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Totally Synthetic by Paul H. Docherty, 6 December 2006

Total Synthesis of Vigulariol


J. S. Clark, S. T. Hayes, C. Wilson, L. Gobbi, Angew. Chem. Int. Ed. 2007, 46, 437-440.

DOI: 10.1002/anie.200603880

Another medium-ring ether synthesis, but using completely different methodology to last months excellent synthesis by Kim. The paper by Steve Clark is a great read, so on with the synthesis (no retroanalysis; you’ll see why…).

To build up some functionality for their crucial rearrangement, they used a great Sm mediated reductive cyclisation, starting with the acyclic precursor. This work was apparently developed by Nakata a few years back, and gives the resulting pyran in great yield and diastereoselectivity. However, I can’t help thinking that the enantiomerically pure starting materials (SM) would generate the corresponding high e.e. product… and the authors state that Williams has made that SM…

Anyway, with the product quickly transformed to the above diazo compound in gram quantities, they were set for the exciting [2,3]-sigmatropic rearrangment; look at that yield! I’m yet again surprised at the trans product, but they were able to convert the ~20% or so of that to the desired cis material in a useful yield, completing that funky nine-member ring. With two rings in the bag, they pushed on and finished the next in only four steps:

They deprotonated the ketone in a regioselective manner, and trapped with triflate to give them a coupling partner for a Stille coupling. This then gave them a diene to do a Diels-Alder with MVK, resulting in a 2:1 mixture of exo and endo diastereoisomers… which they epimerised with potassium carbonate to give them only the desired exo adduct. 58% over four steps - nice work!!

They then only required a few relatively simple steps to generate the precursor for the final cyclisation and step:

A deceptively simple piece of chemistry, well conceived, to generate a complex product in relative ease; my definition of elegance in total synthesis. And that sums up this concise synthesis effort and great read.