Synthesis of Cyclopropane-Fused 1,5-Diazocin-2-ones via Metal-Templated Intramolecular Addition of Nitrogen Nucleophiles to Pre-Generated Cyclopropenes

This thesis is concerned with the development of methods by which to access compounds possessing the 3,4-cyclopropane-annulated 1,5-diazocin-2-one scaffold. The methods described herein are based on the intramolecular nucleophilic addition of nitrogen nucleophiles to the cyclopropene double bond in a direct 8-membered cyclization. This method allows for access to previously-unknown diazocines of their type – namely, 1,5-diazocin-2-ones possessing fusion to a cyclopropane moiety. The described method allows for potential diversification of the cyclic products via a modular approach to the linear precursors which affords the possibility to easily explore new chemical space by the variation of simple building blocks. Chapter one provides a review of the known methods by which to synthesize 1,5-diazocin-2-ones. The chapter begins by highlighting the importance of members of this class of molecules as effective pharmaceutical agents and as drug candidates. Synthetic methods involving the direct 8-membered cyclization of linear precursors are then discussed – as well as their modes of activation. Furthermore, synthetic approaches to the scaffold by cycloaddition, transition metal-catalyzed tandem reactions, multicomponent reactions, and various rearrangements and fragmentations are discussed. Chapter two describes the development of a synthetic pathway to the direct precursors to the cyclopropane-annulated 1,5-diazocin-2-one scaffolds that are the targets of the efforts of this project. Synthetic strategies are developed and improved upon in order to afford substrates that are relatively easy to construct and assemble in a modular fashion so as to provide easy access to a plethora of new compounds having potentially interesting bioactivities. Chapter three focuses on the strain release-driven cyclizations of the previously described precursors to afford the diazocinone scaffold of interest. The optimization of the reaction and tolerance of the method to the electronic nature of the various nucleophiles employed is discussed. This method is one requiring mild conditions by taking advantage of the high energy and electrophilicity of the cyclopropene moiety. Several novel diazocines are synthesized with the developed method.

Grantor dc:publisher

University of Kansas

Year dc:date.issued

2018

Author dc:creator

• Matheny, Jonathon Paul

Advisor dc:contributor.advisor

• Rubin, Michael

• Organic chemistry
• azalactam
• cyclization
• cyclopropane
• cyclopropene
• diazocinone
• medium-sized heterocycle

Statement dc:rights

• Copyright held by the author.

Language dc:language.iso

en

Dc Identifier Other

http://dissertations.umi.com/ku:16071

OAI identifier oai:identifier

oai:kuscholarworks.ku.edu:1808/27827