Rhodium-Catalyzed Allylic Addition as an Atom-Efficient Approach in Total Synthesis.

ConspectusFinding efficient synthetic methods for the asymmetric synthesis of complex molecules has always been of interest to organic chemists. Creating and controlling the stereochemistry of stereogenic centers bearing branched allylic moieties in organic molecules using a catalytic process is an attractive and successful method for the synthesis of several natural products and medicinally important compounds. Remarkable progress toward their synthesis has been achieved via transition-metal catalysis, especially in the case of allylic substitution and allylic C-H oxidation chemistry. However, for allylic substitution the preinstallation of a leaving group is essential, and for allylic C-H oxidation, stoichiometric amounts of oxidant are required. Besides that, the control of regioselectivity with these methods is often problematic because the linear product can be produced as a major isomer. Our research group has developed a regioselective, enantioselective, and atom economic route toward the more valuable branched product via a Rh-catalyzed coupling of easily accessible alkynes or the double-bond isomeric allenes with pronucleophiles. It was demonstrated that, using this new approach, it is possible to add different pronucleophiles to alkynes or allenes to form branched allylic moieties through C-C and C-heteroatom bond formation. Since new organic reactions offer new opportunities in chemical synthesis and the benchmark for new synthetic methods is their application in target-oriented synthesis, we have demonstrated several successful syntheses of natural products and medicinally relevant targets. For example, in the total syntheses of Quercuslactones, Helicascolides A-C, Epothilone D, Homolargazole, and Thailandepsin B, the Rh-catalyzed hydro-oxycarbonylation of allenes was used as key step via C-O bond formation. Remarkably, the Rh-catalyzed C2-symmetric dimerization strategy was used to synthesize the complex molecules Clavosolide A and Vermiculine, leading to an extreme increase in structural complexity within a single step. For the total syntheses of Centrolobine, Pitavastatin, and Rosuvastatin, C-O bond formation was achieved through the addition of a hydroxy function to the allene moiety. The potential of the addition of nitrogen pronucleophiles to allenes was demonstrated in the total syntheses of Cusparein, Angusterein, Cermicin C, Senepodin G, Homoproline, Pipecolinol, Coniceine, Coniine, Ruxolitinib, Sitagliptin, Abacavir, Glucokinase activators, and Chaetominine. All of these examples testify to the wide applicability of the Rh-catalyzed addition of pronucleophiles to allenes or alkynes in target-oriented synthesis, and in this Account we summarize our contribution.

Rhodium-Catalyzed Asymmetric Macrocyclization towards Crown Ethers Using Hydroamination of Bis(allenes).

Enantiomerically enriched crown ethers (CE) exhibit strong asymmetric induction in phase transfer catalysis, supramolecular catalysis and molecular recognition processes. Traditional methods have often been used to access these valuable compounds, which limit their diversity and consequently their applicability. Herein, a practical catalytic method is described for the gram scale synthesis of a class of chiral CEs (aza-crown ethers; ACEs) using Rh-catalyzed hydroamination of bis(allenes) with diamines. Using this approach, a wide range of chiral vinyl functionalized CEs with ring sizes ranging from 12 to 36 have been successfully prepared in high yields of up to 92 %, dr of up to >20 : 1 and er of up to >99 : 1. These vinyl substituted CEs allow for further diversification giving facile access to various CE derivatives as well as to their three-dimensional analogues using ring-closing metathesis. Some of these chiral CEs themselves display high potential for use in asymmetric catalysis.

Synthesis of new curcumin-based aminocarbonitrile derivatives incorporating 4H-pyran and 1,4-dihydropyridine heterocycles.

A multicomponent reaction containing curcumin, aldehydes, malononitrile and amine was developed for the one-pot synthesis of a novel library of 4H-pyran and 1,4-dihyropyridin heterocycles incorporating curcumin moiety. The products were obtained in the presence of p-toluenesulfonic acid as catalyst in ethanol as solvent in good to excellent yields.

