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SELECTIVE TRANSFORMATIONS OF EPOXIDES USING BIMETALLIC CATALYSTS: CATALYST DEVELOPMENT, METHODOLOGY, AND MECHANISTIC STUDIES

A Dissertation Presented to the Faculty of the Graduate School of Cornell University

In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy

by Jessica Rachel Lamb August 2017

SELECTIVE TRANSFORMATIONS OF EPOXIDES USING BIMETALLIC CATALYSTS: CATALYST DEVELOPMENT, METHODOLOGY, AND MECHANISTIC STUDIES

Jessica Rachel Lamb, Ph.D. Cornell University 2017

Epoxides are versatile building blocks in organic chemistry due to their inherent reactivity and synthetic availability. One particularly interesting reaction is the carbonylation of epoxides to β-lactones. β-Lactones are themselves high-value intermediates for natural-product and aliphatic-polyester synthesis. Bimetallic [Lewis

+ − acid] [Co(CO)4] catalysts allow for the mild and economical synthesis of β-lactones from epoxides and the inexpensive feedstock carbon monoxide. The modular salen ligand is a common framework for the Lewis acid portion of these catalysts and recent extensive tuning of the ligand sterics has improved the regio- and enantioselectivity for the carbonylation of 2,3-disubstituted epoxides.

Herein, we report further development and application of these bimetallic catalysts to a variety of reactions. First, electronic variations are studied for the enantioselective carbonylation of meso- and racemic cis-epoxides. Enantioselectivity was improved for every substrate, resulting in some of the highest levels of enantioenrichment for epoxide carbonylation. We then applied the knowledge gained from previous catalyst development to design a new ligand for the contrasteric carbonylation of isobutylene oxide to the important polyester monomer pivalolactone. This catalyst is the first to give

pivalolactone as the major product of an epoxide carbonylation reaction, representing a major advance in the field.

Next, we applied previously developed bimetallic catalysts to the isomerization of epoxides to ketones. A wide array of monosubstituted epoxides were rearranged to methyl ketones under mild conditions and low catalyst loadings. We further expanded this methodology to the regioselective isomerization of trans-epoxides. This method displayed high and complementary selectivities to the Wacker oxidation of internal olefins. The mechanism of this reaction was thoroughly studied and additional catalyst tuning allowed for the first kinetic resolution of benzyl-substituted trans-epoxides with synthetically useful selectivity factors.

Finally, related [Lewis acid][Mn(CO)5] catalysts were developed and applied to the deoxygenation of epoxides to alkenes using carbon monoxide as the terminal reductant.

This is a rare example of a catalytic system that proceeds with clean inversion of stereochemistry for cis- and trans-epoxides, highlighting the potential for stereospecific alkene inversion through a two-step epoxidation-deoxygenation. Collectively, these studies demonstrate the utility of these catalysts for a range of selective epoxide transformations.

BIOGRAPHICAL SKETCH

Jessica Lamb was born in Madison, WI and grew up in Fargo, ND. She attributes her love of science to teachers in middle and high school who inspired her and helped her test out of sophomore general chemistry, starting her love affair with the central science. Upon graduating from South High School in 2008, she attended the University of North Dakota as a chemistry major with minors in mathematics and Spanish. After one semester of inorganic chemistry research, she found her home in organic and organometallic chemistry in the lab of Prof. Irina Smoliakova, where she worked on the synthesis of cyclopalladated complexes on silica gel for her senior honors thesis. She also did two summers of research in the coatings and polymeric materials lab of Prof. Victoria Johnston-Gelling. This background in organic and polymer chemistry drew her to the research of Prof. Geoffrey Coates. After graduating summa cum laude with a B.S. in chemistry as a scholar in the

Honors Program in 2012, she moved to Cornell University and joined the Coates group for her graduate career. As an NSF graduate research fellow, she worked on selective reactions of epoxides using [Lewis acid][nucleophilic anion] catalysts. Outside of lab, she joined the ballroom dance team, engaged in science outreach, and tried to keep up with her unreasonable number of hobbies, including crafting, music, reading, and photography. Upon completing her Ph.D. in 2017, she will begin her professional career as a postdoctoral researcher in the lab of Jeremiah Johnson at M.I.T.

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ACKNOWLEDGMENTS

First and foremost, I have to thank my advisor, Prof. Geoff Coates, for supporting me during the last five years. He is an endless fountain of new ideas and he has inspired me to become a better scientist and mentor. I learned so much about how to ask the right questions, how to troubleshoot difficult reactions (run it neat and heat it up!), and how to optimize white space in a figure. I wouldn’t be the chemist I am today if it wasn’t for all of your guidance and advice. The Coates group is a special place to do research and it wouldn’t be possible without you. Next, I have to thank Prof. William Dichtel and Prof. Chad Lewis for serving on my A exam committee and Prof. Brett Fors and Prof. Song Lin for stepping up and serving on my B exam committee. I have been fortunate to have not two, but four amazing chemists available for discussions and answering my unending questions. I am grateful for the opportunity to know and have learned from you all.

Thank you to all of the previous members of the Coates group who have contributed to the great group culture of excellent science and comradery, especially to the carbonylation subgroup; I feel like I know you all even if we haven’t met. Furthermore, thank you to all of the members of 572 during my tenure. Special shout out to Michael Mulzer for laying the ground work for all of my projects; teaching me how to make catalysts, run columns, and set up carbonylations; bequeathing me countless ligands, catalysts, and epoxides; helping me write my first Coates group paper; answering all of my questions; and generally being an awesome inspiration. If I have had any success in graduate school, it is from standing on your giant shoulders. Chad Ellis taught me how to cannula transfer and crystallize things. Brandon Tiegs taught me about the glovebox and so much more during our two years as the sole (permanent) inhabitants of 572. I have also had the pleasure to work with Zachary Nelson, Veronika

Kottisch, Xiaopeng Yu, Michelle Lee, and Aran Hubbell. You have all made coming to work more enjoyable and you have made me a better mentor, colleague, and friend. I am fortunate to have gone through this amazing adventure with the other fifth years in the Coates group: Kyle O’Connor, Qi Zheng, and Dave Vaccarello. You have all provided emotional support, especially during this last crazy year! We are almost done! Thank you to all of the other members of the Coates group with whom I have overlapped during my five years! Everyone has always been open for great discussions or a trip to the Dairy bar. I will forever look back at my time in this group with fond memories because of all the wonderful people I met here. Special thanks to Anne LaPointe and Kelly Case for keeping the Coates group running! We wouldn’t be able to do anything without the two of you. Other people in the chemistry department I have to thank are Sam MacMillan for helping me get my first crystal structure, Anthony Condo for helping me with GCMS and DART, and especially Ivan Keresztes for all of the NMR help and discussions on the “beast” that is the mechanism paper, which is unfortunately (or fortunately?) not included herein. Of course, I must also thank the National Science Foundation for a graduate research fellowship and the Department of Energy for supporting my research. Outside of lab, I need to thank the members of the Cornell DanceSport Team and Expanding Your Horizons, particularly Maria Carrizales and Lilli Morris; it was a great honor to serve as your Finance Chair. The ballroom team and EYH will always have a special place in my heart as the non-lab things that kept me sane.

Finally, I need to thank all of my friends and family who have stood by me and supported me throughout graduate school and my whole life. There are too many to list, but I would be nothing without you. You have all dealt with my crazy, Dan more than most, and I will be forever grateful for the shoulders to lean on, encouraging words, and funny distractions that have helped me through this journey.

TABLE OF CONTENTS

BIOGRAPHICAL SKETCH iii

ACKNOWLEDGMENTS iv

LIST OF FIGURES x

LIST OF SCHEMES xiii

LIST OF TABLES xv

CHAPTER 1: Overview of Properties and Reactions of Epoxides 1

1.1 Introduction and Synthetic Routes to Epoxides 2

1.2 Carbonylation of Epoxides to β-Lactones 4 1.2.1 Background 4 1.2.2 Carbonylation of Epoxides Using [Lewis acid]+[Co(CO) ]− 4 5 Catalysts 1.2.3 Recent Catalyst Advances for Regio- and Enantioselective 8 Carbonylation of Epoxides

1.3 Isomerization of Epoxides to Carbonyl Compounds 12

1.4 Deoxygenation of Epoxides to Alkenes 16

REFERENCES 19

CHAPTER 2: Catalyst Development for the Enantio- and Regioselective 29 Carbonylation of Disubstituted Epoxides

2.1 Introduction 30

2.2 Catalyst Electronic Variation for the Enantioselective Carbonylation 33 of Cis-Epoxides to Trans-β-Lactones 2.2.1 Background 33 2.2.2 Previous Catalyst Development 37 2.2.3 Catalyst Electronic Variations for Meso-Desymmetrization 39 2.2.3.1 Effect of Lower Temperature 43 2.2.4 Electronic Catalyst Variations for the Carbonylation of 44 Racemic Cis-Epoxides

2.2.5 Conclusion 47

2.3 Catalyst Development for the Contrasteric Carbonylation of 48 Isobutylene Oxide to Pivalolactone 2.3.1 Background 48 2.3.2 Catalyst Optimization 50 2.3.3 Reaction Optimization 53 2.3.4 Conclusion 55

2.4 Synopsis 55

2.5 Experimental Procedures 56 2.5.1 General Considerations 56 2.5.2 Synthetic Procedures 60 2.5.2.1 General Procedures 60 2.5.2.2 Synthesis of Starting Materials 63 2.5.2.3 Synthesis of Catalyst Precursors 71 2.5.2.4 Carbonylative Desymmetrization of Meso-Epoxides 82 using Catalysts (R)-1c–h at 22 °C 2.5.2.5 Carbonylative Desymmetrization of Racemic-Epoxides 99 using Catalysts (R)-1c, e, g, and h at 22 °C 2.5.2.6 Carbonylative Desymmetrization of Meso-Epoxides 109 Using (R)-1e and 1h at 0 °C 2.5.2.7 Contrasteric Carbonylation of Isobutylene Oxide 110

REFERENCES 111

CHAPTER 3: Rearrangement of Monosubstituted Epoxides to Methyl 118 Ketones Using an Aluminum Porphyrin Cobaltate Catalyst

3.1 Introduction 119

3.2 Reaction Optimization 120

3.3 Substrate Scope and Limitations 121

3.4 Mechanistic Explorations and Control Experiments 124

3.5 Conclusion 130

3.6 Experimental Procedures 130 3.6.1 General Considerations 130 3.6.2 Mechanistic Experiments 133 3.6.3 Synthetic Procedures 135

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3.6.3.1 General Procedures 135 3.6.3.2 Synthesis of Starting Materials 136 3.6.3.3 Isomerization of Monosubstituted Epoxides to Methyl 140 Ketones

REFERENCES 147

CHAPTER 4: Regioselective Isomerization of 2,3-Disubstituted Epoxides 152 to Ketones: An Alternative to the Wacker Oxidation of Internal Alkenes

4.1 Introduction 153

4.2 Reaction Optimization 156

4.3 Substrate Scope 158

4.4 Mechanistic Experiments 161 4.4.1 Proposed Mechanism 161 4.4.2 Control Experiments 162 4.4.3 Kinetics Experiments 164 4.4.4 Kinetic Isotope Effect 165

4.5 Kinetic Resolution of Trans-Epoxides 168

4.6 Conclusions 172

4.7 Experimental Methods 173 4.7.1 General Considerations 173 4.7.2 Kinetics Data 176 4.7.3 Isolation of Deuterated Ketones 180 4.7.4 Kinetic Resolution Data 180 4.7.5 Synthetic Procedures 186 4.7.5.1 General Procedures 186 4.7.5.2 Synthesis of Starting Materials 189 4.7.5.3 Isomerization of Epoxides to Ketones 197

REFERENCES 204

CHAPTER 5: Catalyst Development for the Deoxygenation of Epoxides with Inversion of Stereochemistry Using Carbon Monoxide as the 211 Reductant

5.1 Introduction 212

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5.2 Catalyst Optimization and Reaction Development 214

5.3 Scope of the Epoxide Deoxygenation 217

5.4 Mechanistic Experiments 221

5.5 Solid State Structure of Catalyst 3b 226

5.6 Conclusion 227

5.7 Experimental Procedures 228 5.7.1 General Considerations 228 5.7.2 Synthetic Procedures 231 5.7.2.1 General Procedures 231 5.7.2.2 Synthesis of Starting Materials 232 5.7.2.3 Deoxygenation of Epoxides to Alkenes 237 5.7.3 Crystallographic Data for Catalyst 3b 238

REFERENCES 267

LIST OF FIGURES

Figure 1.1 Selected carbonylation catalysts of the form [Lewis 5 acid][Co(CO)4] and their applications. Figure 2.1 (A) Selected examples of natural products containing a β-lactone and (B) an approved anti-obesity drug containing a trans-β- 30 lactone. Figure 2.2 (A) Modular sites for tuning the salen ligand and (B) the 33 relationship between ligand backbone and catalyst geometry. Figure 2.3 Electronic effects on the meso-desymmetrization of epoxides 3 40 using catalysts (R)-1c–h. 1 Figure 2.4 Hammett plots containing (R)-1i (R = NO2) continuing the LFER for lactone 4b (blue circles) and breaking linearity for 43 lactone 4d (red squares). Figure 2.5 Electronic effects on the regiodivergent carbonylation of 45 epoxides 5 using catalysts (R)-1c, 1e, 1g, and 1h. Figure 2.6 (A) Structure and properties of poly(pivalolactone) and (B) a decomposition pathway of poly(3-hydroxybutyrate) via α- 48 proton abstraction. Figure 2.7 Catalysts screened for the contrasteric carbonylation of 51 isobutylene oxide. Figure 2.8 (A) Ligand coordination geometries and (B) a model for the S 1 N 53 mechanism. Figure 2.9 New carbonylation catalysts for the enantio- and regioselective 56 carbonylation of disubstituted epoxides to β-lactones. Figure 2.10 Representative GC chromatograms for 4b on β-Dex 120 column. 83 Figure 2.11 Representative GC chromatograms for 4b on Chiraldex A-TA 84 column. Figure 2.12 Representative GC chromatograms for 4b on β-Dex225 column. 85 Figure 2.13 Representative GC chromatograms for 4c on β-Dex120 column. 88 Figure 2.14 Representative GC chromatograms for 4c on β-Dex225 column. 89 Figure 2.15 Representative GC chromatograms for 4a on β-Dex120 column. 92 Figure 2.16 Representative GC chromatograms for 4a on β-Dex225 column. 93 Figure 2.17 Representative GC chromatograms for 4d on Chiraldex A-TA 96 column. Figure 2.18 Representative GC chromatograms for 4d on β-Dex225 column. 97

Figure 2.19 Representative GC chromatograms for 6a and 7a on β-Dex225 100 column. Figure 2.20 Representative GC chromatograms for 6b and 7b on β-Dex225 103 column. Figure 2.21 Representative GC chromatograms for 6c and 7c on β-Dex225 105 column. Figure 2.22 Representative GC chromatograms for 6d and 7d on β-Dex225 107 column. Figure 3.1 Isolated yields and substrate scope for the rearrangement of 122 monosubstituted epoxides. Figure 3.2 1H and 13C NMR spectra of 2r. 139 Figure 3.3 1H and 13C NMR spectra of 3r. 146 Figure 4.1 Order in catalyst rac-4 by initial rate kinetics. 164 Figure 4.2 Order in epoxide by long term kinetics. 165 Figure 4.3 1H NMR spectra of isolated deuterated ketones (bottom) versus 167 3-octanone (top). Figure 4.4 Experimental kinetic resolution data (red circles) for rac-1m 170 compared to a simulated first-order krel = 17 curve (black line). Figure 4.5 Plot of concentration of epoxide and ketone over time to 177 calculate rate at [rac-4] = 0.005 M. Figure 4.6 Kinetic isotope effect raw data. 179 Figure 4.7 Product inhibition test raw data. 180 Figure 4.8 (A) Kinetic resolution plot and (B) GC traces for epoxide 1m. 182 Figure 4.9 (A) Kinetic resolution plot and (B) GC traces for epoxide 1p. 183 Figure 4.10 (A) Kinetic resolution plot and (B) GC traces for epoxide 1q. 184 Figure 4.11 (A) Kinetic resolution plot and (B) GC traces for epoxide 1r. 185 Figure 4.12 (A) Kinetic resolution plot and (B) GC traces for epoxide 1n. 186 Figure 4.13 1H NMR spectrum of (rel-R,R)-2,3-d -3-chloro-2-octanol and 2 192 (rel-R,R)-2,3-d2-2-chloro-3-octanol in CDCl3. Figure 4.14 1H NMR spectrum of (rel-S,R)-2,3-d -2-acetate-3-chloro-2- 2 193 octanol and 2,3-d2-3-acetate-2-chloro-3-octanol in CDCl3. 1 Figure 4.15 H NMR spectrum of 2h and 3h in CDCl3. 200 1 Figure 4.16 H NMR spectrum of 2i and 3i in CDCl3. 201 Figure 5.1 Catalysts investigated for the deoxygenation of epoxides. 214 Figure 5.2 Crude reaction mixture of the deoxygenation of cis-2-octene oxide (red, bottom) compared to E- (blue, top) and Z-2-octene 218 (green, middle) to show inversion of stereochemistry.

Figure 5.3 Crude reaction mixture of the deoxygenation of trans-2-octene oxide (orange, bottom) compared to E- (blue, top) and Z-2- 220 octene (green, middle) to show inversion of stereochemistry. Figure 5.4 Thermal ellipsoid representation of one of the independent molecules of [(salen)Al(THF)2][Mn(CO)5] (A) and (salen)Al(THF) viewed from the side (B) in the crystal structure 2 226 of 3b. Ellipsoids are drawn at the 50% probability level. All hydrogen atoms and atoms of the minor disorder component (and Mn(CO)5 anion for B) are omitted for clarity. Figure 5.5 Thermal ellipsoid representation of the two independent [(salen)Al(THF)2][Mn(CO)5] ion pairs in the crystal structure of 3b. Ellipsoids are drawn at the 50% probability level. All 239 hydrogen atoms and free THF in the lattice are omitted for clarity. Both components of the disorder are shown.

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LIST OF SCHEMES

Scheme 1.1 Common routes to epoxides 2 Scheme 1.2 Selected reactions of epoxides to polymers (pathways A–C) 3 and small molecules (pathways D–G) Scheme 1.3 Overview of β-lactone synthesis and applications 4 Scheme 1.4 Proposed mechanism for the carbonylation of epoxides using + − 7 [Lewis acid] [Co(CO)4] catalysts Scheme 1.5 Observed regioselectivity from standard carbonylation 9 catalysts for selected classes of epoxides Scheme 1.6 S 2 and S 1-type nucleophilic attack on 2,2-disubstituted N N 10 epoxides Scheme 1.7 Regioselective catalysts for steric and contrasteric 11 carbonylation of cis- and trans-2,3-disubstituted epoxides Scheme 1.8 Catalysts for the regiodivergent carbonylation of cis-epoxides 12 Scheme 1.9 Complication of the Meinwald rearrangement arising from 13 unselective ring opening and substituent migration Scheme 1.10 Proposed mechanisms for the isomerization of epoxides by 14 [Co(MeOH)6][Co(CO)4]2 Scheme 1.11 The Wacker oxidation of terminal olefins to ketones and 15 examples of complementary epoxidation/isomerization Scheme 1.12 Copper-catalyzed deoxygenation of epoxides to alkenes with retention of stereochemistry (A) and chemoselective reduction 18 of a disubstituted epoxide in the presence of a trisubstituted epoxide (B) Scheme 2.1 Reactivity of β-lactones with (A) hard and (B) soft nucleophiles and (C) the ring-opening polymerization to 31 aliphatic polyesters Scheme 2.2 Synthetic routes to β-lactones 32 Scheme 2.3 Carbonylative meso-desymmetrization of epoxides 34 Scheme 2.4 Enantioselective (A) kinetic resolution and (B) regiodivergent 35 carbonylation of racemic cis-epoxides Scheme 2.5 (A) Polymerization pathways of PVL and the synthesis of PVL using known methods (B) or an unprecedented contrasteric 49 carbonylation of IBO (C) Scheme 2.6 S 2 and S 1-type mechanisms of carbonylation of isobutylene N N 50 oxide Scheme 3.1 Mechanism of the Meinwald rearrangement of epoxides 119 activated by a Lewis acid (LA)

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Scheme 3.2 Catalytic (A) carbonylation and (B) isomerization of 120 monosubstituted epoxides by [Lewis acid][Co(CO)4] Scheme 3.3 Proposed cobalt carbonyl deactivation by β-lactone formation 122 Scheme 3.4 Wacker oxidation of a diene to form a diketone as the major 123 product Scheme 3.5 Viable pathways for aldehyde formation from isobutylene 126 oxide

Scheme 3.6 Intermediate HCo(CO)4 decomposition at room temperature 128 Scheme 3.7 Proposed decomposition pathway of HCo(CO) in the 4 129 presence of hydrogen gas Scheme 4.1 Known regioselective Wacker oxidation using unbiased monosubstituted (A) and electronically biased terminal (B) 153 and internal (C) substrates Scheme 4.2 Effect of directing group distance on the regioselectivity of 154 Wacker oxidation of internal olefins Scheme 4.3 Possible pathways for the net oxidation of unbiased 154 disubstituted alkenes to ketones Scheme 4.4 Proposed catalytic cycle for regioselective isomerization of 161 trans-epoxides to ketones using rac-4 Scheme 4.5 Product inhibition test with 2-butanone 163 Scheme 4.6 Isotope labeling studies 166 Scheme 4.7 Previous results for the kinetic resolution of epoxides using 169 [salenAl(THF)2][Co(CO)4] (R,R)-5 Scheme 5.1 Alkene isomerization and an alternative two-step epoxidation- 213 deoxygenation pathway Scheme 5.2 Preliminary experiment on the deoxygenation of cis-epoxides 221 in the presence of trans-epoxides Scheme 5.3 Possible deoxygenation mechanism with net inversion via 223 carbonylation-decarboxylation Scheme 5.4 Control experiment to show that β-lactone is not a competent 223 intermediate of the epoxide deoxygenation Scheme 5.5 Proposed mechanism for the deoxygenation of epoxides by 224 [Lewis acid (LA)][Mn(CO)5] catalysts Scheme 5.6 Alkene and ketone product distribution from cis- and trans-2- 225 octene oxide using catalyst 1 Scheme 5.7 Explanation of alkene to ketone product distribution for cis- 225 and trans-epoxides

xiv

LIST OF TABLES

Table 2.1 Previous catalyst optimization for the carbonylative meso- 37 desymmetrization Table 2.2 Scope of the carbonylative desymmetrization of meso-epoxides 38 3 Table 2.3 Change in conversion and enantioselectivity for a given meso- 41 epoxide using catalysts (R)-1c–h Table 2.4 Low conversion control experiments at 22 °C using (R)-1h 42 Table 2.5 Carbonylative meso-desymmetrization with strongly electron- 1 42 withdrawing catalyst (R)-1i (R = NO2) Table 2.6 Effect of lowered temperature on enantioselectivity using 44 catalysts (R)-1e and 1h Table 2.7 Change in enantioselectivity for a given racemic cis-epoxide 46 using catalysts (R)-1c, 1e, 1g, and 1h Table 2.8 Catalyst optimization for the contrasteric carbonylation of IBO 52 Table 2.9 Solvent effects on the contrasteric carbonylation of IBO by (R)- 54 10a Table 3.1 Evaluation of solvents and epoxide concentration for the 121 isomerization of epoxide 2a by catalyst 1 Table 3.2 Substrate limitations of epoxide rearrangement using 1 124 Table 3.3 Catalyst control experiments for the isomerization of 2a 125 Table 3.4 Competition experiments between propylene oxide and 127 isobutylene oxide Table 3.5 Effect of solvent polarity on the isomerization of 2a 128 Table 3.6 Effect of hydrogen pressure on epoxide isomerization by catalyst 129 1 Table 4.1 Evaluation of reaction conditions for the regioselective 157 isomerization of epoxide 1a by rac-4 Table 4.2 Isomerization of symmetrical substrates using rac-4 158 Table 4.3 Regioselectivity and substrate scope of unbiased epoxides 159 Table 4.4 Regioselectivity and substrate scope of biased trans- and 160 unbiased cis-epoxides Table 4.5 Catalyst control experiments 162 Table 4.6 Kinetic resolution catalyst optimization for epoxide 1m 169 Table 4.7 Kinetic resolution of benzyl-substituted trans-epoxides 171

Table 5.1 Catalyst optimization for the deoxygenation of epoxides 215 Table 5.2 Concentration and catalyst loading screens 216 Table 5.3 Initial scope of terminal epoxides using 3b 217 Table 5.4 Further optimization for the deoxygenation of trans-epoxides 219 Table 5.5 Catalyst control experiments for the deoxygenation of 4c 222 Table 5.6 Crystal data and structure refinement for catalyst 3b 239 Table 5.7 Atomic coordinates (x104) and equivalent isotropic displacement 240 parameters (Å2x103) for 3b Table 5.8 Bond lengths [Å] and angles [°] for 3b 244 Table 5.9 Anisotropic displacement parameters (Å2x103) for 3b. The anisotropic displacement factor exponent takes the form: 259 −2π2[h2 a*2U11+ ... + 2 h k a* b* U12] Table 5.10 Hydrogen coordinates (x104) and isotropic displacement 262 parameters (Å2x103) for 3b

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Overview of Properties and Reactions of Epoxides

1 1.1 Introduction and Synthetic Routes to Epoxides

Epoxides, also known as oxiranes, are three-membered rings consisting of two carbons and one oxygen. The cyclic nature of this functional group distorts the bond angles of the atoms, imparting high ring strain (ca. 27 kcal/mol)1 which contributes to the reactivity of epoxides towards a number of useful reactions in organic synthesis.

Additionally, the electronegativity of the oxygen atom makes both epoxy-carbons electrophilic, further driving many nucleophilic reactions at these sites.

Epoxides are readily available from a variety of synthetic routes (Scheme 1.1). Most commonly, organic peroxy acids,2 dioxiranes,3 or transition metals4 convert alkenes to epoxides. The Corey-Chaykovsky reaction,5 which converts carbonyl groups into epoxides using sulfur ylide reagents, and the ring-closure of halohydrins2 are also common methods to form epoxides.

Scheme 1.1 Common routes to epoxides Due to the possibility of setting two adjacent stereogenic centers upon ring opening, enantioenriched epoxides have been important intermediates in asymmetric synthesis.6

Since the seminal work of Sharpless and coworkers on asymmetric epoxidation of allylic alcohols,7 many more asymmetric epoxidations have been developed in recent

years.4,8 Enantioenriched epoxides can also be accessed through the kinetic resolution of racemic epoxides.9

Epoxides can be transformed into to a variety of useful polymers and small molecules (Scheme 1.2).10 They can be homopolymerized to form polyethers (pathway

A)11 or copolymerized with carbon dioxide (pathway B)12 or cyclic anhydrides (pathway

C)13 in an alternating fashion to form polycarbonates or polyesters, respectively. These chain-growth polymerization methods allow for the synthesis of well-controlled materials and the diversity of available epoxides allows for the precise tuning of polymer properties.

Scheme 1.2 Selected reactions of epoxides to polymers (pathways A–C) and small molecules (pathways D–G) The class of reactions most commonly studied and utilized for epoxides is nucleophilic ring opening (pathway D).8g,14 The broad scope of both epoxides and nucleophiles make these transformations very versatile, such that nucleophilic ring opening has been applied to a number of natural product syntheses.6,15 One limitation of current systems is that the regioselectivity of the SN2-type attack on unsymmetrical cis- or trans-disubstituted epoxides is difficult to control14c,16 due to the almost identical

electrophilicity of the two methine carbons. Strategies that have been employed to address this limitation include: (1) use of epoxides that carry a strong electronic or steric

17 18 bias, (2) switching to a non-SN2-mechanism, (3) performing the reaction intramolecularly,19 and (4) using a directing group present in the epoxide.16b,20

The final pathways shown in Scheme 1.2 – epoxide carbonylation (E), isomerization

(F), and deoxygenation (G) – will be discussed in more detail in the subsequent sections.

1.2 Carbonylation of Epoxides to β-Lactones

1.2.1 Background β-Lactones are motifs in natural products21 and are versatile synthetic intermediates for the formation of aldol-type products22 and a class of aliphatic polyesters known as polyhydroxyalkanoates (Scheme 1.3).23 Previous routes to β-lactones have included the

(formal) [2+2] cycloaddition of ketenes and carbonyl compounds24 and the intramolecular ring closure of acyclic precursors.25

Scheme 1.3 Overview of β-lactone synthesis and applications The final approach, which has recently emerged as a convenient and direct route to

β-lactones, is the ring-expansion carbonylation of epoxides. In the 1980’s and 1990’s, alkenyl-substituted epoxides were carbonylated with late transition metals, such as

rhodium,26 palladium,27 or stoichiometric amounts of iron carbonyls.28 In the early

2000’s, a second class of carbonylation catalysts consisting of a Lewis acid and a metal

− carbonyl, such as Co(CO)4 , were discovered and found to be more versatile and applicable to a large scope of epoxides. The mechanism and scope of this second class will be discussed in the next sections.

1.2.2 Carbonylation of Epoxides Using [Lewis acid]+[Co(CO)4]− Catalysts

In 2001, Alper and coworkers first demonstrated that neutral Lewis acids could be paired with a salt containing cobalt tetracarbonyl to effect epoxide carbonylation.29

While this was a vast improvement on the existing systems at the time, it still required high reaction temperatures, long reaction times, and had a limited substrate scope. In

2002, Coates and coworkers reported the first well-defined ionic [Lewis

Figure 1.1 Selected carbonylation catalysts of the form [Lewis acid][Co(CO)4] and their applications.

+ − 30 acid] [Co(CO)4] catalysts. These systems showed high chemoselectivity, activity, and functional group tolerance. Over the next decade, a variety of Lewis acids were

− 30,31 paired with Co(CO)4 for numerous applications (Figure 1.1). The most recent

Lewis acid variants will be discussed in Section 1.2.3.

The high chemoselectivity of these well-defined catalysts generally allows for the isolation of the β-lactone products through a simple distillation. The only side products observed in appreciable amounts are ketones (vide infra, Section 1.3),32 though these side reactions can be suppressed by cooling the reactor prior to pressurization and using

CO pressures exceeding 300 psi.31b,c Other possible side reactions include ring-opening polymerization of the lactone to polyesters, double carbonylation to succinic anhydrides, or decarboxylation to the underlying alkene.33 The first two routes can be suppressed by the proper choice of solvent,31c and the third pathway is avoided by adjusting the reaction temperature.34 If desired, all four side products – ketones

(chapters 3 and 4), polyesters,35 anhydrides,31c and alkenes (chapter 5) – can be accessed as the major product (instead of β-lactone) by appropriate changes to the catalyst system and reaction conditions.

Mechanistic investigations have led to the proposed mechanism shown in Scheme

31c,36 1.4. The isolated, well-defined [Lewis acid][Co(CO)4] complex (A) is not the active catalyst because of the bound solvent molecules that saturate the coordination sites of the Lewis acid. This has been confirmed by X-ray analysis of single crystals.30a,31a,c

Therefore, the active catalyst is generated in situ by loss of a solvent molecule (B). An epoxide can bind in the vacated coordination site (C), which activates the substrate for an SN2-type nucleophilic attack by the cobaltate anion. During the ring-opening step,

the metal center transitions from cationic to neutral aluminum and loses another solvent molecule ligand. The resulting cobalt-alkyl complex (D) undergoes migratory insertion of the alkyl to carbon monoxide to give compound E. This coordinatively unsaturated cobalt then recruits an additional molecule of carbon monoxide from the surrounding solution to form the cobalt-acyl complex F.

Intermediate F was observable by in situ-IR and was the proposed resting state of the catalytic cycle. This was supported by trapping F with the very electrophilic

Scheme 1.4 Proposed mechanism for the carbonylation of epoxides using [Lewis + − acid] [Co(CO)4] catalysts 7

isocyanate 1-fluoro-4-isocyanatobenzene to form a six-membered 1,3-oxazine-2,4- dione.36b Next, a solvent molecule re-coordinates to the metal center, triggering a ring- closure of the organic substrate to form the β-lactone (G). This was determined to be the rate-determining step for monosubstituted epoxides. The key interactions between the solvent molecules and the metal center rationalize the large solvent effects observed for rate and product distribution (e.g. mono- versus biscarbonylation).31c Finally, release of the product regenerates the active catalyst B.

1.2.3 Recent Catalyst Advances for Regio- and Enantioselective Carbonylation of Epoxides Despite our mechanistic understanding and the advantages of ring-expansion carbonylation of epoxides using bimetallic [Lewis acid][Co(CO)4] catalysts, regio- and enantioselective variants have been slow to develop. Monosubstituted epoxides are carbonylated with regioselectivities of >100 : 1 in favor of CO insertion at the methylene carbon (Scheme 1.5A). This steric preference aligns with the expected selectivity from an SN2 mechanism (Scheme 1.4). The only exception is alkenyl-substituted epoxides, such as styrene oxide, which show preferential attack and CO insertion at the methine carbon due to an enhanced rate of SN2 attack at the benzylic or allylic position (Scheme

1.5B).37

Based on the SN2 mechanism and the regioselectivity of monosubstituted epoxides, one might expect that the carbonylation of 2,2-disubstituted epoxides would yield the

“steric” product (insertion of CO by the methylene) exclusively. However, the experimental result is a mixture of regioisomers, though the steric product is favored

(ca. 4 : 1 for isobutylene oxide) (Scheme 1.5C).30 A possible explanation for the minor

Scheme 1.5 Observed regioselectivity from standard carbonylation catalysts for selected classes of epoxides product formation is the very electrophilic nature of the Lewis acid catalyst. Epoxides bound to strong Lewis acids are known to form carbocation intermediates,32a especially for stabilized tertiary carbocations. In the case of 2,2-disubsituted epoxide carbonylation, it is unclear if a full carbocation forms or just a partial positive charge on the tertiary carbon. Either way, the ionic interaction of the (partial) positive charge and the cobaltate anion causes attack at the tertiary position in an SN1-type manner in addition to the sterically more favorable methylene, resulting in the observed mixture

(Scheme 1.6)

While all current catalysts result in a mixture of the β,β- and α,α-lactones from 2,2- disubstituted epoxides, there is considerable interest in developing new catalysts that

Scheme 1.6 SN2 and SN1-type nucleophilic attack on 2,2-disubstituted epoxides could make these products selectively. The β,β-disubstituted β-lactones can be ring opened to form difficult-to-access aldol-type products as an alternative to performing an aldol reaction with acetaldehyde38 and ketones,39 which have a number of limitations.

The contrasteric (α,α-disubstituted) products are targets for the production of aliphatic polyesters because the double substitution in the α-position minimizes thermal, UV, and chemical degradation.40 In particular, poly(pivalolactone) is a highly crystalline, thermally stable polymer with a Tm of 240 °C made from the ring-opening polymerization of pivalolactone (α,α-disubstituted β-lactone, R = Me).41 Therefore, the production of pivalolactone from isobutylene oxide and carbon monoxide has been a long standing goal in our group (see Chapter 2, Section 2.3).

The final class of epoxides in Scheme 1.5 is 2,3-disubstituted epoxides, which represent the most challenging substrates in terms of regiocontrol. Similar to other nucleophilic reactions of epoxides (vide supra), the carbonylation of these substrates using the classic catalysts results in a mixture of regioisomers. Recent work from the

Coates group presented four new carbonylation catalysts capable of accessing all four isomers of 3,4-disubstituted lactones from cis- and trans-disubstituted epoxides

(Scheme 1.7).42 These complementary reactivities provide access to complex vicinally

Scheme 1.7 Regioselective catalysts for steric and contrasteric carbonylation of cis- and trans-2,3-disubstituted epoxides disubstituted β-lactones in a direct and synthetically useful manner from readily available cis- and trans-epoxides. These studies also represent significant progress towards other regioselective reactions of epoxides, such as regioselective isomerization to ketones (see Chapter 4).

Enantioenriched β-lactones are also of interest due to their presence in natural products and the variety of compounds that can be derived from lactone intermediates.21

Since stereochemistry is reliably inverted at the site of CO insertion, enantioenriched epoxides can be converted to the corresponding lactone without a loss of enantiopurity.30a However, enantioenriched epoxides are more expensive starting materials and this is not an option for β-lactones derived from meso-epoxides.

Therefore, we are interested in developing enantioselective carbonylation from achiral

or racemic epoxides, though such methodology has been slow to develop.43 In 2014, the

Coates group detailed the first catalysts to achieve synthetically useful enantioselectivity for the regiodivergent16a carbonylation of cis-epoxides to trans-β- lactones.44 Similar ligands have been used for the regiodivergent nucleophilic ring- opening of aziridines.45 This work lays the foundation for further catalyst development for enantioselective variants of epoxide carbonylation (see Chapter 2, Section 2.2).

Scheme 1.8 Catalysts for the regiodivergent carbonylation of cis-epoxides

1.3 Isomerization of Epoxides to Carbonyl Compounds

Carbonyl compounds are essential building blocks in chemistry, traditionally synthesized via oxidation of alcohols, hydration of alkynes,2 or oxidation of alkenes

(Wacker oxidation).46 Another route to aldehydes and ketones is through the rearrangement of epoxides.10,47 The most common variant, known as the Meinwald rearrangement,32a is mediated by a protic or Lewis acid. This seemingly simple reaction proceeds via a carbocation intermediate; therefore, substrates that are able to form stable

(e.g. benzylic, allylic, tertiary) carbocations readily undergo this rearrangement and are utilized to favor a single product.48 Terminal epoxides generally give aldehydes due to

the instability of primary carbocations.49

Complications arise if the substrate is not biased to form a single, stable carbocation, such as for unbiased 2,3-disubstituted epoxides. Furthermore, competition between migrating groups can produce a mixture of products from this rearrangement (Scheme

1.9). The general migratory aptitude has been found to be aryl > acyl > H > ethyl > methyl,10a however this is dependent on the particular substrate and the Lewis acid used.50 New catalytic systems with higher selectivities (for the aldehyde product) and mild conditions have been developed using transition metal catalysis.51

Scheme 1.9 Complication of the Meinwald rearrangement arising from unselective ring opening and substituent migration Even though the traditional product from the rearrangement of terminal epoxides is an aldehyde, the selectivity can be reversed such that the major product is the methyl ketone. This is done be altering the mechanism of ring-opening using lithium iodide52 or transition metals, such as Fe,53 Co,54 Ru,55 Rh,56 or Pd.57 The cobalt systems of

Eisenmann54a and Kagan54b are of particular interest because of their similarity to the

[Lewis acid][Co(CO)4] catalysts developed in the Coates group for carbonylation (vide supra). The researchers mixed Co2(CO)8 and methanol to form

2+ [Co(MeOH)6] [Co(CO)4]2, which contains a cobalt Lewis acid and the same cobaltate anion as the carbonylation catalysts.

The proposed mechanisms for the isomerization of epoxides by

2+ 54a,b [Co(MeOH)6] [Co(CO)4]2 are shown in Scheme 1.10. In the first step, the epoxide displaces a solvent molecule (methanol) on the cobalt cation of A to form the coordination complex B. One of the Co(CO)4 anions then ring opens the epoxide in an

SN2-manner to give complex C. The SN2 attack at the sterically unhindered methylene accounts for the methyl ketone selectivity. Classical β-hydrogen elimination forms an enolate (D) or an α-substituted ketone (E), depending on which cobalt performs the elimination. The final step is not explained in detail, but is presumably protonation by the newly formed HCo(L)x complex and displacement by a solvent molecule to regenerate catalyst A (see Chapter 3, Section 3.4 and Chapter 4, Section 4.4 for further

Scheme 1.10 Proposed mechanisms for the isomerization of epoxides by [Co(MeOH)6][Co(CO)4]2

refinement of and evidence for this mechanism).

Eisenmann probed the mechanism by reacting Co2(CO)8 with pyridine instead of

2+ 54a methanol to form a similar ionic compound, [Co(py)6] [Co(CO)4]2. No isomerization was observed when employing this new complex. Because pyridine is a better donor than methanol, it is too tightly bound to the cobalt cation to be replaced by the epoxide. This demonstrates the importance of the cation to act as a Lewis acid and activate the epoxide for nucleophilic attack.

While important progress has been made for the methyl-ketone selective isomerization of terminal epoxides, existing systems still have limitations, including modest yields, poor functional group tolerance, high reaction temperatures, and high catalyst loadings. This field currently lacks a reliable, active catalyst capable of rearranging a wide scope of epoxides under mild conditions (see Chapter 2).

Epoxide isomerization has been presented as a complementary alternative to the important Wacker oxidation of alkenes to ketones. The Wacker oxidation is a palladium-catalyzed oxidation of terminal olefins to methyl ketones and is used extensively in synthesis (Scheme 1.11A).46 Che and coworkers proposed a one-pot

Scheme 1.11 The Wacker oxidation of terminal olefins to ketones and examples of complementary epoxidation/isomerization

epoxidation/isomerization method to reverse the selectivity and form the aldehyde instead of the methyl ketone from terminal olefins (Scheme 1.11B). 51c,58 More recently, there have been direct Wacker methods reported to achieve aldehyde selectivity, particularly if an electronic directing group is added to the allylic or homoallylic position.59 Kulawiec and coworkers also present epoxidation/isomerization as an alternative method to the Wacker oxidation when two alkenes are present in a molecule that can both react via the Wacker oxidation.57a Utilizing the orthogonal reactivity of an alkene and an epoxide, a single methyl ketone can be made.

