Current Organic Synthesis - Volume 9, Issue 3, 2012

In past decades, the pharmacopoeia was dominated by racemates, but since the emergence of new technologies in the 1990s that allowed the preparation of pure enantiomers in significant quantities, the awareness and interest in the stereochemistry of drug actions have increased. In this short review, the implementation of several hosts, guests, building blocks and methods in host-guest supramolecular chemistry was outlined with an emphasis on the synthetic aspects, catalyst libraries and molecular recognition. Solid-state host-guest interactions, intra- and intermolecular host-guest photoreactions in solution and in the solid state, molecular and supramolecular self-assembly and molecular recognition between host and guests, and some specific and important reactions, such as aldol and Michael reactions, were reviewed.

This review describes the synthesis, biological interest and importance of the α-aminophosphonic acids analogs of the 20 proteinogenic α-amino acids. Special attention is devoted to those stereoselective procedures that allow the synthesis of the required compounds in enantiomerically pure form.

Melamine (2,4,6-triamino-1,3,5-triazine) was first synthesized by Liebig in 1834 and its industrial application, starting with the development of melamine formaldehyde resins in the late 1930ies, has boomed since. In the last 80 years a vast number of different melamine derivatives have been prepared in order to provide structures for applications such as polymers, medicinal drugs, or biologically active compounds. It is the purpose of this review to give an overview on the currently available melamine derivatives and the synthesis strategies leading to their formation.

This micro review focuses on the application of the modified Pictet-Spengler reaction to the synthesis of diverse polyheterocycles with structural resemblance to natural products. The modified Pictet-Spengler reaction takes use of tethered biheterocycles comprising nucleophilic partner and a source for electrophilic partner followed by their condensation with aldehydes/ketones to furnish annulated polyheterocycles. Using this strategy engineering of numerous tethered biheterocycles into annulated polyheterocycles has been successfully carried out using both 6-endo as well as 7-endo cyclizations.

δ-Carboline and its naturally obtained analogs are of importance due to their wide range of biological properties. In the present review, we intend to discuss the main trends in the synthesis of δ-carboline analogs based on pyridine derivatives (including the Fischer synthesis, Graebe-Ullmann reaction, photochemical cyclization, arylation of substituted pyridines, quinolines, etc.) and indole derivatives in order to compare the potential of finding novel drugs in this series. In other words the development, current status and innovative new options for the design and synthesis of δ-carboline analogs are reviewed here. Published data about the various pharmacological functions and the spectroscopy of compounds belonging to this series are summarized. It also discusses the scope, future perspectives and the problems yet to be explored with respect to the synthesis of functionalised bioactive heteroannulated δ-carbolines in search of novel drugs.

In this short review article, we highlight the application of the olefin metathesis reaction as a key step in the total synthesis of (-)-kendomycin, a macrocyclic polyketide ansamycin exhibiting pronounced activity as an endothelin receptor antagonist and antiosteoporotic agent, as well as important antibiotic potency against multiresistant bacteria and remarkable cytotoxicity versus a series of human tumour cell lines. By selecting this example from the recent literature, we hope to illustrate the great synthetic ability of olefin metathesis, while also revealing some problems encountered in the syntheses.

A series of macrocyclic Schiff-bases and hexadecaazatricyclo-carboxamides has been prepared via the cyclocondensation of pyridine-2,6-dicarbonyl dichloride (1) or pyridine-2,6-dicarboxylic acid dihydrazide (3) or N,N-bis-[1- hydrazinyl-2-(substituted)]-pyridine-2,6-dicarboxamides (5a-d) with appropriate difunctional reagents. The coupling of 3 with tertacarboxylic acid dianhydride gave the macrocyclic tetraimidetetracarboxamides 6 and 7. Condensation of 5a-d with 3,3'-binaphthyl-dialdehyde yielded the corresponding macrocyclic hydrazones 8a-d, while compound 5a reacted with tertacarboxylic acid dianhydrides to give macrocyclic tetraimide octacarboxamide pyridine derivatives 9 and 10. The tricyclo-8,18-dimethyl ester derivative 12 was chemically synthesized, starting from the acid chloride 1 by coupling with L-lysine methyl ester. The tricyclo-8,18-dimethyl ester derivative 12 was treated with hydrazine hydrate to afford the corresponding hydrazide 13, which was condensed with aromatic aldehydes to afford tricyclo-bis-hydrazones 14a,b. The structure assignments of the new compounds are based on chemical and spectroscopic evidence. The biological activity screening tests showed that many of the obtained compounds exhibit high antimicrobial activity comparable to ampicillin and chloramphenicol which are used as reference compounds.

The pyridine derivative 3-cyano-4-(4-isopropylphenyl)-6-(pyridin-2-yl)-1H-pyridine-2-one 1 was obtained via the reaction of 2-acetylpyridine with cuminaldehyde and ethyl cyanoacetate in the presence of ammonium acetate. The pyridine-2-one 1 reacted with different alkyl halides, namely, allyl bromide, propargyl bromide, methyl bromoacetate, epichlorohydrin, 3-chloro-1-propanol, 1,3- dichloro-2-propanol, 4-bromobutyl acetate and 2-(bromomethoxy)ethyl acetate to give the corresponding nicotinonitrile Oacyclonucleosides 2-9 and 11, respectively. Subsequently, 9 and 11 were deacetylated to give the corresponding deprotected acyclonucleosides 10 and 12, respectively. In contrast, 4-(4-isopropylphenyl)-2-(2',3',4',6'-tetra-O-acetyl-β-D-gluco(galacto)pyranosyloxy)-6- (pyridin-2-yl)nicotinonitrile 13, 14, riboside 17 and lactoside 19 were prepared by the reaction of 1 with glycosyl/galactosyl/lactosyl bromide and peracetylated ribose using conventional and microwave irradiation methods. The reaction was regioselective and yielded the O-glycosides instead of the expected N-glycosides. The glycosides 13 and 14, riboside 17, and lactoside 19 were deacetylated in the presence of Et3N/MeOH and a few drops of water to give 15, 16, 18 and 21, respectively. The structure of the newly synthesized compounds was confirmed using IR, 1H and 13C NMR spectra, mass spectra and microanalysis. All synthesized compounds showed high antibacterial activity but the antifungal activity shown only by the glycoside compounds. Also, some of the new compounds showed anticancer activities.