[Development of Organocatalytic Reactions for the Synthesis of Natural Products and Pharmaceuticals].

This review describes novel organocatalytic methods for the enantioselective construction of spiroindans and spirochromans and the application of the methods to the total synthesis of natural products. We developed an intramolecular Friedel-Craftstype 1,4-addition in which the substrates were a resorcinol derivative and 2-cyclohexenone linked by an alkyl chain. The reaction proceeded smoothly in the presence of a cinchonidine-based primary amine (30 mol%) with water and p-bromophenol as additives. A variety of spiroindanes were obtained with high enantioselectivity under these conditions. The reaction was applied in the first total synthesis of the unusual proaporphine alkaloid (-)-misramine, which included the key steps of enantioselective spirocyclization and double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. The total synthesis of misrametine was achieved by selective demethylation of the methoxy group from the precursor to misramine. Next, a method for highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. An intramolecular oxy-Michael addition was catalyzed by a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivity of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.

Mechanistic investigations of polyaza[7]helicene in photoredox and energy transfer catalysis.

Organic photocatalysts frequently possess dual singlet and triplet photoreactivity and a thorough photochemical characterization is essential for efficient light-driven applications. In this article, the mode of action of a polyazahelicene catalyst (Aza-H) was investigated using laser flash photolysis (LFP). The study revealed that the chromophore can function as a singlet-state photoredox catalyst in the sulfonylation/arylation of styrenes and as a triplet sensitizer in energy transfer catalysis. The singlet lifetime is sufficiently long to exploit the exceptional excited state reduction potential for the activation of 4-cyanopyridine. Photoinduced electron transfer generating the radical cation was directly observed confirming the previously proposed mechanism of a three-component reaction. Several steps of the photoredox cycle were investigated separately, providing deep insights into the complex mechanism. The triplet-excited Aza-H, which was studied with quantitative LFP, is formed with a quantum yield of 0.34. The pronounced triplet formation was exploited for the isomerization reaction of (E)-stilbene to the Z-isomer and the cyclization of cinnamyl chloride. Catalyst degradation mainly occurs through the long-lived Aza-H triplet (28 µs), but the photostability is greatly increased when the triplet efficiently reacts in a catalytic cycle such that turnover numbers exceeding 4400 are achievable with this organocatalyst.

Recent Progress on Synthesis of Functionalized 1,5-Disubstituted Triazoles.

Immediately after the invention of 'Click Chemistry' in 2002, the regioselective 1,2,3- triazole scaffolds resulted from respective organic azides and terminal alkynes under Cu(I) catalysis have been well recognized as the functional heterocyclic core at the centre of modern organic chemistry, medicinal chemistry, and material sciences. This CuAAC reaction has several notable features including excellent regioselectivity, high-to-excellent yields, easy to execute, short reaction time, modular in nature, mild condition, readily available starting materials, etc. Moreover, the resulting regioselective triazoles can serve as amide bond isosteres, a privileged functional group in drug discovery and development. More than hundreds of reviews had been devoted to the 'Click Chemistry' in special reference to 1,4-disubstituted triazoles, while only little efforts were made for an opposite regioisomer i.e., 1,5-disubstituted triazole. Herein, we have presented various classical approaches for an expeditious synthesis of a wide range of biologically relevant 1,5- disubstituted 1,2,3-triazole analogues. The syntheses of such a class of diversly functionalized triazoles have emerged as a crucial investigation in the domain of chemistry and biology. This tutorial review covers the literature assessment on the development of various synthetic protocols for the functionalized 1,5-disubstituted triazoles reported during the last 12 years.

Atmospheric Gas-Phase Catalyst Etching of SiO2 for Deep Microfabrication Using HF Gas and Patterned Photoresist.

