Intramolecular Aldol Condensation Research Articles

Synergistic Rh(II)- and Zn(II)-Catalyzed [3 + 3] Annulation of Diazoenals and α-Hydroxy Ketones for the Direct Synthesis of 2H-Pyrans, A Gateway Toward γ-Pyrones.

A new synergistic Rh(II)/Zn(II)-catalyzed [3 + 3] annulation has been developed between diazoenals and α-hydroxy ketones enabling the direct synthesis of 4-formyl-2H-pyrans. The reaction involves the formation of protic oxonium ylides from highly electrophilic Rh-enalcarbenoids followed by Zn-templated regioselective intramolecular aldol condensation. Subsequent investigations demonstrated that 4-formyl-2H-pyrans are unique precursors of γ-pyrones. The γ-pyrones were obtained via Et3N-mediated oxidative deformylation. Further, the triflic-acid-promoted double Schmidt reaction of 4-formyl-2H-pyrans provides synthetically important carboxamide-substituted 4-cyano 2H-pyrans.

Bioinspired Total Synthesis of 3-epi-Junipercedrol.

A bioinspired total synthesis of 3-epi-junipercedrol, which contains a strained tricyclo[5.2.2.03,7]undecane allo-cedrane framework and five stereocenters, was accomplished via an effective anionic semipinacol rearrangement of a tricyclic cedrane mesylate. The corresponding cedrane precursor was synthesized efficiently by employing the reductive oxy-Nazarov cyclization and an intramolecular aldol condensation as the key steps. This synthetic approach provided a further evidence for the biogenetic relationship between the typical cedrane and allo-cedrane sesquiterpenoids.

Ring Rearrangement Reactions of 4-Alkenylisocoumarins and Photophysical Evaluation of Multi-Substituted Anthracene Products.

Herein we report that readily available 4-alkenylisocoumarins can be regarded as potent dienolate equivalents. For example, lactol silyl ethers derived from 4-alkenylisocoumarins were selectively converted to the corresponding benzo-homophthalates through a fluoride-induced ring opening step that was followed by a ring closure through a vinylogous intramolecular aldol condensation. Likewise, nucleophilic activation of 4-alkenylisocoumarins directly yields diversely poly-substituted naphthalenes and anthracenes without formation of any regioisomer. Photophysical evaluation of a set of thus obtained 1,3-di- and 1,3,4-trisubstituted anthracenes reveals their distinct intramolecular charge transfer (ICT) character during light absorption in polar solutions and excimer emission from the solid state when a face-to-face π-stacked molecular assembly is present in the crystal packing.

One-Pot Synthesis of Functionalized Benzotropones via a Phthalide Ring-Opening/Intramolecular Aldol Condensation Cascade.

A one-pot protocol was developed for the synthesis of functionalized benzotropone derivatives via a nucleophilic phthalide ring opening by a 5-lithiated dioxinone derivative, followed by an intramolecular aldol condensation. The method demonstrates exceptional versatility with diverse substrates, yielding a variety of functionalized benzotropones. Subsequent transformations of the obtained benzotropone derivatives were explored for their potential applications.

НЕОБЫЧНЫЕ ПРЕВРАЩЕНИЯ АДДУКТА МИХАЭЛЯ ЛЕВОГЛЮКОЗЕНОНА И ЦИКЛОГЕКСАНОНА

Academician Genrikh Alexandrovich Tolstikov is a unique personality, a world-class scientist. During the years of his work as director of Institute of Organic Chemistry of the USC RAS (now the Ufa Institute of Chemistry of the Ufa Federal Research Center, Russian Academy of Sciences), new scientific directions were opened that are relevant and continue to this day. Research using sugars and anhydrous sugars, in particular, levoglucosane in the synthesis of prostaglandins and other bioactive structures, originates in the laboratory for the synthesis of low molecular weight bioregulators under the direction of prof. M.S. Miftakhov. After the creation of the laboratory for the synthesis of secondary metabolites (now the laboratory of pharmacophore cyclic systems) under the guidance of prof. Valeev F.A. Since the 90 s to the present, scientific research has been successfully conducted on the use of levoglucosenone and its derivatives in the synthesis of natural biologically active compounds and their analogues. Levoglucosenone attracted the attention of researches due to its availability and reactive, chiral structure. Its solubility in all organic solvents, and even in water, makes it a unique starting compound for organic synthesis. When describing the chemical behavior of levoglucosenone, it is important to note that many of its transformations proceed in a nontrivial manner and lead to unexpected products, which makes levoglucosenone an even more interesting object for study. Moreover, it turned out that the chemical transformations of its derivatives, in particular the Michael adducts of levoglucosenone and cycloalkanones, turned out to be even more unpredictable. This article is devoted to consideration of aspects of these transformations. Thus, it was found that two keto groups in the Michael adduct of levoglucosenone and cyclohexanone are not equivalent, the keto group of the carbohydrate fragment is more reactive. At the same time, when searching for the possibility of implementing intramolecular aldol condensation, it was unexpectedly found that the keto group of the carbohydrate fragment remains inert. Intramolecular carbocyclization could only be carried out in the Michael adduct of levoglucosenone and cyclododecanone. Based on the Michael adduct of levoglucosenone and cyclohexanone, a ten-membered lactone annelated with a carbohydrate fragment was synthesized. The problem of introducing substituents into the lactone cycle and modifying the carbohydrate part of the resulting lactone has been solved. On the basis of this adduct, an analog of the natural lactone, foracantholide, was synthesized. All results presented in the article include research conducted in our laboratory from 2014 to the present day.

