title: Total synthesis of phorboxazole A via de novo oxazole formation: convergent total synthesis.
abstract: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: T Matthew
authors.initials: TM
authors.lastname: Hansen
authors.forename: Lynn
authors.initials: L
authors.lastname: Weyer
authors.forename: Dimao
authors.initials: D
authors.lastname: Wu
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Mathias
authors.initials: M
authors.lastname: Christmann
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Lu
authors.forename: Lu
authors.initials: L
authors.lastname: Ying
authors.forename: Mary M
authors.initials: MM
authors.lastname: Engler
authors.forename: Russell D
authors.initials: RD
authors.lastname: Cink
authors.forename: Chi-Sing
authors.initials: CS
authors.lastname: Lee
authors.forename: Feryan
authors.initials: F
authors.lastname: Ahmed
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Forsyth
mesh_terms: D000179:Acrylates / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry*; D018942:Macrolides / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D000179:Acrylates; D001688:Biological Products; D006576:Heterocyclic Compounds, 4 or More Rings; D018942:Macrolides; D010080:Oxazoles; C408887:phorboxazole A; C036658:acrylic acid