Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 16 September 2006

Total Synthesis of Marinomycin


K. C. Nicolaou, A. L. Nold, R. R. Milburn, C. S. Schindler, Angew. Chem. Int. Ed. 2006, 45, 6527-6532.

DOI: 10.1002/anie.200601867

A very nice total synthesis of this potent antibiotic (we need new antibiotics), with top MRSA (Methicillin-resistant Staphylococcus aureus) and VREF (Vancomycin-resistant Enterococcus faecium) killing action. Using it’s dimeric nature to their advantage, they started with the synthesis of the monomers. Very early in this synthesis, they have need of a trisubstituted olefin, which they produce from the propargyl alcohol in a nice preparation:

Now, I’ve used Red-Al many times to reduce an acetylene, and have been impressed with it, but this really nice. I guess it’s similar to the hydroalumination/iodation preparation for vinyl iodides; anyway - here’s the original reference.

A little later in the fragment synthesis, they have to do the first of their Suzuki reactions, starting with an acetylene, which they hydroborate to produce the required boronic acid. For the hydroboration, though, they used a reagent I’ve never seen before, taken from a top Snieckus preparation:

So how does this one work? Well, I had a look at the original paper, and their explanation goes like this:

The paper also mentions a preparation for the hydroboration reagent using sodium borohydride and (MeO)2SO2. Certainly cheaper and less “exciting” than borane-THF, but I have a feeling that the sulfone may smell…

With a later boronic acid in hand, it was time to perform the dimerisation. However, things certainly didn’t go to plan (taken from the pdf):

300 equivs of TlOEt?!! Now that is one reaction I wouldn’t want to repeat! And yes, they only got a 2% yield of dimer. In the event, the monomeric ring closure was favoured massively, which the authors presume was caused by configurational predisposition for that ring formation. So they simply did the dimerisation stepwise - coupling of two ends followed by macrocyclisation. A great paper, with some top reactions!