Photophysical Properties of a Donor-π-Acceptor Distyrylbenzene Derivative in Solution and Solid state.

In this study, a π-conjugated organic compound based on distyrylbenzenes contains an amino substituent (as an electron-donor group) and a sulfone moiety (as an electron-withdrawing group) was investigated in the viewpoint of solvatochromism effects and the possibility of pH-sensitivity. This fluorescence dye (2-(ethyl(4-((E)-4-((E)-4-(methylsulfonyl)styryl)styryl)phenyl)amino)ethan-1-ol, ASDSB) showed Uv-Vis absorption in the range of 377-407 nm with high molar extinction coefficients (ε = 0.05 × 105-1.05 × 105 M-1.cm-1) in tested solvents with different polarities. This fluorescent compound emits in the region of visible spectrum (513-631 nm) with Stokes shifts of 5077.02-8912.66 cm-1. The combination of ASDSB with poly(methyl methacrylate) (PMMA) and polyvinyl alcohol(PVA) polymers exhibits different photophysical properties which related to the polarity of polymers. By change of pH of dissolved ASDSB in methanol, a hypsochromic shift was observed. This phenomena is correspond to the change of chromophore upon protonation of amino group and its conversion to ammonium salt. In the case of solid samples, the bathochromic shifts (426-535 nm) were observed at the maximum emission wavelength for PMMA polymer. While no significant change in the maximum emission wavelength of ASDSB in PVA polymer were detected.

Amino acids and peptides as reactants in multicomponent reactions: modification of peptides with heterocycle backbones through combinatorial chemistry.

In this study, amino acids and peptides were used as reactants in a Hantzsch multicomponent reaction in order to synthesize new structurally diverse molecules containing these synthons. As well, an applicable strategy for modification of these natural molecules with heterocycle backbones such as pyrimidine, xanthene and acridine is introduced. Using this method, a set of new amino acid- and peptide-functionalized heterocycles were synthesized in good to excellent yields under mild conditions. Furthermore, carbohydrates were used as substrates in the synthesis of some derivatives. Overall, this methodology allows the possibility of synthesis of large numbers of natural product-based libraries, using amino acids, peptides and carbohydrates through combinatorial chemistry.

Nickel-Catalyzed Reductive Etherification of Aldehydes at Room Temperature: C-O vs C-C Bond Formation.

The reaction of secondary and tertiary benzyl alcohols activated by 2,4,6-trichloro-1,3,5-triazine (TCT) with aldehydes in the presence of NiCl2·dmg as a precatalyst in ethylene glycol afforded ethers at room temperature. A selective C-O vs C-C bond formation was observed for the secondary and tertiary benzyl alcohols in comparison with primary ones.

L-cysteine functionalized magnetic nanoparticles (LCMNP): a novel magnetically separable organocatalyst for one-pot synthesis of 2-amino-4H-chromene-3-carbonitriles in water.

In this study, L-cysteine was chemically grafted to magnetic nanoparticles in order to prepare a reusable magnetic material incorporating an amino acid moiety. For this purpose, silica-coated magnetic nanoparticles (Fe3O4@SiO2) were reacted with trimethoxy(vinyl)silane to produce vinyl-functionalized magnetic nanoparticles (VMNP). Reaction of a VMNP substrate with L-cysteine in the presence of azobisisobutyronitrile (AIBN) resulted in the production of L-cysteine-functionalized magnetic nanoparticles (LCMNP). The LCMNP material was characterized using different microscopy and spectroscopy techniques such as FT-IR, XRD, TEM, SEM, EDX, VSM, and elemental analysis. Also, LCMNP was analyzed by thermogravimetric analysis (TGA) in order to determine its thermal behavior. The applicability of the LCMNP material was evaluated in a three-component coupling reaction between a nucleophile, salicylaldehyde and malononitrile as the catalyst for one-pot synthesis of 2-amino-4H-chromene-3-carbonitrile derivatives. The catalyst system showed high catalytic activity in this process and target products were obtained in high isolated yields in water as a green solvent. The LCMNP catalyst was reusable in this reaction at least 7 times with no significant decrease in its catalytic activity.

