employed as an efficient organocatalyst for aldol reactions, with the ability to promote the creation of stereoselective C-C bonds. Even though the Houk-List transition state model is able to explain the stereoselectivity observed when proline is used as a catalyst, few studies investigate the role of microheterogeneous media in modulating the reaction outcome. In this work, molecular dynamics and electronic structure calculations were used to investigate the aldol reaction in the condensed phase. Our research focused on a lipopeptide compound incorporating the proline residue within the sequence PRWG-(C18H37), where P represents l-proline, R stands for l-arginine, W for l-tryptophan, and G for l-glycine. This sequence is covalently bonded to a hydrophobic segment formed by a long aliphatic chain, acting as an organocatalyst in an aqueous solution. This catalytic phase utilizes the complex chemical environment of the solution to achieve high selectivity. Our findings indicate a Houk-List-like mechanism, in which the amide acts as an H-bond donor, complemented by a mechanism in which the counter ion, trifluoracetic acid (TFA), acts as a proton shuttle. Both mechanisms demonstrated low energy barriers-12.23 and 1.42 kcal mol-1 for the (S,R) stereoisomer formation, computed using DLPNO-CCSD with def2-TZVPP basis set. Further, to explore the catalytic effect of the PRWG-(C18H37) lipopeptide in water, molecular dynamics simulations were conducted. It was observed that the micellar phase significantly enhances stereospecific encounters, favouring the experimentally observed ratio of (SR/SS) isomers, in contrast to reactions in a pure cyclohexanone medium. By quantifying the effects enabled by the supramolecular assembly, we were able to shed light on the factors that modify and enhance the stereoslectivity of the reaction.

Synthesis of the bicyclic butenolide core of pallamolide A: a biomimetic approach.

Pallamolide A is a 7,8-seco-labdane terpenoid possessing a unique bicyclo[2.2.2]octane core and a spiro-butenolide moiety. A biomimetic synthesis of the bicyclic butenolide core over 10 steps is reported, featuring an unexpected autoxidation ring opening, and a vinylogous Mukaiyama aldol reaction which was spontaneously followed by an unusual intramolecular vinylogous aldol reaction to assemble the spiro-butenolide moiety and bicyclic core of pallamolide A.

A serendipitous crossed aldol reaction in the ligand periphery of a Ru(II) polypyridyl complex in silica bed: prospects for delivering anticancer agents for photoactivated chemotherapy.

The localized drug action in tumors to overcome the side effects of chemotherapy has become an impetus for the development of photoactivated chemotherapy (PACT). As potential PACT agents, ruthenium(II) polypyridyl complexes have emerged as efficient photocages for anticancer agents. Bioactive molecules possessing functional groups such as nitrile, thioether, pyridine, imidazole, etc. are often directly attached to the primary coordination sphere of Ru(II) polypyridyl complexes for this purpose. Herein, we propose an alternative design strategy to attach potential anticancer agents lacking these functional groups with Ru(II) polypyridyl complexes through a pyridyl linker moiety. The proposition is, however, a thoughtful extrapolation of a serendipitous crossed aldol reaction that took place between the Ru(II)-coordinated 4-Pyridinecarboxaldehyde (4-PyCHO) and acetone, discovered while the Ru(II)-complex [Ru(ttp)(dppz)(4-PyCHO)]2+ {[1]} [ttp = p-tolyl terpyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine, 4-PyCHO = 4-Pyridinecarboxaldehyde] was being purified by silica gel column chromatography with acetone/water/saturated aqueous KNO3 solution as the eluent. The resultant pure aldol product [Ru(ttp)(dppz)(4-PyCHAc)]2+ {[1-Ac]} [4-PyCHAc = aldol modified 4-Pyridinecarboxaldehyde, i.e., 4-hydroxy-4-(pyridin-4-yl)butan-2-one)], was unambiguously characterized by a variety of spectroscopic techniques and X-ray crystallography. Furthermore, a 1H NMR study after 470 nm light irradiation and subsequent ESI-MS analysis revealed that 4-PyCHO could be photo-released from [1-Ac] as its in situ generated aldol adduct 4-PyCHAc. Therefore, this finding serves as a proof-of-concept that provides a simpler alternative design strategy for appending cancer-selective agents having carbonyl groups with α-hydrogens to ruthenium(II) polypyridyl complexes and their photorelease for selective and targeted anticancer chemotherapy.

Hydrodeoxygenation of biomass-derived furans into liquid alkanes over a Ru/WO3–ZrO2 catalyst

Complete and selective hydrodeoxygenation of biomass-derived furfural-acetone aldol adducts to liquid alkanes was achieved over Ru/5WO3–ZrO2 catalyst at 150 °C and 2 MPa H2, attributed to the synergistic cooperation of Ru and WO3–ZrO2 support.

Visible-light-driven asymmetric aldol reaction of ketones and glycinates via synergistic Lewis acid/photoredox catalysis.

Visible-light-driven direct asymmetric α-C(sp3)-H bond functionalization of glycinate provides a direct and efficient route for the synthesis of diverse optically enriched α-amino acid derivatives. However, asymmetric coupling between glycinate radical species and ketones faces significant challenges, including competitive pathways, mutable intermediates, as well as congested stereogenic centers. Herein, we disclose the first example for the asymmetric photocatalytic synthesis of a diverse array of β-diaryl-β-hydroxy-α-amino acetate derivatives from glycinates and heteroaryl ketones through the synergistic catalysis of achiral iridium photoredox catalyst and chiral lanthanide Lewis acid catalysts. The enantioselective radical addition pathway is supported by spectroscopic experiments, control experiments and DFT calculations.

Methods and Case Studies for in-Depth Learning of the Aldol Reaction Based on Its Reversible Nature

Methods and Case Studies for in-Depth Learning of the Aldol Reaction Based on Its Reversible Nature

A transaminase-mediated aldol reaction and applications in cascades to styryl pyridines.

Transaminase enzymes are well established biocatalysts that are used in chemical synthesis due to their beneficial sustainability profile, regio- and stereoselectivity and substrate specificity. Here, the use of a wild-type Chromobacterium violaceum transaminase (CvTAm) in enzyme cascades revealed the formation of a novel hydroxystyryl pyridine product. Subsequent studies established it was a transaminase mediated reaction where it was exhibiting apparent aldolase reactivity. This promiscuous enzyme reaction mechanism was then explored using other wild-type transaminases and via the formation of CvTAm mutants. Application of one pot multi-step enzyme cascades was subsequently developed to produce a range of hydroxystyryl pyridines.

Recent advances in enzymatic carbon-carbon bond formation.

Enzymatic carbon-carbon (C-C) bond formation reactions have become an effective and invaluable tool for designing new biological and medicinal molecules, often with asymmetric features. This review provides a systematic overview of key C-C bond formation reactions and enzymes, with the focus of reaction mechanisms and recent advances. These reactions include the aldol reaction, Henry reaction, Knoevenagel condensation, Michael addition, Friedel-Crafts alkylation and acylation, Mannich reaction, Morita-Baylis-Hillman (MBH) reaction, Diels-Alder reaction, acyloin condensations via Thiamine Diphosphate (ThDP)-dependent enzymes, oxidative and reductive C-C bond formation, C-C bond formation through C1 resource utilization, radical enzymes for C-C bond formation, and other C-C bond formation reactions.