Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 4 December 2008

Total Synthesis of Bryostatin 16


B. M. Trost, G. Dong, Nature 2008, 456, 485-488.

DOI: 10.1038/nature07543

The target is one Trost has been working on for quite a while, but with good reason, as it’s quite a complex molecule. They also speak of ‘exceptional biological activity’ and back this up with references to use of bryostatins in the clinic. However, only 18 grammes were isolated from 14 tonnes of the marine species! That’s quite a column…

One of the fragments that serve as starting point in this total synthesis was already discussed in a previous Trost paper on this molecule, but a different, and shorter synthesis is used here. One step I found particularly interesting was a propargylation of an aldehyde using chemistry developed by Teck-Peng Loh a few years back. The reagents are quite exotic, but it’s a neat way to build this homopropagylic alcohol. However, the result is still racemic, so an oxidation and CBS reduction was used to induce an enantiomeric excess.

For the coupling of this fragment with a partner, Trost used ruthenium chemistry developed in his labs. In this case, the situation is complicated by the highly functionalised nature of the partners; ligation of the metal to the olefins in both starting materials or the product is the reason given for the low yield. However, the starting materials were easily isolated and resubmitted to the reaction conditions.

Transformation of the vinyl silane into a vinyl bromide was done with NBS. This reaction offered astonishingly high yield (98%) and selectivity in such a substrate. Some acid mediated reactions in one pot followed, that selectively removed the TBS group and performed a neat transesterification/ketalisation.

The vinyl bromide was carbonylated in a very good yield (83%) using a standard method. More problematic seems the required selective saponification of the β-hydroxyl methyl ester. Trimethyl tin hydroxide, and heating did the job amazingly well, which Trost suggests is due to the lewis acidity of the reagent. So complexation with the hydroxyl group delivered the impressive selectivity.

Last is a seriously impressive sequence of reactions. First, a palladium mediated coupling of the diyne, using a method developed by Trost. The selectivity is very impressive  again, but as with most macrocyclisations dilution was key to keeping the reactivity intramolecular. An impressive example of a new macrocyclisation method - even if the yield is only moderate. More impressive was the fact that they were now perfectly set up for the final cyclisation. They needed to run trials with a few different gold catalysts due to a regioselectivity problem, but finally found a combination of reagents that work.

Pivalation and deprotection rounded off an incredible total synthesis, using impressive methodology in exactly the right way. A master class…