Micro/nanoscale structure fabrication is an important process for designing miniaturized devices. Recently, three-dimensional (3D) integrated circuits using SiO2 via-holes interlayer filling by copper have attracted attention to extend the lifetime of Moore's law. However, the fabrication of vertical and smooth-sidewall via-hole structures on SiO2 has not been achieved using the conventional dry etching method due to the limitation of the selective etching ratio of SiO2 and hard mask materials. In this study, we developed a unique method for the deep anisotropic dry etching of SiO2 using atmospheric gas-phase HF and a patterned photoresist. The hydroxyl groups in the photoresist catalyzed the HF gas-phase dry etching of SiO2 at high-temperature conditions. Therefore, fabrication of vertical with smooth-sidewall deep microstructures was demonstrated in the photoresist-covered area on SiO2 at a processing rate of 1.3 µm/min, which is 2-3 times faster than the conventional dry etching method. Additionally, the chemical reaction pathway in the photoresist-covered area on SiO2 with HF gas was revealed via density functional theory (DFT) calculations. This simple and high-speed microfabrication process will expand the commercial application scope of next-generation microfabricated SiO2-based devices.

Use of Novel Homochiral Thioureas Camphor Derived as Asymmetric Organocatalysts in the Stereoselective Formation of Glycosidic Bonds.

We synthesized six new camphor-derived homochiral thioureas 1-6, from commercially available (1R)-(-)-camphorquinone. These new compounds 1-6 were evaluated as asymmetric organocatalysts in the stereoselective formation of glycosidic bonds, with 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl and 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates as donors, and several alcohols as glycosyl acceptors, such as methanol, ethanol, 1-propanol, 1-butanol, 1-octanol, iso-propanol, tert-butanol, cyclohexanol, phenol, 1-naphtol, and 2-naphtol. Optimization of the asymmetric glycosylation reaction was achieved by modifying reaction conditions such as solvent, additive, loading of catalyst, temperature, and time of reaction. The best result was obtained with 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates, using 15 mol% of organocatalyst 1, in the presence of 2 equiv of MeOH in solvent-free conditions at room temperature for 1.5 h, affording the glycosidic compound in a 99% yield and 1:73 α:ß stereoselectivity; under the same reaction conditions, without using a catalyst, the obtained stereoselectivity was 1:35 α:ß. Computational calculations prior to the formation of the products were modeled, using density functional theory, M06-2X/6-31G(d,p) and M06-2X/6-311++G(2d,2p) methods. We observed that the preference for ß glycoside formation, through a stereoselective inverted substitution, relies on steric effects and the formation of hydrogen bonds between thiourea 1 and methanol in the complex formed.

Catalytic Synthesis of Silanols by Hydroxylation of Hydrosilanes: From Chemoselectivity to Enantioselectivity.

As a crucial class of functional molecules in organosilicon chemistry, silanols are found valuable applications in the fields of modern science and will be a potentially powerful framework for biologically active compounds or functional materials. It has witnessed an increasing demand for non-natural organosilanols, as well as the progress in the synthesis of these structural features. From the classic preparative methods to the catalytic selective oxidation of hydrosilanes, electrochemical hydrolysis of hydrosilanes, and then the construction of the most challenging silicon-stereogenic silanols. This review summarized the progress in the catalyzed synthesis of silanols via hydroxylation of hydrosilanes in the last decade, with a particular emphasis on the latest elegant developments in the desymmetrization strategy for the enantioselective synthesis of silicon-stereogenic silanols from dihydrosilanes.

Vicinal All-Carbon Quaternary Stereocenter Construction with Trifluoromethyl Groups via Organocatalytic Asymmetric Cascade Michael/Michael Reaction.

A thiourea organocatalyst efficiently promoted the asymmetric cascade Michael/Michael reactions between isatin-derived trifluoromethylacrylate and α-alkylidene succinimide, resulting in high yields of spirooxindole derivatives. These compounds exhibit vicinal all-carbon quaternary stereocenters and bear a trifluoromethyl group, with excellent enantioselectivities reaching up to 99 % ee. This work represents the first successful organocatalyst application for the direct construction of vicinal all-carbon quaternary stereocenters, featuring a trifluoromethyl group.

Development of Bifunctional Chiral Thioureas and Thiosquaramides in the Synthesis of Betti Bases.

Bifunctional thioureas and, for the first time, bifunctional thiosquaramides as organocatalysts were used in the asymmetric Betti reaction involving 1-, 2-naphthols and hydroxyquinoline with N-tosylimine and ketimine. The described methodology affords direct access to chiral aminoarylnaphthols in excellent yield (up to 98%) with high enantioselectivity (up to 80% ee) and enantioenriched 3-amino-2-oxindoles (up to 78% yield, up to 98% ee).

