Palmerolide A: redux
You’d be forgiven for a feeling of dÃ©jÃ vu when looking at the post – yes, you have seen it before. Originally described in an Angewandte paper last year (which was discussed on this blog), Nicolaou and Chen achieved a smart, logical synthesis of the marine macrolide. The main problem was not the synthesis (which, at least from their description, was achieved without adversity), but the stereochemistry. The stereochemical relationship between the pair of distinct domains was unknown, so their approach was to dissect the molecule into bitesize chunks, 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 a piece of Brown’s chemistry to do a hydroxy-crotylation. 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 to cyclisation were RCM and Yamaguchi macrolactonisation. Perhaps more surprising was that they could do the RCM with the enamide sidechain inplace. The starting material for this cyclisation contains eight double-bonds, so there was every opportunity for havoc, but the reaction went in a rather pleasing 73% yield.
The overlap between last years Angewandte paper and this JACS troubles me a little; I can see that this paper goes further in it’s discussion of the strategic alternatives, but much of the first half of the paper is a repeat. But that shouldn’t distract from an excellent synthesis and a worthy analysis of strategy.
InChi Key Dump: HEOKDDVDVGNHMR-DAUCKHFQBA MLCUMJCCPMSERM-UHFFFAOYAZ PBDZPIOAJVSYJJ-CHWSQXEVBQ JLEWWMVEZDWKSF-OPNQXQEIBH JLEWWMVEZDWKSF-OPNQXQEIBH IULWLDNNGGDOLC-QEHWCHDUBC WHNPOQXWAMXPTA-UHFFFAOYAG