UC Berkeley

The efficient synthesis of organic molecules hinges on the development of concise synthetic strategies. Sequences of chemical reactions can be rendered shorter by employing cascade processes, which accomplish multiple bond formations in a single operation. The direct functionalization of C-H groups with carbon or heteroatom groups offers an additional platform for streamlining synthesis by circumventing the need for an additional pre-functionalization step. This work describes the development of two direct functionalization methods (Chapters 1 and 2), as well as a cascade approach to a family of natural products (Chapter 3).

An overview of intramolecular C(sp³)-H amination is presented in Chapter 1. Recent approaches to C(sp³)-N bond construction are described and categorized according to the nature of the required precursors. First, C(sp³)-H amination methods that require substrates containing electron-withdrawing substituents on the nitrogen coupling partner are examined. Next, a C(sp³)-H amination method that relies on the oxidation of C,N-dianions generated from N,N-dialkylamines and benzylic carbon groups is discussed.

The alkylation of pyridines and pyridine derivatives is examined in Chapter 2. The direct functionalization of pyridine derivatives is described and the challenges associated with direct C(6) alkylation of picolines are outlined. The direct C(6) alkylation of pyridyl alcohols using alkyl lithium reagents was developed after the initial observation that, when heated to 110 °C in toluene, n-butyl lithium adds selectively to the C(6) position of the pyridyl alcohol derived from cycloheptenopyridine. The substrate scope and reagent scope were investigated. Mechanistic studies of the direct alkylation of pyridyl alcohols were performed.

Dimeric natural products derived from resveratrol are described in Chapter 3. Synthetic studies on resveratrol-based natural products are summarized and an overview of a previous synthetic strategy towards this family of natural products is presented. A palladium-catalyzed domino reaction was developed as part of a synthetic strategy to access dimeric resveratrol-derived natural products. The domino process involved sequential Heck-type coupling reactions and provided access to the benzofulvene-based core of various resveratrol-derived natural products. A related approach was applied to the synthesis of the natural product pauciflorol F.