Expanding the Scope of Donor/Acceptor Rhodium-Carbene Chemistry Público

Abstract

The reactions of donor/acceptor rhodium-carbenes have been studied widely for the last 25 years, and a variety have become widely accepted. These include, most notably, cyclopropanation and C-H insertion reactions. This work attempts to address some of the outstanding challenges in field of donor/acceptor rhodium-carbene chemistry. In particular, this work focuses on expanding the scope of C-H functionalization reactions by carbene induced C-H insertion.

The first part of this thesis describes work attempting to apply the combined cyclopropanation/Cope rearrangement (CPCR) to the total synthesis of (-)-Pseudolaric Acid B. The synthetic route relied on two sequential rhodium-carbene reactions to install the core of the natural product. Unfortunately, the CPCR reaction led to a product that was diastereomeric relative to the desired product, and this could not be overcome but altering the substrate. A second approach attempted to avoid this issue, but reached other roadblocks as well. Nevertheless, an interesting kinetic resolution was developed, in which a racemic substrate could be converted to a single enantiomer using the rhodium-catalyzed CPCR.

The second part of this thesis describes the application of 2-(trialkylsilyl)ethyl aryl- and styryldiazoacetates to the synthesis of Z-allylsilanes. The reaction is believed to proceed through an intramolecular C-H insertion to give a b-lactone, which then stereospecifically extrudes CO2 under mild conditions to give the observed allylsilane products.

The third part of this thesis describes the application of 2,2,2-trichloroethyl aryldiazoacetates to the site-selective C-H functionalization of benzylic methyl groups and methyl ethers. The unique ester is believed to reduce the propensity of the intermediary rhodium-carbenes to undergo both destructive intramolecular C-H insertion chemistry as well as intermolecular dimerization reactions.

Finally, the application of the novel 2-(trimethylsilyl)ethyl and 2,2,2-trichloroethyl aryldiazoacetates to asymmetric cyclopropanation reactions is described. These esters are capable of being removed selectively under mild conditions, giving the synthetic chemist a variety of options for deprotection of cyclopropylcarboxylic acids.

Table of Contents

Table of Contents

Chapter 1 -Introduction to Donor/Acceptor Rhodium-Carbene Chemistry

1.1 Introduction

1.2 Cyclopropanation

1.3 C-H Insertion

1.4 Conclusion

1.5 References

Chapter 2 - Reactions of Donor/Acceptor Rhodium-Carbenes with Electron-Deficient Dienes and Alkenes

2.1 Towards a Total Synthesis of Pseudolaric Acid

2.1.1 Introduction

2.1.1.1 Pseudolaric Acid B 2.1.1.2 Reactions of Carbenes with Furans 2.1.1.3 The Cyclopropanation/Cope Rearrangement 2.1.1.4 A Retrosynthetic Route to Pseudolaric Acid B

2.1.2 Results and Discussion

2.1.2.1 Furan Ring-Opening Model Study 2.1.2.2 First Generation Approach 2.1.2.3 Hypothesis for Diastereoselectivity and Model Study 2.1.2.4 Second Generation Approach

2.1.3 Conclusion

2.2 Cyclopropanation of Electron-Deficient Alkenes

2.2.1 Introduction

2.2.2 Results and Discussion

2.2.3 Conclusion

2.3 Experimental Section

2.3.1 Furan Ring-Opening

2.3.2 First generation synthetic approach

2.3.3 Model Study for [4+3] Cycloaddition

2.3.4 Second Generation Synthesis

2.3.5 Cyclopropanation of Electron-Deficient Alkenes

2.3.5.1 Synthesis of styryldiazoacetates 2.3.5.2 General Procedure for Cyclopropanation 2.3.5.3 Experimental Data for Cyclopropanes

