L-776967

A new approach to 2,3-disubstituted cyclopentenones has been developed. This approach consists of a two-step protocol involving the cyclization of a Z-vinyl bromide under Barbier type conditions to form a cyclopentenol, which is then oxidatively rearranged to generate the cyclopentenone. The Z-vinyl bromide is in turn derived from a ruthenium catalyzed three-component coupling of an alkyne, an enone, and a HBr equivalent. A range of 2,3-disubstituted cyclopentenones has been generated, including short syntheses of jasmone and dihydrojasmone. Further applicability of this strategy is shown in the total syntheses of tetrahydrodicranenone B, rosaprostol, and a selective COX-2 inhibitor.

Methods using solid phase extraction in the 96-well format, together with HPLC and UV detection, are described for the determination of low ng/mL concentrations of 2-(3,5-difluorophenyl)-3-(4-methanesulfonylphenyl)-cyclo-pent-2-enone, a cyclooxygenase II inhibitor, in human plasma and urine.The plasma assay uses a packed-bed SPE plate, while the urine assay employs a 96 well plate containing membrane-based extraction disks.Both matrixes are diluted with 17% MeCN in H₂O prior to application to the extraction plates.Following sample application, the plates are washed with MeCN/H₂O mixtures to remove endogenous components prior to elution of the analytes with 100% MeCN.The urine extracts are diluted with H₂O and injected directly into the HPLC system.The plasma extracts, however, require evaporation and reconstitution prior to injection.An HPLC/column switching system is employed to sep. the analyte and an internal standard from coextd. endogenous species.The compounds are detected based on their UV absorbance at 288 nm.The 96-well SPE assays were validated over concentration ranges of 5 to 500 ng/mL for plasma (1 mL sample) and 10 to 1000 ng/mL for urine (0.5 mL sample).Replicate analyses (n = 5) of spiked plasma and urine standards yielded linear responses with coefficients of variation <10% and accuracy within 6% of nominal concentrations