Isoquinuclidine analogs

HERG ("Human-ether-a-go-go related gene) at low concentrations. Conformationally constrained isoquinuclidine analogs of BRL-32872 were also prepared to study the effects of molecular flexibility towards class III and class IV anti-arrhythmic properties [48]. Both standard microelectrode and patch clamp assays indicated that while both epimers displayed a pharmacological profile similar to BRL-32872, epimer 52b was more effective than 52a. 

In a manner similar to N-substituted 2-pyridones, 2-methylene analogs such as 74, were found to react stereoselectively with various dienophiles to give endo adducts 75 [79,80]. This approach allowed for the synthesis of isoquinuclidines having a carbon side chain at the 3-position ... 

Horii and co-workers discovered that the aminolactone 97 (Scheme 15) upon standing at room temperature or upon distillation produced the isoquinuclidine derivative 105 in good yield (Scheme 16) (40). This interesting isomerization has its counterpart in the degradative chemistry of securinine (Section II, A, 3) but requires milder conditions. The structure of 105 rests mainly on this securinine analogy and on spectral evidence. The presence of an a,j8-unsaturated y-lactone was indicated by IR and NMR spectroscopy. The absence of IR absorption due to NH and the inability to obtain an X-acetyl derivative showed the tertiary nature of the nitrogen. Furthermore, the presence in the... 

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