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Totally Synthetic by Paul H. Docherty, 18 October 2006

Total Synthesis of RK-397


M. J. Mitton-Fry, A. J. Cullen, T. Sammakia, Angew. Chem. Int. Ed. 2007, 46, 1066-1070.

DOI: 10.1002/anie.200602601

The target (the imaginatively named RK-397) is a popular one, with previous syntheses by McDonald and Denmark. This is less surprising when one considers its antifungal, antitumor, and antibacterial activities! So to the retrosynthesis:

All your favourite disconnection in one retrosynthesis! Okay, perhaps some of these are a given, but navigating the best disconnections amongst those polyol and polyene domains is pretty tricky! Once they had decided, chopping up the molecule left them with two distinct polyol fragments, one made from consecutive aldol reactions, the other through a really nice two-directional approach. (The use of acetal protecting groups in this stage of the synthesis is exceptional.) Coupling these fragments must have been difficult, but they had a lot of success with a Paterson 1,5-anti-aldol reaction:

The synthesis was soon complete, with metathesis to build the majority of the polyene domain. Well, it's quite brave to add Grubbs I catalyst to a triene! A Horner-Wadsworth-Emmons reaction followed. Lastly, macrolactonisation did its usual finale, finishing the job.