Carbohydrates as a reagent in multicomponent reactions: one-pot access to a new library of hydrophilic substituted pyrimidine-fused heterocycles.

In this study a multicomponent reaction involving carbohydrate derivatives as the main component in order to prepare a new library of polyhydroxy compounds incorporating pyrimidine-fused heterocycles (PFHs) is introduced. A set of polyhydroxy functionalized PFHs were synthesized using multicomponent reactions of sugar (glucose, galactose, arabinose and lactose), barbituric acid and amines. Also, the three-component condensation reaction between D-glucosamine, aldehyde, and barbituric acid efficiently provided polyhydroxy substituted PFH derivatives in a one-pot reaction under mild and green conditions. These new one-pot reactions gave a range of polyhydroxy substituted PFHs in good to excellent yield.

Synthesis of α-aminonitriles with benzimidazolic and theophyllinic backbones using the Strecker reaction.

An example of the application of the Strecker reaction in the synthesis of a new class of α-aminonitriles with benzimidazole and theophylline backbones has been developed. For the synthesis of these compounds, first 4-hydroxybenzaldehyde was reacted with 1,3- and 1,5-dibromides/epibromohydrin to produce the corresponding bromo-substituted aldehydes. Then, benzimidazole/theophylline was reacted with the latter to generate the related benzimidazolic/theophyllinic aldehydes. Finally, the Strecker reactions of the synthetic benzimidazolic and theophyllinic aldehydes with different amines afforded the target products.

Pyrimidine-fused heterocycle derivatives as a novel class of inhibitors for α-glucosidase.

The needs for diverse inhibitors of α-glucosidase (α-Gls) encouraged us to synthesize five different poly-hydroxy functionalized pyrimidine-fused heterocyclic (PHPFH) molecules, having either aliphatic or aromatic side chains (C1-C5) and their inhibitory activities were examined spectroscopically against yeast and mouse intestinal α-Gls. The results revealed that aromatic substitution of the synthetic compounds has significant impact on their inhibitory properties. Moreover C3 with the substituted moiety as 4-(4-aminophenylsulfonyl) phenyl (4-APSP) revealed strong inhibitory activity with non-competitive and competitive inhibition modes against yeast and mouse α-Gls, respectively. Furthermore, in the presence of increasing concentration of C3, both Trp and 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence intensities of yeast α-Gls were gradually decreased, suggesting that C3 binding induced significant structural alteration which was accompanied with the reduction of hydrophobic surfaces. Also, the interaction between yeast α-Gls and C3 was proved to be spontaneous and driven mainly by hydrophobic forces. Overall, this study suggests that aromatic substitution on pyrimidine-fused heterocyclic (PFH) scaffold may represent a novel class of promising inhibitors of α-Gls.

One-pot, three-component, iron-catalyzed synthesis of benzimidazoles via domino C-N bond formation.

An efficient one-pot, three-component process for the synthesis of benzimidazole derivatives using a catalytic amount of Fe(iii) porphyrin has been developed. The reaction proceeds via domino C-N bond formation and cyclization reactions of benzo-1,2-quinone, aldehydes and ammonium acetate as a nitrogen source to selectively produce benzimidazole. A number of benzimidazole derivatives have been synthesized using this method in high yields under mild reaction conditions.

The structural and functional consequences of melatonin and serotonin on human αB-crystallin and their dual role in the eye lens transparency.

