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Totally Synthetic by Paul H. Docherty, 10 May 2006

Total Synthesis of iso-Epoxy-Amphidinolide N


K. C. Nicolaou, W. E. Brenzovich, P. G. Bulger, T. M. Francis, Org. Biomol. Chem. 2006, 4, 2119-2157.

DOI: 10.1039/b602020h

K. C. Nicolaou, P. G. Bulger, W. E. Brenzovich, Org. Biomol. Chem. 2006, 4, 2158-2183.

DOI: 10.1039/b602021f

Two papers in OBC this week from the Nicolaou labs, concerning the synthesis of the related structures iso-epoxy-amphidinolide N and des-epoxy-caribenolide I. We’ll consider their initial strategy, and a further, more successful attempt.

Their initial synthesis relied upon a late-stage epoxidation, as the allylic epoxide was deemed too sensitive to survive even a standard deprotection. Thus, taking that back to the exocyclic alkene, they were left with a possible enyne metathesis - either ring-closing or in a acyclic cross-metathesis fashion. The other obvious disconnection is the ester, which, again, could be ring-closing in a Yamaguchi sense.

Disconnection of the pyran moiety to a masked 1,3-dihydroxyketone was then proposed, used technology developed by Enders:

They then tried to couple this advanced fragment in a cross-metathesis, but were unable to perform this as either an alkene or enyne metathesis. Thus, they performed the esterifcation mentioned above, and then attempted an enyne RCM, which, unfortunately, again failed.

A second synthesis, aiming at inserting this diene moiety via a either a Sonagashira or Stille coupling also failed. However, much was learnt in these routes, and a total synthesis of the related iso-epoxy-amphidinolide N was successful. In an old-school move, they used a Horner-Wadsworth-Emmons olefination (HWE) to create the enone, which, when methylenated, delivered the troublesome 1,3-diene required.

They then completed a model study to consider methods for selective epoxidation of the 1,3-diene. As both alkenes were allylic, Sharpless epoxidation might be the obvious route, and worked incredibly selectively in their case, specifically a Katsuki-Sharpless epoxidation. They attribute the success of this work to the empirical model described by Sharpless for kinetic resolutions.

Using the similar methodology to their previous paper, the fragment of the two natural products were assembled quickly and successfully, leading to macrolactonisation using the Yamaguchi protocol. However, to achieve this, they first had to saponify the methyl ester added in the HWE. This was done selectively using their own methodology; Me3SnOH. Having completed the ring closure, they then attempted to epoxidise as in their model study. However, none of the desired epoxide was received; other epoxidation methods led to various undesired oxidation products, denying them access to the natural product.

However, completion of the iso-epoxy-amphidinolide has allowed for assignment of previously unknown stereochemistry, and a good lesson in the pitfalls of total synthesis for us!