Synthetic studies on novel 1,4-dihydro-2-methylthio-4,4,6-trisubstituted pyrimidine-5-carboxylic acid esters and their tautomers.

A mixture of alkyl 1,4-dihydro-2-methylthio-4,4,6-trisubstituted pyrimidine-5-carboxylate 1 and its tautomeric isomer, alkyl 1,6-dihydro-2-methylthio-4,6,6-trisubstituted pyrimidine-5-carboxylate 2 is synthesized by the Atwal-Biginelli cyclocondensation reaction of S-methylisothiourea hemisulfate salt 3 with 2-(gem-disubstituted)methylene-3-oxoesters 4 that can be accessed by the Lehnert procedure for the Knoevenagel-type condensation. The structures of the tautomeric products of the Atwal-Biginelli cyclocondensation reaction, 1 and 2, which are inseparable from each other, are determined unambiguously by (1)H-NMR spectroscopy at various temperatures and nuclear Overhauser enhancement spectroscopy (NOESY) experiment. Because these dihydropyrimidine products are otherwise inaccessible and thus hitherto unavailable, the synthetic methods established in this study will help to expand the molecular diversity of their related derivatives.

Stereoselective synthesis of a novel 2-aza-7-oxabicyclo[3.3.0]octane as neurokinin-1 receptor antagonist.

A novel neurokinin-1 receptor antagonist, (+/-)-(1R( *),3S( *),4S( *),5S( *))-4-[(N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-3-phenyl-2-aza-7-oxabicyclo[3.3.0]octane (1), was synthesized stereoselectively using Padwa's intramolecular 1,3-dipolar cycloaddition methodology as the key step. Compound (+/-)-1 showed high affinity for the NK-1 receptors in human IM-9 cells with an IC(50) value of 0.22 nM. This new structural scaffold demonstrated significant in vivo antagonistic activity in the guinea pig ureter capsaicin-induced plasma extravasation model with an ED(50) value of 1-10mg/kg, po.

Microbial hydroxylation of indole to 7-hydroxyindole by Acinetobacter calcoaceticus strain 4-1-5.

A screening study yielded Acinetobacter calcoaceticus strain 4-1-5, which is capable of hydroxylating indole to 7-hydroxyindole. Strain 4-1-5 grew on terephthalate as the sole source of carbon and energy and hydroxylated indole to 7-hydroxyindole by cometabolism of indole using terephthalate as cosubstrate. Strain 4-1-5 produced 0.574 mM of 7-hydroxyindole at 2.38 mM indole in 24 h with the cell growth.

A process in need is a process indeed: scalable enantioselective synthesis of chiral compounds for the pharmaceutical industry.

This report deals with enantioselective synthesis of viracept 1 (nelfinavir mesylate, AG 1343), a potent HIV protease inhibitor, and 3-hydroxytetradecanoic acid 3, a component of lipid A comprising lipopolysaccharide embedded in the cell surface of Gram-negative bacteria, from both strategic and practical perspectives. As regards the synthesis of 1, the synthetic approaches to its central intermediate 2 possessing the common structural motif of 1,4-differentially substituted-2-amino-3-hydroxylbutane are mainly discussed with emphasis on the molecular symmetry that has helped streamline the synthetic strategy. In the discussion of the synthetic strategies to access a single enantiomer of 3, the chiral methodologies that have been applied so far are assessed for industrial viability; the synthetic alternatives explored include resolution via diastereomeric salt formation, lipase-catalyzed kinetic resolution, asymmetric synthesis, and chiral pool approaches.