Crystallins are the major soluble lens proteins, and α-crystallin, the most important protective protein of the eye lens, has two subunits (αA and αB) with chaperone activity. αB-crystallin (αB-Cry) with a relatively wide tissue distribution has an innate ability to interact effectively with the misfolded proteins, preventing their aggregation. Melatonin and serotonin have also been identified in relatively high concentrations in the lenticular tissues. This study investigated the effect of these naturally occurring compounds and medications on the structure, oligomerization, aggregation, and chaperone-like activity of human αB-Cry. Various spectroscopic methods, dynamic light scattering (DLS), differential scanning calorimetry (DSC), and molecular docking have been used for this purpose. Based on our results, melatonin indicates an inhibitory effect on the aggregation of human αB-Cry without altering its chaperone-like activity. However, serotonin decreases αB-Cry oligomeric size distribution by creating hydrogen bonds, decreases its chaperone-like activity, and at high concentrations increases protein aggregation.

New white light-emitting halochromic stilbenes with remarkable quantum yields and aggregation-induced emission.

Highly efficient single-component white light emitters (SWLEs), are attractive candidates for the simple and cost-effective fabrication of high-performance lighting devices. This study introduced a donor-π-acceptor and a donor-π-donor stilbene-based chromophores, representing pH-responsive fluorescence. The emitters showed yellow and green fluorescence in their neutral form. At the same time, protonation of the chromophores caused blue fluorescence color with a strong hypsochromic shift. The white light emission (WLE) for these chromophores was observed at approximately pH 3 due to the simultaneous presence of the neutral and protonated forms of the chromophores, covering almost all the emission spectra in the visible region (400-700 nm). These chromophores presented exceptional white light quantum yields (Φ) between 31 and 54%, which was desirable for producing white light-emitting devices. Density functional theory (DFT) and time-dependent (TD)-DFT were applied to study the structural and electronic properties of the chromophores.

Iodine-catalyzed synthesis of benzoxazoles using catechols, ammonium acetate, and alkenes/alkynes/ketones via C-C and C-O bond cleavage.

An efficient metal-free synthesis strategy of benzoxazoles was developed via coupling catechols, ammonium acetate, and alkenes/alkynes/ketones. The developed methodology represents an operationally simple, one-pot and large-scale procedure for the preparation of benzoxazole derivatives using molecular iodine as the catalyst.

Mechanisms behind the Fibrillation and Toxicity of Insulin Fibrils on Neuron Cells by Engineered Curcumin Analogs.

Among foods, the use of plant derivatives as promising drugs and/or excipients has been considered from various perspectives. In the present study, curcumin, which is one of the most important plant derivatives for biological uses, and four curcumin-based pyrido[2,3-d]pyrimidine analogs (C2-C5) were used for investigating the mechanism of insulin fibrillation and evaluating the cytotoxicity of insulin fibrils. The synthesized analogs differed in terms of hydrophobicity and electrostatic charge. The analogs with more hydrophobicity (C1 and C4) in both acidic and neutral environments were able to reduce the rate of insulin fibrillation and the degree of cross-linking in the produced fibrils. Additionally, the toxicity of these fibrils for neural cells (N2a cell line) was very low. However, they did not show any significant effects on the toxicity of non-neural cells (HEK293 cell line), indicating the effect of the biochemical surface diversity on determining the vulnerability to fibrils and even the mechanism of action of additives on cell line survival. Although negatively charged analogs were able to reduce insulin fibrillation in the acidic environment, they indicated an opposite effect in the neutral environment. The resultant fibrils in the acidic medium appeared with a well-distinguished filament, but they were very close at neutral pH levels. Moreover, such fibrils indicated very poor toxicity against the N2a cell line and had no significant effects on HEK293 cells. Considering the docking studies, by creatively using the size exclusion chromatography, it was suggested that analogs C2 and C3 were capable of binding to the C-terminal end of the insulin B chain (low affinity) and HisB10 (high affinity). Hence, it was suggested that different compounds could play different protecting and/or destroying roles in cell toxicity by blocking some ligands at the surface of neuron cells.

