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Monday, June 22, 2009
Douglass F. Taber
University of Delaware

Total Synthesis by Alkene Metathesis: Amphidinolide X (Urpí /Vilarrasa), Dactylolide (Jennings), Cytotrienin A (Hayashi), Lepadin B (Charette), Blumiolide C (Altmann)

To assemble the framework of the cytotoxic macrolide Amphidinolide X (3), Fèlix Urpí and Jaume Vilarrasa of the Universitat de Barcelona devised (Org. Lett. 2008, 10, 5191. ) the ring-closing metathesis of the alkenyl silane 1. No Ru catalyst was effective, but the Schrock Mo catalyst worked well.

In the course of a synthesis of (-)-Dactylolide (6), Michael P. Jennings of the University of Alabama offered (J. Org. Chem. 2008, 73, 5965. ) a timely reminder of the particular reactivity of allylic alcohols in ring-closing metathesis. The cyclization of 4 to 5 proceeded smoothly, but attempted ring closing of the corresponding bis silyl ether failed.

Polyenes such as (+)-Cytotrienin A (8) are notoriously unstable. It is remarkable that Yujiro Hayashi of the Tokyo University of Science could (Angew. Chem. Int. Ed. 2008, 47, 6657. ) assemble the triene of 8 by the ring-closing metathesis of the highly functionalized precursor 7.

Bicyclo [2.2.2] structures such as 9 are readily available by the addition of, in this case, methyl acrylate to an enantiomerically-pure 2-methylated dihydropyridine. André B. Charette of the Université de Montréal found (J. Am. Chem. Soc. 2008, 130, 13873. ) that 9 responded well to ring-opening/ring-closing metathesis, to give the octahydroquinoline 10. Functional group manipulation converted 10 into the Clavelina alkaloid (+)-Lepadin B (11).

The construction of trisubstituted alkenes by ring-closing metathesis can be difficult, and medium rings with their transannular strain are notoriously challenging to form. Nevertheless, Karl-Heinz Altmann of the ETH Zürich was able (Angew. Chem. Int. Ed. 2008, 47, 10081. ), using the H2 catalyst, to cyclize 12 to cyclononene 13, the precursor to the Xenia lactone (+)-Blumiolide C (14).

It is noteworthy that these five syntheses used four different metathesis catalysts in the key alkene forming step. For the cyclization of 7, the use of the Grubbs first generation catalyst G1, that couples terminal alkenes but tends not to interact with internal alkenes, was probably critical to success. The Hoveyda catalyst H2 is more expensive than the Grubbs second generation catalyst G2, but can often be effective in applications in which G2 is sluggish. The Schrock Mo catalyst is less user friendly than the (relatively) air and moisture stable Ru catalysts, but is very reactive.

D. F. Taber, Org. Chem. Highlights 2009, June 22.
URL: http://www.organic-chemistry.org/Highlights/2009/22June.shtm