2.3.6 X-Ray Crystal Structure Data for 2.81

2.4 References

Chapter 3 - Stereoselective Synthesis of Allylsilanes

3.1 Introduction

3.1.1 Uses for Allylsilanes

3.1.1.1 Properties and Reactions of Allylsilanes 3.1.1.2 Allylsilanes in Total Synthesis

3.1.2 Preparation of Allylsilanes

3.1.2.1 Preparation of allylsilanes by forming the C-Si bond 3.1.2.2 Preparation of allylsilanes by forming the C-C single bond 3.1.2.3 Preparation of allylsilanes by forming the C-C double bond 3.1.2.4 Preparation of Allylsilanes: Conclusion 3.1.3 b-lactones by Intramolecular C-H Insertion of Diazo Compounds

3.2 Results and Discussion

3.2.1 Initial Reaction Discovery

3.2.2 Forming a Hypothesis for Reaction Optimization

3.2.3 Reaction Scope

3.2.4 Mechanistic Investigation and Control Reactions

3.3 Conclusion

3.4 Experimental Section

3.4.1 Synthesis of Achiral Diazos

3.4.1.1 Preparation of 2-silylethanols 3.4.1.2 Preparation of Diazos 3.67a-g 3.4.1.3 Preparation of Diazos 3.69a-k 3.4.1.4 Preparation of Diazos 3.71 and 3.80

3.4.2 Preparation of Chiral Diazos

3.4.2.1 Synthesis of 3.77a-c 3.4.2.2 Synthesis of Diazos 3.74a-c

3.4.3 General Procedure for Allyl Silane Reaction

3.4.4 Experimental Data for Allyl Silanes

3.4.5 Control Reactions

3.4.6 Crystal Structure Data for 3.81

3.5 References

Chapter 4 - Expanding the Scope of Intermolecular Donor/Acceptor Carbene C-H Functionalization

4.1 Introduction

4.2 Effect of ester on site-selective C-H functionalization with donor/acceptor diazoacetates

4.2.1 Introduction to site-selective C-H functionalization

4.2.2 Results and Discussion

4.2.3 Conclusion

4.3 Developing a predictive model for site-selective C-H functionalization

4.3.1 Introduction

4.3.2 Results and Discussion

4.3.3 Conclusion

4.4 Asymmetric C-H functionalization of methyl ethers

4.4.1 Introduction to C-H functionalization of methyl ethers

4.4.2 Results and Discussion

4.4.2.1 Optimization of Methyl Ether Functionalization 4.4.2.2 Reaction Scope

4.4.2.3 Advantages of the Trichloroethyl Ester in Methyl Ether C-H Functionalization

4.4.3 Conclusion

4.5 Asymmetric functionalization of electron-deficient substrates

4.5.1 Results and Discussion

4.5.2 Conclusion

4.6 Experimental Section

4.6.1 Site Selective C-H Functionalization

4.6.1.2 Preparation of Diazo Compounds 4.6.1.3 Experimental Data for C-H functionalization Compounds

4.6.2 Modeling Site-Selective C-H Functionalization

4.6.2.1 Preparation of Diazo Compounds

4.6.2.2 General Procedures for C-H Functionalization Reactions and Measuring Site-Selectivity Ratios

4.6.3 Functionalization of Methyl Ethers

4.6.3.1 Acquisition and Preparation of Substrates 4.6.3.2 Preparation of Diazo Compounds 4.6.3.3 General Procedures for C-H Functionalization Reactions 4.6.3.4 Experimental Data for C-H Functionalization Products

4.6.4 Functionalization of Electron-Deficient Substrates

4.6.5 Crystal Structure Data for 4.55

4.7 References

Chapter 5 - Asymmetric Cyclopropanation with Novel Diazo Esters

5.1 Introduction

5.2 Results and Discussion

5.2.1 Cyclopropanation with 2-(trimethylsilyl)ethyl diazoacetates

5.2.2 Cyclopropanation with 2,2,2-trichloroethyl aryldiazoacetates

5.3 Conclusion

5.4 Experimental Section

5.5 References

Appendix A - Structures of Dirhodium Catalysts

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Palabra Clave	Rhodium Carbene
Committee Chair / Thesis Advisor	Davies, Huw, Emory University
Committee Members	Menger, Fred M, Emory University McDonald, Frank, Emory University

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