Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 18 September 2007

Total Synthesis of Sarain A


M. H. Becker, P. Chua, R. Downham, C. J. Douglas, N. K. Garg, S. Hiebert, S. Jaroch, R. T. Matsuoka, J. A. Middleton, F. W. Ng, L. E. Overman, J. Am. Chem. Soc. 2007, 129, 11987-12002.

DOI: 10.1021/ja074300t

This is one mammoth piece of work. And that was the understatement of the week! Loads of research groups have been working on this beast, including Weinreb, Heathcock, Cha, and Marazano. And to the uninitiated, it might look like a relatively simple target… However, the heavy 16 page JACS article shows how difficult it can be. Anyway, retroanalysis time:

As you can see, this retrosynthesis is a bit more complex than the average retroanalysis I draw. Also, the structure I’ve taken it back to still has four stereocenters, and isn’t exactly a trivial synthesis itself. I should also point out that this retrosynthesis is based on the forward synthesis that worked, not the groups original plan. Plans evolve…

It’s interesting that in all this work, there aren’t any particularly standout steps (other than one specific example I will highlight). Rather, the synthesis is full of logical and reasonable transformations; no exotic catalysts or weird reagents have been tried. So what I’ll focus on in this post is the reactions that built the complexity.

The synthesis really starts with a Michael addition to an unsaturated ester. The stereochemistry of the oxazoline starting material was sufficient to direct the addition in great d.r. The Boc group was removed by heating like stupid, and then a bit of Me3Al to induce amidation. They were then able to alkylate the lactam with 3-bromo-2-methylpropene with good control of stereochemistry. Then a little bit of acid did quite a lot…

Taking this rather complex lactam, a reduction took care of that carbonyl, and forming the spiro-fused lactone was relatively straight forward. Reducing this lactone to the lactol promoted a cyclisation of the tosyl amine, completing the six-member ring, and producing something reminiscent of the natural product core.

Formation of a carbamate with the free hydroxyl was simple, and tied up the core nicely. They then cleaved the double bond with ozone to give a handle for a olefination with a one-carbon substrate that allowed for aldehyde formation. The silyl enol ether was formed and a bit of a rather hindered base promoted an iminium ion cyclization - and my favourite piece of chemistry in this paper.

With four rings intact, and functional plenty of groups for functionalisation, I’ll quit discussing the forward synthesis here. The macrocycle construction gave the group quite a headache, but the results and methodology used is self-evident from the retroanalysis. However, they go into quite some detail about what didn’t work, and why it didn’t work, which makes this paper more than just a great synthesis, and more than a great read.