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Totally Synthetic by Paul H. Docherty, 11 September 2006

Total Synthesis of Polygalolide A


S. Nakamura, Y. Sugano, F. Kikuchi, S. Hashimoto, Angew. Chem. Int. Ed. 2006, 45, 6532-6535.

DOI: 10.1002/anie.200602030

Some very smart cyclisation action in this paper by Hashimoto; the target is a component of a traditional Chinese herbal medicine, and their retrosynthesis hangs upon a powerful 1,3-dipolar cyclisation. The synthesis of the cyclisation precursor, whilst not trivial, was completed in rather laborious fifteen steps. With this in hand, the cyclisation may commence!

Treatment of the diazo compound with catalytic rhodium complex, and heating to 100C for five minutes allowed carbonyl ylide formation, promptly follwed by 1,3-dipolar cyclisation. This tandem reaction sequence generated the complex tricyclic core of the target, which, using relatively well-known chemistry, was elaborated in twelve steps to the target (including the aldol condensation and lactonisation mentioned in the title diagram). Interestingly, the step after cyclisation was the removal of the PMP group, for which they employed (NH4)2Ce(NO3)6, introduced by Fukuyama. This was complete in 91% after 2 hours at RT, which is quite impressive for such a (potentially) sensitive compound.