7-Substituted 2-Azabicyclo[2.2.1]heptanes as Key Intermediates for the Synthesis of Novel Epibatidine Analogues; Synthesis of syn- and anti-Isoepiboxidine

Abstract

Neighboring group participation by the 2-nitrogen in anti-7-bromo-2-benzyl-2-azabicyclo[2.2.1]heptane allows ready nucleophilic substitution at the 7-position by C, N, O, and halogen nucleophiles and opens the way to a range of novel 7-substituted 2-azabicyclo[2.2.1]heptanes. Conversion of an anti-7-ethoxycarbonyl group into a methylisoxazole ring provides anti-isoepiboxidine, a conversion that is possible even without protection of the secondary bicyclic nitrogen. Successful base-induced epimerization alpha to the carbonyl of the anti-7-ethoxycarbonyl derivative gives the syn-stereoisomer and hence syn-isoepiboxidine.

Biogenic Nano-CuO-Catalyzed Facile C–N Cross-Coupling Reactions: Scope and Mechanism

“…The reaction is found to be very selective toward the iodo functionality, keeping the bromo functional group unaffected in the case of bromoiodobenzene ( 5d , 5i, Table ). Vince lactam units are found as the active scaffold in pharmaceuticals, , and they are also used as building blocks for the synthesis of several biologically important molecules. − By using this protocol, we have synthesized a number of diversely substituted aryl vince lactums with bridged amide and aryl halides under the standardized conditions ( 5i , 5j , Table ).…”

2-Azanorbornane – a versatile chiral aza-Diels–Alder cycloadduct: preparation, applications in stereoselective synthesis and biological activity

“…17), the alkaloid isolated from the skin of the Equadorian poison tree frog, Epipedobates Tricolor. 53,[149][150][151][152][153] This compound exhibits high analgesic activity as an agonist at the nicotinic acetylcholine receptors of the nervous system; however, its therapeutic application is hindered by the extreme toxicity. This fact stimulated work on analogues and isomers devoid of drawbacks of the original alkaloid while preserving its antinociceptive activity.…”

“…53,[149][150][151] Also 7-substituted isomers, syn-and anti-isoepibatidine (131) in which the positions of the heterocycle and the amine were reversed as compared to epibatidine itself, and their methyl- isoaxolyl analogs (isoepiboxidines 132) were obtained. [152][153][154] Studies on structure-activity relationships showed that compounds endo-53, endo-130, syn-131 and syn-132 with similar N-N distances to 129 (4.3-4.8 Å) retain their high affinity at nicotinic receptors, while exo-and anti-derivatives were inactive. 151,154 However, the new compounds did not exhibit the desired receptor subtype selectivity which is regarded as a key factor for lower toxicity and fewer undesirable side effects.…”

Bicyclic β-amino acids

“…As it was mentioned in the first paragraph of this section, apart from derivatives of 7-azabicyclo[2.2.1]heptane-2-carboxylic acids (267a,b), derivatives of isomeric β-amino acids 268a and 268b were described in the literature. 151 Their synthesis commenced from azanorbornene 335, which reacted with bromine to provide tricyclic azidirinium salt 336 (Scheme 82) Reduction of 336 gave 6-bromo derivative 337, which reacted with KCN with retention of configuration to give amino nitrile 338. After hydrolysis and esterification, derivative 339a of the amino acid 268a was obtained.…”