3+3] Annulation of Diazoenals and α-Mercapto Ketones via Protic Sulfonium Ylides: Direct Synthesis of 2H-Thiopyrans, Innovative Progenitors for Unstudied 2H-Thiopyran-2-ones and 4H-Thiopyran-4-ones.

Herein, we report a new Rh(II)/Sc(III)-catalyzed [3+3] annulation between diazoenals and α-mercapto ketones for the direct synthesis of 4-formyl-2H-thiopyrans. The reaction proceeds via protic sulfonium ylides derived from highly electrophilic Rh-enalcarbenoids, followed by regioselective intramolecular aldol condensation. Further studies revealed that 4-formyl-2H-thiopyrans are novel precursors for unstudied 2H-thiopyran-2-ones and 4H-thiopyran-4-ones. The 4H-thiopyran-4-ones were obtained via a novel O2/Et3N-mediated oxidative deformylation. This methodology was applied to the short synthesis of structurally complex pyrimidine-fused 2H-thiopyran via cascade Schmidt, Ritter, and intramolecular cyclization reactions.

An efficient one-pot synthesis of p-xylene from bio-based 2,5-hexanedione and ethanol

A brand-new p-xylene (PX) production route via 2,5-hexanedione (HDO) and ethanol was put forward. And the reaction was successfully catalyzed by organic base - tetrapropylammonium hydroxide modified HZSM-5 zeolite. Under optimum condition, the conversion of 2,5-HDO and selectivity to PX was 89.6 % and 35.2 %, respectively, much higher than the patent HZSM-5 zeolite. For comparison, PX was also produced from 2,5-dimethyfuran (2,5-DMF) and ethanol or 2,5-HDO and ethylene under the same conditions. However, the PX selectivity and yield obtained from 2,5-HDO and ethanol was much poorer than that when 2,5-DMF or ethylene as reactant due to the series competitive dehydration reactions. To investigate the relationship between catalyst properties and performance, the physicochemical properties of catalysts were comprehensively characterized by XRD, N2 adsorption-desorption isotherms, ICP, NH3/CO2-TPD, pyridine-IR, SEM, TEM and MAS NMR. Conclusion can be drawn that the appropriate acidity and hierarchical pore structure in T0.5-HZ catalyst (HZSM-5 modified by 0.5 M tetrapropylammonium hydroxide) were beneficial to high PX selectivity and yield. Among them, the acid site with weak acid site would catalyze 2,5-HDO intramolecular aldol condensation to 3-methylcyclopentenone (MCO), while strong acid site was beneficial for 2,5-DMF hydrolysis to 2,5-HDO. Thus, acid site with moderate strength was advantageous to the conversion of 2,5-HDO to 2,5-DMF. Besides, the enough amount of acid sites and suitable B/L ratio of 0.98 can satisfy the requirements of various dehydration reactions and Diels-Alder reaction between 2,5-DMF and dienophiles, enhancing PX selectivity and yield. Additionally, the hierarchical pore structure enhanced mass transfer efficiency and improved the reaction rate. The promising production for bio-based PX via 2,5-HDO and ethanol lay solid foundation for industrialized production route from lignicellulose.

