Expanding the Scope of Donor/Acceptor Rhodium-Carbene Chemistry Open Access

Guptill, David Matthew (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/jw827b74h?locale=en


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

2.1.2 Results and Discussion Furan Ring-Opening Model Study First Generation Approach Hypothesis for Diastereoselectivity and Model Study 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 Synthesis of styryldiazoacetates General Procedure for Cyclopropanation 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 Properties and Reactions of Allylsilanes Allylsilanes in Total Synthesis

3.1.2 Preparation of Allylsilanes Preparation of allylsilanes by forming the C-Si bond Preparation of allylsilanes by forming the C-C single bond Preparation of allylsilanes by forming the C-C double bond 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 Preparation of 2-silylethanols Preparation of Diazos 3.67a-g Preparation of Diazos 3.69a-k Preparation of Diazos 3.71 and 3.80

3.4.2 Preparation of Chiral Diazos Synthesis of 3.77a-c 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 Optimization of Methyl Ether Functionalization Reaction Scope 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 Preparation of Diazo Compounds Experimental Data for C-H functionalization Compounds

4.6.2 Modeling Site-Selective C-H Functionalization Preparation of Diazo Compounds General Procedures for C-H Functionalization Reactions and Measuring Site-Selectivity Ratios

4.6.3 Functionalization of Methyl Ethers Acquisition and Preparation of Substrates Preparation of Diazo Compounds General Procedures for C-H Functionalization Reactions 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

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