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Totally Synthetic by Paul H. Docherty, 20 April 2008

Total Synthesis of Octalactin A


A. T. Radosevich, V. S. Chan, H.-W. Shih, F. D. Toste, Angew. Chem. Int. Ed. 2008, 47, 3755-3758.

DOI: 10.1002/anie.200800554

Octalactin A is a medium ring lactone, that offers activity against murine melanoma and colon tumor. Previous syntheses have been reported by Buszek, Clardy, Shiina and Holmes.

A full retroanalysis cannot be featured, because there’s a lot going on in a tight space. However, a key fragment is the olefin shown below. Toste noticed that this building block contains two units of similar relative stereochemistry and connectivity, and that they might be produced together as the two products formed in a kinetic resolution of a racemic mixture.

Said racemic compound was produced quickly using a rather neat Darzens condensation, rearrangement and oxidative hydroboration protocol. Aerobic oxidation using a chiral vanadium catalyst resulted in an excellent mass recovery of two products, both in good enantiomeric excess.

Transformation of these products into the desired partners for the Horner-Wadsworth-Emmons reaction was efficient and quick. The α-keto ester required decarboxylation which they performed using iodosobenzene in an intriguing oxidation of the analogous α-keto carboxylic. The procedure was developed by Robert Moriarty and follows this mechanism:

Transformation of the product into a mixed anhydride, and addition of a lithium phosphonate gave the desired ketophosphonate, and allowed a high yielding coupling of the two fragments.

A Wolff rearrangement is an underused protocol for the formation of lactones, but completed here the medium ring. Of course, there are two main methods for the expulsion of nitrogen: silver salts and light. In this case, they tried both, and found that the photo-Wolff was the more efficient process, despite the high dilution required for the reaction for the prevention of intermolecular reactions.

Synthesis of the sidechain used the interesting Kocienski procedure for the opening of dihydrofurans via a 1,2- metalate rearrangement (discussed in detail in this previous post). Coupling of the two fragments using an Nozaki-Hiyama-Kishi coupling completed the carbon skeleton, leaving them with only a few more steps to finish the molecule. A smart total synthesis!