Current Organic Synthesis - Volume 11, Issue 5, 2014

Alkaloids isolated from the amphibian skin have shown interesting biological profiles especially relevant to neurology. The skin of the Ecuadorian frog tricolor has provided as a source for novel quinolizidine alkaloid epiquinamide, albeit in the minute quantities (240 µg from 183 frogs) representing a new class of nicotinic agonists in CNS disorders. Significant efforts have been devoted to the stereoselective synthesis of epiquinamide and its isomers with different strategies since 2005. Till date, about seventeen total syntheses of natural epiquinamide and its isomers have been published. This review aims to analyze the advances in the developed strategies and methodologies for stereoselective total syntheses of target molecule epiquinamide and its isomers.

Triazoles and their derivatives have been widely utilized as precursors in the syntheses of biologically active systems such as anticancers, antimicrobials, antifungals and other cytotoxic active agents. In this review, we tried to highlight the recent advances (2010- 2013) in the syntheses of 1,2,3-triazoles, bis-1,2,3-triazoles and fused triazoles via click reaction. Click reaction provides substances quickly and reliably by combining small units together. Click chemistry can also be applied widely for the syntheses of biologically active compounds. Since the 1,2,3-triazole scaffold is present in many beneficial biologically structures, we hope this review attracts the attentions of synthetic organic chemists to make use of the advantages of click reaction in the total syntheses of natural products containing 1,2,3-triazoles.

Aryl-fused 1,4-oxazine derivatives have been recently studied with growing interest due to their pesticidal, especially antifeedant and antifungal, as well as pharmacological activities. These promising biological properties have encouraged the development of efficient synthetic strategies toward 3,4-dihydro-2H-1,4-benzoxazines and their 2-oxo, 3-oxo and 2,3-dioxo derivatives. Most of the available methods for preparing these heterocycles involve the annulation of a 1,4-benzoxazine ring to an arene scaffold. The present review reports a number of representative examples of the novel and modern synthetic strategies used for the ring closure reactions involving transition metal catalysis, microwave-assistance, metal-free or solid-state processes. Some of these syntheses are carried out in mild reaction conditions, employing room temperature and/or environmentally friendly solvents.

The pseudo-trisaccharide allosamidin 1 is a potent inhibitor of all family 18 chitinases, and it is confirmed to have biological activities against insects and fungi. The solid/liquid phase syntheses of allosamidin 1 and its analogues have been developed in recent years, and these compounds can be obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, deacetylation, or photolysis, respectively.

Quinolines as one of the most important classes of heterocyclic compounds are widely present as key structural motifs in many natural products, particularly in alkaloids and numerous bioactive drugs. Various name reactions for the syntheses of quinolines such as Skraup, Camps, Combes, Conrad-Lympach, Knorr, Gould-Jacobs, Povarov, Doebner and Doebner-von Miller, Pfitzinger and Niementowski, and Friedländer have already been discovered and extensively developed and modified. This review covers the most recent applications of Doebner and Doebner-von Miller reactions in organic syntheses. In addition the developments of the Knoevenagel- Doebner reaction in the synthesis of α,β-unsaturated carboxylic acids were demonstrated. In this paper we provide extensive compilation of the development of the Doebner reaction and variations for the synthesis of quinolines published from 2006 to 2013.

Organic chemists utilize azide synthons to generate a wide variety of functionalities, such as triazoles, tetrazoles, and diazo compounds. Though these products are often pharmacophores for biologically active molecules, the potentially hazardous nature of azides can act as a deterrent to their use in conventional reaction settings as they and diazo compounds are both explosive and toxic. Consequently, safer and greener methods of handling such reagents are needed and are being pursued. Among emerging methods are technology assisted syntheses by means of continuous flow processes, and processes where the compounds are generated in situ, eliminating the need for isolation. Additionally, new diazo-transfer agents have been developed that utilize polymer supports to minimize handling concerns. This mini-review will highlight recent advances in the field.

The solvent effect of different imidazolium, phosphonium and quaternary ammonium based ionic liquids was studied for the synthesis of amidoximes, demonstrating enhanced selectivity when using IL’s as the reaction medium.

Three benzylated triazole-linked nonionic locked nucleoside dimers TL-t-TL, TL-t-ABzL and TL-t-CBzL have been synthesized by Cu(I) catalyzed Huisgen-Sharpless-Meldal [3+2] cycloaddition reaction of 3'-azido-3'-deoxy-2'-O,4'-C-methylenethymidine with 3'-Obenzyl- 5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylenethymidine, 3'-O-benzyl-5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-6-N-benzoyladenosine and 3'-O-benzyl-5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-4-N-benzoylcytidine, which on debenzylation afforded the corresponding hydroxy analogs TL-t-TL and TL-t-ABzL in 69% and 63% overall yields. An effort to debenzylate TL-t-CBzL failed. Hydroxy TL-t- TL, TL-t-ABzL have alternatively been synthesized by the reaction of azidonucleoside with 5'-deoxy-5'-C-ethynyl-2'-O,4'-Cmethylenethymidine and 5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-6-N-benzoyladenosine in 79% and 76% overall yields, respectively. Among the two Cu(I) reagents used for cycloaddition (click) reaction, CuSO4.5H2O-sodium ascorbate in THF:tBuOH:H2O (1:1:1) was found to be better yielding than CuBr.SMe2 in THF.

Alkyl phenyl-H-phosphinates were synthesized by microwave(MW)-assisted direct esterification of phenyl-H-phosphinic acid. The phosphinates were then oxidized by m-chloroperbenzoic acid to the corresponding phenylphosphonic ester-acids that were esterified further under MW conditions to afford dialkyl phenylphosphonates. This is the first case that a mixed phosphonic derivative was esterified directly that is possible only under MW conditions. The mechanism and energetics of the esterifications investigated were evaluated by high level B3LYP calculations in solution applying the solvent model. The relatively high enthalpy of activation values of 175-186 kJ mol-1 prevents the direct esterifications on conventional heating, but may be overcome on MW irradiation.

In this work we report the highly efficient solvent-free and self-catalyzed three-component approach for the synthesis of pyrazolo[ 3,4-e][1,4]thiazepin-7(4H)-ones. The reaction between 5-aminopyrazoles, benzaldehydes and mercaptoacetic acid, acting both as reagent and catalyst, at 120 °C lead to the sequential formation of three new single bonds and the release of water as unique by-product, which demonstrates this to be an environmentally friendly three-component procedure. Selected products were evaluated by the NCI (USA) for their antitumor activity. Compound 16b displayed the most remarkable activity against different strains of human tumor cell lines with several GI50 values less than 1.0 µM (i.e. MDA-MB-435 (Melanoma, GI50 = 0.304 µM), A498 (Renal Cancer, GI50 = 0.353 µM) and SR (Leukemia, GI50 = 0.413 µM)), making it a promising building block for development of potential antitumor agents.