title: Total synthesis and biological evaluation of pacidamycin D and its 3'-hydroxy analogue.
abstract: Full details of the total synthesis of pacidamycin D (4) and its 3'-hydroxy analogue 32 are described. The chemically labile Z-oxyacyl enamide moiety is the most challenging chemical structure found in uridylpeptide natural products. Key elements of our approach to the synthesis of 4 include the efficient and stereocontrolled construction of the Z-oxyvinyl halides 6 and 7 and their copper-catalyzed cross-coupling with the tetrapeptide carboxamide 5, a thermally unstable compound containing a number of potentially reactive functional groups. This synthetic route also allowed us to easily prepare 3'-hydroxy analogue 32. The assemblage by cross-coupling of the Z-oxyvinyl halide 6 and the carboxamide 5 at a late stage of the synthesis provided ready access to a range of uridylpeptide antibiotics and their analogues, despite their inherent labile nature with potential epimerization, simply by altering the tetrapeptide moiety.
authors.affiliation: Shionogi Innovation Center for Drug Discovery, Shionogi & Co., Ltd., Kita-21 Nishi-11, Kita-ku, Sapporo 001-0021, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Okamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakagami
authors.forename: Fei
authors.initials: F
authors.lastname: Feng
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togame
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ichikawa
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D003300:Copper / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D011741:Pyrimidine Nucleosides; C569211:pacidamycin D; D003300:Copper