title: A practical total synthesis of hapalosin, a 12-membered cyclic depsipeptide with multidrug resistance-reversing activity, by employing improved segment coupling and macrolactonization.
abstract: A practical total synthesis of hapalosin, a compound with multidrug resistance-reversing activity, has been carried out using an unprecedented macrolactonization strategy. One of the features of the new approach is the straightforward and fully stereocontrolled access to the key gamma-amino beta-hydroxy carboxylic acid subunit via an efficient acetate aldol addition reaction with N-methyl alpha-aminoaldehydes, which relies on a camphor-derived chiral lithium acetate enolate reagent. The scope of this aldol reaction is investigated and its potential application to the synthesis of other structurally related, biologically relevant compounds illustrated. Remarkably, the chiral tether in the resulting gamma-amino aldol adducts sterically protect the carbonyl group, thus avoiding intramolecular cyclization during the amino group deprotection and the subsequent segment coupling event. After successful segment coupling and smooth, clean release of the chiral auxiliary, a new macrolactonization protocol, based on the principle of double activation of both reactive sites, is applied, which leads to the 12-membered macrolactone hapalosin in unprecedented chemical efficiency.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, Apdo. 1072, 20080 San Sebastián, Spain.
authors.forename: Claudio
authors.initials: C
authors.lastname: Palomo
authors.forename: Mikel
authors.initials: M
authors.lastname: Oiarbide
authors.forename: Jesús M
authors.initials: JM
authors.lastname: García
authors.forename: Alberto
authors.initials: A
authors.lastname: González
authors.forename: Raquel
authors.initials: R
authors.lastname: Pazos
authors.forename: José M
authors.initials: JM
authors.lastname: Odriozola
authors.forename: Patricia
authors.initials: P
authors.lastname: Bañuelos
authors.forename: Mónica
authors.initials: M
authors.lastname: Tello
authors.forename: Anthony
authors.initials: A
authors.lastname: Linden
mesh_terms: D047630:Depsipeptides; D018432:Drug Resistance, Multiple; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis
chemical_list: D047630:Depsipeptides; D007769:Lactams; D007783:Lactones; D010456:Peptides, Cyclic; C111358:hapalosin