Aldol Reaction Research Articles

Asymmetric synthesis of a stereopentade fragment toward latrunculins.

Latrunculins are marine toxins used in cell biology to block actin polymerization. The development of new synthetic strategies and methods for their synthesis is thus important in order to improve, modulate or control this biological value. The total syntheses found in the literature all target similar disconnections, especially an aldol strategy involving a recurrent 4-acetyl-1,3-thiazolidin-2-one ketone partner. Herein, we describe an alternative disconnection and subsequent stereoselective transformations to construct a stereopentade amenable to latrunculin and analogue synthesis, starting from (+)-β-citronellene. Key stereoselective transformations involve an asymmetric Krische allylation, an aldol reaction under 1,5-anti stereocontrol, and a Tishchenko-Evans reduction accompanied by a peculiar ester transposition, allowing to install key stereogenic centers of the natural products.

CuCo Nanoparticle, Pd(II), and l-Proline Trifunctionalized UiO-67 Catalyst for Three-Step Sequential Asymmetric Reactions.

Metal-organic frameworks (MOFs) have become a promising support for different active sites to construct multifunctional and heterogeneous catalysts. However, the related investigation mainly focuses on introducing one or two active sites into MOFs and trifunctional catalysts have been very rarely reported. Herein, non-noble CuCo alloy nanoparticles, Pd2+, and l-proline, as encapsulated active species, functional organic linkers, and active metal nodes, respectively, were successfully decorated to UiO-67 to construct a chiral trifunctional catalyst by the one-step method, which was further applied to asymmetric three-step sequential oxidation of aromatic alcohols/Suzuki coupling/asymmetric aldol reactions with excellent oxidation and coupling performance (yields up to 95 and 96%, respectively), as well as good enantioselectivities (eeanti value up to 73%) in asymmetric aldol reactions. The heterogeneous catalyst can be reused at least five times without obvious deactivation due to the strong interaction between the MOFs and the active sites. This work provides an effective strategy to construct multifunctional catalysts via the introduction and combination of three or more of active sites, including encapsulated active species, functional organic linkers, and active metal nodes, into stable MOFs.

Microwave assisted Schiff base metal complexes as potential anticancer and antimicrobial agents: A critical review

Schiff bases are organic compounds which contain azomethine group (-C=N-) by reacting primary amines and carbonyl compounds. The presence of an azomethine group in the Schiff base facilitates coordination with transition metal ions. The term Schiff base is normally applied to these compounds when they are being used as ligands to form coordination complexes with metal ions. Such complexes occur naturally, but the majority of Schiff bases are artificial and are used to form many important catalysts. Schiff base metal complexes prepared using microwave irradiation have gained more attention because of their excellent strategy in generating quick and stable products in higher yields by improving the speed of reaction with lesser energy and exhibits various biological activities including antifungal, antibacterial, anti-tubercular, antiviral, antimalarial, anti-diabetic, anticancer, antioxidant, antidiuretic, anti-inflammatory, antipyretic and anti-HIV agents. Apart from biological applications, they are also used as a catalyst in Aldol reactions, polymerization reactions, oxidation reactions and other chemical reactions. Imine-ligand containing transition metal complexes including copper, zinc and cadmium, have proven to be effective starting points for the synthesis of metal or metal chalcogenide nanoparticles. In this review, various metal complexes derived from Schiff bases synthesised using microwave approaches are discussed along with their antibacterial, antifungal and anticancer activities.

Organocatalytic Assembly Based on Aromatic Donor–Acceptor Interactions for the Asymmetric Aldol Reaction on Water

AbstractAromatic donor modified prolinamide and aromatic acceptor modified thiourea were synthesized. They self‐assembled into a cooperative organocatalytic system through the aromatic donor‐acceptor interaction and catalyzed aldol reactions in high yields and stereoselectivity on water. The aromatic donor‐acceptor interaction was confirmed by mass spectrum, UV‐vis titraition and 1H‐NMR titration experiments.

A catalytic enantioselective stereodivergent aldol reaction.

The aldol reaction is among the most powerful and strategically important carbon-carbon bond-forming transformations in organic chemistry. The importance of the aldol reaction in constructing chiral building blocks for complex small-molecule synthesis has spurred continuous efforts toward the development of direct catalytic variants. The realization of a general catalytic aldol reaction with control over both the relative and absolute configurations of the newly formed stereogenic centers has been a longstanding goal in the field. Here, we report a decarboxylative aldol reaction that provides access to all four possible stereoisomers of the aldol product in one step from identical reactants. The mild reaction can be carried out on a large scale in an open flask, and generates CO2 as the only by-product. The method tolerates a broad substrate scope and generates chiral β-hydroxy thioester products with substantial downstream utility.

