An Interrupted Fischer Indolization Approach Toward the Akuammiline Alkaloids

Chapter one provides an overview of the history of the akuammiline alkaloids, includingtheir isolation, structural features, biological activity, and biosynthesis. This chapter provides adiscussion of synthetic efforts toward these intriguing alkaloids, in addition to detaileddescriptions of several recently completed total syntheses. Chapter two discusses an efficientmethod to access the fused indoline ring system present in a multitude of bioactive molecules.The strategy involves the condensation of hydrazines with latent aldehydes to ultimately deliverindoline-containing products by way of an interrupted Fischer indolization sequence. Themethod is convergent, mild, operationally simple, broad in scope, and can be used to accessenantioenriched products. In addition, the synthesis of furoindoline and pyrrolidinoindolinenatural products is demonstrated by the concise formal total syntheses of physovenine andii idebromoflustramine B. Chapter three explores the mechanisms of the Fischer indole synthesisand competing cleavage pathways with SCS-MP2/6-31G(d) and aqueous solvation calculations.Electron-donating substituents divert the reaction pathway to heterolytic N-N bond cleavage andpreclude the acid-promoted [3,3]-sigmatropic rearrangement. Chapters four reports the totalsynthesis of (±)-aspidophylline A, one of many complex furoindoline-containing alkaloids thathas not been synthesized previously. Our route features a number of key transformations,including a Heck cyclization to assemble the [3.3.1]-bicyclic scaffold, as well as a late-stageinterrupted Fischer indolization to install the furoindoline and construct the natural product'spentacyclic framework