RESEARCH

Our research is focused on the development of concise and stereoselective synthetic methods and strategies that permit rapid access to biologically important natural products. Central to our research philosophy is an emphasis on step economy and flexibility in the overall synthetic routes. Ultimately, these processes should lend themselves to the production of sufficient quantities of the biologically-relevant targets and analogues of these substances for structure-activity profiling.


Synthetic Methodology

Chlorohydrins as natural product building blocks

The stereoselective synthesis of heterocyclic compounds is a longstanding synthetic challenge. In recent years we have made several advances in this area by exploiting α-chloroaldehydes as versatile building blocks for the synthesis of tetrahydrofuran, tetrahydropyran, and pyrrolidine-containing natural products and therapeutic leads (including carbohydrate analogues, iminosugars). These efforts rely on highly diastereoselective aldol reactions of α-chloroaldehydes, affording β-ketochlorohydrins that can be rapidly converted into stereochemically rich heterocycles and natural products. We have also reported a one-pot organocatalytic aldehyde chlorination/aldol reaction that proceeds with dynamic kinetic resolution and provides direct entry to a new class of carbohydrate building blocks.

Photocatalytic fluorination

Over the past several years we have reported several methods for introducing fluorine into complex molecules including a direct fluorination of unactivated C-H bonds. This reaction utilizes the decatungstate anion and N-fluorobenzenesulfonimide (NFSI) for photocatalytic hydrogen atom abstraction and fluorine atom transfer. The decatungstate/NFSI fluorination displays excellent functional group tolerance including the ability to cleanly and selectively fluorinate unprotected amino acids and leucine residues in unprotected peptides. Current work in this area involves exploring the scope and limitations of our fluorination reaction with a goal of assisting medicinal chemistry efforts.

Other fluorination strategies

Our continuing interests in unique fluorination processes led to the discovery that thionoesters undergo fluorodesulfuration using silver(I) fluoride, rapidly affording difluoroethers. We have also synthesized and studied tertiary alkylammonium trifluoromethoxide salts as bench stable sources of trifluoromethoxide and have developed late-stage heterobenzylic mono and difluorination using N-fluorobenzenesulfonimide (NFSI).

Radiofluorination

Positron emission tomography (PET) imaging is an imaging technique that allows functional measurement of biochemical and physiological processes in living tissue. Commonly used in oncology, PET relies on radiotracers - a ligand labeled with a positron-emitting isotope - whose distribution and concentration can be detected through isotopic decay. Of all the radionuclides used in PET, 18F is closest to being an ideal radionuclide (t1/2 = 110 min, good metabolic stability, small size), and is used in the most common PET radiotracer, 18F-fluorodeoxyglucose (18F-FDG). However, the introduction of 18F into sensitive organic frameworks remains a challenge, thus limiting the structures available to nuclear medicine clinics. The Britton group, in collaboration with TRIUMF - Canadas national particle accelerator facility - has been involved in the discovery of novel methods for 18F fluorination since 2014. One of these, the DT-PhotoFluor platform has been extensively used for the 18F fluorination of unactivated C-H bonds, such as the 3o position of leucine and leucine analogues. This platform has allowed us to generate novel oncological PET radiotracers which may be of use in imaging multiple myeloma - a disease that is not well served by current imaging technologies. Other radiofluorination reactions currently under investigation are the 18F fluorination of thiocarbonyls via Ag18F.

Total Synthesis

A major focus of our program is the total synthesis of structurally complex natural products. We are particularly interested in targets that exhibit rich stereochemical features and potentially useful biological activity. Examples of ongoing total synthesis targets include eribulin, an analogue of the natural product halichondrin B and an approved drug for metastatic breast cancer, and of the potent marine cytotoxic agent eleutherobin. We have also recently disclosed the synthesis of key fragments of phormidolide A, a toxic metabolite of the cyanobacterium Phormidium sp. and stereochemical reassignment of the natural product with Professor Ian Paterson (Cambridge). Examples of recently completed natural products, as well as current targets are depicted below.


Pheromones

In collaboration with the Gries lab (Biological Sciences, SFU), we have reported the isolation, synthesis and field testing of a number of insect pheromones. This includes pheromones from ecologically and economically relevant bugs including the pistachio twig borer moth, bald-faced hornets, and bedbugs. This research has led to the development of Ortho® Home Defense Max®, a cost-effective lure and trap for early detection of bedbugs.