Chiral Amine Catalyzed Reductive Aldol/Reductive Michael Addition Cascade Towards Enantioselective Synthesis of Benzannulated Diquinanes

AbstractDisclosed here an amine‐catalyzed reductive aldol‐condensation followed by an intramolecular reductive Michael‐addition cascade employing Hantzsch ester as hydride source to a keto‐bis‐enone to provide enantio‐ and diastereoselective benzannulated diquinanes having three consecutive stereocenters, one of which is an all‐carbon quaternary formyl stereocenter. Interestingly, on changing a tether connecting the ketone and an enone moiety from an aliphatic to an aromatic, a change in reactivity is observed. In this case, instead of the above‐mentioned reductive aldol condensation, an asymmetric aldol reaction occurs, followed by an iminium/enamine isomerization and, finally diastereoselective Michael addition reaction occurs. As a result, a bis‐benzannulated diquinane is obtained with vicinal congested quaternary chiral centers.

Photochemical diastereoselective synthesis and spectral characterization of (E)-3-(2-benzoylstyryl)-4H-chromen-4-ones

An efficient, concise, and green photochemical vinylogous aldol reaction for the diastereoselective synthesis of novel trans-3-(2-benzoylstyryl)-4H-chromen-4-ones starting from readily available methylbenzophenone and 3-formylchromone in the absence of any bases, metals, or other catalysts is described. The products could be obtained under UV LED (365 nm) irradiation at room temperature in 9 h with perfect diastereoselectivity. To discuss the special patterns of alkene protons, to identify its trans-conformation and verify the two trans-alkene protons (β-H and γ-H), NMR spectra analysis (1D-NMR and 2D-NMR) was conducted in details by the chemical shifts, couplings and correlations. Single crystal X-ray analysis confirmed the trans-conformation and all the compounds were unequivocally confirmed by NMR, HRMS and XRD analysis. XRD analysis of 3a further aids to disclose the reason why the alkene moiety presented a better planarity than that of benzophenone moiety of the title compounds.

Caesium carbonate functionalized magnetic nanoparticles: An efficient heterogeneous and reusable inorganic catalyst for aldol reaction in water

Caesium carbonate functionalized magnetic nanoparticles: An efficient heterogeneous and reusable inorganic catalyst for aldol reaction in water

Total Synthesis of (+)-Coriamyrtin via a Desymmetrizing Strategy Involving a 1,3-Cyclopentanedione Moiety.

We describe the total synthesis of (+)-coriamyrtin, which bears a highly functionalized cis-hydrindane skeleton and is a widely known neurotoxin of the Coriariaceae family. Our synthetic strategy involves the highly stereoselective construction of the cis-hydrindane skeleton via a desymmetrizing strategy involving a 1,3-cyclopentanedione moiety using an intramolecular aldol reaction and the formation of the 1,3-diepoxide moiety of coriamyrtin through the elaborate functionalization of the cyclopentane ring in the bicyclic structure.

Total Syntheses of Kopsaporine, Kopsinol and Kopsiloscine A

AbstractKopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure‐unit‐based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza‐Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all‐carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α‐hydroxyketone moiety, and a bioinspired retro‐Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.

Recent Advances in Asymmetric Synthesis of Pyrrolidine-Based Organocatalysts and Their Application: A 15-Year Update

In 1971, chemists from Hoffmann-La Roche and Schering AG independently discovered a new asymmetric intramolecular aldol reaction catalyzed by the natural amino acid proline, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction. These remarkable results remained forgotten until List and Barbas reported in 2000 that L-proline was also able to catalyze intermolecular aldol reactions with non-negligible enantioselectivities. In the same year, MacMillan reported on asymmetric Diels-Alder cycloadditions which were efficiently catalyzed by imidazolidinones deriving from natural amino acids. These two seminal reports marked the birth of modern asymmetric organocatalysis. A further important breakthrough in this field happened in 2005, when Jørgensen and Hayashi independently proposed the use of diarylprolinol silyl ethers for the asymmetric functionalization of aldehydes. During the last 20 years, asymmetric organocatalysis has emerged as a very powerful tool for the facile construction of complex molecular architectures. Along the way, a deeper knowledge of organocatalytic reaction mechanisms has been acquired, allowing for the fine-tuning of the structures of privileged catalysts or proposing completely new molecular entities that are able to efficiently catalyze these transformations. This review highlights the most recent advances in the asymmetric synthesis of organocatalysts deriving from or related to proline, starting from 2008.

