Author ORCID Identifier

https://orcid.org/0000-0002-2422-0281

Year of Publication

2022

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department/School/Program

Chemistry

First Advisor

Dr. Robert B. Grossman

Abstract

1,2-Diamine substructures are prevalent functional motifs in natural products, pharmaceutical compounds, and ligands. The interesting functionalities of 1,2-diamines have inspired many synthetic chemists to design various methodologies for preparing these structures from simple precursors such as alkenes. In this work, we described two different but related methods using simple and easily accessible reagents for 1,2-diamination of alkenes. In the first method, an alkene undergoes 1,3-dipolar cycloaddition with an organic azide to form a 1,2,3-triazoline. Subsequent N-alkylation of the generated 1,2,3-triazoline gives the 1,2,3-triazolinium ion, which is then hydrogenated over Raney Ni with a balloon of H2 to produce 1,2-diamine. Traditionally, it has been believed that a 1,2,3-triazoline is an unstable species in the presence of heat or light and will readily extrude N2 to form an imine or an aziridine. However, most of the 1,2,3-triazolines prepared in this work were stable to the extrusion of N2 at the temperature required for their formation.

In the second method, an alkene undergoes 1,3-dipolar cycloaddition with a 1,3-diaza-2-azoniaallene (azidium ion, our neologism) to afford a 1,2,3-triazolinium ion directly. The 1,2,3-triazolinium ions are reduced to the corresponding 1,2-diamines using the same conditions described above. As was expected, cyclic alkenes provide cis 1,2-diamines, and acyclic trans alkenes provide threo 1,2-diamines due to syn cycloaddition of the alkene to the azidium ion and preservation of the stereochemistry of the 1,2,3-triazolinium ion during the hydrogenation. Surprisingly, the reduction of acyclic cis alkenes proceeded with complete or partial inversion of relative stereochemistry instead of the complete formation of the expected erythro isomer. We hypothesized that this isomerization occurs during the hydrogenation step by Raney Ni. More surprisingly, the reduction of the 1,2,3-triazolinium derived from 5-hexen-2-one produced the diamine product with an additional C–C bond. The X-ray crystallographic analysis and 1D/2D NMR spectra confirmed the structure and the relative stereochemistry of the synthesized 1,2,3-triazolinium ions and 1,2-diamines.

Additionally, we had planned to apply the developed 1,2-diamination methodology toward the total synthesis of loline alkaloids. Lolines are a group of nitrogen-containing natural products produced in cool-season grasses and have shown insecticidal and antifeedant properties. In our designed retrosynthesis, disconnection between C(3) and N(4) in loline tricyclic ring, will lead us to the bicyclic intermediate consist of tetrahydrofuran and pyrrolidine ring. We hypothesized that this intermediate can be produced by hydrogenolysis of the corresponding 1,2,3-triazolinium ion synthesized from 2-deoxy-D-ribose (the ether linkage provider). In my attempt toward this total synthesis, the corresponding 1,2,3-triazoline was synthesized as a first key intermediate in seven steps from 2-deoxy-D-ribose. The N-alkylation of the 1,2,3-triazoline, reduction of the produced 1,2,3-triazolinium ion, and completion of the final stages of this total synthesis are still under investigation.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.319

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