Danishefsky and Sun-Joon Min. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200605058. Another top synthesis from the Danishefsky labs this month (is that four published this year so far? He must be cracking the whip!), this time of the biologically exciting terpeniod, paecilomycine A. The biological profile is well documented in the paper, but the headlines are 10 nM neurite outgrowth activity in PC12 cells, and significant nerve growth factor stimulation.
Their retro-synthesis is simplicity itself, using a intermolecular DA to construct the initial cyclohexane, then a Pauson-Khand to complete the decalin and fused five-member ring. The synthesis, then, relied upon getting that DA to go in both a good yield and diastereomeric ratio.
Of course, for this to happen, the group had to use the correct coupling partners. Indeed, when they started, a 6:1 d.r. was obtained using the silyl enol ether and the aldehyde dieneophile. Whilst this went in cracking yield (87%), they weren’t happy with the diastereoselectivities, so proceeded to use the enyne ester as the diene partner. Along with the similar yield, they obtained an improved selectivity, but whilst moving to the aldehyde analogue of the enyne gave an even better d.r., the yield was reduced to 58%.
I can’t see mention of which to the latter partners they used on scale, but either product allowed them to continue to the Pauson Khand reaction (I’m sure you all know that horrific mechanism!):
Okay, the yield isn’t great, but the outcome is fantastic! Cyclopropanation allowed introduction of the remaining methyl group from the top-face, and an epoxidation remaining hydroxyl group, all via substrate control, allowing completion of the synthesis in a pleasing sequence.