Biogenesis-Inspired Synthesis of Penicillitone

AbstractThe biogenesis-inspired synthesis of the structurally unique 15(14→11)abeo-steroid penicillitone starting from commercially available ergosterol is reported. Key to the strategy is an intramolecular vinylogous aldol reaction of a 14,15-secoergostane obtained from the previously reported 14,15-secosteroid platform. Since a similar intermediate has been employed to access the strophasterol class of natural products, this work points at a possible biosynthetic connection between penicillitone and the strophasterols.

One-Pot Tandem Aldol-Cycloetherification Protocol in the Enantioselective Synthesis of Davanoids.

Total synthesis of cis and trans diastereomers of prenylated davanoids like davanone, nordavanone, and davana acid ethyl ester was achieved in an enantioselective strategy. Various other davanoids could also be synthesized using standard procedures from the Weinreb amides derived from davana acids. Enantioselectivity in our synthesis was achieved employing a Crimmins' non-Evans syn aldol reaction that fixed the stereochemistry of the C3-hydroxyl group, while the C2-methyl group was epimerized in a late stage of the synthesis. A Lewis acid-mediated cycloetherification reaction was used to establish the tetrahydrofuran core of these molecules. Interestingly, a slight alteration of the Crimmins' non-Evans syn aldol protocol led to the complete conversion of the aldol adduct to the core tetrahydrofuran ring of davanoids, thus essentially dovetailing two important steps in the synthesis. The resulting one-pot tandem aldol-cycloetherification strategy enabled the enantioselective synthesis of trans davana acid ethyl esters and 2-epi-davanone/nordavanone in just three steps in excellent overall yields. The modularity of the approach will enable the synthesis of various other isomers in stereochemically pure forms for further biological profiling of this important class of molecules.

An accelerated Rauhut-Currier dimerization enabled the synthesis of (±)-incarvilleatone and anticancer studies.

The total synthesis of racemic incarvilleatone has been achieved by utilizing unexplored accelerated Rauhut-Currier (RC) dimerization. The other key steps of the synthesis are oxa-Michael and aldol reactions in a tandem sequence. Racemic incarvilleatone was separated by chiral HPLC and the configuration of each enantiomer was determined by single-crystal X-ray analysis. In addition, a one-pot synthesis of (±)-incarviditone has been achieved from rac-rengyolone by using KHMDS as a base. We have also assessed the anticancer activity of all the synthesized compounds in breast cancer cells nonetheless, they exhibited very limited growth suppression activity.

Triethylammonium 2-(3-Hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate

In recent years, the application of privileged structures has become a powerful approach in the discovery of new biologically active molecules. Ion pairing is a strategy used to enhance the permeation of ionized topical drugs. A convenient and efficient method for the synthesis of triethylammonium 2-(3-hydroxy-2-oxoindolin-3-yl)-5,5-dimethyl-3-oxocyclohex-1-en-1-olate has been developed. The presented protocol includes an aldol reaction and the formation of an ammonium salt. Triethylamine is both a reactant and a catalyst in the process. The structure of the synthesized title compound has been established by 1H, 13C-NMR and IR spectroscopy, mass spectrometry, and elemental analysis.

Catalyst-Free Reactions under Biocompatible Conditions

AbstractCatalyst-free biocompatible reactions are a class of green chemical processes that are also applicable to the field of chemical biology. In this account, we detail our journey in this exciting area of research since 2000. Various types of catalyst-free biocompatible reactions, such as the Mukaiyama aldol reactions and thiol-specific click reactions, and their applications to the functionalization of proteins are described. These reactions work well without destroying the three-dimensional structures of the proteins. Other reactions, including the C–SO2 and C–N bond-forming reactions, are also discussed. These reactions work in a truly green manner in which the use of organic solvents can be totally avoided. This toolbox of green chemical processes will certainly facilitate the work of researchers in the pharmaceutical industries.1 Introduction2 C–C Bond-Formation Reactions: The Mukaiyama Aldol Reaction3 C–S Bond-Formation Reactions: Allenic Amide as the Electrophiles4 C–SO2R Bond-Formation Reactions4.1 Allylic Alcohols as the Electrophiles4.2 Allenic Carbonyl Compounds as the Electrophiles5 C–N Bond-Formation Reactions6 Conclusions and Outlook

Enantioselective and Chemoselective Phosphine Oxide-catalyzed Aldol Reactions of N-Unprotected Cyclic Carboxyimides.