A Wacker-type oxidation of internal olefins has been slow to develop due to low reactivity and poor regioselectivity. New catalytic systems can now oxidize internal alkenes with high activity, but electronic biasing groups in the allylic or homoallylic position are necessary to achieve high levels of regioselectivity.60A regioselective

Wacker oxidation of unbiased olefins is still an unmet goal in the field and presents an opportunity for a two-step epoxidation-regioselective isomerization to solve this challenging problem (see Chapter 4).

1.4 Deoxygenation of Epoxides to Alkenes Deoxygenation of epoxides is the reverse reaction of epoxidation of alkenes. If the deoxygenation proceeds without changing the double bond stereochemistry (e.g. monosubstituted or disubstituted with retention), then the epoxide can be considered an alkene protecting group. The other possibility for 2,3-di- or trisubstituted epoxides is that deoxygenation proceeds with inversion of stereochemistry. Clean inversion allows for synthetic control of double bond stereochemistry, which can significantly affect the

molecule’s properties. Deoxygenation of epoxides with both retention61 and inversion62 have been used in natural product synthesis.

This reaction is conventionally performed using stoichiometric procedures, often with highly basic conditions and limited substrate scopes.63 In an early catalytic system,

Co2(CO)8 reduced trisubstituted epoxy-esters to the corresponding alkene with >95% inversion.64 A big advance in catalytic deoxygenation used precious metals such as Rh65 and Re66 to achieve mostly retentive reduction to alkenes. Reusable heterogenous catalysts, such as supported Au nanoparticles, have also been developed for this

67 transformation. The latter system uses CO/H2O as the reductant, which simplifies purification because the byproduct is gaseous CO2, which is easily separable from the product.

The most recent systems attempt to avoid using precious metals in favor of the more abundant molybdenum and copper. The molybdenum system pairs MoO2Cl2 with different mono- and bidentate phosphines to switch the mechanism of deoxygenation, thereby favoring inversion or retention.68 While this is the only system that allows for the rational choice between retention and inversion based on ligand, both reaction conditions yield a mixture of E and Z olefins that must be separated. In addition, trans- epoxides are difficult substrates for inversion, either resulting in low stereoselectivity or low conversion.

The copper system developed by Lin and Tong et al. pairs a copper salt (IMesCuCl or Cu(TFA)2) with diazo malonate to achieve high yields of alkene with complete retention (Scheme 1.12A).69 This system works with mono- and disubstituted epoxides, but is slow for tri- and tetrasubstituted substrates such that a disubstituted epoxide can

Scheme 1.12 Copper-catalyzed deoxygenation of epoxides to alkenes with retention of stereochemistry (A) and chemoselective reduction of a disubstituted epoxide in the presence of a trisubstituted epoxide (B) be deoxygenated in the presence of a trisubstituted epoxide (Scheme 1.12B). One drawback of this method is that 1.5–3 equivalents of diazo malonate is required, which must be separated from the product.

The copper-catalyzed system represents the most advanced method for the stereoretentive, chemoselective, and functional group tolerant deoxygenation with an inexpensive, earth-abundant metal.69 No analogous system exists for deoxygenation with inversion. Beyond the molybdenum system by Takai and coworkers,68 current inversion methods either rely on stoichiometric reagents,70 are not functional group tolerant,71 or result in a mixture of cis- and trans-isomers.72 In particular, the more thermodynamically stable trans-epoxides are difficult to invert to cis-olefins. A system that could catalytically convert both cis- and trans-epoxides to the inverted olefins in a single step would be an important advance in this field. Additionally, using a reductant that is easily separable from the product, such as CO to CO2, would be an advantage by simplifying the purification process (see Chapter 5).

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Catalyst Development for the Enantio- and Regioselective Carbonylation of Disubstituted Epoxides

2.1 Introduction

β-Lactones, or 2-oxetanones, are highly reactive and versatile intermediates in nature and organic synthesis. Two examples of natural products containing the β-lactone motif1 are shown in Figure 2.1A. Because β-lactones are potent electrophiles that can irreversibly acylate critical functional groups in enzymes, many natural products containing β-lactones act as antibiotics.2 At least one such natural product has been further developed into an approved, over-the-counter anti-obesity drug named Orlistat

(tetrahydrolipstatin, Figure 2.1B).

Figure 2.1 (A) Selected examples of natural products containing a β-lactone and (B) an approved anti-obesity drug containing a trans-β-lactone. In addition to targeting the 2-oxetanone functional group for natural product synthesis, chemists have been interested in β-lactones as intermediates that can be ring opened to aldol-type moieties and aliphatic polyesters. The innate ring strain of four- membered lactones (ca. 23 kcal/mol)3 drives many nucleophilic reactions. Hard nucleophiles, such as alcohols or amines, generally attack the carbonyl group (pathway

A) resulting in the cleavage of the acyl-oxygen bond to yield aldol-type carboxylic acids, esters, or amides (Scheme 2.1A).4 This reaction is a useful route to stereo-pure aldol-type products due to the mild conditions, high conversions, and stereospecific ring

Scheme 2.1 Reactivity of β-lactones with (A) hard and (B) soft nucleophiles and (C) the ring-opening polymerization to aliphatic polyesters opening.

In contrast, soft nucleophiles generally attack the β position (pathway B) resulting in alkyl-oxygen bond cleavage and stereochemical inversion (Scheme 2.1B). Thiols, azides,4a and cuprates4c have been known to react by this mode. Another important reaction of β-lactones is the ring-opening polymerization by alkoxide or carboxylate initiators (Scheme 2.1C).5,6 Depending on the identity of R′, R′′, and the initiator, the polymerization could proceed via either pathway A (alkoxide propagating chain) or pathway B (carboxylate propagating chain).7

Even though β-lactones are highly versatile and useful functional groups, their synthesis has been rather limited (Scheme 2.2). One route relies on the (formal) [2+2] cycloaddition of ketenes and carbonyl compounds.8 If catalyzed, this route can give a range of mono- and cis-disubstituted β-lactones. There have only been a limited number of examples to make trans-disubstituted β-lactones.9 Unfortunately, these reactions require basic conditions, stoichiometric additives, and a low temperature to generate the ketenes.

The other major route consists of the cyclization of acyclic aldol-type precursors.

These routes are not atom economical and often require many synthetic steps and

Scheme 2.2 Synthetic routes to β-lactones stoichiometric additional reagents. Nevertheless, many methods are available to carry out this approach,10

Epoxide carbonylation is a promising alternative that is atom economical, does not require stoichiometric additives, and has control of stereochemistry due to the SN2 mechanism and synthetic availability of a variety of epoxides (Scheme 2.2). A lot of work has been done over the past 15 years on the carbonylation of monosubstituted epoxides,11 but disubstituted epoxide carbonylation is more difficult due to lower activity and selectivity.

In recent years, the regio-12 and enantioselective13 carbonylation of 2,3-disubstituted epoxides have significantly advanced (see Chapter 1, Section 1.2.3) due to the highly modular salen ligand framework which allows for extensive tuning of the Lewis acid

(Figure 2.2A). The most important advances during the catalyst development were (1) introducing a bulky aryl group in the ortho-position of the phenoxide (R2) and (2) recognizing the relationship between the salen ligand backbone and the geometry of the catalyst (Figure 2.2B). In particular, it was found that catalysts containing the 2,2′- diamino-1,1′-binaphthalene backbone adopted a cis-α geometry (1), which was a change from the standard enantiopure catalysts that had a cyclohexyldiamine backbone and

Figure 2.2 (A) Modular sites for tuning the salen ligand and (B) the relationship between ligand backbone and catalyst geometry. adopted a trans-planar geometry (2). While significant steric variations were screened in both the R1 and R2 positions, we had not explored the electronic effects in the R1 position.

Herein, we report the effect of electronic variations on the enantioselective carbonylation of meso- and racemic cis-epoxides. We also sought to use the insights gained from our previous studies to design a catalyst for the challenging contrasteric regioselective carbonylation of 2,2-disubstituted epoxides.

2.2 Catalyst Electronic Variation for the Enantioselective Carbonylation of Cis-Epoxides to Trans-β-Lactones

2.2.1 Background Enantioenriched trans-3,4-disubstituted β-lactones are of special interest due to their occurrence as structural motifs in pharmaceuticals and many natural products.1

Furthermore, they can be easily converted into valuable enantioenriched anti-aldol-type products.4 Unfortunately, only a few methods provide direct access to enantioenriched trans-β-lactones,14 one of the best being the (formal) [2+2]-cycloadditions of ketenes with aldehydes.9 Disadvantages of this route include the need for multiple reagents and

careful control of the reaction conditions.

Carbonylative ring-expansion of cis-2,3-disubstituted epoxides to trans-β-lactones has some distinct advantages such as readily available starting materials, mild reaction

11,15 conditions, and a well-defined SN2-mechanism. Lamentably, the development of enantioselective epoxide carbonylation reactions has been slow and remains a challenge to the present day.16

The most straight-forward enantioselective carbonylation to trans-β-lactones would be the desymmetrization of meso-epoxides (Scheme 2.3). Meso-epoxides are achiral due to their internal mirror plane, such that the catalyst does not have to differentiate between two enantiomers, just two prochiral electrophilic centers. Meso- desymmetrization is a general route to enantioenriched products17 and epoxides have a rich history in ring-opening meso-desymmetrization with a variety of nucleophiles.18

Scheme 2.3 Carbonylative meso-desymmetrization of epoxides Enantioselective reactions of non-meso-disubstituted epoxides are more complex due to the necessity of the catalyst to differentiate both the enantiomers and the two electrophilic methines. There are two general scenarios that will lead to enantioenriched products from racemic epoxides. First, if an enantiopure catalyst converts one enantiomer much faster than the other, the enantioenriched product will be mixed with enantioenriched starting material (due to the unreacted enantiomer) in a classic kinetic resolution (Scheme 2.4A).19 In practice, 2,3-disubstituted epoxides tend to react with

comparable rates and, in many cases, the product is still a mixture of regioisomers with only modest enantioenrichment. As a result, efficient kinetic resolutions of racemic internal epoxides are rare (see Section 4.5).20

Scheme 2.4 Enantioselective (A) kinetic resolution and (B) regiodivergent carbonylation of racemic cis-epoxides The other possibility belongs to the relatively new field of (regio-)divergent reactions.19b,21 In this case, the enantiopure catalyst reacts with both enantiomers of the epoxide, but the catalyst displays opposing regioselectivities for each enantiomer, resulting in the formation of two regioisomeric β-lactones that are both enantioenriched

(Scheme 2.4B). In order to be successful, the catalyst’s regio-preference has to be stronger than any steric or electronic biases in the epoxide substituents, and the catalyst must be able to differentiate between the epoxide enantiomers. With these stringent requirements, it is unsurprising that few regiodivergent reactions based on an SN2 mechanism have been reported outside of enzyme-catalysis, particularly with epoxide

substrates.22

Significant progress came in 2012 from Ibrahim and coworkers who reported moderate enantiomeric excesses (ee’s) (11–56%) in the carbonylative desymmetrization of alicyclic meso-epoxides.16c Our group then reported two new catalysts for the regiodivergent carbonylation of cis-epoxides with synthetically useful ee’s (92–96%).13

We were interested in applying these regiodivergent catalysts to the meso- desymmetrization of epoxides as well as exploring the effect of electronic variation on enantioselectivity.

Electronic variation of related salen-based catalytic systems23 has led to improved selectivity as well as mechanistic insights. Mechanistic information can be extracted through linear free energy relationships (LFERs) of Hammett plots, where the Hammett parameter (σ) of the electronic variation is used to correlate changes in the reaction (e.g. rate or enantioselectivity).

Values of σ were initially calculated from the ionization constants of substituted benzoic acids in water and are dependent on both the identity and position of the substitution.24 Hydrogen is defined as having a Hammett parameter of 0 with electron donating substituents having negative values of σ and electron withdrawing substituents having positive values of σ. There have been a variety of extended Hammett equations that are able to separate the effects of resonance and inductive components,24b but for this study, we use the most basic Hammett parameter which measures the total polar effect exerted by a substituent on the reaction center. For asymmetric catalysis, log(ratio of enantiomers) is plotted against the Hammett parameter. A linear trend indicates a consistent mechanism over all variations, whereas a break in linearity indicates a change

in mechanism or selectivity-determining step. Moreover, the slope of the LFER (ρ) can provide information about the diastereomeric transition states that lead to the observed enantioselectivity.25

2.2.2 Previous Catalyst Development Catalysts (R)-1a–c and (S,S)-2a were initially investigated for the carbonylative meso-desymmetrization of epoxides (Table 2.1). The two catalysts that were developed in the Coates group for the regiodivergent carbonylation of racemic cis-epoxides ((R)-

1b and c)13 were competent for the carbonylative desymmetrization of aliphatic meso- epoxides. This was unsurprising, considering the analogous mechanisms for regiodivergent and meso-desymmetrization carbonylation; in both cases, the (R)- catalyst preferentially attacks the (S)-stereogenic center, regardless of substituent, to Table 2.1 Previous catalyst optimization for the carbonylative meso- desymmetrization

β-lactone 4ac entrya catalystb conversion (%) % ee 1 (R)-1c >70 94 2 (S,S)-2a >43 16 3 (R)-1a >89 58 4 (R)-1b >42 97 aConditions:[3a] = 0.5 M in THF, 5 mol % catalyst, CO (900 psi), 22 °C, 12 h. bCatalysts c (R)-1a–c generated in situ (LnAlCl + NaCo(CO)4). Conversion to β-lactone 4a and enantiomeric excess determined by GC analysis.

produce enantioenriched β-lactones.

For cis-4-octene oxide (3a), the best result in terms of activity and enantioselectivity was obtained with catalyst (R)-1c (94% ee, entry 1). Control reactions using (R)-1a and

(S,S)-2a demonstrated that while the 2,2′-diamino-1,1′-binaphthalene (DABN)26 backbone improved selectivity to some extent, the bulky aryl-substituents in the ortho- position (R2) were essential for achieving satisfactory levels of enantioenrichment

(entries 2 and 3). Increasing the steric bulk around the Lewis acidic metal center

(catalyst (R)-1b) further improved selectivity to 97% ee but simultaneously decreased activity (entry 4).

Once the catalyst and reaction conditions had been established, the scope of the enantioselective carbonylative desymmetrization of meso-epoxides was explored

(Table 2.2). Of the meso-epoxides tested with catalyst (R)-1c, each resulted in yields greater than 70% and good to excellent levels of enantioenrichment (entries 1–4).

Moreover, an inverse correlation between the steric size of the substrate and the activity of (R)-1c was observed, with bulkier epoxides requiring higher catalyst loadings

Table 2.2 Scope of the carbonylative desymmetrization of meso-epoxides 3

mol % % ketone side entrya β-lactone R % yieldb % eec (R)-1c productc 1 Me (4b) 2.5 d95d 83 3 2 Et (4c) 4 70 96 4 3 nPr (4a) 7 77 94 7 4 nBu (4d) 8 72 92 12 aConditions: [3] = 0.5 M in THF, CO (900 psi), 22 °C, 24 h. bAll reactions gave full conversion by GC analysis. cDetermined by GC analysis. dYield determined by GC analysis (method of standard addition). Catalyst (R)-1c was generated in situ (LnAlCl + NaCo(CO)4).

(compare entries 1 and 4). The slower reaction rate of bulky epoxides also correlates to larger amounts of ketone side-products, which stem from rearrangement reactions of the epoxide prior to carbon monoxide insertion (see Chapters 3 and 4).15d In addition, meso-epoxides with longer alkyl substituents such as 3a, c, and d gave substantially higher % ee’s than cis-2-butene oxide (3b).

2.2.3 Catalyst Electronic Variations for Meso-Desymmetrization

Building off of this previous work, we varied the electronics in the R1-position while keeping the required steric bulk in the ortho-position and observed the changes in enantioselectivity and activity for epoxides 3a–d (Figure 2.3 and Table 2.3). The small epoxide 3b (R = Me) was previously unaffected by the increased steric bulk of catalyst

(R)-1b (83% ee),27 but electronic variation was able to increase enantioselectivity up to

87% ee (Table 2.3, entry 1–6). The observed negative LFER in the case of 3b indicates higher selectivity with more electron-donating substituents (Figure 2.3, blue line).

An opposite electronic effect was observed for the larger epoxides 3a, c, and d

(entries 7–24). In these cases, LFERs with positive slopes (ρ) indicate enhanced enantioselectivity with more electron-withdrawing substituents (Figure 2.3, red, green, and orange lines). While the observed ρ values are only modestly positive (+0.45 to

+0.87), this change is enough to greatly affect the observed enantiomeric ratio. Notably, the selectivity for 4d increased from 10 : 1 to 48 : 1 by changing this electronic parameter (entry 19–24). Overall, catalysts (R)-1g (R1 = F) and 1h (R1 = Cl) were more active and yielded less ketone side-products than their electron-rich counterparts.

Catalyst (R)-1f (R1 = H) was generally more selective than expected, but produced more ketone side-product. The highest % ee with all catalysts (R)-1c–h was always obtained

1.8

) 4 1.6

1.4 4c (R = Et) 4a (R = Pr) 1.2 4d (R = Bu)

4b (R = Me) log (enantiomeric ratio of

0.8 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4

 (Hammett parameter)

Figure 2.3 Electronic effects on the meso-desymmetrization of epoxides 3 using catalysts (R)-1c–h. with meso-epoxide 3c.

The opposing electronic effects observed for the small meso-epoxide 3b and the larger epoxides 3a, c, and d indicate an unexpected interplay between the size of the substrate and the electronic properties of the catalyst. This observation suggests the possibility of different reaction mechanisms, or different selectivity determining steps, depending on the nature of the substrate. The kinetics of the carbonylation also support this hypothesis. While not rigorously quantified, it appears that all catalysts were equally active for epoxide 3b, but electron-withdrawing catalysts increased the rate for

Table 2.3 Change in conversion and enantioselectivity for a given meso-epoxide using catalysts (R)-1c–h

ratio (%)b entrya R catalyst erb lactone ketone epoxide 1c Me (4b) (R)-1d n.d. n.d. n.d. 93.5 : 6.5 c,d2c,d Me (4b) (R)-1e 94 6 <1 93.0 : 7.0 ,d3c,d Me (4b) (R)-1c 97 3 <1 91.5 : 8.5 c,d4c,d Me (4b) (R)-1f 96 4 <1 91.6 : 8.4 c,d5c,d Me (4b) (R)-1g 84 4 12 87.9 : 12.1 c,d6 c,d Me (4b) (R)-1h 97 3 <1 87.9 : 12.1 7 Et (4c) (R)-1d 88 6 6 97.1 : 2.9 8 Et (4c) (R)-1e 87 5 8 97.6 : 2.4 9c Et (4c) (R)-1c 96 4 <1 97.8 : 2.2 10 Et (4c) (R)-1f 97 3 54 98.5 : 1.5 11c Et (4c) (R)-1g 96 4 <1 98.2 : 1.8 12 Et (4c) (R)-1h 96 4 <1 98.4 : 1.6 13 nPr (4a) (R)-1d 52 8 41 93.0 : 7.0 14 nPr (4a) (R)-1e 58 5 36 96.0 : 4.0 15 nPr (4a) (R)-1c 81 6 13 97.1 : 2.9 16 nPr (4a) (R)-1f 78 4 17 97.7 : 2.3 17 nPr (4a) (R)-1g 94 3 3 97.0 : 3.0 18 nPr (4a) (R)-1h 95 2 4 97.9 : 2.1 19 nBu (4d) (R)-1d 52 13 35 90.9 : 9.1 20 nBu (4d) (R)-1e 64 9 27 95.1 : 4.9 21 nBu (4d) (R)-1c 83 11 6 96.1 : 3.9 22 nBu (4d) (R)-1f 60 7 33 96.6 : 3.4 23 nBu (4d) (R)-1g 92 4 5 96.5 : 3.5 24c nBu (4d) (R)-1h 84 3 14 97.9 : 2.1 aConditions: [3] = 0.5 M in THF, 5 mol % (R)-1, CO (900 psi), 22 °C, 20 h. bDetermined by GC analysis. c4 mol % catalyst. dConversion determined by 1H NMR spectroscopy. Catalysts

generated in situ (LnAlCl + NaCo(CO)4). epoxides 3a, c, and d. It is unclear at this time how the mechanisms differ. Nonetheless, the linear trends observed in Figure 2.3 seem to indicate that each substrate undergoes carbonylation with a consistent mechanism for all catalysts (R)-1c–h.

As a control, epoxide 3d was run to low conversion (Table 2.4, entry 1) to show that

enantioselectivity is not changing throughout the course of the reaction (cf. Table 2.3, entry 24). Additionally, 3b and 3d were run in the same pot to low conversion to ensure the presence of a different epoxide did not affect the enantioselectivity (Table 2.4, entry

2, cf. Table 2.3, entries 6 and 24)

Table 2.4 Low conversion control experiments at 22 °C using (R)-1h

ratio (%)b entrya R time (h) erb lactone ketone epoxide 1 nBu (4d) 2.5 24 1 75 98.3 : 1.7 Me (4b) 93c 7c <1c 87.5 : 12.5 d2d 6 nBu (4d) 38 3 59 97.4 : 2.6 aConditions: [3] = 0.5 M in THF, 5 mol % (R)-1h, CO (900 psi), 22 °C, 20 h. bDetermined by GC analysis. cConversion determined by 1H NMR spectroscopy. dBoth epoxides combined in

one pot. Catalyst generated in situ (LnAlCl + NaCo(CO)4).

One final catalyst, (R)-1i with the very electron-withdrawing nitro group in the R1 position, was tested for all epoxides (Table 2.5). In the case of 3b, (R)-1i continued the previous trend of electron-withdrawing catalysts decreasing the selectivity, resulting in the lowest enantioenrichment (60% ee). For the larger epoxides where electron- withdrawing substituents previously improved enantioselectivity, (R)-1i broke the linear trend and again resulted in lower ee’s. Figure 2.4 shows the full Hammett plot for

Table 2.5 Carbonylative meso-desymmetrization with strongly electron- 1 withdrawing catalyst (R)-1i (R = NO2)

ratio (%)b entrya R erb lactone ketone epoxide 1c Me (4b) 68 2 29 79.9 : 20.1 2b Et (4c) 83 2 15 95.4 : 4.6 3b nPr (4a) 78 1 21 94.3 : 5.7 4b nBu (4d) 64 2 34 93.8 : 6.2 aConditions: [3] = 0.5 M, 5 mol % (R)-1i, CO (900 psi), 22 °C, 20 h. bDetermined by GC analysis. cConversion determined by 1H NMR spectroscopy. Catalyst generated in situ

(LnAlCl + NaCo(CO)4).

lactones 4b and 4d to compare the linear trend (blue line) and break from linearity (red squares), respectively. This deviation from linearity could indicate a change in mechanism between catalyst (R)-1h and (R)-1i for the non-methyl substrates. The nitro group also has the possibility to be redox non-innocent or to coordinate to the metal center, both of which could affect the carbonylation enantioselectivity. We attempted to make the para-CF3 catalyst to get an intermediate point between (R)-1h and (R)-1i, but we were unable to synthesize the corresponding ligand.

1.8

) 4 1.6

1.4

1.2

0.8 4d (R = Bu)

log (enantiomeric ratio of 0.6 4b (R = Me)

0.4 -0.8 -0.4 0 0.4 0.8  (Hammett parameter)

1 Figure 2.4 Hammett plots containing (R)-1i (R = NO2) continuing the LFER for lactone 4b (blue circles) and breaking linearity for lactone 4d (red squares).

2.2.3.1 Effect of Lower Temperature To test the effect of temperature, each substrate was carbonylated at 0 °C; the electron-donating catalyst (R)-1e was used for cis-butene oxide (3b) and the electron- withdrawing catalyst (R)-1h was used for epoxides 3a, 3c, and 3d. For each system, the

% ee increased by about 1% but reduced activity was also observed (Table 2.6, entries

1–8). In addition, less ketone side-products were observed at the lower temperature, which agrees with previous observations that epoxide isomerization is slow at lower

temperatures.11d Epoxides 3b and 3c were also run at 0 °C for a shorter time (5 hours) to confirm that the enantioselectivity is not changing over the course of the reaction

(compare entries 1 and 9, 3 and 10).

Table 2.6 Effect of lowered temperature on enantioselectivity using catalysts (R)- 1e and 1h

temp ratio (%)b entrya R catalyst erb (°C) lactone ketone epoxide 1c,d Me (4b) (R)-1e 0 96 4 <1 93.9 : 6.1 2c,e Me (4b) (R)-1e 22 94 6 <1 93.0 : 7.0 3 Et (4c) (R)-1h 0 85 2 13 98.8 : 1.2 4 Et (4c) (R)-1h 22 96 4 <1 98.4 : 1.6 5 nPr (4a) (R)-1h 0 32 2 66 98.3 : 1.7 6 nPr (4a) (R)-1h 22 95 2 4 97.9 : 2.1 7 nBu (4d) (R)-1h 0 58 2 40 98.5 : 1.5 8d nBu (4d) (R)-1h 22 84 3 14 97.9 : 2.1 9c,f Me (4b) (R)-1e 0 50 <1 50 93.7 : 6.3 10f Et (4c) (R)-1h 0 54 2 44 98.9 : 1.1 aConditions: [3] = 0.5 M (22 °C) or 1.5 M (0 °C), 5 mol % catalyst, CO (900 psi), 21 h. bDetermined by GC analysis. cConversion determined by 1H NMR of the crude reaction d e f mixture. 3 mol % catalyst. 4 mol % catalyst. 5 h. Catalysts generated in situ (LnAlCl +

NaCo(CO)4).

2.2.4 Electronic Catalyst Variations for the Carbonylation of Racemic Cis-Epoxides In light of the surprising, contrasting behavior of methyl-containing 3b and larger meso-epoxides, we were interested in exploring non-meso cis-epoxides with mixed

substituents. The enantioselective carbonylation of racemic cis-epoxides is much more challenging than meso-epoxides because the catalyst must differentiate between both the two enantiomers of the substrate and the two different epoxy-methine-carbons.

Catalyst (R)-1c was previously demonstrated to perform the regiodivergent carbonylation of aliphatic cis-epoxides 5 to lactones 6 and 7 with good and excellent enantioselectivities.13 The enantioenriched β-lactones 7 were, in many cases, ring opened to form the aldol-type product in high enantioenrichment.

2.4

2.2

1.8

1.6

1.4

log (ratio of log lactone(ratio enantiomers) 1.2

0.8 -0.3 -0.2 -0.1 0 0.1 0.2 0.3

 (Hammett parameter)

Figure 2.5 Electronic effects on the regiodivergent carbonylation of epoxides 5 using catalysts (R)-1c, 1e, 1g, and 1h.

We applied a subset of our electronic variations to four racemic epoxides to probe the effects on enantioselectivity (Figure 2.5 and Table 2.7). Again, an increase in enantioenrichment was seen in every case. Similar to the meso-desymmetrization, two diverging trends were observed. All epoxides with one methyl substituent yielded lactones with higher levels of enantioenrichment for both 6 (filled circles, dashed lines) and 7 (open squares, solid lines) when using the electron-donating catalyst (R)-1e

(green, blue, and purple lines, entries 1–11). This agrees with the trend for meso-epoxide

3b, which also had methyl substituents.

Table 2.7 Change in enantioselectivity for a given racemic cis-epoxide using catalysts (R)-1c, 1e, 1g, and 1h

%eec entrya epoxide R3 R4 catalyst ratio 6 : 7b 6 7 1 5a Me Et (R)-1e 52 : 48 90.7 94.1 2 5a Me Et (R)-1c 49 : 51 88.3 93.2 3 5a Me Et (R)-1g 51 : 49 88.0 92.4 4 5a Me Et (R)-1h 50 : 50 85.9 93.0 5 5b Me nPr (R)-1e 54 : 46 88.0 94.0 6 5b Me nPr (R)-1c 49 : 51 83.5 92.2 7 5b Me nPr (R)-1g 53 : 47 83.2 91.9 8 5b Me nPr (R)-1h 53 : 47 79.9 92.4 9 5c Me nBu (R)-1e 50 : 50 90.1 94.5 10 5c Me nBu (R)-1c 53 : 47 87.4 93.8 11 5c Me nBu (R)-1h 57 : 43 82.7 94.1 12 5d Et nBu (R)-1e 62 : 38 90.1 96.0 13 5d Et nBu (R)-1c 56 : 44 90.0 96.0 14 5d Et nBu (R)-1g 53 : 47 90.9 97.5 15 5d Et nBu (R)-1h 53 : 47 92.7 98.6 aConditions: [3] = 0.5 M in THF, 5 mol % catalyst, CO (900 psi), 22 °C, 18 h. bDetermined 1 c by H NMR analysis. Determined by GC analysis. Catalysts generated in situ (LnAlCl +

NaCo(CO)4).

Conversely, epoxide 5d (R3 = Et, R4 = nBu) was carbonylated with higher selectivities when using the electron-withdrawing catalysts (R)-1g and (R)-1h (red, entries 12–15), agreeing with the trend of the larger meso-epoxides (no methyl substituents). For all catalysts, the highest enantiomeric excess was observed with lactone 7d.

It is unclear at this time why a methyl substituent causes this shift in behavior. The methyl substrates appear to have a different mechanism of stereoinduction compared to the non-methyl epoxides; however, it is difficult to draw definitive mechanistic conclusions when such similar substrates give opposing trends.

2.2.5 Conclusion In conclusion, electronic variation of the salen ligand framework, as well as a lower reaction temperature, resulted in improved enantioselectivity for all meso- and racemic cis-epoxides tested. The LFER for epoxides containing at least one methyl substituent indicates that electron-donating catalysts improve enantioselectivity. Conversely, epoxides without any methyl substituents were carbonylated with the highest enantioselectivity with the electron-withdrawing catalyst (R)-1h (R1 = Cl). These opposing trends indicate an unexpected relationship between the sterics of the substrate and the electronic properties of the catalyst. A better understanding of this relationship may provide insight into the mode of stereoinduction with these catalysts and will guide design of future catalysts with improved activity and selectivity. Even though the nature of the opposing trends is unknown, enantioselectivity was improved in all cases, resulting in some of the highest % ee’s ever observed for β-lactones from achiral or

racemic epoxides.

2.3 Catalyst Development for the Contrasteric Carbonylation of Isobutylene Oxide to Pivalolactone

2.3.1 Background Due to the industrial success of polymers such as poly(ethylene terephthalate) (PET) and nylon-6, other polyester and polyamide materials with a wide variety of properties have been sought.28 One target material has been poly(pivalolactone) (PPVL) due to its high crystallinity and thermal stability (Figure 2.6A). This polymer is a target for fiber applications due to its high elastic recovery, chemical resistance, and low deformation at elevated temperatures.29 PPVL’s good elasticity is attributed to a reversible transformation between a 2/1 helix phase and a planar zig-zag phase upon stretching.30

The chemical stability of PPVL, which is superior to PET fibers, is attributed to the disubstitution at the α-position of the ester. This substitution eliminates α-protons, which can be abstracted intramolecularly to induce chain scission. This polymer

Figure 2.6 (A) Structure and properties of poly(pivalolactone) and (B) a decomposition pathway of poly(3-hydroxybutyrate) via α-proton abstraction.

decomposition pathway is well known for other polyhydroxyalkanoates that have α- protons, such as poly(3-hydroxybutyrate) (P3HB) (Figure 2.6B).31

PPVL is most easily prepared through the living anionic polymerization of pivalolactone (PVL),32 which can occur via two mechanisms (Scheme 2.5A). There are a few examples of strong nucleophilic initiators attacking the carbonyl of PVL to cause acyl-oxygen bond cleavage, but this is relatively rare.33 The more common mechanism involves attack at the β-position, alkyl-oxygen bond cleavage, and a carboxylate propagating chain end.28,32 A number of initiators can be used to make pseudo-living polymers with a wide range of molecular weights. Many copolymers and polymer blends of PPVL have also been studied in order to tune the properties of the material.28

Currently, the best method to produce PVL is the (formal) [2+2] cycloaddition of dimethylketene and formaldehyde (Scheme 2.5B);34 however, this procedure requires precise control of the reaction conditions and side products complicate the purification process. Another route to PVL is the ring-closure of β-substituted pivalic acid.29 These

Scheme 2.5 (A) Polymerization pathways of PVL and the synthesis of PVL using known methods (B) or an unprecedented contrasteric carbonylation of IBO (C)

methods have been used to generate PVL for the commercial production of PPVL but were ultimately determined to be economically unfeasible.29 We propose to prepare

PVL via contrasteric carbonylation of the inexpensive and potentially renewable isobutylene oxide (IBO) and CO (Scheme 2.5C), which could make the production of

PPVL economically viable on an industrial scale.

2.3.2 Catalyst Optimization We anticipated the regioselective carbonylation of IBO to the contrasteric product to be challenging. Because epoxide carbonylation reactions typically undergo an SN2 ring-opening mechanism (blue, Scheme 2.6),15b steric hindrance prevents cobaltate attack at the more highly substituted carbon. Therefore, the Lewis acid catalyst must promote the “contrasteric” SN1-like pathway (red, Scheme 2.6) and disfavor the dominant SN2 (“steric”) mechanism. Previous carbonylations of isobutylene oxide with

[Lewis acid][Co(CO)4] catalysts have resulted in the β,β-disubstituted lactone as the major product in approximately a 4 : 1 ratio (see Chapter 1).15a,b

Scheme 2.6 SN2 and SN1-type mechanisms of carbonylation of isobutylene oxide

A variety of [Lewis acid][Co(CO)4] catalysts were screened for the carbonylation of

IBO at 22 °C for 18 h in THF (Figure 2.7). As expected, our first-generation porphyrin

Figure 2.7 Catalysts screened for the contrasteric carbonylation of isobutylene oxide. and salen catalysts (8, 9, and rac-2a, Table 2.8, entries 1–3) resulted in predominantly the steric (ββ) product due to the preferred SN2 mechanism.

Our previous success with using steric bulk to control regioselectivity12 led us to try catalysts with bulky aryl groups in the ortho-position of the phenoxide. Catalyst rac-2b has been used for the regioselective carbonylation12a and isomerization (see Chapter 4)35 of trans-2,3-disubstituted epoxides to cis-β-lactones and ketones with steric attack on the epoxide. For IBO, rac-2b again gave steric regioselectivity, but isomerization to isobutyraldehyde was the major pathway (entry 4). Catalyst rac-1j, which was previously utilized for the contrasteric carbonylation of cis-epoxides,12b still resulted in steric regioselectivity for IBO (entry 5). Bulky substitution in both the ortho- and para- positions ((R)-1b) gave substantially more of the preferred contrasteric product (entry

6, 12a : 12b 43 : 57), but PVL remained the minor regioisomer.

On the basis of the X-ray structure of catalyst (R)-1c,13 we believe that the DABN

Table 2.8 Catalyst optimization for the contrasteric carbonylation of IBO

% conversionb entrya catalyst 12a 12b 13 14 1 8 7 86 5 2 2 9 5 71 10 2 3 rac-2a 5 46 18 2 4 rac-2b 9 13 77 1 5 rac-1jc 3 43 20 1 6 (R)-1bc 15 26 d41d <1 7 (R)-10ac 26 <1 d74d <1 8 (R)-10bc 6 18 3 <1 aConditions: [IBO] = 0.5 M in THF, 3 mol % catalyst, CO (900 psi), 22 °C, 18 h. bDetermined 1 c by H NMR spectroscopy of the crude reaction mixture. Catalyst made in situ (LnAlCl + d NaCo(CO)4). Combination of isobutyraldehyde and the ester formed through the Tischenko reaction36 of two isobutyraldehyde molecules. backbone of (R)-1b and rac-1j aids in the contrasteric regioselectivity by forcing the ligand out of coplanarity and into a cis-α configuration (Figure 2.8A). We further propose that the restricted rotation of Ar3 imposed by the 2,6-substitution (compared to the 3,5-substitution pattern of Ar2) contributes to imparting a bowl-shape to the Lewis acid, which blocks the methylene from SN2 attack and thus promotes the SN1 mechanism (Figure 2.8B).

To test this hypothesis, we modified the catalyst by replacing the salicylaldimine moiety with an aryl-substituted iminonaphthol (catalyst (R)-10a). This led to a major improvement in the regiochemistry for PVL 12a, such that the steric product 12b was not observed in the crude 1H NMR spectrum (Table 2.8, entry 7). Unfortunately, favoring the SN1 pathway increases the rate of epoxide isomerization to

Figure 2.8 (A) Ligand coordination geometries and (B) a model for the SN1 mechanism. isobutyraldehyde,37 but the improved regioselectivity led us to explore this catalyst in more depth. As a control, catalyst (R)-10b was prepared in which the phenoxide moiety of the ligand was replaced with an iminonaphthol lacking the phenyl used to complete the “dog collar” model. This catalyst again favored 12b, most likely due to insufficient bulk to block all sides of the epoxide methylene (entry 8). As an alternative hypothesis to the steric model shown in Figure 2.8B, electrostatic cation-π interactions between the phenyl substituents and the (partial) positive charge on the substrate could stabilize the

SN1 pathway relative to the SN2 pathway.

2.3.3 Reaction Optimization We have previously found that solvent can influence the product distribution for epoxide mono- and biscarbonylation.11d We thus decided to screen a variety of solvents for the carbonylation of IBO (Table 2.9). Non-coordinating solvents such as hexanes and toluene resulted in little to no conversion to lactone after 18 h at 22 °C (entry 1–2).

DME resulted in lower regioselectivity and less isomerization, but there was still a large proportion of aldehyde compared to lactone (entry 3). While dioxane switched the regioselectivity to steric selective, it was the most successful at shutting down the

Table 2.9 Solvent effects on the contrasteric carbonylation of IBO by (R)-10a

% conversionb entrya solvent 12a 12b 13 14 1 Hexanes <1 <1 <1 <1 2 Toluene 5 4 <1 5 3 DME 25 11 12 <1 4 Dioxane 9 20 3 <1 5 THF:Dioxane (3 : 1) 43 <1 57c <1 6 THF:Dioxane (1 : 1) 45 <1 55c <1 7 THF:Dioxane (1 : 3) 81 1 19 <1 a Conditions: [IBO] = 0.5 M, 3 mol % (R)-10a (made in situ from LnAlCl + NaCo(CO)4), CO (900 psi), 22 °C, 18 h. bDetermined by 1H NMR spectroscopy of the crude reaction mixture. cCombination of isobutyraldehyde and the ester formed through the Tischenko reaction36 of two isobutyraldehyde molecules. isomerization pathway (entry 4).

We hypothesized that solvent mixtures of THF and dioxane would suppress the aldehyde formation while maintaining the high contrasteric selectivity. A variety of solvent mixtures (entries 5–7) showed that increasing the amount of dioxane relative to

THF did suppress the aldehyde formation while maintaining high conversion to PVL.

This is the first example of contrasteric epoxide carbonylation to give PVL (12a) as the major product of the reaction. While this is a major advancement for the field, more work is needed to further understand the mode of regioselectivity by catalyst 10a and to expand this reaction to other 2,2-disubstituted epoxides.

2.3.4 Conclusion In conclusion, we have developed a catalyst for the contrasteric carbonylation of isobutylene oxide to pivalolactone. We hypothesize that the high contrasteric regioselectivity is due in part from the ligand’s bowl shape blocking nucleophilic attack at the epoxide methylene. Isomerization to aldehyde was suppressed by using solvent mixtures of THF and 1,4-dioxane such that PVL was achieved in 81% conversion from

IBO. PVL is an important monomer for the production of PPVL, but it has not been industrialized due to economic considerations. This novel transformation enables a potentially cheaper and renewable route to pivalolactone compared to current technology, hopefully making the commercial production of PPVL economically feasible.

2.4 Synopsis New catalysts were presented that improve upon the enantio- and regioselectivity of disubstituted epoxide carbonylation (Figure 2.9). Catalysts (R)-1d and e are electron- donating catalysts that improve the meso-desymmetrization and regiodivergent carbonylation of cis-epoxides with methyl substituents. Conversely, the electron- withdrawing catalyst (R)-1h improves the meso-desymmetrization and regiodivergent carbonylation for cis-epoxides without methyl substituents. Catalyst (R)-10a has a unique aryl-substituted iminonaphthol moiety that improves the contrasteric carbonylation of isobutylene oxide to give, for the first time, pivalolactone as the major product.

All of the new catalysts contain the interesting 2,2′-diamino-1,1′-binaphthalene

Figure 2.9 New carbonylation catalysts for the enantio- and regioselective carbonylation of disubstituted epoxides to β-lactones. (DABN) backbone, which changes the geometry of the catalyst from planar to cis-α.

This effectively installs a permanent trans-donor to the epoxide binding sites, which may affect the mechanism of carbonylation. These advancements highlight the challenging products that can now be accessed through catalyst development.

2.5 Experimental Procedures

2.5.1 General Considerations Methods and instruments

Unless stated otherwise, all synthetic manipulations were carried out using standard

Schlenk techniques under a nitrogen atmosphere or in an MBraun Unilab glovebox under an atmosphere of purified nitrogen. Reactions were carried out in oven-dried glassware cooled under vacuum. High-pressure reactions were performed in a custom- designed and -fabricated, six-chamber, stainless steel, high-pressure reactor.38 The reactor design allowed for incorporation of six 1 or 2 fluid dram glass vials.

IR spectra were recorded on a Nicolet iS10 FT-IR spectrometer. 1H NMR and

13C{1H} NMR spectra were recorded on a Varian 300, 400, 500, or 600 MHz instrument or on a 500 MHz Bruker AV III HD with broadband Prodigy Cryoprobe at 22 °C (unless indicated otherwise) with shifts reported relative to the residual solvent peak (CDCl3:

7.26 ppm (1H), and 77.16 ppm (13C)). 19F NMR spectra were recorded on a Varian 400 or 500 MHz instrument at 22 °C (unless indicated otherwise) with shifts referenced to an external standard of neat CFCl3 (0 ppm) or neat C6F6 (164.9 ppm); both external standards were recorded at 22 °C. All J values are given in Hertz. NMR solvents were purchased from Cambridge Isotope Laboratories and stored over K2CO3 (CDCl3).

