Modular total synthesis of archazolid A and B.
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.
Menche
Dirk
D
Institut für Organische Chemie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg. dirk.menche@oci.uni-heidelberg.de
Hassfeld
Jorma
J
Li
Jun
J
Mayer
Kerstin
K
Rudolph
Sven
S
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
D018942:Macrolides; D013844:Thiazoles; C519727:archazolid A; C519728:archazolid B; D025262:Vacuolar Proton-Translocating ATPases