Development of aza-Heck reactions, the total synthesis of impatien A, and ee mesurement by low-cost MS

Abstract

Nitrogen-containing compounds, particularly nitrogen heterocycle-containing compounds, are ubiquitous in natural products and pharmaceuticals. For this reason, there is great interest in the development of new methods for the synthesis of these heterocycles as well as interest in the synthesis of nitrogen heterocycle-containing natural products. In this thesis, I will describe the development of an aza-Heck reaction for the synthesis of indolines as well as demonstrate the use of an aza-Heck reaction in the total synthesis of the natural product Impatien A. Additionally, I will describe the use of low-cost mass spectrometers in the enantiomeric excess determination of high throughput samples. ☐ In Chapter 1, I will describe the development of a 5-exo aza-Heck reaction of aniline-derived electrophiles for the synthesis of indolines. In addition to demonstrating the first use of aniline electrophiles in the aza-Heck field, this reaction is tolerant of a variety of functionality. This reaction can also deliver highly sterically congested products which pose a significant challenge to other methodologies. ☐ In Chapter 2, I will describe the first total synthesis of the spirocyclic natural product Impatien A using an aza-Heck reaction. The key steps in the synthetic sequence include an a-arylation to couple an indanone fragment and a substituted aryl bromide. Following Grignard addition, oxidation, and hydroxamic ether synthesis the key aza-Heck reaction was optimized initially using high throughput experimentation. A phosphite ligand novel to the aza-Heck field was found optimal for the challenging aza-Heck reaction of the tetra-substituted alkene. Impatien A is ultimately delivered in seven linear steps from known compounds. ☐ In Chapter 3, I will demonstrate the use of low-cost mass spectrometers in the determination of enantiomeric excesses of high throughput samples. High throughput experimentation presents an analytical challenge in that samples are analyzed with little to no purification and, consequently, the presence of reaction components and byproducts can interfere in accurate data collection. This is especially a challenge in enantiomeric separations which are often non-trivial. Mass spectrometry has been utilized in applications as it allows for the discrimination of compounds selectively by mass but use of low-cost mass spectrometers, which are often the only accessible instrumentation to academic laboratories, has not been rigorously explored. In chapter 3, I will describe such studies to validate this approach.