Recent advances in synthesizing and utilizing nitrogen-containing heterocycles.

The use of organocatalysts and a pot economy has strengthened recent organic syntheses. Synthetic methodologies may be applicable in laboratory preparation or in the industrial production of valuable organic compounds. In most cases, synthetic challenges are overcome by highly efficient and environmentally benign organocatalysts in a pot-economical manner. This is exemplified by the recent synthesis of tetrahydropyridine-containing (-)-quinine.

Multicomponent Synthesis Strategies, Catalytic Activities, and Potential Therapeutic Applications of Pyranocoumarins: A Comprehensive Review.

Fused coumarins, because of their remarkable biological and therapeutic properties, particularly pyranocoumarins, have caught the interest of synthetic organic chemists, leading to the development of more efficient and environmentally friendly protocols for synthesizing pyranocoumarin derivatives. These compounds are the most promising heterocycles discovered in both natural and synthetic sources, with anti-inflammatory, anti-HIV, antitubercular, antihyperglycemic, and antibacterial properties. This review employed the leading scientific databases Scopus, Web of Science, Google Scholar, and PubMed up to the end of 2022, as well as the combining terms pyranocoumarins, synthesis, isolation, structural elucidation, and biological activity. Among the catalysts employed, acidic magnetic nanocatalysts, transition metal catalysts, and carbon-based catalysts have all demonstrated improved reaction yields and facilitated reactions under milder conditions. Herein, the present review discusses the various multicomponent synthetic strategies for pyranocoumarins catalyzed by transition metal-based catalysts, transition metal-based nanocatalysts, transition metal-free catalysts, carbon-based nanocatalysts, and their potential pharmacological activities.

Spectroscopic and Computational Study of the Organocatalytic Umpolung of Bromocations: An Accelerated Stereoselective Dibromination Protocol.

Herein, organocatalytically achieved polarity reversal of cationic bromine is presented. The proven bromocation source N-bromosuccinimide (NBS) was converted to a superior bromoanion reagent by H/Br exchange with a secondary amine, substantiated with spectroscopic and computational evidence. The concept has further been used in a successfully accelerated organocatalyzed dibromination of olefins in a non-hazardous, commercially viable process with a wide range of substrate scope. The reactivity of key entities observed through NMR kinetics and reaction acceleration using only 10 mol % of catalyst account for its major success. The nucleophilicity of the bromoanion was found to be superior in comparison to other nucleophiles such as MeOH and H2 O also the protocol dominates over the competing allylic bromination reaction.

Secondary Amine-Mediated Domino Reaction for the Synthesis of Substituted Quinolines from Dicyanoalkenes and Enynals.

Substituted quinolines, tricyclic and tetracyclic molecules with a quinoline moiety are synthesized by a domino reaction from dicyanoalkenes and 3-aryl-pent-2-en-4-ynals in one pot. We established two methods: one is catalyzed by chiral diphenylprolinol silyl ether, and the other is catalyzed by di(2-ethyl)hexylamine, in combination with p-nitrophenol. A wide variety of dicyanoalkenes can be employed. As the catalysts are secondary amines, and water is the only by-product, this is an environmentally benign synthetic method for the preparation of substituted quinolines.

Utilization of vanillin to prepare sulfated Calix[4]resorcinarene as efficient organocatalyst for biodiesel production based on methylation of palmitic acid and oleic acid.

