Recyclable Aliphatic Nitrile-Template Enabled Remote meta-C-H Functionalization at Room Temperature.

This article describes the development of a new aliphatic nitrile-template-directed remote meta-selective C-H olefin functionalization reaction of arenes. Remarkably, unlike the previous reports, this process is feasible at room temperature and enabled the formation of products with excellent regioselectivity. The present protocol encompasses a broad spectrum of substituted dihydrocinnamic acids and olefins, producing meta-C-H olefinated products (up to 96% yield). In addition, the efficacy of the present method has been showcased by the synthesis of various drug analogues (e.g., cholesterol, estrone, ibuprofen, and naproxen). Significantly, the robustness of meta-olefination was also demonstrated by gram-scale synthesis. The new nitrile-based meta-directing template, in particular, could be easily synthesized in two steps and recycled under mild conditions.

Development of a triazolobenzodiazepine-based PET probe for subtype-selective vasopressin 1A receptor imaging.

OBJECTIVES: To enable non-invasive real-time quantification of vasopressin 1A (V1A) receptors in peripheral organs, we sought to develop a suitable PET probe that would allow specific and selective V1A receptor imaging in vitro and in vivo. METHODS: We synthesized a high-affinity and -selectivity ligand, designated compound 17. The target structure was labeled with carbon-11 and tested for its utility as a V1A-targeted PET tracer by cell uptake studies, autoradiography, in vivo PET imaging and ex vivo biodistribution experiments. RESULTS: Compound 17 (PF-184563) and the respective precursor for radiolabeling were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. An inhibitory constant of 0.9 nM towards the V1A receptors was measured, while excellent selectivity over the related V1B, V2 and OT receptor (IC50 >10,000 nM) were obtained. Cell uptake studies revealed considerable V1A binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. In vitro autoradiography and PET imaging studies in rodents indicated specific tracer binding mainly in the liver. Further, the pancreas, spleen and the heart exhibited specific binding of [11C]17 ([11C]PF-184563) by ex vivo biodistribution experiments. CONCLUSION: We have developed the first V1A-targeted PET ligand that is suitable for subtype-selective receptor imaging in peripheral organs including the liver, heart, pancreas and spleen. Our findings suggest that [11C]PF-184563 can be a valuable tool to study the role of V1A receptors in liver diseases, as well as in cardiovascular pathologies.

Palladium-Catalyzed Aerobic Oxidative Coupling of ortho-(Alkynyl)styrenes with Allylic Alcohols via 6-endo-dig Cyclization: Regioselective Construction of Polysubstituted Naphthalenes.

An efficient protocol is described for the regioselective construction of polysubstituted functionalized naphthalenes from easily accessible ortho-(alkynyl)styrenes under mild reaction conditions. The reaction proceeds via cycloaromatization and intermolecular coupling of ortho-(alkynyl)styrenes with allylic alcohols catalyzed by PdCl2. Notably, the reaction is successful under open air as the green oxidant source. A range of functional groups (F, Cl, Br, NO2, and ester) including protecting free OH groups were found to be compatible.

Biosynthesis-Inspired Total Synthesis of Bioactive Styryllactones (+)-Goniodiol, (6S,7S,8S)-Goniodiol, (-)-Parvistone D, and (+)-Parvistone E.

A protecting-group-free total synthesis of (+)-goniodiol (1), (6S,7S,8S)-goniodiol (2), (-)-parvistone D (4), and (+)-parvistone E (6) was efficiently achieved in five steps from commercially available trans-cinnamaldehyde with high overall yields (72-75%). The synthesis strategy was inspired from the proposed biosynthesis pathway of styryllactones. Key transformations of the strategy include a one-pot conversion of goniothalamin oxide to goniodiol or 9-deoxygoniopypyrone in aqueous media, stereoselective epoxidation, ring-closing metathesis, and stereoselective Maruoka allylation. The route is amenable to synthesis of various analogues for biological evaluation.