Organic & Biomolecular Chemistry Blog

The importance of natural products in health and medicine is enormous owing to their diverse biological activities and their role as a basis for drug development. Endeavours in total synthesis have attracted some of the most talented organic chemists–providing intellectual and creative outlets–and have been central to the evolution and technical development of organic synthesis.

In the early 1990’s, Professor Hideo Kigoshi of the University of Tsukuba reported the first total synthesis of the marine macrolide Aplyronine A which is still a highly desirable synthetic target due to its potent and unique biological properties.

In collaboration with Professor Ichiro Hayakawa of Okayama University, the group has recently published a highly efficient second-generation total synthesis of Aplyronine A which requires fewer synthetic steps and boasts an improved overall yield. Issues with poor stereoselectivity, regioselectivity and isomerization were overcome through the optimization of a Ni/Cr-mediated coupling.

As shown in the retrosynthetic pathway below, Aplyronine A was obtained from 10, the same intermediate used in the first generation synthesis however, instead of the Julia coupling between ketone and sulfone-containing fragments, the macrolactone 11 was cyclized via an intramolecular Ni/Cr-mediated coupling. This modification drastically reduced the number of unwanted byproducts obtained from the Julia coupling and eliminated the need to employ a modified Yamaguchi lactonization which had resulted in the formation of an undesired 26-membered lactone that required an additional isomerization to yield the desired product. Precursor 11 was constructed through an intermolecular esterification between carboxylic acid 12 and alcohol 13 which were each prepared through asymmetric Ni/Cr-mediated couplings. In the case of the carboxylic acid, route efficiency was further enhanced as this strategy resulted in the simultaneous formation of the C14–C15 (E)-trisubstituted double bond and the C13 stereogenic center through the use of a chiral ligand.

In addition to establishing an efficient synthetic pathway to Aplyronine A, the Ni/Cr-mediated coupling has significant potential in the preparation of structurally diverse derivatives which may result in enhanced biological activity and the discovery of a novel lead.

The popularity of natural products as synthetic targets will continue as they provide unparalleled inspiration for drug leads and the synthesis of non-natural compounds. Strategies to develop concise and efficient synthetic routes are significantly important not only in terms of their utility in medicine but in the downstream application of novel synthetic methodologies developed during the process of their total synthesis.

To find out more see:

Second generation total synthesis of aplyronine A featuring Ni/Cr-mediated coupling reactions
Ichiro Hayakawa, Keita Saito, Sachiko Matsumoto, Shinichi Kobayashi, Ayaka Taniguchi, Kenichi Kobayashi, Yusuke Fujii, Takahiro Kanekob and Hideo Kigoshi
DOI: 10.1039/C6OB02241C

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

As part of an ongoing research programme in host-guest supramolecular chemistry, Professor Paul Beer of Oxford University has been developing methods for the synthesis of interlocking molecular architectures based on halogen bond donor motifs.

Halogen bonding interactions—the noncovalent, attractive interaction between an electron deficient halogen (X) and a Lewis base (B)—are slowly becoming more prevalent as a complimentary alternative to more commonly used binding interactions. Since its discovery in the late 1960’s, anion recognition chemistry has developed from an interesting area of academic research to a pillar of supramolecular chemistry. In recent years, there has been dramatic advancements within the field that have resulted in a number of practical applications such as organocatalysis involving ion complexation, ion extraction from mixtures and the development of sensory devices and molecular switches.

Anions play fundamental roles in a large number of biological, chemical, medicinal and environmental processes and nature’s binders typically complex anions through intricate networks of electrostatic interactions. The ability to mimic the selectivity of biological systems in artificial settings has been a longstanding challenge in this field.

In a recent OBC publication, the Beer group successfully synthesized two mono-cationic and two dicationic halogen and hydrogen bonding rotaxane anion recognition systems (see figure) and successfully demonstrated the enhanced binding affinity and selectivity of the dicationic halogen bonding analogue relative to its hydrogen bond-containing counterpart. In addition, the dicationic halogen bonding system displayed an enhanced preference for binding to bromine anions over other halides, nitrate and dihydrogen phosphate oxoanions. NMR binding studies reveal that the enhanced strength and selectivity of halide recognition is the result of chelated charge assisted halogen bonding interactions in the dicationic system. This study elegantly demonstrates efforts in exploiting the XB chelate effect to improve anion binding affinity and selectivity. Halogen bonding is still an emerging area of research however, examples such as this highlight its utility as a complementary mode of binding when compared to other more established interactions and will no doubt lead to an evolution in anion receptor design.


