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


(+/-)-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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(+)-Loline Alkaloids

2330 - update: Just noticed the Tot. Syn. writeup. Check it out for an alternative discussion! Funny that this work's two weeks old, yet we both write about it today!

An Efficient Synthesis of (+)-Loline Alkaloids

D. Trauner et al., Nature Chemistry, 2011, 3, 543 [PDF][SI][GROUP]

DOI: 10.1038/nchem.1072

I just noticed this very efficient enantioselective synthesis of a trio of the loline pyrrolizidine alkaloids reported by Trauner and coworkers back in June. Although loline has been known for more than a century, prior to this work only one enantioselective synthesis had been reported, and at 20 steps in length - that's well over two synthetic operations per carbon atom - it's as good an example as any to illustrate the point that size isn't always what makes a target challenging. Trauner, with characteristic German efficiency, took only 9 steps to reach loline through clever use of some simple and largely well established chemistry. Reading this paper reminds me of one of the most important axioms for designing anything (syntheses, websites, software, machinery...): that a thing should only be as complicated as it needs to be - and no more.

Filed under: Current Literature, Total Synthesis | 14,507 views | 3 comments Continue reading