Dissertation
Alkyl radical additions to aliphatic and aromatic N-acylhydrazones via photoredox catalysis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2020
DOI: 10.17077/etd.005372
Abstract
The chiral amine is a motif that has garnered great interest in organic chemistry due to its widespread presence in biologically active molecules. In particular, a wide variety of structurally diverse chiral amine motifs are present in pharmaceuticals. The prevalence of this functional group in key synthetic targets necessitates efficient syntheses capable of forming a broad spectrum of compounds. Chiral amine synthesis has always been a great challenge in organic chemistry, and several unique methods have been reported. Early in the twenty-first century, several reports of radical additions to imino compounds emerged, which mitigated the shortcomings of previously practiced methods. Our group pioneered the use of aliphatic and aromatic N-acylhydrazones as radical acceptors to synthesize chiral amines with high levels of stereoselectivity.
Despite the noticeable improvement of radical additions to imino compounds over more traditional methods, these methods did share some undesirable traits. In particular, the large excess of radical precursors and radical initiators required for successful addition was costly and wasteful, with some systems forming highly toxic byproducts as a result. The recent rise of photoredox catalysis has remedied some of these problems by allowing for highly efficient and catalytic radical generation processes.
Photoredox catalysis has benefited chiral amine synthesis both by enhancing the efficiency of radical generation to improve existing methods and by allowing for new synthetic pathways not previously allowed by traditional radical chemistry. Several new methods of chiral amine synthesis using α-amino radicals have emerged as a result of photoredox catalysis. Additionally, photoredox catalysis was also effectively utilized to facilitate highly efficient radical additions to imino compounds. Despite the increased efficiency of these transformations, these radical addition processes were limited to imines bearing aromatic side chains and incompatible with aliphatic imines.
We sought to overcome the substrate limitations displayed by previous examples of radical additions under photoredox conditions through the use of N-acylhydrazone radical acceptors. Successful radical addition to N-acylhydrazones bearing both aliphatic and aromatic side chains has been demonstrated by past work in our group, but at the expense of high reagent loading. We hypothesized that photoredox-catalyzed radical addition conditions would allow for highly efficient radical addition reactions to aliphatic and aromatic N-acylhydrazone acceptors, which would represent the broadest range of possible chiral amine products to date. Successful radical addition to N-benzoylhydrazones using alkylbiscatecholatosilicates as radical precursors and 2,4,5,6-tetracarbazolylisophthalonitrile (4CzIPN) as a photocatalyst was demonstrated. This method was compatible with hydrazones bearing both aliphatic and aromatic side chains, which was previously unprecedented at the beginning of the project.
In order to demonstrate the synthetic utility of this method, a formal synthesis of racemic repaglinide was targeted. Repaglinide is a drug used for managing the blood glucose levels of diabetics. Synthesis of the N-terminus of the drug was achieved in three steps from commercial materials. Initial studies on facilitating enantioselective radical addition under these conditions were performed. To date, only slight levels of enantioselectivity have been achieved. Future studies will be aimed towards further development of asymmetric radical additions to N-acylhydrazones to yield optically enriched chiral amines.
Details
- Title: Subtitle
- Alkyl radical additions to aliphatic and aromatic N-acylhydrazones via photoredox catalysis
- Creators
- Stephen T J Cullen
- Contributors
- Gregory K Friestad (Advisor)F Christopher Pigge (Committee Member)David F Wiemer (Committee Member)Louis Messerle (Committee Member)Scott R Daly (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Spring 2020
- DOI
- 10.17077/etd.005372
- Publisher
- University of Iowa
- Number of pages
- xix, 186 pages
- Copyright
- Copyright 2020 Stephen T J Cullen
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 125-133).
- Public Abstract (ETD)
Many target compounds of synthetic chemistry are complex molecules with biological activity. One structural feature present in many biologically active compounds is the chiral amine, a carbon with four different atoms or groups of atoms attached to it, one being nitrogen. Chiral amines have always been recognized as important synthetic targets because they are featured in many drugs and drug candidates, but their syntheses have always presented challenges. As a result, many different methods of chiral amine synthesis have been reported, each with their own unique strengths and weaknesses. Recent reports have demonstrated the use of visible light to promote synthesis of chiral amines, but these methods were limited in the diversity of different products which were accessible.
We sought to overcome the substrate limitations displayed by previous examples. We hypothesized that N-acylhydrazones, substrates bearing a C=N double bond which our group has successfully used to synthesize chiral amines in the past, could be used to efficiently synthesize a broader range of chiral amine products than previously reported methods. Our hypothesis was proven to be correct, and we have developed a method of radical addition to aromatic and aliphatic N-acylhydrazones using visible light. Future work on this project will be aimed towards invoking stereocontrol to allow for the exclusive synthesis of the desired stereoisomer of the target products.
- Academic Unit
- Chemistry
- Record Identifier
- 9983968395602771
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