Asymmetric total synthesis of (+)-cannabisativine.
The asymmetric total synthesis of natural (+)-cannabisativine 1 was completed in 19 steps and 7% overall yield. The key synthetic intermediate 29 was prepared with a high degree of stereocontrol in 12 steps starting from chiral 1-acylpyridinium salt 10. Addition of zinc enolate 11 to pyridinium salt 10 furnished dihydropyridone 12 containing two contiguous stereocenters of the correct absolute configuration. Luche reduction of ketone 16 afforded diol 17 in high yield (96%) and excellent diastereoselectivity. The Mukaiyama-Michael reaction of pyridones 27a/b with O-silyl ketene acetal 32 gave phenyl selenyl ketones 33a/b with complete stereoselectivity. Elimination of cis-beta-hydroxyselenides 34 and 35 effected the regiocontrolled preparation of tetrahydropyridine derivative 29. Several approaches to the macrocyclic ring closure of the 13-membered ring were investigated, ultimately leading to the completion of an asymmetric synthesis of the target compound with a high degree of stereocontrol.
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204, USA.
Jeffrey T
JT
Kuethe
Daniel L
DL
Comins
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D002186:Cannabinoids / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009942:Organometallic Compounds; D011726:Pyridinium Compounds; D013237:Stereoisomerism
D000470:Alkaloids; D002186:Cannabinoids; D009942:Organometallic Compounds; D011726:Pyridinium Compounds; C012801:cannabisativine