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Totally Synthetic by Paul H. Docherty, 17 June 2010

Total Synthesis of Fawcettimine


M. E. Jung, J. J. Chang, Org. Lett. 2010, 12, 2962-2965.

DOI: 10.1021/ol1009762

Although the number of actual steps in a formal synthesis is (or at least should be) smaller than in a full total-synthesis, I often feel that the actual work is harder. Afterall, one is directly comparing ones work with that of another researcher, and in this case Michael Jung has got his work cut-out. There aren’t many professors whose work is truly that daunting, but Clayton Heathcock is one of them. Jung’s work intercepts the Heathcock synthesis eight steps from the end of the total synthesis, so is certainly a very worthy addition to the literature - and does things asymmetrically, which is notably absent from the former paper. However, the overall strategy is shared between the papers - using cycloaddition/alkene chemistry to build that complex ring-system, starting with the 6,5-bicycle.

Jung’s approach was to use some rather novel cyclopropane chemistry to trigger a cycloaddition - but first he had to build his cyclopropane fragment. The difficult thing here is that it needed to be a single enantiomer, so he chose to use a modified chiral auxiliary to get going. A Corey-Chaykovsky reaction was used to install the three-member-ring, leaving the group with only a simple hydrolysis in methanol to complete the malonate group and free the cyclopropane.

This fragment was put to work immediately in a Michael addition into a known cyclohexenone, promoted by triflimide. Not only did this reaction form a carbon-carbon bond, but a new stereocenter was installed, and the required silyl enol ether was formed too. Following this, a methylenation of the ketone provided the substrate for the key cyclopropane chemistry. Treating this loaded intermediate with a Lewis acid promoted a Mukaiyama-like collapse of the silyl enol ether, which adds into the cyclopropane, thereby completing the 6,5-system and providing a pair of stereocenters.

Importantly, it also provides a useful functional handle (in the form of the malonate), allowing the group to quickly converge with Heathcock after a microwave-assisted decarboxylation. Rather than just concluding here, I thought I’d have a look back at the Heathcock paper. Heathcock set the precedent, working with a molecule very similar to that of Jung. Some Wittig chemistry creates a diene, which undergoes a 5-exo-trig cyclisation to build the cyclopentane, featuring the same exocyclic methylene as Jung. The catch here is the ester side-chain - Jung’s innovative route places this one methylene group further away from the ring system. This is key, as Heathcock then needs four more steps to do the same thing (effectively a Arndt-Eistert homologation).


This is where the routes converge, but for Heathcock, targeting the first total synthesis, the work was a long way from done. Completing a larger nine-member cyclic amine was next on the agenda, using nothing too spectacular to achieve this. However, the final cyclisation to complete the molecule really is very interesting, so here it is in its fineness:

Impressive work by all involved, and due praise to Jung for bringing some interesting chemistry to this natural product.