Deconstructing cytisine: The syntheses of (+/-)-cyfusine and (+/-)-cyclopropylcyfusine, fused ring analogs of cytisine.
A novel fused tricyclic analog (11) of cytisine has been prepared (coined 'cyfusine') and determined to have high affinity at neuronal nicotinic acetylcholine receptors. A [3+2] cycloaddition protocol permitted entry into a 3,4-differentially difunctionalized dihydropyrrole (7). The penultimate cyclization was accomplished using the modified Van Tamelen conditions developed in our earlier synthesis of (+/-)-cytisine. Sequential ring-forming reactions ([3+2] cycloaddition/cyclopropanation/pyridone cyclization) gives a unique cyclopropyl analog (16) possessing a skeleton isoatomic with that of cytisine.
Yohannes
Daniel
D
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. daniel.yohannes@targacept.com
Procko
Kristen
K
Lebel
Lorraine A
LA
Fox
Carol B
CB
O'Neill
Brian T
BT
D000470:Alkaloids / Q000737:chemistry*; D001392:Azocines / Q000737:chemistry; D003500:Cyclization; D003521:Cyclopropanes / Q000737:chemistry; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry*; D008956:Models, Chemical; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011807:Quinolizines / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D003521:Cyclopropanes; D006575:Heterocyclic Compounds, 3-Ring; D011728:Pyridones; D011758:Pyrroles; D011807:Quinolizines; D011978:Receptors, Nicotinic; C013231:pyrroline; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C030797:cyclopropane