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Part I: Carbonyl-Olefin Metathesis of Norbornene

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Part I: Carbonyl-Olefin Metathesis of Norbornene Part I: Carbonyl-Olefin Metathesis of Norbornene Part II: Cyclopropenimine-Catalyzed Asymmetric Michael Reactions Zara Maxine Seibel Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2016 1 © 2016 Zara Maxine Seibel All Rights Reserved 2 ABSTRACT Part I: Carbonyl-Olefin Metathesis of Norbornene Part II: Cyclopropenimine-Catalyzed Asymmetric Michael Reactions Zara Maxine Seibel This thesis details progress towards the development of an organocatalytic carbonyl- olefin metathesis of norbornene. This transformation has not previously been done catalytically and has not been done in practical manner with stepwise or stoichiometric processes. Building on the previous work of the Lambert lab on the metathesis of cyclopropene and an aldehyde using a hydrazine catalyst, this work discusses efforts to expand to the less stained norbornene. Computational and experimental studies on the catalytic cycle are discussed, including detailed experimental work on how various factors affect the difficult cycloreversion step. The second portion of this thesis details the use of chiral cyclopropenimine bases as catalysts for asymmetric Michael reactions. The Lambert lab has previously developed chiral cyclopropenimine bases for glycine imine nucleophiles. The scope of these catalysts was expanded to include glycine imine derivatives in which the nitrogen atom was replaced with a carbon atom, and to include imines derived from other amino acids. i Table of Contents List of Abbreviations…………………………………………………………………………..iv Part I: Carbonyl-Olefin Metathesis…………………………………………………………… 1 Chapter 1 – Metathesis Reactions of Double Bonds………………………………………….. 1 Introduction………………………………………………………………………………. 1 Olefin Metathesis………………………………………………………………………… 2 Wittig Reaction…………………………………………………………………………... 6 Tebbe Olefination………………………………………………………………………... 9 Carbonyl-Olefin Metathesis…………………………………………………………….. 10 References………………………………………………………………………………. 14 Chapter 2 – Progress Towards Carbonyl-Olefin Metathesis of Norbornene……………… 17 Introduction……………………………………………………………………………... 17 [3+2] Metathesis Paradigm……………………………………………………………... 18 Cycloaddition Precedence………………………………………………………………. 19 Cycloreversion Precedence……………………………………………………………... 22 Carbonyl-Olefin Metathesis of Cyclopropene………………………….………………. 24 Computational Work……………………………………………………………………. 26 Carbonyl-Olefin Metathesis of Norbornene………………………….…………………. 29 i Conclusions……………………………………………………………………………... 42 References………………………………………………………………………………. 44 Acknowledgements……………………………………………………………………... 46 Experimental Data………………………………………………………………………. 47 NMR Spectra……………………………………………………………………………. 59 Part II: Cyclopropenimine-Catalyzed Asymmetric Michael Reactions…………………… 95 Chapter 3 – Asymmetric Catalysis with Chiral Brønsted Superbases……………………… 95 Introduction……………………………………………………………………………... 95 Guanidines……………………………………………………………………………… 96 Iminophosphoranes……………………………………………………………………. 105 Proazaphosphatranes…………………………………………………………………... 108 Cyclopropenimines……………………………………………………………….…… 110 Higher-Order Superbases……………………………………………………………… 114 Summary………………………………………………………………………………. 117 References……………………………………………………………………………... 118 Chapter 4 – Asymmetric Michael Reactions with Cyclopropenimines……………………. 122 Introduction……………………………………………………………………………. 122 Cyclopropenimine Synthesis and Properties…………………………………………... 122 ii 3-butenoates…………………………………………………………………………… 124 α-substituted glycine imines…………………………………………………………… 131 Conclusions……………………………………………………………………………. 145 References……………………………………………………………………………... 146 Acknowledgements……………………………………………………………………. 148 Experimental Data……………………………………………………………………... 149 NMR Spectra…………………………………………………………………………... 174 Chiral HPLC Traces…………………………………………………………………… 260 iii List of Abbreviations BINOL 1,1’-bi-2-naphthol BOC tert-butoxycarbonyl BTMG 2-tert-butyl-1,1,3,3-tertamethylguanidine CPI cyclopropenimine Cy cyclohexyl d day DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCB dichlorobenzene DCM dichloromethane DFT density functional theory DMA dimethylacetamide DMF dimethylformamide DMSO dimethyl sulfoxide dr diastereomeric ratio ee enantiomeric excess FMO frontier molecular orbital h hour iv H-bond hydrogen bond HMDS hexamethyldisilazide HOMO highest occupied molecular orbital HTE high-throughput experimentation LUMO lowest unoccupied molecular orbital min minute MOM methoxymethyl MTBD 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene NMP N-methylpyrrolidine NMR nuclear magnetic resonance PS polystyrene PTC phase-transfer catalysis ROMP ring-opening metathesis polymerization rt room temperature TBAI tetrabutylammonium iodide TBD 1,5,7-triazabicyclo[4.4.0]dec-5-ene