Date of Award

August 2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John D. Chisholm

Subject Categories

Physical Sciences and Mathematics

Abstract

Alcohols are a common form of functionality in organic chemistry, and are often present in biologically active molecules. The protection of hydroxy groups is crucial in long multi-step synthetic routes, as the unprotected alcohol is typically not compatible with many reagents. Alcohols are often protected as corresponding benzyl ether, which can then be removed when desired to reveal the alcohol functional group. Classic methodology for protection of alcohols as benzyl ethers requires harsh conditions utilizing strong acids and bases, which functions well for simple substrates. In more complex multifunctional molecules this can lead to degradation and side products. Therefore, there is a need for the development of milder conditions for the protection of alcohols.

Recently a number of reagents have been developed to form benzyl ethers under mild, neutral conditions that and do not disturb the sensitive functionality in complex molecules. Many of these reagents have been based on imidate-type systems. The most common imidate system, the trichloroacetimidate, is often utilized for the installation of ethers under Lewis acid catalyzed conditions. Given their ready availability, a reevaluation of the reactivity of alcohols and trichloroacetimidates has been undertaken. In many cases, simply heating the imidate with an alcohol in refluxing toluene without an exogenous acid or base is an effective method for the formation of the desired ether. This operationally simple procedure is most effective for trichloroacetimidates that are precursors to highly stabilized cations (i.e. the 4-methoxybenzyl and diphenylmethyl group). The use of this new procedure with a number of acid and base sensitive substrates, which are protected in excellent yield without disturbing the delicate functionality present in these molecules, is presented.

Cancer is a group of disorders that are all defined by abnormal cell growth in an organism. This is a very broad set of diseases that can affect multiple organs. While classic cancer treatments have focused on killing all cells that divide quickly, more modern treatments attempt to selectively stop cancer progression by influencing cell signaling pathways. There are many studies about how cancer cells coopt cell signaling pathways and use these systems, which control cell growth in normal cells, to facilitate their own uncontrolled progression. One of the major cell signaling pathways implicated in tumor development is the PI3K pathway, which is governed by the kinase PI3K and the phosphatases PTEN and SHIP.

SHIP1 is an SH2-containing inositol 5’-phosphatase found in blood cells that is responsible for the hydrolysis of phosphatidylinositol-3,4,5-trisphosphate to phosphatidylinositol-4,5-bisphosphate. This enzyme is part of a major cellular signaling pathway (the PI3K pathway) that controls many important cellular events such as proliferation, differentiation and adhesion. SHIP1 inhibition has been found to increase blood cell production and slow the growth of blood cancer cells. Certain aminosteroids show selectivity as SHIP1 inhibitors and therefore may have therapeutic applications. In this study, syntheses of a number of aminosteroid derivatives were performed and these compounds are evaluated for their potential as SHIP1 inhibitors.

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