Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 27 March 2008

Total Synthesis of Axinellamine A, B, and 1,9-Dideoxy-pre-axinellamine


D. P. O'Malley, J. Yamaguchi, I. S. Young, I. B. Seiple, P. S. Baran, Angew. Chem. Int. Ed. 2008, 3581-3583.

DOI: 10.1002/anie.200801138

J. Yamaguchi, I. B. Seiple, I. S. Young, D. P. O'Malley, M. Maue, S. S. Baran, Angew. Chem. Int. Ed. 2008, 47, 3578-3580.

DOI: 10.1002/anie.200705913

There’s been a bit of excitement about this synthesis, perhaps because it's completion hints further towards a total synthesis of Palau'amine. The target of this synthesis contains the tetracyclic bisguanidine core common to these natural products, including eight contiguous stereocenters, making it quite a challenge. No biological activity is mentioned, but when the molecular architecture is interesting, do you need another reason to make it?!

A retrosynthetic analysis of the molecule reveals at least two simple disconnections, that of the amide bonds. (However, the reaction used for this coupling is worthy of a brief mention: The acid-partner used was actually a trichloroketone, a nice way of activating an acid for coupling, which can be made via a haloform reaction.) Far less intuitive was formation of the aminal centre by addition of a free amine onto an imine; quite ambitious if one considers the number of amine moieties in this molecule.

The chemistry starts in the second of the two papers linked above, with a short synthesis of the diazide shown below via a Diels-Alder reaction, followed by ozonolysis to provide both ketones. Formation of the first ring then followed by first forming a pair of enol-ethers, brominating and then an aldol reaction to give the the cyclopentane with great selectivity and a very reasonable yield. The authors reference some work by Ho in "Tactics of Organic Synthesis" for this.

Shortly afterwards it was time to provide the second ring, this time oxidatively. They found that oxidation of the allylic alcohol at RT gave the wrong spirodiasteromer at C-14, but heating to reflux in benzene gave the desired diastereomer in a small excess. A nice way to construct the spirocycle.

The last sequence to consider is the pièce de résistance, and the main topic of discussion in the title paper. Treatment of the bisguanidine with DMDO performed a selective oxidation of the alkene to provide a mixture of diols (where their relative configuration was presumably -cis). This was then dehydrated using TFA (again selectively) to provide the product of intramolecular cyclisation (where the imine intermediate has been attacked by the desired nitrogen in the other guanidine). Again as a mixture of distereoisomers, this product was oxidised by silver(II) picolinate (which is most usefully referenced in this paper) to give the desired tetracyclic core.

To finish the synthesis, what was required was a reduction of the azides (using 1,3-propanedithiol - referenced here - leaving the corresponding cyclic dithiane as a biproduct), and coupling of the pyrrole units. This, of course, was received as a mixture of diastereoisomers - which happen to be Axinellamine A & B.

Loads to read here, and most of the papers referenced are worth a thorough read too!