Total Synthesis of Natural  Products

The histrionicotoxins are a family of sixteen spirocyclic alkaloids isolated from the skin extracts of the Columbian "poison arrow" frogs, of the family Dendrobatidae. Histrionicotoxin (HTX) and its hydrogenation product, the non-natural perhydrohistrionicotoxin (pHTX), are both useful biochemical tools for probing the mechanisms of transsynaptic transmission of neuromuscular impulses. This remarkable biological activity, in combination with the parent compound's low abundance in nature (less than 200 μg is isolated per frog skin), and challenging azaspirocyclic framework, have prompted considerable synthetic interest over the last few decades, culminating in four syntheses of HTX and numerous syntheses of pHTX. We have written a review on synthetic approaches to the histrionicotoxins, which was published in Natural Product Reports in 2007. 

We have developed an entirely two-directional synthesis of (±)–perhydrohistrionicotoxin, utilising a tandem oxime formation / Michael addition / [3+2] cycloaddition as the key step, forming the core structure of the histrionicotoxins in one step from a linear symmetrical substrate. This approach has yielded a 9-step synthesis of perhydrohistrionicotoxin that also constitutes formal syntheses of (±)–histrionicotoxin and (±)–histrionicotoxin 235A. This work was published in J. Org. Chem. in 2004.

We have recently refined our synthesis of the symmetrical tandem reaction precursors by using cross-metathesis, and, in collaboration with Prof. Philip Fuchs (Purdue), who contributed a solution for the bis-enyne synthesis, we have developed a 9 step synthesis of histrionicotoxin. The synthesis was published in J. Am. Chem. Soc. in 2006.

We have also demonstrated the use of combining bi-directional synthesis with tandem reactions in a very concise entry into the quinolizidine skeleton. Protected amine B was converted in just one step to 4,6-disubstituted quinolizidine C, using a tandem deprotection / double intramolecular Michael addition. We have subsequently converted C into (±)-hippodamine, providing the shortest synthesis of this natural product to date. We have just completed a second generation synthesis of hippodamine which does not require the use of protecting groups - this has been published in a themed issue of Beilstein Journal of Organic Chemistry on indolizidines and quinolizidines

Using a desymmetrising ozonolysis, followed by a Horner-Wadsworth Emmons homologation and a tandem Michael Addition / Mannich cyclisation / elimination reaction, we have developed a short and efficient route to the fresh water algal bloom toxin anatoxin-a. This was published in 2008 in Chem. Commun. We have also extended this method for the synthesis of other bioactive analogues of anatoxin a, the results of which are disclosed in a full paper in Synthesis.

We have recently completed the first total synthesis of alkaloid cis-223B using a two-directional strategy with a tandem deprotection / double intramolecular aza-Michael addition to form the cis-2,3-pyrrolizidine core in a single tranformation. Read more about  this in our Chem Commun paper. Other research in the group is also concerned with the use of two-directional strategies towards the synthesis of pinnaic acid (and the biogenetically related halichlorine - see model studies in Tetrahedron Lett. and our full paper in Org. Biomol. Chem.) and dispiroketals of the type found in many marine toxins such as pinnatoxin and ionophores (model studies in Org. Lett.).




Anatoxin A

Alkaloid 223B and Halichlorine