Optical rotations were measured on a Perkin- Elmer 241 polarimeter, and are given in

10−1 deg cm2 g−1.

GC analyses were performed on a Hewlett Packard 6890 gas chromatograph equipped with a Supelco β-Dex225 and either a Supelco β-Dex120 or Astec

CHIRALDEX A-TA column (switched during the course of this work), and a flame ionization detector. Helium (Airgas, UHP grade) was used as carrier gas. Reported percentages of epoxide, ketone, and β-lactone are uncorrected relative areas. HRMS analyses were either performed at the Mass Spectrometry Laboratory at the University of Illinois at Urbana-Champaign (ESI) or on a Thermo Scientific Exactive Orbitrap MS system with an Ion Sense DART ion source (Cornell University).

Chemicals

Anhydrous 1,4-dioxane, 1,2-dimethoxyethane (DME) and tetrahydropyran (THP) were purchased from Sigma-Aldrich and degassed via three freeze-pump-thaw cycles prior to use. Anhydrous toluene, dichloromethane (DCM), hexanes, and tetrahydrofuran

(THF) were purchased from Fischer Scientific and sparged vigorously with nitrogen for

40 minutes prior to first use. The solvents were further purified by passing them under nitrogen pressure through two packed columns of neutral alumina (tetrahydrofuran was also passed through a third column packed with activated 4Å molecular sieves) or through neutral alumina and copper(II) oxide (for toluene and hexanes).

Tetrahydrofuran and dichloromethane were degassed via three freeze-pump-thaw cycles prior to use. 1,4-Dioxane was dried over activated 3Å molecular sieves, syringe filtered, and sparged for 1 hour. Paraformaldehyde was dried in vacuo in the presence of P2O5 overnight. N,N,N′,N′-Tetramethylethylenediamine and triethylamine were dried over calcium hydride and degassed via sparging or three freeze-pump-thaw cycles

(respectively) prior to use. All epoxides used in this study were dried over calcium hydride and degassed via three freeze-pump-thaw cycles prior to use. All non-dried solvents used were reagent grade or better and used as received.

Carbon monoxide (Airgas or Matheson, 99.99% min. purity) was used as received.

All other chemicals were purchased from Aldrich, Alfa-Aesar, Combi-Blocks, or GFS

Chemicals and used as received. Flash column chromatography was performed with silica gel (particle size 40–64 μm, 230–400 mesh) using mixtures of ethyl acetate and hexanes as eluent.

The following compounds were prepared according to literature procedures: a) catalysts and catalyst precursors

39 NaCo(CO)4,

2-hydroxy-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-3-carbaldehyde12a

(R)-tBuBinamAlCl (precursor to (R)-1a, (R)-tBuBinam = (R)-N,N'-bis(2-hydroxy-

3,5-di-tert-butylbenzylidene)-1,1'-binaphthyl-2,2'-diamine),40

(R)-Xyl2BinamAlCl (precursor to (R)-1b, (R)-Xyl2Binam = (R)-5',5''''-((1E,1'E)-

([1,1'-binaphthalene]2,2'-diylbis(azanylylidene))bis(methany-

lylidene))bis(2,2'',6,6''tetramethyl-[1,1':3',1''-terphenyl]-4'-olate)13

(R)-pMeMesBinamAlCl (precursor to (R)-1c, (R)-MesBinam = (R)-3,3''-(([1,1'-

binaphthalene]-2,2'-diylbis(azanylylidene))bis(methanylylidene))bis(2',4',5,6'-

tetramethyl-[1,1'-biphenyl]-2-olate)13

rac-3,3′′-((1E,1′E)-([1,1′-Binaphthalene]-2,2′-diylbis(azanylylidene))-

bis(methanylylidene))bis(3′,5′-di-tert-butyl-5-methyl[1,1′-biphenyl]-2-

olate)aluminum chloride (precursor to (R)-1j)12b

+ − [salcyAl(THF)2] [Co(CO)4] (2a, salcy = N,Nʹ-bis(3,5-di-tert-butyl-salicyl-idene)-

1,2-cyclohexanediamine. (S,S) and rac versions made analogously)16a

rac-3,3ʹʹ-((1E,1ʹE)-((1S,2S)-Cyclohexane-1,2-diylbis(azanylylidene))bis-

(methanylylidene))bis(4ʹ-(tert-butyl)-2ʹ,5,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-

olate)aluminum cobaltate (rac-2b)12a

+ − + [pClTPPAl(THF)2] [Co(CO)4] (8, pClTPPAl(THF)2 = bis(tetrahydrofuran)-meso-

tetra(4-chlorophenyl)porphyrinato aluminum)11d

N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-phenylenediaminoaluminum cobaltate

(9)15a b) epoxides

meso-(2R,3S)-2,3-dipropyloxirane (3a),41

meso-(2R,3S)-2,3-diethyloxirane (3c),42

meso-(2R,3S)-2,3-dibutyloxirane (3d),43

rac-(2R,3S)-2-ethyl-3-methyloxirane (5a)13

rac-(2R,3S)-2-methyl-3-propyloxirane (5b)13

rac-(2R,3S)-2-butyl-3-methyloxirane (5c)44

rac-(2R,3S)-2-butyl-3-ethyloxirane (5d)45

2.5.2 Synthetic Procedures

2.5.2.1 General Procedures General procedure A: Kumada coupling of 2-bromophenols with mesitylmagnesium bromide

(1 M, THF), and the resulting mixture was refluxed for 12 h. Upon cooling to 0 °C,

H2O was carefully added to destroy any residual Grignard reagent and sodium hydride.

HCl (2 M, aq.) followed by celite were added and the resulting mixture was filtered through a pad of celite. The resulting phases were separated and the aqueous phase extracted with Et2O (3x). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography.

General procedure B: Formylation of 2-arylphenols to the corresponding salicylaldehyde derivatives

Methylmagnesium bromide (Acros, 3 M, Et2O) was added slowly to the

corresponding coupled phenol in THF at 0 °C. After warming to 22 °C, toluene, triethylamine, and paraformaldehyde were added, and the resulting reaction mixture stirred at 80 °C for 12 h. After cooling to 0 °C, H2O and then HCl (2 M, aq.) were added, and the resulting phases were separated. The aqueous phase was extracted with

Et2O (3x). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography or recrystallization.

General procedure C: Imine condensation of salicylaldehydes onto (R)-2,2ʹ- diamine-1,1ʹ-binaphthalene

The corresponding salicylaldehyde, (R)-2,2ʹ-diamine-1,1ʹ-binaphthalene, and methanol were mixed and then refluxed for 18 h. After allowing the reaction mixture to reach 22 °C, the resulting precipitate was isolated by filtration, washed with a small amount of cold methanol and pentane, and dried in vacuo at 80 °C.

General procedure D: Metalation of salen-compounds using Et2AlCl

Et2AlCl (Aldrich, 0.98 M, hexanes, pyrophoric) was added to a solution of the corresponding salen-compound in dried DCM (0.04 M) at 0 °C. The resulting solution was stirred at 22 °C for 12 h. Volatiles were removed in vacuo, the solid was washed with hexanes, cannula filtered, and dried in vacuo overnight.

General procedure E: Carbonylation of epoxides using (R)-1b–1i or (R)-10a.

In a glove box, a 1 fluid dram glass vial equipped with a Teflon-coated magnetic stir

bar was charged with the appropriate precursor to (R)-1b–1i, NaCo(CO)4, and THF.

After 1 minute of stirring at 22 °C, the vial was placed in a custom-made 6-well high- pressure reactor which itself was placed in a glove box freezer (−32 °C) for 30 minutes.

The appropriate epoxide (also cooled to −32 °C) was then added to the vial, the reactor removed from the freezer, subsequently sealed, taken out of the glove box, placed in a well-ventilated hood and pressurized with carbon monoxide (900 psi). It is important to keep the temperature of the reactor below 0 °C once it is removed from the freezer to minimize isomerization of the epoxide to ketone products. The reactor was then sealed again, placed in a 22 °C water bath (unless noted otherwise) and the reaction mixture stirred for the time indicated. The reactor was then carefully vented in a well-ventilated hood and the product isolated as indicated.

General procedure F: Carbonylation of epoxides using (R)-1e or (R)-1h at 0 °C.

In a glove box, a 1 fluid dram glass vial equipped with a Teflon-coated magnetic stir bar was charged with the appropriate precursor to (R)-1e or 1h, NaCo(CO)4, and THF.

After 1 minute of stirring at 22 °C, the vial was placed in a custom-made 6-well high- pressure reactor which itself was placed in a glove box freezer (−32 °C) for 30 minutes.

The appropriate epoxide (also cooled to −32 °C) was then added to the vial, the reactor removed from the freezer, subsequently sealed, taken out of the glove box, placed in a well-ventilated hood and pressurized with carbon monoxide (900 psi). It is important to keep the temperature of the reactor below 0 °C once it is removed from the freezer to minimize isomerization of the epoxide to ketone products. The reactor was then sealed again, placed in a 0 °C ice bath in an insulated box and the reaction mixture stirred for

21 hours (unless otherwise noted). The reactor was then carefully vented in a well- ventilated hood and the crude reaction mixture run through a silica plug to remove the catalyst. The product was then analyzed by 1H NMR and chiral gas chromatography.

2.5.2.2 Synthesis of Starting Materials 5-Methoxy-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-ol (SM1)

Following general procedure A, 2-bromo-4-methoxyphenol (2.86 g, 14.1 mmol) was treated with sodium hydride (0.506 g, 20.0 mmol) in THF (28 ml), followed by addition of Pd(OAc)2 (0.160 g, 0.696 mmol, 4.93 mol %), and mesitylmagnesium bromide (1 M,

THF, 27 ml, 27.0 mmol) to give SM1 (3.30 g, 65%) as a yellow oil. Analytical data for

46 1 SM1 has previously been reported. H NMR (400 MHz, CDCl3): δ 6.99 (s, 2H), 6.92

(d, J = 8.8, 1H), 6.84 (dd, J = 8.8, 3.0, 1H), 6.58 (d, J = 3.0, 1H), 4.29 (s, 1H), 3.76 (s,

13 1 3H), 2.34 (s, 3H), 2.04 (s, 6H). C{ H} NMR (101 MHz, CDCl3): δ 153.5, 146.6, 137.9,

137.5, 132.2, 128.6, 127.1, 115.9, 115.0, 114.2, 55.6, 21.0, 20.2.

2-Hydroxy-5-methyoxy-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-3-carbaldehyde (SM2)

Following general procedure B, SM1 (2.66 g, 11.0 mmol) was treated with methylmagnesium bromide (4.1 ml, 12.3 mmol) in THF (20 ml), followed by addition of toluene (38 ml), triethylamine (2.5 ml, 34.0 mmol), and paraformaldehyde (0.824 g,

27.5 mmol). The product was recrystallized from methanol to give SM2 (2.90 g, 98 %)

1 as a gold-colored powder. MP 59–61 °C. H NMR (400 MHz, CDCl3): δ 10.73 (s, 1H),

9.93 (s, 1H), 7.04 (d, J = 3.1, 1H), 6.99 (d, J = 3.1, 1H), 6.97 (s, 2H), 3.84 (s, 3H), 2.33

13 1 (s, 3H), 2.03 (s, 6H)f. C{ H} NMR (101 MHz, CDCl3): δ 196.3, 153.4, 152.6, 137.6,

136.5, 132.6, 131.2, 128.3, 126.3, 120.3, 114.5, 55.9, 21.2, 20.3. IR (neat, cm−1): 2916,

1652, 1600, 1433, 1316, 1214, 1046, 850, 794, 702. HRMS (DART) m/z calculated for

+ + C17H18O3 (M+H) 271.13287, found 271.13325.

5-Fluoro-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-ol (SM3)

Following general procedure A, 2-bromo-4-fluorophenol (2.30 g, 12.0 mmol) was treated with sodium hydride (0.432 g, 17.1 mmol) in THF (24 ml), followed by addition of Pd(OAc)2 (0.136 g, 0.593 mmol, 4.93 mol %), and mesitylmagnesium bromide (1 M,

THF, 20 ml, 20.0 mmol) to give SM3 (0.976 g, 35%) as a yellow oil. 1H NMR (400

MHz, CDCl3): δ 6.99 (s, 2H), 6.94 (m, 2H), 6.74 (dd, J = 8.7, 2.9, 1H), 4.45 (s, 1H),

13 1 2.34 (s, 3H), 2.02 (s, 6H). C{ H} NMR (101 MHz, CDCl3): δ 157.1 (d, J = 238.5),

148.7 (d, J = 2.1), 138.6, 137.7, 131.0, 128.9, 127.6 (d, J = 7.8), 116.3 (d, J = 22.6),

19 116.1 (d, J = 8.4), 115.4 (d, J = 23.0), 21.17, 20.20. F NMR (376 MHz, CDCl3, ref.

−1 C6F6): δ −122.7 (td, J = 8.4, 5.0). IR (neat, cm ): 3489, 2917, 1611, 1477, 1257, 1178,

+ + 1150, 783. HRMS (DART) m/z calculated for C15H15FO (M) 230.11014, found

230.11056.

2-Hydroxy-5-fluoro-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-3-carbaldehyde (SM4)

Following general procedure B, SM3 (2.656 g, 11.0 mmol) was treated with methylmagnesium bromide (4.1 ml, 12.3 mmol) in THF (20 ml), followed by addition of toluene (38 ml), triethylamine (2.5 ml, 34.0 mmol), and paraformaldehyde (0.824 g,

27.5 mmol). The product was recrystallized from methanol to give SM4 (0.958 g, 43%)

1 as white spindly crystals. MP 119–120 °C. H NMR (400 MHz, CDCl3): δ 10.89 (s,

1H), 9.92 (s, 1H), 7.28 (dd, J = 7.5, 3.1, 1H), 7.12 (dd, J = 8.5, 3.1, 1H), 6.97 (s, 2H),

13 1 2.33 (s, 3H), 2.02 (s, 6H). C{ H} NMR (101 MHz, CDCl3): δ 195.7 (d, J = 2.5), 155.5

(d, J = 241.3), 155.3 (d, J = 1.5), 138.0, 136.4, 132.1 (d, J = 6.7), 131.8 (d, J = 1.2),

128.4, 126.0 (d, J = 22.8), 120.3 (d, J = 6.6), 117.2 (d, J = 22.4), 21.2, 20.3. 19F NMR

−1 (376 MHz, CDCl3, ref. C6F6): δ −121.8 (t, J = 8.0). IR (neat, cm ): 2916, 1650, 1438,

+ 1316, 1201, 1093, 985, 882, 858, 797. HRMS (DART) m/z calculated for C16H15FO2

(M+H)+ 259.11288, found 259.11332.

5-Chloro-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-ol (SM5)

Following general procedure A, 2-bromo-4-chlorophenol (2.42 g, 11.7 mmol) was treated with sodium hydride (0.433 g, 17.1 mmol) in THF (24 ml), followed by addition of Pd(OAc)2 (0.135 g, 0.588 mmol, 5.03 mol %), and mesitylmagnesium bromide (1 M,

THF, 20 ml, 20.0 mmol) to give SM5 (1.11 g, 39%) as a light beige powder. MP 77–

1 80 °C. H NMR (400 MHz, CDCl3): δ 7.23 (dd, J = 8.7, 2.6, 1H), 7.00 (d, J = 2.6, 1H),

6.99 (s, 2H), 6.93 (d, J = 8.7, 1H), 4.62 (s, 1H), 2.34 (s, 3H), 2.02 (s, 6H). 13C{1H} NMR

(101 MHz, CDCl3): δ 151.3, 138.6, 137.7, 130.6, 129.7, 128.94, 128.90, 128.1, 125.4,

116.7, 21.2, 20.3. IR (neat, cm−1): 3467, 3419, 2917, 1468, 1227, 1151, 852, 822, 714,

+ + 648. HRMS (DART) m/z calculated for C15H15ClO (M) 246.08059, found 246.08109.

2-Hydroxy-5-chloro-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-3-carbaldehyde (SM6)

Following general procedure B, SM5 (1.00 g, 4.05 mmol) was treated with methylmagnesium bromide (1.5 ml, 4.6 mmol) in THF (8 ml), followed by addition of toluene (16 ml), triethylamine (0.9 ml, 6.5 mmol), and paraformaldehyde (0.334 g, 11.1 mmol). The product was purified via flash column chromatography (hexanes/EtOAc)

to give SM6 (0.730 g, 66%) as an off-white powder. MP 120–122 °C. 1H NMR (400

MHz, CDCl3): δ 11.04 (s, 1H), 9.91 (s, 1H), 7.57 (d, J = 2.6, 1H), 7.32 (d, J = 2.6, 1H),

13 1 6.97 (s, 2H), 2.33 (s, 3H), 2.02 (s, 6H). C{ H} NMR (101 MHz, CDCl3): δ 195.7,

157.6, 138.2, 138.0, 136.4, 132.3, 131.7, 131.5, 128.4, 124.6, 121.3, 21.2, 20.4. IR (neat, cm−1): 2914, 1645, 1445, 1294, 1207, 1093, 852, 730. HRMS (DART) m/z calculated

+ + for C16H15ClO2 (M+H) 275.08333, found 275.08377.

2-Hydroxy-5-nitro-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-3-carbaldehyde (SM7)

In a 1 dram vial, 2-hydroxy-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-3-carbaldehyde (0.3001 g,

1.25 mmol) was taken up in glacial acetic acid (1 ml). The aldehyde did not fully dissolve. To this slurry, nitric acid (0.08 ml) in glacial acetic acid (0.36 ml) was added and stirred at 22 °C for 18 h. The solid was isolated by filtration and washed with hexanes to give the title compound SM7 (0.161 g, 45%) as an orange powder. 1H NMR

(400 MHz, CDCl3): δ 11.76 (s, 1H), 10.06 (s, 1H), 8.59 (d, J = 2.8, 1H), 8.25 (d, J =

13 1 2.8, 1H), 6.99 (s, 2H), 2.35 (s, 3H), 2.01 (s, 6H). C{ H} NMR (126 MHz, CDCl3): δ

195.8, 163.8, 140.6, 138.6, 136.3, 132.9, 132.0, 130.5, 128.8, 128.6, 119.6, 21.2, 20.4.

+ + HRMS (DART) m/z calculated for C16H16NO4 (M+H) 286.10738, found 286.10751

(error 0.44).

2-Hydroxy-5-(N,N-dimethylamino)-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-3- carbaldehyde (SM8)

In a Fisher-Porter bottle, SM7 (0.387 g, 1.36 mmol) and palladium on carbon (5%, 0.072 g) were taken up in ethanol (5 ml). Formaldehyde (37%(aq), 1.1 ml) was added and

ethanol (5 ml) was used to wash the walls of the tube. A stirbar was added before the

Fisher-Porter head was attached to seal the reactor. The apparatus was pressurized with hydrogen gas (28 psig) and stirred at 22 °C. After 2 h, the reaction was re-pressurized to 28 psig and left to stir an additional 18 h. The solution was filtered through celite to remove the black solid. Ethanol was used to wash the celite until colorless. The filtrate was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (15% EtOAc/hexanes) to give the title compound

1 (0.236, 62%) as an orange-red powder. H NMR (400 MHz, CDCl3): δ 10.55 (br s, 1H),

9.95 (s, 1H), 6.99 (s, 2H), 6.92 (br s, 2H), 2.94 (s, 6H), 2.35 (s, 3H), 2.06 (s, 6H).

13 1 C{ H} NMR (101 MHz, CDCl3): δ 196.9, 151.1, 144.6, 137.4, 136.5, 133.4, 130.2,

128.2, 125.1, 120.6, 115.5, 41.5, 21.1, 20.3. HRMS (DART) m/z calculated for

+ + C18H22NO2 (M+H) 284.16451, found 284.16463 (error 0.42).

8-Phenylnaphthalen-1-ol (SM9)

1-Naphthol (Alfa Aesar 99%, 1.23 g, 8.4 mmol), cesium carbonate (Aldrich 99%, 7.73 g, 23.5 mmol), and DMF (Aldrich anhydrous, 30 ml) were added to a Schlenk flask under a flow of nitrogen. Iodobenzene (Aldrich 98%, 1.1 ml, 9.6 mmol) added to the reaction mixture via syringe and the flask was put in an oil bath (110 °C). A solution of

Pd(OAc)2 (0.0908 g, 0.40 mmol) in anhydrous DMF (10 ml) was cannula transferred into the reaction flask in portions over a period of 5 hours. Once all of the palladium catalyst had been added, the reaction was stirred at 110 °C for 48 hours. The reaction was then cooled to room temperature before quenching with 1 M HCl until the solution turns tan or clear yellow. The solution was filtered through celite to remove residual

palladium black using lots of distilled water and ethyl acetate. Next, the aqueous layer was extracted with EtOAc (3x) to remove the yellow color (using more water helped this by diluting the DMF in the aqueous layer). The combined organic layers were washed with water (3x), dried over Na2SO4, gravity filtered, and concentrated. The product was purified by flash column chromatography (hexanes:EtOAc 75:1  50:1)

1 to yield a yellow oil (1.06 g, 57%). H NMR (500 MHz, CDCl3): δ 7.87 (dd, J = 8.3,

1.0, 1H), 7.50–7.54 (m, 5H), 7.45 (dd, J = 8.2, 7.1, 1H), 7.41 (t, J = 7.8, 1H), 7.21, (dd,

J = 7.0, 1.1, 1H), 6.92 (dd, J = 7.6, 1.1, 1H), 5.41 (s, 1H). 13C{1H} NMR (126 MHz,

CDCl3): δ 153.2, 141.5, 136.3, 135.9, 129.6, 129.1, 128.9, 128.7, 128.6, 127.0, 125.0,

+ + 121.5, 121.2, 112.0. HRMS (DART) m/z calculated for C16H13O (M+H) 221.09609, found 221.09711 (error 4.60 ppm).

1-(Methoxymethoxy)-8-phenylnaphthalene (SM10)

In a glovebox, SM9 (1.30 g, 5.9 mmol) transferred to a pear-shaped flask topped with a

Schlenk adapter using THF (10 ml). Sodium hydride (0.23 g, 9.1 mmol) was measured out in a separate Schlenk flask and THF (14 ml) was added. Both flasks were pumped onto a Schlenk line and the sodium hydride solution was cooled to 0 °C. The naphthol solution was slowly cannula transferred into the sodium hydride as H2 was evolved.

Chloromethyl methyl ether (Aldrich, 0.7 ml, 8.8 mmol) was added dropwise via syringe.

The reaction was then put in a preheated oil bath (60 °C) and stirred for 18 hours, after which the solution was cooled to 22 °C and quenched with the dropwise addition of 1

M HCl until no more H2 was produced. Diethyl ether was then added and allowed to stir for 1 hour to let the reaction fully quench. The organics were extracted with ether

(3x), washed with brine, dried over Na2SO4, gravity filtered, and concentrated. The product was purified via flash column chromatography (hexanes:EtOAc 60:1  40:1)

1 to yield an off-white solid (1.30 g, 83%). H NMR (500 MHz, CDCl3): δ 7.83 (dd, J =

8.2, 0.8, 1H), 7.57 (d, J = 8.2, 1H), 7.47 (dd, J = 8.0, 7.1, 1H), 7.39 (t, J = 7.9, 1H),

7.29–7.36 (m, 5H), 7.28 (dd, J = 7.0, 1.1, 1H), 7.04 (dd, J = 7.6, 0.8, 1H), 4.71 (s, 2H),

13 1 3.16 (s, 3H). C{ H} NMR (126 MHz, CDCl3): δ 154.1, 145.5, 138.9, 135.9, 129.3,

128.9, 127.9, 126.8, 126.2, 125.9, 125.4, 124.0, 122.5, 110.13, 94.8, 56.2. HRMS

+ + (DART) m/z calculated for C18H17O2 (M+H) 265.12231, found 265.12284 (error 2.00 ppm).

1-(Methoxymethoxy)-8-phenyl-2-naphthaldehyde (SM11)

In a glovebox, SM10 (0.86 g, 3.3 mmol) was transferred to a Schlenk flask using diethyl ether (80 ml). The flask was pumped onto a Schlenk line and dried N,N,N′,N′- tetramethylethylenediamine (TMEDA, 2 ml, 13 mmol) was added via syringe as the flask was cooled to 0 °C. n-Butyllithium (Acros, 1.6 M in hexanes, 5.8 ml, 9.3 mmol) was added dropwise over 15 minutes then stirred for 1 hour at 0 °C. DMF (Aldrich, anhydrous, 1.3 ml, 16.9 mmol) was added dropwise over 10 minutes then stirred for 2 hours at 0 °C. The reaction was quenched with 1 M HCl and stirred for at least an hour.

The organics were extracted with EtOAc (3x), then the combined organic layers were washed with NaHCO3, washed with brine, dried over Na2SO4, filtered, and concentrated. The product was purified via flash column chromatography

(hexanes:EtOAc 75:1  30:1) to give a yellow oil (0.76 g, 80%). The product partially crystallized after standing at room temperature for four days, but a solid product is

1 unnecessary to carry forward to the deprotection step. H NMR (600 MHz, CDCl3): δ

10.48 (d, J = 0.8, 1H), 7.93 (d, J = 8.5, 1H), 7.89 (dd, J = 8.2, 1.1, 1H), 7.76 (d, J = 8.6,

1H), 7.63 (dd, J = 8.1, 7.2, 1H), 7.41–7.46 (m, 5H), 7.37–7.41 (m, 1H), 4.14 (s, 2H),

13 1 3.22 (s, 3H). C{ H} NMR (101 MHz, CDCl3): δ 191.4, 160.0, 142.7, 139.8, 139.5,

131.2, 129.7, 128.7, 128.3, 127.8, 127.4, 127.0, 125.9, 125.5, 122.7, 101.3, 57.9. HRMS

+ + (DART) m/z calculated for C19H17O3 (M+H) 293.11722, found 293.11769 (error 1.60 ppm).

1-Hydroxy-8-phenyl-2-naphthaldehyde (SM12)

SM11 (0.76 g, 2.6 mmol) was dissolved in EtOAc (2.6 ml). Aqueous HCl (12 M, 1.1 ml) was added dropwise at room temperature and then left to stir for 4 h. EtOAc and

H2O were added to separate the layers. Organics were extracted with EtOAc (3x). The combined organic layers were washed with NaHCO3 (3x), washed with brine (1x), dried over Na2SO4, gravity filtered, and concentrated. Flash column chromatography

(hexanes:EtOAc 30:1) gave the product as a yellow oil (0.60 g, 92%). Note that in order to fast-track the synthesis, the column purification steps for SM10 and SM11 may be skipped, only fully purifying SM12, without any loss in yield (and generally higher

1 yield) over the three steps. H NMR (500 MHz, CDCl3): δ 12.79 (s, 1H), 9.91 (s, 1H),

7.80 (dd, J = 8.2, 0.9, 1H), 7.65 (dd, J = 7.9, 7.3, 1H), 7.50 (d, J = 8.5, 1H), 7.45 (d, J =

8.5, 1H), 7.37-7.43 (m, 5H), 7.34 (dd, J = 7.1, 1.1, 1H). 13C{1H} NMR (101 MHz,

CDCl3): δ 196.2, 163.7, 143.7, 142.2, 139.0, 130.2, 129.7, 128.9, 127.9, 127.3, 127.2,

+ + 126.8, 122.2, 120.3, 115.1. HRMS (DART) m/z calculated for C17H13O2 (M+H)

249.09101, found 249.09058 (error −1.70 ppm)

2.5.2.3 Synthesis of Catalyst Precursors Synthesis of (R)-ML1 (precursor to (R)-1e):

(R)-3,3ʹʹ-(([1,1ʹ-Binaphthalene]-2,2ʹ- diylbis(azanylylidene))bis(methanylylidene))bis(5-methoxy-2ʹ,4ʹ,6ʹ-trimethyl-

[1,1ʹ-biphenyl]-2-ol) ((R)-pOMeMesBinam, L1)

Following general procedure C, SM2 (0.217 g, 0.803 mmol) was treated with (R)-2,2ʹ- diamine-1,1ʹ-binaphthalene (0.114 g, 0.397 mmol) in methanol (2 ml). The filtered solid was recrystallized from toluene to give L1 (0.245 g, 78%) as a dark orange powder.

1 MP >200 °C. H NMR (400 MHz, CDCl3): δ 11.66 (s, 2H), 8.23 (s, 2H), 7.98 (d, J =

8.7, 2H), 7.88 (d, J = 8.3), 7.38 (ddd, J = 8.1, 6.3, 1.6, 2H), 7.33 (d, J = 8.7, 2H), 7.18

(m, 4H), 6.92 (app s, 2H), 6.87 (app s, 2H), 6.69 (d, J = 3.0, 2H), 6.39 (d, J = 3.0, 2H),

13 1 3.67 (s, 6H), 2.29 (s, 6H), 2.05 (s, 6H), 1.86 (s, 6H). C{ H} NMR (101 MHz, CDCl3):

δ 164.2, 152.3, 151.7, 146.2, 137.0, 136.4, 136.2, 133.9, 133.2, 132.3, 130.3, 129.9,

129.1, 128.4, 128.3, 128.1, 126.8, 125.6, 121.8, 119.0, 118.4, 114.1, 55.5, 21.2, 20.5,

+ + 20.4. HRMS (DART) m/z calculated for C54H48N2O4 (M+H) 789.36868, found

789.36633.

(R)-pOMeMesBinamAlCl ((R)-ML1, (R)-pOMeMesBinam = (R)-3,3ʹʹ-(([1,1ʹ-

Binaphthalene]-2,2ʹ-diylbis(azanylylidene))bis(methanylylidene))bis(5-methoxy-

2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-olate))

General Procedure D was followed using Et2AlCl (Aldrich, 0.98 M in hexanes, 265 μl,

0.260 mmol), (R)-pOMeMesBinam (L1, 183 mg, 0.232 mmol), and DCM (6 ml) to give the title compound ((R)-ML1, 152 mg, 76%) as a reddish-orange solid. MP >200 °C.

1 H NMR (500 MHz, CDCl3, −55 °C): δ 8.41 (s, 1H), 8.27 (s, 1H), 8.04 (d, J = 8.6, 1H),

7.97 (d, J = 8.2, 1H), 7.92 (m, 2H), 7.62 (d, J = 8.5, 1H), 7.51 (m, 2H), 7.41 (d, J = 8.5,

1H), 7.30 (m, 2H), 7.12 (d, J = 8.4, 1H), 7.08 (s, 1H), 7.04 (d, J = 8.6, 1H), 6.97 (s, 1H),

6.89 (m, 2H), 6.89 (s, 1H), 6.76 (s, 1H), 6.61 (d, J = 2.9, 1H), 6.51 (d, J = 2.9, 1H), 3.67

(s, 3H), 3.64 (s, 3H), 2.45 (s, 3H), 2.37 (s, 3H), 2.05 (s, 3H), 1.91 (s, 3H), 1.88 (s, 3H),

13 1 1.62 (s, 3H). C{ H} NMR (126 MHz, CDCl3, −55 °C): δ 173.5, 168.9, 161.1, 156.5,

150.0, 149.6, 144.1, 143.9, 138.9, 137.7, 136.8, 136.2, 135.9, 135.4, 135.3, 134.6, 133.9,

133.6, 132.4, 132.2, 131.9, 130.0, 129.7, 129.5, 128.6, 128.2, 127.9, 127.8, 127.7, 127.6,

127.2, 127.1, 127.0, 126.9, 126.6, 126.34, 126.26, 126.2, 126.0, 125.6, 125.2, 118.1,

117.9, 113.1, 111.2, 55.6, 55.4, 21.6, 21.5, 21.4, 21.2, 20.4, 19.1. HRMS (DART) m/z

+ + calculated for C54H46AlClN2O4 (M−Cl) 813.32675, found 813.32322.

Note: NMR spectra collected in CDCl3 at 22 °C displayed very broad resonances.

Synthesis of (R)-ML2 (precursor to (R)-1g):

(R)-3,3ʹʹ-(([1,1ʹ-Binaphthalene]-2,2ʹ- diylbis(azanylylidene))bis(methanylylidene))bis(5-fluoro-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ- biphenyl]-2-ol) ((R)-pFMesBinam, L2)

Following general procedure C, SM4 (0.207 g, 0.801 mmol) was treated with (R)-2,2ʹ- diamine-1,1ʹ-binaphthalene (0.114 g, 0.395 mmol) in methanol (3 ml) to give L2 (0.282

1 g, 92%) as an orange powder. MP >200 °C. H NMR (400 MHz, CDCl3): δ 11.94 (s,

2H), 8.31 (s, 2H), 7.99 (d, J = 8.8, 2H), 7.88 (d, J = 8.0, 2H), 7.39 (m, 2H), 7.37 (d, J =

8.8, 2H) 7.22 (m, 2H), 7.15 (app d, J = 8.4, 2H), 6.91 (s, 2H), 6.87 (s, 2H), 6.81 (dd, J

= 8.7, 3.1, 2H), 6.69 (dd, J = 8.3, 3.1, 2H), 2.29 (s, 6H), 1.96 (s, 6H), 1.81 (s, 6H).

13 1 C{ H} NMR (101 MHz, CDCl3): δ 162.9, 155.1 (d, J = 237.9), 154.3, 145.1, 137.3,

136.4, 136.3, 133.2, 133.1, 132.5, 130.5 (d, J = 7.1), 130.4, 128.4, 128.3, 128.2, 127.7,

127.0, 126.7, 125.9, 121.6 (d, J = 22.5), 119.0, 118.9, 118.2, 21.2, 20.3, 20.3. 19F NMR

(376 MHz, CDCl3, ref. C6F6): δ −124.3 (t, J = 8.4 Hz). HRMS (DART) m/z calculated

+ + for C52H42F2N2O2 (M+H) 765.32871, found 765.32939.

(R)-pFMesBinamAlCl ((R)-ML2, (R)-pFMesBinam = (R)-3,3ʹʹ-(([1,1ʹ-

Binaphthalene]-2,2ʹ-diylbis(azanylylidene))bis(methanylylidene))bis(5-fluoro-2ʹ,4ʹ,6ʹ- trimethyl-[1,1ʹ-biphenyl]-2-olate))

General Procedure D was followed using Et2AlCl (Aldrich, hexanes, 0.98 M, 400 μl,

0.393 mmol), (R)-pFMesBinam (L2, 265 mg, 0.346 mmol), and DCM (10 ml) to give the title compound ((R)-ML2, 214 mg, 75%) as an orange solid. MP >200 °C. 1H NMR

(500 MHz, CDCl3, −55 °C): δ 8.40 (s, 1H), 8.22 (s, 1H), 8.04 (d, J = 8.5, 1H), 7.95 (m,

3H), 7.59 (d, J = 8.5, 1H), 7.52 (m, 2H), 7.38 (d, J = 8.5, 1H), 7.30 (m, 2H), 7.12 (d, J

= 8.4, 1H), 7.07 (s, 1H), 7.05 (d, J = 8.7, 1H), 6.99 (m, 2H), 6.96 (s, 1H), 6.85 (m, 2H),

6.81 (dd, J = 8.0, 3.1, 1H), 6.77 (s, 1H), 2.44 (s, 3H), 2.38 (s, 3H), 2.02 (s, 3H), 1.88 (s,

13 1 19 3H), 1.84 (s, 3H), 1.58 (s, 3H). C{ H} NMR (126 MHz, CDCl3, −55 °C): δ F NMR

(376 MHz, CDCl3): δ 125.25, 125.83. HRMS (DART) m/z calculated for

+ + C52H40AlClF2N2O2 (M−Cl) 789.28677, found 789.28306.

Note: NMR spectra collected in CDCl3 at 22 °C displayed very broad resonances.

Synthesis of (R)-ML3 (precursor to (R)-1h):

(R)-3,3ʹʹ-(([1,1ʹ-Binaphthalene]-2,2ʹ- diylbis(azanylylidene))bis(methanylylidene))bis(5-chloro-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ- biphenyl]-2-ol) ((R)-pClMesBinam, L3)

Following general procedure C, SM6 (0.500 g, 1.92 mmol) was treated with (R)-2,2ʹ- diamine-1,1ʹ-binaphthalene (0.261 g, 0.910 mmol) in methanol (4.5 ml). The filtered solid was washed with cold methanol and dried overnight at 80 °C to give L3 (0.684 g,

1 94%) as a light orange powder. MP >200 °C. H NMR (400 MHz, CDCl3): δ 12.14 (s,

2H), 8.30 (s, 2H), 7.99 (d, J = 8.8, 2H), 7.88 (d, J = 8.2, 2H), 7.38 (m, 4H), 7.21 (m,

2H), 7.14 (d, J = 8.4, 2H), 7.01 (d, J = 2.6, 2H), 6.99 (d, J = 2.6, 2H), 6.90 (s, 2H), 6.86

13 1 (s, 2H), 2.29 (s, 6H), 1.94 (s, 6H), 1.80 (s, 6H). C{ H} NMR (101 MHz, CDCl3): δ

162.66, 156.7, 144.8, 137.3, 136.4, 136.3, 134.1, 133.2, 132.8, 132.5, 130.9, 130.4,

129.2, 128.39, 128.36, 128.3, 128.2, 127.1, 126.7, 125.9, 123.2, 120.0, 118.1, 21.2, 20.4,

+ + 20.3. HRMS (DART) m/z calculated for C52H42Cl2N2O2 (M+H) 797.26961, found

797.27019.

(R)-pClMesBinamAlCl ((R)-ML3, (R)-pClMesBinam = (R)-3,3ʹʹ-(([1,1ʹ-

Binaphthalene]-2,2ʹ-diylbis(azanylylidene))bis(methanylylidene))bis(5-chloro-2ʹ,4ʹ,6ʹ- trimethyl-[1,1ʹ-biphenyl]-2-olate))

General Procedure D was followed using Et2AlCl (Aldrich, hexanes, 0.98 M, 335 μl,

0.329 mmol), (R)-pClMesBinam (L3, 0.231 g, 0.289 mmol), and DCM (7.5 ml) to give the title compound ((R)-ML3, 0.185 g, 72 %) as a yellow solid. MP >200 °C. 1H NMR

(500 MHz, CDCl3, −55 °C): δ 8.53 (s, 1H), 8.34 (s, 1H), 3.17 (d, J = 8.4, 1H), 8.08 (m,

3H), 7.69 (d, J = 8.5, 1H), 7.65 (m, 2H), 7.49 (d, J = 8.6, 1H), 7.43 (m, 2H), 7.39 (s,

1H), 7.29 (m, 1H), 7.26 (s, 1H), 7.24 (m, 2H), 7.20 (s, 1H), 7.17 (d, J = 8.7, 1H), 7.09

(s, 1H), 6.98 (s, 1H), 6.89 (s, 1H), 2.57 (s, 3H), 2.51 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H),

13 1 1.96 (s, 3H), 1.70 (s, 3H). C{ H} NMR (126 MHz, CDCl3, −55 °C): δ 173.6, 168.3,

163.6, 159.8, 143.4, 143.3, 138.9, 138.5, 137.9, 137.4, 136.7, 136.4, 136.2, 136.0, 135.3,

134.7, 133.7, 132.7, 132.6, 132.3, 131.8, 131.7, 131.5, 131.4, 130.4, 129.7, 128.6, 128.2,

127.93, 127.91, 127.7, 127.3, 127.1, 127.0, 126.63, 126.58, 126.3, 126.0, 125.7, 125.0,

121.6, 120.9, 119.7, 119.5, 21.5, 21.42, 21.36, 21.2, 20.3, 19.1. HRMS (DART) m/z

+ + calculated for C52H40AlCl3N2O2 (M−Cl) 821.22767, found 821.22470.

Note: NMR spectra collected in CDCl3 at 22 °C displayed very broad resonances. Two

13C peaks not observed due to pseudohomotopic aryl peaks.

Synthesis of (R)-ML4 (precursor to (R)-1d):

(R)-3,3ʹʹ-(([1,1ʹ-Binaphthalene]-2,2ʹ- diylbis(azanylylidene))bis(methanylylidene))bis(5-(N,N-dimethylamino)-2ʹ,4ʹ,6ʹ- trimethyl-[1,1ʹ-biphenyl]-2-ol) ((R)-pNMe2MesBinam, L4)

Following general procedure C, SM8 (0.316 g, 1.12 mmol) was treated with (R)-2,2ʹ- diamine-1,1ʹ-binaphthalene (0.161 g, 0.56 mmol) in methanol (2.8 ml). The filtered solid was washed with cold methanol and dried overnight to give L4 (0.337, 74%) as

1 an orange powder. H NMR (400 MHz, CDCl3): δ 11.46 (br s, 2H), 8.29 (s, 2H), 7.99

(d, J = 8.8, 2H), 7.88 (d, J = 8.3, 2H), 7.31–7.43 (m, 4H), 7.13–7.23 (m, 4H), 6.93 (s,

2H), 6.88 (s, 2H), 6.62 (br s, 2H), 6.31 (br s, 2H), 2.77 (s, 6H), 2.30 (s, 3H), 2.09 (s,

3H), 1.88 (s, 3H).

(R)-pNMe2MesBinamAlCl ((R)-ML4, (R)-pNMe2MesBinam = (R)-3,3ʹʹ-(([1,1ʹ-

Binaphthalene]-2,2ʹ-diylbis(azanylylidene))bis(methanylylidene))bis(5-(N,N- dimethylamino)-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-olate))

General Procedure D was followed using Et2AlCl (Aldrich, hexanes, 0.98 M, 206 μl,

0.202 mmol), (R)-pNMe2MesBinam (L4, 0.150 g, 0.184 mmol), and DCM (5 ml) to give (R)-pNMe2MesBinamAlCl ((R)-ML4, 0.126 g, 78%) as an orange solid. MP >200

°C. 1H NMR resonances are broad at 22 °C.