Recently, biodiesel production from palm oils has been thoroughly investigated to substitute crude oil due to its scarcity. However, the biodiesel production process is time-consuming due to its slow kinetics; thus, concentrated sulfuric acid has been used to fasten the reaction process in some industries. Unfortunately, sulfuric acid is a toxic, corrosive, and non-environmentally friendly catalyst. In this study, we prepared sulfated Calix[4]resorcinarene derived from vanillin as an efficient organocatalyst to replace sulfuric acid. The catalytic activity of sulfated Calix[4]resorcinarenes was evaluated through the methylation of palmitic acid and oleic acid as model compounds due to their abundant amounts in palm oil. The Calix[4]resorcinarene and sulfated Calix[4]resorcinarenes have been obtained through a one-pot reaction in 71.8-98.3% yield. Their chemical structures were confirmed by using FTIR, NMR and HRMS spectrometry analyses. The results showed that the sulfated Calix[4]resorcinarene exhibited high catalytic activity for methyl palmitate and methyl oleate productions in 94.8 ± 1.8 and 97.3 ± 2.1% yield, respectively, which was comparable to sulfuric acid (96.3 ± 1.8 and 95.9 ± 2.5%). The optimum condition was achieved by using 0.020 wt equivalent of organocatalyst for 6 h reaction process at 338 K. The methylation of palmitic acid and oleic acid fits well with the first-order kinetic model (R2 = 0.9940-0.9999) with a reaction rate constant of 0.6055 and 1.1403 h-1, respectively. Further investigation reveals that the hydroxyl group of vanillin plays a pivotal role in the organocatalytic activity of sulfated Calix[4]resorcinarene.

Tropylium Ion, an Intriguing Moiety in Organic Chemistry.

The tropylium ion is a non-benzenoid aromatic species that works as a catalyst. This chemical entity brings about a large number of organic transformations, such as hydroboration reactions, ring contraction, the trapping of enolates, oxidative functionalization, metathesis, insertion, acetalization, and trans-acetalization reactions. The tropylium ion also functions as a coupling reagent in synthetic reactions. This cation's versatility can be seen in its role in the synthesis of macrocyclic compounds and cage structures. Bearing a charge, the tropylium ion is more prone to nucleophilic/electrophilic reactions than neutral benzenoid equivalents. This ability enables it to assist in a variety of chemical reactions. The primary purpose of using tropylium ions in organic reactions is to replace transition metals in catalysis chemistry. It outperforms transition-metal catalysts in terms of its yield, moderate conditions, non-toxic byproducts, functional group tolerance, selectivity, and ease of handling. Furthermore, the tropylium ion is simple to synthesize in the laboratory. The current review incorporates the literature reported from 1950 to 2021; however, the last two decades have witnessed a phenomenal upsurge in the utilization of the tropylium ion in the facilitation of organic conversions. The importance of the tropylium ion as an environmentally safe catalyst in synthesis and a comprehensive summary of some important reactions catalyzed via tropylium cations are described.

Synthesis of Sequence-specific Poly(ester-carbonate) Copolymers via Chemoselective Terpolymerization Controlled by the Stoichiometric Ratio of Phosphazene/Triethylborane.

Chemoselective terpolymerization can produce polymer materials with diverse compositions and sequential structures, and thus have attracted considerable attention in the field of polymer synthesis. However, the intrinsic complexity of three-component system also brings great chanllenge, in regard to the reactivity and selectivity of different monomers. Herein, we report the terpolymerization of CO2 /epoxide/anhydride by a binary organocatalytic C3 N3 -Py-P3 /TEB (triethylborane) system. Both the activity and chemoselectivity were highly dependent upon the molar ratio of C3 N3 -Py-P3 to TEB, and sequence-controlled poly(ester-carbonate) copolymers were readily synthesized through one-pot/one-step methodology by tuning the stoichiometric ratio of phosphazene/TEB. In particular, C3 N3 -Py-P3 /TEB with a molar ratio of 1/0.5 exhibited an unprecedentedly high chemoselectivity for ring-opening alternating copolymerization (ROAC) of cyclohexene oxide (CHO) and phthalic anhydride (PA) first and then ROAC of CO2 /CHO. Thus, well-defined triblock polycarbonate-b-polyester-b-polycarbonate copolymers can be produced from the mixture of CO2 , CHO and PA using a bifunctional initiator. With C3 N3 -Py-P3 /TEB=1/1, tapered copolymers were obtained, while random copolymers with high content of polycarbonate (PC) were synthesized with further increasing the amount of TEB. The mechanism of the unexpected chemoselectivity was further investigated by DFT calculations.

Organocatalytic Synthesis of Chiral Halogenated Compounds.

