Overcoming the Limitations of Rhodium-Catalyzed Asymmetric Cyclopropanation and Other Adventures in Strained Ring Synthesis Pubblico
Sharland, Jack (Spring 2023)
Abstract
Rhodium-catalyzed carbenoid reactions have been extensively explored over the past 40 years. While much of recent studies in this field of chemistry have been devoted to exploring Csp3 C–H functionalization reactions and expanding both the synthetic scope and site-selectivity of these transformations, they are rarely used outside of the academic lab. More industrially relevant is the enantioselective cyclopropanation enabled by dirhodium(II) tetracarboxylate catalysts. This reaction is uniquely selective, offering unparalleled diastereoselectivity and enantioselectivity when a donor/acceptor carbene is used, allowing chemists to generate these strained rings in a predictable and controllable manner with excellent yield. While substantial research has already been performed in this arena, there are significant concerns with practicality, scalability, and scope. The work is divided into several chapters devoted to a detailed discussion of three major subjects. Additive enhanced cyclopropanation, computational studies of these additive effects, and a new synthesis of difluorobicyclo[1.1.1]pentanes. A brief summary of the chapter contents follows.
Chapter 1: This chapter will discuss the discovery of (MeO)2CO as a enantioenhancing reaction media using a medium-throughput condition screen and application towards highly selective asymmetric cyclopropanations at extremely low catalyst loadings.
Chapter 2: This section will discuss the discovery of general cyclopropanation conditions for highly enantioselective transformations of ortho-substituted aryldiazoacetates and its application to a broad scope of vinyl aza-heterocycles. This chemistry has also been of significance to an ongoing medicinal chemistry program at AbbVie and this will be discussed briefly.
Chapter 3: This section will explore the role of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), including its ability to selectively deactivate poisonous and reactive nucleophiles in asymmetric cyclopropanation. This additive has profound effects on catalyst enantioselectivity, reactivity and substrate scope.
Chapter 4: This chapter will explore computational endeavors to rationalize the remarkable effect additives can have on rhodium carbene chemistry. Three additives will be explored in this chapter, N,N’- dicyclohexylcarbodiimide (DCC) in C–H functionalization, 2-chloropyridine in asymmetric cyclopropanation, and HFIP’s ability to manipulate catalyst selectivity.
Chapter 5: The final chapter will discuss a novel synthetic strategy to access difluorobicyclo[1.1.1]pentanes in one-pot. The generation of unexpected reaction products when difluorocarbene is reacted with 2-aryl bicyclo[1.1.0]butanes will also be explored.
Table of Contents
Introduction…………………………………………………………………………………………………………………..……...1 References……………………………………………………………………………………………………………………………24
Chapter 1: Enhancement of asymmetric cyclopropanation with dimethyl carbonate as solvent and applications for low catalyst loading
1.1 Introduction…………………………………………………………………………………………….…..33
1.2 Results and Discussions………………………………………………………………………………..38
1.3 Conclusions………………………………………………………………………………………………….53
1.4 References……………………………………………………………………………………………………54
Chapter 2: Cyclopropanation of vinyl-azaheterocycles and the 2-Chloropyridine additive effect.
2.1 Introduction…………………………………………………………………………………………………58
2.2 Results and Discussions………………………………………………………………..………………62
2.3 Conclusions……………………………………………………………………………………………….…80
2.4 References……………………………………………………………………………………………………81
Chapter 3: 1,1,1,3,3,3-Hexafluoroisopropanol for the selective deactivation of poisonous nucleophiles, diversification of complex alkenes, and as a paradigm warping additive for rhodium carbene chemistry.
3.1 Introduction…………………………………………………………………………………………………87
3.2 Results and Discussions……………………………………………………………….…………….…95
3.3 Conclusions………………………………………………………………………………………………..131
3.4 References………………………………………………………………………………………………….132
Chapter 4: Unmasking the additive effect: in silico evaluation of rhodium carbene chemistry
4.1 Introduction……………………………………………………………………………………………….140
4.2 Results and Discussions………………………………………………………………………………143
4.3 Conclusions………………………………………………………………………………………………..168
4.4 References………………………………………………………………………………………………….168
Chapter 5: One-pot synthesis of difluorobicyclo[1.1.1]pentanes and related gemdifluorinated carbocycles from α-allyl diazoacetates.
5.1 Introduction……………………………………………………………………………………………….173
5.2 Results and Discussions…………………………………………………………………………..….178
5.3 Conclusions…………………………………………………………………………………….………….190
5.4 References………………………………………………………………………………………………….191
Appendices:
Appendix A: Chapter 1 Supporting Information………………………………………………….…….A1-A95
Appendix B: Chapter 2 Supporting Information………………………………………………….……B1-B200
Appendix C: Chapter 3 Supporting Information………………………………………………….……C1-C416
Appendix D: Chapter 4 Supporting Information…………………………………………………..….D1-D155
Appendix E: Chapter 5 Supporting Information…………………………………………………..…….E1-E91
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