Synthesis of (R)-ML5 (precursor to (R)-1f):

(R)-3,3ʹʹ-(([1,1ʹ-Binaphthalene]-2,2ʹ- diylbis(azanylylidene))bis(methanylylidene))bis(2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-

2-ol) ((R)-pHMesBinam, L5)

Following general procedure C, 2-hydroxy-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-3- carbaldehyde (0.241 g, 1.00 mmol) was treated with (R)-2,2ʹ-diamine-1,1ʹ- binaphthalene (0.142 g, 0.499 mmol) in ethanol (10 ml). The filtered solid was washed with cold ethanol and dried overnight to give L5 (0.327 g, 90%) as an orange powder.

1 H NMR (300 MHz, CDCl3): δ 12.13 (s, 2H), 8.31 (s, 2H), 7.98 (d, J = 8.8, 2H), 7.88

(d J = 8.2, 2H), 7.33–7.42 (m, 4H), 7.13–7.24 (m, 4H), 7.03 (dd, J = 7.3, 1.8, 2H), 6.78–

6.95 (m, 8H), 2.29 (s, 3H), 1.98 (s, 3H), 1.83 (s, 3H).

(R)-pHMesBinamAlCl ((R)-ML5, (R)-pHMesBinam = (R)-3,3ʹʹ-(([1,1ʹ-

Binaphthalene]-2,2ʹ-diylbis(azanylylidene))bis(methanylylidene))bis(2ʹ,4ʹ,6ʹ- trimethyl-[1,1ʹ-biphenyl]-2-olate))

General Procedure F was followed using Et2AlCl (Aldrich, hexanes, 1.0 M, 350 μl,

0.350 mmol), (R)-pHMesBinam (L5, 0.232 g, 0.319 mmol), and DCM (6 ml) to give

(R)-pHMesBinamAlCl ((R)-ML5, 0.165 g, 65%) as an orange solid. MP >200 °C. 1H

NMR resonances are broad at 22 °C.

Synthesis of (R)-ML6 (precursor to (R)-1i):

(R)-3,3ʹʹ-(([1,1ʹ-Binaphthalene]-2,2ʹ- diylbis(azanylylidene))bis(methanylylidene))bis(5-nitro-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ- biphenyl]-2-ol) ((R)-pNO2MesBinam, L6)

Following general procedure D, 2-hydroxy-5-nitro-2ʹ,4ʹ,6ʹ-trimethyl-[1,1ʹ-biphenyl]-3- carbaldehyde (SM7, 0.151 g, 0.53 mmol) was treated with (R)-2,2ʹ-diamine-1,1ʹ- binaphthalene (0.076 g, 0.26 mmol) in methanol (1.4 ml). The filtered solid was washed with cold methanol and dried overnight to give L6 (0.197, 91%) as an orange powder.

1 H NMR (400 MHz, CDCl3): δ 13.32 (s, 2H), 8.59 (s, 2H), 8.10 (s, 2H), 8.03 (d, J =

9.3, 2H), 7.85–7.97 (m, 4H), 7.37–7.52 (m, 4H), 7.14 (d, J = 8.2, 2H), 6.90 (d, J = 8.7,

4H), 2.32 (s, 3H), 1.86 (s, 3H), 1.71 (3H).

(R)-pNO2MesBinamAlCl ((R)-ML6, (R)-pNMe2MesBinam = (R)-3,3ʹʹ-(([1,1ʹ-

Binaphthalene]-2,2ʹ-diylbis(azanylylidene))bis(methanylylidene))bis(5-nitro-2ʹ,4ʹ,6ʹ- trimethyl-[1,1ʹ-biphenyl]-2-olate))

General Procedure D was followed using Et2AlCl (Aldrich, hexanes, 0.98 M, 295 μl,

0.290 mmol), (R)-pNO2MesBinam (L6, 0.202 g, 0.247 mmol), and DCM (6 ml) to give

(R)-pNO2MesBinamAlCl ((R)-ML6, 0.186 g, 85%) as an orange solid. MP >200 °C.

1H NMR resonances are broad at 22 °C.

Synthesis of (R)-ML7 (precursor to 10a):

(R)-2,2'-((1E,1'E)-([1,1'-binaphthalene]-2,2'- diylbis(azanylylidene))bis(methanylylidene))bis(8-phenylnaphthalen-1-ol) (L7)

SM12 (0.596 g, 2.40 mmol) and (R)-2,2ʹ-diamine-1,1ʹ-binaphthalene (Aldrich 99%,

0.345 g, 1.20 mmol) were suspended in DCM (3 ml). A scoop of Na2SO4 was added before sealing the vial and stirring in a preheated oil bath (65 °C). After 14 hours, the reaction was cooled and Na2SO4 was filtered off. The product was purified by flash column chromatography (dry load, hexanes:EtOAc 9:1) to give a reddish-orange solid

1 (0.511 g, 57%). H NMR (500 MHz, CDCl3): δ 14.14 (d, J = 5.0, 2H), 8.24 (d, J = 5.0,

2H), 7.91 (apparent t, J = 7.8–8.8, 4H), 7.56 (dd, J = 8.0, 1.0, 2H), 7.27–7.50 (m, 12H),

7.20 (m, 2H), 7.04–7.16 (m, 10H), 6.99 (d, J = 8.7, 2H). 13C{1H} NMR (101 MHz,

CDCl3): δ 170.0, 157.0, 145.0, 142.2, 140.3, 137.8, 133.2, 132.0, 130.4, 129.2, 128.7,

128.51, 128.49, 128.1, 127.4, 127.0, 126.3, 125.73, 125.68, 125.5, 124.8, 117.5, 116.7,

112.3 (Note: There should be 25 13C resonances, but only 24 were observed. We believe that two signals coincidentally overlap). HRMS (DART) m/z calculated for

+ + C54H37N2O2 (M+H) 745.28495, found 745.28797 (error 4.05 ppm).

(R)-2,2'-((1E,1'E)-([1,1'-binaphthalene]-2,2'- diylbis(azanylylidene))bis(methanylylidene))bis(8-phenylnaphthalen-1- olate)aluminum chloride ((R)-ML7)

L7 (0.362 g, 0.486 mmol) added to pumped down schlenk flask. Dried and degassed

DCM (12 ml) was cannula-transferred into the flask, which was then cooled to 0 °C.

Et2AlCl (0.98 M in hexanes, 0.580 ml) was then added dropwise via gastight syringe.

The reddish solution was taken out of the ice bath and allowed to warm to 22 °C and stirred overnight. The DCM was removed in vacuo and the solid residue was re- dissolved in toluene and layered in pentane to crash out the complex. The orange powder was isolated via filtration, washed with pentane, and dried overnight in vacuo (0.301 g,

1 77%). H NMR (600 MHz, CDCl3, 22 °C): δ 8.23 (s, 2H), 7.97 (d, J = 8.7, 2H), 7.89

(d, J = 8.3, 2H), 7.65 (dd, J = 8.1, 1.2, 2H), 7.27–7.61 (m, two sharp at 7.55 (t, J = 7.5) and 7.44 (dd, J = 6.9, 1.0) with broad signals overlapping and underneath, 10H), 7.19–

7.23 (m, 4H, Note: this signal is surrounded by residual toluene peaks. 600 MHz necessary to separate completely, but may add extra integration value), 7.12 (d, J = 8.7,

2H), 7.08 (d, J = 8.7, 2H), 7.02 (br, 2H), 6.92 (br, 4H), 6.65 (t, J = 7.2, 2H). 13C{1H}

NMR (126 MHz, CDCl3, 22 °C): δ 144.7, 143.4, 139.8, 132.54, 132.48, 130.1, 129.8,

129.4, 128.7, 128.4, 127.3, 127.0, 126.9, 126.4, 126.1, 125.9, 125.8, 125.4, 118.1, 113.9.

(Note: Signals at 138.1, 129.2, 128.37, 125.44, and 21.6 are due to residual toluene.

Some signals are difficult to see due to broadness at 22 °C). 13C{1H} NMR (126 MHz,

CDCl3, −55 °C): δ 172.1, 169.2, 167.1, 165.0, 144.5, 143.9, 143.7, 143.3, 142.8, 141.8,

139.7, 138.8, 132.1, 132.04, 131.96, 131.1, 130.4, 130.1 (2C), 129.9, 129.7, 129.30,

129.26, 128.8, 128.7, 128.46, 128.44, 128.4, 128.1, 127.5, 127.2, 127.1, 127.04, 127.00,

126.9, 126.7 (2C), 126.5, 126.22, 126.17, 126.0, 125.8, 125.7, 125.6, 125.5, 125.40,

125.37, 125.3, 125.1, 124.8, 117.9 (2C), 113.6, 113.1 (Note: signals at 138.04, 129.1,

128.3, 125.30 are due to residual toluene. There is also another small impurity in this sample with peaks at 171.5, 165.8, 143.8, 142.9, and 139.6. Signals of 2 carbons were

assigned using band-selective HSQC that shows each of those carbon signals coupling

+ to two separate proton signals). HRMS (DART) m/z calculated for C54H35N2O2AlCl

(M+H)+ 805.21970, found 805.217274 (error −3.01 ppm).

Synthesis of (R)-ML4 (precursor to 10b):

(R)-2,2'-((1E,1'E)-([1,1'-binaphthalene]-2,2'- diylbis(azanylylidene))bis(methanylylidene))bis(naphthalen-1-ol) (L8)

1-Hydroxy-2-naphthaldehyde (TCI 98%, 0.30 g, 1.7 mmol) and (R)-2,2ʹ-diamine-1,1ʹ- binaphthalene (Aldrich 99%, 0.25 g, 0.85 mmol) were suspended in MeOH (5.3 ml).

The vial was sealed and heated at 65 °C for 6 hours. Hot filtered away from black goo using DCM. Crystallized from MeOH to give a reddish powder (0.31 g, 60%). 1H NMR

(500 MHz, CDCl3): δ 13.91 (d, J = 4.0, 2H), 8.54 (d, J = 4.0, 2H), 8.16 (d, J = 8.9, 2H),

8.13 (d, J = 8.3, 2H), 8.01 (d, J = 8.2, 2H), 7.74 (d, J = 8.9, 2H), 7.55 (d, J = 8.0, 2H),

7.43–7.50 (m, 4H), 7.26–7.36 (m, 6H), 7.00 (d, J = 8.7, 2H), 6.94 (d, J = 8.7, 2H).

13 1 C{ H} NMR (126 MHz, CDCl3): δ 167.1, 158.7, 141.8, 136.5, 133.5, 132.5, 130.6,

129.5, 128.5, 127.7, 127.4, 127.3, 127.0, 126.7, 126.4, 125.9, 125.2, 124.8, 117.3, 117.1,

+ + 111.8. HRMS (DART) m/z calculated for C42H29N2O2 (M+H) 593.22235, found

593.22482 (error 4.16 ppm).

(R)-2,2'-((1E,1'E)-([1,1'-binaphthalene]-2,2'- diylbis(azanylylidene))bis(methanylylidene))bis(naphthalen-1-olate)aluminum chloride ((R)-ML8)

L8 (0.231 g, 0.389 mmol) added to pumped down schlenk flask. Dried and degassed

DCM (10 ml) was cannula-transferred into the flask, which was then cooled to 0 °C.

Et2AlCl (0.98 M in hexanes, 0.500 ml) was then added dropwise via gastight syringe.

The orange solution was taken out of the ice bath and allowed to warm to 22 °C and stirred overnight. The DCM was removed in vacuo and the solid residue was re- dissolved in toluene and layered in pentane to crash out the complex. The orange powder was isolated via filtration, washed with pentane, and dried overnight in vacuo (0.198 g,

1 78%). H NMR (600 MHz, CDCl3, −55 °C): δ 8.83 (d, J = 8.0, 1H), 8.74 (d, J = 8.1,

1H), 8.53 (s, 1H), 8.35 (s, 1H), 8.05 (d, J = 8.7, 1H), 8.00 (d, J = 8.2, 1H), 7.90 (d, J =

8.3, 2H), 7.45–7.75 (m, 10H), 7.27–7.38 (m, 3H), 7.07–7.17 (m, 5H) (Note: 7.17–7.25

(m) and 2.36 (s) are residual toluene from the recrystallization). 13C{1H} NMR (126

MHz, CDCl3, −55 °C): δ 172.2, 169.3, 168.0, 164.2, 144.1, 143.9, 138.1, 137.4, 132.4,

132.3, 132.0, 131.9, 131.1, 130.4, 130.3, 129.6, 128.6, 128.4, 128.3, 127.9, 127.83,

127.82, 127.5, 127.3, 127.2, 127.0, 126.9, 126.8, 126.5, 126.3, 126.2 (2C), 126.1, 126.0,

125.9, 125.7, 125.6, 125.4, 118.0 (2C), 113.5, 112.0 (Note: peaks at 138.1, 129.1, 128.3,

125.3, and 21.7 are due to residual toluene. Peaks at 126.2 and 118.0 were assigned to two carbons based on a band-selective HSQC that shows each of those carbon signals coupling to two separate proton signals: 126.2 couples to 1H signals at 8.83 and 7.66,

118.0 couples to 1H signals 7.17 and 7.12). HRMS (DART) m/z calculated for

+ + C42H27N2O2AlCl (M+H) 653.15710, found 653.15696 (error −0.20 ppm).

2.5.2.4 Carbonylative Desymmetrization of Meso-Epoxides using Catalysts (R)-1c–h at 22 °C (3R,4R)-3,4-Dimethyloxetan-2-one (4b)

Using (R)-1c:

General procedure E was followed using (R)-pMeMesBinamAlCl (0.025 M, THF, 400

μl, 0.010 mmol, 2.5 mol %), NaCo(CO)4 (0.0250 M, THF, 400 μl, 0.010 mmol, 2.5 mol

%) and meso-(2R,3S)-2,3-dimethyloxirane (3b, 28.7 mg, 0.398 mmol). The reaction mixture was stirred at 22 °C for 24 h. The volatility of 4b interfered with its quantitative isolation, thus the yield of the reaction was determined using the method of standard addition. To this end, the crude reaction mixture was filtered through a short plug of silica gel using THF as eluent. The entire eluate was placed in a volumetric flask and diluted with THF to a total volume of 5 ml. A 0.5 ml aliquot of this solution was then analyzed via GC analysis. Additional 0.5 ml aliquots from this stock solution were subsequently treated with increasing amounts of independently isolated 4b, and the resulting mixtures also analyzed via GC analysis. The observed increase in signal for

4b was then used to determine that the yield of 4b was approximately 18.7 mg (94 %).

The enantiomeric ratio (er) was determined to be 91.5 : 8.5 by GC analysis (β-Dex120 column) in comparison to authentic racemic material (Figure 2.10).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 8.449 MM 0.0808 144.69809 29.85658 49.99824 2 8.817 MM 0.0897 144.70828 26.88497 50.00176

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 8.287 MM 0.14 1217.60522 144.94244 91.50513 2 8.823 MM 0.1098 113.03628 17.16434 8.49487 Figure 2.10 Representative GC chromatograms for 4b on β-Dex 120 column.

Using (R)-1d:

General procedure E was followed using (R)-ML4 (6.1 mg, 0.0070 mmol, 6.4 mol %),

NaCo(CO)4 (1.5, 0.0077 mmol, 7.0 mol %) and meso-(2R,3S)-2,3-dimethyloxirane (3b,

8.0 mg, 0.11 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 93.5 : 6.5 by GC analysis (Chiraldex A-

TA column) in comparison to authentic racemic material (Figure 2.11).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 14.552 MM 0.3299 33.89559 1.71235 50.23935 2 22.516 MM 0.1113 33.57262 5.02586 49.76065

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 13.895 MM 0.4342 37.71891 1.44772 93.46777 2 21.436 MM 0.2691 2.63608 0.163291 6.53223 Figure 2.11 Representative GC chromatograms for 4b on Chiraldex A-TA column.

Using (R)-1e:

General procedure E was followed using (R)-ML1 (5.9 mg, 0.0069 mmol, 4.2 mol %),

NaCo(CO)4 (1.3, 0.0067 mmol, 4.1 mol %) and meso-(2R,3S)-2,3-dimethyloxirane (3b,

11.8 mg, 0.164 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 93.0 : 7.0 by GC analysis (β-Dex225 column) in comparison to authentic racemic material (Figure 2.12).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 29.079 MM 0.0821 47.62315 9.66924 50.15866 2 29.604 MM 0.0868 47.32187 9.08220 49.84134

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 29.052 MM 0.0959 76.76054 13.34069 93.01227 2 29.695 MM 0.0510 5.76679 1.88377 6.98773 Figure 2.12 Representative GC chromatograms for 4b on β-Dex225 column.

Using (R)-1f:

General procedure E was followed using (R)-ML5 (3.9 mg, 0.0049 mmol, 3.7 mol %),

NaCo(CO)4 (1.1, 0.0057 mmol, 4.3 mol %) and meso-(2R,3S)-2,3-dimethyloxirane (3b,

9.6 mg, 0.133 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 91.6 : 8.4 by GC analysis (Chiraldex A-

TA column) in comparison to authentic racemic material.

Using (R)-1g:

General procedure E was followed using (R)-ML2 (5.7 mg, 0.0069 mmol, 4.4 mol %),

NaCo(CO)4 (2.7, 0.0139 mmol, 8.9 mol %) and meso-(2R,3S)-2,3-dimethyloxirane (3b,

11.3 mg, 0.157 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 87.9 : 12.1 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1h:

General procedure E was followed using (R)-ML3 (6.1 mg, 0.0071 mmol, 4.4 mol %),

NaCo(CO)4 (1.3, 0.0067 mmol, 4.2 mol %) and meso-(2R,3S)-2,3-dimethyloxirane (3b,

11.6 mg, 0.161 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

Using (R)-1i:

General procedure E was followed using (R)-ML6 (4.4 mg, 0.0050 mmol, 3.1 mol %),

NaCo(CO)4 (1.2, 0.0062 mmol, 3.8 mol %) and meso-(2R,3S)-2,3-dimethyloxirane (3b,

11.8 mg, 0.163 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 79.9 : 20.1 by GC analysis (Chiraldex A-

TA column) in comparison to authentic racemic material.

Stereochemical assignment of 4b:

The stereochemical identity of 4b was determined by two methods. First, the specific rotation of 4b was compared under identical conditions to that reported in the literature for (3S,4S)-3,4-dimethyloxetan-2-one47 and found to be of the opposite sign. Second, a racemic mixture of trans-3,4-dimethyloxetan-2-one was kinetically resolved to enantiopure (3R,4R)-3,4-dimethyloxetan-2-one by adapting a published procedure48 using Lipase PS and benzyl alcohol. The β-lactone isolated from this reaction was identical with 3b with regard to the sign of its specific rotation, and its GC retention time.

(3R,4R)-3,4-Diethyloxetan-2-one (4c)

Using (R)-1c:

General procedure E was followed using (R)-pMeMesBinamAlCl (8.2 mg, 0.010 mmol,

3.9 mol %), NaCo(CO)4 (0.0500 M, THF, 200 μl, 0.0100 mmol, 3.91 mol %) and meso-

(2R,3S)-2,3-diethyloxirane42 (3c, 1.28 M, THF, 200 μl, 0.256 mmol). After stirring at

22 °C for 24 h, the crude reaction mixture was subjected to bulb-to-bulb distillation to

1 give 4c (23.0 mg, 70 %) as a yellow oil. H NMR (400 MHz, CDCl3): δ 4.17 (td, J =

6.6, 3.9 Hz, 1H), 3.12 (ddd, J = 8.5, 6.5, 4.0 Hz, 1H), 1.93–1.69 (m, 4H), 1.02 (t, J =

13 7.5 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H). C NMR (75 MHz, CDCl3): δ 171.5, 78.8, 57.2,

27.6, 21.2, 11.4, 9.2. IR (neat, cm−1): 2969, 2939, 2880, 1812, 1461, 1386, 1120, 1062,

+ + 954. HRMS (ESI) m/z calculated for C7H13O2 (M+H) 129.0916, found 129.0922. The enantiomeric ratio (er) was determined to be 97.8 : 2.2 by GC analysis (β-Dex120 column) in comparison to authentic racemic material (Figure 2.13).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 18.646 MM 0.1879 359.66174 31.89876 49.97826 2 20.026 MM 0.2194 359.97464 27.34226 50.02174

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 18.372 MM 0.3339 1927.21753 96.18916 97.76224 2 20.308 MM 0.2035 44.11358 3.61259 2.23776 Figure 2.13 Representative GC chromatograms for 4c on β-Dex120 column.

Using (R)-1d:

General procedure E was followed using (R)-ML4 (6.1 mg, 0.0070 mmol, 5.6 mol %),

42 NaCo(CO)4 (1.6, 0.0082 mmol, 6.1 mol %) and meso-(2R,3S)-2,3-diethyloxirane (3c,

12.4 mg, 0.124 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 97.0 : 3.0 by GC analysis (β-Dex225 column) in comparison to authentic racemic material (Figure 2.14).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 20.593 MM 0.3477 145.21936 6.96069 49.98645 2 31.208 MM 0.6370 145.29810 3.80148 50.01355

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 20.928 MM 0.2072 33.95492 2.73062 96.97485 2 31.225 MM 0.1870 1.05923 9.43983e−2 3.02515 Figure 2.14 Representative GC chromatograms for 4c on β-Dex225 column.

Using (R)-1e:

General procedure E was followed using (R)-ML1 (5.9 mg, 0.0069 mmol, 5.4 mol %),

42 NaCo(CO)4 (1.4, 0.0072 mmol, 5.6 mol %) and meso-(2R,3S)-2,3-diethyloxirane (3c,

12.9 mg, 0.129 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 97.6 : 2.4 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1f:

General procedure E was followed using (R)-ML5 (3.9 mg, 0.0049 mmol, 5.7 mol %),

42 NaCo(CO)4 (1.0, 0.0052 mmol, 6.0 mol %) and meso-(2R,3S)-2,3-diethyloxirane (3c,

8.6 mg, 0.086 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 98.5 : 1.5 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1g:

General procedure E was followed using (R)-ML2 (5.8 mg, 0.0070 mmol, 3.9 mol %),

42 NaCo(CO)4 (1.5, 0.0077 mmol, 4.3 mol %) and meso-(2R,3S)-2,3-diethyloxirane (3c,

17.9 mg, 0.179 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 98.2 : 1.8 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1h:

General procedure E was followed using (R)-ML3 (6.4 mg, 0.0075 mmol, 4.7 mol %),

42 NaCo(CO)4 (1.3, 0.0067 mmol, 4.2 mol %) and meso-(2R,3S)-2,3-diethyloxirane (3c,

15.9 mg, 0.159 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio

(er) was determined to be 98.5 : 1.5 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1i:

General procedure E was followed using (R)-ML6 (4.5 mg, 0.0051 mmol, 4.5 mol %),

42 NaCo(CO)4 (1.8, 0.0093 mmol, 8.2 mol %) and meso-(2R,3S)-2,3-diethyloxirane (3c,

11.4 mg, 0.114 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio

(er) was determined to be 95.4 : 4.6 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Stereochemical assignment of 4c:

The stereochemical identity of 4c was determined by comparing the order of elution of the two enantiomers during GC analysis with that of 4b and 4a.

(3R,4R)-3,4-Dipropyloxetan-2-one (4a)

Using (R)-1c:

General procedure E was followed using (R)-pMeMesBinamAlCl (14.3 mg, 0.0175 mmol, 7.00 mol %), NaCo(CO)4 (0.100 M, THF, 175 μl, 0.0175 mmol, 7.00 mol %) and meso-(2R,3S)-2,3-dipropyloxirane41 (3a, 1.00 M, THF, 250 μl, 0.250 mmol). After stirring at 22 °C for 24 h, the crude reaction mixture was subjected to bulb-to-bulb distillation to give 4a (30.1 mg, 77 %) as a yellow oil. Analytical data for 4a has

49 1 previously been reported. H NMR (400 MHz, CDCl3): δ 4.22 (ddd, J = 7.4, 5.9, 4.0

Hz, 1H), 3.17 (ddd, J = 8.8, 6.6, 4.0 Hz, 1H), 1.88–1.77 (m, 2H), 1.75–1.64 (m, 2H),

1.51–1.37 (m, 4H), 0.97 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). 13C{1H} NMR

(126 MHz, CDCl3): δ 171.7, 78.1, 56.1, 36.6, 30.1, 20.4, 18.5, 13.86, 13.86. The

enantiomeric ratio (er) was determined to be 96.9 : 3.1 by GC analysis (β-Dex120 column) in comparison to authentic racemic material (Figure 2.15).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 33.247 MM 0.1152 253.54163 36.67054 49.95223 2 34.725 MM 0.1338 254.02655 31.6324 50.04777

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 33.188 MM 0.1271 539.11475 70.71523 96.852 2 34.796 MM 0.123 17.52294 2.37393 3.148 Figure 2.15 Representative GC chromatograms for 4a on β-Dex120 column.

Using (R)-1d:

General procedure E was followed using (R)-ML4 (6.1 mg, 0.0070 mmol, 5.7 mol %),

41 NaCo(CO)4 (1.7, 0.0088 mmol, 7.2 mol %) and meso-(2R,3S)-2,3-dipropyloxirane

(3a, 15.6 mg, 0.122 mmol) After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 92.9 : 7.1 by GC analysis (β-Dex225 column) in comparison to authentic racemic material (Figure 2.16).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 26.686 MM 0.2965 134.09883 7.53866 49.92820 2 29.099 MM 0.3501 134.48454 6.40236 50.07180

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 27.025 MM 0.2044 14.48102 1.18099 92.94158 2 29.587 MM 0.1983 1.09976 9.24507e−2 7.05842 Figure 2.16 Representative GC chromatograms for 4a on β-Dex225 column.

Using (R)-1e:

General procedure E was followed using (R)-ML1 (5.9 mg, 0.0069 mmol, 5.0 mol %),

41 NaCo(CO)4 (1.5, 0.0077 mmol, 5.6 mol %) and meso-(2R,3S)-2,3-dipropyloxirane

(3a, 17.7 mg, 0.138 mmol). After stirring at 22 °C for 20 h, the reaction mixture was

1 run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 96.0 : 4.0 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1f:

General procedure E was followed using (R)-ML5 (4.0 mg, 0.0051 mmol, 4.8 mol %),

41 NaCo(CO)4 (1.1, 0.0072 mmol, 6.8 mol %) and meso-(2R,3S)-2,3-dipropyloxirane

(3a, 13.6 mg, 0.106 mmol). After stirring at 22 °C for 20 h, the reaction mixture was

1 run through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography.

The enantiomeric ratio (er) was determined to be 97.7 : 2.3 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1g:

General procedure E was followed using (R)-ML2 (5.8 mg, 0.0070 mmol, 5.4 mol %),

41 NaCo(CO)4 (2.3, 0.0119 mmol, 9.2 mol %) and meso-(2R,3S)-2,3-dipropyloxirane

(3a, 16.5 mg, 0.129 mmol). After stirring at 22 °C for 20 h, the reaction mixture was

1 run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 97.0 : 3.0 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1h:

General procedure E was followed using (R)-ML3 (6.1 mg, 0.0071 mmol, 5.4 mol %),

41 NaCo(CO)4 (1.6, 0.0082 mmol, 6.3 mol %) and meso-(2R,3S)-2,3-dipropyloxirane

(3a, 16.9 mg, 0.132 mmol). After stirring at 22 °C for 20 h, the reaction mixture was

1 run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 97.9 : 2.1 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1i:

General procedure E was followed using (R)-ML6 (4.3 mg, 0.0049 mmol, 5.8 mol %),

41 NaCo(CO)4 (1.8, 0.0093 mmol, 10.9 mol %) and meso-(2R,3S)-2,3-dipropyloxirane

(3a, 10.9 mg, 0.085 mmol). After stirring at 22 °C for 20 h, the reaction mixture was

1 run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 94.3 : 5.7 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Stereochemical assignment of 4a:

The stereochemical identity of 4a was determined by comparing the specific rotation of

4a under identical conditions to that reported in the literature for (3R,4R)-3,4-dipropyloxetan-2-one.49 The literature known compound and 4a displayed the same sign of rotation.

(3R,4R)-3,4-Dibutyloxetan-2-one (4d)

Using (R)-1c:

General procedure E was followed using (R)-pMeMesBinamAlCl (13.1 mg, 0.0160 mmol, 8.04 mol %), NaCo(CO)4 (0.0800 M, THF, 200 μl, 0.0160 mmol, 8.00 mol %) and meso-(2R,3S)-2,3-dibutyloxirane43 (3d, 0.994 M, THF, 200 μl, 0.199 mmol). After stirring at 22 °C for 24 h, the crude reaction mixture was subjected to bulb-to-bulb

1 distillation to give 4d (26.7 mg, 72 %) as a yellow oil. H NMR (400 MHz, CDCl3): δ

4.20 (ddd, J = 7.4, 6.0, 4.0 Hz, 1H), 3.15 (ddd, J = 8.7, 6.6, 3.9 Hz, 1H), 1.89–1.65 (m,

4H), 1.44–1.29 (m, 8H), 0.91 (t, J = 7.0 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H). 13C{1H} NMR

(75 MHz, CDCl3): δ 171.8, 78.3, 56.2, 34.2, 29.2, 27.7, 27.2, 22.50, 22.46, 14.0, 13.9.

IR (neat, cm−1): 2957, 2931, 2861, 1817, 1466, 1125, 1064, 838. HRMS (ESI) m/z

+ + calculated for C11H21O2 (M+H) 185.1542, found 185.1543. The enantiomeric ratio

(er) was determined to be 95.9 : 4.1 by GC analysis (CHIRALDEX A-TA column) in comparison to authentic racemic material (Figure 2.17).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 62.178 MM 0.2419 192.76053 13.28018 50.05796 2 63.666 MM 0.2295 192.31415 13.96905 49.94204

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 62.081 MM 0.2552 412.22443 26.91874 95.91271 2 63.686 MM 0.2309 17.5668 1.2679 4.08729 Figure 2.17 Representative GC chromatograms for 4d on Chiraldex A-TA column.

Using (R)-1d:

General procedure E was followed using (R)-ML4 (6.2 mg, 0.0071 mmol, 5.1 mol %),

43 NaCo(CO)4 (1.5, 0.0077 mmol, 5.6 mol %) and meso-(2R,3S)-2,3-dibutyloxirane (3d,

21.5 mg, 0.138 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The

enantiomeric ratio (er) was determined to be 90.9 : 9.1 by GC analysis (β-Dex225 column) in comparison to authentic racemic material (Figure 2.18).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 41.635 MM 0.3793 190.40520 8.36624 50.12667 2 43.484 MM 0.4239 189.44292 7.44791 49.87333

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 41.831 MM 0.2993 15.53877 8.65317e−1 90.86318 2 43.705 MM 0.2244 1.56251 1.16028e−1 9.13682 Figure 2.18 Representative GC chromatograms for 4d on β-Dex225 column.

Using (R)-1e:

General procedure E was followed using (R)-ML1 (5.9 mg, 0.0069 mmol, 4.6 mol %),

43 NaCo(CO)4 (1.5, 0.0077 mmol, 5.1 mol %) and meso-(2R,3S)-2,3-dibutyloxirane (3d,

23.5 mg, 0.150 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio

(er) was determined to be 95.0 : 5.0 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1f:

General procedure E was followed using (R)-ML5 (4.1 mg, 0.0052 mmol, 5.7 mol %),

43 NaCo(CO)4 (1.1, 0.0057 mmol, 6.2 mol %) and meso-(2R,3S)-2,3-dibutyloxirane (3d,

14.4 mg, 0.092 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral gas chromatography. The enantiomeric ratio (er) was determined to be 96.6 : 3.4 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1g:

General procedure E was followed using (R)-ML2 (5.8 mg, 0.0070 mmol, 4.6 mol %),

43 NaCo(CO)4 (1.5, 0.0077 mmol, 5.0 mol %) and meso-(2R,3S)-2,3-dibutyloxirane (3d,

24.0 mg, 0.154 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio

(er) was determined to be 96.5 : 3.5 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1h:

General procedure E was followed using (R)-ML3 (5.9 mg, 0.0069 mmol, 3.7 mol %),

43 NaCo(CO)4 (1.5, 0.0077 mmol, 4.2 mol %) and meso-(2R,3S)-2,3-dibutyloxirane (3d,

28.8 mg, 0.184 mmol). After stirring at 22 °C for 20 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio

(er) was determined to be 97.9 : 2.1 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1i:

General procedure E was followed using (R)-ML6 (4.3 mg, 0.0049 mmol, 5.4 mol %),

43 NaCo(CO)4 (1.0, 0.0052 mmol, 5.7 mol %) and meso-(2R,3S)-2,3-dibutyloxirane (3d,

14.2 mg, 0.091 mmol). After stirring at 22 °C for 18 h, the reaction mixture was run

1 through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio

(er) was determined to be 93.8 : 6.2 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Stereochemical assignment of 4d:

The stereochemical identity of 4d was determined by comparing the order of elution of the two enantiomers during GC analysis with that of 4b and 4a.

2.5.2.5 Carbonylative Desymmetrization of Racemic-Epoxides using Catalysts (R)-1c, e, g, and h at 22 °C Stereochemical assignments are all based on ref 13.

(3R,4R)-3-Ethyl-4-methyloxetan-2-one (6a) and (3R,4R)-4-Ethyl-3-methyloxetan-

2-one (7a)

Using (R)-1c:

General procedure E was followed using (R)-pMeMesBinamAlCl (6.1 mg, 0.0075 mmol, 3.8 mol %), NaCo(CO)4 (1.4 mg, 0.0072 mmol, 3.7 mol %) and meso-(2R,3S)-

2-ethyl-3-methyloxirane (5a, 16.9 mg, 0.196 mmol). After stirring at 22 °C for 18 h, the

1 reaction mixture was run through a plug of SiO2 and analyzed by H NMR and chiral

GC. The enantiomeric ratio (er) was determined to be 94.2 : 5.8 for 6a and 96.6 : 3.4 for 7a by GC analysis (β-Dex225 column) in comparison to authentic racemic material

(Figure 2.19).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 (7a) 44.790 MM 0.7096 65.83521 1.54631 37.92832 2 (6a) 48.045 MM 0.4955 20.22541 6.80307e−1 11.65206 3 (ent-7a) 63.950 MM 1.1084 67.10660 1.00908 38.66077 4 (ent-6a) 72.018 MM 0.7843 20.41078 4.33736e−1 11.75885

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 (7a) 42.811 MF 1.4811 403.65076 4.54214 46.41260 2 (6a) 45.946 FM 1.9717 425.52673 3.59692 48.92794 3 (ent-7a) 66.139 MM 0.6753 14.16304 3.49524e−1 1.62850 4 (ent-6a) 73.132 MF 0.3763 26.36028 1.16751 3.03096 Figure 2.19 Representative GC chromatograms for 6a and 7a on β-Dex225 column.

100

Using (R)-1e:

General procedure E was followed using (R)-ML1 (6.0 mg, 0.0071 mmol, 4.6 mol %),

NaCo(CO)4 (1.4 mg, 0.0072 mmol, 4.6 mol %) and meso-(2R,3S)-2-ethyl-3- methyloxirane (5a, 13.4 mg, 0.156 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 95.4 : 4.6 for 6a and 97.1 : 2.9 for 7a by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1g:

General procedure E was followed using (R)-ML2 (7.3 mg, 0.0088 mmol, 5.6 mol %),

NaCo(CO)4 (1.7 mg, 0.0088 mmol, 5.6 mol %) and meso-(2R,3S)-2-ethyl-3- methyloxirane (5a, 13.6 mg, 0.158 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 94.0 : 6.0 for 6a and 96.2 : 3.8 for 7a by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1h:

General procedure E was followed using (R)-ML3 (6.0 mg, 0.0070 mmol, 4.3 mol %),

NaCo(CO)4 (1.8 mg, 0.0093 mmol, 5.8 mol %) and meso-(2R,3S)-2-ethyl-3- methyloxirane (5a, 13.9 mg, 0.161 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 93.0 : 7.0 for 6a and 96.5 : 3.5 for 7a by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

101

(3R,4R)-4-Methyl-3-propyloxetan-2-one (6b) and (3R,4R)-3-Methyl-4- propyloxetan-2-one (7b)

Using (R)-1c:

General procedure E was followed using (R)-pMeMesBinamAlCl (5.7 mg, 0.0070 mmol, 5.2 mol %), NaCo(CO)4 (1.7 mg, 0.0088 mmol, 6.5 mol %) and meso-(2R,3S)-

2-methyl-3-propyloxirane (5b, 13.5 mg, 0.135 mmol). After stirring at 22 °C for 18 h,

1 the reaction mixture was run through a plug of SiO2 and analyzed by H NMR and chiral

GC. The enantiomeric ratio (er) was determined to be 91.8 : 8.2 for 6b and 96.0 : 4.0 for 7b by GC analysis (β-Dex225 column) in comparison to authentic racemic material

(Figure 2.20).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 (7b) 46.304 MM 0.5319 39.43163 1.23567 13.94985 2 (6b) 61.604 MM 1.1067 103.34750 1.55639 36.56157 3 (ent-7b) 66.171 MM 0.7492 37.70441 8.38796e−1 13.33881 4 (ent-6b) 68.196 MM 1.4265 102.18344 1.19390 36.14976

102

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 (7b) 45.059 MM 1.3522 333.04303 4.10504 49.01616 2 (6b) 61.282 MM 1.8138 303.76385 2.79119 44.70695 3 (ent-7b) 67.894 MM 0.7747 30.06365 6.46745e−1 4.42467 4 (ent-6b) 71.243 MM 0.5411 12.58498 3.87659e−1 1.85221 Figure 2.20 Representative GC chromatograms for 6b and 7b on β-Dex225 column.

Using (R)-1e:

General procedure E was followed using (R)-ML1 (5.9 mg, 0.0069 mmol, 4.7 mol %),

NaCo(CO)4 (1.4 mg, 0.0072 mmol, 4.9 mol %) and meso-(2R,3S)-2-methyl-3- propyloxirane (5b, 14.8 mg, 0.148 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 94.0 : 6.0 for 6b and 97.0 : 3.0 for 7b by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1g:

General procedure E was followed using (R)-ML2 (6.1 mg, 0.0074 mmol, 5.0 mol %),

NaCo(CO)4 (1.7 mg, 0.0088 mmol, 6.0 mol %) and meso-(2R,3S)-2-methyl-3- propyloxirane (5b, 14.7 mg, 0.147 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 91.6 : 8.4 for 6b and 96.0 : 4.0 for 7b by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

103

Using (R)-1h:

General procedure E was followed using (R)-ML3 (6.1 mg, 0.0071 mmol, 4.7 mol %),

NaCo(CO)4 (1.7 mg, 0.0088 mmol, 5.8 mol %) and meso-(2R,3S)-2-methyl-3- propyloxirane (5b, 15.2 mg, 0.152 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 89.9 : 10.1 for 6b and 96.2 : 3.8 for 7b by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

(3R,4R)-3-Butyl-4-methyloxetan-2-one (6c) and (3R,4R)-4-butyl-3-methyloxetan-

2-one (7c)

Using (R)-1c:

General procedure E was followed using (R)-pMeMesBinamAlCl (5.8 mg, 0.0071 mmol, 4.4 mol %), NaCo(CO)4 (1.4 mg, 0.0072 mmol, 4.4 mol %) and meso-(2R,3S)-

2-butyl-3-methyloxirane (5c, 18.4 mg, 0.161 mmol). After stirring at 22 °C for 18 h, the

1 reaction mixture was run through a plug of SiO2 and analyzed by H NMR and chiral

GC. The enantiomeric ratio (er) was determined to be 93.7 : 6.3 for 6c and 96.9 : 3.1 for

7c by GC analysis (β-Dex225 column) in comparison to authentic racemic material

(Figure 2.21).

104

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 (7c) 38.707 MM 0.2247 49.44768 3.66761 13.92647 2 (ent-7c) 46.681 MF 0.3545 48.35259 2.27335 13.61805 3 (6c) 47.396 FM 0.4658 128.79604 4.60877 36.27418 4 (ent-6c) 49.902 MM 0.5672 128.46625 3.77474 36.18130

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 (7c) 38.277 MM 0.5457 415.41385 12.68641 49.23901 2 (ent-7c) 46.858 MF 0.3855 27.89673 1.20606 3.30660 3 (6c) 47.341 FM 0.7592 387.90149 8.51545 45.97797 4 (ent-6c) 51.105 MM 0.4549 12.45606 4.56377e−1 1.47642 Figure 2.21 Representative GC chromatograms for 6c and 7c on β-Dex225 column.

