28. Total Synthesis of Phorboxazole A via de Novo Oxazole Formation: Convergent Total Synthesis

B. Wang, T. M. Hansen, L. Weyer, D. Wu, T. Wang, M. Christmann, Y. Lu, L. Ying, M. M. Engler, R. D. Cink, C.-S. Lee, F. Ahmed, C. J. Forsyth

The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3−C17 and C18−C30 building blocks via formation of the C16−C18 oxazole, followed by macrolide ring closure involving an intramolecular Still−Genarri olefination at C2−C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product’s (2Z)-acrylate with remarkable geometrical selectivity. The C31−C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural product’s oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation−cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3−C17 and C18−C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.

Title28. Total Synthesis of Phorboxazole A via de Novo Oxazole Formation: Convergent Total Synthesis
AuthorB. Wang, T. M. Hansen, L. Weyer, D. Wu, T. Wang, M. Christmann, Y. Lu, L. Ying, M. M. Engler, R. D. Cink, C.-S. Lee, F. Ahmed, C. J. Forsyth
IdentifierDOI: 10.1021/ja1089099
Source(s)
CitationJ. Am. Chem. Soc. 2011, 133, 1506-1516