Totally Synthetic by Paul H. Docherty, 10 May 2009
Total Synthesis of Amphidinolide X
J. H. Jung, E. Lee, Angew. Chem. Int. Ed. 2009, 48, 5698-5700.
There are so many amphidinolides, that we’re getting pretty close to the end of the alphabet now. We have not covered that many, for example Fürstner's syntheses of X & Y were described in 2006, where the focus was on tetrahydrofuran (THF) synthesis. This is the case again with Eun Lee’s synthesis, which almost disregards the polyketide sections.
The key to his synthesis of the THF is a new methodology, capable of creating two new stereocenters in the process. The key elements are the two existing stereocenters, and an olefin, which combine to impart asymmetric control. The actual degree of control stemming from these elements is considered thoroughly in the paper, with a large array of possible substrates that undergo radical reactions. The 5-exo radical cyclisation seems to be stereospecific, and to quote Lee, ‘the structures of the major products may be predicted on the basis of the double-bond stereochemistry and the sulfoxide configuration.’ As there are two control elements, there are a pair of matched and unmatched possibilities, with the distereomeric ration ranging from 15:1 to 3:1. Interestingly, the reactions of the less-substituted secondary alcohol starting materials is stereochemically unrelated…
After an interesting protection using a p-nitro benzyl group, it was time to remove the auxilliary group: a simple treatment with TFAA and a base resulted in a Pummerer rearrangement and generated the aldehyde in high yield. A nice result! Going back to the chiral sulfoxide used in this chemistry, it should actually be fairly easy to make using Kagan’s approach. This uses almost identical conditions to the Sharpless asymmetric epoxidation to allow asymmetric oxidation of a sulfide, and normally works really well if the two sides of the prochiral sulfide are sufficiently differentiated as in the CBS reduction.
As I said in the intro, Lee doesn’t go into detail about the rest of the synthesis, aware that the fragments required for the rest of the macrocycle are well documented. That leaves us with the strategy for coupling, which works well for them, starting with a pair of olefinations to homologate the aldehyde, and then cross metathesis. A pair of acylations builds up the bottom-half, with RCM to complete the ring.