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A series of (2-pyridyl)indoles was synthesized from the palladium(0)-mediated reaction of (1-(tert-nutyldimethylsilyl)-3- indolyl)zinc chloride and (1-(benzenesulfonyl)-2-indolyl)zinc chloride. The resulting products were utilized for the synthesis of the indolo[2,3-alpha]quinolizidine system via the stereoselective hydrogenation of thge pyridine ring followed by electrophilic cyclization in the indole 3-position.

The cyclization of pure all-cis 3-(2-piperidyl)indole was carried out to examine epimerization reactions at the C-2 and C-4 positions of the piperidine ring. Specifically, the piperidine-4-carboxylic acids obtained from the saponification of the 3-(2-piperidyl)indoles were reesterified with excess diazomethane. The results revealed that epimerization occurs at the C-2 position of the piperidine during alkaline hydrolysis of the ester.

Halogen-metal exchange from the corresponding 3-bromoderivative yields 1-(tert-butyldimethylsilyl)-3-lithioindole which reacts with electrophiles to form 3-substituted indoles. The N-silyl-3-lithioindole is of value in the synthesis of 3-substituted indoles due to the absence of ring fragmentation and rearrangement and the easy elimination of the protecting group.

Describes the palladium-catalyzed heteroarylation of 2- and 3-indolyzinc derivatives. Method for the preparation of (2-pyrisdyl)indoles; Demonstration of the potential of (2-pyridyl)indoles in the alkaloid synthesis; Study of the Pummerer cyclizations.

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated Cl(-) channel. The most common mutation results in a deletion of phenylalanine at position 508 (DeltaF508-CFTR) that impairs protein folding, trafficking, and channel gating in epithelial cells. In the airway, these defects alter salt and fluid transport, leading to chronic infection, inflammation, and loss of lung function. There are no drugs that specifically target mutant CFTR, and optimal treatment of CF may require repair of both the folding and gating defects. Here, we describe two classes of novel, potent small molecules identified from screening compound libraries that restore the function of DeltaF508-CFTR in both recombinant cells and cultures of human bronchial epithelia isolated from CF patients. The first class partially corrects the trafficking defect by facilitating exit from the endoplasmic reticulum and restores DeltaF508-CFTR-mediated Cl(-) transport to more than 10% of that observed in non-CF human bronchial epithelial cultures, a level expected to result in a clinical benefit in CF patients. The second class of compounds potentiates cAMP-mediated gating of DeltaF508-CFTR and achieves single-channel activity similar to wild-type CFTR. The CFTR-activating effects of the two mechanisms are additive and support the rationale of a drug discovery strategy based on rescue of the basic genetic defect responsible for CF.