One of the many reasons cited for the contraction of the pharma giants is the difficulty in finding new drugs using the traditional small molecule research model. This relies on synthesising ‘relatively’ simple and small (low molecular weight) molecules and investigating their potential as medicines, but unfortunately the pharmaceutical industry are finding drugs of this type are getting harder to discover and to get to market.
An alternative to this approach is the development of ‘natural products’- chemical compounds which are produced by biological organisms – as medicines. Erythromycin and Taxol are highly successful drugs of this nature, but compared to small molecules, natural product drugs are few and far between. One of the main reasons for this is the complexity of natural products; from a chemical synthesis perspective they are very challenging to make, and would traditionally require a very large investment of both time and money, without any more guarantee of success than the small molecule approach. Solutions to this problem are much sought after, and there may now be a very small glimmer at the end of what, as natural product chemists will tell you, is often a long and dark tunnel.
(“and now for the sciencey bit”)
Inspired by natural biosynthetic pathways in which common intermediates are synthesised enzymatically and then derivatised to a number of natural products, Macmillan (published in Nature) has shown that from a simple tryptamine derivative it is possible to generate in a single step a fuctionalised tetracyclic intermediate common to a number of natural products (Strychnos, Aspidosperma and Kopsia alkaloids). This single reaction utilises – as those who know Macmillan’s work would expect- a highly efficient and atom economical organocatalytic cascade, with the functionalised polycyclic product then successfully derivatised to six complex natural products. The longest linear sequence in any of these syntheses is twelve steps, and the lowest overall yield a whopping 6.4% (both for (-)-strychnine).
Not only does this paper demonstrate some amazingly powerful chemistry, but it shows us that with vision (inspired by nature in this case), natural product synthesis is not always as formidable as it once was. Maybe this can open the door a little further when considering the development of natural products as drugs, and give a little hope to an unfortunately flagging pharmaceutical industry.