Using (R)-1e:

General procedure E was followed using (R)-ML1 (6.1 mg, 0.0072 mmol, 4.7 mol %),

NaCo(CO)4 (1.3 mg, 0.0067 mmol, 4.4 mol %) and meso-(2R,3S)-2-butyl-3- methyloxirane (5c, 17.6 mg, 0.154 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 95.0 : 5.0 for 6c and 97.3 : 2.7 for 7c by

105

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1h:

General procedure E was followed using (R)-ML3 (5.9 mg, 0.0069 mmol, 5.5 mol %),

NaCo(CO)4 (1.4 mg, 0.0072 mmol, 5.7 mol %) and meso-(2R,3S)-2-butyl-3- methyloxirane (5c, 14.4 mg, 0.126 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 91.4 : 8.6 for 6c and 97.0 : 3.0 for 7c by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

(3R,4R)-3-Butyl-4-ethyloxetan-2-one (6d) and (3R,4R)-4-butyl-3-ethyloxetan-2- one (7d)

Using (R)-1c:

General procedure E was followed using (R)-pMeMesBinamAlCl (8.4 mg, 0.010 mmol,

5.0 mol %), NaCo(CO)4 (0.050 M, THF, 200 μl, 0.010 mmol, 5.0 mol %) and meso-

(2R,3S)-2-butyl-3-ethyloxirane (5d, 1.00 M, THF, 200 μl, 0.200 mmol). After stirring at 22 °C for 18.5 h, the crude reaction mixture was subjected to bulb-to-bulb distillation to give a 44 : 56 mixture of 6d and 7d (22.8 mg, 73 %) as a yellow oil. Analytical data

10b 1 for racemic 7d has previously been reported. H NMR (300 MHz, CDCl3): δ 4.22–

4.17 (m, 1H, 7d), 4.17–4.11 (m, 1H, 6d), 3.17–3.07 (m, 2H), 1.92–1.62 (m, 8H), 1.44–

1.26 (m, 8H), 1.00 (t, J = 7.4, 3H), 0.98 (t, J = 7.5, 3H), 0.90–0.86 (m, 6H). 13C{1H}

NMR (75 MHz, CDCl3): δ 171.6 (7d), 171.5 (6d), 79.2 (6d), 77.7 (7d), 57.5 (7d), 55.7

(6d), 34.2 (7d), 29.2 (6d), 27.6 (6d), 27.5 (6d), 27.1 (7d), 22.41 (7d), 22.38 (6d), 21.1

106

(7d), 13.9 (7d), 13.8 (6d), 11.3 (7d), 9.1 (6d). IR (neat, cm-1): 2960, 2993, 2863, 1816,

+ + 1462, 1382, 1123, 851. HRMS (ESI) m/z calculated for C9H17O2 (M+H) 157.1223,

22 found 157.1233. Specific rotation: [α] D = +5.2 (c = 0.35, CHCl3). The enantiomeric ratio (er) was determined to be 95.0 : 5.0 for 6d and 98.6 : 1.4 for 7d by GC analysis (β-

Dex225 column) in comparison to authentic racemic material (Figure 2.22).

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 (7d) 31.387 MM 0.2586 71.44564 4.60474 26.74727 2 (ent-7d) 40.304 MM 0.3871 70.55064 3.03754 26.41220 3 (6d) 41.757 MM 0.4551 63.09148 2.31040 23.61970 4 (ent-6d) 45.961 MM 0.4795 62.02603 2.15614 23.22083

RetTime Width Area Height Area Peak # Type [min] [min] [pA*s] [pA] % 1 (7d) 30.895 MM 0.4506 370.07291 13.68907 53.58688 2 (ent-7d) 40.331 MF 0.2743 19.55349 1.1881 2.83136 3 (6d) 41.109 FM 0.7601 296.6904 6.50563 42.96103 4 (ent-6d) 46.483 MM 0.3529 4.28672 2.02e−1 0.62072 Figure 2.22 Representative GC chromatograms for 6d and 7d on β-Dex225 column.

107

Using (R)-1e:

General procedure E was followed using (R)-ML1 (5.9 mg, 0.0069 mmol, 4.0 mol %),

NaCo(CO)4 (1.6 mg, 0.0082 mmol, 4.7 mol %) and meso-(2R,3S)-2-butyl-3- ethyloxirane (5d, 22.3 mg, 0.174 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 95.1 : 4.9 for 6d and 98.0 : 2.0 for 7d by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1g:

General procedure E was followed using (R)-ML2 (5.8 mg, 0.0070 mmol, 4.7 mol %),

NaCo(CO)4 (1.6 mg, 0.0082 mmol, 5.5 mol %) and meso-(2R,3S)-2-butyl-3- ethyloxirane (5d, 19.2 mg, 0.150 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 95.4 : 4.6 for 6d and 98.8 : 1.2 for 7d by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

Using (R)-1h:

General procedure E was followed using (R)-ML5 (5.8 mg, 0.0070 mmol, 5.1 mol %),

NaCo(CO)4 (1.6 mg, 0.0082 mmol, 6.0 mol %) and meso-(2R,3S)-2-butyl-3- ethyloxirane (5d, 17.6 mg, 0.137 mmol). After stirring at 22 °C for 18 h, the reaction

1 mixture was run through a plug of SiO2 and analyzed by H NMR and chiral GC. The enantiomeric ratio (er) was determined to be 96.4 : 3.6 for 6d and 99.3 : 0.7 for 7d by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

108

2.5.2.6 Carbonylative Desymmetrization of Meso-Epoxides Using (R)-1e and 1h at 0 °C (3R,4R)-3,4-Dimethyloxetan-2-one (4b)

General procedure F was followed using (R)-ML1 (5.0 mg, 0.0059 mmol, 3.3 mol %),

NaCo(CO)4 (1.5, 0.0077 mmol, 4.3 mol %) and meso-(2R,3S)-2,3-dimethyloxirane (3b,

12.9 mg, 0.179 mmol). The enantiomeric ratio (er) was determined to be 93.9 : 6.1 by

GC analysis (CHIRALDEX A-TA column) in comparison to authentic racemic material.

(3R,4R)-3,4-Diethyloxetan-2-one (4c)

General procedure F was followed using (R)-ML3 (6.3 mg, 0.0073 mmol, 4.6 mol %),

42 NaCo(CO)4 (1.5, 0.0077 mmol, 4.9 mol %) and meso-(2R,3S)-2,3-diethyloxirane (3c,

15.9 mg, 0.159 mmol). The enantiomeric ratio (er) was determined to be 98.8 : 1.2 by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

(3R,4R)-3,4-Dipropyloxetan-2-one (4a)

General procedure F was followed using (R)-ML3 (6.5 mg, 0.0076 mmol, 5.2 mol %),

41 NaCo(CO)4 (1.7, 0.0088 mmol, 6.0 mol %) and meso-(2R,3S)-2,3-dipropyloxirane

(3a, 18.6 mg, 0.145 mmol). The enantiomeric ratio (er) was determined to be 98.3 : 1.7 by GC analysis (β-Dex225 column) in comparison to authentic racemic material.

(3R,4R)-3,4-Dibutyloxetan-2-one (4d)

General procedure F was followed using (R)-ML3 (6.4 mg, 0.0075 mmol, 4.8 mol %),

109

43 NaCo(CO)4 (1.8, 0.0093 mmol, 6.0 mol %) and meso-(2R,3S)-2,3-dibutyloxirane (3d,

24.1 mg, 0.154 mmol). The enantiomeric ratio (er) was determined to be 98.5 : 1.5 by

GC analysis (β-Dex225 column) in comparison to authentic racemic material.

2.5.2.7 Contrasteric Carbonylation of Isobutylene Oxide Pivalolactone (12a)

General procedure E was followed using (R)-ML7 (8.1 mg, 0.0101 mmol, 6.0 mol %),

NaCo(CO)4 (2.2 mg, 0.0113 mmol, 6.6 mol %) and isobutylene oxide (11, 12.3 mg,

0.171 mmol). After stirring at 22 °C for 18 h, the reaction mixture was run through a plug of neutral alumina and analyzed by 1H NMR spectroscopy. 1H NMR (500 MHz,

CDCl3): δ 4.08 (s, 2H), 1.41 (s, 6H). Product peaks were compared to isobutyraldehyde

(13) peaks at 2.41 (septet, J = 7.0, 1H), 1.11 (d, J = 7.0, 6H); 12b peaks at 3.18 (s, 2H),

1.62 (s, 6H); and isobutylene oxide (11) at 2.59 (s, 2H), 1.32 (s, 6H).

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117

Rearrangement of Monosubstituted Epoxides to Methyl Ketones Using an Aluminum Porphyrin Cobaltate Catalyst

Reproduced adapted from Lamb, J. R.; Jung, Y.; Coates, G. W. Org. Chem. Front.

2015, 2, 346–349. DOI: 10.1039/C4QO00324A with permission from the Chinese

Chemical Society (CCS), Shanghai Institute of Organic Chemistry (SIOC), and the

Royal Society of Chemistry.

118 3.1 Introduction

Epoxides are versatile intermediates in organic chemistry due to their inherent high reactivity and synthetic availability. The oxirane polarity and ring strain enable these functional groups to undergo a variety of useful reactions, including nucleophilic ring opening, deoxygenation, and a variety of rearrangements.1 One reaction that has attracted a great deal of attention due to its high efficiency and synthetic potential is the

Lewis-acid induced isomerization of epoxides to carbonyl compounds, known as the

Meinwald rearrangement (Scheme 3.1).1,2

Scheme 3.1 Mechanism of the Meinwald rearrangement of epoxides activated by a Lewis acid (LA) Despite previous work to make this transformation synthetically useful, multiple products are commonly observed due to unselective ring opening and substituent migration (see Chapter 1, Scheme 1.9).3 While the migratory aptitude of various substituents can often be tuned by the Lewis acid and conditions employed,4 selective ring opening using Lewis acids generally relies on substrate bias to form a single, stable tertiary (Scheme 3.1, R3 and R4 ≠ H) or benzylic (R3 or R4 = aryl) carbocation.5

Similarly, terminal epoxides generally yield aldehyde products because the instability of primary carbocations (R3 = R4 = H) disfavors ketone formation.6

Methyl ketones have been observed as the major isomerization product of monosubstituted epoxides when lithium iodide7 or transition metals—such as Fe,8 Ru,9

Co,10 Rh,11 or Pd12—are used to alter the mechanism of ring opening. While important progress has been made in this field, existing systems still have drawbacks, including

119

limited substrate scope, modest yields, high reaction temperature, and high catalyst loading.

During our group’s investigation of carbonylative ring expansion of epoxides to β-

+ − 13 lactones using catalysts of the form [Lewis Acid] [Co(CO)4] , we observed concurrent ketone formation, especially at low pressures of carbon monoxide (Scheme 3.2).14 We decided to explore this reaction in more detail and selected the porphyrin-based catalyst

+ − [pClTPPAl(THF)2] [Co(CO)4] (1) because of its straightforward synthesis and known functional group tolerance.15 Iron,6b,16 ruthenium,17 and chromium18 porphyrin catalysts have precedents in the Meinwald rearrangement literature, but they generally operate via the Lewis acidic mechanism which results in aldehyde products from terminal epoxides (Scheme 3.1).

Scheme 3.2 Catalytic (A) carbonylation and (B) isomerization of monosubstituted epoxides by [Lewis acid][Co(CO)4]

3.2 Reaction Optimization Optimization of the reaction conditions with 1-hexene oxide (2a, Table 3.1) showed that the best solvent for this transformation was THF (entries 1–6). A concentration screen revealed 1.0 M as the most effective, with both higher and lower concentrations

120

resulting in lower conversions (entries 6–11). Increasing the catalyst loading from 1 to

2 mol % resulted in full conversion of epoxide at room temperature (entry 12).

Table 3.1 Evaluation of solvents and epoxide concentration for the isomerization of epoxide 2a by catalyst 1

entrya mol % 1 solvent concentration (M) conversion 3a (%)b 1 1 1,4-Dioxane 0.5 21 2 1 Benzene 0.5 27 3 1 Toluene 0.5 31 4 1 Ether 0.5 36 5 1 Hexanes 0.5 28 6 1 THF 0.5 45 7 1 THF 1.0 82 8 1 THF 1.5 72 9 1 THF 2.0 67 10 1 THF 4.0 71 11 1 none 8.7 38 12 2 THF 1.0 >99> aConditions: 22 °C, 20 h. bDetermined by 1H NMR of the crude reaction mixture.

3.3 Substrate Scope and Limitations Once viable reaction conditions were found, the substrate scope of the isomerization was explored (Figure 3.1). Aliphatic epoxides, including those containing substantial α- branching, were rearranged in excellent yields (≥89%, 3a–i), and no aldehyde or alcohol side products were observed. Capillary GC analysis of the crude reaction mixtures revealed trace amounts of β-lactone formation, which would result in partial

121

aQuantitative GC yield versus dodecane as an internal standard. b5 mol % 1 used. c2 mol % 1 per epoxide moiety used based on the molecular weight of the repeat unit. Figure 3.1 Isolated yields and substrate scope for the rearrangement of monosubstituted epoxides.

Scheme 3.3 Proposed cobalt carbonyl deactivation by β-lactone formation deactivation of 1 via loss of a CO ligand bound to the cobaltate counterion (Scheme

3.3).

As previously reported,15 the aluminum porphyrin catalyst 1 tolerates a variety of functionality – including esters, amides, alcohols, and ethers – under mild reaction conditions while maintaining high isolated yields (Figure 3.1, 3j–p). Notably, this

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system tolerates a terminal olefin (3q), which demonstrates its potential over other ketone-forming reactions such as the Wacker oxidation. Even though this substrate required 5 mol % catalyst to achieve full conversion of epoxide, we were able to access the methyl ketone in the presence of a terminal olefin by utilizing the difference in reactivity of an epoxide and a double bond. In contrast, the Wacker oxidation of a diene would predominantly result in a diketone. For example, Kaneda and coworkers oxidized

19 1,7-octadiene to a mixture of mono- and diketone using PdCl2 (Scheme 3.4).

Scheme 3.4 Wacker oxidation of a diene to form a diketone as the major product In addition to small molecule substrates, this transformation works cleanly on polycarbonate 2r using standard reaction conditions with 2 mol % 1 per epoxide moiety.

This substrate is prepared via a Zn-catalyzed copolymerization of vinylcyclohexene

20 dioxide and CO2. As expected, the molecular weight and molar mass distribution of the polymer did not change during this transformation, but a clear change in the 1H

NMR and IR spectra indicate clean conversion to the ketone-functionalized polymer

(3r). Polymer 2r was prone to crosslinking during polymerization to form an insoluble powder. Interestingly, the isomerization chemistry still worked on this insoluble substrate, giving rise to an identical IR spectrum to that of the soluble polymer.

A limitation of this method was revealed during our attempt to rearrange terminal epoxides with aromatic substituents. Styrene oxide resulted in a 1 : 1.6 mixture of acetophenone and phenylacetaldehyde due to competing SN2 attack at the sterically unhindered methylene and the adjacent benzylic methine (Table 3.2, entry 1). While a

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variety of catalysts are known to selectively isomerize styrene oxide to either acetophenone21 or phenylacetaldehyde,5c–d,22 cobaltate-based catalysts have been reported to give a mixture of products with this substrate.23 Attempts to rearrange 2,3- disubstituted epoxides with 1 led to low conversions under standard reaction conditions

(entry 2).

Table 3.2 Substrate limitations of epoxide rearrangement using 1

entrya substrate product(s) conversion (%)b 90 (3s : 4s 1 c 1 : 1.6)

2 31

aConditions: [epoxide] = 1.0 M in THF, 2 mol % 1, 22 °C, 18 h. bConversion determined by GC or 1H NMR analysis of the crude reaction mixture. cDetermined by GC analysis.

3.4 Mechanistic Explorations and Control Experiments We propose that 1 reacts via a similar mechanism to that reported by Eisenmann10a

10c and Kagan, in which Co2(CO)8 was combined with MeOH to form

+2 − [Co(MeOH)6] [Co(CO)4]2 in situ. Kagan’s proposed catalytic cycle involves ring opening via a Lewis acid-assisted SN2 attack of the cobaltate at the least substituted carbon followed by classical β-hydrogen elimination from cobalt (Scheme 3.2B). This proposal was based on the observed epoxide reactivities and product distributions, but the full mechanism has yet to be thoroughly studied.

In Kagan’s system, there are two cobalt metal centers potentially capable of performing the β-hydrogen elimination; therefore, he proposes an enolate or an α- substituted ketone as two possible intermediates (see Chapter 1, Scheme 1.10). In our

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system, the aluminum Lewis acid is unlikely to perform β-hydrogen elimination (and cannot adopt the proper geometry), supporting β-hydrogen elimination from Co(CO)4.

We utilized our well-defined complexes to probe the synergistic nature of this bimetallic catalyst system by replacing either the aluminum porphyrin with the less

Lewis acidic sodium cation or the cobalt tetracarbonyl with the non-nucleophilic tetraphenyl borate anion. Neither of these variants was able to promote the isomerization of 2a (Table 3.3, entries 2 and 3). Eisenman performed a similar experiment by

+2 +2 replacing [Co(MeOH)6] with [Co(pyridine)6] which was unable to coordinate an epoxide due to the strongly bound pyridine ligands. Similarly, pClTPPAlCl, the precursor to catalyst 1, does not lead to any conversion to ketone (entry 4). These experiments conclusively show that both the Lewis acid cation and nucleophilic anion are necessary for this reaction, which supports the first step in Kagan’s proposed mechanism and parallels the ring-opening step of carbonylation (Scheme 3.2A).24 The fact that cobalt is required to effect β-hydrogen elimination clearly distinguishes this mechanism from the Lewis acid pathway previously depicted in Scheme 3.1.

Table 3.3 Catalyst control experiments for the isomerization of 2a

entrya catalyst conversion 3a (%)b + − 1 [pClTPPAl(THF)2] [Co(CO)4] >99> + − 2 [pClTPPAl(THF)2] [BPh4] <1

3 Na[Co(CO)4] <1 4 pClTPPAlCl <1 aConditions: [2a] = 1 M in THF, 2 mol % catalyst, 22 °C, 18 h. bDetermined by 1H NMR spectroscopy of the crude reaction mixture.

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The β-hydrogen elimination step was investigated by subjecting isobutylene oxide

(IBO) to standard reaction conditions. This 2,2-disubstituted epoxide results in a tertiary alkoxide upon SN2 ring opening which cannot undergo β-hydrogen elimination (Scheme

3.5A). As expected, no methyl shift to form a ketone was observed. Less than 2% conversion to isobutyraldehyde occurred, which could arise from two different pathways. An SN1-type attack of the cobaltate, which is a known minor pathway for isobutylene oxide carbonylation,25 could lead to aldehyde formation (Scheme 3.5B).

The other possibility is that the classic Lewis-acid mediated mechanism (Scheme 3.5C) is enhanced due to the formation of a stabilized tertiary carbocation. Pathway C is further favored when using a non-nucleophilic anion such that conversion to

+ − isobutyraldehyde increased to 62% with [pClTPPAl] [BPh4] .

Scheme 3.5 Viable pathways for aldehyde formation from isobutylene oxide Another, less likely explanation for the low conversion of IBO is that the epoxide, or an impurity in the substrate, deactivates the catalyst. To test this hypothesis, a competition experiment was performed between propylene oxide (PO) and isobutylene oxide (Table 3.4). A 1 : 1 molar mixture of PO and IBO was subjected to standard reaction conditions with 2 mol % catalyst with respect to PO (1 mol % with respect to total epoxide, entry 1). PO only achieved 50% conversion, while no conversion of IBO

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was observed. If the catalyst loading was increased to 4 mol % with respect to PO (2 mol % with respect to total epoxide, entry 2), PO was fully isomerized to acetone and

IBO was still unreacted. These experiments clearly show that this system is able to rearrange monosubstituted epoxides in the presence of 2,2-disubstituted epoxides.

While it appears that IBO does deactivate a portion of the catalyst, IBO’s low reactivity is predominantly due to the lack of β hydrogens after nucleophilic ring opening.

Table 3.4 Competition experiments between propylene oxide and isobutylene oxide

b mol% catalyst 1 conversion of epoxide (%) entrya (with respect to PO) PO IBO 1 2 50 <1 2 4 >99> <1 aConditions: [2b] = [2u] = 1.0 in THF, 22 °C, 18 h. bDetermined by 1H NMR spectroscopy of the crude reaction mixture.

Finally, our observation that higher concentrations of epoxide led to decreased product formation was intriguing and warranted further study (Table 3.1, entries 7–11).

We initially hypothesized that at higher concentrations the polarity of the ketone product might affect the rate of the reaction; however, adding 1–2 equivalents of acetone at the beginning of the reaction did not appreciably affect the conversion (Table 3.5). This also indicates there is no product inhibition that could arise from the carbonyl binding to the metal center.

Next, we considered catalyst decomposition as the cause of the reduced conversion

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Table 3.5 Effect of solvent polarity on the isomerization of 2a

entrya acetone (equivalents) conversion 3a (%)b 1 0 53 2 1 54 3 2 47 aConditions: [2a] = 2 M in THF, 1 mol % 1, 22 °C, 20 h. bDetermined by 1H NMR of the crude reaction mixture. at higher concentrations. It is well known from the hydroformylation literature that our proposed intermediate HCo(CO)4 decomposes to Co2(CO)8 and hydrogen gas at room temperature (Scheme 3.6). 26 The rate of this decomposition is proportional to the square of HCo(CO)4 concentration. This trend agrees with our experimental results because when increasing the concentration of epoxide at a fixed catalyst loading, the catalyst concentration also increases. Higher concentrations of catalyst lead to a proportional increase in the catalytic intermediate HCo(CO)4.

Scheme 3.6 Intermediate HCo(CO)4 decomposition at room temperature The reversible nature of the equilibrium shown in Scheme 3.6 led us to hypothesize that an overpressure of hydrogen gas would decrease the catalyst decomposition. Side by side reactions of no hydrogen pressure and increased hydrogen pressure were performed to account for the headspace of the high-pressure reactors. A lower catalyst loading was utilized to ensure less than full conversion in all cases so any changes in conversion could be detected. Surprisingly, we observed that hydrogen gas actually

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inhibits the reaction (Table 3.6). A slight pressure of 30 psi hydrogen gas only moderately decreased the activity, while a higher pressure of 600 psi dramatically deactivated the catalyst.

Table 3.6 Effect of hydrogen pressure on epoxide isomerization by catalyst 1

a b entry reactor H2 pressure (psi) conversion 3a (%)

1 Fisher-Porter Bottle 0 38 2 Fisher-Porter Bottle 30 20 3 6-Well 0 44 4 6-Well 600 6

a b 1 Conditions: [2a] = 1.0 M in THF, 1 mol % 1, H2, 22 °C, 18 h. Determined by H NMR spectroscopy of the crude reaction mixture.

We propose that under these conditions of high H2 pressure – but no external CO pressure – HCo(CO)4 loses one carbon monoxide ligand to form the known

27 hydroformylation intermediate HCo(CO)3. Exogenous H2 can trap this intermediate to form H3Co(CO)3, which we presume to be catalytically inactive (Scheme 3.7). This proposal is consistent with known HCo(CO)4 behavior in hydroformylation and would explain why the catalyst is more dramatically deactivated with higher pressures of hydrogen.

Scheme 3.7 Proposed decomposition pathway of HCo(CO)4 in the presence of hydrogen gas

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3.5 Conclusion

We have presented a new application of a readily available, well-defined catalyst for the isomerization of monosubstituted epoxides to methyl ketones in excellent yields.

Compared to previous systems, catalyst 1 is effective under mild conditions, low catalyst loading, and has good functional group tolerance. In addition to the small molecule substrates, a polycarbonate with pendant epoxides was successfully isomerized with no loss in molecular weight or broadening of the molar mass distribution. We utilized the well-defined nature of our catalysts to demonstrate that both halves of the catalyst (i.e. Lewis acid and nucleophilic anion) are necessary to enact the transformation, ruling out the Meinwald rearrangement mechanism which is solely mediated by a Lewis acid. We also showed that the 2,2-disubstituted epoxide isobutylene oxide was unreactive due to its lack of β hydrogens, further supporting our proposed mechanism.

3.6 Experimental Procedures

3.6.1 General Considerations Methods and Instruments

Unless stated otherwise, all synthetic manipulations were carried out using standard

Schlenk techniques under a nitrogen atmosphere or in an MBraun Unilab glovebox under an atmosphere of purified nitrogen. Flash column chromatography was performed using silica gel (particle size 40–64 µm, 230–400 mesh). High-pressure reactions were performed in a commercial Fisher-Porter bottle or a custom-designed and -fabricated, six-chamber, stainless steel, high-pressure reactor.28 The reactor design allowed for incorporation of six 1 or 2 fluid dram glass vials. Reactions were carried out in oven-

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dried glassware cooled under vacuum.

IR spectra were recorded on a Nicolet iS10 FT-IR spectrometer. 1H NMR and

13C{1H} NMR spectra were recorded on a Varian 300, 400, or 500 MHz instrument at

1 22 °C with shifts reported relative to the residual solvent peak (CDCl3: 7.26 ppm ( H), and 77.16 ppm (13C)). All J values are given in Hertz. Deuterated chloroform was purchased from Cambridge Isotope Laboratories and stored over K2CO3.

Gas chromatography (GC) analyses were performed on a Hewlett Packard 6890 gas chromatograph equipped with a Astec Chiraldex A-TA and a Supelco β-Dex225 column, and a flame ionization detector. Helium (Airgas, UHP grade) was used as carrier gas. Quantitative GC analysis to determine the yield of volatile products was performed by adding the internal standard dodecane to the reaction mixture. Response factors for the products relative to the internal standard were obtained using commercially available materials. HRMS analyses were performed on a Thermo

Scientific Exactive Orbitrap MS system with an Ion Sense DART ion source.

Gel permeation chromatography (GPC) analyses were carried out using an Agilent

Technologies PL-GPC 50 Integrated GPC equipped with a UV detector and a refractive index detector as well as a Polymer Laboratories PL-AL RT GPC autosampler. The

GPC used two PL gel Mini-MIX C columns (5 micron, 4.6 mm ID). The GPC columns were eluted with THF at 30 °C at 0.3 ml/min and were calibrated using monodisperse polystyrene standards.

Chemicals

Anhydrous 1,4-dioxane was purchased from Sigma-Aldrich and degassed via three freeze-pump-thaw cycles prior to use. Thiophene free benzene was purchased from

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EMD Millipore and dried over activated 3Å molecular sieves and sparged vigorously with nitrogen for 40 minutes prior to first use. Anhydrous toluene, dichloromethane

(DCM), hexanes, diethyl ether, and tetrahydrofuran (THF) were purchased from Fischer

Scientific and sparged vigorously with nitrogen for 40 minutes prior to first use. The solvents were further purified by passing them under nitrogen pressure through two packed columns of neutral alumina (tetrahydrofuran was also passed through a third column packed with activated 4Å molecular sieves) or through neutral alumina and copper(II) oxide (for toluene and hexanes). Tetrahydrofuran, diethyl ether, and dichloromethane were degassed via three freeze-pump-thaw cycles prior to use. All epoxides used in this study except 2n were dried over calcium hydride and degassed via three freeze-pump-thaw cycles prior to use. Epoxide 2n was dried overnight over activated 3Å molecular sieves, filtered, and degassed via three freeze-pump-thaw cycles prior to use. All non-dried solvents used were reagent grade or better and used as received. Hydrogen was purchased from Airgas (99.999% min purity) and used as received. All other chemicals were purchased from Aldrich, Alfa-Aesar, TCI America, or Macron and used as received.

The following compounds were prepared according to literature procedures: a) catalysts and catalyst precursors

29 NaCo(CO)4

+ − + [pClTPPAl(THF)2] [Co(CO)4] (1, pClTPPAl(THF)2 = bis(tetrahydrofuran)-meso-

tetra(4-chlorophenyl)porphyrinato aluminum)15a

pClTPPAl–Cl15a

(BDI)ZnOAc (BDI = N-(4-(((1S,2S)-2-(benyloxy)cyclohexyl)amino)-5,5,5-

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trifluoropent-3-en-2-ylidene)-2,6-dimethylaniline, ligand 5 from ref 20)20 b) epoxides

2-propyl oxirane (2d)30

4,5-epoxypentyl butyrate (2j)31

ethyl 4,5-epoxypentanoate (2k)32

2-(4-methoxybenzyl)oxirane (2m)33

1-(2-oxiranylmethyl)-cyclopentanol (2n)34

3.6.2 Mechanistic Experiments Monosubstituted and 2,2-Disubstituted Epoxide Competition Experiment

In a glove box, a 1 fluid dram glass vial equipped with a Teflon-coated magnetic stir bar was charged with the appropriate amount of 1 (0.008 or 0.016 mmol) and THF (0.4 ml). After stirring at 22 °C until the solution was homogeneous, isobutylene oxide (0.4 mmol), followed by propylene oxide (0.4 mmol), were added to the vial, which was then sealed and left to stir overnight at room temperature. After 18 hours, the reactions were opened to air and a small aliquot was diluted in CDCl3 and run through a short plug of alumina over glass wool microfibre to remove the catalyst. Conversion was determined by 1H NMR spectroscopy.

Solvent Polarity/Product Inhibition Test

In a glove box, a 1 fluid dram glass vial equipped with a Teflon-coated magnetic stir bar was charged with 1 (0.004 mmol), THF (0.2 ml), and appropriate amount of acetone

(0, 0.4, or 0.8 mmol). After 1 minute of stirring at 22 °C, 1-hexene oxide (2a, 0.4 mmol)

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was added to the vial, which was then sealed and left to stir overnight at room temperature. After 18 hours, the reactions were opened to air and a small aliquot was diluted in CDCl3 and run through a short plug of alumina over glass wool microfibre to remove the catalyst. Conversion was determined by 1H NMR spectroscopy.

Hydrogen Pressure Tests

Fisher-Porter Bottle Reactions (low H2 pressure)

In a glove box, A 20 ml glass vial was charged with 1 (0.08 mmol) and THF (4 ml).

The vial and epoxide were then cooled to −32 °C for 30 minutes. 1-Hexene oxide (2a,

4 mmol) was added by weight via a syringe. The homogeneous reaction mixture was evenly divided between two 2 dram vials equipped with Teflon-coated stir bars. Each vial was put inside different Fisher-Porter reactors, which were subsequently sealed.

The first was set to stir at room temperature. The second rector was pressurized with 30 psig hydrogen gas taking care to purge the H2 line to minimize exposure to air. After 18 hours, the reactions were opened to air and a small aliquot was diluted in CDCl3 and run through a short plug of alumina over glass wool microfibre to remove the catalyst.

Conversion was determined by 1H NMR spectroscopy.

6-Well Reactions (high H2 pressure)

In a glove box, two 1 fluid dram glass vials equipped with a Teflon-coated magnetic stir bar were charged with 1 (0.004 mmol) and THF (0.2 ml). After 1 minute of stirring at 22 °C, the vials were placed in a custom-made 6-well high-pressure reactor which itself was placed in a glove box freezer (−32 °C) for 30 minutes. 1-Hexene oxide (2a,

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0.4 mmol, also cooled to −32 °C) was then added to the vials, which were then capped with a septum cap and pierced with a vent needle. The 6-well reactor was subsequently sealed and taken out of the glove box. Only one of the reactions was pressurized with hydrogen (600 psi). The reactor was then sealed again, placed in a 22 °C water bath and the reaction mixture stirred for 18 hours. The reactor was then carefully vented and a small aliquot was diluted in CDCl3 and run through a short plug of alumina over glass wool microfibre to remove the catalyst. Conversion was determined by 1H NMR spectroscopy.

3.6.3 Synthetic Procedures

3.6.3.1 General Procedures General procedure A: Epoxidation of alkenes to epoxides using mCPBA

mCPBA (Aldrich, ≤77 %) was added in portions at 0 °C to a solution of the corresponding alkene in DCM and the resulting mixture was stirred at room temperature until TLC analysis indicated complete consumption of the alkene. After destroying excess mCPBA by adding aqueous NaHSO3 and stirring for 1 h, the reaction mixture was filtered through celite, the organic phase washed with NaHCO3 (sat., aq., 3x), dried with sodium sulfate, filtered, and concentrated under reduced pressure.

General procedure B: Isomerization of epoxides with quantitative GC yield

In a glove box, a 1 fluid dram glass vial equipped with a Teflon-coated magnetic stir bar was charged with 1, dodecane, and THF. After 1 minute of stirring at 22 °C, the corresponding epoxide was added to the vial, which was then sealed and left to stir

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overnight at room temperature. After the indicated time, a drop of the reaction mixture was diluted with ether and passed through a neutral alumina plug to remove the catalyst before being subjected to quantitative GC analysis.

General procedure C: Isomerization of epoxides with isolation

In a glove box, a 1 fluid dram glass vial equipped with a Teflon-coated magnetic stir bar was charged with 1 and THF. After 1 minute of stirring at 22 °C, the corresponding epoxide was added to the vial, which was then sealed and left to stir overnight at room temperature. After the indicated time, the vial was taken out of the glove box and a saturated aqueous solution of Rochelle salt (potassium sodium L-(+)-tartrate tetrahydrate) was added and stirred at room temperature overnight. (Note: Rochelle salt binds the aluminum of the catalyst to help with isolation. It was found that stirring for only 1–2 hours resulted in slightly lower isolated yields.) The purple catalyst was filtered off using celite. The resulting green filtrate was extracted with ether 3x and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. Ether was used to pass the resulting green oil through a small plug of decolorizing carbon to remove the color, followed by stripping off the solvent to give the pure ketone without the need of further purification.

3.6.3.2 Synthesis of Starting Materials N,N-Bis(1-methylethyl)-10-undecenamide (SM1)

10-Undecenoyl chloride (98%, 10.5 ml, 48.9 mmol) was taken up in benzene (46 ml) and added dropwise to a solution of diisopropyl amine (99%, 13.5 ml, 95.5 mmol) in

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tetrahydrofuran (80 ml). A white precipitate immediately formed, so an extra 50 ml THF was added throughout the addition to facilitate stirring. After stirring overnight at room temperature, the ammonium chloride salt was filtered off and the resulting solution was washed three times with water and dried over Na2SO4. Removing the solvent in vacuo followed by vacuum distillation afforded the title compound (12.6 g, 96%) as a colorless

1 oil. H NMR (400 MHz, CDCl3): δ 5.80 (ddt, J = 17.1, 10.3, 6.7, 1H), 4.89–5.02 (m,

2H), 3.96 (septuplet, J = 6.8, 1H), 3.48 (m, 1H), 2.26 (t, J = 7.7, 2H), 2.03 (q, J = 6.9,

2H), 1.60 (m, 2H), 1.24–1.40 (m, 18H), 1.18 (d, J = 6.7, 6H). 13C{1H} NMR (101 MHz,

CDCl3): δ 171.6, 138.8, 113.9, 48.0, 45.2, 35.1, 33.6, 29.22, 29.21, 29.1, 28.8, 28.7,

25.2, 20.8, 20.5. IR (neat, cm−1): 2966, 2924, 2852, 1639, 1437, 1368, 1301, 1214, 1134,

+ + 1043, 906. HRMS (DART) m/z calculated for C17H34NO (M+H) 268.26459, found

268.26341.

N,N-Bis(1-methylethyl)-2-oxiranenonanamide (2o)

Following general procedure A, SM1 (2.442 g, 9.130 mmol), mCPBA (<77%, 2.664 g,

11.89 mmol), and DCM (20 ml) were used to produce the title compound 2o (2.304 g,

1 89%) as a yellow oil. H NMR (400 MHz, CDCl3): δ 3.96 (septet, J = 6.7, 1H), 3.46

(m, 1H), 2.90 (m, 1H), 2.74 (dd, J = 5.0, 4.1, 1H), 2.46 (dd, J = 5.0, 2.7, 1H), 2.26 (m,

2H), 1.55–1.66 (m, 2H), 1.47–1.55 (m, 2H), 1.39–1.47 (m, 2H), 1.37 (d, J = 6.8, 6H),

13 1 1.24–1.33 (m, 8H), 1.18 (d, J = 6.7, 6H). C{ H} NMR (101 MHz, CDCl3): δ 172.1,

52.5, 48.3, 47.2, 45.6, 35.5, 32.6, 29.53, 29.49, 29.47, 26.0, 25.5, 21.1, 20.8. (Note: there are three missing 13C NMR signals, which we attribute to coincidentally overlapping signals.) IR (neat, cm−1): 2964, 2927, 2853, 1636, 1439, 1369, 1303, 1213, 1133,

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+ + 1043832. HRMS (DART) m/z calculated for C17H34NO2 (M+H) 284.25895, found

284.25880.

Poly(4-oxiranylcyclohexene carbonate) (2r)

In a glove box, an oven dried Fisher-Porter bottle equipped with a Teflon-coated magnetic stir bar was charged with toluene (1.2 ml), vinylcyclohexene dioxide (0.5 ml,

3.9 mmol), and (BDI)ZnOAc (7.4 mg, 0.012 mmol, 0.31 mol %). The Fisher-Porter bottle was sealed with the reactor head and removed from the box. The vessel was placed in a 0 °C bath and allowed to equilibrate for 10 minutes. The vessel was charged to 100 psig CO2 and vented to ~30 psig 3 times before being recharged to 100 psig. The vessel was left open to 100 psig for 5 minutes at 0 °C to allow saturation of the reaction mixture. The vessel was stirred at 0 °C for ~2 hours before being vented to atmospheric pressure and warmed to room temperature (Note: the polymerization was stopped at ~2 hours, corresponding to 10–20% conversion, to avoid crosslinking). The reaction mixture was diluted with ~1 mL DCM and precipitated into 100 mL rapidly stirring methanol. The polymer (106 mg, 15%) was isolated by vacuum filtration and dried in vacuo at 22 °C overnight to give a white powdery precipitate. 1H NMR (400 MHz,

CDCl3): δ 4.88 (br m, 1H), 4.77 (br m, 1H), 2.78 (br m, 1H), 2.72 (br m, 1H), 2.55 (br m, 1H), 1.38–1.98 (br m, 7H). IR (neat, cm−1): 2936, 1739, 1228, 1153, 960, 854, 785.

GPC: Mn = 15,300 g/mol, Mw = 25,500 g/mol, PDI = 1.67.

Note: broad 1H NMR resonances are normal for polymers because of very similar, but not identical, environments of each enchained monomer. This is exacerbated by the use of a diastereomeric mixture of monomers. The 1H and 13C{1H} NMR spectra of 2r are

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shown in Figure 3.2.

1 H NMR (400 MHz, CDCl3):

13 1 C{ H} NMR (126 MHz, CDCl3):

Figure 3.2 1H and 13C NMR spectra of 2r.

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3.6.3.3 Isomerization of Monosubstituted Epoxides to Methyl Ketones Acetone (3b)

Following general procedure B, 2b (19.0 mg, 0.327 mmol), dodecane (18.7 mg, 0.110 mmol), [pClTPPAl(THF)2][Co(CO)4] (1, 7.5 mg, 0.0070 mmol, 2.1%), and THF (0.35 mL) were used. Quantitative GC analysis resulted in 96% yield.

2-Butanone (3c)

Following general procedure B, 2c (25.9 mg, 0.359 mmol), dodecane (18.9 mg, 0.111 mmol), [pClTPPAl(THF)2][Co(CO)4] (1, 7.6 mg, 0.0071 mmol, 2.0%), and THF (0.35 mL) were used. Quantitative GC analysis resulted in 97% yield.

2-Pentanone (3d)

Following general procedure B, 2d (33.9 mg, 0.394 mmol), dodecane (19.3 mg, 0.113 mmol), [pClTPPAl(THF)2][Co(CO)4] (1, 8.5 mg, 0.0079 mmol, 2.0%), and THF (0.40 mL) were used. Quantitative GC analysis resulted in 90% yield.

2-Hexanone (3a)

Following general procedure B, 2a (36.7 mg, 0.367 mmol), dodecane (19.0 mg, 0.112 mmol), [pClTPPAl(THF)2][Co(CO)4] (1, 7.5 mg, 0.0070 mmol, 1.9%), and THF (0.35 mL) were used. Quantitative GC analysis resulted in 96% yield.

2-Heptanone (3e)

Following general procedure B, 2e (33.1 mg, 0.290 mmol), dodecane (17.2 mg, 0.101

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mmol), [pClTPPAl(THF)2][Co(CO)4] (1, 6.6 mg, 0.0061 mmol, 2.1%), and THF (0.30 mL) were used. Quantitative GC analysis resulted in 92% yield.

2-Dodecanone (3f)

Following general procedure C, 2f (370.0 mg, 2.007 mmol),

[pClTPPAl(THF)2][Co(CO)4] (1, 43.0 mg, 0.0399 mmol, 2.0%), and THF (2 mL) were used to produce 3f (332.1 mg, 90%) as a colorless oil. Analytical data for 3f matched

35 1 those previously been reported. H NMR (400 MHz, CDCl3): δ 2.40 (t, J = 7.5, 2H),

2.12 (s, 3H), 1.54 (m, 2H), 1.24 (m, 14H), 0.86 (t, J = 6.5, 3H). 13C{1H} NMR (101

MHz, CDCl3): δ 209.3, 43.9, 32.0, 29.9, 29.7, 29.6, 29.5, 29.4, 29.3, 24.0, 22.8, 14.2.

3-Methyl-2-butanone (3g)

Following general procedure B, 2g (29.5 mg, 0.343 mmol), dodecane (18.6 mg, 0.109 mmol), [pClTPPAl(THF)2][Co(CO)4] (1, 7.6 mg, 0.0071 mmol, 2.1%), and THF (0.35 mL) were used. Quantitative GC analysis resulted in 89% yield.

3,3-Dimethyl-2-butanone (3h)

Following general procedure B, 2h (33.1 mg, 0.330 mmol), dodecane (18.7 mg, 0.110 mmol), [pClTPPAl(THF)2][Co(CO)4] (1, 7.5 mg, 0.0070 mmol, 2.1 %), and THF (0.35 mL) were used. Quantitative GC analysis resulted in 97% yield.

Cyclohexyl methyl ketone (3i)

Following general procedure C, 2i (109.2 mg, 0.865 mmol),

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[pClTPPAl(THF)2][Co(CO)4] (1, 21.5 mg, 0.020 mmol, 2.3%), and THF (1 mL) were used to give 3i (79.3 mg, 73%). Quantitative GC analysis resulted in 92% yield. The difference is attributed to the volatility of the compound. Analytical data for 3i matched

36 1 those previously been reported. H NMR (400 MHz, CDCl3): δ 2.27–2.26 (m, 1H),

2.12 (s, 3H), 1.83–1.90 (m, 2H), 1.73–1.80 (m, 2H), 1.63–1.69 (m, 1H), 1.14–1.38 (m,

13 1 5H). C{ H} NMR (101 MHz, CDCl3): δ 212.4, 51.6, 28.6, 28.0, 26.0, 25.8.

