Formal Total Synthesis of Diazonamide†A by Indole Oxidative Rearrangement.

A short formal total synthesis of the marine natural product diazonamide A is described. The route is based on indole oxidative rearrangement, and a number of options were investigated involving migration of tyrosine or oxazole fragments upon oxidation of open chain or macrocyclic precursors. The final route proceeds from 7-bromoindole by sequential palladium-catalysed couplings of an oxazole fragment at C-2, followed by a tyrosine fragment at C-3. With the key 2,3-disubstituted indole readily in hand, formation of a macrocyclic lactam set the stage for the crucial oxidative rearrangement to a 3,3-disubstituted oxindole. Notwithstanding the concomitant formation of the unwanted indoxyl isomer, the synthesis successfully delivered, after deprotection, the key oxindole intermediate, thereby completing a formal total synthesis of diazonamide A.

Aminophenoxazinones as inhibitors of indoleamine 2,3-dioxygenase (IDO). Synthesis of exfoliazone and chandrananimycin A.

A range of 2-aminophenoxazin-3-ones has been prepared by oxidative cyclocondensation of 2-aminophenols, including the natural products exfoliazone and chandrananimycin A, both synthesized for the first time. The compounds were evaluated for their ability to inhibit indoleamine 2,3-dioxygenase. Compounds containing additional electron-withdrawing carboxylate groups, such as cinnabarinic acid, showed modest inhibitory activity with a dose response.

Nucleophilic fluorination of ß-ketoester derivatives with HBF4.

Treating readily available α-diazo-ß-ketoesters with HBF(4) results in nucleophilic fluorination by the usually inert and stable tetrafluoroborate anion. The resulting α-fluoro-ß-ketoesters are highly versatile synthetic intermediates, for example in the preparation of fluoro-heterocycles, as illustrated by the direct formation of fluoro-pyrimidines, -pyrazoles and -coumarins in a single step.

Diverse trifluoromethyl heterocycles from a single precursor.

Ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate is a highly versatile intermediate for the synthesis of a wide range of trifluoromethyl heterocycles. With the use of rhodium(II) or copper(II) catalyzed carbene X-H insertion reactions as key steps, a diverse set of trifluoromethyl-oxazoles, -thiazoles, -imidazoles, -1,2,4-triazines, and -pyridines are available from the diazoketoester, either directly in a single step or with just one additional step.

Simple choline esters as potential anti-Alzheimer agents.

In this manuscript we report an integrated study to develop simple choline esters as cholinergic agents potentially useful against the Alzheimer disease. In previously reported experiments we demonstrated the capability of the pivaloylcholine to exert cholinergic effects into the Central Nervous System, so we decided to explore small variants of choline esters. The knowledge of crystallographic models of the enzymes involved in the hydrolysis of the acetylcholine allowed to consider the steric compatibility of some choline derivatives within their catalytic sites. The purpose of the work was to find out analogues with increased selectivity toward the acetylcholinesterase versus the butyrrylcholinesterase. Theoretical models were compared to enzymatic tests carried out with both enzymes and two different methods. In this screening we have selected two candidates for the in vivo experiments with pre-treated rats. Their electroencephalographic profiles were recorded and averaged before and after the intraperitoneal treatment with two compounds in comparison to the pivaloyl lead ester. The results demonstrated that one of the esters can exert biological effects similar to the parent compound.

Rational design, synthesis, biophysical and antiproliferative evaluation of fluorenone derivatives with DNA G-quadruplex binding properties.

Molecular modeling studies carried out with experimental DNA models with the sequence d[AG(3)(T(2)AG(3))(3)] suggest that the introduction of a net positive charge onto the side chain of a series of fluorenone carboxamides can improve G-quadruplex binding. The terminal morpholino moiety was replaced with a novel N-methylmorpholinium cation starting from two 4-carboxamide compounds. A different substitution on the fluorenone ring was also investigated and submitted to the same quaternarization process. All compounds were analyzed for their DNA binding properties by competition dialysis methods. In vitro antiproliferative tests were carried out against two different tumor cell lines. Docking experiments were conducted by including all four known human repeat unit G-quadruplex DNA sequences (27 experimentally determined conformations) against the most active fluorenone derivatives. The results of theoretical, biophysical, and in vitro experiments indicate two novel derivatives as lead compounds for the development of a new generation of G-quadruplex ligands with greater potency and selectivity.