A Generalized Approach to Deliver Functionalized Isoindolines in Macrocycles Open Access

Abstract

Macrocyclic peptides are a growing class of compounds that have shown promise in drug development by improving pharmacological properties. There are currently four cyclization strategies to close macrocycles; however, methods of sidechain-to-sidechain macrocyclization have shown to be more difficult without sulfide bridging, lactonization, or lactamization. We aim to develop a generalized strategy for sidechain-to-sidechain macrocyclization to form an isoindoline core via an intramolecular [2+2+2] cycloaddition. Transition metal catalyzed [ 2+2+2] cycloaddition reactions are attractive for constructing functionalized benzene rings and heterocyclic compounds. These reactions are known to have high atom efficiency, as well as good enantio-, regio-, and diastereoselectivity. However, there is little precedent using this approach on non-natural amino acid to synthesize fused pyrrolidine motifs in a macrocyclic form. We have begun developing an effective [2+2+2] method utilizing amino acid derived alkynes and we plan to use this method to conduct macrocyclizations on linear peptides. This work will aid in the development of a generalized method to close macrocyclic peptides, as well as building a library of unnatural cyclic peptides.

Table of Contents

Table of Content

Introduction…………………………………………………………………………..……………2

Figure 1……………………………………………………………………..……………..2

Figure 2……………………………………………………………………………………4

Methodology background…………………………………………………………………5

Figure 3……………………………………………………………………………………7

Results and Discussion…………………………………………………………………………….8

Scheme 1…………………………………………………………………………………..8

Scheme 2……………………………………………………………………….………...11

Table 1……………………………………………………………………………………12

Figure 4…………………………………………………………………………………..12

Scheme 4a and 4b………………………………….………………………………...…...13

Conclusion and Future work……………………………………………………………………...14

References………………………………………………………………………………………..15

Experimental Section……………………………………………………………………………19

About this Master's Thesis

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School	Laney Graduate School
Department	Chemistry
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Chemistry, Organic Chemistry, General
Keyword	cyclization peptides methodology macrocycles Rh-mediated non-natural amino acids
Committee Chair / Thesis Advisor	Simon B. Blakey, Emory University Monika Raj, Emory University Frank McDonald, Emory University

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