Synthetic studies toward Swinhoeisterol A: Synthesis of the 6/6/5/7 tetracyclic core

6/6/5/7 Tetracyclic core of Swinhoeisterol A was constructed starting from Wieland-Miescher ketone and silylated ethyl 5–hydroxyvalerate. After modification, the bicyclic and linear subunits were assembled by means of cross-metathesis reaction. Then, cyclopentane C ring was formed by the intramolecular aldol condensation. C17-stereocenter was constructed using Claisen rearrangement followed by the decarbonylation step. Finally, ene reaction was applied for the simultaneous formation of cycloheptane d-ring and tetrasubstituted double bond between rings B and C.

An aza-Robinson Annulation Strategy for the Synthesis of Fused Bicyclic Amides: Synthesis of (±)-Coniceine and Quinolizidine.

An aza-Robinson annulation strategy is described using a NaOEt-catalyzed conjugate addition of cyclic imides onto vinyl ketones, followed by a TfOH-mediated intramolecular aldol condensation to afford densely functionalized fused bicyclic amides. The potential use of these amides in the synthesis of alkaloids is demonstrated by the sequential conversion of appropriate precursors to (±)-coniceine and quinolizidine in two additional steps, thus allowing their preparation in overall 40 and 44% yields, respectively.

Retraction of Activating Imides with Triflic Acid: A General Intramolecular Aldol Condensation Strategy Toward Indolizidine, Quinolizidine, and Valmerin Alkaloids.

Retraction of Activating Imides with Triflic Acid: A General Intramolecular Aldol Condensation Strategy Toward Indolizidine, Quinolizidine, and Valmerin Alkaloids.

Synthesis of valuable benzenoid aromatics from bioderived feedstock

Aromatic chemicals play indispensable roles in our daily lives, having broad applications in household goods, textiles, healthcare, electronics and automotive, but their production currently relies on fossil resources that have heavy environmental burdens. Synthesis of aromatic chemicals from bio-based resources would be a viable approach to improve their sustainability. However, very few methods are available for achieving this goal. Here we present a strategy to synthesize aromatics from 5-hydroxymethylfurfural (HMF), an organic compound derived from sugars under mild conditions. HMF was first converted in two high-yielding steps into 2,5-dioxohexanal (DOH), a novel C6-compound containing three carbonyl groups. Subsequently, acid-catalysed intramolecular aldol condensation of DOH in the presence of secondary amines selectively produced a range of bio-based 4-dialkylamino substituted phenols and 1,4-di-(dialkylamino)benzenes (Wurster’s blue analogues) in 15–88% yields. In the absence of amines, the industrially important hydroquinone was also synthesized from DOH under acidic conditions. Using a similar approach where 4,5-dioxohexanal was the intermediate, we were also able to prepare catechol, a compound with important industrial applications, from HMF. The proposed approach can pave the way for the production of sustainable aromatic chemicals and move their industrial applications closer to achieving a bioeconomy.

Robinson Annulation Applied to the Total Synthesis of Natural Products

AbstractThe Robinson annulation is a significant reaction for the synthesis of α,β‐unsaturated ketone ring including the generation of two C−C bonds. It involves a Michael addition of a ketone and a methyl or ethyl vinyl ketone with subsequent intramolecular aldol condensation. Natural products and their structurally related analogues have historically made a major contribution to pharmacotherapy, particularly for cancer and infectious diseases. The Robinson annulation has frequently been employed as a vital step in the total synthesis of these important naturally occurring compounds and related complex biologically active products. In this review, we try to underscore the applications of the Robinson annulation in the total synthesis of biologically active natural products.

Preparation of Ionic Liquid Supported Organocatalysts for the Synthesis of Stereoselective (R)-9-Methyl-5(10)-Octaline-1,6-Dione

