title: Scalable solution-phase synthesis of the biologically active cyclodepsipeptide destruxin E, a potent negative regulator of osteoclast morphology.
abstract: The scalable solution-phase synthesis of the cyclodepsipeptide destruxin E (1) has been achieved. Diastereoselective dihydroxylation of the terminal alkene in a 2-alkoxy-4-pentenoic amide, 7, was successfully accomplished utilizing (DHQD)2PHAL as the chiral ligand, and it was found that the use of the l-proline moiety in the substrate as a chiral auxiliary was essential for the induction of high diastereoselectivity to afford the key compound 4 on a gram scale. MNBA-mediated macrolactonization of 3 was also performed without formation of the dimerized product even under higher-dilution conditions, and it is noteworthy that the internal hydrogen bonds and s-cis configuration of the amide bond between N-methylalanine and N-methylvaline in the cyclization precursor 3 would assist in the macrolactonization to provide the macrolactone 2 without forming a dimerized product. Finally, epoxide formation in the side chain afforded destruxin E (1) on a gram scale in high purity (>98%).
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ishida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Doi
mesh_terms: D003500:Cyclization; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry*; D005656:Fungal Proteins / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D007783:Lactones / Q000737:chemistry*; D015394:Molecular Structure; D010010:Osteoclasts / Q000737:chemistry*; D013237:Stereoisomerism; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: D047630:Depsipeptides; D004852:Epoxy Compounds; D005656:Fungal Proteins; D007783:Lactones; D025262:Vacuolar Proton-Translocating ATPases; C040425:destruxin E