Volume 84, Issue 7

It is a privilege to act as the conference editor for this issue of Pure and Applied Chemistry . The 11 papers in this issue constitute selected contributions from the 23rd International Congress on Heterocyclic Chemistry, which was held in the Scottish Exhibition and Conference Centre in Glasgow between 31 July and 4 August 2011. This congress of the International Society of Heterocyclic Chemistry was attended by over 400 participants from over 40 different countries. The conference papers in this issue arise from plenary (Profs. Magid Abou-Gharbia and David O’Hagan), invited (Profs. Janine Cossy, Keiji Maruoka, Ganesh Pandey, Philippe Renaud, and Vinod Singh), and some selected exciting contributions from younger participants (Dr. David Barker, Prof. Tom Pettus, Dr. Jun Shimokawa, and Dr. Michael Smietana). These contributions reflect the main congress themes: - Synthetic methodology - Synthesis - Natural product and complex molecule synthesis materials - Medicinal chemistry - Nanochemistry - Chemical biology/biosynthesis - Chemical biology/DNA and nucleoside analogues It is a pleasure to acknowledge the valuable contributions made to the highly successful conference, especially by the conference chair, Prof. Colin Suckling, the local organizing and scientific advisory committees, and the sponsors of the event: Edward C. and Virginia Taylor, Astra Zeneca, Chemical Sciences Scotland, Eisai, EPSRC, Glasgow City Council, GSK, IUPAC, Pfizer, Scottish Enterprise, Syngenta, and the University of Strathclyde. The professional conference organizers, Meeting Makers, did a sterling service in keeping everything on track and the organizers in check. Of course, no conference is possible without the willing participation of the contributors to the scientific program, speakers and poster presenters, session chairs as well as the audience. I would also like to thank the contributors to this issue for agreeing to provide manuscripts and for their timely efforts and to the editorial staff for their valuable help. Colin Gibson Conference Editor [Back to Contents]

The benefits of utilizing marketed drugs as starting points to discover new therapeutic agents have been well documented within the IUPAC series of books that bear the title Analogue-based Drug Discovery (ABDD). Not as clearly demonstrated, however, is that ABDD also contributes to the elaboration of new basic principles and alternative drug design strategies that are useful to the field of medicinal chemistry in general. After reviewing the ABDD programs that have evolved around the area of microtubule-stabilizing chemo-therapeutic agents, the present article delineates the associated research activities that additionally contributed to general strategies that can be useful for prodrug design, identifying pharmacophores, circumventing multidrug resistance (MDR), and achieving targeted drug distribution.

Neurodegenerative diseases represent one of the health care community’s truly unmet medical needs. They can be loosely classified into two categories, acute and chronic. One of the best known chronic neurodegenerative diseases, Alzheimer’s disease, represents a serious health care problem that may well exceed the limits of current fiscal and care giver resources. No disease-modifying therapeutic agents have been identified, and the few available symptomatic treatments possess limitations in their duration of action and side effects. Despite decades of drug discovery research and numerous clinical trials, no truly effective treatment for stroke, the most prevalent acute neurodegenerative disease, has been identified. This article summarizes two recent drug discovery projects, one targeting Alzheimer’s disease and the other targeting ischemic stroke. Both projects involved design, synthesis, and biological evaluation of a novel series of heterocyclic derivatives.

The acyl-Claisen rearrangement, also called a zwitterionic aza-Claisen rearrangement, allows for the synthesis of 2,3- syn -substituted morpholine pent-4-eneamides with high levels of diastereoselectivity. A wide variety of alkyl and aryl substituents can be introduced with yields highly dependent on the stoichiometry of the Lewis acid catalyst. The use of these morpholine amides in the synthesis of the tetrasubstituted tetrahydrofuran lignans fragransin A 2 , talaumidin, and galbelgin is summarized. The conversion of the Claisen-derived amides into aryl tetraline and 1,1-diarylbutanol lignans via alteration of the protecting groups is also described. Nucleophilic addition of an organometallic reagent to the morpholine amide followed by Wacker oxidation of the alkene gives highly substituted 1,4-diketones, which can be easily converted into fully substituted pyrroles.

An advanced spiroketal intermediate toward the synthesis of 39-oxobistramide K was prepared, fragment C14–C40. This fragment was obtained in 19 steps with an overall yield of 6.2 % using a FeCl 3 -catalyzed spiroketalization as the key step.

A series of chiral quaternary ammonium salts derived from commercially available ( R )- or ( S )-binaphthol have been designed as new C 2 -symmetric chiral phase-transfer catalysts. In order to realize the flexible design of these phase-transfer catalysts, the combinatorial design approach has been developed. Chiral high-performance organocatalysts, thus obtained, have been successfully applied to the highly practical asymmetric synthesis of various amino acid derivatives, including α-alkyl and α,α-dialkyl-α-amino acids in addition to alkaloids. Furthermore, several chiral bifunctional phase-transfer catalysts have been designed and synthesized for effecting base-free phase-transfer reactions under essentially neutral conditions in order to realize green sustainable chemistry.

