Asymmetric alpha-Stannylation of Heterocycles and Their Subsequent Use in Cross-coupling Reactions

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Asymmetric alpha-Stannylation of Heterocycles and Their Subsequent Use in Cross-coupling Reactions, Is A Well-Researched Topic, It Is To Be Used As A Guide Or Framework For Your Research

ABSTRACT

Heterocyclic components exist in the majority of physiologically important compounds. Incorporation of these heterocyclic units modulate solubility, enhance membrane permeability, and control the activity of compounds in drug discovery. Therefore, the development of a reliable method to incorporate heterocyclic units into small molecules is attractive to chemical researchers.

Transition metal catalysis displays remarkable efficiency for the formation of new carboncarbon bonds. While the bond formation between two C(sp2) centers has been extensively studied, the construction of C(sp3)-C(sp2) bonds are much less common due to slow transmetallation and competitive β-hydride elimination. Herein, the first chapter illustrates the robustness, reliability, and versatility of palladium-catalyzed Stille cross-coupling reaction. Through the use of isolable, configurationally stable organotin nucleophiles, our lab has developed methods that enable unactivated secondary units to undergo cross-coupling reactions with high stereofidelity.

α-Substituted oxygen-containing heterocycles are commonly present in biologically active molecules. Statistics shows that at least one α substituted ether moiety appears in over 20% of the top 200 small-molecule pharmaceuticals. The second chapter illustrates a reliable regioselective method to introduce simple cyclic ethers towards the diversification of small molecules. Aryl halides bearing various functional groups were well tolerated independent of their electronic properties. It was found that cyclohexyl spectator ligands on tin selectively slows transmetallation of undesired units, circumventing the competitive transfer of n-butyl group from nBu3SnR reagents.

Compared to the normally used nBu3SnR reagents, Cy3SnR organometallics benefits from lower toxicity and significantly higher crystallinity, which should become more appealing to synthetic
chemists. Nitrogen is the most abundant heteroatom among FDA approved pharmaceuticals.

Particularly, α-chiral pyrrolidines are not only useful building blocks of pharmaceuticals, but also chiral controlling ligands in asymmetric synthesis. The third chapter reveals a general approach to
stereospecific palladium-catalyzed cross-coupling reactions of enantioenriched nitrogencontaining heterocycles. α-Stannylated pyrrolidine and azetidine organometallic reagents undergo
stereospecific arylation and acylation reactions against a variety of aryl and heteroaryl electrophiles. High stereofidelity is achieved with predictable reagent-controlled stereochemistry regardless of electronic properties of electrophiles and existing stereocenters on chiral substrates.

Late-stage functionalization could benefit from this protocol through a streamlined synthetic approach, avoiding the requisite time and labor consuming resolution of desired enantiomer from the corresponding racemic mixtures.

TABLE OF CONTENTS

ABSTRACT ………………………………………………………………………………………………………………….iv
ACKNOWLEDGEMENTS ……………………………………………………………………………………………vi
LIST OF FIGURES ……………………………………………………………………………………………………….ix
CHAPTER ONE: Introduction………………………………………………………………………………………..1
1.1 Background………………………………………………………………………………………………………………..1
1.2 Cross-coupling reactions………………………………………………………………………………………………3
1.3 Palladium as metal catalyst…………………………………………………………………………………………..6
1.4 C(sp3) hybridized organometallic reagent in cross-coupling reactions……………………………….9
1.5 Organotin nucleophiles for asymmetric cross-coupling reactions…………………………………….12
1.6 Summary………………………………………………………………………………………………………………….14
References……………………………………………………………………………………………………………………..15
CHAPTER TWO: Formation of α-Oxygen Heterocycles by Palladium-Catalyzed Stille
Cross-Coupling Reactions……………………………………………………………………………………………..18
2.1 Background………………………………………………………………………………………………………………18
2.2 Optimization of reaction conditions………………………………………………………………………………23
2.3 Introducing tricyclohexyltin nucleophiles into Stille reactions………………………………………….28
2.4 Substrate scope………………………………………………………………………………………………………….30
2.5 Chiral nuclei synthesis………………………………………………………………………………………………..32

2.6 Conclusion………………………………………………………………………………………………………………..35
2.7 Experimental section………………………………………………………………………………………………….36
References……………………………………………………………………………………………………………………..95
CHAPTER THREE: A General Approach to Stereospecific Cross-Coupling Reactions of
Nitrogen-Containing Stereocenters………………………………………………………………………………..97
3.1 Background………………………………………………………………………………………………………………97
3.2 Reaction condition optimization…………………………………………………………………………………101
3.3 Substrate scope………………………………………………………………………………………………………..106
3.4 Nucleophile expansion……………………………………………………………………………………………..108
3.5 Conclusion………………………………………………………………………………………………………………111
3.6 Experimental section………………………………………………………………………………………………..113
References……………………………………………………………………………………………………………………227

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YourPastQuestions Brand

Additional information

Author

Haoran Zhao

No of Chapters

3

No of Pages

239

Reference

YES

Format

PDF

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