Current Organic Synthesis - Volume 12, Issue 2, 2015

The importance of diaminomaleonitrile (DAMN) as a readily available and cheap building block for the synthesis of various nitrogen heterocycles has attracted the attention of organic chemists worldwide. An enormous number of research studies have focused on the preparation of various heterocycles that play a role in the pharmaceutical, cosmetics, dyes, and pigment industries, among others. This review details developments in the chemistry and reactions of DAMN over the last decade including novel methods utilised, new compounds prepared, and significant applications.

Saccharide microarray technology has emerged as a powerful tool for studying the interactions of saccharides with a variety of biomolecules in high-throughput manner. An efficient and selective immobilization technique of saccharides on the surface is essential for successful preparation of saccharide microarrays. Carbohydrates can be immobilized on the support surface by covalent or noncovalent binding. The methods of preparing saccharide microarrays were summarized herein.

Organoselenium compounds have attracted special attention over the last years mainly because of their diversified biological activity. In particular, 1,3-selenazoles are interesting five-membered heterocycles that are being reported for their potential pharmacological profile. Efforts have been made in search or novel derivatives with improved biological activity, which include novel synthetic strategies. Owing to the importance of this system, the aim of this review is to provide an update on the synthesis and biological activity of 1,3-selenazole derivatives covering the main articles published between 2004 and 2014. This review is divided into two main sections: (i) a discussion of novel synthetic procedures for the preparation of 1,3- selenazoles and (ii) a report of recent findings regarding the biological activity of 1,3-selenazoles.

In the post-genomic era, more and more interests have been focusing on epigenetics. The histones studded with certain post-translational modifications (PTMs) are becoming one of the cores in protein chemical biology research. The biological generations and functions of these “histone codes”, such as their structural diversity, sophisticated regulations and complex cross-talks, are gradually discovered but still waiting to be deciphered. However, to prepare enough amount of homogeneously modified histones remain a challenge for chemical biologists. To overcome the shortage of traditional expression, protein total synthesis, semi-synthesis, and unnatural amino acid incorporation are becoming major approaches to fulfill this goal. In this review, we will summarize some typical examples for chemical prepared modified histone proteins for further biological study. The introduction of synthetic chemistry into this realm largely exhibited the importance and potential of chemical tools in biological and biomedical fertile grounds.

A highly efficient method for synthesis of multifunctionalized benzenes by one-pot multicomponent condensation between malononitrile, substituted aldehyde and cycloheptanone catalyzed by Zn-VCO3 hydrotalcite is reported. With water as solvent, this green chemistry reaction entails mild conditions. It is atom-efficient, high-yielding and pertinent to an extensive variety of multicomponent reactions.

Highly efficient, synthetic procedure for bis-(α-hydroxyalkyl)phosphinic acids is described using N-O-bis( trimethylsilyl)acetamide (BSA). Various substituted aldehydes undergo the addition of hypophosphorous acid in good to excellent yields. Operational simplicity, high yield and shorter reaction time are the key features associated with this protocol.

We report a simplified protocol for the routine direct chemoselective preparation of various piperazines substituted in the 1-position by an electron withdrawing group. These syntheses are based on the reaction of piperazine-1- ium cation with different electrophilic reagents such as acyl chlorides, anhydrides, sulfonyl chlorides, carbamoyl chlorides, and nitrourea as well. Piperazine-1-ium cation was chosen because the reactions of piperazine with electrophilic reagents in different solvents at usual temperatures are not chemoselective and provide mixtures comprising 1- substituted, 1,4-disubstituted and unsubstituted piperazine as well. Simultaneously, the mono-protonation of piperazine is the simplest synthetic method for its protection/deprotection in comparison with the currently used mono-benzylation, mono-Boc-protection, etc. Computer modeling of acid-base equilibria for piperazine and model 1-acetylpiperazine was used as the basis for the prediction of reaction conditions suitable for the synthesis. It was found that for in situ generating of starting piperazine-1-ium cation from piperazine the application of acetic acid as reaction medium or the chemisorption of piperazine on weakly acidic cationexchanger resin were highly acceptable in terms of both reaction times and yields. The using of resin supported piperazine-1-ium cation in reaction with carboxylic anhydrides or nitrourea is an example of the solid phase synthesis with ionically bonded substrate. Furthermore, syntheses in acetic acid medium were effectively catalyzed by Cu+, Cu+2 or Al+3 ions supported on weakly acidic cation-exchanger resin as well. Finally, it was observed that application of the solid support metal catalysis afforded target products in shortened reaction times and in 82-95% yields.