: The synthesis of Proline-2-triethyl-ethylamide hexafluorophosphate (ILPA-PF6) (with 96% yield) and further the application during the synthesis of (R)-9-Methyl-5(10)-octaline-1,6-dione (Wieland-Miescher ketone molecule) are defined in this manuscript. The suggested protocol signifies one of the most efficient methods for the synthesis of these flexible chiral building blocks in good yield. The evident solubility of ionic liquids allows straightforward isolation of the (R)-9-Methyl- 5(10)-octaline-1,6-dione product from reaction mass. Additionally, six times catalyst recycling was considered the main conclusion of this proposed procedure. Background: The synthesis of WMK starts with the Michael Addition step, where the α, β- unsaturated ketone reacts with 2-methyl-1,3-cyclohexanedione followed by the nucleophilic attack and produces the triketone. Further, the isolated triketone goes to intramolecular Aldol Condensation, (in the Robinson Annulation reaction cascade) to get an enolate. Later, followed by the dehydrogenation reaction of enolate (to expel hydroxide ion) the desired product Wieland Miescher Ketone was isolated in good yield. The above conventional method suffers from several drawbacks like a slow reaction rate, the requirement of high boiling point solvent systems, and low reaction yield. Objective:: To prepare ionic liquid-supported organocatalysts for the synthesis of stereoselective (R)- 9-Methyl-5(10)-octaline-1,6-dione Method: This report summarizes the synthesis and its application of triethyl salt-supported prolinebased organocatalysts as recyclable and highly efficient for the asymmetric Wieland-Miescher ketone ((R)-9-Methyl-5(10)-octaline-1,6-dione). An ionic liquid-supported proline (as a catalyst) is equipped with basic proline and a significantly acidic amide moiety to promote the reaction rate, and synchronously having a specialty of ionic liquid could be easy to separate and recycle. Results:: The report simply defined the WMK molecule in good yield and enantioselectivity followed by minimal ether washing. During the reaction, low catalyst loading i.e., 0.5 g of catalyst was found enough to attain the maximum yield and enantioselectivity in 2 hours. Furthermore, catalyst recycling was observed 6 times as a significant element of the suggested catalytic method. Conclusion:: The synthesis of an extremely dynamic and enantioselective ILPA-PF6 catalytic approach is demonstrated in the report. The ILPA-PF6 catalyst was further modified after its characterization for use in the synthesis of the WMK molecule and the subsequent intramolecular aldol reaction of triketone. The WMK molecule was isolated with good yield and enantioselectivity followed by minimal ether washing. During the reaction, low catalyst loading i.e., 0.5 g of catalyst was found enough to get the maximum yield and enantioselectivity in 2 hours. Additionally, catalyst recycling was observed 6 times as a significant element of the suggested catalytic method.

Artificial microRNA mediated silencing of cyclase and aldo-keto reductase genes reveal their involvement in the plumbagin biosynthetic pathway.

Plumbagin and other naphthoquinone derivatives from the Plumbago zeylanica L. (Plumbaginaceae) are known for their anticancer and other medicinal properties. Previous reports suggest that 3-methyl-1,8-naphthalene-diol is an intermediate of the plumbagin biosynthetic pathway and is synthesized from hexaketide backbone; a reaction catalyzed by type III polyketide synthase (PKS) along with certain accessory enzymes. Our earlier transcriptomic and metabolomic studies suggest that along with PKS, putative cyclase and aldo-keto reductase might be involved in the formation of 3-methyl-1,8-naphthalene-diol. The present study probed young leaf transcriptome and identified cyclase and aldo-keto reductase like transcripts that might be involved in the intramolecular aldol condensation of hexaketide intermediate and decarboxylation, carbonyl reduction and hydroxyl elimination of keto or enol forms of hexaketide intermediates respectively. Moreover, sequence alignment of identified cyclase1 possesses signature β-α-β-β-α-α-β topology, which belongs to the dimeric α + β barrel (DABB) protein family and is involved in the C2-C11 and C4-C9 intramolecular aldol condensation of hexaketide intermediates. Along with cyclase1, we further identified and characterized P. zeylanica specific aldo-keto reductase1 (AKR1) which is a novel member of the aldo-keto reductase (AKR) multi-gene family that possesses the conserved Asp60, Tyr65, Lys91, and His132 residues and is proposed to be involved in the C1 decarboxylation, C3 carbonyl reduction and C7 hydroxyl elimination of keto or enol form of hexaketide intermediate to form 3-methyl-1,8-naphthalene-diol. Further, the functional characterization using the artificial microRNA mediated transient silencing approach confirmed the involvement of cyclase1 and AKR1 in the plumbagin biosynthetic pathway. This is the first study reporting the identification and functional characterization of cyclase1 and AKR1 genes involved in the plumbagin biosynthetic pathway and general plant polyketide biosynthesis.

