Stereocontrolled synthesis of functionalized 1-azaspirans : Efficient synthesis of perhydrohistrionicotoxin

A formal total synthesis of perhydrohistrionicotoxin (H₁₂-HTX) is described based on a stereocontrolled α-acyliminium ion-olefin cyclisation. In the key step of the synthesis three asymmetric C atoms (C₆ C₇ and C₈) are introduced in a single operation leading to the formation of the spiro formate ester 15. Compound 15 is converted to the spirothiolactam alcohol 17, a known precursor of H₁₂-HTX.The versatility of the synthetic approach is further demonstrated by the stereocontrolled syntheses of other functionalized 1-azaspirans, viz the 6-Endo-Trig products 20 and 24 and the 5-Exo-Trig products 26 and 28. The formation of the latter two compounds is remarkable with respect to the mechanism.¹³C NMR data of a series of 1-azaspirans are provided, which inter alia show the existence of a conformational equilibrium in 1-azaspiro alcohol 16,Mass spectral criteria are used for assignment 5-Exo-or 6-Endo-cyclisation products.