4-Oxopentyl ester butanoic acid (3j)

Following general procedure C, 2j (347.6 mg, 2.018 mmol),

[pClTPPAl(THF)2][Co(CO)4] (1, 43.3 mg, 0.0402 mmol, 2.0%), and THF (2 mL) were

1 used to produce 3j (313.6 mg, 90%) as a colorless oil. H NMR (400 MHz, CDCl3): δ

4.07 (t, J = 6.4, 2H), 2.51 (t, J = 7.2, 2H), 2.27 (t, J = 7.4, 2H), 2.16 (s, 3H), 1.91 (app quintet, J = 6.6, 2H), 1.64 (sextet, J = 7.4, 2H), 0.94 (t, J = 7.4, 3H). 13C{1H} NMR

(101 MHz, CDCl3): δ 207.6, 173.6, 63.3, 39.9, 36.1, 29.9, 22.9, 18.4, 13.7. IR (neat, cm−1): 2959, 2873, 1710, 1714, 1354, 1163, 1087, 981, 729. HRMS (DART) m/z

+ + calculated for C9H16O3 (M+H) 173.11722, found 173.11745.

Ethyl-4-oxopentanoate (3k)

Following general procedure C, 2k (54.8 mg, 0.380 mmol),

[pClTPPAl(THF)2][Co(CO)4] (1, 8.6 mg, 0.00799 mmol, 2.1%), and THF (0.4 mL) were used to produce 3k (44.0 mg, 80%) as a colorless oil. Analytical data for 3k

37 1 matched those previously been reported. H NMR (300 MHz, CDCl3): δ 4.12 (q, J =

7.1, 2H), 2.4 (t, J = 6.6, 2H), 2.56 (t, J = 6.6, 2H), 2.19 (s, 3H), 1.25 (t, J = 7.1, 3H).

142

13 1 C{ H} NMR (76 MHz, CDCl3): δ 206.8, 172.8, 60.6, 38.0, 29.9, 28.0, 14.2.

1-Phenylpropan-2-one (3l)

Following general procedure C, 2l (40.1 mg, 0.299 mmol),

[pClTPPAl(THF)2][Co(CO)4] (1, 6.5 mg, 0.00603 mmol, 2.0%), and THF (0.3 mL) were used to produce 3l (34.4 mg, 86%) as a colorless oil. Analytical data for 3l matched

38 1 those previously been reported. H NMR (400 MHz, CDCl3): δ 7.34–7.39 (m, 2H),

7.27–7.32 (m, 1H), 7.21–7.25 (m, 2H), 3.72 (s, 2H), 2.18 (s, 3H). 13C{1H} NMR (101

MHz, CDCl3): δ 206.2, 134.3, 129.4, 128.7, 127.0, 50.9, 29.2.

1-(4-Methyoxyphenyl)-2-propanone (3m)

Following general procedure C, 2m (65.2 mg, 0.397 mmol),

[pClTPPAl(THF)2][Co(CO)4] (1, 8.5 mg, 0.00790 mmol, 2.0%), and THF (0.4 mL) were used to produce 3m (60.6 mg, 93%) as a colorless oil. Analytical data for 3m

39 1 matched those previously been reported. H NMR (400 MHz, CDCl3): δ 7.10–7.15

(m, 2H), 6.85–6.89 (m, 2H), 3.80 (s, 3H), 3.63 (s, 2H), 2.14 (s, 3H). 13C{1H} NMR (101

MHz, CDCl3): δ 206.9, 158.7, 130.4, 126.3, 114.2, 55.3, 50.1, 29.2.

1-(1-Hydroxycyclopentyl)-2-propanone (3n)

Following general procedure C, 2n (285.1 mg, 2.00 mmol),

[pClTPPAl(THF)2][Co(CO)4] (1, 43.2 mg, 0.0401 mmol, 2.0%), and THF (2 mL) were

1 used to produce 3n (238.0 mg, 83%) as a colorless oil. H NMR (400 MHz, CDCl3): δ

3.46 (s, 1H), 2.76 (s, 2H), 2.18 (s, 3H), 1.77–1.87 (m, 4H), 1.56–1.64 (m, 2H), 1.40–

143

13 1 1.50 (m, 2H). C{ H} NMR (101 MHz, CDCl3): δ 210.9, 79.9, 52.9, 39.9, 31.4, 23.8.

IR (neat, cm−1): 3404 (br), 2951, 2866, 1697, 1355, 1162, 1025, 798. HRMS (DART)

+ + m/z calculated for C8H15O2 (M+H) 143.10666, found 143.10684.

N,N-Bis(1-methylethyl)-10-oxo-undecanamide (3o)

Following general procedure C, 2o (55.0 mg, 0.194 mmol),

[pClTPPAl(THF)2][Co(CO)4] (1, 4.3 mg, 0.00399 mmol, 2.1%), and THF (0.2 mL)

1 were used to produce 3o (52.3 mg, 95%) as a colorless oil. H NMR (400 MHz, CDCl3):

δ 3.95 (septuplet, J = 6.7, 1H), 3.47 (m, 1H), 2.41 (t, J = 7.5, 2H), 2.25 (m, 2H), 2.13 (s,

3H), 1.50–1.64 (m, 4H), 1.37 (d, J = 6.8, 6H), 1.23–1.34 (m, 8H), 1.18 (d, J = 6.7, 6H).

13 1 C{ H} NMR (101 MHz, CDCl3): δ 209.5, 172.1, 48.3, 45.6, 43.8, 35.5, 30.4, 29.9,

29.5, 29.4, 29.3, 29.2, 25.5, 23.9, 21.1, 20.8. IR (neat, cm−1): 2923, 2852, 1714, 1634,

+ + 1441, 1368, 1044. HRMS (DART) m/z calculated for C17H34NO2 (M+H) 284.25841, found 284.25816.

1-Butoxy-2-propanone (3p)

Following general procedure C, 2p (195.6 mg, 1.502 mmol),

[pClTPPAl(THF)2][Co(CO)4] (1, 32.3 mg, 0.0300 mmol, 2.0%), and THF (1.5 mL) were used to produce 3p (157.3 mg, 80%) as a colorless oil. 1H NMR (400 MHz,

CDCl3): δ 4.01 (s, 2H), 3.48 (t, J = 6.6, 2H), 2.16 (s, 3H), 1.60 (m, 2H), 1.39 (m, 2H),

13 1 0.93 (t, J = 7.4, 3H). C{ H} NMR (101 MHz, CDCl3): δ 207.3, 76.4, 71.5, 31.6, 26.3,

19.2, 13.8. IR (neat, cm−1): 2959, 2933, 2870, 1719, 1354, 1118. HRMS (DART) m/z

+ + calculated for C7H15O2 (M+H) 131.10666, found 131.10701.

144

5-Hexene-2-one (3q)

Following general procedure B, 2q (36.2 mg, 0.369 mmol), dodecane (23.1 mg, 0.136 mmol), [pClTPPAl(THF)2][Co(CO)4] (1, 21.6 mg, 0.0201 mmol, 5.4%), and THF (0.4 mL) were used. Quantitative GC analysis resulted in 85% yield.

Poly(4-acetylcyclohexene carbonate) (3r)

In a glove box, a 1 fluid dram glass vial equipped with a Teflon-coated magnetic stir bar was charged with the epoxide-functionalized polycarbonate (2r, 48.6 mg, 0.264 mmol epoxide moieties) and [pClTPPAl(THF)2][Co(CO)4] (1, 5.9 mg, 0.00548 mmol,

2.1% per epoxide group). THF (0.3 mL) was added and the solution was stirred for 18 hours at room temperature. Dichloromethane was used to dilute the reaction mixture and pass it through a plug of decolorizing carbon to remove the color. One ml methanol was added to promote precipitation before stripping off the solvent to produce 3r (36.8

1 mg, 76%) as a white solid. H NMR (500 MHz, CDCl3): δ 4.90 (br m, 1H), 4.76 (br m,

1H), 2.73 (br m, 1H), 2.19 (br s, 3H), 2.05 (br m, 1H), 1.90 (br m, 3H), 1.76 (br m, 2H).

−1 IR (neat, cm ): 2940, 1741, 1703, 1228, 1153, 959, 782. GPC: Mn = 15,500 g/mol, Mw

= 27,600 g/mol, PDI = 1.78.

145

1 H NMR (500 MHz, CDCl3):

13 1 C{ H} NMR (126 MHz, CDCl3):

Figure 3.3 1H and 13C NMR spectra of 3r.

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151

Regioselective Isomerization of 2,3-Disubstituted Epoxides to Ketones: An Alternative to the Wacker Oxidation of Internal Alkenes

Reprinted adapted with permission from Lamb, J. R.; Mulzer, M.; LaPointe, A. M.;

Coates, G. W. J. Am. Chem. Soc. 2015, 137, 15049–15054.

Chemical Society and is available under the terms of the ACS AuthorChoice license.

152 4.1 Introduction

The Wacker oxidation is an important, well-established method for the oxidation of terminal alkenes to methyl ketones using Pd catalysts paired with a re-oxidant (Scheme

4.1A).1 This transformation has proven to be functional group tolerant and efficient with a variety of oxidants, making it a very useful tool for synthetic chemists. While the methyl ketone product is generally favored, it has been well documented that the presence of a heteroatom or electron-withdrawing group in the allylic or homoallylic position can change the regioselectivity such that the aldehyde becomes the favored product (Scheme 4.1B).1,2 Changing the catalyst system can again switch the selectivity back to methyl ketone for these electronically biased substrates.3

Scheme 4.1 Known regioselective Wacker oxidation using unbiased monosubstituted (A) and electronically biased terminal (B) and internal (C) substrates The Wacker oxidation of 1,2-disubstituted alkenes has been slower to develop, mostly due to low activity and poor regioselectivity. Tsuji systematically investigated the internal Wacker oxidation in the 1980’s using carbonyl, ether, and ester directing groups to achieve regioselectivity, though with limited yields.4 Following suit, some researchers who observed aldehyde selectivity for terminal olefins were able to use

153

similar directing groups to achieve regioselective oxidation for internal alkenes

(Scheme 4.1C).2a,b Recently, Grubbs,5 Sigman,6 and Kaneda7 have revisited the Wacker oxidation of internal olefins by developing systems that reliably oxidize internal double bonds with high activity. All found strong directing effects to give oxidation at the distal carbon. Selectivity dramatically decreased if the directing group was moved farther away than the homoallylic position (Scheme 4.2).7b

Scheme 4.2 Effect of directing group distance on the regioselectivity of Wacker oxidation of internal olefins When no electronic bias was present, steric differences were not sufficient to achieve high levels of selectivity, as evidenced by trans-2-octene resulting in ratios of

3-octanone (2a) and 2-octanone (3a) ranging from 1 : 1 to 1 : 2.5 (Scheme 4.3, middle pathway). This is not ideal not only because the modest selectivity lowers the maximum yield of the desired regioisomer, but also because the major product observed in these reactions is a methyl ketone, which would be more efficiently produced from a terminal

Scheme 4.3 Possible pathways for the net oxidation of unbiased disubstituted alkenes to ketones

154

olefin (Scheme 4.1A).

A different pathway resulting in net alkene oxidation is the two-step hydroboration- oxidation sequence. Hydroboration proceeds via concerted syn-addition of hydrogen and boron across an olefin in an anti-Markovnikov fashion. The organoborane can then be oxidized to the alcohol or directly to the corresponding carbonyl compound.8 Only a few methods of regioselective hydroboration-oxidation of unsymmetrically 2,3- disubstituted alkenes have been developed, most of which are substrate-controlled.

Most commonly, directing groups such as amines9 or amides10 have been used, but this limits the applicability and substrate scope of this method. Bulky boron reagents have been shown to improve regioselectivity for specific substrates, but none have been widely studied or applied.11 In contrast, hydroboration/oxidation of undirected alkenes generally either shows little to no regioselectivity (Scheme 4.3, top pathway)12 or yields the terminally functionalized organoborane via alkene isomerization.13 Developments by Curran and Vedejs have resulted in improved selectivity for unbiased substrates, but borane migration leads to side products and time-dependent product distributions.14

Another two-step alternative to the Wacker oxidation is an epoxidation/isomerization pathway (Scheme 4.3, bottom pathway). The atom- economical epoxide rearrangement to carbonyl compounds has been studied using a variety of catalysts for biased substrates that aid in regioselective ring-opening via either a Lewis-acid induced or nucleophilic mechanism.15 Epoxidation-isomerization as an alternative to the Wacker oxidation has been introduced by Kulawiec16 and Che17 for the regioselective oxidation of aryl-substituted internal and conjugated terminal olefins, respectively. This strategy has not been applied to internal alkenes lacking an electronic

155

bias. Since alkene epoxidation is a well-established reaction, this procedure would only require the development of regioselective isomerization of unbiased epoxides.

On the basis of prior observations that ketone forms as a side product during epoxide carbonylation at low pressures of carbon monoxide,18 we used a previously developed carbonylation catalyst for the isomerization of terminal epoxides to methyl ketones (see

Chapter 3).15c Using this same approach, we hypothesized that catalyst rac-4, which is known to catalyze regioselective carbonylation of trans-epoxides to cis-β-lactones,19 would similarly accomplish regioselective isomerization to ketones.

4.2 Reaction Optimization Optimization of the reaction conditions was done using trans-2-octene oxide (1a) and catalyst rac-4 (Table 4.1). A solvent screen revealed that diethyl ether resulted in good activity, high selectivity for ethyl ketone (2a), and a low amount of side reactions as evidenced by good agreement between conversion of the epoxide and yield of the products (entries 1–5). More polar, coordinating solvents resulted in lower conversion and yield, presumably due to competitive binding to the metal center. It is unclear at this time why ether improves regioselectivity compared to the more nonpolar solvents.

Varying the epoxide concentration from 0.5 to 1.5 M revealed that while regioselectivity was unaffected, the reaction proceeded to full conversion under more dilute conditions (entries 5–7). Surprisingly, a further drop in concentration enabled a reduction in catalyst loading to 2 mol % while further decreasing unwanted side reactions (entries 8–10). Any attempt to further lower the catalyst loading resulted in lower conversion (entries 11–12).

We suspect that the catalyst decomposes throughout the reaction via a bimolecular

156

Table 4.1 Evaluation of reaction conditions for the regioselective isomerization of epoxide 1a by rac-4

mol % conc. 1a conv. 1a yield ratio entrya solvent rac-4 (M) (%)b 2a + 3ab 2a : 3ab 1 3 THF 1.0 >13 12 12.0 : 1 2 3 Dioxane 1.0 >31 25 13.2 : 1 3 3 Toluene 1.0 >85 66 12.4 : 1 4 3 Hexanes 1.0 >88 76 11.9 : 1 5 3 Et2O 1.0 >75 69 13.1 : 1 6 3 Et2O 1.5 >72 58 13.8 : 1 7 3 Et2O 0.5 >99 88 13.5 : 1 8 2 Et2O 1.0 >63 57 13.3 : 1 9 2 Et2O 0.5 >79 76 13.4 : 1 10 2 Et2O 0.25 >99 99 13.5 : 1 11 1 Et2O 0.25 >43 43 12.9 : 1 12 1 Et2O 0.1 >62 58 13.4 : 1 aConditions: 22 °C, 18 h. bDetermined by capillary GC analysis versus dodecane as an internal standard. pathway due to the observation that the reaction proceeds to higher conversions at lower concentrations. While the reaction should be slower under these dilute conditions due to lower catalyst concentrations, a longer lifetime of rac-4 accounts for this effect.

Visual inspection of the reaction also supports catalyst decomposition, as the solution changes from orange to dark brown and becomes cloudy over time. As with our previous studies on monosubstituted epoxides, we believe the decomposition pathway to be

HCo(CO)4 dimerization to Co2(CO)8 and hydrogen gas (see Section 3.4).

157

4.3 Substrate Scope Having determined the optimal reaction conditions, we investigated the scope of the reaction. First, symmetrical trans-epoxides were isomerized to show the efficiency and high activity of rac-4, resulting in high yields (Table 4.2). Quantitative GC yields versus dodecane as an internal standard were used for substrates with fewer than 8 carbons due to the volatility of the products.

Table 4.2 Isomerization of symmetrical substrates using rac-4

entrya substrate product yield (%)

1 1b (R = Me) 2b (R = Me) b95b 2 1c (R = Et) 2c (R = Et) b92b 3 1d (R = nPr) 2d (R = nPr) 87 aConditions: [1] = 0.25 M in ether, 2 mol % rac-4, 22 °C, 18 h. bQuantitative GC yield versus dodecane as an internal standard.

Next, unsymmetrical, unbiased substrates with one methyl and one linear alkyl substituent were investigated and resulted in high regioselectivities for the ethyl ketone

2 over the methyl ketone 3 (Table 4.3, entries 1–5). These regioselectivities closely tracked with those seen for the corresponding carbonylation using catalyst rac-4.19 Not only is this the opposite selectivity than that found by Grubbs5a and Kaneda7a for the regioselective Wacker oxidation, but it also allows access to a different major product than that obtained from terminal substrates. For epoxide 1a, for which the optimized conditions yielded a mixture of 2a and 3a in 99% yield (Table 4.1, entry 10), the products were separable by column chromatography such that the major isomer 2a was isolated in 78% yield (Table 4.3, entry 4).

When neither alkyl substituent was a methyl group (R = Et, R1 = nBu, 1i, entry 6),

158

Table 4.3 Regioselectivity and substrate scope of unbiased epoxides

entrya substrate product(s) ratio 2 : 3b yield (%)

1 1e (R1 = Et) 2e + 3e (R1 = Et) 5.5 : 1 c78c 2 1f (R1 = nPr) 2f + 3f (R1 = nPr) 10.7 : 1 c98c 3 1g (R1 = nBu) 2g + 3g (R1 = nBu) 16.6 : 1 c98c 4 1a (R1 = nPent) 2a (R1 = nPent) 14.2 : 1 78 5 1h (R1 = nHex) 2h + 3h (R1 = nHex) 14.3 : 1 82 6 3.1 : 1 98

7d 1j (R1 = iPr) 2j + 3j (R1 = iPr) 5.8 : 1 e99e aConditions: [Epoxide] = 0.25 M in diethyl ether, 2 mol % rac-4, 22 °C, 18 h. bDetermined by 1H NMR spectroscopy or GC analysis. cQuantitative GC yield versus dodecane as an internal standard. d3 mol % catalyst used. eConversion by GC analysis. regioselectivity dropped off substantially to 3.1 : 1 favoring the propyl ketone (2i).

While not ideal, this selectivity is still greater than that seen for the Wacker oxidation of unbiased substrates. Note that compounds were numbered according to their respective starting materials and site of ring opening. As such, the same product can be formed from two different epoxides and thus have two different numbers for consistency of mechanism (2c = 2f, 2d = 2i, 2a = 3i).

We anticipated that increasing the bulk of the R1 group would improve regioselectivity, but surprisingly the selectivity of 1j (R1 = iPr, entry 7) was lower compared to the nPr analog (1f, entry 2). In addition, 1j required an increased catalyst loading of 3 mol % rac-4 to achieve full conversion.

Some electronically biased substrates were investigated to expand the scope of the reaction (Table 4.4). Alcohols protected with the bulky TBS (tert-butyl dimethyl silyl)

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group were tolerated to give ethyl ketones 2k and 2l in high isolated yields (entries 1–

2), though higher catalyst loadings were required. The electronic bias introduced by the silyl ether group would give product 3 (oxidation at the distal carbon) as the major isomer if a regioselective Wacker oxidation was employed on the corresponding alkene, once again showing the complimentary nature of the epoxidation/isomerization approach. Also, unlike Kaneda’s observation that selectivity dramatically declines as the electronic group is moved farther from the double bond,7b regioselectivity remained high for substrate 1l, in which the OTBS group is three carbons away from the epoxide.

The very high selectivity of benzyl-substituted epoxides (1m and 1n) resulted in sole detection of product 2 using 1H NMR spectroscopy (entries 3–4). Aryl substituents, such as the phenyl group in trans-β-methyl styrene oxide (1o, entry 5), promote SN2 attack at the benzylic position and cause a complete reversal of regioselectivity. The

Table 4.4 Regioselectivity and substrate scope of biased trans- and unbiased cis- epoxides

ratio entrya substrate product(s) yield (%) 2 : 3b

c c 1 1 1 1k (R = CH2OTBS) 2k (R = CH2OTBS) >50 : 1 98 d d 1 1 2 1l (R = (CH2)3OTBS) 2l (R = (CH2)3OTBS) 14.6 : 1 88 3 1m (R1 = Bn) 2m (R1 = Bn) >50 : 1 85 4 1n (R1 = p-OMeBn) 2n (R1 = p-OMeBn) >50 : 1 93

5 <1 : >50 83

6 2.4 : 1 e40e aConditions: [1] = 0.25 M in diethyl ether, 2 mol % rac-4, 22 °C, 18 h. bDetermined by 1H NMR spectroscopy or GC analysis. c5 mol % catalyst used at 0.1 M. d3.4 mol % catalyst used. eConversion based on 1H NMR analysis of the crude reaction mixture.

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major product 3o was isolated in high yield and no minor isomer 2o was observed.

A limitation of this system is that cis-epoxides are both less reactive and less regioselective. For example, cis-2-hexene oxide resulted in 40% conversion and displayed relatively low regioselectivity (2.4 : 1) under standard reaction conditions

(Table 4.4, entry 6). This is unsurprising considering that catalyst rac-4 is known to be good at regioselective carbonylation of trans-epoxides only.19 There are other previously developed carbonylation catalysts that may be better suited for the regioselective isomerization of cis-epoxides.20

4.4 Mechanistic Experiments

4.4.1 Proposed Mechanism We propose the nucleophilic mechanism shown in Scheme 4.4 on the basis of the

21 22 work by Eisenmann and Kagan on [Co(MeOH)6][Co(CO)4]2 as well as our own previous mechanistic observations for the isomerization of terminal epoxides (see

Scheme 4.4 Proposed catalytic cycle for regioselective isomerization of trans- epoxides to ketones using rac-4

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Section 3.4).15c After the displacement of a solvent molecule on the Lewis acid by an

− epoxide, Co(CO)4 regioselectively ring opens the epoxide via an SN2 mechanism to give the corresponding alkoxide complex. β-Hydrogen elimination forms an enolate and

23 HCo(CO)4. The active catalyst is regenerated by the very acidic HCo(CO)4 protonating the enolate to the enol. Tautomerization of the enol produces the ketone as the major product.

4.4.2 Control Experiments + − [(salcy)Al(THF)2] [Co(CO)4] (rac-5, salcy = N,Nʹ-bis(3,5-di-tert-butylsalicylidene)-rac-1,2-cyclohexanediamine) was also tested as a catalyst for this reaction to show that the bulky aryl group in the ortho-position of the phenoxide was necessary Table 4.5 Catalyst control experiments

conversion entry catalyst %yielda 2a : 3aa (%)a 1 rac-4 >99> 99 13.5 : 1 2 rac-5 >99> 85 1 : 1 3 rac-4-Al-Cl <1 -

4 rac-4-Al-Cl+NaBPh4 <1 -

5 NaCo(CO)4 <1 -

6 Co2(CO)8 <1 - aConditions: [1a] = 0.25 M in ether, 2 mol % catalyst, 22 °C, 18 h. bDetermined by quantitative GC analysis versus dodecane as an internal standard.

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for the observed regioselectivity. We found that while rac-5 was active for the isomerization, there was no regioselectivity between ketones 2 and 3 (Table 4.5, entry

2).

As previously observed for the isomerization of terminal epoxides (see Section 3.4), we confirmed that the presence of both the Lewis acid and the nucleophilic anion were necessary to enact this transformation (entries 3–5). We additionally tested Co2(CO)8, the precursor to NaCo(CO)4, and confirmed that it was not an active catalyst (entry 6).

These experiments rule out the carbocation-mediated mechanism of the Meinwald rearrangement24 solely activated by a Lewis acid.15

Because carbonyl groups could potentially bind to the Lewis acid in competition with the epoxide, we decided to check for product inhibition by adding an equivalent of

2-butanone relative to epoxide at the beginning of the reaction (Scheme 4.5).

Experimental data showed no decrease in rate (in fact a slight increase, though probably within error of the measurement) indicating that there is no product inhibition. This result is in agreement with our previous experiments with monosubstituted epoxides

(see Section 3.4).

Scheme 4.5 Product inhibition test with 2-butanone

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4.4.3 Kinetics Experiments We sought to better understand the kinetics of this transformation in order to determine the turnover-limiting step. First, initial rate kinetics were performed using 1a with different starting concentrations of rac-4. Due to the volatility of ether, the reactions were very sensitive to headspace effects, meaning aliquots could not be taken of a single reaction. Instead, parallel reactions under each set of conditions were performed and stopped sequentially (see Section 4.4.3 for more details). Each reaction was analyzed by GC versus dodecane as an internal standard. The initial rate of both epoxide consumption (red squares, solid line) and ketone production (blue circles, dashed line) suggest that the reaction is first order in catalyst (Figure 4.1)

The order in epoxide was determined using long term kinetics where reactions with different starting concentrations of epoxide were allowed to react for a precise length of time before being quenched and analyzed by GC versus dodecane as an internal standard

Order in Catalyst 1.5

Rate by [epoxide] Rate by [ketone]

(M/min) 3 3

0.5

Ratex 10 y = -0.0714 + 156x R= 0.996 y = -0.0751 + 135x R= 0.994

0 0 0.002 0.004 0.006 0.008 0.01 0.012 [catalyst] (M) Figure 4.1 Order in catalyst rac-4 by initial rate kinetics.

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(see Section 0 for more details). This experiment was run with two different epoxides and each point was set up in duplicate. All three starting concentrations produced the same amount of ketone in the set time which indicates that the reaction is zeroth order in substrate. Because the reaction is not first order in substrate, epoxide binding was ruled out as the rate-determining step, leaving three other possibilities: (1) epoxide ring opening, (2) β-hydrogen elimination, or (3) protonation of the enolate.

Order in Epoxide 0.6

0.5

0.4 1a Me/nPent, t = 3 h

1c Et/Et epoxide, t = 5 h 0.3

0.2 [ketone]at t hours (M)

0.1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 [Epoxide] (M) 0

Figure 4.2 Order in epoxide by long term kinetics.

4.4.4 Kinetic Isotope Effect Since both the β-hydrogen elimination and protonation steps involve a proton transfer, a notable primary kinetic isotope effect (KIE) is expected if either of these steps is turnover limiting. KIE’s arise because the heavier deuterium atom lowers the zero- point energy of a molecule compared to protium. There are multiple ways to perform a

KIE experiment,25 but arguably the most straight forward is to run parallel experiments of a deuterated and protonated substrate and compare the initial rates. If the rate is

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significantly slower for the deuterated substrate, that suggests that a bond containing the deuterium is changing during the rate-limiting step (primary KIE). If the rate is unchanged, then the perturbation most likely does not affect the rate-limiting step.

A deuterated version of trans-2-octene oxide (1a-d2) was synthesized and subjected to identical reaction conditions as 1a (Scheme 4.6). The initial rates were identical within error of the experiment, indicating no primary KIE. Therefore, it is unlikely that

β-hydrogen elimination or protonation are turnover-limiting in this system.

Scheme 4.6 Isotope labeling studies Additionally, the deuterated products were isolated to show the expected isotopic labeling in a single α position (Figure 4.3). For the protonated ketone 2a (top) the signal around 2.4 ppm integrates to 4 protons and is comprised of two overlapping triplets due to the four protons in the α and α′ positions. In the deuterated ketones (bottom), this signal integrates to 2 protons and is a single triplet due to the two α protons (the α′ position being fully deuterated). Additionally, the β′ position around 1.05 ppm goes from a triplet, split by the two α′ protons (top), to a more complex multiplet from coupling to the two α′ deuteriums (bottom). These spectra demonstrate the potential for utilizing this reaction as a selective deuteration method, as these products would be

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difficult to make using current deuteration procedures.26

Figure 4.3 1H NMR spectra of isolated deuterated ketones (bottom) versus 3- octanone (top).

These data are most consistent with SN2 ring opening of the epoxide as the turnover- limiting step for this transformation. To account for the order in substrate, the resting state of the catalyst must be after epoxide binding, which could be driven by the relatively poor binding ability of diethyl ether.27 These observations are also consistent with the similarities seen between this isomerization and the corresponding carbonylation using the same catalyst.19 The longer reaction times of 2,3-disubstituted epoxide carbonylation as compared to terminal epoxides19,28 can be rationalized by slower SN2 attack at a methine (disubstituted epoxide) compared to a methylene

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(terminal epoxide), and the similar regioselectivities arise from the selectivity- determining step also being rate limiting.

4.5 Kinetic Resolution of Trans-Epoxides This method was then applied to the kinetic resolution29 of select trans-epoxides.

Kinetic resolution occurs when an enantiopure catalyst reacts with one enantiomer faster than the other. The selectivity factor of the kinetic resolution is defined by the ratio of the rates at which the enantiomers react (krel). It is typical to recover the unchanged enantiomer of the substrate because its enantiomeric excess improves throughout the reaction;30 therefore, it is possible to get highly enantioenriched starting material from lower krel's by running the reaction to higher conversion. In order to isolate a synthetically useful amount of enantioenriched starting material, a general target for the selectivity factor is at least 20. Note that for a perfect kinetic resolution, the theoretical maximum yield is 50% if starting from a racemic mixture. First-order selectivity factors can be calculated from equation (1) based on the conversion and ee of the starting material.30

ln[(1−푐표푛푣)(1−푒푒)] 푘 = (1) 푟푒푙 ln[(1−푐표푛푣)(1+푒푒)]

While the kinetic resolution of terminal epoxides has been widely studied and applied by Jacobsen and others,31 kinetic resolution of internal epoxides remains in its infancy. Chromium salen complexes have been known to catalyze ring-opening kinetic resolution of internal trans-epoxides, but the substrate scope remains limited to trans- butene oxide and aryl epoxides.32 Few examples in the literature could be found on the resolution of non-aryl 2,3-disubstituted epoxides,33 and this remains a challenge in the

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Scheme 4.7 Previous results for the kinetic resolution of epoxides using [salenAl(THF)2][Co(CO)4] (R,R)-5 field. Our previous attempts to kinetically resolve epoxides with aluminum salen cobaltate catalysts resulted in low selectivity factors (Scheme 4.7).34

We hypothesized that high regioselectivity would be required for high krel’s and therefore chose to initially focus on epoxide 1m. Further optimization of the reaction conditions revealed that a variant of catalyst (S,S)-4, in which the methyl group in the para-position is substituted with a tert-butyl group (catalyst (S,S)-6), gives higher selectivity factors in THF (Table 4.6, entry 2). We also found that the identity of the aryl-substituent in the ortho-position of the phenoxide dramatically effects the

Table 4.6 Kinetic resolution catalyst optimization for epoxide 1m

a b b st entry catalyst conversion (%) % ee ~krel (1 order) 1 (S,S)-4 48 70 15 2 (S,S)-6 45 67 17 3 b(S,S)-7c 21 12 3 4 b(S,S)-8c 16 7 2 aConditions: [1m] = 0.5 M in THF, 5 mol % catalyst, 22 °C, 2 h. bDetermined by quantitative GC analysis versus dodecane as an internal standard. cCatalyst formed in

situ (LnAlCl + NaCo(CO)4).

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efficiency of the resolution. When either a mesityl or 2,6-dimethyl phenyl group was used, very low krel’s were observed (entries 3–4).

The reaction is much slower in THF, which helps stop the reaction at the desired level of conversion and improves selectivity. The concentration of epoxide 1m was monitored throughout the reaction by analyzing aliquots with chiral GC versus dodecane as an internal standard. All selectivity factors were calculated from at least four points using equation (1). The experimental data for 1m fit well to an approximate first order krel of 17 (Figure 4.4). We were initially surprised that the data gave first order selectivity factors when we had determined that the reaction was zeroth order in

Figure 4.4 Experimental kinetic resolution data (red circles) for rac-1m compared to a simulated first-order krel = 17 curve (black line).

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epoxide. We attribute this difference to the identity of the solvent. THF has much better donor abilities than diethyl ether, such that the resting state of the catalyst may have shifted from epoxide bound (ether, 0th order) to solvent bound (THF, 1st order). We still believe that epoxide ring-opening is the turnover-limiting step.

Encouraged by this result, we investigated how the substitution on the benzyl aromatic ring affects the selectivity factor, but found it had little influence (Table 4.7).

Both sterics and electronics were tested by adding a methyl or methoxy substituent, but in each case the selectivity factor was approximately 20 (entries 2–5). Note that all trans-epoxides with only alkyl substituents were not evaluated for the kinetic resolution because no method could be found to separate any of these substrates on our current chiral GC columns: Astec Chiraldex A-TA, Supelco β-Dex225, and J&W Scientific

Cyclodex-B.

One feature of this isomerization kinetic resolution is that time, not stoichiometry,

Table 4.7 Kinetic resolution of benzyl-substituted trans-epoxides

a b b c entry epoxide conversion (%) % ee krel 1 1m (R = H) 63 >98 17 2 1p (R = o-Me) 54 >85 23 3 1q (R = m-Me) 59 >97 21 4 1r (R = p-Me) 64 >99 18 5 1n (R = p-OMe) 65 >99 19 aConditions: [1] = 0.5 M in THF, 5 mol % (S,S)-6, 0.3 eq dodecane, 22 °C. bDetermined by chiral GC analysis versus dodecane as an internal standard. cCalculated from equation (1).

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is used to dictate conversion. We have shown that similar Lewis acid aluminum complexes can be used in conjunction with nucleophiles to enact epoxide ring-opening with similar regioselectivities to carbonylation.20 These results paired with the high selectivities observed in Table 4.7 provide the opportunity for the development of a nucleophilic ring-opening kinetic resolution of internal epoxides in the future.

4.6 Conclusions We have developed a mild and highly regioselective isomerization of trans-

+ − epoxides to ketones using a [Lewis acid] [Co(CO)4] catalyst previously developed for regioselective carbonylation. This transformation could be useful in organic synthesis as part of an epoxidation/isomerization pathway as an alternative to the Wacker oxidation of trans-alkenes, which currently suffers from low regioselectivity in the absence of an electronic directing group. Additionally, it can be used as a selective deuteration technique to install two deuterium atoms in a single α position of an aliphatic ketone.

Kinetic and isotope labeling data suggest epoxide ring opening as the turnover- limiting step followed by β-hydrogen elimination, protonation, and tautomerization to give the desired product. Finally, this method was applied to the kinetic resolution of non-aryl trans-epoxides to yield selectivity factors that are synthetically useful (krel ≈

20). To the best of our knowledge, this is the first time a kinetic resolution has been accomplished for benzyl-substituted internal epoxides. Based on our mechanistic insights that epoxide ring-opening is rate limiting, future work will focus on tuning the nucleophilicity of the anion to achieve higher activity and selectivity as well as further

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developing the kinetic resolution of internal epoxides using similar catalyst systems.

4.7 Experimental Methods

4.7.1 General Considerations Methods and Instruments

Unless stated otherwise, all synthetic manipulations were carried out using standard

Schlenk techniques under a nitrogen atmosphere or in an MBraun Unilab glovebox under an atmosphere of purified nitrogen. Reactions were carried out in oven-dried glassware cooled under vacuum. IR spectra were recorded on a Nicolet iS10 FT-IR spectrometer. 1H NMR and 13C{1H} NMR spectra were recorded on a Varian 300, 400, or 500 MHz instrument at 22 °C with shifts reported relative to the residual solvent peak

1 13 (CDCl3: 7.26 ppm ( H), and 77.16 ppm ( C)). All J values are given in Hertz.

Deuterated chloroform was purchased from Cambridge Isotope Laboratories and stored over K2CO3.

Optical rotations were measured on a Perkin-Elmer 241 polarimeter, and are given in 10−1 deg cm2 g−1. Gas chromatography (GC) analyses were performed on a Hewlett

Packard 6890 gas chromatograph equipped with an Astec Chirladex A-TA and a

Supelco β-Dex225 column or a Shimadzu GC-2010 Chromatograph equipped with a

J&W Scientific Cyclodex-B column. Both were equipped with a flame ionization detector and used Helium (Airgas, UHP grade) as carrier gas. Quantitative GC analysis was performed by adding the internal standard dodecane to the reaction mixture.

Response factors versus dodecane for the epoxides were obtained using the synthesized substrates, while the products’ response factors were obtained using commercially

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available materials. HRMS analyses were performed on a Thermo Scientific Exactive

Orbitrap MS system with an Ion Sense DART ion source.

The initial rate kinetics experiments were conducted on a Freeslate Core Module 3

(CM3) robotic platform located inside an MBraun drybox. The experiment was designed and executed using Library Studio(TM) and Automation Studio(TM) software. All solutions were dispensed robotically using a syringe dispense.

Chemicals

Anhydrous 1,4-dioxane was purchased from Sigma-Aldrich and degassed via three freeze-pump-thaw cycles prior to use. Anhydrous toluene, dichloromethane (DCM), hexanes, diethyl ether, and tetrahydrofuran (THF) were purchased from Fischer

Triethylamine was dried over calcium hydride and degassed via three freeze-pump-thaw cycles prior to use. Paraformaldehyde was dried overnight in vacuo in the presence of

P2O5. All epoxides used in this study were dried over calcium hydride and degassed via three freeze-pump-thaw cycles prior to use. All non-dried solvents used were reagent grade or better and used as received.

All other chemicals were purchased from Aldrich, Alfa-Aesar, TCI America, Strem, or Macron and used as received. Flash column chromatography was performed with

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silica gel (particle size 40–64 µm, 230–400 mesh) using either mixtures of ethyl acetate and hexanes or mixtures of diethyl ether and pentane as eluent. Before GC analysis, the catalyst was removed using a plug of alumina (neutral, 80–200 mesh) using ether as eluent.

The following compounds were prepared according to literature procedures: a) catalysts and catalyst precursors

35 NaCo(CO)4

rac-3,3ʹʹ-((1E,1ʹE)-((1S,2S)-cyclohexane-1,2-diylbis(azanylylidene))bis-

(methanylylidene))bis(4ʹ-(tert-butyl)-2ʹ,5,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-

olate)aluminum chloride (rac-4-Al-Cl)36

rac-3,3ʹʹ-((1E,1ʹE)-((1S,2S)-cyclohexane-1,2-diylbis(azanylylidene))bis-

(methanylylidene))bis(4ʹ-(tert-butyl)-2ʹ,5,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-

olate)aluminum cobaltate (rac-4, (S,S)-4 made analogously to rac-4)36

+ − [rac-salcyAl(THF)2] [Co(CO)4] (rac-5, salcy = N,Nʹ-bis(3,5-di-tert-butyl-salicyl-

idene)-1,2-cyclohexanediamine)34

3,3ʹʹ-((1E,1ʹE)-((1S,2S)-cyclohexane-1,2-diylbis(azanylylidene))bis-

(methanylylidene))bis(2ʹ,4 ʹ,5,6ʹ-tetramethyl-[1,1ʹ-biphenyl]-2-olate)aluminum

chloride ((S,S)-7-Al-Cl, made analogously to rac catalyst reported)36

3,3ʹʹ-((1E,1ʹE)-((1S,2S)-cyclohexane-1,2-diylbis(azanylylidene))bis-

(methanylylidene))bis(2ʹ,4,5,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-olate)aluminum

chloride ((S,S)-8-Al-Cl, made analogously to rac catalyst reported)36

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b) epoxides

rac-trans-2,3-diethyloxirane (1c)37

rac-trans-2,3-dipropyloxirane (1d)38

rac-trans-2-ethyl-3-methyloxirane (1e)39

rac-trans-2-methyl-3-propyloxirane (1f)36

rac-trans-2-butyl-3-methyloxirane (1g)40

rac-trans-2-methyl-3-pentyloxirane (1a)40

rac-trans-2-hexyl-3-methyloxirane (1h)40

rac-trans-2-butyl-3-ethyloxirane (1i)41

rac-trans-2-isopropyl-3-methyloxirane (1j)42

rac-trans-butyldimethyl((trans-3-methyloxiran-2-yl)methoxy)-silane (1k)43

rac-tert-butyldimethyl(3-(trans-3-methyloxiran-2-yl)propoxy)silane (1l)36

rac-trans-2-benzyl-3-methyloxirane (1m)36

rac-trans-β-methylstyrene oxide (1o)44 c) epoxide precursors

(E)-1-(but-2-en-1-yl)-4-methoxybenzene45

(E)-1-(but-2-en-1-yl)-4-methylbenzene46

(E)-1-(but-2-en-1-yl)-3-methylbenzene46

(E)-1-(but-2-en-1-yl)-2-methylbenzene46

4.7.2 Kinetics Data Initial rate kinetics by GC analysis: Order in Catalyst

The kinetics experiments were conducted on a Freeslate Core Module 3 (CM3)

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robotic platform located inside an MBraun drybox. 20–200 μl (8 vials each) of a stock solution of rac-4 in THF (10 mM) was dispensed robotically into 2 mL GC vials containing disposable stir bars. Volatiles were then removed from the vials using a

Speedvac vacuum centrifuge (40 °C, 45 minutes) attached to a liquid nitrogen trap. At the start of each kinetics experiment, the temperature in the reaction block was set to 20

°C and the stir rate was set to 300 rpm. A stock solution of epoxide 1a (0.25 M) and an internal standard (dodecane, 0.3 eq) in ether was made and 200 μl was dispensed robotically into 8 vials containing the catalyst and capped immediately. Each of the 8 identical vials was stopped sequentially at regular intervals by opening the vial and pipetting the contents into another 2 ml GC vial containing water-doped alumina and ether cooled to −32 °C.

