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Totally Synthetic by Paul H. Docherty, 3 September 2006

Total Synthesis of Leucascandrolide A


Q. Su, L. A. Dakin, J. S. Panek, J. Org. Chem. 2007, 2-24.

DOI: 10.1021/jo0610412

One of the best papers I’ve read in a while, this total synthesis by Panek is full of interesting ideas. At first glance, I was a little disappointed to see them starting with a hydrolytic kinetic resolution; throwing away half of the starting material on the first steps seems like a bad start. However, I quickly realised that they actually use both enantiomerically enriched products, and thus start with a great step.

The real interest starts with their own methodology, using a Lewis acid promoted annulation to produce dihydropyrans:

Functional group conversions led then to an iodide, which was alkylated with the corresponding dithiane, introducing the fatty sidechain. However, removal of the dithane protecting group proved troublesome. N-halosuccinimide reagents, mercury perchlorate and CAN all failed, but they managed to succeed with Dess-Martin periodinane (DMP), in one neat transformation:

Their use of DMP a few steps later to oxidise the freed alcohol to the aldehyde make me think that this may have been discovered by accident - but all the best chemistry is! Formation of the macrocycle proved more difficult, however, as they had great difficulty removing a benzyl protecting group without reducing other functionality. This left them with the difficult path of restarting the synthesis from an early stage. However, they have had the opportunity to perform their novel cyclisation on two more systems, again to good results.

A great paper, with good measures of success and problems, this is well worth a read.

Selected Comments

4 September, 2006 at 23:45, secret milkshake says:
The C1-C8 fragment (7) can be made from the Lipitor protected sidechain alcohol in two steps… We have a kilo of unused stuff on the shelf.
The Jacobsen asym resolution is exceptionaly nice and easy method, especialy suitable for scale-up.
I am realy surprised they could do the homologation on the 3,4-epoxybutyrate with lithiated tBu-acetate. This epoxide ester is infamous for its ease of elimination to hydroxycrotonate.