Fecik, Lakshmanan, Salomon and Sherman. JOC, 2006, ASAP. DOI: 10.1021/jo062047u.

An interesting paper, this ‘un. The group are targeting the two macrolides; narbonolide and it’s big brother, pikromycin, using a biotransformation to perform the glycosidation and oxidation. However, they’ve got to make narbonolide first!

As shown in the retro, the linear molecule is constructed through a pair of Evan’s aldols. 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 SM and product.

Overall, a very competent macrolide synthesis, and a nice application of a biological transformation (that keep you happy ddd??!:))