Catalysis-based and protecting-group-free total syntheses of the marine oxylipins hybridalactone and the ecklonialactones A, B, and C

Volker Hickmann, Azusa Kondoh, Barbara Gabor, Manuel Alcarazo, Alois Fürstner

Research output: Contribution to journalArticlepeer-review

101 Citations (Scopus)

Abstract

Concise and protecting-group-free total syntheses of the marine oxylipins hybridalactone (1) and three members of the ecklonialactone family (2-4) were developed. They deliver these targets in optically pure form in 14 or 13 steps, respectively, in the longest linear sequence; five of these steps are metal-catalyzed and four others are metal-mediated. The route to either 1 or 2-4 diverges from the common building block 22, which is accessible in 7 steps from 2[5H]furanone by recourse to a rhodium-catalyzed asymmetric 1,4-addition reaction controlled by the carvone-derived diene ligand 35 and a ring-closing alkene metathesis (RCM) catalyzed by the ruthenium indenylidene complex 17 as the key operations. Alternatively, 22 can be made in 10 steps from furfural via a diastereoselective three-component coupling process. The further elaboration of 22 into hybridalactone as the structurally most complex target with seven contiguous chiral centers was based upon a sequence of cyclopropanation followed by a vanadium-catalyzed epoxidation, both of which were directed by the same free hydroxy group at C15. The macrocyclic scaffold was annulated to the headgroup by means of a ring-closing alkyne metathesis reaction (RCAM). In response to the unusually high propensity of the oxirane of the targeted oxylipins for ring opening, this transformation had to be performed with complexes of the type [(Ar 3SiO) 4Mo≡CPh] [K·OEt 2] (43), which represent a new generation of exceedingly tolerant yet remarkably efficient catalysts. Their ancillary triarylsilanolate ligands temper the Lewis acidity of the molybdenum center but are not sufficiently nucleophilic to engage in the opening of the fragile epoxide ring. A final semireduction of the cycloalkyne formed in the RCAM step to the required (Z)-alkene completed the total synthesis of (-)-1. The fact that the route from the common fragment 22 to the ecklonialactones could follow a similar logic showcased the flexibility inherent to the chosen approach.

Original languageEnglish
Pages (from-to)13471-13480
Number of pages10
JournalJournal of the American Chemical Society
Volume133
Issue number34
DOIs
Publication statusPublished - 2011 Aug 31
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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