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Totally Synthetic by Paul H. Docherty, 3 March 2008

Total Synthesis of Palmerolide A


K. C. Nicolaou, Y.-P. Sun, R. Guduru, B. Banerji, D. Y.-K. Chen., J. Am. Chem. Soc. 2008, 130, 3633-3644.

DOI: 10.1021/ol070563g

Nicolaou and Chen achieved a smart, logical total synthesis of the marine macrolide palmerolide some months ago, described in a paper in Angewandte (which was recently discussed). The main problem was not the synthesis, but the stereochemistry. The stereochemical relationship between the pair of distinct domains was unknown, so their approach was to dissect the molecule into parts, which could be produced as pairs of enantiomers without difficulty. These fragments could then be assembled in a combinatorial manner to provide a range of macrocycles, one of which should match the natural product.

I discussed the synthesis of the fragments in the previous post, but missed out one rather nice reaction, using Brown’s  hydroxycrotylation. Using a simple starting material, application of this one-pot reaction allowed construction of a complex chiral allylic diol with excellent control and a great yield. Great stuff!

The crux of this paper, however, was an analysis of the coupling stragety. With the four key fragments (2-4 as numbered in the paper) complete, they tried a variety of strategies to first build the acylic precursor, and then close the macrocycle. Somewhat unsurprisingly, they found that the two reactions most suited for the cyclisation were ring closing metathesis (RCM) and Yamaguchi macrolactonisation. The starting material for the RCM contained eight double bonds, but the reaction went selectively in a rather pleasing 73% yield.

Although some overlap between last years paper in Angewandte and this one in JACS exists; this shouldn’t distract from an excellent total synthesis and a worthy analysis of strategy.