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Totally Synthetic by Paul H. Docherty, 26 November 2006

Total Synthesis of Pikromycin

Fecik

L. Venkatraman, C. E. Salomon, D. H. Sherman, R. A. Fecik, J. Org. Chem. 2006, 71, 9853-9856.

DOI: 10.1021/jo062047u

This is an interesting paper. The group are targeting the two macrolides; narbonolide and its big brother, pikromycin, using a biotransformation to perform the glycosidation and oxidation. However, they’ve got to make narbonolide first!

As shown in the retrosynthesis, the linear molecule is constructed through a pair of Evan’s aldol reactions. The synthesis of the constituents was not discussed, primarily because this is a second generation synthesis. These earlier works were generally found wanting in the macrocyclisation, but Fecik and his team excelled, with a 90% yield. This then allowed them to proceed to the biotransformation.

This must have been a fairly scary step; the group did the reaction on a 4mg scale, which a reasonable amount to submit to such an advance precursor, especially considering the lack of presidence. The experimental details mean nothing to me; lots to learn, as ever: "A concentrated spore stock (10 μL) of the Streptomyces venezuelae pikAI deletion mutant BB138 was used to inoculate 50 mL of ATCC172 media (10 g of glucose, 20 g of soluble starch, 5 g of yeast extract, 5 g of NZ amine type A, and 1 g of CaCO3 per 1 L of H2O) in a 250 mL baffled flask and incubated at 30 C for 2 days with shaking. This seed culture (5 mL) was used to inoculate fresh ATCC172 media (50 mL) containing narbonolide (1, 4 mg in 400 μL EtOH) or EtOH (400 μL) and incubated at 30 C for 3 days with shaking…"

No yield was given for the transformation, just a HPLC trace, showing both starting material and product.

Overall, a very competent macrolide synthesis, and a nice application of a biological transformation.