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30 December 2009 60,320 views 109 Comments


Baran, Seiple, Su, Young, Lewis and Yamaguchi. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200907112. Article PDF Supporting InformationGroup Website

Y’know, I was kinda hoping for a bit of break between blog-posts this winter, as the amount of online publications tends to tail-off around the year-end.  However, not only have the publications been thick-‘n’-fast (got quite a lot of material to get through), but up pops palau’amine.  I really did think that Angewandte would hold-off until sometime in early 2010, but here it is – and it lives up to Baran’s reputation.  I mean that in every sense, as in some ways there’s a slight dissapointment, as he has a way of making the synthesis look to obivious, too easy.  However, it was undoubtedly a challenge; Baran states that ‘the 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 goes some-way to explaining the brevity of this blog post, but I intend to follow-up this post with a quick review of other routes that have been attempted in other labs.

Cutting to the chase, 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 it’s siblings, such as the axinellamines (more on that soon). Anyway, on with the synthesis of our favourite apostrophied natural product.

The starting point to the chemistry should be familiar to regular readers – hark back to Baran’s 2007 synthesis of the axinellamines, and a familiar intermediate crops up.  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, and remains un-molested in the subsequent synthesis.  From there, building a second 2-aminoimidazole was done by simply adding cyanamide in brine – rationalised by the propensity in other solvents for the secondary chloride to be displaced.  Presumably have a load of chloride ions in solutions favours the desired side of that equilibrium.  Bromination of the new aminoimidazole provided a functional handle for the next fragment coupling – a masked pyrrole synthesis.  Estchewing more modern methods using palladium (which failed when attempted) to perform a direct coupling, Baran did an alkylation to complete the C-N linkage, followed by a series of acid-mediate methanol eliminations to give the aromatic heterocycle, conveniently with the free acid functional group.


Next up, and completing the synthesis (!!!) are the final three reactions.  A bit of hydrogenation using palladium acetate – conditions new to me – in a hydrogen atmosphere reduced the azide groups to a pair of primary amines.  Treatment of the amino-acid system with a bit of EDC/HOBt formed a macrolactone, presumably favouring the nine-member ring over the ten.  This macrocycle, dubbed ‘macro-palau’amine‘ by Baran was the key to his synthesis, as the addition of a bit 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 damn nice piece of work.  But I’m eagerly waiting for the full paper, which I’m sure will put this synthesis in context, as then we’ll have a better idea of what didn’t work.  That is perhaps the legacy of palau’amine – confounded logic, and ultimately the triumph of human endeavour.  So what’s next?

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