Asymmetric hydroalkylation of alkynes and allenes with imidazolidinone derivatives: α-alkenylation of α-amino acids.

This work reports a new method for the synthesis of quaternary α-alkenyl substituted amino acids by the enantio- and diastereoselective addition of imidazolidinone derivatives to alkynes and allenes. Further hydrolysis of the imidazolidinone products under acidic conditions afforded biologically relevant amino acid derivatives. This method is geometry-selective (E-isomer), enantio- and diastereoselective, and products were obtained in good to excellent yields. The utility of this new methodology is proved by its operational simplicity and the successful accomplishment of gram-scale reactions. Experimental and computational studies suggest the key role of Li in terms of selectivity and support the proposed reaction mechanism.

One-Pot Multicomponent Coupling Reaction of Catechols, Benzyl Alcohols/Benzyl Methyl Ethers, and Ammonium Acetate toward Synthesis of Benzoxazoles.

The multicomponent coupling reaction of catechol, ammonium acetate, and benzyl alcohol/benzyl methyl ether in the presence of a Fe(III) catalyst precursor afforded benzoxazole derivatives in good to excellent yields. The notable features of this protocol are abundant availability of the catalyst system, large-scale synthesis, high diversity, and high yields of products.

Synthesis of some new distyrylbenzene derivatives using immobilized Pd on an NHC-functionalized MIL-101(Cr) catalyst: photophysical property evaluation, DFT and TD-DFT calculations.

In this study the catalytic application of a heterogeneous Pd-catalyst system based on metal organic framework [Pd-NHC-MIL-101(Cr)] was investigated in the synthesis of distyrylbenzene derivatives using the Heck reaction. The Pd-NHC-MIL-101(Cr) catalyst showed high efficiency in the synthesis of these π-conjugated materials and products were obtained in high yields with low Pd-contamination based on ICP analysis. The photophysical behaviors for some of the synthesized distyrylbenzene derivatives were evaluated. The DFT and TD-DFT methods were employed to determine the optimized molecular geometry, band gap energy, and the electronic absorption and emission wavelengths of the new synthesized donor-π-acceptor (D-π-A) molecules in the gas phase and in various solvents using the chemical model B3LYP/6-31+G(d,p) level of theory.

Nickel-catalyzed reductive amidation of aryl-triazine ethers.

The reaction of activated phenolic compounds, 2,4,6-triaryloxy-1,3,5-triazine (aryl-triazine ethers), with various isocyanates or carbodiimides in the presence of a nickel pre-catalyst resulted in the synthesis of aryl amides in good to excellent yields.

A novel donor-π-acceptor halochromic 2,6-distyrylnaphthalene chromophore: synthesis, photophysical properties and DFT studies.

In this study a new 2,6-distyryl naphthalene [2-((4-((E)-2-(6-((E)-2,4-bis(methylsulfonyl)styryl)naphthalen-2-yl)vinyl)phenyl)(ethyl)amino)ethan-1-ol; ASDSN] was synthesized successfully using Heck chemistry as the main reaction. The ASDSN compound is a donor-pi-acceptor (D-π-A) conjugated system with amino as electron donating and sulfonyl as electron withdrawing groups. The UV-vis absorption of ASDSN was observed in the range of 403-417 nm with high molar extinction coefficients (ε = 15 300-56 200 M-1 cm-1) in some different solvents. This new fluorescent 2,6-distyryl naphthalene compound emits in the yellow region of the visible spectrum (557 nm) with Stokes shifts of 5930 cm-1. ASDSN is a pH-responsive fluorescence compound that shows yellow fluorescence in neutral form and blue fluorescence in the protonated form. A white light emission (WLE) for the chromophore was observed at pH = 3.0. The ASDSN chromophore presented a satisfactory white light quantum yield (Φ) of 13% which was desirable for producing white light emitting devices. Density functional theory (DFT) and time-dependent (TD)-DFT were applied to study structural and electronic properties of the chromophore.