An Admix Approach To Determine Counter Anion Effects on Metal-Free Arylation Reactions with Diaryliodonium Salts.

A method to determine the effect of counter anions in metal-free arylation reactions of diaryliodonium salts is described. This approach avoids the independent synthesis of individual diaryliodonium salts and potentially enables assessment of a large number of different counter anions, including those that are synthetically challenging to install. Diaryliodonium tosylate salts serve as a general precursor for this approach, and an azide arylation reaction was used to develop this strategy. Further optimization and representative scope of azide arylation is demonstrated in yields that range from 74-95% (89% average). The use of this method as a screening tool has also been validated with arylation reactions of three different nucleophiles employing diphenyliodonium tosylate.

A Selective C-H Deprotonation Strategy to Access Functionalized Arynes by Using Hypervalent Iodine.

Described here is an efficient method to access highly functionalized arynes from unsymmetrical aryl(mesityl)iodonium tosylate salts. The iodonium salts are prepared in a single pot from either commercially available aryl iodides or arylboronic acids. The aryne intermediates are generated by ortho-C-H deprotonation of aryl(mesityl)iodonium salt with a commercially available amide base and trapped in a cycloaddition reaction with furan in moderate to good yields. Coupling partners for the aryne intermediates beyond furan are also described, including benzyl azide and alicyclic amine nucleophiles. The regio- and chemoselectivity of this reaction is discussed and evidence for the spectator aryl ligand of the iodonium salt as a critical control element in selectivity is presented.

Unsymmetrical Aryl(2,4,6-trimethoxyphenyl)iodonium Salts: One-Pot Synthesis, Scope, Stability, and Synthetic Studies.

Diaryliodonium salts have recently attracted significant attention as metal-free-arylation reagents in organic synthesis, and efficient access to these salts is critical for advancement of their use in reaction discovery and development. The trimethoxybenzene-derived auxiliary is a promising component of unsymmetrical variants, yet access remains limited. Here, a one-pot synthesis of aryl(2,4,6-trimethoxyphenyl)iodonium salts from aryl iodides, m-CPBA, p-toluenesulfonic acid, and trimethoxybenzene is described. Optimization of the reaction conditions for this one-pot synthesis was enabled by the method of multivariate analysis. The reaction is fast (<1 h), provides a high yield of product (>85% average), and has broad substrate scope (>25 examples) including elaborate aryl iodides. The utility of these reagents is demonstrated in moderate to high yielding arylation reactions with C-, N-, O-, and S-nucleophiles including the synthesis of a liquid crystal molecule.

Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome.

To elucidate the pathomechanism leading to obstructive vascular disease in patients with elastin deficiency, we compared both elastogenesis and proliferation rate of cultured aortic smooth-muscle cells (SMCs) and skin fibroblasts from five healthy control subjects, four patients with isolated supravalvular aortic stenosis (SVAS), and five patients with Williams-Beuren syndrome (WBS). Mutations were determined in each patient with SVAS and in each patient with WBS. Three mutations found in patients with SVAS were shown to result in null alleles. RNA blot hybridization, immunostaining, and metabolic labeling experiments demonstrated that SVAS cells and WBS cells have reduced elastin mRNA levels and that they consequently deposit low amounts of insoluble elastin. Although SVAS cells laid down approximately 50% of the elastin made by normal cells, WBS cells deposited only 15% of the elastin made by normal cells. The observed difference in elastin-gene expression was not caused by a difference in the stability of elastin mRNA in SVAS cells compared with WBS cells, but it did indicate that gene-interaction effects may contribute to the complex phenotype observed in patients with WBS. Abnormally low levels of elastin deposition in SVAS cells and in WBS cells were found to coincide with an increase in proliferation rate, which could be reversed by addition of exogenous insoluble elastin. We conclude that insoluble elastin is an important regulator of cellular proliferation. Thus, the reduced net deposition of insoluble elastin in arterial walls of patients with either SVAS or WBS leads to the increased proliferation of arterial SMCs. This results in the formation of multilayer thickening of the tunica media of large arteries and, consequently, in the development of hyperplastic intimal lesions leading to segmental arterial occlusion.

Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6).

Mutations in the ABCC6 (MRP6) gene cause pseudoxanthoma elasticum (PXE), a rare heritable disorder resulting in the calcification of elastic fibers. In the present study a cDNA encoding a full-length normal variant of ABCC6 was amplified from a human kidney cDNA library, and the protein was expressed in Sf9 insect cells. In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6. Organic anions (probenecid, benzbromarone, indomethacin), known to interfere with glutathione conjugate transport of human ABCC1 and ABCC2, inhibited the ABCC6-mediated NEM-GS transport in a specific manner, indicating that ABCC6 has a unique substrate specificity. We have also expressed three missense mutant forms of ABCC6, which have recently been shown to cause PXE. MgATP binding was normal in these proteins; ATP-dependent NEM-GS or leukotriene C(4) transport, however, was abolished. Our data indicate that human ABCC6 is a primary active transporter for organic anions. In the three ABCC6 mutant forms examined, the loss of transport activity suggests that these mutations result in a PXE phenotype through a direct influence on the transport activity of this ABC transporter.