The CF 2 group has found applications as a substituent in all classes of organic chemical products from medicinal products to materials, although it is less frequently encountered than the C–F and CF 3 substituents. In this review, the geometric influence of placing two fluorine atoms on carbon is considered and in particular, deviations from tetrahedral geometry are noted. The incorporation of the CF 2 group into CF 2 phosphonates as phosphate mimics is reviewed and the geometric and steric influences of the CF 2 group are considered when the substituent is placed within aliphatic chains and aliphatic ring (cyclododecane) systems.

The core structure of the complex pentacyclic 5,11-methanomorphanthridine skeleton and the vicinal quaternary and tertiary stereocenters of the 5,10b-phenanthridine skeleton are constructed stereospecifically in one step employing intramolecular 1,3-dipolar cycloaddition of a nonstabilized azomethine ylide (AMY) generated by the sequential double desilylation of appropriate bis-trimethylsilylmethyl amines using Ag(I)F as a single-electron oxidant. The strategy is successfully applied for the total synthesis of biologically active alkaloids such as (±)-pancracine, (±)-brunsvigine, (±)-maritidine, and (±)-crinine.

Two cycloaddition strategies are described that lead to various chroman spiroketals from assorted exocyclic enol ethers. Unlike conventional thermodynamic ketalization strategies, the stereochemical outcome for this approach is determined by a kinetic cycloaddition reaction. Thus, the stereochemical outcome reflects the olefin geometry of the starting materials along with the orientation of the associated transition state. However, the initial kinetic product can also be equilibrated by acid catalysis and reconstituted into a thermodynamic stereochemical arrangement. Thus, these strategies uniquely enable synthetic access to either the thermodynamic or kinetic conformation of the spiroketal stereocenter itself. Applications of these strategies in the syntheses of berkelic acid, β-rubromycin, and paecilospirone are presented along with the use of a chroman spiroketal for the construction of heliespirones A and C.

Recent advances in radical azidation using sulfonyl azides are presented. For instance, radical carboazidation using α - iodoketones, desulfitative carboazidation, and anti -Markovnikov hydroazidation of alkenes are described. These novel methods tolerate a large number of functional groups and allow the synthesis of organic azides that would be difficult to synthesize otherwise. The transformation of the azides using reductive processes as well as a Schmidt reaction under nonacidic conditions were used to synthesize alkaloids including indolizidine 167B, monomorine I, cylindricine C, and lepadiformine C.

The first total synthesis of gelsemoxonine has been accomplished. A divinylcyclopropane–cycloheptadiene rearrangement of the highly functionalized substrate successfully assembled the spiro-quaternary carbon center connected to the bicyclic seven-membered core structure. A one-pot isomerization reaction of the α,β-unsaturated aldehyde to the saturated ester via a trimethylsilyl cyanide–diazabicycloundecene (TMSCN–DBU) reagent combination allowed a facile and diastereoselective introduction of the latent nitrogen functionality in the unique azetidine moiety.

A modified tridentate pyridine bisoxazoline (pybox) ligand, possessing gem -diphenyl substitution at C-5 of the oxazoline rings, has been proved to be a very efficient ligand for enantioselective allylic oxidation, one-pot three-component synthesis of propargy-amines, and Friedel–Crafts alkylation of various aromatic compounds. We have shown that a 5',5'-diphenyl grouping in the oxazoline rings of chiral ligands is crucial for higher reaction rates as well as enhanced enantioselectivity.

The single common feature of all biological systems is the dependence on self-assembly of molecular units to be morphed into well-defined functional architectures. Thanks to a dynamic equilibrium process, incorrect structural units are rejected with high levels of fidelity. The development of synthetic systems displaying similar attributes is an emerging field with wide applications from biotechnology to medicine. In this context, we developed a stimuli-responsive nucleic acid-based system relying on the reversible formation of cyclic boronate internucleosidic linkages. The dynamic assembly of this new borono-based helix has been accomplished through a DNA- and an RNA-templated autoligation process featuring a 5'-ended boronic acid oligonucleotide connecting to a 3'-ended ribonucleosidic oligonucleotide partner.

A joint IUPAC/IUPAP Working Party (JWP) has confirmed the discovery of the elements with atomic numbers 114 and 116. In accordance with IUPAC procedures, the discoverers proposed names as follows: flerovium with the symbol Fl for the element with Z = 114 and livermorium with the symbol Lv for the element with Z = 116. The IUPAC Inorganic Chemistry Division recommended these proposals for acceptance, and they were adopted on 23 May 2012 by the IUPAC Bureau as delegated to act by the IUPAC Council meeting on 3–4 August 2011.