Surface Chemistry of Ketones and Diketones on Lewis Acidic γ-Al2O3 Probed by Infrared Spectroscopy

To advance the understanding of surface reactions of biomass-derived oxygenates, adsorption and conversion of ketones and diketones on Lewis acidic γ-Al2O3 are studied. The model compounds include ketones with hydroxyl groups (di/hydroxyacetone) as well as diketones with different distances between the two carbonyl groups (2,3-butanedione and 3,4-hexanedione, 2,4-pentanedione, and 2,5-hexanedione as α-, β-, γ-diketones, respectively). In situ infrared (IR) spectroscopy is utilized to experimentally observe the surface species. The deconvoluted IR spectra acquired between 50 and 250 °C suggest that intermolecular aldol condensation is the most common reaction path for the studied di/ketone reagents. This reaction path consists of sequential enolization, dimerization, and dehydration to form conjugated products with lower ν(C═O) and ν(C═C) frequencies. Exceptions included intramolecular aldol condensation of 2,5-hexanedione and isomerization and dehydration of dihydroxyacetone. Density functional theory calculations suggest that diketones bind as monodentate surface species provided their stability on γ-Al2O3. This study provides insight on di/ketone chemistry on Lewis acidic γ-Al2O3 that will be relevant for many fields including prebiotic and industrial chemistry.

Vapor-phase intramolecular aldol condensation of 2,5-hexanedione over calcium hydroxyapatite catalyst

Vapor-phase production of 3-methylcyclopent-2-en-1-one (MCP) via intramolecular aldol condensation of 2,5-hexanedione (HD) was performed over calcium hydroxyapatite (HAP) catalysts aged under various conditions. The aging temperature and time of the as-prepared apatite precipitate significantly affected the catalytic activity of the resulting HAP catalyst by influencing its residual carbonate and nitrate species and specific surface area. The HAP aged at a temperature between 50 and 200 ºC showed the highest catalytic activity with a high MCP selectivity of ca. 95%. However, serious deactivation was observed in an N2 carrier gas flow due to coke formation. The modification of the HAP catalyst with silver and the utilization of H2 as a carrier gas significantly reduced the coke formation and improved the catalytic stability during aldol condensation of HD to MCP.

Nickel-Catalyzed Carbonylation of Cyclopropanol with Benzyl Bromide for Multisubstituted Cyclopentenone Synthesis.

Herein, we reported a Ni-catalyzed carbonylation of cyclopropanol with benzyl bromide to afford multisubstituted cyclopentenone under 1 atm of CO. The reaction proceeds through cascade carbonylation of benzyl bromides, followed by generation of nickel homoenolate from cyclopropanols via β-C elimination to afford 1,4-diketones, which undergoes intramolecular Aldol condensation to furnish highly substituted cyclopentenone derivatives in moderate to good yields. The reaction exhibits high functional group tolerance with broad substrate scope.

Toporosides A and B, Cyclopentenyl-Containing ω-Glycosylated Fatty Acid Amides, and Toporosides C and D from the Northwestern Pacific Marine Sponge Stelodoryx toporoki.

Toporosides A-D (1-4), new ω-glycosylated fatty acid amides, were isolated from the sponge Stelodoryx toporoki. The structures of these compounds, including absolute configurations of stereogenic centers, were established using analysis of 1D and 2D NMR, ECD, and HR mass spectra as well as chemical transformations. Toporosides A (1) and B (2) are the first lipids containing a cyclopentenyl α,β-unsaturated carbonyl moiety in the polymethylene chain. Toporoside C (3) is likely a precursor, which undergoes intramolecular aldol condensation to produce 1 and 2. Toporosides A, C, and D showed protective effects against TNF-α-induced injury in H9c2 cardiomyocytes.

Stereoselective Formal Synthesis of Platencin

AbstractA stereoselective formal synthesis of platencin was accomplished from bromophenol 8 in eleven synthetic steps with 6 % overall yield. The intramolecular Diels‐Alder reaction of masked o‐benzoquinone, intramolecular aldol condensation, and stereoselective hydrogenation were the key steps in the construction of the tricyclic core of platencin.

Boehmite-derived Aluminum Oxide Catalyst for a Continuous Intramolecular Aldol Condensation of 2,5-Hexanedione to 3-Methyl-2-cyclopentenone in a Liquid-flow Reactor System

Abstract After thermal treatment of boehmite at higher than 600 °C and 1100 °C, the crystal phase transformation from AlOOH to γ-Al2O3 and/or δ-Al2O3 and the further transformations to the mixed phases of θ-Al2O3 and α-Al2O3, are respectively observed. Genesis of γ-Al2O3 (and/or δ-Al2O3) emphasizes the reactivity on an intramolecular aldol condensation of 2,5-hexanedione to 3-methyl-2-cyclopentenone (MCP) and its recyclability: approx. 70% yield with more than 80% selectivity for MCP generation are achieved in a liquid-flow reactor system for 9 h.