Asymmetric catalytic transformations of N-unprotected cyclic carboxyimides such as succinimides, hydantoins, oxazolidinediones, and glitazones, is a powerful way of directly accessing variety of biologically valuable chiral compounds. Herein, a bis(trichlorosilyl) nucleophilic intermediate formed from cyclic carboxyimides was reacted with aldehydes via (S)-SEGPHOS dioxide (SEGPHOSO), proceeding the aldol reaction in highly enantioselective fashion through a cyclic transition state. Furthermore, N-unprotected carboxyimides were chemoselectively activated, even in the presence of N-alkylated carboxyimides, to undergo stereoselective and chemoselective aldol reactions via in situ silicon tetrachloride activation. The functionalized cyclic carboxyimides is readily derived to the several synthetic units derivatization to various chiral building blocks without unnecessary protection/deprotection steps.

Structure of pyridoxal 5'-phosphate-bound D-threonine aldolase from Chlamydomonas reinhardtii.

D-Threonine aldolase (DTA) is a pyridoxal-5'-phosphate-dependent enzyme which catalyzes the reversible aldol reaction of glycine with a corresponding aldehyde to yield the D-form β-hydroxy-α-amino acid. This study produced and investigated the crystal structure of DTA from Chlamydomonas reinhardtii (CrDTA) at 1.85 Å resolution. To our knowledge, this is the first report on the crystal structure of eukaryotic DTA. Compared with the structure of bacterial DTA, CrDTA has a similar arrangement of active-site residues. On the other hand, we speculated that some non-conserved residues alter the affinity for substrates and inhibitors. The structure of CrDTA could provide insights into the structural framework for structure-guided protein engineering studies to modify reaction selectivity.

A fast and efficient method for the analysis of α-dicarbonyl compounds in aqueous solutions: Development and application

Among the highly oxygenated species formed in situ in the atmosphere, α-dicarbonyl compounds are the most reactive species, thus contributing to the formation of secondary organic aerosols that affect both air quality and climate. They are ubiquitous in the atmosphere and are easily transferred to the atmospheric aqueous phase due to their high solubility. In addition, α-dicarbonyl compounds are toxic compounds found in food in biochemistry studies as they can be produced endogenously through various pathways and exogenously through the Maillard reaction. In this work, we take advantage of the high reactivity of α-dicarbonyl compounds in alkaline solutions (intramolecular Cannizzaro reaction) to develop an analytical method based on high performance ion chromatography. This fast and efficient method is suitable for glyoxal, methylglyoxal and phenylglyoxal which are detected as glycolate, lactate and mandelate anions respectively, with 100% conversion at pH > 12 and room temperature for exposure times to hydroxide ranging from 5 min to 4 h. Diacetyl is detected as 2,4-dihydroxy-2,4-dimethyl-5-oxohexanoate due to a base-catalysed aldol reaction that occurs before the Cannizzaro reaction. The analytical method is successfully applied to monitor glyoxal consumption during aqueous phase HO∙-oxidation, an atmospherically relevant reaction using concentrations that can be observed in fog and cloud water. The method also reveals potential analytical artifacts that can occur in the use of ion chromatography for α-hydroxy carboxylates measurements in complex matrices due to α-dicarbonyl conversion during the analysis time. An estimation of the artifact is given for each of the studied α-hydroxy carboxylates. Other polyfunctional and pH-sensitive compounds that are potentially present in environmental samples (such as nitrooxycarbonyls) can also be converted into α-hydroxy carboxylates and/or nitrite ions within the HPIC run. This shows the need for complementary analytical measurements when complex matrices are studied.

Synthesis of 2-Alkyl-2-(2-furanyl)-1,3-cyclopentanediones

Abstract2,2-Disubstituted 1,3-cyclopentanediones are versatile building blocks for synthesizing complex natural products with bicyclic structures including cyclopentane rings. The reported method for the synthesis of these compounds involves the semi-pinacol rearrangement of a Mukaiyama aldol adduct prepared from a ketone/ketal and 1,2-bis(trimethylsilyloxy)cyclobutene. However, the adoption of α-oxy-functionalized ketones/ketals is quite difficult, as demonstrated by our experiments. To overcome this limitation of the method, 2-acylfuran derivatives were used as the reactants to synthesize 2,2-disubstituted 1,3-cyclopentanediones. Furthermore, two reaction conditions, that is, the use of 1.4 equivalents of a boron trifluoride-diethyl ether complex or 0.4 and 0.2 equivalent of trimethylsilyl triflate and methoxytrimethylsilane, respectively, were established for the conversion of 2-acylfurans into the corresponding 1,3-cyclopentanediones in acceptable yields. The transformations of the furan rings in the obtained products were also investigated.