Frank J. Urban

Synthesis of tigogenyl β-O-cellobioside heptaacetate and glycoside tetraacetate via Schmidt's trichloroacetimidate method; some new observatons.

Abstract In studying the synthesis of tigogenyl β-O-cellobioside 1 via the trichloroacetimidate method of Schmidt, cesium carbonate was found to be an efficient reagent for the synthesis of peracetylated disacchadde α-trichloroacetimidates. Zinc bromide was superior to BF 3 ·Et 2 O for coupling these disaccharide α-trichloroacetimidates with the steroid tigogenin.

The important role of residue F268 in ligand binding by LXRβ

Liver X receptors (LXRs) are nuclear receptors that regulate the metabolism of cholesterol and bile acids. Despite information on the specificity of their natural ligands, oxysterols, relatively little is known about the ligand binding site in LXRs. The helix 3 region in the ligand binding domain (LBD) of peroxisome proliferator‐activated receptors (PPARs) has been implicated in ligand entry. Sequence alignment of LXRs, farnesoid X receptor (FXR), and PPARs identified the corresponding helix 3 region in the LXRβ LBD. Residues F268 and T272, which are conserved in all the aligned sequences and only in LXRs and FXR, respectively, were replaced with alanine. The effects of these mutations on ligand binding and receptor activation were examined using an in vitro ligand binding assay and a cell based reporter assay, respectively. The LXRβ mutant F268A did not bind ligand. In contrast, conversion of T272 to alanine has no effect on ligand binding. By transiently expressing a chimeric receptor containing Escherichia coli tetracycline repressor (TetR) and LXRβ LBD and a reporter with a TetR binding site, we show that mutant F268A lost the ability to activate transcription of the reporter, whereas mutant T272A still has an activity similar to that of the wild‐type LXRβ. These data, consistent with the findings in the in vitro ligand binding assay and our 3D modeling, are the first study that identifies a residue critical for ligand binding in LXRβ.

Novel Synthesis of 1-(1,2,3,5,6,7-Hexahydro- s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl]urea, an Anti-inflammatory Agent

Abstract A novel synthesis of the anti-inflammatory agent 1-(1,2,3,5,6,7- hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonyl] urea 1 is described. Sulfonamide 5 was prepared starting from ethyl 3-furoate 2. Key steps were a one-pot sulfonylation with chlorosulfonic acid in methylene chloride followed by pyridinium salt formation and reaction with phosphorus pentachloride to provide ethyl 2-(chlorosulfonyl)-4-furoate 7. This sulfonyl chloride was treated with ammonium bicarbonate to form sulfonamide 8, followed by treatment with excess methyl magnesium chloride to provide 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide 5. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene 16 was prepared from indan in five steps. The formation of the desired sulfonyl urea was carried out both with the isolated isocyanate 16 and via an in situ method.

Synthesis of an optically active octahydro-2H-pyrido[1,2-a]pyrazine based CNS agent

Abstract A synthesis of an optically active octahydro-2H-pyrido[1,2-a]pyrazine is presented. The key sequence involved the equilibration of an optically active cis-aldehyde to give the thermodynamic trans-aldehyde that was trapped by nitromethane anion.

New synthesis of spiro-benzopyran amino acids by intramolecular amidoalkylation

Abstract A new synthesis of spiro-benzopyran amino acids is presented. The key reaction is the intramolecular amidoalkylation of methyl 2-benzamido-4-(4-fluorophenoxy)-2-methoxybutyrate to yield methyl 4-benzamido-2,3-dihydro-6- fluoro-4H-benzopyran-4-carboxylate.

Observation of a new dimeric amino acid derivative in the reaction of methyl N-BOC-(S)-(3-fluorophenyl)alanate with DIBAL-H and lithio ethyl propiolate

Abstract A novel amino acid dimer 9a was isolated while trying to apply a known reduction/nucleophilic addition sequence. This dimer provided information both on the mechanism of the process and on the dependence of the desired reaction on the stoichiometry of reagents.

An Efficient Synthesis Of 6-Substituted 2-(2H-[1,2,4]Triazol-3-Ylmethyl)-1,2,3,4-Tetrahydro-Isoquinolines

Abstract A synthesis of 6-nitro and 6-amino 2-(2H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolines using a bis-alkylation process is described. 5-(Aminomethyl)-1-(p-methoxybenzyl)-triazole was prepared by a regioselective route from 1,2,4-triazole.

A Novel Synthesis of the Antipsychotic Agent Ziprasidone

Abstract A new synthesis of the antipsychotic ziprasidone from 2,5-dichloro-4-nitrotoluene 3 is presented. The nitro group in 3 was used to activate the ortho-chlorine for displacement and the methyl group for enamine formation and introduction of the piperazinyl moiety.

Synthesis of R- and S-3-Oxo-2-oxaspiro[4.4]-nonane-1-carboxylic acid.

Abstract An efficient synthesis and temperature dependent resolution of R- and S-3-Oxo-2-oxaspiro[4.4]-nonane-1-carboxylic acid are described. The assignment of absolute configuration is based on single crystal X-ray analysis of an amide derivative.

An efficient preparation of tetrahydropyran-(3R)-carboxaldehyde, a key intermediate for the synthesis of a novel 5-lipoxygenase inhibitor.

Abstract A novel process based on the efficient resolution of rac-2 and suitable for preparing kilogram quantities of the chemically sensitive aldehyde tetrahydropyan-3R-carboxaldehyde R-2 of >-98% ee is described.