B.R.S.M. Yield isn't everything


Taxol Time Again: What now, Phil?

Update 20-11-2011: Reference added and a couple of mistakes removed. Why can I never see those the first time?

Scalable Enantioselective Total Synthesis of Taxanes

Baran et al., Nature Chemistry, 2011, [PDF][SI][GROUP]


The taxanes are a large family of 350 or so natural products, of which the best known is taxol itself, a multibillion dollar anticancer drug with a rich and storied history, whose name and distinctive tetracyclic system are instantly recognisable to most organic chemists. Taxol itself has already been the subject of 7 epic total syntheses (see BRSM Reviews: Taxol In 10 Minutes if you need a quick reminder), all using conventional functional group lead approaches to bond formation. Nature's (and Phil's) approach is a bit different, though, as we'll see.

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BRSM Reviews: Taxol In 10 Minutes


If you're reading this then I reckon you've probably heard of taxol, as it's one of the most talked about synthetic targets of all time. It's a molecule with a fascinating history, from its isolation and structural assignment in 1971, to discovery of its potent activity and interesting mode of action, and the ensuing scrabble to solve the supply problems plaguing its development as a drug.[1] Its rise to success as a billion dollar pharmaceutical was stellar, and is one of my favourite examples of how useful and important synthetic organic chemistry is. Although it's been 5 years since the most recently reported synthesis of taxol, last week's Baran synthesis of taxadiene (following his cyclase-oxidase mimic plan for elaboration of this hydrocarbon into taxol) seems to have again gotten chemists talking excitedly about this target. After overhearing things like 'didn't Nicolaou make it first?', 'there've only been x syntheses so far' (where x is 0-6) and other such misinformation in our office I've decided to take action. Yes, there are already numerous reviews, book chapters and even entire books on this subject, but it seems that a lot of people don't have the time or inclination to read them. So, here's a brief summary of the 7 syntheses published so far, in the order they were completed. Hopefully this'll help put recent developments in perspective.

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Enantioselective Total Synthesis of (-)-Acetylaranotin, a Dihydrooxepine Epidithiodiketopiperazine

Reisman et al., J. Am. Chem. Soc., 2011, Early View; [PDF][SI][GROUP]

DOI: 10.1021/ja209354e

This week saw another brilliant synthesis from the still fairly new Reisman group over at Caltech, this time an epidithiodiketopiperazine (ETP),[1] the group's first. These interesting secondary metabolites have so far only been isolated from fungi, and owe their toxicity to their disulfide bridges that generate reactive oxygen species by redox cycling. Although ETPs have been popular targets for the last 40 years, and the field has seen some impressive chemistry from Kishi in the 70s to more recent efforts by Movassaghi, Overman and Nicolaou. More challenging still are the dihydrooxepine containing ETPs such as acetylaranotin, which has stood unconquered since its isolation 1968, and in fact no synthesis of such a compound has been reported, until now.

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