Methodological Developments and Synthetic Applications of Strained Rings and Allylic C-H Functionalization of Hindered Substrates

Citation

O'Connor, Nicholas R. (2017) Methodological Developments and Synthetic Applications of Strained Rings and Allylic C-H Functionalization of Hindered Substrates. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9JS9NF6. https://resolver.caltech.edu/CaltechTHESIS:03072017-164212272

Abstract

Formal dipolar cycloadditions of cyclopropanes and aziridines are useful methods for the formation of carbo- and heterocycles. Given our group’s previous interest in this area, we sought to expand the scope of strained ring cycloadditions by employing heterocumulenes as dipolarophiles. This thesis describes our development of Lewis acid catalyzed formal (3 + 2) cycloadditions between donor–acceptor cyclopropanes and isocyanates, isothiocyanates, and carbodiimides to furnish various five-membered heterocycles. Enantioenriched cycloadducts can be accessed through a stereospecific reaction if enantiopure substrates are employed. We also present a method to access more highly nitrogenated heterocycles by replacing donor–acceptor cyclopropanes with activated aziridines. These aziridines react smoothly with isothiocyanates and carbodiimides in the presence of zinc Lewis acids to afford iminothiazolidine and iminoimidazolidine products in good yields. Our efforts to apply a cyclopropane cycloaddition toward the total synthesis of the indole alkaloid calophyline A are also described.

In addition, a method for the activation of sterically hindered allylic C–H bonds is presented. Despite numerous recent advances in the functionalization of allylic C–H bonds and the general utility of these transformations, reactions of sterically hindered substrates remain challenging. In this thesis we describe the development of a novel system for the palladium(II)-catalyzed allylic C–H acetoxylation of α-allyl lactams. We believe the lactam moiety may act as a directing group to aid in the palladation of these generally unreactive substrates. During optimization, we also discovered enal products were formed if water was added. These conditions represent the first example of a transition metal catalyzed C–H oxidation system with tunable selectivity over the extent of oxidation.

Thesis Files