Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 8 August 2006

Total Synthesis of Rasfonin


R. K. Boeckman, Jr., J. E. Pero, D. J. Boehmler, J. Am. Chem. Soc. 2006, 128, 11032-11033.

DOI: 10.1021/ja063532+

A masterclass in the use of chiral auxiliaries, Boeckman et al. have used this total synthesis to showcase the power of the camphor lactam chiral auxiliary. A potent target, rasfonin is cytotoxic to cells dependent upon the Ras protein, a known oncogene. However, other cell lines are unaffected by rasfonin at ten times the IC50. So certainly a valid target. As inferred above, their approach utilises campor lactam chiral auxiliaries rather heavily, and start with an interesting elaboration of the parent camphor:

I certainly hadn’t seen (triphenylphosphoranylidene)ketene before, and must admit that I’m surprised it’s isolable. The authors reference a Org. Syn. paper for the use of the reagent, and Boeckman himself was the "checker", so it’s safe to say he was impressed by it! Simple Wittig olefination was then completed.

A second piece of methodology that impressed me was their vinylogous Mukaiyama aldol addition. Using BF3.OEt2 delivered the desired product in good yield, but in poor diastereoselectivity. They then tried the chiral oxazaborolidines used by Corey for asymmetric Diels-Alder reactions, and got a fantastic level of diastereomeric control after only three runs.

I haven’t gone into their use of the auxiliaries here, mostly because it’s hard to pick a specific example. However, the paper is invaluable as an introduction to the camphor lactam chemistry, as well as a nice total synthesis.