An efficient total synthesis of the antiproliferative macrolide and cell migration inhibitor lactidomycin relying on ring-closing alkyne metathesis was published recently by the Fürstner group. Lactidomycin contains a very strained 12-membered lactone which incorporates seven sp2-carbon atoms. If that’s not enough, the authors opted for an intermediate which is even more strained than the final product and contains an alkyne instead of olefin. They put a lot of trust in the alkyne metathesis catalyst developed in the Fürstner lab, but the catalyst passed the test: the 12-membered cycle was formed in 95% yield on small scale and 84% on 1.2g scale1. It’s noteworthy, that the ring closing metathesis reaction with the second generation Grubbs catalyst used to prepare another member of the same family of macrolides by Danishefsky’s group delivered only 21% of the desired E-isomer along with 36% of the unwanted Z-isomer2. In contrast, the alkyne can be converted selectively and in good yield into the desired E-olefin by trans-hydrosilylation /protodesilylation sequence.
The Mo-catalyst used in this study is one of a number of new silyloxy-based metathesis catalysts developed recently3. These new catalyst contain triphenylsilanoate ligands and have excellent reactivity and functional group tolerance. Catalyst 1 is somewhat air and moisture-sensitive, but has excellent reactivity and can be used in low loadings. Precatalyst 2 can be handled under air, but has to be activated with MnCl2. The nitride catalyst 3 needs to be converted into the reactive alkylidyne in situ under heating, but is totally air stable. All three catalysts behave similarly with a diverse set of substrates. The nitride 3 requires larger loadings, higher reaction temperature and longer reaction times than the alkylidynes 1 and 2. The compatibility of the catalysts with various functional groups is outstanding. Esters, ethers, thioethers, sulfonates, amides, carbamates, ketones, acetals, and nitro compounds are generally well tolerated. The only problematic compounds were aldehydes, which quickly destroyed the catalyst. These new, easier to make and more stable catalysts should make the use of alkyne metathesis more common and wide spread.
1 Micoine, K. and A. Fürstner, J. Am. Chem. Soc. 2010, ASAP.
2 Krauss, I. J., Mandal, M. and Danishefsky, S. J., Angew. Chem. Int. Ed. 2007, 46, 5576.
3 Hepperkausen, J., Stade, R., Goddard, R. and A. Fürstner, J. Am. Chem. Soc. 2010, 132, 11045.