Concise Total Syntheses of Amphidinolides C and F. Issue 6 (17th December 2014)

• Record Type: Journal Article
• Authors: Valot, Gaëlle; Mailhol, Damien; Regens, Christopher S.; O'Malley, Daniel P.; Godineau, Edouard; Takikawa, Hiroshi; Philipps, Petra; Fürstner, Alois
• Is Part Of: Chemistry. Volume 21:Issue 6(2015)
• Page Start: 2398
• Page End: 2408
• Publication Date: 2014-12-17
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201405790
• Languages: English
• ISSNs: 0947-6539

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>The marine natural products amphidinolide C (<bold>1</bold>) and F (<bold>4</bold>) differ in their side chains but share a common macrolide core with a signature 1, 4‐diketone substructure. This particular motif inspired a synthesis plan predicating a late‐stage formation of this non‐consonant ("umpoled") pattern by a platinum‐catalyzed transannular hydroalkoxylation of a cycloalkyne precursor. This key intermediate was assembled from three building blocks (<bold>29</bold>, <bold>41</bold> and <bold>47</bold> (or <bold>65</bold>)) by Yamaguchi esterification, Stille cross‐coupling and a macrocyclization by ring‐closing alkyne metathesis (RCAM). This approach illustrates the exquisite alkynophilicity of the catalysts chosen for the RCAM and alkyne hydroalkoxylation steps, which activate triple bonds with remarkable ease but left up to five other π‐systems in the respective substrates intact. Interestingly, the inverse chemoselectivity pattern was exploited for the preparation of the tetrahydrofuran building blocks <bold>47</bold> and <bold>65</bold> carrying the different side chains of the two target macrolides. These fragments derive from a common aldehyde precursor <bold>46</bold> formed by an exquisitely alkene‐selective cobalt‐catalyzed oxidative cyclization of the diunsaturated alcohol <bold>44</bold>, which left an adjacent acetylene group untouched. The northern sector <bold>29</bold> was prepared by a two‐directional Marshall propargylation strategy, whereas the highly adorned acid subunit <bold>41</bold> derives from <sc>D</sc>‐glutamic acid by an intramolecular oxa‐Michael addition and a proline‐mediated hydroxyacetone aldol reaction as the key steps; the necessary Me<sub>3</sub>Sn‐group on the terminus of <bold>41</bold> for use in the Stille coupling was installed via enol triflate <bold>39</bold>, which was obtained by selective deprotonation/triflation of the ketone site of the precursor <bold>38</bold> without competing enolization of the ester also present in this particular substrate.</p> </abstract>