Investigation into the origins of diastereoselection in spirocyclic oxindole forming intramolecular Heck cyclizations

As introduced in Chapter 1, previous studies had demonstrated a pair of highly diastereoselective spirocyclic oxindole-forming intramolecular Heck reactions that established vicinal all-carbon quaternary stereocenters. Depending upon the protecting group applied to the transannular diol, either acetonide or bis-silyl, either cis or trans bis-oxindoles could be selectively prepared with high degrees of diastereoselection. The studies reported herein investigated the origins of diastereoselection in the formation of these rings.; Chapter 2 is an annotated review of diastereoselective intramolecular Heck cyclizations published in the chemical literature. Emphasis is placed on those cyclizations that are not readily explained by the topology of the ring formed in the reaction. Models previously advanced in the chemical literature are critically examined and, where applicable, applied to the rationalization of other cyclizations.; Chapter 3 describes studies of the first Heck cyclization of both the acetonide and bis-silyl protected substrates. The method of study involved the synthesis of numerous model substrates that contained various substructures of the original substrates. These model substrates were then cyclized, and the ratio of the products was determined. These studies show that stereoselection in the original substrates is a highly complicated process. In the acetonide series, two factors contribute to stereoselection; both a conformationally defined cyclohexene rings and a non-reacting C-2 anilide are required for high levels of diastereoselection. Models to describe the means of stereoselection imparted by these structural elements are advanced. On the other hand, cyclization of model compounds of the bis-silyl protected substrate, as well as other non-fused-ring substrates, provided only low levels of diastereoselection. Analysis of these results suggests that cyclohexene boat conformations may contribute to the diminished stereoselection in these cases.; Chapter 4 describes the studies of the second Heck cyclization of both the acetonide and bis-silyl protected substrates. Using similar techniques as described for Chapter 3, these studies find that steric influences dominated stereoselection in the second cyclization. These studies also unveiled a new mode of β-siloxy elimination.; Chapter 5 presents a revision of the previously reported diastereoselection in the original bis-silyl protected substrate and offers conclusions regarding this study.