Each reaction mixture was run through a plug of alumina using ether to remove the catalyst and analyzed by gas chromatography. The concentrations of starting material

Monitoring Concentration for Kinetics 0.4

0.35 [Epoxide] 0.3 Total [Ketone] 0.25

0.2

0.15 y = 0.25 - 0.00071x R= 0.99 Concentration(M) 0.1 y = 0.0031 + 0.00055x R= 0.99

0.05

0 0 10 20 30 40 50

Time (min) Figure 4.5 Plot of concentration of epoxide and ketone over time to calculate rate at [rac-4] = 0.005 M.

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and product were plotted over time (example see Figure 4.5). The rate of the disappearance of epoxide was compared to the rate of the appearance of ketone (2a +

3a) up to 10% conversion. This was repeated at the different starting concentrations of rac-4 (0.001, 0.003, 0.005, 0.007, 0.010 M) (Figure 4.1).

Long term kinetics by GC analysis: Order in Epoxide

A solution of rac-4 in THF (100 μl, 10 mM) was dispensed robotically into 2 mL

GC vials containing disposable stir bars. Volatiles were then removed from the vials using a Speedvac vacuum centrifuge (40 °C, 45 minutes) attached to a liquid nitrogen trap. A stock solution was made of 1a or 1c with an approximate epoxide concentration of 0.6 M in ether containing 0.3 equivalents of dodecane as an internal standard.

Portions of this stock solution were diluted to make 0.4 M and 0.2 M stock solutions.

At the start of each kinetics experiment, the temperature in the reaction block was set to

20 °C and the stir rate was set to 300 rpm. An Eppendorf 1000 μl (blue) reference hand pipettor was used to dispense 200 μl of each standard to two separate catalyst vials (t =

0). All reactions in the set were quenched after being allowed to react for the indicated time by opening the vial and pipetting the contents into another 2 ml GC vial containing water-doped alumina and ether cooled to −32 °C. Each reaction mixture was run through a plug of alumina using ether to remove the catalyst and analyzed by gas chromatography. The molarity of total ketone product produced in that set time (as a proxy for reaction rate) was compared for the different starting concentrations of epoxide.

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Kinetic isotope effect

Using the initial rate procedure described above, 1a and 1a-d2 were compared to determine if there was a kinetic isotope effect. Only epoxide concentrations were compared because we did not have an independent source of deuterated ketone to make a GC calibration curve and response factor. Note that the slight variation in starting concentration is due to error measuring small amounts of epoxide.

Kinetic Isotope Effect of 1a 0.5

0.4 y = 0.25 - 0.00071x R= 0.99 y = 0.22 - 0.00079x R= 0.97 0.3

[epoxide] 0.2

1a-h 0.1 2 1a-d 2

0 0 10 20 30 40 50 Time (min)

Figure 4.6 Kinetic isotope effect raw data.

Product Inhibition Test Using the initial rate procedure above, product inhibition was tested by adding an equivalent of ketone (2-butanone) to the reaction and comparing the initial rate to the normal reaction conditions without the extra ketone added. (Note that the slight variation in starting concentration is due to error measuring small amounts of epoxide.)

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Product Inhibition test 0.3

y = 0.27 - 0.001x R= 0.97 0.25

0.2 y = 0.25 - 0.00071x R= 0.99

[1a], 1 eq Butanone Added 0.15 [1a], No Butanone Added [2a]+[3a], 1 eq Butanone Added

0.1 [2a]+[3a], No Butanone Added Concentration (M) y = 0.0039 + 0.00066x R= 0.97 0.05 y = 0.0031 + 0.00055x R= 0.99

0 0 10 20 30 40 50 60 Time (min) Figure 4.7 Product inhibition test raw data.

4.7.3 Isolation of Deuterated Ketones

2,2-d2-3-Octanone + 3,3-d2-2-Octanone (2a-d2 + 3a-d2)

In a glove box, a 20 ml scintillation vial equipped with a Teflon-coated magnetic stir bar was charged with rac-4 (15.3 mg, 0.0151 mmol, 2.0 mol %) and ether (3 ml).

After 1 minute of stirring at 22 °C, the vial was cooled to −32 °C for 10 minutes to minimize the amount of ether lost to evaporation while adding the epoxide. 2,3-d2- trans-2-Methyl-3-pentyloxirane (1a-d2, 96.4 mg, 0.740 mmol) was added by weight via a syringe. The vial was then sealed and left to stir overnight at room temperature. After

18 hours, the vial was taken out of the glove box and concentrated in vacuo at 0 °C. The residue was purified through a plug of alumina using pentane as eluent. The solution

1 was concentrated again before preparing a sample for H NMR (CDCl3, 400 MHz).

4.7.4 Kinetic Resolution Data A standard solution of catalyst (S,S)-6 (0.05 M, THF) and a standard solution of the

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epoxide (1.0 M, THF) with dodecane (0.3 eq) as an internal standard were made in a glovebox.

For epoxide 1m: 150 μl of the epoxide standard were put in each of three vials. 150

μl of the catalyst solution were added to each vial (t = 0). Aliquots were taken at various time intervals (0.25, 0.5, 0.75, 1, 2, 3, 4.5, 6, 8, 10, 20 hours), diluted in THF, and cooled in the glovebox freezer (−32 °C; the isomerization reaction is very slow at this temperature). The vials were subsequently taken out of the glovebox, the reaction mixture filtered through a plug of SiO2 using ether to remove the catalyst and analyzed by chiral GC analysis. It was observed that when taking aliquots, the reaction slowed down and did not achieve as high of conversions. We suspect this is due to a strong headspace effect, where larger headspace (opening the vial) increases the rate of catalyst decomposition. The two high conversion data points were done using the method for the other epoxides (see below).

For other epoxides: 50 μl of the catalyst solution was added to multiple vials and cooled (−32 °C) for 10 minutes. 50 μl of the epoxide standard was added to the catalyst vials, which were then allowed to stir at room temperature inside the glovebox. Vials were stopped sequentially (such that each data point comes from a different reaction vial) by opening to air and run through a plug of alumina using ether to remove the catalyst. Conversion and % ee data were collected using chiral GC analysis.

Representative GC traces are included to show how % ee of the remaining epoxides changes over time.

The identity of the remaining epoxide enantiomer for trans-2-benzyl-3- methyloxirane (1m) was determined by comparison to an independently synthesized

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sample of (S,S)-2-benzyl-3-methyloxirane.36 All substituted benzyl epoxides were assumed to react similarly and elute in the same order.

A Kinetic Resolution of 1m (Me/Bn)

100

Epoxide %ee 40 Simulated k = 17 rel 20 Experimental Data

0 0 20 40 60 80 100

% Conversion B

67% ee

>99% ee Figure 4.8 (A) Kinetic resolution plot and (B) GC traces for epoxide 1m.

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A Kinetic Resolution 1p (Me/ o-MeBn)

100

Simulated k = 23

40 rel Epoxide %ee Experimental Data 20

0 0 20 40 60 80 100 % Conversion B

41% ee

85% ee Figure 4.9 (A) Kinetic resolution plot and (B) GC traces for epoxide 1p.

183

A Kinetic Resolution of 1q (Me/m-MeBn)

100

Simulated k = 21 40 rel Epoxide % ee Experimental Data

0 0 20 40 60 80 100 % Conversion B

63% ee

>99% ee Figure 4.10 (A) Kinetic resolution plot and (B) GC traces for epoxide 1q.

184

A Kinetic Resolution of 1r (Me/p-MeBn)

100

60 Simulated k = 18 rel 40

Experimental Data Epoxide % ee

0 0 20 40 60 80 100 % Conversion

57% ee

>99% ee Figure 4.11 (A) Kinetic resolution plot and (B) GC traces for epoxide 1r.

185

A Kinetic Resolution of 1n (Me/p-OMeBn)

100

Epoxide % ee Simulated k = 19 rel Experimental Data 20

0 0 20 40 60 80 100 % Conversion B

61% ee

>99% ee Figure 4.12 (A) Kinetic resolution plot and (B) GC traces for epoxide 1n.

4.7.5 Synthetic Procedures

4.7.5.1 General Procedures General procedure A: Epoxidation of alkenes to epoxides using mCPBA

Under ambient atmosphere, mCPBA (Aldrich, ≤77 %) was added in portions at 0

°C to a solution of the corresponding alkene in DCM and the resulting mixture was

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stirred at room temperature until TLC analysis indicated complete consumption of the alkene. After destroying excess mCPBA by adding aqueous NaHSO3, the reaction mixture was filtered through celite, the organic phase washed with NaHCO3 (sat., aq.,

3x), dried with sodium sulfate, filtered, and concentrated under reduced pressure.

General procedure B: Kumada coupling of 2-bromophenols with 4-(tert-butyl)-2,6- dimethylphenyl magnesium bromide

The appropriate brominated phenol was added dropwise to a mixture of sodium hydride (Aldrich, dry, 95%) and THF at 0 °C, followed by stirring at 22 °C for 10 minutes. Pd(OAc)2 (Strem, ≥98%) was added, followed by 4-(tert-butyl)-2,6- dimethylphenyl magnesium bromide47 (1 M, THF), and the resulting mixture was refluxed for 12 h. Upon cooling to 0 °C, H2O was carefully added to destroy any residual Grignard reagent and sodium hydride. HCl (2 M, aq.) followed by celite were added, and the resulting mixture was filtered through a pad of celite. The resulting phases were separated and the aqueous phase extracted with Et2O (3x). The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography (ethyl acetate/hexanes).

General procedure C: Formylation of 2-arylphenols to the corresponding salicylaldehyde derivatives

Methylmagnesium bromide (Acros, 3 M, Et2O) was added slowly to the corresponding coupled phenol in THF at 0 °C. After warming to 22 °C, toluene,

187

triethylamine, and paraformaldehyde were added, and the resulting reaction mixture stirred at 80 °C for 12 h. After cooling to 0 °C, H2O and then HCl (2 M, aq.) were added, and the resulting phases were separated. The aqueous phase was extracted with

General procedure D: Imine condensation of salicylaldehydes onto (1S,2S)-1,2- diaminocyclohexane

The corresponding salicylaldehyde, (1S,2S)-1,2-diaminocyclohexane, and ethanol were mixed and then refluxed for 18 h. After allowing the reaction mixture to reach 22

°C, the resulting precipitate was isolated by filtration, washed with a small amount of cold methanol and pentane, and then dried in vacuo at 80 °C.

General procedure E: Isomerization of epoxides with quantitative GC yield

In a glove box, a 1 fluid dram glass vial equipped with a Teflon-coated magnetic stir bar was charged with rac-4, dodecane, and ether. After 1 minute of stirring at 22 °C, the vial was cooled to −32 °C for 10 minutes to minimize the amount of ether lost to evaporation while adding the epoxide. The corresponding epoxide was added by weight via a syringe. The vial was then sealed and left to stir overnight at room temperature.

After 18 hours, a drop of the reaction mixture was diluted with ether and passed through a neutral alumina plug to remove the catalyst before being subjected to quantitative GC analysis.

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General procedure F: Isomerization of epoxides with isolation

In a glove box, a 20 ml scintillation vial equipped with a Teflon-coated magnetic stir bar was charged with rac-4 and ether. After 1 minute of stirring at 22 °C, the vial was cooled to −32 °C for 10 minutes to minimize the amount of ether lost to evaporation while adding the epoxide. The corresponding epoxide was added by weight via a syringe. The vial was then sealed and left to stir overnight at room temperature. After

18 hours, the vial was taken out of the glove box and concentrated in vacuo at 0 °C. The residue was purified by flash column chromatography (silica gel, pentane/ether).

4.7.5.2 Synthesis of Starting Materials rac-trans-2-Methyl-3-[(4-methoxyphenyl)methyl]-oxirane (1n)

Following general procedure A, (E)-1-(but-2-en-1-yl)-4-methoxybenzene (1.40 g, 8.63 mmol) was treated with mCPBA (2.55 g, 11.4 mmol) in DCM (10 ml) to give 1n (1.15

1 g, 75%) as a colorless oil. H NMR (400 MHz, CDCl3): δ 7.15 (m, 2H), 6.85 (m, 2H),

3.80 (s, 3H), 2.65–2.95 (m, 4H), 1.30 (d, J = 5.1, 3H). 13C{1H} NMR (101 MHz,

−1 CDCl3): δ 158.5, 130.0, 129.6, 114.1, 60.0, 55.4, 54.6, 37.6, 17.7. IR (neat, cm ): 2964,

2932, 2834, 1612, 1511, 1243, 1177, 1034, 823, 729. HRMS (DART) m/z calculated

+ + for C11H15O2 (M+H) 179.10666, found 179.105894.

rac-trans-2-Methyl-3-[(2-methylphenyl)methyl]-oxirane (1p)

Following general procedure A, (E)-1-(but-2-en-1-yl)-2-methylbenzene (1.79 g, 12.2 mmol) was treated with mCPBA (3.63 g, 16.2 mmol) in DCM (14 ml) to give 1p (1.68

1 g, 85%) as a colorless oil. H NMR (400 MHz, CDCl3): δ 7.11–7.23 (m, 4H), 2.97 (dd,

189

J = 14.5, 5.0, 1H), 2.88 (td, J = 5.2, 2.0, 1H), 2.73–2.85 (m, 2H), 2.32 (s, 3H), 1.31 (d,

13 1 J = 5.3, 3H). C{ H} NMR (101 MHz, CDCl3): δ 136.5, 135.9, 130.3, 129.5, 126.8,

126.2, 59.1, 54.8, 35.6, 19.8, 17.7. IR (neat, cm−1): 2967, 2924, 1494, 1446, 1378, 741,

+ + 726. HRMS (DART) m/z calculated for C11H15O (M+H) 163.11174, found

163.110998.

rac-trans-2-Methyl-3-[(3-methylphenyl)methyl]-oxirane (1q)

Following general procedure A, (E)-1-(but-2-en-1-yl)-3-methylbenzene (1.63 g, 11.1 mmol) was treated with mCPBA (3.31 g, 14.8 mmol) in DCM (13 ml) to give 1q (1.51

1 g, 84%) as a colorless oil. H NMR (400 MHz, CDCl3): δ 7.19 (t, J = 7.8, 1H), 6.98–

7.06 (m, 3H), 2.80–2.90 (m, 3H), 2.74 (dd, J = 15.8, 6.9, 1H), 2.32 (s, 3H), 1.29 (d, J =

13 1 5.1, 3H). C{ H} NMR (101 MHz, CDCl3): δ 138.2, 137.5, 129.8, 128.5, 127.4, 126.0,

59.9, 54.8, 38.5, 21.5, 17.7. IR (neat, cm−1): 2979, 2921, 1608, 1488, 1445, 1378, 950,

+ + 860, 759, 698. HRMS (DART) m/z calculated for C11H15O (M+H) 163.11174, found

163.11094.

rac-trans-2-Methyl-3-[(4-methylphenyl)methyl]-oxirane (1r)

Following general procedure A, (E)-1-(but-2-en-1-yl)-4-methylbenzene (1.38 g, 9.45 mmol) was treated with mCPBA (2.83 g, 12.6 mmol) in DCM (20 ml) to give 1r (1.34

1 g, 87%) as a colorless oil. H NMR (400 MHz, CDCl3): δ 7.12 (pseudo s, 4H), 2.63–

13 1 2.95 (m, 4H), 2.33 (s, 3H), 1.30 (d, J = 5.1, 3H). C{ H} NMR (101 MHz, CDCl3): δ

136.2, 134.4, 129.3, 128.9, 59.9, 54.7, 38.1, 21.2, 17.7. IR (neat, cm−1): 2979, 2922,

+ 1515, 1446, 1378, 952, 867, 803, 723. HRMS (DART) m/z calculated for C11H15O

190

(M+H)+ 163.11174, found 163.11093.

48 2,3-d2-cis-2-Octene (SM1)

2-Octyne (2.80 g, 25.5 mmol) was added to a flask charged with Lindlar’s catalyst (1.0 g) and pentane (43 ml). D2 gas (Cambridge Isotope, D = 99.6%) was bubbled through the reaction mixture at room temperature for 4 hours. The black solid was filtered off using celite and the resulting clear solution was concentrated in vacuo at 0 °C to give

1 the title compound (1.78 g, 62%) as a colorless oil. H NMR (400 MHz, CDCl3): δ

5.41 (residual 1H signal in deuterated positions), 2.03 (m, 2H), 1.60 (m, 3H), 1.31 (m,

13 1 6H), 0.90 (t, J = 6.4, 3H). C{ H} NMR (101 MHz, CDCl3): δ 130.6 (pseudo t, JC–D =

−1 23.1), 123.3 (pseudo t, JC–D = 23.4), 31.7, 29.4, 26.9, 22.8, 14.2, 12.7. IR (neat, cm ):

2938, 2923, 2856, 2247, 1633, 1456, 1377, 1189, 727. HRMS (DART) m/z calculated

+ + for C8H13D2 (M–H) 113.12938, found 113.129663.

(rel-R,R)-2,3-d2-3-Chloro-2-octanol and (rel-R,R)-2,3-d2-2-chloro-3-octanol

(SM2)49

Deuterated alkene SM1 (2.95 g, 25.8 mmol) was taken up in acetone:water (5.5 : 1, 84 ml) and cooled to 0 °C. Trichloroisocyanuric acid (2.33 g, 10.0 mmol) was added in portions. The reaction mixture was warmed to room temperature and stirred for 2.5 hours before quenching with saturated NaHSO3. The solution was filtered through celite to remove the white precipitate, extracted with DCM, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield the product mixture (2.54 g,

13 1 59%) as a colorless oil. C{ H} NMR (101 MHz, CDCl3): δ 74.7 (pseudo triplet, JC–D

191

= 21.7), 69.9 (overlapping pseudo triplet, JC–D = 22.0), 69.7 (overlapping pseudo triplet,

JC–D = 22.8), 63.0 (pseudo triplet, JC–D = 22.8), 34.3, 34.0, 31.8, 31.3, 26.2, 25.3, 22.6,

22.5, 21.4, 20.0, 14.03, 14.00. IR (neat, cm−1): 3395 (br), 2958, 2929, 2860, 1699, 1595,

+ 1455, 1377, 1154, 932, 766, 727, 665. HRMS (DART) m/z calculated for C8H15D2O

+ 1 (M–Cl) 131.13995, found 131.13999. The H NMR (400 MHz, CDCl3) spectrum of the title compounds is shown in Figure 4.13.

1 Figure 4.13. H NMR spectrum of (rel-R,R)-2,3-d2-3-chloro-2-octanol and (rel- R,R)-2,3-d2-2-chloro-3-octanol in CDCl3.

(rel-S,R)-2,3-d2-2-Acetate-3-chloro-2-octanol and 2,3-d2-3-acetate-2-chloro-3- octanol (SM3)50

A Schlenk flask was charged with triphenylphosphine (4.2 g, 21 mmol). Dry THF (60 ml) was cannula transferred to the flask, which was then cooled to 0 °C.

Diisopropylazodicarboxylate (5.2 ml, 20 mmol) was added dropwise to the solution, which turned from clear to milky yellow. The mixture of chlorohydrins (SM2, 2.27 g,

192

13.6 mmol) was added followed by glacial acetic acid (1.3 ml, 23 mmol). The clear gold reaction was stirred at room temperature under a flow of nitrogen overnight then concentrated in vacuo. Hexanes were added and the resulting white solid was filtered off. After re-concentrating, the product was purified by flash column chromatography

(hexanes:ether 10 : 1) to yield a 3 : 2 mixture of two regioisomers (1.46 g, 51%) as a

13 1 colorless oil. C{ H} NMR (101 MHz, CDCl3): δ 170.4, 170.2, 75.9 (pseudo triplet,

JC–D = 22.6), 71.9 (pseudo triplet, JC–D = 22.6), 64.3 (pseudo triplet, JC–D = 23.1), 57.8

(pseudo triplet, JC–D = 23.3), 34.0, 31.6, 31.2, 30.0, 26.2, 24.9, 22.48, 22.47, 21.1, 20.9,

20.2, 15.1, 13.96, 13.95. IR (neat, cm−1): 2927, 2860, 1737 (sharp), 1455, 1368, 1238,

+ + 1021, 936. HRMS (DART) m/z calculated for C10H18D2O2Cl (M+H) 209.12719,

1 found 209.12772. The H NMR (400 MHz, CDCl3) spectrum of the title compounds is shown in Figure 4.14.

1 Figure 4.14 H NMR spectrum of (rel-S,R)-2,3-d2-2-acetate-3-chloro-2-octanol and 2,3-d2-3-acetate-2-chloro-3-octanol in CDCl3.

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2,3-d2-trans-2-Methyl-3-pentyloxirane (1a-d2)

Potassium carbonate (6.04 g, 43.7 mmol) was suspended in methanol (15.5 ml). The mixture of chloro acetates (SM3, 1.21 g, 5.81 mmol) was added to the reaction dropwise and stirred at room temperature for 1.5 hours. The methanol was removed in vacuo before adding water and DCM, extracting with DCM (2x), drying over NaSO4, filtering, and concentrating at 0 °C to give the product (0.673 g, 89%) as a colorless oil. 1H NMR

(400 MHz, CDCl3): δ 2.72 (q, J = 5.3, deuterated position), 2.61 (t, J = 5.4, deuterated position), 1.34–1.57 (m, 4H), 1.18–1.34 (m, 7H), 0.88 (m, 3H). 13C{1H} NMR (101

MHz, CDCl3): δ 59.2 (pseudo triplet, JC–D = 25.9), 54.0 (pseudo triplet, JC–D = 26.1),

31.8, 31.6, 25.6, 22.5, 17.4, 13.9. IR (neat, cm−1): 2956, 2928, 2858, 1455, 1375, 1132,

+ + 918, 770, 732. HRMS (DART) m/z calculated for C8H15D2O (M+H) 131.13995, found 131.14060.

4ʹ,5-di(tert-Butyl)-2ʹ,6ʹ-dimethyl-[1,1ʹ-biphenyl]-2-ol (SM4)

Following general procedure B, 2-bromo-4-(tert-butyl)phenol (3.30 g, 14.4 mmol) was treated with sodium hydride (0.480 g, 20.0 mmol) in THF (24 ml), followed by addition of Pd(OAc)2 (0.161 g, 0.717 mmol, 5 mol %), and 4-(tert-butyl)-2,6-dimethylphenyl magnesium bromide (0.92 M THF, 25 ml, 23 mmol) to give SM4 (2.79 g, 62%) as a

1 white powder. MP 86–87 °C. H NMR (500 MHz, CDCl3): δ 7.29 (dd, J = 8.5, 2.5,

1H), 7.20 (s, 2H), 7.06 (d, J = 2.5, 1H), 6.93 (d, J = 8.5, 1H), 4.51 (s, 1H), 2.08 (s, 6H),

13 1 1.37 (s, 9H), 1.31 (s, 9H). C{ H} NMR (126 MHz, CDCl3): δ 151.2, 150.2, 143.5,

137.6, 132.5, 127.2, 125.9, 125.6, 125.1, 114.4, 34.6, 34.3, 31.8, 31.5, 20.8. IR (neat, cm−1): 3522, 3026, 2956, 2864, 1498, 1360, 1220, 1164, 1021, 871, 820, 716. HRMS

194

+ + (DART) m/z calculated for C22H30O (M) 310.22912, found 310.22899.

2-Hydroxy-4ʹ,5-di(tert-butyl)-2ʹ,6ʹ-dimethyl-[1,1ʹ-biphenyl]-3-carbaldehyde

(SM5)

Following general procedure C, SM4 (2.74 g, 8.83 mmol) was treated with methylmagnesium bromide (3 M ether, 3.6 ml, 10.8 mmol) in THF (24 ml), followed by addition of toluene (45 ml), triethylamine (2.2 ml, 16 mmol), and paraformaldehyde

(0.766 g, 25.5 mmol). The product was purified via flash column chromatography

1 (hexanes/Et2O) to give SM5 (2.48 g, 83%) as a white powder. MP 123–124 °C. H

NMR (400 MHz, CDCl3): δ 11.04 (s, 1H), 9.96 (s, 1H), 7.53 (d, J = 2.5, 1H), 7.44 (d, J

= 2.5, 1H), 7.15 (2H), 2.06 (s, 6H), 1.35 (s, 9H), 1.34 (s, 9H). 13C{1H} NMR (101 MHz,

CDCl3): δ 197.1, 156.9, 150.5, 142.8, 136.8, 136.2, 133.4, 129.5, 128.9, 124.6, 120.2,

34.5, 34.4, 31.6, 31.4, 20.9. IR (neat, cm−1): 2958, 2866, 1649, 1451, 1272, 1219, 1091,

+ + 864, 705. HRMS (DART) m/z calculated for C23H31O2 (M+H) 339.23186, found

339.23064.

3,3ʹʹ-((1E,1ʹE)-((1S,2S)-Cyclohexane-1,2- diylbis(azanylylidene))bis(methyanylylidene))-bis(4ʹ,5-di(tert-butyl)-2ʹ,6ʹ- dimethyl-[1,1ʹ-biphenyl]-2-ol) (SM6)

Following general procedure D, SM5 (0.676 g, 2.00 mmol) was treated with (S,S)- cyclohexyldiammine (0.117 g, 1.02 mmol) in ethanol (8 ml). The filtered solid was recrystallized from toluene to give SM6 (0.642 g, 85 %) as a yellow powder. MP >200

1 °C. H NMR (500 MHz, CDCl3): δ 13.51 (s, 2H), 8.28 (s, 2H), 7.17 (d, J = 2.1, 4H),

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7.15 (m, 2H), 7.11 (d, J = 2.4, 2H), 3.23 (m, 2H), 2.10 (s, 6H), 1.97 (s, 6H), 1.93 (m,

2H), 1.85 (m, 2H), 1.66 (m, 2H), 1.44 (m, 2H), 1.37 (s, 18H), 1.26 (s, 18H). 13C{1H}

NMR (126 MHz, CDCl3): δ 165.3, 155.9, 149.7, 141.0, 136.1, 136.0, 134.7, 131.3,

128.2, 126.5, 124.4, 124.3, 117.8, 72.7, 34.3, 34.0, 33.0, 31.5, 31.4, 24.2, 20.9, 20.8. IR

(neat, cm−1): 2951, 2865, 1626, 1449, 1361, 1272, 1225, 1154, 1093, 866, 823, 774,

+ + 727, 709. HRMS (DART) m/z calculated for C52H70N2O2 (M+H) 755.55101, found

20 755.54811. Specific rotation: [α] D = +376 (c = 0.0055, CHCl3).

3,3ʹʹ-((1E,1ʹE)-((1S,2S)-Cyclohexane-1,2- diylbis(azanylylidene))bis(methyanylylidene))-bis(4ʹ,5-di(tert-butyl)-2ʹ,6ʹ- dimethyl-[1,1ʹ-biphenyl]-2-olate)aluminum cobaltate ((S,S)-6)

Et2AlCl (Aldrich, 0.98 M, hexanes, pyrophoric, 0.994 M, 900 μl, 0.260 mmol) was added to a solution of SM6 (0.611 g, 0.810 mmol) in DCM (6 ml) at 0 °C. The resulting solution was stirred at 22 °C for 12 h. Volatiles were removed and dried in vacuo overnight to give the corresponding Al–Cl (0.614 g, 93%) as a yellow solid, which was used directly without further purification or isolation. The Al–Cl (0.0995 g, 0.122 mmol) was mixed with NaCo(CO)4 (0.0255 g, 0.131 mmol) in THF (3 ml) for 3.5 hours in a glovebox at ambient temperature. The cloudy orange solution was filtered through a PTFE syringe filter and layered with hexanes to crystallize at −32 °C overnight. The solid was isolated by filtration through a glass filter frit inside the glovebox, washed with hexanes, and dried in vacuo overnight to give (S,S)-6 (0.0997 g, 75%) as a yellow solid. Occasionally subsequent recrystallizations from THF/hexanes were required to achieve the highest levels of purity. The catalyst rapidly decomposes upon exposure to

196

air or water or if stored for an extended period of time at room temperature. MP >200

1 °C. H NMR (500 MHz, CDCl3): δ 8.55 (s, 2H), 7.36 (d, J = 2.6, 2H), 7.34 (d, J = 2.6,

2H), 7.23 (m, 2H), 7.08 (m, 2H), 3.66 (m, 8H, THF), 3.50 (m, 2H), 2.70 (m, 2H), 2.14

(m, 2H), 1.87 (s, 6H), 1.77 (m, 8H, THF), 1.72 (s, 6H), 1.63 (m, 4H), 1.44 (s, 18H), 1.29

13 1 (s, 18H). C{ H} NMR (126 MHz, CDCl3): δ 168.7, 159.8, 149.6, 140.9, 137.9, 137.3,

135.9, 135.0, 132.2, 129.8, 124.4, 123.9, 118.1, 69.9, 64.9, 34.6, 34.2, 31.8, 31.3, 28.2,

25.4, 23.7, 21.3, 20.0.

4.7.5.3 Isomerization of Epoxides to Ketones 2-Butanone (2b)

Following general procedure E, 1b (14.2 mg, 0.197 mmol), dodecane (9.0 mg, 0.053 mmol), rac-4 (4.0 mg, 0.0040 mmol, 2 mol %), and ether (0.8 mL) were used to produce the title compound. Quantitative GC analysis resulted in 95% yield.

3-Hexanone (2c)

Following general procedure E, 1c (23.8 mg, 0.238 mmol), dodecane (14.3 mg, 0.0840 mmol), rac-4 (5.2 mg, 0.0051 mmol, 2.2 mol %), and ether (1 mL) were used to produce the title compound. Quantitative GC analysis resulted in 92% yield.

4-Octanone (2d)

Following general procedure F, 1d (255.9 mg, 1.996 mmol), rac-4 (40.5 mg, 0.0401 mmol, 2.0 mol %), and ether (8 ml) were used to give the title compound (221.9 mg,

87%) as a colorless oil. Analytical data for 2d matched those previously reported.51 1H

197

NMR (400 MHz, CDCl3): δ 2.39 (overlapping t, J = 7.4, 2H), 2.37(overlapping t, J =

7.3, 2H), 1.46–1.68 (m, 4H), 1.31 (sextet, J = 7.4, 2H), 0.91 (overlapping t, J = 7.4, 3H),

13 1 0.90 (overlapping t, J = 7.3, 3H). C{ H} NMR (101 MHz, CDCl3): δ 211.4, 44.7, 42.6,

26.0, 22.4, 17.3, 13.9, 13.8.

3-Pentanone + 2-Pentanone (2e + 3e)

Following general procedure E, 1e (19.4 mg, 0.225 mmol), dodecane (13.8 mg, 0.0810 mmol), rac-4 (5.2 mg, 0.0051 mmol, 2.3 mol %), and ether (1 mL) were used to produce the title compound. Quantitative GC analysis resulted in 66% 3-pentanone and 12% 2- pentanone, for a total of 78% yield and a ratio of 5.5 : 1.

3-Hexanone + 2-Hexanone (2f + 3f)

Following general procedure E, 1f (18.8 mg, 0.188 mmol), dodecane (10.1 mg, 0.0593 mmol), rac-4 (4.1 mg, 0.0041 mmol, 2.2 mol %), and ether (0.8 mL) were used to produce the title compounds. Quantitative GC analysis resulted in 89% 3-hexanone and

9% 2-hexanone, for a total of 98% yield and a ratio of 10.7 : 1.

3-Heptanone + 2-Heptanone (2g + 3g)

Following general procedure E, 1g (23.6 mg, 0.207 mmol), dodecane (9.8 mg, 0.058 mmol), rac-4 (3.9 mg, 0.0039 mmol, 1.9 mol %) in ether (0.8 mL) were used to produce the title compounds. Quantitative GC analysis resulted in 92% 3-heptanone and 6% 2- heptanone, for a total of 98% yield and a ratio of 16.6 : 1.

198

3-Octanone (2a)

Following general procedure F, 1a (254.6 mg, 1.985 mmol), rac-4 (40.5 mg, 0.0401 mmol, 2.0%), and ether (8 ml) were used to give the title compound (197.9 mg, 78%) as a colorless oil. Analytical data for 2a matched those previously reported.52 1H NMR

(400 MHz, CDCl3): δ 2.29–2.48 (m, 4H), 1.57 (quintet, J = 7.4, 2H), 1.19–1.36 (m, 4H),

13 1 1.05 (t, J = 7.3, 3H), 0.88 (t, J = 7.0, 3H). C{ H} NMR (101 MHz, CDCl3): δ 211.6,

42.3, 35.7, 31.4, 23.6, 22.4, 13.8, 7.7.

3-Nonanone + 2-Nonanone (2h + 3h)

Following general procedure F, 1h (143.0 mg, 1.005 mmol), rac-4 (20.1 mg, 0.0199 mmol, 2.0 mol %), and ether (4 ml) were used to give the title compounds (117.9 mg,

82%) as a colorless oil. Analytical data for 2h and 3h matched those previously reported.53,54 Note that the Jun group from Yonsei University in South Korea reports a different 13C NMR for 3-nonanone, however their spectrum is missing the characteristic

55 13 1 ethyl CH3 at around 7 ppm. C{ H} NMR (101 MHz, CDCl3): 3-Nonanone: δ 211.6,

42.3, 35.7, 31.5, 28.8, 23.8, 22.4, 13.9, 7.7. 2-Nonanone: 209.0, 43.8, 31.7, 29.8, 29.14,

29.08, 23.9, 22.6, 14.0. The 1H NMR spectrum of the product mixture taken on a 400

MHz instrument is shown in Figure 4.15.

199

1 Figure 4.15 H NMR spectrum of 2h and 3h in CDCl3.

4-Octanone + 3-Octanone (2i + 3i)

Following general procedure F, 1i (256.3 mg, 1.999 mmol), rac-4 (40.5 mg, 0.0401 mmol, 2.0 mol %), and ether (8 ml) were used to give a 3.1 : 1 mixture of 4-octanone to

3-octanone (251.3 mg, 98%) as a colorless oil. Analytical data for 2i and 3i matched

51,52 13 1 those previously been reported. C{ H} NMR (101 MHz, CDCl3): 4-Octanone: δ

211.6, 44.8, 42.6, 26.0, 22.4, 17.4, 13.9, 13.8. 3-Octanone: δ 212.0, 42.4, 35.9, 31.5,

23.7, 22.5, 14.0, 7.9. The 1H NMR spectrum of the product mixture taken on a 400 MHz instrument is shown in Figure 4.16.

200

1 Figure 4.16 H NMR spectrum of 2i and 3i in CDCl3.

1-tert-Butyldimethylsilyloxy-2-butanone (2k)

Following general procedure F, 1k (60.6 mg, 0.299 mmol), rac-4 (15.2 mg, 0.0150 mmol, 5.0%), and ether (3 ml) were used to give the title compound (59.1 mg, 98%) as a yellow oil. Analytical data for 2k matched those previously reported.56 1H NMR (400

MHz, CDCl3): δ 4.17 (s, 2H), 2.53 (q, J = 7.3, 2H), 1.06 (t, J = 7.3, 3H), 0.92 (s, 9H),

13 1 0.09 (s, 6H). C{ H} NMR (101 MHz, CDCl3): δ 211.9, 69.2, 31.8, 25.9, 18.4, 7.3,

−5.4.

6-tert-Butyldimethylsilyloxy-3-hexanone (2l)

Following general procedure F, 1l (38.6 mg, 0.168 mmol), rac4 (6.1 mg, 0.0060 mmol,

3.5%), and ether (4 ml) were used to give the title compound (34.0 mg, 88%) as a

201

colorless oil. Analytical data for 2l matched those previously reported.57 1H NMR (400

MHz, CDCl3): δ 3.61 (t, J = 6.1, 2H), 2.48 (t, J = 7.3, 2H), 2.44 (q, J = 7.3, 2H), 1.78

(m, 2H), 1.05 (t, J = 7.3, 3H), 0.88 (s, 9H), 0.03 (s, 6H). 13C{1H} NMR (101 MHz,

CDCl3): δ 211.7, 62.3, 38.8, 36.1, 27.0, 26.1, 18.4, 8.0, −5.2.

1-Phenylbutan-2-one (2m)

Following general procedure F, 1m (221.3 mg, 1.493 mmol), rac-4 (30.2 mg, 0.0299 mmol, 2.0 %), and ether (6 ml) were used to give the title compound (188.0 mg, 85%) as a colorless oil. Analytical data for 2m matched those previously reported.58 1H NMR

(400 MHz, CDCl3): δ 7.14–7.39 (m, 5H), 3.69 (s, 2H), 2.48 (quartet, J = 7.3, 2H), 1.03

13 1 (t, J = 7.3, 3H). C{ H} NMR (101 MHz, CDCl3): δ 208.9, 134.5, 129.4, 128.7, 126.9,

49.8, 35.2, 7.8.

1-(4-Methoxyphenyl)butan-2-one (2n)

Following general procedure F, 1n (179.8 mg, 1.009 mmol), rac-4 (20.3 mg, 0.0201 mmol, 2.0%), and ether (4 ml) were used to give the title compound (167.1 mg, 93%) as a colorless oil. Analytical data for 2n matched those previously been reported.59 1H

NMR (400 MHz, CDCl3): δ 7.12 (m, 2H), 6.86 (m, 2H), 3.80 (s, 3H), 3.62 (s, 2H), 2.46

13 1 (q, J = 7.3, 2H), 1.02 (t, J = 7.3, 3H). C{ H} NMR (101 MHz, CDCl3): δ 209.4, 158.6,

130.4, 126.6, 114.2, 55.3, 48.9, 35.1, 7.8.

1-Phenyl-2-propanone (3o)

Following general procedure F, 1o (135.0 mg, 1.006 mmol), rac-4 (20.2 mg, 0.0200 mmol, 2.0 mol %), and ether (4 ml) were used to give the title compound (112.3 mg,

202

83%) as a colorless oil. Analytical data for 3o matched those previously been reported.60

1 H NMR (400 MHz, CDCl3): δ 7.31–7.37 (m, 2H), 7.25–7.30 (m, 1H), 7.19–7.22 (m,

13 1 2H), 3.70 (s, 2H), 2.16 (s, 3H). C{ H} NMR (101 MHz, CDCl3): δ 206.4, 134.3, 129.5,

128.8, 127.1, 51.1, 29.3.

203 REFERENCES

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210

Catalyst Development for the Deoxygenation of Epoxides with Inversion of Stereochemistry Using Carbon Monoxide as the Reductant

211 5.1 Introduction

Alkenes are ubiquitous in organic synthesis as both target functional groups and versatile starting materials for a variety of transformations. The stereochemistry of the olefin (i.e. E or Z) can have profound effects on the compound’s properties and, in many cases, affects the stereochemical outcome of subsequent reactions.1 Unfortunately, many methods that are currently used to produce internal olefins in organic synthesis – such as Wittig olefination and cross metathesis – result in a mixture of E- and Z- alkenes,2 though the E isomer is generally favored because of its increased thermodynamic stability.

Modifications to the Wittig reaction (e.g. Still-Gennari and Horner-Wadworth-

Emmons olefination) have improved the selectivity for both E-3 and Z-olefins,4 but the scope is limited to α,β-unsaturated ketones, esters, and cyanides.2a Recent advances in cross metathesis have also greatly improved E-5 and Z-selectivities,2b,6 but the selectivity for Z-alkenes degrades at high conversion.2b The ability to cleanly invert from an undesired olefin isomer to the desired isomer would give chemists more synthetic control and flexibility.

Palladium complexes have been known to selectively isomerize Z-double bonds to the more thermodynamically stable E- isomers, but the alkenes must be conjugated with aromatic or carbonyl moieties to avoid competing olefin migration pathways (Scheme

5.1).7 This limitation could be addressed by a two-step protocol. First, the alkene could be epoxidized, which generally proceeds with retention of stereochemistry, followed by epoxide deoxygenation with inversion. Selective epoxidation techniques, such as dimethyldioxirane (DMDO), have been shown to react ~8 times faster with Z-alkenes

212

compared to the E isomer,8 allowing for the possibility of applying this method to a mixture of E- and Z-olefins. This could be particularly useful for E-selective ring- closing metathesis reactions that still produce a small amount of the Z isomer.9 The Z alkene could be selectively epoxidized in the mixture followed by stereospecific deoxygenation with inversion to give solely the E isomer without the need to separate the diastereomers.

Scheme 5.1 Alkene isomerization and an alternative two-step epoxidation- deoxygenation pathway Epoxide deoxygenation has been used for decades in total synthesis, though generally with stoichiometric reagents.10 Catalytic methods have since been developed, but most either result in a mixture of E- and Z-olefins11 or proceed with retention of stereochemistry.12 Additionally, many systems require cyclic or activated epoxides to achieve high reactivity. Stereoretentive systems are interesting because it allows for the epoxide to act as an alkene protecting group. There have been many important advances in recent years; in particular, Tong and coworkers developed a Cu-catalyzed deoxygenation of mono- and disubstituted epoxides with complete retention of stereochemistry.12b Methods that proceed with clean inversion of stereochemistry are less advanced and either require harsh conditions or have a limited scope.13 Therefore,

213

there is still a need for a catalytic deoxygenation that proceeds with complete inversion of stereochemistry for both cis- and trans-epoxides.

Our group has a history of developing bimetallic catalysts of the type [Lewis acid][nucleophilic anion] for epoxide reactions.14 While exploring new anions for

− epoxide carbonylation, we discovered that the Mn(CO)5 anion instead mediated deoxygenation. Herein we report initial reaction development and mechanistic studies of a mild, catalytic epoxide deoxygenation that uses carbon monoxide as the terminal reductant and proceeds with clean inversion of stereochemistry.

