Total Synthesis Blog

To little time, to many tasks to do…

But, fortunately, I always find time to publish some nice total synthesis. Today – one of an ergot alkaloid – (-)-cis-Clavicipitic Acid:

Nice tricyclic structure, isn’t it? This compound was isolated from Clavicepis fusiformis (some kind of fungis, I guess) and SD58. Biological activity of (-)-cis-Clavicipitic Acid is still under investigation (and total synthesis of that target is part of the program). But, let’ see some retrosynthetic analysis…

The key reaction is Pd(II)-catalyzed aminocyclization. Synthesis is shown below:

Thallium-mediated iodination is the first step of that synthesis. Next – Boc-protection, catalyzed by DMAP. Transformation 5 to 7 is interesting stereoselective phase transfer catalyzed alkylation. The PTC is naturally-derived quartenary-ammonium salt 6. Looks pretty nice

Next, from 7 to 9, is paladium-catalyzed Heck reaction. Interesting step is aminocylization. Stereoselectivity of that transformation is 5:1 (cis:trans isomer) and preferable transition state (for cis isomer formation) is believed to look just like below:

Also, the last step is really interesting to me: zinc bromide-mediated deprotection 12 to desired target. There’s no epimerization (-)-cis-Clavicipitic Acid here. Nice trick.

For more information of course see to paper:

J. Ku, B. Jeong, S. Jew, H. Park, J. Org. Chem., 2007, 72, 8115.

Oh… There’s one mistake in picture: of course indole-nitrogen atom in 12 sill bears Boc group