SYNTHESIS OF CYCLOPROPANES AND DIHYDROFURANS BY METAL CARBENOID REACTIONS Público

Abstract

Rhodium-catalyzed carbenoid reactions of donor/acceptor diazo compounds afford the product in high yield and with high stereoselectivity. The primary objective of this thesis is to explore the new reactivity of donor/acceptor carbenoids, especially in a multicatalytic process.

The first chapter of the thesis is devoted to studying the cyclopropanation of electron-deficient alkenes through donor/acceptor carbenoid intermediates. Under the optimized conditions, the cyclopropanation reaction of electron-deficient alkenes was achieved in high yields and with high diastereo- and enantioselectivity.

The second chapter focuses on the synthesis of dihydrofurans through sequential transition metal-catalyzed reactions. A triple cascaded reaction sequence was developed. The reaction process begins with a rhodium-catalyzed cyclopropanation, followed by a silver-catalyzed ring-opening reaction. The last step is a gold-catalyzed cyclization reaction. Starting with alkynyl-ketone diazo compounds, this reaction sequence afforded polycyclic benzo-fused dihydrofurans in high yield. A one-pot protocol for the cascaded reactions was then developed. The progress of applying this methodology to the synthesis of natural products is also described.

The third chapter presents the development on the synthesis of dihydrofurans by C-H functionalizations. Through the rhodium-catalyzed intramolecular C-H insertion reaction, the core structure of lithospermic acid was constructed in a highly diastereo- and enantioselective manner. An intermolecular process for the enantioselective synthesis of dihydrofurans is also described. The reaction sequence features the combination of two distinct types of C-H functionalizations. The process begins with a rhodium-catalyzed C-H insertion reaction of TBS benzyl ethers with donor/acceptor carbenoids, followed by the deprotection of the TBS group to afford adol-type alcohols. Lastly, the palladium-catalyzed C-H functionalization reaction of those alcohols produces dihydrofurans with high regio-, diastereo- and enantioselectivity.

Table of Contents

Table of Contents

Chapter I Asymmetric Cyclopropanation of Electron-Deficient Alkenes via Carbenoid Reactions...1

1.1 Introduction...1

1.1.1 Asymmetric Cyclopropanations of Donor/Acceptor Carbenoids...6
1.1.2 Cyclopropanation of Electron-Deficient Alkenes...11

1.2 Results and Discussion...16
1.3 Conclusion...32

Chapter II Synthesis of Fused Dihydrofurans via Transition Metal-Catalyzed Sequential Reactions...33

2.1 Introduction...33

2.1.1 Ruthenium- and Rhodium-Catalyzed Sequential Reactions...33
2.1.2 Rhodium- and Palladium-Catalyzed Sequential Reactions...35
2.1.3 Synthesis of Heterocycles via Cycloisomerization Reaction...38
2.1.4 Generation of all Carbon Dipoles via Cycloisomerization of Alkynyl Cyclopropanyl Ketones...42

2.2 Results and Discussion...45

2.2.1 Sequential Reactions for the Synthesis of Fused Dihydrofurans...46
2.2.2 Application of the Sequential Reactions to the Synthesis of Cassigarol D...59

2.3 Conclusion...67

Chapter III Synthesis of Dihydrobenzofurans via Sequential C-H Functionalizations...68

3.1 Introduction...68

3.1.1 Synthesis of Lactones via Intramolecular C-H Insertions...71
3.1.2 Synthesis of benzofurans via C-H insertion reactions...78
3.1.3 Intermolecular Insertions into Benzylic C-H Bonds...82
3.1.4 Palladium-Catalyzed C-H Functionalization/C-O Cyclization for the Synthesis of Benzofurans...86

3.2 Results and Discussion...89

3.2.1 Application of the Intramolecular C-H Insertion to the Synthesis of the Core Structure of Lithospermic Acid...89
3.2.2 Synthesis of Dihydrobenzofurans via Sequential C-H Functionalizations...94
3.2.3 Synthesis of β-Lactones via Reactions of Donor/Acceptor Carbenoid...107

3.3 Conclusion...114

Experimental Section...115

General Methods...115
Experimental for Chapter I: Asymmetric Cyclopropanation of Electron-Deficient Alkenes via Carbenoid Reactions...116
Experimental for Chapter II: Synthesis of Fused Dihydrofurans via Sequential Reactions...139
Experimental for Chapter III: Synthesis of Dihydrobenzofurans via Sequential C-H Functionalizations...190

References...234
Appendix: X-Ray Crystallographic Data...240

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Palavra-chave	C-H functionalization cyclopropane dihydrofuran rhodium multicatalytic carbenoid
Committee Chair / Thesis Advisor	Davies, Huw, Emory University
Committee Members	Liotta, Dennis C, Emory University McDonald, Frank, Emory University

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