The first total syntheses of salmoxanthin and deepoxysalmoxanthin were accomplished by stereoselective Wittig reaction of a C15-tri-n-butylphosphonium salt bearing a 3,6-dihydroxy-ε-end group with the corresponding C25- apocarotenals. The 3,6-dihydroxy-ε-end moiety was constructed by chemo- and stereoselective reduction of the γ- hydroxy-α,β-cyclohexenone derivative.

A new approach for aminodehalogenation reaction between 3-chloropyrazine-2-carboxamide and ringsubstituted anilines is described. A series of 16 compounds (15 of them novel) derived from pyrazinamide have been synthesized successfully using the advantage of microwave-assisted reaction. The conditions for this aminodehalogenation reaction have been put to investigation to optimize the conversion, yield and time. The final methodology reduces the time needed for reaction from 24 hours using conventional heating to 30 minutes under microwave irradiation and increases the yield. The synthetic procedure together with analytical data of all compounds is presented. Lipophilicity properties were calculated and experimentally determined.

N-Methyl-D-aspartic acid (NMDA) has significant potential as a drug to treat diabetes, Parkinson’s and Alzheimer’s disease. Consequently, many efforts have been made for synthesis of NMDA, but there exist some flaws yet. In this paper, we report an improved method for Large-Scale Synthesis of optically pure NMDA by Eschweiler–Clarke reaction and deprotection of benzyl by ACE-Cl reagent. The synthesis has been achieved in five steps with an overall yield of 70% and an enantiomeric excess over 99.5%, in particularly, the method avoided the use of toxic methylation reagent. This method can be scaled up to kilogram quantities, providing a solid basis for its further bioactivity studies and drug development.

A workable method for the preparation of short oligoribonucleotides from commercially available 5´-O-(4,4´- dimethoxytrityl)-2´-O-(tert-butyldimethylsilyl)ribonucleoside 3´-(2-cyanoethyl-N,N-diisopropylphosphoramidite) building blocks on a soluble tetrakis-O-[4-(1,2,3-triazol-1-yl)methylphenyl]pentaerythritol support has been developed. The 3´-terminal nucleoside was attached as a 3´-O-(4-pentynoyl) derivative to the support by Cu(I) catalyzed click reaction. The coupling cycle consisted of 4,5-dicyanoimidazole promoted coupling in MeCN with 1.5 equiv. of the monomeric building block, conventional iodine oxidation and precipitation from water followed by flash chromatographic purification. Treatment with triethylamine, followed by ammonolysis and desilylation with Et3N(HF)3 afforded the oligoribonucleotide. As a proof of concept, a pentamer 3´-UUGCA-5´ was prepared in 46% overall yield.

A Knoevenagel one-pot synthesis of 6-amino-4-oxo-8-(2-thienyl)-3-[2-(2-thienyl)vinyl]-4H-pyrimido[2,1- c][1,2,4]triazine-7-carbonitrile 2 via the reaction of 3-amino-6-[2-(2-thienyl)vinyl]-1,2,4-triazin-5(4H)-one 1 with thiophene- 2-carbaldehyde and malononitrile under basic conditions is described. New fused heterotricyclic nitrogen systems, such as pyrimido[5',4':5,6]pyrimido[2,1-c][1,2,4]triazine 5, 7, 9, 12, 13, 20 and pyrido[3',2':5,6]pyrimido[2,1- c][1,2,4]triazine 10, 11, 14 were achieved by treating 2 with cyanamide, urea, thiourea, and CS2 in ethanolic ethoxide, formamide, triethyl orthoformate and then ammonia, malononitrile, ethyl cyanoacetate, chloroacetyl chloride and phenyl isothiocyanate. The structures of the products have been deduced from their elemental analysis and spectral data (IR, 1H-NMR, 13C-NMR). The antimicrobial activity of all synthesized compounds was screened.

Highly efficient one-pot solvent-free grinding method was reported for synthesis of chalcones 3a-j, 5a,b, 7 and bis-chalcones 9, 11. Cyclodehydration of bis-chalcones 9, 11 and chalcones 3 with hydrazine derivatives under solvent- free grinding method afforded bis-pyrazolines 12a,b, 13a,b and pyrazoline derivatives 14a-g, respectively. In a similar manner, grinding of bis-chalcones 9, 11 and chalcones 3 with hydroxylamine hydrochloride under the employed reaction conditions gave bis-isoxazolines 15, 16 and isoxazoline derivatives 17a-e, respectively. The antioxidant activity of the selected products was studied using 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay. Also, the antidiabetic activity of the selected products against normal and alloxan induced diabetic mice was evaluated.