title: Modular total synthesis of archazolid A and B.
abstract: A modular total synthesis of the potent V-ATPase inhibitors archazolid A and B is reported. The convergent preparation was accomplished by late-stage diversification of joint intermediates. Key synthetic steps involve asymmetric boron-mediated aldol reactions, two consecutive Still-Gennari olefinations to set the characteristic (Z,Z)-diene system, a Brown crotyboration, and a diastereoselective aldol condensation of highly elaborate intermediates. For macrocyclization, both an HWE reaction and a Heck coupling were successfully employed to close the 24-membered macrolactone. During the synthetic campaign, a generally useful protocol for an E-selective Heck reaction of nonactivated alkenes and a method for the direct nucleophilic displacement of the Abiko-Masamune auxiliary with sterically hindered nucleophiles were developed. The expedient and flexible strategy will enable further SAR studies of the archazolids and more detailed evaluations of target-inhibitor interactions.
authors.affiliation: Institut für Organische Chemie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg. dirk.menche@oci.uni-heidelberg.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Menche
authors.forename: Jorma
authors.initials: J
authors.lastname: Hassfeld
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Kerstin
authors.initials: K
authors.lastname: Mayer
authors.forename: Sven
authors.initials: S
authors.lastname: Rudolph
mesh_terms: D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors
chemical_list: D018942:Macrolides; D013844:Thiazoles; C519727:archazolid A; C519728:archazolid B; D025262:Vacuolar Proton-Translocating ATPases