This account summarizes our recent efforts in the enantioselective organocatalytic synthesis of chiral halogenated compounds. The enantioselective α-halogenation of aldehydes, decarboxylative chlorination of ß-keto acids, and enantioselective C-C bond formation at the trifluoromethylated prochiral carbon to yield the corresponding organohalides with chlorinated, fluorinated, or trifluoromethylated chiral stereogenic centers are discussed. We applied common organocatalysts, such as Jørgensen-Hayashi catalyst and cinchona alkaloid-derivatived catalyst, and developed novel chiral amine catalysts for these reactions. This account also discusses stereospecific derivatizations of the resulting chiral halogenated compounds via nucleophilic substitution. Thus, we synthesized many novel chiral compounds that have not been reported, even as racemates.

A novel heterogeneous acid-base nano-catalyst designed based on graphene oxide for synthesis of spiro-indoline-pyranochromene derivatives.

Nano graphene oxide/3-aminopyridine has been introduced as a new, efficient and robust heterogeneous organic catalyst for synthesis of spiro-indoline-pyranochromene derivatives. Nano graphene oxide/3-aminopyridine was provided in an easy and green way from GO. Firstly, graphene oxide (GO) was synthesized and then 3-aminopyridine was immobilized with covalent bonds on its surface as a nitrogenous organic compound, in this step we didn't use any organic or toxic substance. This bonding was easily performed due to the presence and reactivity of the epoxy groups in the GO structure. Because of its vast-surface nano-layers, GO could be effective in appropriate dispersion of 3-aminopyridine on its surface and increasing the catalyst performance. The new catalyst was analysed using different microscopic and spectroscopic techniques such as Fourier-transform infrared (FT-IR), field emission scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Our results showed that the distance between GO plates was increased in the presence of the modifying agent. This is due to the placement of the organic compound between the GO sheets. Finally, the ability of our new nano-catalyst in the synthesis of some spiro-indoline-pyranochromene and dihydropyranochromene derivatives was evaluated and acceptable results were obtained. Eight analogous of spiro-indoline-pyranochromene (4a-4 h) were synthesized in high yields and characterized. Using 3-aminopyridine as an organic and efficient catalyst, its stabilization by a simple method on GO, recycling of the catalyst up to 7 times and obtaining a highly pure product were the points that made the present work more attractive.

Exploring Guanidinium Organocatalysts for Hypoiodite-Mediated Reactions.

This account describes our recent work on developing guanidinium hypoiodite- catalysts for oxidative carbon-nitrogen and carbon-carbon bond-forming reactions. These reactions proceeded smoothly using guanidinium hypoiodite generated in situ by treating 1,3,4,6,7-hexahydro-2H-pyrimido[1,2-a]pyrimidine hydroiodide salts with an oxidant. In this approach, the ionic interaction and hydrogen bonding ability of the guanidinium cations enable bond-forming reactions that have been difficult with conventional methods. Enantioselective oxidative carbon-carbon bond-forming reaction was also achieved by using a chiral guanidinium organocatalyst.

Recent Asymmetric Phase-Transfer Catalysis with Chiral Binaphthyl-Modified and Related Phase-Transfer Catalysts over the Last 10 Years.

In this personal account, we describe our recent advances in the three types of phase-transfer catalysis for various transformations including asymmetric induction: Firstly, asymmetric phase-transfer catalysis with Maruoka-type C2 -symmetric chiral biaryl-modified tetraalkylammonium salts and phosphonium salts; Secondly, asymmetric phase-transfer catalysis under base-free and neutral conditions; Thirdly, hydrogen-bonding catalysis using tetraalkylammonium and trialkylsulfonium salts. These three different strategies are illustrated by using various phase-transfer catalyzed transformations.

Synthesis of cinchona urea polymers using Yamamoto coupling and their application to asymmetric reaction.

Cinchona urea compounds having 3,5-diiodophenyl moieties were subjected to Yamamoto coupling polymerization to afford the chiral urea polymers. These polymers showed high activities as heterogeneous catalysts in asymmetric Michael reactions comparable with those of the corresponding monomeric catalyst in solution systems. Furthermore, the polymeric catalysts are easily recovered from their reaction mixtures due to their insolubility and can be reused several times without loss of catalytic activity.