Date of Award

May 2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

M. Mahmun Hossain

Committee Members

James M. Cook, Graham M. Moran, Guilherme Indig, Xiaohua Peng

Keywords

Asymmetric Allylic Alkylation, Asymmetric Synthesis, Organometallic Chemistry, Phase Transfer Catalysis, Synthesis of Chiral Tryptophans and Total Synthesis of Tryprostatin, Synthesis of Quaternary Stereocenter

Abstract

The development of efficient catalytic enantioselective synthesis of all carbon quaternary centers is a significant challenge in chemical synthesis due to the difficulties of carbon-carbon bond formation at quaternary center. Using phase transfer catalyst we attempted to create quaternary carbon center via direct C-alkylation of hydroxyarylacrylates, instead we obtained O-alkylated acrylates. We succeeded in C-alkylation which involves an indirect method via the O-alkylation of 3-hydroxy aryl acrylates and a subsequent [3, 3] sigmatropic rearrangement (Claisen rearrangement). The O-alkylated products are obtained in yields ranging from 65-85%, and the corresponding Claisen rearrangement products in yields ranging from 55-90%. Typically Pd(II) catalysts are used for this type of transformation. But several attempts at accomplishing an asymmetric Claisen rearrangement using metal Lewis acid catalysis failed due to insufficient activation of the Claisen substrate. Herein, we report the creation of all carbon stereocenters starting from 3-hydroxyarylacrylates modified allyl enol ether rearrangement reaction. We believe this is the first example of allyl enol ether rearrangement employing Pd(0) catalysts. The rearrangement reaction analogs takes place in excellent yields ranging from 80-95% and enantioselectivity ranging from 50-90% ee. Asymmetric synthesis of indole alkaloids is a major area in organic synthesis. Synthesis of chiral Tryptophans and its unnatural analogs has immense importance as they are building blocks for many natural products. Herein we describe the enantiospecific synthesis of ring-A substituted tryptophan derivatives from commercially available gramines using chiral phase transfer conditions. This one-pot reaction avoids protecting/de-protecting the indolylic nitrogen of gramine by choosing a chemoselective quaternization reagent, 4-(trifluoromethoxy)benzyl bromide to produce an electrophilic salt intermediate, which is subsequently alkylated in good yield and high %ee. In an application of chiral tryptophans we attempted to synthesize tryprostatins. Tryprostatins are potent cancer drug, tryptostatin A reverses the resistance of cancer cells against antitumor drugs by arresting cell cycle progression at the G2/M phase. We have been able to make tryprostatin B using our proposed synthesis scheme, where one of the key intermediate is C-2 alkylated chiral tryptophan. Several challenges in the synthesis protocol and optimization of the chiral phase transfer catalyzed reaction are described.

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