To find out more see:

Chelated charge assisted halogen bonding enhanced halide recognition by a pyridinium-iodotriazolium axle containing [2]rotaxane
Alexander E. Hess and Paul D. Beer
DOI: 10.1039/C6OB01851C

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

Antibiotic resistance has become a major clinical issue in recent decades and is one of the greatest health problems of our time. Tuberculosis (TB) has been present for thousands of years and according to WHO is globally, one of the leading causes of death from a curable infectious disease. The advent of the antibiotic era represented a major breakthrough for those suffering from TB however the spread of multi-drug resistant strains, which have propagated due to incorrect drug use, prescription errors or low patient compliance has become a major threat to disease control. In order to mitigate this, new drugs and diagnostic tools are desperately needed.

A collaborative study between Peter Woodruff of the University of Southern Maine and Benjamin Swarts of Central Michigan University has looked at in vivo nuclear imaging as a non-invasive means of diagnosing TB as well as disease monitoring and treatment response in real time. This means that vital information regarding disease progression that is complimentary to other forms of diagnosis can be quickly attained.

Current imaging methods rely on radiotracers to provide information on host inflammatory response to the infection however there can be some inaccuracy due to a lack of specificity in cellular uptake. An attractive alternative are radiolabeled analogues of antimycobacterial compounds which specifically label the desired bacteria and can provide in vivo imaging.

In the past, the disaccharide trehalose and its analogues have been applied to study metabolic mechanisms of mycobacteria and provide a means to design specifc probes for the mycobacteria induced infections. In this current publication, the researchers successfully developed a robust and concise synthetic route to access a number of fluorinated trehalose (FDTre) analogues using a rapid chemoenzymatic process followed by a simple purification by ion exchange chromatography. This drastic improvement compared to previously reported synthetic routes, which require lengthy reaction times and often result in low recovery, makes this new route highly desirable as well as compatible with timescale required for radiolabel synthesis. In addition, the authors demonstrated the ability of their FDTre analogues to be successfully recognized and taken up through trehalose transporter pathways in M. smegmatis and pathogenic mycobacteria, allowing for FDTre accumulation within cells.

Further investigations are still required to overcome remaining hurdles such as the cost associated with synthesis, assessment of uptake efficiencies at concentrations closer to in vivo radiotracer concentrations as well as evaluation of the speficity of the FDTre radioprobes. Regardless, the methodology established in this study provides an exceptional platform for the development of a new class of nuclear imaging probes to help treat multi-drug resistant TB and other mycobacterial infections.

To find out more see:

Deoxyfluoro-D-trehalose (FDTre) analogues as potential PET probes for imaging mycobacterial infection
Sarah R. Rundell, Zachary L. Wagar, Lisa M. Meints, Claire D. Olson, Mara K. O’Neill, Brent F. Piligian, Anne W. Poston, Robin J. Hood, Peter J. Woodruff and Benjamin M. Swarts
DOI: 10.1039/C6OB01734G

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

Nature uses a cooperative interplay of noncovalent interactions to control complex self-assembly of organized nanostructures with extreme precision. Taking this as inspiration, the field of structural DNA nanotechnology has been working toward the development of programmable, self-assembling nanomaterials and motion control at the nanoscale level by exploiting the remarkable molecular recognition properties of DNA. A number of basic structural motifs using branched DNA have been designed and are key elements for the construction of supramolecular arrays, molecular scaffolds and mechanical and logical nanodevices.

The paranemic crossover (PX) motif, as described in a recent OBC publication, has been of particular interest due to its unique ability to behave as both a self-assembling building block or tile and cohesive linker. Its application, until now, has been limited to 1D arrays as the level of flexibility within PX tiles needed to be controlled in order to access well-defined 2D and 3D DNA structures.

PX DNA arises from the fusion of two parallel double helices through strand cross-overs wherever the two strands come in contact. The component double strands are not linked and can hypothetically pair with each other indefinitely in a manner similar to the pairing of a buldged double helix. Advantageously, the PX structural motif reduces the need for sticky end cohesion, traditionally used in DNA-based self-assembly, which leads to an overall increase in nanostructure stability as sticky ends are susceptible to enzymatic degradation. In addition, complex DNA nanostructures made solely from PX motifs reduce topological problems during self-assembly thus minimizing error.

Researchers from the National Centre for NanoScience and Technology in Beijing, Anhui Normal University in China and Purdue University in the United States have collaboratively studied various structural parameters in order to optimize PX DNA’s ability to participate in the assembly of highly desirable 2D nanostructures. By varying the number of base pairs that make up the major (wide, W) and minor (narrow, N) grooves of the bulged double helix, several versions of PX tiles were prepared. Optimal parameters were observed when T₆₅ (according to the formula T_WN), which assembled into an extended, flat and regular 2D array (see image). Any deviation from this number of base pairs resulted in the tile becomes stressed and twisted leading to random aggregates.

This discovery has made possible the application of the highly desirable PX motif in 2D nanoconstruction which will no doubt lead to the synthesis of more stable and structurally and functionally intricate DNA self-assembling nanostructures.

To find out more see: