Total Synthesis of Phorboxazole A via de Novo Oxazole Formation: Convergent Total Synthesis
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- 作者：Bo Wang ; T. Matthew Hansen ; Lynn Weyer ; Dimao Wu ; Ting Wang ; Mathias Christmann ; Yingtao Lu ; Lu Ying ; Mary M. Engler ; Russell D. Cink ; Chi-Sing Lee ; Feryan Ahmed ; Craig J. Forsyth
- 刊名：Journal of the American Chemical Society
- 出版年：2011
- 出版时间：February 9, 2011
- 年：2011
- 卷：133
- 期：5
- 页码：1506-1516
- 全文大小：1266K
- 年卷期：v.133,no.5(February 9, 2011)
- ISSN：1520-5126
文摘
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鈭扖17 and C18鈭扖30 building blocks via formation of the C16鈭扖18 oxazole, followed by macrolide ring closure involving an intramolecular Still鈭扜enarri olefination at C2鈭扖3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product鈥檚 (2Z)-acrylate with remarkable geometrical selectivity. The C31鈭扖46 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鈥檚 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鈭抍yclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3鈭扖17 and C18鈭扖30 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.