Enantioselective Michael addition in the total synthesis of strychnos alkaloids

3 Apr 2014

Adam Gammack, an Old Carthusian who left Charterhouse's Saunderites House in 2007, began by defining natural products as 'substances made by organisms which can be used for a variety of purposes' and total synthesis as 'a chemical synthesis using simple starting reagents'. He then gave examples of natural products; one of the most famous being penicillin from the Penicillium fungus.

Humans also produce natural products - our hormones are the basis for hormonal therapies. The newest natural products to be extracted are those from marine organisms. These are relatively new as the marine environment has only become accessible to humans with the use of SCUBA (diving) in the 1960s. Using natural products is not a new concept in the pharmaceutical sphere; Hippocrates noted in the 5th century BCE that chewing the bark of the willow reduced pain. We know now willow extract contains salicylic acid - the active metabolite of aspirin.

To obtain natural products directly from living organisms is not feasible. Mr Gammack said 1000g of sea cucumber would produce 0.006g of natural product thus showing there needs to be alternative ways of obtaining these useful molecules. One viable method is via total synthesis. In reactions that synthesise enantiomers, the enantiomers are usually produced in equimolar concentrations - a racemate. Despite having identical chemical properties, each enantiomer may have different biological effects. Mr Gammack demonstrated this by passing around samples of the two enantiomers of carvone (2-Methyl-5-(1-methylethenyl)-2-cyclohexenone).

The R-enantiomer smells of spearmint whereas the S-enantiomer smells of caraway. This phenomenon occurs because the receptors in our nose that register smell are chiral as well, hence will send different signals to our brain when they bind to different chiral molecules. This is why drugs are usually prescribed as a single enantiomer.

Using an enantioselective catalyst, a greater quantity of a single enantiomer will be produced as the enantioselective catalyst provides a lower energy pathway to a single enantiomer. Enantioselective catalysts are often organocatalyst ie catalysts which are derived from natural products.

Strychnine is an infamous poison. Taking just 5mg will kill an adult. It is also the most complex molecule for its size by containing five stereocentres. Strychnine is an alkaloid. Other members of its family of molecules show promising anti-cancer properties but there are insufficient quantities available. Mr Gammack is working towards a divergent synthesis (one molecule that can be changed into many other molecules quickly and easily) in order to meet the supply/demand for these alkaloids.

He first drew up a retrosynthesis of the reaction he proposed to do. He started with the chemical structure common to all alkaloids and removed functional groups, eventually ending up with a simple molecule. When planning the forward reaction, he highlighted the key step would have an enantioselective catalyst. Using computational studies, he has found a catalyst which causes the enantiomer produced to be 24.6kJ/mol lower in energy. This large energy difference explains the enantioselectivity.

Currently he is at a point in the synthesis where his yield in one of the steps is 42%. This is too low to make it a viable reaction to synthesise these alkaloids so is currently reviewing this stage. The molecules that are made at each step are tested against cancer cell lines. This is done to see if any compounds generated during the synthesis have the anti-cancer properties similar to the alkaloids he is working produce.

The Society thanked Mr Gammack, of the University of Oxford, for a most stimulating and clear lecture.

James Nugent, Charterhouse

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