Concise enantioselective total syntheses of (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine and (+)-norchelidonine by a Pd II-catalyzed ring-opening strategy.
New enantioselective syntheses of the B/C hexahydrobenzo[c]phenanthridine alkaloids (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine, and (+)-norchelidonine are described. Our rapid and convergent route to this class of natural products involved the development and application of a Pd II-catalyzed asymmetric ring-opening reaction of a meso-azabicyclic alkene with an aryl boronic acid as the key step. By screening a variety of functionalized ortho-substituted aryl boronic acids, chiral ligands and reaction conditions we were able to prepare the requisite cis-1-amino-2-aryldihydronaphthalenes in high yield and in up to 90 % ee. Early attempts to complete the synthesis of (+)-homochelidonine using an N-Boc azabicyclic alkene are described in full. The successful route required a protecting group alteration followed by B ring formation and then stereoselective installation of the C-11 syn-hydroxy group by regioselective epoxide ring-opening using a hydride source. Ring-opening of the same epoxide intermediate with water ultimately led to the synthesis of (+)-chelamidine. The same strategy was then used to synthesize the other structurally similar B/C hexahydrobenzo[c]phenanthridine alkaloids, (+)-chelidonine, (+)-chelamidine, and (+)-norchelidonine.
Fleming
Matthew J
MJ
Department of Chemistry, Davenport Chemical Laboratories, University of Toronto, 80 St. George St., Toronto, ON M5S 3H6, Canada.
McManus
Helen A
HA
Rudolph
Alena
A
Chan
Walter H
WH
Ruiz
Jérémy
J
Dockendorff
Chris
C
Lautens
Mark
M
D053119:Benzophenanthridines / Q000138:chemical synthesis* / Q000737:chemistry; D001600:Berberine Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D001897:Boronic Acids / Q000737:chemistry; D002384:Catalysis; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000737:chemistry*; D010165:Palladium / Q000737:chemistry*; D013237:Stereoisomerism
D053119:Benzophenanthridines; D001600:Berberine Alkaloids; D001897:Boronic Acids; D009942:Organometallic Compounds; C528543:chelamine; D010165:Palladium; C062047:chelidonine; C517745:homochelidonine