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Totally Synthetic by Paul H. Docherty, 26 January 2007

Total Synthesis of Hedychilactone B


M. E. Jung, M. Murakami, Org. Lett. 2007, 9, 461-463.

DOI: 10.1021/ol062811z

Just something short; a nice Org. Lett. paper by Jung, published at the start of the year. The target has an interesting biological profile, with anti-inflammatory activity and inhibition of nitric oxide production. The potency of the latter is also interesting, with an IC50 of 28 µM. The isolation was published back in 2002, so I’m slightly surprised that this is the first total synthesis of such an attractive target, but this is a great approach to a congested decalin system.

I’ve not provided a retroanalysis for this synthesis, as the construction of much of the structure originates with one reaction; the [4+2] cycloaddition of a diene with allene carboxylate. This initially generated a cyclobutane via a [2+2] cycloaddition, which then rearranged via a [4+2] to leave a pair of diastereomeric cycloadducts, with a 23% yield of the desired product. Although this is a relatively poor yield, this is still an amazing transformation on such a hindered diene. However, check the conditions; fourteen days at reflux in what is presumably toluene! I wonder if they tried using a microwave…

With this intermediate produced so quickly (seven steps), the overall synthesis was complete in 18 steps; somewhat linear, but a very interesting paper.