Totally Synthetic by Paul H. Docherty, 8 November 2006

Total Synthesis of Latrunculin A, B, C, M, S and 16-epi-Latrunculin B

Fürstner

A. Fürstner, D. De Souza, L. Turet, M. D. B. Fenster, L. Parra-Rapado, C. Wirtz, R. Mynott, C. W. Lehmann, Chem. Eur. J. 2006, 13, 115-134.

DOI: 10.1002/chem.200601135

Another interesting macrolide in the bag for the Fürstner group with a bit more alkyne metathesis and iron catalysis. The disconnections are relatively straight-forward, but the implementation rather nice:

As the paper point out, standard RCM tends to give a mixture of predominately trans products, and thus isn’t as useful for the disconnection intended. However, their alkyne metathesis, coupled with a Lindlar hydrogenation gave the desired cis,trans configuration required. Simple esterification then put in the top fragment, leaving construction of the pyran unit. This came from the linear precursor, developed from an aldol reaction (in this case, the titanium enolate); however, the ratio of diastereomers was only 2:1 - rather disappointing. Impressively, though, they were able to improve this via the pyran formation:

So, elimination of two units of water from the hemiketal led to formation of the oxocarbenium cation, probably due to the 1,3-syndiaxial steric repulsion of the hydroxyls. Addition of water again will selectively give the desired diastereomer, as the anomeric effect will dispose the hemiketal into the axial position, and thus the other hydroxyl equitorial.

A nice synthesis, if lacking in new methodology.

Selected Comments