B.R.S.M. Home of Woodward Wednesdays

19Aug/1110

(+/-)-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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10Jul/114

Schindilactone A

Here's an impressive total synthesis of schindilactone A by Tang, Chen, Yang,[1] and 14 coworkers. At 29 steps in the longest linear sequence that's comfortably fewer than two per author. Still, the route is entirely linear and it's a fairly heroic effort, as we'll see.

Work began sometime ago as the group published syntheses of the ABC (Org. Lett., 2006, 8, 107) and FGH (Org. Lett., 2005, 7,885) fragments of the slightly more complex micrandilactone A some time ago. Apparently that unique, ketal spanned, 7-8 carbocyclic system in the middle took some time to work out. I'll cover the older work on those fragments as well, as it shows the origins of some of the key steps in the schindilactone A total synthesis.

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