Sammakia, Mitton-Fry and Cullen. ACIEE, 2006, Early View. DOI: 10.1002/anie.200602601.
IHMO, not the most inventive synthesis of the month, but still a deft display of macrolide synthesis. 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 retro:
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’d decided, chopping up the molecule left them with two distinct polyol fragments, one made from consecutive aldol condensations, 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 a traumatic experience, but they had a lot of success with a Paterson 1,5-anti-aldol:
I really must do an aldol reaction some day…! Anyway, the synthesis was soon complete, with metathesis to build the majority of the polyene domain (also quite brave to add Grubbs I to a triene…), and a Horner-Wadsworth-Emmons completing it. Lastly, macrolactonisation did it’s usual finale, finishing the job.