Lee, Jung. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200900865.
Another month, another amphidinolide – but we’re getting pretty close to the end of the alphabet now. Actually, I’m (as ever) being rather over-the-top – we’ve not actually covered that many, but X & Y (as well as being an affront to my ears) were blogged in 2006, where the focus was on the THF synthesis. This is the case again with Eun Lee’s synthesis, which almost disregards the polyketide-style sections.
The key to his synthesis of the THF is a bit of new methodology, capable of creating two new stereocenters in the process. The key elements are the two existing stereocenters, and the 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 substrate chucked into the radical pot. 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 depending on the case. 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’, and this is perhaps where the methodology wins it’s ‘keeper’ status. A simple treatment with TFAA and a bit of base resulted in a Pummerer rearrangement, and generation of the aldehyde in cracking 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 exactly wax lyrical 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 metathesis to bolt-on the rest of the top. A pair of esterifications (using acid-chloride chemistry) builds up the bottom-half, with RCM to complete the ring.
This paper isn’t really about the total-synthesis, but the methodology, and it’s pretty neat; the succinctness of the rest of the synthesis is testament to Lee’s retrosynthetic skill.