Pergamon 0040-4039(95)00681-8 Tetrahedron Letters, Vol. 36, No. 23, pp. 4063-4064, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00 Thermal Rearrangement of Enantioenriched ¢t-Hydroxy Imines -II. Formal Synthesis of (-)-Perhydrohistrionicotoxin. Philippe Compain, Jacques Gor6 and Jean-Michel Vat~le* Laboratoire de Chimie Organique I, associd au CNRS, Universit~ Claude Bernard CPE-Lyon, 43 Bd. du 11 Novembre 1918, 69622 Villeurbanne, France. Abstract : Synthesis of(+)-l-benzyl-l-azaspiro[5.5]undecan-7-one 6 from ct-ketol 1,via a 1,2-suprafacial chirality transfer, is described. In the preceding paper l, we have shown that thermal rearrangement of enantioenriched ct-allyl and a- trimethylsilylpropargyl c~-hydroxy imines proceeded with a complete 1,2-transfer of chirality. However, it still remained to determine the sense of chirality of the newly created stereogenic center formed in the transposition. In this communication, we answer unambiguously this question via a correlative asymmetric synthesis involving an iminium ion-vinylsilane cyclization as a key step. Moreover, 1-benzyl-1-azaspiro[5.5]undecan-7- one 62,3 implicated in the correlation is a precursor of (-)-perhydrohistrionicotoxin 84 obtained via its depentyl derivative 7, a significant neurophysiological tool to study the mechanism of action of cholinergic agonists in the neuromuscular system5. Firstly, enantioenriched ct-ketol 1 (>96% ee), obtained as described in the preceding paper, was converted to the N-benzyl imine 26 which was in turn heated at diglyme reflux for 2h to provide a-amino ketone 3 in 84% yield [ [a]D-86 (c 1.93, CHCI3)] (Scheme 1). O Ph~'N Ph/XN- ~ "- ~,..OH.~ _ SiMe 3 BnNHx Toluene e~.OH1~ SiMe3 A, diglyme, 2 h H ~ O [.31 - U - v 1 2 3 Scheme 1 SiMe3 As a prelude to cyclization, semi-hydrogenation of 3 was performed in the presence of Pd/BaSO4 and quinoline to give stereochemically pure Z-vinylsilane 47 [COD-54 (c2.27,CHC13) in 67% yield (Scheme 2). Then, cyclization8 was efficiently accomplished by treatment of 4 with an excess of paraformaldehyde at 70°C in acetonitrile in the presence of 1 equiv, of camphorsulfonic acid to afford the spirotetrahydropyridine 59 in 73% yield [ [Ct]D +11 (c 1.88, CHCI3)]. Finally, hydrogenation of the double bond of 5 was sucaessfully realized, without affecting the N-benzyl group, in the presence of Adams' catalyst to provide (+)-6 in 54% yield 4063