TBME tert-butylmethyl ether TEA triethylamine v THF tetrahydrofuran TLC thin-layer chromatography TMG tetramethylguanidine TMS trimethylsilyl Troc 2,2,2-trichloroethoxycarbonyl Ts p-toluenesulfonyl vi For my grandparents, Mema and Pepa vii 1 Part I: Carbonyl-Olefin Metathesis Chapter 1 – Metathesis Reactions of Double Bonds Introduction Double bond metathesis, shown conceptually in Figure 1, encompasses a wide variety of chemical transformations, most prominently olefin metathesis1 via transition metal catalysts, and the Wittig olefination2. In both of these cases, two reactive double bonds come together to form a [2+2] cycloadduct. This cycloadduct then undergoes a [2+2] cycloreversion to release the metathesis products. These transformations are a powerful way to form carbon-carbon double bonds and are used in a variety of industrial procedures, including drug development and material synthesis. The progress and importance of these reactions will be discussed in this chapter. Figure 1. Double bond metathesis. While these types of metathesis reactions are well developed and synthetically useful, carbonyl-olefin metathesis remains an underdeveloped platform, despite its potential to be very impactful. There exists a few limited cases in which carbonyl-olefin metathesis has been done in a step-wise fashion using transition metal alkylidenes,3 photochemistry,4 or Lewis acid activation.5 More recently catalytic processes have been developed using a Lewis acid catalyst.6 My colleagues in the Lambert lab have also established a carbonyl-olefin metathesis reaction using a hydrazine catalyst.7 These reactions will also be discussed in this chapter. 2 Figure 2: Select Categories of Double Bond Metathesis Reactions Olefin Metathesis Olefin metathesis is a robust reaction which has transformed organic chemistry. It has myriad applications, and its utility and importance was recognized in 2005 when Yves Chauvin, Robert Grubbs, and Richard Schrock were awarded the Nobel Prize in Chemistry. There are three major types of olefin metathesis, shown below in Figure 3. Ring-opening metathesis is frequently driven by ring-strain, and can be used to form polymers in a process known as ring opening metathesis polymerization (ROMP). Ring-closing metathesis is often driven by entropy from the release of a molecule of ethylene gas. Cross metathesis can be the most difficult type of metathesis to enact selectively because the reaction is in principle reversible. However, this can be mitigated by catalyst design, steric and electronic factors, and, in some reactions, the release of ethylene as a driving force.8 3 Figure 3. Major types of olefin metathesis reactions. The earliest olefin metathesis reaction was observed in 1955 by Karl Ziegler.9 He was studying propylene polymerization and, instead of the expected polymer product, noticed the formation of 1-butene from certain aluminum and nickel catalysts. In 1960, DuPont reported the ring-opening polymerization of norbornene to polynorbornene using titanium tetrachloride and lithium aluminum tetraheptyl, a process they called “coordination polymerization”.10 A few years later a group at the Phillips Petroleum Company reported what they called “olefin disproportionation” with molybdenum and tungsten catalysts.11 They were able to convert propylene to a mixture of 2-butene and ethylene and incorrectly proposed a cyclopropene-metal complex as a reaction intermediate. The term “olefin metathesis” was coined in 1967 by researchers at Goodyear Tire and Rubber Company. They observed that 2-pentene quickly became a mixture of 2-pentene, 3-hexene, and 2-butene upon exposure to a tungsten catalyst and an aluminum Lewis acid.12 In 1971, Chauvin proposed the mechanism for olefin metathesis that is widely accepted today.13 As shown below in Figure 4, a metal alkylidene coordinates to an olefin and then reacts to form a metallacyclobutane, which can then undergo a cycloreversion to produce a new olefin and a new alkylidene. The other olefin product is formed when the new 4 metal alkylidene reacts with a different olefin in the same process. The first transitional metal alkylidene discovered was a tungsten alkylidene observed by Fischer in 1964.14 Figure 4. Basic mechanism for the olefin metathesis reaction. Catalysts that are significantly more stable and well-behaved than those early catalysts have been developed. Grubbs has developed a number of effective ruthenium-based catalysts,15 and Hoyveda has built on that by incorporating a chelating ligand for increased stability.16 Shrock has developed a series of molybdenum catalysts for metathesis.17 In general, the Shrock catalysts are more active (and thus more useful for sterically bulky substrates), while the Grubbs catalysts are more air-stable.8 These catalysts also have
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