Expanding the Scope of Donor/Acceptor Rhodium-Carbene Chemistry Pubblico
Guptill, David Matthew (2014)
Published
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 B2.1.2 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 Approach2.1.3 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 Cyclopropanes2.3.6 X-Ray Crystal Structure Data for 2.81
2.4 References
Chapter 3 - Stereoselective Synthesis of Allylsilanes3.1 Introduction
3.1.1 Uses for Allylsilanes
3.1.1.1 Properties and Reactions of Allylsilanes 3.1.1.2 Allylsilanes in Total Synthesis3.1.2 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 Compounds3.2 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 3.803.4.2 Preparation of Chiral Diazos
3.4.2.1 Synthesis of 3.77a-c 3.4.2.2 Synthesis of Diazos 3.74a-c3.4.3 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 Scope4.4.2.3 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 Compounds4.6.2 Modeling Site-Selective C-H Functionalization
4.6.2.1 Preparation of Diazo Compounds4.6.2.2 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 Products4.6.4 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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