An important objective in organic synthesis is the rapid development of molecular complexity in a stereocontrolled manner. The Prins-pinacol cascade reaction developed in the Overman laboratories allows the concise stereocontrolled synthesis of a variety of complex heterocycles, and has been implemented in the synthesis of several natural products. While pinacol-terminated Prins cyclizations have successfully enabled the expedient generation of many complex carbocyclic and heterocyclic compounds, there are several limitations to their utility. The research reported in this dissertation provides additional insight into the scope and limitation of the Prins-pinacol reaction in the context of two natural product total syntheses.

Chapter 1 describes the successful total synthesis of the Lycopodium alkaloid (+)-sieboldine A. A number of pinacol-terminated cyclizations, including a Prins-pinacol cascade, were examined to form the cis-hydrindanone core of sieboldine A. Of these, the mild Au(I) activation of an alkyne to promote a 1,6-enyne cyclization terminated by a semipinacol rearrangement proved to be the most synthetically useful. Formation of the unprecedented N-hydroxyazacyclononane ring embedded within the bicyclo[5.2.1]decane- N,O-acetal of sieboldine A was a substantial challenge. In the end, activation of a thioglycoside precursor enabled a remarkably efficient cyclization, which ultimately led to the first enantioselective total synthesis of (+)-sieboldine A.

Chapter 2 describes mechanistic investigations conducted to rationalize the unexplained stereochemical outcome of an intended Prins-pinacol cascade reaction for construction of the 8-oxabicyclo[3.2.1]octane ring system of (+)-aspergillin PZ. Deuterium labeling of the precursor substrate provided the first unambiguous evidence of a competitive 2-oxonia[3,3]sigmatropic/aldol mechanism to the desired Prins-pinacol reaction.