Total synthesis of epohelmin B and its analogues.
A concise synthesis of the pyrrolizidine alkaloid epohelmin B (1) and a series of analogues is described. The key steps en route to this lanosterol synthase (oxidosqualene cyclase) inhibitor comprise a highly practical "azonia-Cope rearrangement", which sets the chiral amine center with excellent optical purity, a ring-closing metathesis (RCM) reaction catalyzed by a readily prepared and now also commercially available ruthenium-indenylidene complex, a manganese-catalyzed epoxidation of the resulting eight-membered cycloalkene derivative, and a nosyl-deprotection/transannular-epoxide-opening cascade to forge the pyrrolizidine core. Digression from the route leading to the natural product in the final stages allowed for the preparation of several "epohelmin-like" compounds with modified side chains, which is necessary for investigations into a possible functional relationship with other known lanosterol synthase inhibitors.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Korte
Alexander
A
D001577:Benzophenones / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004852:Epoxy Compounds / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism
D001577:Benzophenones; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004852:Epoxy Compounds; C494515:epohelmin B; C105726:Ro 48-8071