Deaminative ring contraction for the synthesis of polycyclic heteroaromatics: a concise total synthesis of toddaquinoline.

A concise strategy to prepare polycyclic heteroaromatics involving a deaminative contraction cascade is detailed. The efficient deaminative ring contraction involves the in situ methylation of a biaryl-linked dihydroazepine to form a cyclic ammonium cation that undergoes a base-induced [1,2]-Stevens rearrangement/dehydroamination sequence. The presence of pseudosymmetry guides the retrosynthetic analysis of pyridyl-containing polycyclic heteroaromatics, enabling their construction by the reductive cyclization and deaminative contraction of tertiary amine precursors.

Design and Evaluation of Ambiphilic Aryl Thiol-Iminium-Based Molecules for Organocatalyzed Thioacyl Aminolysis.

Progress toward the design and synthesis of ambiphilic aryl thiol-iminium-based small molecules for organocatalyzed thioacyl aminolysis is reported. Here we describe the synthesis of a novel tetrahydroisoquinoline-derived scaffold, bearing both thiol and iminium functionalities, capable of promoting the transthioesterification and subsequent amine capture reactions necessary to achieve organocatalyzed thioacyl aminolysis. Model studies demonstrate the ability of this designed organocatalyst to deliver critical intermediates capable of undergoing these individual reactions necessary for the proposed process. Future design improvements and directions toward cysteine-independent organocatalyzed native chemical ligation are discussed.

Design and synthesis of astatinated benzothiazole compounds for their potential use in Targeted Alpha Therapy (TAT) strategies to treat Alzheimer's disease-associated amyloid plaques.

PURPOSE: Alzheimer's disease (AD) is a terminal neurodegenerative disease characterized by the buildup of amyloid fibrils, amorphous aggregates and tauopathies. Several treatment modalities, which rely on various biological processes to reduce disease burden, have been largely ineffective at treating Alzheimer's disease. Targeted alpha therapy (TAT) has demonstrated positive results in the treatment of cancer. Benzothiazole derivatives have been successfully shown to target these plaques and are used in several imaging applications. One such derivative, Flutemetamol (VizamylTM) is an FDA approved diagnostic tool for PET imaging of AD-associated plaques. We report the radiolabeling of benzothiazole derivatives with 211At, a 7.2 h alpha emitting radionuclide, using a copper catalyzed reaction with a boronic acid precursor molecule. Our final compound [211At]3'-At-PIB-OMe had a radiochemical yield of 55% and was found to be stable for at least 3 h in phosphate buffered saline.

Design, synthesis and characterization of structurally dynamic cyclic N,S-acetals.

We report the synthesis, characterization and comparison of a series of electronically perturbed, cyclic N,S-acetals. Inspired by electrophilic auxiliaries utilized for amine capture and concomitant peptide ligation, we studied these N,S-acetal systems and evaluated their propensity to generate zwitterionic intermediates in situ. Certain N,S-acetals in this study exhibit structurally dynamic properties through a solvent and pH-dependent ability to ring-open and ring-close via C1-S bond ionization at room temperature.