Current Organic Chemistry - Volume 18, Issue 11, 2014

γ-Lactams (pyrrolidin-2-ones) and products containing the γ-lactam core are important synthetic targets and often display interesting biological activities, so that the development of improved synthetic methodologies for their preparation has become the objective of many synthetic chemists. This review is presented in two parts: Part I highlights efficient synthetic strategies (issued between 2001 and 2013), which are classified according to the last step of the lactam ring formation, starting from acyclic or cyclic precursors, whereas Part II deals with functionalization of γ-lactam ring via C-C or C-Heteroatom bond formation. Enantioselective synthesis is thoroughly emphasized in both sections, also exploiting catalytic systems, since pure enantiomeric derivatives are important for biological testing.

The physiological importance of proteins that can regulate ion balance and transmembrane transport is highlighted by different diseases where ion channel dysfunction is observed. During the past two decades, considerable effort has been devoted to develop synthetic ionophores that can insert or cross cell membranes and restore the dysfunction of highly complex protein channels. Not withstanding the remarkable structural advances made, only a few classes of synthetic ionophores were studied in complex with proand eukaryote cells in order to obtain information about their biological activity and potential application in ion channel replacement therapy, anti-cancer therapy or antimicrobial treatments. However, only a few synthetic ionophores showed promising biological activity in cellular assays. This review aims to show the utility of synthetic ionophores for different biological applications, including: restoring ion concentration, inducing cell death in different cancer cells, and protecting against a variety of pathogenic microbes. Because the activities of these ionophores depend primarily on their overall physicochemical properties and structure, we discuss here specific functional units and scaffolds that are important for obtaining selective, non-toxic transporters for specific biological applications.

Mono- and difluoromethylenebisphosphonates are of great synthetic and biological interest since they are among the best isopolar pyrophosphate mimics. This review will emphasize preparation and some of the most important applications of these compounds. The following synthetic approaches to fluoromethylenebisphosphonates are summarized: (i) electrophilic halogenation, (ii) Arbuzov and Michaelis-Becker reactions, (iii) direct electrophilic phosphorylation of fluoromethylphosphonate carbanions, and (iv) autocondensation of fluoromethylphosphonate carbanions. Emphasis is given to the synthesis and biomedical application of modified nucleoside polyphosphates, incorporating fluoromethylenebisphosphonate scaffold.

Clarification of the confusion previously reported will prevent the proliferation of scientific mistakes and consequently avoid a negative domino effect due to today’s rapid divulgation of information. The complex structures of asperjinone, (+)-pestalazine B and aquatolide have been revised in recent years and these studies have been included herein. However, there may be some misunderstanding on simpler structures such as 2,3,4,5-tetrahydro-1,5-benzoxazepine-3-ol (3), which has been mistaken for 3,4-dihydro-2H-3- hydroxymethyl-1,4-benzoxazine (1); both compounds have been synthesized via different routes with the aim of clarifying the structural elucidation. In a subsequent paper the misunderstanding between the six- and seven-membered structures has been repeated. We also redress some points of earlier papers on these compounds, and on the chemical conditions for the preparation of intermediates of the target molecules 1 and 3. The situation can be even more critical with important economical consequences when the mistakes affect patented structures, because the company's competitors might attack the validity of the patents. The principal researchers of any laboratory from which the work originates have an absolute and unavoidable responsibility to ensure the quality of the data from their laboratories, even if the main work is done by experienced postdocs. Both imaginative detective work using Mass Spectra, 2D Nuclear Magnetic Resonance data and chemical synthesis still have important roles to play in the process of solving molecular puzzles. The investigation of structural mistakes is very instructive and facilitates a deeper understanding of the complicated logical process for deducing molecular scaffolds.

The application of 9,10-dihydroanthracene in a sequence of dehydrogenation/Diels-Alder cycloaddition reactions with a variety of N-substituted maleimides is described. The in situ transformation of the 9,10-dihydroanthracene into the corresponding anthracene, which is acting as a diene, is accelerated by activated carbon (Darco® KB). The anthracene/maleimide cycloadducts thus obtained might offer some important biochemical applications. The role of the activated carbon in this domino reaction is to accelerate the elimination of hydrogen from the 9,10-dihydroanthracene. The starting maleimides (i.e., dienophiles) were shown to also act as the actual oxidants as they are transformed into the corresponding succinimides. However, the atmospheric oxygen, at least partially, also plays the role of oxidant.