CYCLOADDITION REACTION OF MESOIONIC BETAINES AS AN APPROACH TOWARD TRIALKYLINDOLINE ALKALOIDS

Intramolecular 1,4-dipolar cycloaddition of an anhydro-4-hydroxy-2-oxo -1,3-thiazium hydroxide across a tethered indole pi-bond has been used for the construction of the pentacyclic skeleton of epi-16,17-dihydro eburnamenine. The reaction of 3-ethyl-3-(alkenyl)piperidinones with di ketene and trimethylsilyl triflate in benzene at ambient temperature p roduced annulated pyridones in good yield. The initial reaction involv ed formation of a N-acetoacetylated amide which was further converted to the pyridone with TMSOTf. The overall process was found to proceed with complete stereospecificity. Treating a sample of 3-ethyl-3-[(E)-4 -phenyl-3-butenyl]-2-piperidone with diketene and TMSOTf produced a cy cloadduct in 63% yield whose stereochemistry was elucidated by a X-ray crystallographic study. The epimeric Z-isomer produced a different st ereoisomer of the annulated dihydropyridone. The mechanism of the annu lation involves a TMSOTf induced cyclization followed by proton remova l and generation of a cross-conjugated heteroaromatic betaine. This 1, 4-dipole undergoes a subsequent intramolecular dipolar cycloaddition a cross the neighboring pi-bond, and the resulting cycloadduct is subseq uently converted to the annulated lactam. A related annulation sequenc e leading to a key intermediate previously utilized in the synthesis o f the (+/-)-vallesamidine has been developed which is based on the int ramolecular dipolar cycloaddition of a mesoionic betaine intermediate.