Date of Award

August 2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

M. Mahmun Hossain

Committee Members

James M. Cook, Jian Chen, Guilherme L. Indig, Mark L. Dietz

Keywords

Asymmetric, Catalysis, DAAA, Quaternary, Stereocenters, Tsuji-Trost

Abstract

The asymmetric synthesis of all carbon quaternary stereocenters poses a particular challenge due to the steric congestion inherent in the formation of such centers and has been the object of intense research these last 20-30 years. However, the amount of literature for the synthesis of aldehydes bearing quaternary stereocenters via enolate type chemistry is much more limited due to problems associated with the alkylation of such substrates including such types as Cannizzaro and Tischenko related reactions or self aldol condensations. The formation of aldehydes with quaternary stereocenters via use of enolate equivalents such as the DAAA (decarboxylative asymmetric allylic alkylation) of ally enol carbonates has also not been fully explored. Herein, we describe the creation of all carbon stereocenters starting from 3-hydroxy aryl acrylates via several routes. The first method employs organocatalysts; reactions that have been investigated using this route are phase transfer catalyzed alkylations and organocatalytic Michael additions catalyzed by Cinchona alkaloid catalysts. The phase transfer catalyzed alkylation is less successful than the Michael addition due to competing C- vs. O-alkylation. The second method involves the well known Claisen rearrangement via the O-alkylation of 3-hydroxy aryl acrylates and the subsequent [3,3] sigmatropic rearrangement. The O-alkylated products are obtained in yields ranging from 65-84%, and the corresponding Claisen rearrangement products in yields ranging from 55-91%. Multiple attempts at achieving an asymmetric Claisen rearrangement employing Lewis acid metal catalysts failed either due to insufficient activation of the Claisen substrate or due to cleavage of the oxygen allyl bond. The last method involves the DAAA of allyl enol carbonates derived from 3-hydroxy aryl acrylates. A stereoselective synthesis of these carbonates was devised that can form the Z- or E- stereoisomer in very high Z/E ratios (50:1 and 1:99 respectively). The stereochemical outcome depends on the choice of base, addition of TMEDA and reaction temperature. The Z- and E- stereoisomers have different reactivities towards the DAAA reaction, with the E-stereoisomer displaying both greater reactivity and enantio-differentiation with chiral ligands. The DAAA of E- stereoisomer analogues takes place in excellent yields ranging from 96-99% and enatioselectivities ranging from 42-78% ee.

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