Harnessing Imine Photochemistry for the Synthesis of Important Building Blocks
Creators: name: Collins, James
Publisher: name: My University
Year: 2022
Subjects: subject: Imine Photochemistry
subject: Bioisosterism
subject: Aniline
subject: Bicyclic Motif
subject: Chemistry
subject: Science

description: Over the years, aniline has become extremely prevalent throughout the pharmaceutical industry. This is due to their ease of use, their availability and the positive structure-activity relationship found in multiple drug scaffolds. However, anilines are also one of the most common structural alerts, and are a major reason a number of drugs have been pulled from the market. Upon oxidation by cytochrome P450s (CYP450), they are known to form highly reactive metabolites, which often times lead to negative drug-drug interactions (such as drug-induced liver injury) and CYP450 inhibition. We envision taking advantage of a bioisosterism strategy to overcome these complications brought about by anilines. A bioisostere is a chemical component that can be used to replace a problematic portion of a given molecule to improve the safety of a drug, while also maintaining its efficacy. Herein we disclose work focused around not only synthesizing potential aniline bioisosteres, but also work evaluating these motifs in biological assays. Chapter 1 introduces the concept of aniline bioisosterism and potential isosteres, such as bicyclo[1.1.1]pentanes, are discussed. Also introduced in the first chapter is imine photochemistry as well as photochemistry in flow. The use of photochemistry, especially in flow, has the potential to allow access to otherwise elusive reactivity. Photochemistry has been shown to also provide less harsh strategies to access radical reactivity, which typically requires the use of harsh reagents. Chapter 2 focuses on the development of a “Masked N-centered radical” strategy to allow access to 1-aminonorbornanes as potential aniline bioisosteres. 1-aminonorbornanes are significantly more sp3-rich than their aniline counterparts, however they possess similar physiochemical properties. Current methodologies to access these motifs are underexplored and are limited to primarily para¬-substituted products. Our strategy, however, has the potential further diversify 1-aminonorbornanes through modification of the cyclopropyl starting materials. Chapter 3 expands upon the methodology developed in the previous chapter. In this case, similar reactivity can be observed in an intermolecular fashion, providing a simple method to access 1-aminocyclopentanes. Both imine photochemical methodologies are also amenable to flow, opening the door for potential industrial use of our developed strategies. Lastly, in Chapter 4, ongoing work to incorporate bicyclic motifs into erlotinib and lapatinib scaffolds is discussed. This study explores the use of 1-aminonorboranes, 1-aminobicyclo[1.1.1]pentanes and 1-aminobicyclo[2.2.2] octanes as aniline replacements for both of these anilinoquinazoline drug scaffolds. In collaboration with Prof. Matt Soellner and Prof. Matt O’Meara, we analyzed our synthesized analogs in both binding affinity assays and modeling experiments. Upon completion of the synthesis of the remaining analogs, metabolic stability studies will be done to further analyze these motifs.