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Alkyl Radical Additions to Aliphatic...

Cullen, Stephen T. J.

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Alkyl Radical Additions to Aliphatic and Aromatic N-Acylhydrazones Via Photoredox Catalysis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Alkyl Radical Additions to Aliphatic and Aromatic N-Acylhydrazones Via Photoredox Catalysis./
Author:	Cullen, Stephen T. J.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	207 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-02, Section: B.
Contained By:	Dissertations Abstracts International82-02B.
Subject:	Chemistry. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27961979
ISBN:	9798662496361

Alkyl Radical Additions to Aliphatic and Aromatic N-Acylhydrazones Via Photoredox Catalysis.
Cullen, Stephen T. J.

Alkyl Radical Additions to Aliphatic and Aromatic N-Acylhydrazones Via Photoredox Catalysis. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 207 p.

Source: Dissertations Abstracts International, Volume: 82-02, Section: B.

Thesis (Ph.D.)--The University of Iowa, 2020.

This item is not available from ProQuest Dissertations & Theses.

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 -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.

ISBN: 9798662496361Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Alkyl radical additions

Alkyl Radical Additions to Aliphatic and Aromatic N-Acylhydrazones Via Photoredox Catalysis.
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245 1 0 $a Alkyl Radical Additions to Aliphatic and Aromatic N-Acylhydrazones Via Photoredox Catalysis.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2020
300 $a 207 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-02, Section: B.
500 $a Advisor: Friestad, Gregory K.
502 $a Thesis (Ph.D.)--The University of Iowa, 2020.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a 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 -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.
590 $a School code: 0096.
650 4 $a Chemistry. $3 516420
650 4 $a Organic chemistry. $3 523952
653 $a Alkyl radical additions
653 $a Photoredox catalysis
653 $a N-Acylhydrazones
690 $a 0485
690 $a 0490
710 2 $a The University of Iowa. $b Chemistry. $3 1680584
773 0 $t Dissertations Abstracts International $g 82-02B.
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791 $a Ph.D.
792 $a 2020
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27961979