Date of Award

July 2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

John D. Chisholm

Second Advisor

Scott Erdman

Keywords

Indole, pyrroloindoline, SHIP, Trichloroacetimidates, Tryptamine

Subject Categories

Physical Sciences and Mathematics

Abstract

Indole scaffolds are incorporated in a plethora of clinically useful natural products like ergotamine, reserpine, vincristine. Indole alkaloids have been fascinating chemists and biologists alike because of its diverse biological activity and intrinsic structural complexity. N-alkylated tryptamines, along with their analogs, are recognized as potent SHIP inhibitors and are considered privileged structures due their binding properties and diverse biological targeting. Also, the pyrrolo[2,3-a]indoline frameworks have been recognized as key structural motifs in many anticancer and psychoactive compounds. Thus, the development of a simple, inexpensive, efficient, safe, and environmentally friendly method of accomplishing indole alkylation constitutes an important synthetic goal. This dissertation describes modular approaches to constructing densely functionalized indoles, fused heteroaromatic natural products and alkylated tryptamines.

The first chapter of the dissertation gives a detailed account of reactions of glycosyl or alkyl trichloroacetimidates with various indole derivatives substituted at N-, 2- and 3- position. While Friedel Crafts reactions of indoles with trichloroacetimidates are known, regioselectivity of these reactions is not very clear. The relative utility of all the known reactions is reviewed in order to gauge the potential of this new technology.

Trichloroacetimidates make excellent electrophiles when activated with Brønsted or Lewis acids, and therefore were good substrates for the elaboration of the nucleophilic indole heterocycle. Intriguingly, the primary product of these transformations depends on both the structure of the imidate and the indole nucleophile, with N-alkylation, C2-alkylation, and C3-alkylation products being readily attainable. This transformation is discussed in the second chapter. By exploring modular approaches to constructing these compounds, we envision that this methodology will aid the preparation of densely functionalized tryptamines.

Dearomatization reaction is a powerful tool that converts planar aromatic compounds into interesting highly functionalized three-dimensional structures. The reactions discussed herein include the alkylative dearomatization through activation of trichloroacetimidates for the syntheses of 2,3,3’-trisubstituted indolenine cores. Dearomatization / Cyclization cascade sequences that involve dearomatization as the key step useful in the syntheses of pyrrolo[2,3-a]indoline frameworks are also described in the third chapter.

Phosphatidylinositol 3’-kinase (PI3K) is an important component of an important signaling pathway, which regulates cell growth and cell proliferation. The SH2 containing inositol 5'-phosphatase (SHIP) also plays a regulatory role in the PI3K signaling pathway. Inhibition of SHIP using small molecules has been shown to result in decreased cell growth in a number of cancer cell lines. Thus, SHIP inhibitors are being investigated as potential anti-cancer drugs. In this chapter, synthesis of a tryptaimine based SHIP inhibitor and some analogs is discussed.

Fifth chapter discusses protection of carboxylic acids converted to the corresponding 4-methoxybenzyl (PMB) esters with 4-methoxybenzyl-2,2,2-trichloroacetimidate in the absence of an acid catalyst. This operationally simple procedure is an effective method for the formation of PMB esters. The reaction is promoted by the carboxylic acids themselves in excellent yields (78-99%). No racemization is observed in the case of carboxylic acids bearing a α-stereocenter.

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