Totally Synthetic by Paul H. Docherty, 26 January 2007

Total Synthesis of Hedychilactone B

Jung

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

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.