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Totally Synthetic by Paul H. Docherty, 13 June 2009

Total Synthesis of Napyradiomycin A1


S. A. Snyder, Z.-Y. Tang, R. Gupta, J. Am. Chem. Soc. 2009, 131, 5744-5745.

DOI: 10.1021/ja9014716

The target here is an halogenated natural product, isolated from Streptomyces bacteria with antibacterial activity. With an in vivo activity against MRSA and VRSA strains Napyradiomycin A1 is a guaranteed grant-winner! A racemic synthesis was reported by Tatsuta back in 2002. However, Snyder has set his sights a little higher, with an enantioselective synthesis in this paper.

An important intermediate for Snyders synthesis was flaviolin; which in an old publication needs eight steps to be prepared, but Snyder managed to shorten it to only two - a very interesting work! The first step covered here is a Knoevenagel condensation, followed by a electrocyclic rearrangement to give the the desired tricycle.

For an asymmetric dichlorination with chlorine gas, they had to use first four equivalents of a BINOL-type axially chiral ligand and borane-THF and to isolate the chiral borane adduct intermediate. Chelation of the borane is controlled by π-stacking interaction, and allows selective trans-delivery of chlorine across the double bond. Interesting, but the amount of ligand 9 is quite high - a point addressed by Snyder, who stated that the ligand could be recovered, and the excess was required to prevent chlorination of the aryl moieties.

They then selectively functionalised the allylic chloride by displacing with acetate, and with retention of stereochemistry by using potassium acetate and 18-c-6, which presumably presents a source of naked acetate. After deacylation of the hydroxy group and protection of the remaining phenol group, a Johnson-Claisen reaction followed. This reaction rearranged the allylic alcohol into a hetero-quaternary center, and provided a methyl ester as a functional handle. The yield of product was unfortunately low, but if you consider the congested transition state here, it’s not too surprising; at least they were able to recover the SM.

The completion of the target didn’t take much more effort. The ester was reduced and olefinated, whilst the final stereocenter was imparted using base and NCS. Unfortunately this resulted in the enantiomer of the target, but that doesn’t matter. A very interesting total synthesis!