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RK-397   

18 October 2006 5,217 views 3 Comments

rk397.jpg

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:

rk397_1.jpg

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:

rk397_2.jpg

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.

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3 Comments

  • regular chem says:

    Important news is that Dalibor Sames started publishing in JACS again. Anyone knows anything about the supposedly soon-to-come announcement by Columbia?

  • Andrew Hess says:

    Actually, the one fragment you mentioned was not made so much by consecutive aldol reactions, but by a Sharpless epoxidation followed by a Jung semipinacol-type rearrangement to provide an aldl product followed by and aldol. And the selective elimination reaction near the end of the synthesis of that piece is unusual as well. As for the aldol reaction you must do, they’re over-rated!

  • Tot. Syn. says:

    Well, there were three aldols for that fragment… okay, perhaps not consecutive…! Yeah, the elimination was really nice, but I haven’t got a rational for that selectivity… any ideas?