Next Generation Chemical Synthesis. Our inability to access specific complex organic structures in a practical manner is one of the most significant problems in contemporary science. It is a bottleneck that adversely affects almost all areas of scientific innovation. It slows down new medicine development and hampers the development of new technologies of all kinds. We believe that the existing method of chemical synthesis, involving the formation of one bond at a time, is the origin of the problem. We are addressing this issue through the development of next generation methods for efficient chemical synthesis. Our approach involves domino reaction sequences, spectacular processes that allow the generation of many bonds and a huge amount of new structural complexity in a single chemical process. Using this strategy, we have completed the shortest total syntheses of natural products with both proven and promising medicinal value including triptolide and podophyllotoxin. It is fair to say that podophyllotoxin is one of the most important organic compounds in cancer medicine, since it is the precursor to the chemotherapeutic agents etoposide and teniposide.

These early successes are not the definitive synthesis of either natural product but they do show the pathway forward: our goal is to continue to improve the efficiency of our total syntheses.

Making Organic Molecules That Cannot Be Made! Synthetic chemists are often inspired by nature’s chemical structures. Non-natural structures can also spark the development of important new methods, concepts and principles. Such is the case with the dendralenes, one of the four fundamental classes of conjugated hydrocarbon structures. We devised the first chemical synthesis of this hydrocarbon family, which were widely thought to be too unstable to prepare.

Our 2009 work in this area led to the first observation of alternation in behaviour of a family of hydrocarbons since this property was observed in the early 20th century in the annulenes. The “big picture” result of these studies is a better understanding of the stability and reactivity of organic substances.

Superbowls in Drug Delivery and Catalysis. Building molecules that can carry other molecules inside them has enormous potential in drug delivery and chemical catalysis.Our research in this area is concerned with the design and synthesis of “superbowl” molecules. Superbowls are a new class of synthetic molecules with non-collapsible interiors.

In 1987, Donald Cram, Jean-Marie Lehn and Charles Pedersen were awarded the Nobel Prize in chemistry for their pioneering chemical syntheses of molecules that mimic important biological processes. Cram’s most significant work involved the development of the first fully encapsulating molecules, spherical molecules which were assembled by uniting two hemispheres. These ‘host’ spheres had the interesting property of being able to trap a small ‘guest’ molecule inside when the two halves came together. Since the sphere-trapped guest molecule is isolated from the surrounding medium, it exhibits different physical and chemical properties from the solid, liquid and gas phases. This observation led Cram to describe the interior of a host molecule as a new phase of matter.

Although brilliant in conception, these early sphere hosts were only able to hold small guest molecules of up to a dozen or so atoms. Further, once they were closed, by joining the two hemispheres, the hosts were difficult to open again so the trapped guest molecule was not available for use in chemical and biological processes.

By combining five bowl shaped molecules, rather than just two, we have been able to create a very large (on the molecular scale) “superbowl” host molecule. The superbowl is capable of containing much larger guest molecules, up to 100 atoms in size. The problem with release has been solved by forming of a vessel with a hole at one end, a little bit like a sub-microscopic vessel, the hole of which can be modified in size to allow different guests to enter and leave. Try a Google search on “superbowl molecule” for some news reports on our work in this area.

A significant recent advance is our discovery that superbowl molecules selectively encapsulate medicinal agents. We also have encouraging results to show that chemical reactions can be carried out inside the superbowl and we wish to apply these findings in the development of new catalysts.