Document Type

Dissertation

Date of Degree

Summer 2012

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

David F. Wiemer

Abstract

The importance of phosphorus can be highlighted not only through its biological significance, but also in its many varied industrial, medicinal, and synthetic applications. Phosphonate moieties in particular have broad applications including their use as reagents in the Horner-Wadsworth-Emmons olefination reaction, a widely used synthetic strategy. As an alternative to the often harsh conditions required for phosphonate synthesis, a mild and versatile one-flask protocol has been developed in which a benzylic alcohol can be directly converted to the diethyl benzylphosphonate ester. Moreover, this zinc iodide mediated process provides good yields on both small and larger scale reactions. Explorations into this unique transformation with non-racemic substrates revealed that the reaction may proceed through an SN1-like mechanism.

The new phosphonate methodology has been utilized successfully on allylic, heterocyclic, and both electron poor and rich benzylic systems. This allows the synthesis of many types of dialkyl benzylphosphonate esters. Specific examples include compounds used towards the synthesis of natural product analogues and at least one phosphonate ester not previously attainable under standard conditions. Isotopic labeling provided additional mechanistic insight through evidence of both SN2 and SN2' allylic phosphonate products, suggesting a probable carbocation process. The mild and facile reaction conditions and the good yields of diverse, complex phosphonate products emphasize the broad applicability of this protocol.

To demonstrate the utility of this phosphorus-based methodology, synthetic sequences and Lewis acid-mediated cascade cyclizations towards the synthesis of natural products and analogues have been developed. The natural radulanins, isolated from liverworts, possess a plethora of biological properties and present the opportunity to utilize and expand upon many aspects of this research. Formation of the benzoxepin core of the radulanins through a Lewis acid-mediated cyclization ultimately led to the total synthesis of radulanin A. An additional product consisting of cyclization with electrophilic aromatic substitution of the MOM-protecting group also was discovered, leading to a highly substituted benzoxepin that should be of value in the synthesis of radulanin E.

Pages

xviii, 191 pages

Bibliography

Includes bibliographical references (pages 179-191).

Copyright

Copyright 2012 Rebekah Marie Richardson

Included in

Chemistry Commons

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