B.R.S.M. Help! I'm trapped in a molecule factory!


Projects I’m glad I didn’t work on

Obviously this style of post is borrowed from Derek Lowe's Things I Won't Work With. I'm not the most original person, and this certainly isn't the most original blog.

Hopefully many of you will have now read Baran's axinellamine paper (my take here) - it's an impressive piece of work and worth a few minutes of your time. I've noticed that I keep having the same conversation about it with different people over the last day or two:

BRSM: Have you seen Baran's new axinellamine paper? It's the shit!

Chemist: Yeah, it's pretty cool, but you couldn't pay me to work on that project. Those guys must have spent a lot of time staring off the roof of the Scripps chemistry building.

BRSM: But he's so sexy!

Chemist: I have to go now, I, uh, have a TLC running...

Or variations on that theme. Anyway, I realised that actually: 1. I'm probably inclined to agree, and 2. I find myself thinking this quite a lot. As I told commenter gippgig yesterday, I saw Baran give a talk about this work back in 2009. I remember him describing the silver(ii) picolinate oxidation and saying they had to screen a massive number of oxidants to find this successful reagent. I think he described one of his students as having a 'black tar phase' of 6 months or so, where everything presumably kept degrading when they attempted to install that troublesome hydroxyl. Silver(ii) picolinate obviously wasn't high on the list  of things to try as they had to make it specially, and none of the references they give for its use are later than the early 1970s. Periods of faliure come to everyone who practises chemistry long enough, but when you're pushing the boundaries of what's known, as Baran was here, you can spend months in the lab going nowhere at all.

A couple of other syntheses from this year with similar heroic efforts at optimisation come to mind. I should say now that I think they're both fantastic, but I'm not sure I would have had the dedication and mental fortitude to see them through.

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(+/-)-axinellamines A and B

Update 20/08/11 - Tot. Syn. covers the same paper. Also, check out Tot. Syn. coverage of Baran's original route.

Scalable, Stereocontrolled Total Syntheses of (±)-Axinellamines A and B

Baran et al., J. Am. Chem. Soc., 2011, ASAP; [PDF][SI][GROUP]

DOI: 10.1021/ja206191g

Okay, so this isn't a new synthesis per se as Baran finished his impressive first generation synthesis of these two natural products back in 2008. At the time, this was a real tour de force as they hadn't been made, and are a total pain to draw and handle, let alone actually synthesise. However, as in his cortistatin work, Phil wasn't content to stop at just a first total synthesis, and has apparently spent some time since cleaning up and optimising the route to allow production of decent amounts of material for biological testing. And what a job the group has done! Shown below is the key intermediate used for the axinellamines (as well as previous Baran syntheses of the massadines and palau'amine), which, being a cyclopentane bearing 5 contiguous stereocentres, previously took them 20 steps to make. This paper reports a new pared down route of just 8 steps, all which can be performed on gram scale, which is an amazing achievement for a fragment of this complexity, and presumably will also allow access to larger quantities of the other natural products as well.

Some of the optimised conditions used are fantastically original, betokening the amount of work put into trimming down the route; Zinc mediated Barbier coupling low yielding? Just chuck in some indium! Tricky Pauson-Khand? Add ethylene glycol! Capricious chlorination? Needs more TfNH2! Read on to see how they came up with some of this stuff...

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