J. Am. Chem. Soc. 134, 19362–19365 (2012)

The incorrect functioning of a series of biochemical reactions known as the mitochondrial respiratory chain — responsible for the aerobic production of energy — has been implicated in the development of a variety of diseases. Adjudazols A and B are bacterial natural products that are known to inhibit some of the reactions involved and, as such, are interesting targets for total synthesis. The structures of adjudazols A and B contain three and four stereocentres, respectively; but the unusual architectures and rarity of these compounds mean that the configurations of these stereocentres has been a matter of debate.

Now, a team of researchers in Germany led by Dirk Menche from Bonn University along with co-workers from the universities of Heidelberg and Saarland have analysed the biosynthetic gene cluster responsible for the production of these compounds. This work has enabled them to fully assign the stereochemistry of these compounds and, on that basis, describe the first total synthesis of adjudazol B. Gene-cluster analysis has previously been used to assign the configuration of secondary alcohols in natural products (such as at C9 in adjudazol B, pictured) but, until now, had been less conclusive for stereocentres bearing methyl groups (such as at C10 and C15). Alternative methods of stereochemical assignment often rely on comparisons to known diastereomeric relationships in similar structures. Here, the fact that the C15 methyl substituent is remote from other stereocentres in the structure means that this approach is not particularly useful. Menche and co-workers were able to show that the configuration of the four stereocentres in adjudazol B could be attributed to the presence or absence of single amino acid residues in the enzymes responsible for the biosynthesis of this compound.

Credit: © 2012 ACS

Having fully assigned the stereochemistry, Menche and co-workers set about a total synthesis of adjudazol B. A retrosynthetic analysis produced three fragments (pictured). The isochromanone core (blue) was arguably the most challenging fragment, requiring that chiral information is 'remembered' in the generation and reaction of an aryllithium. A cyclodehydration reaction with the carboxylic acid (green) containing the key C15 stereocentre led to formation of the oxazole and attachment of the polyene side chain (red) — itself constructed using cross metathesis — was achieved using a Suzuki cross-coupling reaction.