Deconstructing cytisine: The syntheses of (±)-cyfusine and (±)-cyclopropylcyfusine, fused ring analogs of cytisine

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 7; pp. 2316 - 2319
• Main Authors: Yohannes, Daniel, Procko, Kristen, Lebel, Lorraine A., Fox, Carol B., O’Neill, Brian T.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2008; Elsevier
• Subjects: (±)-Cyfusine; (±)-Cytisine; (α4) 2(β2) 3; [3 + 2] cycloaddition; Alkaloids - chemistry; Azocines - chemistry; Biological and medical sciences; Cholinergic system; Cyclization; Cyclopropanation; Cyclopropanes - chemistry; Cyfusine; Cytisine; formula omitted; Heterocyclic Compounds, 3-Ring - chemistry; Medical sciences; Models, Chemical; nAChR; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nicotinic acetylcholine receptor; Pharmacology. Drug treatments; Pyridone; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - metabolism; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - metabolism; Quinolizines - chemistry; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - metabolism; Stereoisomerism; Structure-Activity Relationship; Cyclopropanation; ( α 3 ) 2 ( β 4 ) 3; [3 + 2] cycloaddition; nAChR; Cyfusine; Nicotinic acetylcholine receptor; (α4) 2(β2) 3; Cytisine; (±)-Cytisine; Pyridone; (±)-Cyfusine; (α3)2(β4)3; Cyclopropanation: (±)-Cytisine; Lactam; In vitro; Biological activity; Racemic; Alkaloid; Cycloaddition; Cholinergic receptor; (α4)2(β2)3; Chemical synthesis; Nicotinic receptor
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.02.078

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. 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.