Investigations of allylsilane and alkyl azide reactions: Methods development and studies toward the total synthesis of alkaloid 223A

During investigations on imine-olefin cyclization reactions employing chiral allylsilanes and iminium ions, generated in situ from o-N-Boc aryl imines, it was discovered that a suitably positioned substituent bearing a Lewis basic site on the allylsilane component caused a reversal in the diastereoselectivity of these reactions relative to that normally observed with alkyl-substituted substrates. This effect was subsequently observed in two other reaction types, suggesting the possibility of utilizing this approach as a general means of stereocontrol. Investigations into the mechanism behind this effect led to the proposal of product formation through thermodynamic control facilitated by neighboring group interactions with a transient cationic species. This hypothesis was experimentally corroborated through the isolation of an intermediate in the proposed mechanistic pathway.; A second methodology project was undertaken to investigate the reactions of alkyl azides with enones under Lewis acid catalysis. Under these conditions, enones were observed to undergo reaction at the double bond via [3+2] cycloaddition in preference to 1,2-addition to the carbonyl moiety, as is normally exhibited by ketones. Furthermore, reactions occurred at temperatures well below those needed for analogous thermal reactions. Exploration of reaction scope with respect to both the enone and alkyl azide component demonstrated the general applicability of this reaction. In the majority of cases, the initially formed intermediates underwent further reaction via ring-contraction to afford enaminones. Consequently, this method may serve as an alternate synthetic route to these useful compounds.; Efforts were then directed toward the total synthesis of alkaloid 223A, a natural product isolated from the skin extract of a species of dendrobatid frogs. This compound represents the first trialkyl-substituted indolizidine isolated from frogs, and is a member of a structural class that is known to exhibit antagonist effects at nicotinic channels. Two main routes to the target compound were investigated, in which the assembly of the indolizidine core was envisioned to be realized through an intramolecular Schmidt reaction developed in this group. One of these routes ultimately allowed the successful synthesis of the penultimate intermediate with a high degree of diastereoselectivity.