Total Synthesis Blog

Today, some nice total synthesis – Barrenazines A and B. Structure of these C₂-symmetrical molecules is shown below:

These Barrenazines were isolated in 2003 by Kashman from some (according to authors of article) unidentified tunicates from Barren Islands (Madagascar). They exhibit mild cytotoxic activity against certain tumor cells. The retrosynthetic analysis is shown below:

I can only say that concept of that synthesis is very tricky. I’ve tried predict some step myself utilizing C₂-symmetry of target molecule, but I haven’t thought that central pyrazine ring can be done in such way. Oh, maybe I just have to learn more !

Following retrosynthetic steps are drwan below:

Pyridinium cation ! Nice starting material for that total synthesis ! It’s really interesting that organomagnesium halide addition can be completed to such system. Here, carbonyl group seems to be unreactive.

Synthesis of both (-)-Barrenazine A and B is drawn below:

In first step, to disubstituted pyridine chiral auxiliary was introduced and next completely stereoselective addition of Grignard reagent was undergone. Next, methyl ether was cleavaged to form corresponding ketone. That ketone was undergone reaction with trifluoroacetic acid in chloroform to unprotect tri-i-propylsillyl protecting group. In next step, removal of chiral auxiliary group occured, but later in the same place Boc-protecting group was directed. Next, we have reduction of ketone by using L-selectride reducing agent:

Next, we have free radical azidation in the presence of cerium ammonium nitrate (CAN). Formed in such way azidoketone can dimerize under Staudinger condition. In that step, skeleton of Barrenazines was created. Boc-deprotection gave (-)-Barrenazine B and following hydrogenation gave (-)-Barrenazine A.

For more pieces of informations see:

M. M. Martinez, L. A. Sarandeses, J. P. Sestelo, Tetrahedron Lett., 2007, 48, 8536.