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Totally Synthetic by Paul H. Docherty, 30 December 2009

Total Synthesis of Palau'amine


I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, P. S. Baran, Angew. Chem. Int. Ed. 2010, 49, 1095-1098.

DOI: 10.1002/anie.200907112

Palau'amine is undoubtedly a challenge; Baran states that ‘the total synthesis of palau'amine has thus far eluded organic chemists despite the dozens of Ph.D. theses… Many well-founded and logical plans to secure the peculiar trans-5,5 core of palau'amine in our laboratory resulted in unfortunate outcomes‘. This maybe explaines the brevity of this post.

The problem with palau’amine has always been the 5,5′-fused system. For about ten years, this was thought to be in a cisoid-configuration, but a recent publication by Baran and Kock reconfigured this as trans. This both helped and hindered synthesis, as whilst trans-5,5′-fused systems are more difficult to make, it brought the target far closer to that of its related structures, such as the axinellamines.

The starting point to the chemistry should be familiar -  a similar intermediate shows up in Baran’s 2007 total synthesis of the axinellamines. Using very similar chemistry to that used in the earlier synthesis, Baran’s first move was to install the sole hydroxyl group using silver(II)-picolinate. This stereo- and chemoselective transformation targets only the secondary amine. From there, building a second 2-aminoimidazole ring was done by simply adding cyanamide in brine - rationalised by the propensity in other solvents for the secondary chloride to be displaced. Presumably having a load of chloride ions in solutions favours the desired side of that equilibrium. Bromination of the new aminoimidazole ring provided a functional handle for the next fragment coupling: a masked pyrrole synthesis. As modern methods using palladium failed when attempted, Baran performed an alkylation to complete the C-N linkage, followed by a series of acid mediated methanol eliminations to obtain the aromatic heterocycle, conveniently with the free acid functional group.


The final three reactions will complete the total synthesis: hydrogenation using palladium acetate in a hydrogen atmosphere reduced the azide groups to a pair of primary amines. Treatment of the amino acid system with EDC/HOBt formed a macrolactone, presumably favouring the nine-member ring over the ten. This macrocycle, named ‘macro-palau’amine‘ by Baran was the key to his synthesis, as the addition of acid promoted a transannular cyclisation between amide nitrogen N-14 and imine C-10. Astoundingly, this reaction was selective for the trans-configured 5,5′-fused system, and thereby completed the synthesis of palau’amine.

Now that’s a very nice total synthesis. The legacy of palau’amine is confounded logic, and ultimately the triumph of human endeavour.