Novel chemistry of 2-azabicyclo[2.2.0]- and [2.1.1]hexanes.

摘要

The syntheses and reactions of variously substituted N-protected-2-azabicyclo[2.2.0]hex-5-enes were the main foci of this thesis. Methods were found to add groups on all the positions except 3-exo.; Synthesis of 2-azabicyclo[2.2.0]hexane analogs of epibatidine utilized the reductive Heck reaction with 2-chloro-5-iodopyridine. Both exo -5 and exo-6 isomers were obtained with random nonreproducible ratios. The exo-5 or exo-6 isomers were converted to either endo-5 or endo-6 isomers in three additional steps in both cases. The N-ethoxycarbonyl group was difficult to remove without opening the azetidine ring. Attempted N-benzyloxycarbonyl deprotection using hydrogenation resulted in loss of the chloro group on the pyridine moiety. But the N-methoxycarbonyl group could be removed using CH ₃Li/LiBr without loss of the chloro group.; N-Ethoxycarbonyl-5-phenyl-2-azabicyclo[2.2.0]hex-5-ene was also prepared by Suzuki coupling. This is an alternate route to 5-aryl-2-azabicyclo[2.2.0]hexanes.; A novel N-protected-3-endo-hydroxymethyl-2-azabicyclo[2.2.0]hex-5-ene was synthesized and it became the key intermediate for the synthesis of ABT-594 analogs. Both 2-azabicyclo[2.2.0]-hexane and hex-5-ene ABT-594 analogs were synthesized by Mitsunobu coupling reactions.; Both analogs of epibatidine and ABT-594 were tested for nicotinic acetylcholine receptor (nAChR) agonist, Muscarinic agonist and anticancer activities. The 3-endo-(6-chloro-3-pyridoxy)methyl-2-azabicyclo[2.2.0]hex-5-ene (303) was active upon the 3-cell line anticancer activity testing; compound 3-endo-(6-chloro-3-pyridoxy)methyl-2-azabicyclo[2.2.0]hexane (304) exhibited antinociceptive activity at 20 mg/kg, i.p., but not at lower doses.; A selective azetidine ring-opening reaction was found with 2-azabicyclo[2.2.0]hexanes. This reaction has the potential for the synthesis of functionalized cyclobutylamines and cyclobutane-nucleotides. Attempts at OsO₄-NMO mediated hydroxylation of 2-azabicyclo[2.2.0]hex-5-enes was unsuccessful.; Novel 3-endo-substituted-2-azabicyclo[2.1.1]hexanes were prepared by a rearrangement reaction of 3-endo-( p-nitrophenylsulfonyloxy)methyl-2-azabicyclo[2.2.0]-hex-5-ene. These may serve as key intermediates for 3,5-methanoprolines, ABT-594 analogs, and multi-functionalized aminoalcohols.; A azetidinyl carboxylic acid was synthesized from N-methoxycarbonyl-3- endo-hydroxymethyl-2-azabicyclo[2.2.0]hexane.