5.2 Catalyst Optimization and Reaction Development We initially explored which ligand framework would be the most successful for the deoxygenation of cis-epoxides (Figure 5.1). Porphyrin (1), salph (2), and salcy (3) frameworks were explored due to our group’s previous success with these frameworks for epoxide transformations.14

Figure 5.1 Catalysts investigated for the deoxygenation of epoxides. We tested the catalysts with cis-2-octene oxide in THF at 80 °C for 4 hours using

700 psi CO as the reductant (Table 5.1). Carbon monoxide is a cheap and accessible

214

reductant that produces carbon dioxide as the byproduct of the reaction. Since both CO and CO2 are gases, they are easily removed from reaction mixture which simplifies purification of the product. CO/H2O has been previously used as the reductant for epoxide deoxygenation using supported gold nanoparticles.15

The porphyrin catalyst 1 was active to give exclusively trans-alkene but also made appreciable amounts of ketone side products (entry 1). The ketone is presumably from either the Meinwald rearrangement or β-hydrogen elimination (see Chapters 3 and 4), though mechanistic experiments indicate that the major pathway is most likely β- hydrogen elimination (see Section 5.4). The salph catalysts 2 suppressed the ketone formation to 1%, but were less active for the transformation (entries 2 and 3). The salcy catalysts 3 were the most active, with the para-chloro catalyst 3b giving 84% conversion to alkene, while still suppressing epoxide isomerization (entries 4–6). All catalysts in

Table 5.1 were made in situ from the appropriate aluminum chloride and NaMn(CO)5 for ease of screening. When we attempted to make the isolated complexes of 1, 2a, and

Table 5.1 Catalyst optimization for the deoxygenation of epoxides

conversion (%)b entrya catalyst 5a ketones 1 1 35 10 2 2a 15 1 3 2b 25 1 4 3a 37 1 5 3b 84 1 6 3c 28 1 aConditions: [4a] = 1.0 M in THF, 3 mol % catalyst, CO (700 psi), 80 °C, 4 h. bDetermined by 1H NMR of the crude reaction

mixture. Catalysts made in situ (LnAlCl + NaMn(CO)5).

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2b, an ill-defined sticky solid was produced. Luckily, the salcy Lewis acids made crystalline, easily isolable complexes [Lewis acid][Mn(CO)5] (see Section 5.5).

We then sought to optimize the reaction conditions for full conversion to alkene.

Unfortunately, we had some trouble with contamination in our new carbon monoxide cylinder which led to lower conversions. We increased the pressure to 1200 psi to regain some activity, but full conversion was never reached. Therefore, any reaction run at

1200 psi will most likely go to higher conversions with a better source of CO. Some trends and mechanistic information (see Section 5.4) were still gained from these reactions and thus are presented here.

Increasing the concentration of cis-2-heptene oxide (4b) from 1 M to 2 M resulted in lower conversions (62% to 39%), indicating that 1 M is the optimal concentration for the reaction (Table 5.2, entries 1–3). Increasing the catalyst loading to 5 mol % resulted in 94% conversion even with the contaminated CO (entry 4). We are confident that with pure reagents, this will achieve full conversion. We also found that 3 mol % catalyst at

1 M was sufficient to achieve full conversion of the terminal epoxide 2-benzyloxirane

Table 5.2 Concentration and catalyst loading screens

entrya R3 R4 mol % 3b conc. (M) conversion (%) 5b 1 Me nBu (4b) 3 1.0 62 2 Me nBu (4b) 3 1.5 49 3 Me nBu (4b) 3 2.0 39 4 Me nBu (4b) 5 1.0 94 5 H CH2Ph (4c) 3 1.0 >99> aConditions: THF, catalyst 3b, CO (1200 psi), 80 °C, 4 h. bDetermined by 1H NMR of the crude reaction mixture.

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(4c) (entry 5).

5.3 Scope of the Epoxide Deoxygenation Once conditions were found that provide full conversion, at least for terminal epoxides, we began to explore the scope of the reaction (Table 5.3). Unactivated epoxides 4c and 4d were deoxygenated cleanly with high yields (entries 1–2). TBS- protected alcohols are tolerated, as demonstrated by the protected glycidol (4e) that was deoxygenated in 96% yield (entry 3). Ester functional groups seem to hinder catalysis as both 4f and 4g resulted in very low conversion (entries 4–5). Work is ongoing to expand the functional group scope of this reaction.

Table 5.3 Initial scope of terminal epoxides using 3b

entrya R3 % yield 5b 1 Bn (4c) 92 2 nOct (4d) 94 3 CH2OTBS (4e) 96 4 CH2OCOPh (4f) 27

5 CH2CH2CO2Et (4g) 9 aConditions: [4] = 1.0 M in THF, 3 mol % 3b, 80 °C, 4 h. bDetermined by 1H NMR versus para-xylene as an internal standard.

Because of the CO contamination that suppresses the deoxygenation for less reactive internal substrates, a scope was not thoroughly explored for cis- and trans-epoxides.

However, enough substrates were tested to confirm that this system induces complete

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inversion of stereochemistry. The deoxygenation of cis-2-octene oxide (4a) with catalyst 3b (Table 5.1, entry 5) was compared to commercial E-2-octene and Z-2-octene prepared from the Lindlar hydrogenation of 2-octyne (Figure 5.2). The reaction did not go to full conversion so some left over starting epoxide can be seen in the crude reaction mixture. The alkene peaks overlap at 5.41 ppm, so these peaks could not be used to differentiate the Z- and E-alkenes. Note that while not definitive, the peak shape of the deoxygenated alkene matches that of the E-isomer better than the Z-isomer.

Due to the very similar structures, the aliphatic regions of the 2-octene isomers are almost identical except for the 1.5–2.1 ppm region (Figure 5.2 expansion). The reaction product (red, bottom) nicely matches the E-2-octene peaks at 1.64 and 1.96 ppm (blue, top) and not the Z-2-octene peaks at 1.60 and 2.03 ppm (green, middle). This indicates

Figure 5.2 Crude reaction mixture of the deoxygenation of cis-2-octene oxide (red, bottom) compared to E- (blue, top) and Z-2-octene (green, middle) to show inversion of stereochemistry.

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that cis-2-octene oxide was cleanly deoxygenated with inversion to E-2-octene. The additional peak at 1.65–1.72 ppm has not yet been identified, but is definitely not the Z isomer. A similar analysis was done with other cis-substrates versus commercial alkenes or literature data to show inversion in every case.

Since the E-isomer is more thermodynamically stable compared to the Z-isomer, it is not sufficient to show a cis-to-trans change in stereochemistry to claim inversion.

There have been other epoxide deoxygenation systems that result in E-alkenes from both cis- and trans-epoxides solely based on thermodynamics.16 Therefore, we sought to also demonstrate that trans-epoxides would invert to Z-alkenes. However, trans- epoxides are not very reactive under the conditions optimized for cis-epoxides (Table

5.4, entry 1). After more screening, it was found that changing the solvent dramatically affected the activity of the catalyst (entry 2–4). Dioxane gave similar results to THF

(entry 2), but DME shut down catalysis (entry 3). Toluene significantly improved the activity for trans-2-octene oxide, resulting in 70% conversion in 4 h at 80 °C (entry 4).

Table 5.4 Further optimization for the deoxygenation of trans-epoxides

entrya catalyst solvent conversion (%)b 1 3b THF 26 2 3b 1,4-dioxane 30 3 3b DME 2 4 3b toluene 70 5 3c toluene 94 aConditions: [4h] = 1.0 M, 3 mol % 3, 80 °C, 4 h. bDetermined by 1H NMR of the crude reaction mixture.

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Changing to the para-trityl catalyst 3c further increased activity to 94% conversion

(entry 5).

These new conditions (Table 5.4, entry 5) were used when comparing the deoxygenation of trans-2-octene oxide with Z- and E-2-octene (Figure 5.3).

Analogously to the analysis above, the 1.5–2.1 ppm region was compared (expansion).

The product (orange, bottom) now matches the Z-isomer peaks at 1.60 and 2.03 ppm

(green, middle) and not the E-isomer at 1.64 and 1.96 ppm (blue, top), again demonstrating inversion from trans-epoxide to cis-alkene. No minor isomer with opposite stereoselectivity was observed in either the cis- or trans-case, indicating that this reaction truly proceeds with stereospecific inversion.

The fact that the optimized deoxygenation conditions for cis- and trans-epoxides

Figure 5.3 Crude reaction mixture of the deoxygenation of trans-2-octene oxide (orange, bottom) compared to E- (blue, top) and Z-2-octene (green, middle) to show inversion of stereochemistry.

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differ by both solvent and catalyst presents the opportunity of selectively deoxygenating one isomer in a mixture. A preliminary experiment showed that when starting from a

51 : 49 cis : trans mixture using the optimized conditions for cis-epoxides, the cis- isomer was converted to E-2-octene in 48% conversion (Scheme 5.2). No Z-alkene was observed in the 1.5–2.1 ppm region and the final cis : trans ratio of leftover epoxide was

27 : 73. We expect increasing the catalyst loading will push the cis-epoxide deoxygenation to full conversion without reacting the trans-isomer.

Scheme 5.2 Preliminary experiment on the deoxygenation of cis-epoxides in the presence of trans-epoxides Another interesting application of this methodology could be the isomerization of cis-cyclooctenes to trans-cyclooctenes, which are more reactive for ring-opening metathesis polymerization and click chemistry due to increased ring strain.17

Unfortunately, initial experiments indicated <2% conversion for these substrates.

Trisubstituted epoxides also displayed low reactivity, presenting the opportunity for chemoselective deoxygenation of disubstituted epoxides in the presence of trisubstituted epoxides, as was performed by Tong and coworkers in the recent Cu-catalyzed deoxygenation that proceeds with retention of stereochemistry.12b

5.4 Mechanistic Experiments The observed inversion of stereochemistry is an interesting aspect of this

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transformation that we wanted to better understand by probing the mechanism. First, we performed control experiments to show that both halves of the catalyst are necessary for the reaction (Table 5.5). With the full catalyst 3b, benzyloxirane 4c was fully converted

− to allyl benzene 5c (entry 1). When the nucleophilic anion Mn(CO)5 was replaced by

− the non-coordinating anion BPh4 , no conversion to alkene was observed (entry 2).

Similarly, the aluminum chloride precursor to the active catalyst was not competent for the reaction on its own (entry 3). NaMn(CO)5 resulted in 27% conversion to the product, which is drastically reduced from the full catalyst (entry 4). The reason we observe any product formation is presumably because the sodium cation is Lewis acidic enough to activate the reactive terminal epoxide 4c under these high-pressure conditions.

Table 5.5 Catalyst control experiments for the deoxygenation of 4c

entrya catalyst conversion (%)b

1 [pClsalcyAl(THF)2][Mn(CO)5] 3b >99> c 2 [pClsalcyAl(THF)2][BPh4] <1 3 3bAl-Cl <1 4 NaMn(CO)5 27 aConditions: [4c] = 1.0 M in THF, 3 mol % catalyst, CO (1200 psi), 80 °C, 4 h. bDetermined by 1H NMR spectroscopy of the crude reaction mixture. cMade

in situ from LnAl-Cl + NaBPh4.

We originally hypothesized that the deoxygenation occurred via a two-step carbonylation-decarboxylation sequence (Scheme 5.3). First, a β-lactone intermediate

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Scheme 5.3 Possible deoxygenation mechanism with net inversion via carbonylation-decarboxylation would be formed with inversion of stereochemistry (see Scheme 1.4 in Section 1.2.2 for the mechanism).18 The lactone intermediate could then undergo a decarboxylation to release carbon dioxide. Previous studies have shown that thermal β-lactone decarboxylation proceeds with retention of configuration because a zwitterionic intermediate restricts rotation during the stepwise elimination.19 The two steps would result in net inversion of stereochemistry.

If this mechanism was occurring, then β-lactone should be a competent intermediate under identical conditions. We tested this hypothesis by subjecting β-butyrolactone to standard reaction conditions but no product formation was observed (Scheme 5.4). This result indicates that carbonylation-decarboxylation is an unlikely mechanism for this system.

Scheme 5.4 Control experiment to show that β-lactone is not a competent intermediate of the epoxide deoxygenation Our proposed mechanism is shown in Scheme 5.5. The first half of the mechanism is the same as the carbonylation mechanism using [Lewis acid][Co(CO)4] catalysts.

First, the precatalyst A loses a solvent molecule to open a coordination site (B). Next,

− an epoxide binds and gets ring opened by Mn(CO)5 to give species C. Inversion of

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configuration occurs because of the SN2 mechanism of ring opening. Instead of inserting carbon monoxide at this stage, rotation about the C–C bond aligns the manganese metal center and the oxygen atom in a syn periplanar geometry (D). A β-oxygen elimination releases the inverted alkene to give the μ-oxo complex E. A similar β-sulfur elimination is known for related [(dppe)RPt][Mn(CO)5] complexes (dppe = 1,2- bis(diphenylphosphino)ethane) when treated with thiiranes to give sulfur-bridged Pt-S-

Mn complexes.20 While the β-sulfur elimination was stoichiometric, we were able to turn over our catalyst via CO insertion and loss of CO2 to regenerate the active catalyst

Scheme 5.5 Proposed mechanism for the deoxygenation of epoxides by [Lewis acid (LA)][Mn(CO)5] catalysts The mechanism shown in Scheme 5.5 is supported by our observed product distribution when using the porphyrin catalyst 1, which does not fully suppress ketone formation. Cis- and trans-2-octene oxide were subjected to identical conditions using

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Scheme 5.6 Alkene and ketone product distribution from cis- and trans-2-octene oxide using catalyst 1 catalyst 1 (Scheme 5.6). The trans-epoxide 4h produced less of the desired alkene and more ketones compared to the cis-epoxide 4a.

A closer examination of the β-elimination step rationalizes this product distribution

(Scheme 5.7). For cis-epoxides, the two substituents are separated in space when the manganese is syn periplanar to the oxygen, but eclipsed when the manganese is syn periplanar to the hydrogen. Therefore, for cis-epoxides the steric clash disfavors the β- hydrogen elimination pathway that leads to ketone. The reverse is true for trans- substrates; the two substituents are eclipsed in the desired conformation for β-oxygen elimination and separated when in the conformation for β-hydrogen elimination. Now,

Scheme 5.7 Explanation of alkene to ketone product distribution for cis- and trans-epoxides

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the steric clash disfavors the deoxygenation pathway to make isomerization the major reaction for trans-epoxides.

5.5 Solid State Structure of Catalyst 3b

Single crystals of 3b were obtained by layering THF and hexanes. The orange needle-like crystals were subjected to X-ray analysis to further understand the structure of this catalyst compared to the [(salen)Al(THF)2][Co(CO)4] analogs. 3b crystallizes as an inversion twin in the orthorhombic space group P212121 with two independent molecules of [(salen)Al(THF)2][Mn(CO)5] per asymmetric unit. For clarity, only a single molecule is shown in Figure 5.4.

A B

Figure 5.4 Thermal ellipsoid representation of one of the independent molecules of [(salen)Al(THF)2][Mn(CO)5] (A) and (salen)Al(THF)2 viewed from the side (B) in the crystal structure of 3b. Ellipsoids are drawn at the 50% probability level. All hydrogen atoms and atoms of the minor disorder component (and Mn(CO)5 anion for B) are omitted for clarity. The solid state structure shows the expected ion pair composed of [Lewis acid]+ and

− [Mn(CO)5] , analogous to the crystal structures of our previously reported Co(CO)4 catalysts.14a,21 The cyclohexyl diamine backbone gives the expected trans-planar conformation to the salen-based Lewis acid with two THF solvent molecules bound in the axial positions, highlighting the Lewis acid’s ability to coordinate cyclic ethers.

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5.6 Conclusion

We have developed novel [Lewis acid][Mn(CO)5] catalysts for the deoxygenation of epoxides with clean inversion of stereochemistry. Carbon monoxide is used as an abundant and inexpensive reductant that is easily separated from the product.

Monosubstituted and both cis- and trans-disubstituted epoxides are cleanly deoxygenated, but trisubstituted oxiranes are unreactive. Unactivated epoxides are readily reacted and silyl-protected alcohols are tolerated. Alicylic epoxides, which are common substrates for other deoxygenation systems, are thus far unreactive. Different optimized conditions were found for the deoxygenation of cis- and trans-epoxides, presenting the opportunity to use this system to selectively invert a single isomer in a cis/trans mixture.

Our proposed mechanism involves nucleophilic ring opening of the epoxide by

− Mn(CO)5 followed by β-oxygen elimination. The inversion is a result of the SN2 mechanism of ring opening paired with the required syn periplanar geometry for β- oxygen elimination. This mechanism is supported by the product distribution between alkene and ketone when using the porphyrin catalyst 1 and the similar reactivity of

[(dppe)RPt][Mn(CO)5] complexes with thiiranes. X-ray analysis of the catalyst 3b showed a planar Lewis acid cation and a non-coordinating manganese pentacarbonyl anion. This is one of the first catalytic deoxygenation methods that proceeds with complete stereospecific inversion.

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5.7 Experimental Procedures

5.7.1 General Considerations Methods and instruments

Unless stated otherwise, all synthetic manipulations were carried out using standard

Schlenk techniques under a nitrogen atmosphere or in an MBraun Unilab glovebox under an atmosphere of purified nitrogen. Reactions were carried out in oven-dried glassware cooled under vacuum. High-pressure reactions were performed in a custom- designed and -fabricated, six-chamber, stainless steel, high-pressure reactor.22 The reactor design allowed for incorporation of six 1 or 2 fluid dram glass vials.

1H NMR and 13C{1H} NMR spectra were recorded on a Varian 300, 400, 500, or

600 MHz instrument or on a 500 MHz Bruker AV III HD with broadband Prodigy

Cryoprobe at 22 °C (unless indicated otherwise) with shifts reported relative to the

1 13 residual solvent peak (CDCl3: 7.26 ppm ( H), and 77.16 ppm ( C); DMSO-d6: 2.50

(1H), and 39.52 (13C)). All J values are given in Hertz. NMR solvents were purchased from Cambridge Isotope Laboratories and CDCl3 was stored over K2CO3 (CDCl3). The internal standard para-xylene was used to calculate quantitative yields by 1H NMR spectroscopy in CDCl3: 7.06 (s, 4H), 2.31 (s, 6H). HRMS analyses were performed on a Thermo Scientific Exactive Orbitrap MS system with an Ion Sense DART ion source

(Cornell University).

Low-temperature X-ray diffraction data for catalyst 3b were collected on a Rigaku

XtaLAB Synergy diffractometer coupled to a Rigaku Hypix detector with Mo Kα radiation (λ = 0.71073 Å), from a PhotonJet micro-focus X-ray source at 100 K. The diffraction images were processed and scaled using the CrysAlisPro software.23 The

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structure was solved through intrinsic phasing using SHELXT24 and refined against F2 on all data by full-matrix least squares with SHELXL25 following established refinement strategies.26 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms bound to carbon were included in the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the Ueq value of the atoms they are linked to

(1.5 times for methyl groups). Details of the data quality and a summary of the residual values of the refinements are listed in Section 5.7.3.

Chemicals

Anhydrous 1,4-dioxane and 1,2-dimethoxyethane (DME) were purchased from

Sigma-Aldrich and degassed via three freeze-pump-thaw cycles prior to use. Anhydrous toluene, dichloromethane (DCM), hexanes, and tetrahydrofuran (THF) were purchased from Fischer Scientific and sparged vigorously with nitrogen for 40 minutes prior to first use. The solvents were further purified by passing them under nitrogen pressure through two packed columns of neutral alumina (tetrahydrofuran was also passed through a third column packed with activated 4Å molecular sieves) or through neutral alumina and copper(II) oxide (for toluene and hexanes). Tetrahydrofuran and dichloromethane were degassed via three freeze-pump-thaw cycles prior to use.

Paraformaldehyde prills were dried in vacuo overnight in the presence of P2O5. All epoxides used in this study were dried over calcium hydride and degassed via three freeze-pump-thaw cycles prior to use. All non-dried solvents used were reagent grade or better and used as received.

Carbon monoxide (Airgas or Matheson, 99.99% min. purity) was used as received.

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All other chemicals were purchased from Aldrich, Alfa-Aesar, TCI America, Combi-

Blocks, Kodak, or GFS Chemicals and used as received. Flash column chromatography was performed with silica gel (particle size 40–64 μm, 230–400 mesh) using mixtures of ethyl acetate and hexanes.

The following compounds were prepared according to literature procedures: a) catalysts and catalyst precursors

27 NaMn(CO)5

pClTPPAl-Cl (precursor to 1, meso-tetra(4-chlorophenyl)porphyrinato

aluminum chloride)28

3-(tert-butyl)-2-hydroxy-5-methoxybenzaldehyde29

pClSalphAl-Cl (precursor to 2b)30

rac-3,3ʹʹ-((1E,1ʹE)-((1S,2S)-cyclohexane-1,2-diylbis(azanylylidene))bis-

(methanylylidene))bis(4ʹ-(tert-butyl)-2ʹ,5,6ʹ-trimethyl-[1,1ʹ-biphenyl]-2-

olate)aluminum chloride (precursor to 3a)36

rac-6,6'-((1E,1'E)-(((1S,2S)-cyclohexane-1,2-

diyl)bis(azaneylylidene))bis(methaneylylidene))bis(2-(tert-butyl)-4-

chlorophenol) (ligand for 3b)29 b) epoxides

rac-(2R,3S)-2-methyl-3-pentyloxirane (4a)31

rac-(2R,3S)-2-butyl-3-methyloxirane (4b)32

rac-2-octyloxirane (4d)33

rac-ethyl 3-(oxiran-2-yl)propanoate (4g)34

rac-trans-2-methyl-3-pentyloxirane (4h)35

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5.7.2 Synthetic Procedures

5.7.2.1 General Procedures

General procedure A: Metalation of salen-compounds using Et2AlCl

Et2AlCl (Aldrich, 1.00 M, hexanes, pyrophoric) was added to a solution of the corresponding salen-compound in DCM (0.04 M) at 0 °C. The resulting solution was stirred at 22 °C for 12 h. Volatiles were removed in vacuo, the solid was washed with hexanes, cannula filtered, and dried in vacuo overnight.

General procedures B: Salt metathesis between LnAl–Cl and NaMn(CO)5

In a glovebox, NaMn(CO)5 and the appropriate Al–Cl precursor were measured out in a scintillation vial. THF was added and stirred at 22 °C for 12 h. The solution was syringe filtered to remove NaCl and layered with hexanes. The solid or crystals that crashed out were isolated by filtration and washed with hexanes and dried overnight in vacuo.

General procedure C: Deoxygenation of epoxides with internal standard

In a glove box, a 1 fluid dram glass vial equipped with a Teflon-coated magnetic stir bar was charged with the appropriate catalyst, para-xylene, and solvent. After 1 minute of stirring at 22 °C, the vial was placed in a custom-made 6-well high-pressure reactor which itself was placed in a glove box freezer (−32 °C) for 30 minutes. The appropriate epoxide (also cooled to −32 °C) was then added to the vial, the reactor removed from the freezer, subsequently sealed, taken out of the glove box, placed in a well-ventilated hood and pressurized with carbon monoxide (700–1200 psig). It is important to keep

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the temperature of the reactor below 0 °C once it is removed from the freezer to minimize isomerization of the epoxide to ketone products. The reactor was sealed again and heated to 80 °C by inserting the thermocouple with temperature controller of an Ika hot plate into the 6-well high-pressure reactor. Insulating fabric was wrapped around the base of the reactor below the Swagelok valves to mitigate the temperature gradient

(if the fabric was not used, some of the reaction solution is lost through evaporation and condensation on the slightly cooler roof of the reactor). The reaction mixture was stirred for 4 hours before being cooled in dry ice for 15 minutes and carefully vented in a well- ventilated hood. Two drops of the reaction mixture were diluted with CDCl3 and run through a pipette plug of neutral alumina before analyzing by 1H NMR spectroscopy.

5.7.2.2 Synthesis of Starting Materials Z-2-Octene

2-Octyne (3.90 g, 35.4 mmol) was added to Lindlar’s catalyst (3 scoops) in a Parr reactor and pressurized to 600 psi H2. Stirred at 22 °C for 40 min (gauge read 500 psi). Full conversion was confirmed by 1H NMR spectroscopy, which matched previously reported data.36 Due to its volatility, the alkene was used straight for the epoxidation to

1 4a without purification. H NMR (300 MHz, CDCl3): δ 5.41 (m, 2H), 2.03 (m, 2H),

1.60 (d, J = 5.5, 3H), 1.31 (m, 6H), 0.89 (t, J = 6.5, 3H).

2-(tert-Butyl)-4-tritylphenol (SM1)

Trityl alcohol (5.27 g, 20.3 mmol) was taken up in glacial acetic acid (50 ml) in a 100 ml round-bottomed flask. 2-Tert-butylphenol (3 ml, 19.5 mmol) was added and the flask

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was heated to 50 °C. Concentrated H2SO4 (1 ml) was added dropwise before cooling the reaction to 22 °C and stirring overnight. The solid was isolated by filtration, washed with DI water, air-dried, then further dried overnight in vacuo to give the title compound

1 (6.77 g, 88%) as a light yellow powder. H NMR (500 MHz, CDCl3): δ 7.15–7.34 (m,

15H), 7.10 (d, J = 2.4, 1H), 6.86 (dd, J = 8.3, 2.4, 1H), 6.53 (d, J = 8.3, 1H), 4.53 (br s,

13 1 1H), 1.26 (s, 9H). C{ H} NMR (126 MHz, CDCl3): δ 152.1, 147.3, 138.8, 134.7,

131.3, 130.7, 129.7, 128.1, 127.4, 125.9, 115.5, 64.7, 34.8, 29.7 (there is one extra 13C signal in the aromatic region that we cannot account for). HRMS (DART) m/z

+ + calculated for C29H28O (M) 392.21347, found 392.214858 (error 3.55 ppm).

3-(tert-Butyl)-2-hydroxy-5-tritylbenzaldehyde (SM2)

2,6-Lutidine (2.2 ml, 19 mmol) was added to a solution of SM1 (4.97 g, 12.7 mmol) in toluene (20 ml) in a flame-dried Schlenk flask. The solution was cooled to 0 °C and

SnCl4 (0.75 ml, 6.4 mmol) was added dropwise. The reaction was then warmed to 22

°C and paraformaldehyde (1.06 g, 35.3 mmol) was added. The reaction was stirred at

90 °C for 20 h before cooling to 22 °C and being quenched with 2 M HCl. The reaction mixture was extracted with ether (3x) and the combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (5% EtOAc in hexanes, dry load) to give the

1 title compound (4.58 g, 86%) as a yellow powder. H NMR (500 MHz, CDCl3): δ 11.79

(s, 1H), 9.68 (s, 1H), 7.34 (d, J = 2.4, 1H), 7.14–7.30 (m, 16H), 1.25 (s, 9H). 13C{1H}

NMR (126 MHz, CDCl3): δ 197.5, 159.7, 146.5, 138.4, 137.7, 137.2, 133.1, 131.1,

+ 127.8, 126.3, 119.7, 64.5, 35.1, 29.3. HRMS (DART) m/z calculated for C30H28O2

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(M)+ 420.20838, found 420.209321 (error 2.24 ppm).

rac-6,6'-((1E,1'E)-(((1S,2S)-Cyclohexane-1,2- diyl)bis(azaneylylidene))bis(methaneylylidene))bis(2-(tert-butyl)-4-tritylphenol)

(SM3)

1,2-Cyclohexyl diamine (0.257 g, 2.23 mmol) was dissolved in ethanol (9 ml) and added to SM2 (1.893 g, 4.50 mmol) in a scintillation vial. The vial was sealed and heated to

80 °C for 15 h. The reaction was then cooled to 22 °C and the solid was isolated by filtration and washed with ethanol and pentane. The product was dried in vacuo to give

1 the title compound (1.719 g, 84%) as a yellow powder. H NMR (500 MHz, CDCl3): δ

13.90 (s, 2H), 8.17 (s, 2H), 7.13–7.24 (m, 30H), 7.10 (d, J = 2.4, 2H), 6.90 (d, J = 2.3,

2H), 3.28 (m, 2H), 1.78–1.93 (m, 4H), 1.66 (m, 2H), 1.40 (m, 2H), 1.23 (s, 18H).

13 1 C{ H} NMR (126 MHz, CDCl3): δ 165.7, 158.8, 147.0, 136.1, 135.9, 133.7, 131.4,

131.2, 127.5, 126.0, 117.5, 72.3, 64.5, 35.0, 33.5, 29.5, 24.4. HRMS (DART) m/z

+ + calculated for C66H67N2O2 (M+H) 919.51971, found 919.52071 (error 1.09 ppm).

rac-6,6'-((1E,1'E)-(((1S,2S)-Cyclohexane-1,2- diyl)bis(azaneylylidene))bis(methaneylylidene))bis(2-(tert-butyl)-4- chlorophenolate) aluminum chloride (3bAl-Cl)

Following general procedure A, Et2AlCl (0.83 ml, 0.83 mmol), rac-6,6'-((1E,1'E)-

(((1S,2S)-cyclohexane-1,2-diyl)bis(azaneylylidene))bis(methaneylylidene))bis(2-(tert- butyl)-4-chlorophenol) (0.349 g, 0.691 mmol), and DCM (17 ml) were used to give the title compound (0.349 g, 89%) as a light yellow powder. 1H NMR (500 MHz, DMSO-

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d6): δ 8.38 (s, 2H), 7.58 (s, 2H), 7.26 (s, 2H), 3.38 (br m, 2H), 2.57 (br d, J = 10.9, 2H),

13 1 1.94 (br m, 2H), 1.50 (s, 18H), 1.44 (br m, 4H). C{ H} NMR (126 MHz, DMSO-d6):

δ 163.0, 162.2, 142.3, 131.6, 131.0, 120.7, 118.4, 63.4, 35.2, 29.3, 26.9, 23.3.

rac-6,6'-((1E,1'E)-(((1S,2S)-Cyclohexane-1,2- diyl)bis(azaneylylidene))bis(methaneylylidene))bis(2-(tert-butyl)-4- chlorophenolate) aluminum cobaltate (3b)

Following general procedure B, NaMn(CO)5 (0.148 g, 0.678 mmol), 3bAl-Cl (0.358 g,

0.635 mmol), and THF (6 ml) were used to give the title compound (0.410 g, 75%) as a

1 light orange powder. H NMR resonances are very broad in CDCl3. They are sharper in acetone-d6, but the complex decomposes. See Section 5.7.3 for the single crystal X-ray data for 3b.

rac-6,6'-((1E,1'E)-(((1S,2S)-Cyclohexane-1,2- diyl)bis(azaneylylidene))bis(methaneylylidene))bis(2-(tert-butyl)-4- tritylphenolate) aluminum chloride (3cAl-Cl)

Following general procedure A, Et2AlCl (1.85 ml, 1.85 mmol), SM6 (1.504 g, 1.64 mmol), and DCM (40 ml) were used to give the title compound (1.584 g, 99%) as a

1 yellow solid. H NMR (500 MHz, CDCl3): δ 8.20 (s, 1H), 8.00 (s, 1H), 7.16–7.31 (m,

32H), 6.98 (dd, J = 19.4, 2.4, 2H), 3.85 (t, J = 10.5, 1H), 3.11 (t, J = 10.7, 1H), 2.49 (d,

J = 11.5, 1H), 2.36 (d, J = 10.6, 1H), 2.02 (t, J = 11.6, 2H), 1.43–1.53 (m, 2H), 1.37 (s,

13 1 9H), 1.36 (s, 9H), 1.21–1.30 (m, 2H). C{ H} NMR (126 MHz, CDCl3): δ 168.9,

164.04, 164.00, 162.3, 147.02, 146.96, 140.8, 140.7, 138.2, 137.1, 135.2, 134.7, 133.2,

235

133.0, 131.24, 131.22, 127.6, 126.0, 118.0, 117.9, 65.9, 64.48, 64.45, 62.5, 35.6, 35.5,

29.8, 29.7, 28.6, 27.4, 24.1, 23.6. (note: there are 2 missing 13C signals in the aromatic region which we attribute to coincidentally overlapping signals). HRMS (DART) m/z

+ + calculated for C66H64N2O2Al (M−Cl) 943.47777, found 943.47393 (error −4.06 ppm).

rac-6,6'-((1E,1'E)-(((1S,2S)-Cyclohexane-1,2- diyl)bis(azaneylylidene))bis(methaneylylidene))bis(2-(tert-butyl)-4- tritylphenolate) aluminum cobaltate (3c)

Following general procedure B, NaMn(CO)5 (0.245 g, 1.12 mmol), 3cAl–Cl (1.00 g,

1.02 mmol), and THF (10 ml) were used to give the title compound (1.00 g, 77%) as a

1 light orange powder. H NMR resonances are very broad in CDCl3. They are sharper in acetone-d6, but the complex decomposes.

6,6'-((1E,1'E)-(1,2-phenylenebis(azaneylylidene))bis(methaneylylidene))bis(2-

(tert-butyl)-4-methoxyphenol) (SM4)

3-(tert-Butyl)-2-hydroxy-5-methoxybenzaldehyde (1.00 g, 4.80 mmol) was dissolved in ethanol (20 ml). After adding 1,2-diaminobenzene (0.259 g, 2.40 mmol), the reaction mixture was refluxed for 12 h. The reaction mixture was then cooled to 22 °C and the resulting precipitate was isolated by filtration. The solids were washed with small amounts of cold ethanol and dried in vacuo at 60 °C to give the title compound (0.571

1 g, 49%) as an orange powder. H NMR (600 MHz, CDCl3): δ 13.36 (s, 2H), 8.63 (s,

2H), 7.33 (m, 2H), 7.25 (m, 2H), 7.04 (d, J = 3.0, 2H), 6.72 (d, J = 3.0, 2H), 3.79 (s,

6H), 1.42 (s, 18H).

236

rac-6,6'-((1E,1'E)-(((1S,2S)-Cyclohexane-1,2- diyl)bis(azaneylylidene))bis(methaneylylidene))bis(2-(tert-butyl)-4- methoxyphenolate) aluminum chloride (2aAl-Cl)

In a glovebox, SM4 (0.300 g, 0.614 mmol) was dissolved in dry, degassed toluene (20 ml) in a dry Schlenk flask. A solution of Et2AlCl (1.020 M in toluene, 0.662 ml, 0.675 mmol) was added dropwise with stirring, resulting in the precipitation of yellow solids from the reaction mixture. After stirring at 22 °C for 5 minutes in the glovebox, the flask was sealed and removed from the glovebox. The mixture was then heated to 90 °C for

16 h. After cooling to 22 °C, the resulting solids were filtered, washed with dry, degassed hexanes, and dried under vacuum overnight to give the title compound (0.135

1 g, 40%). H NMR (600 MHz, CDCl3): δ 8.95 (s, 2H), 7.76 (m, 2H), 7.43 (m, 2H), 7.28

(d, J = 3.0, 2H), 6.70 (d, J = 3.0, 2H), 3.83 (s, 6H), 1.58 (s, 18H).

5.7.2.3 Deoxygenation of Epoxides to Alkenes Allylbenzene (5c)

Following general procedure C, rac-2-benzyloxirane (4c, 0.0386 g, 0.288 mmol), para- xylene (0.0101 g, 0.0951 mmol), catalyst 3b (0.0078 g, 0.0090 mmol, 3.1 mol %), and

THF (0.3 ml) were used. Quantitative 1H NMR spectroscopy resulted in 92% yield. 1H

37 1 NMR spectrum matched literature data. H NMR (400 MHz, CDCl3): δ 7.24–7.33 (m,

2H), 7.14–7.23 (m, 3H), 5.96 (m, 1H), 5.06 (m, 2H), 3.38 (d, J = 6.3, 2H).

1-Decene (5d)

Following general procedure C, rac-2-octyloxirane (4d, 0.0455 g, 0.291 mmol), para-

237

xylene (0.0098 g, 0.092 mmol), catalyst 3b (0.0078 g, 0.0090 mmol, 3.1 mol %), and

THF (0.3 ml) were used. Quantitative 1H NMR spectroscopy resulted in 94% yield. 1H

38 1 NMR spectrum matched literature data. H NMR (500 MHz, CDCl3): δ 5.80 (m, 1H),

4.98 (d, J = 17.2, 1H), 4.92 (d, J = 10.3, 1H), 2.03 (q, J = 7.0, 2H), 1.36 (m, 2H), 1.19–

1.32 (m, 10H), 0.87 (t, J = 6.5, 3H).

(Allyloxy)(tert-butyl)dimethylsilane (5e)

Following general procedure C, tert-butyldimethyl(oxiran-2-ylmethoxy)silane (4e,

0.0562 g, 0.298 mmol), para-xylene (0.0093 g, 0.088 mmol), catalyst 3b (0.0078 g,

0.0090 mmol, 3.0 mol %), and THF (0.3 ml) were used. Quantitative 1H NMR spectroscopy resulted in 96% yield. 1H NMR spectrum matched literature data.39 1H

NMR (500 MHz, CDCl3): δ 5.91 (m, 1H), 5.26 (d, J = 17.3, 1H), 5.07 (d, J = 10.3, 1H),

4.17 (m, 2H), 0.91 (s, 9H), 0.07 (s, 6H).

5.7.3 Crystallographic Data for Catalyst 3b 3b crystallizes as an inversion twin [twin ratio = 0.579(17):0.421(17)] in the orthorhombic space group P212121 with two independent molecules of Al(salen)(THF)2 per asymmetric unit. Disorder in the bound THF molecules and one Mn(CO)5 unit were modeled and refined with the help of similarity restraints on 1-2 and 1-3 distances and displacement parameters, as well as rigid bond restraints for anisotropic displacement parameters. Both [(salen)Al(THF)2][Mn(CO)5] ion pairs are shown separately in Figure

5.5. Crystal data, refinement details, atomic coordinates, displacement parameters, bond lengths, and bond angles can be found in Table 5.6–Table 5.10.

238

Figure 5.5 Thermal ellipsoid representation of the two independent [(salen)Al(THF)2][Mn(CO)5] ion pairs in the crystal structure of 3b. Ellipsoids are drawn at the 50% probability level. All hydrogen atoms and free THF in the lattice are omitted for clarity. Both components of the disorder are shown.

Table 5.6 Crystal data and structure refinement for catalyst 3b Identification code 3b

Empirical formula C94H124Al2Cl4Mn2N4O21 Formula weight 1951.60 Temperature 100.00(10) K Wavelength 0.71073 Å Crystal system Orthorhombic

Space group P 21 21 21 Unit cell dimensions a = 15.6733(3) Å α= 90° b = 23.5355(4) Å β= 90° c = 26.0438(4) Å γ = 90° Volume 9607.0(3) Å3 Z 4 Density (calculated) 1.349 Mg/m3 Absorption coefficient 0.463 mm−1 F(000) 4112 Crystal size 0.513 x 0.149 x 0.116 mm3 Theta range for data collection 3.388 to 26.372° Index ranges −19<=h<=18, −25<=k<=29, −28<=l<=32

239

Reflections collected 58659 Independent reflections 19346 [R(int) = 0.0278] Completeness to theta = 26.000° 99.6 % Absorption correction Gaussian Max. and min. transmission 1.000 and 0.518 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 19346 / 1577 / 1314 Goodness-of-fit on F2 1.021 Final R indices [I>2sigma(I)] R1 = 0.0404, wR2 = 0.1021 R indices (all data) R1 = 0.0450, wR2 = 0.1044 Absolute structure parameter 0.421(17) Extinction coefficient n/a Largest diff. peak and hole 1.022 and −0.587 e.Å−3

Table 5.7 Atomic coordinates (x104) and equivalent isotropic displacement parameters (Å2x103) for 3b U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

x y z U(eq) Cl(11) 10352(1) 3568(1) 6991(1) 27(1) Cl(12) 6058(1) 8936(1) 6690(1) 25(1) Al(1) 8393(1) 6291(1) 6521(1) 14(1) O(11) 8794(2) 5831(1) 7015(1) 17(1) O(12) 7853(2) 6768(1) 6947(1) 15(1) N(11) 8976(2) 5844(1) 5981(1) 19(1) N(12) 7999(2) 6730(1) 5915(1) 23(1) C(101) 9148(2) 5322(1) 7008(1) 16(1) C(102) 9301(2) 5029(1) 7479(1) 18(1) C(103) 9663(2) 4491(1) 7454(1) 20(1) C(104) 9889(2) 4244(1) 6985(2) 21(1) C(105) 9777(2) 4523(1) 6532(1) 20(1) C(106) 9407(2) 5071(1) 6537(1) 18(1) C(107) 9335(2) 5357(2) 6047(1) 19(1) C(108) 9002(3) 6142(2) 5480(2) 36(1) C(109) 9297(3) 5809(2) 5016(1) 26(1) C(110) 9238(4) 6176(2) 4534(2) 45(1) C(111) 8415(4) 6468(2) 4470(2) 52(1) C(112) 8146(3) 6816(2) 4940(1) 30(1) C(113) 8163(3) 6439(2) 5420(2) 35(1)

240

x y z U(eq) C(114) 7553(2) 7190(2) 5928(1) 21(1) C(115) 7294(2) 7482(1) 6388(1) 16(1) C(116) 6856(2) 8001(1) 6326(1) 18(1) C(117) 6628(2) 8302(1) 6750(1) 19(1) C(118) 6834(2) 8112(1) 7243(1) 18(1) C(119) 7254(2) 7600(1) 7324(1) 17(1) C(120) 7475(2) 7267(1) 6886(1) 15(1) C(121) 7448(2) 7389(1) 7871(1) 19(1) C(122) 8400(2) 7240(2) 7934(1) 22(1) C(123) 6897(2) 6862(2) 7985(1) 23(1) C(124) 7235(3) 7842(2) 8278(2) 31(1) C(125) 9112(2) 5315(1) 7998(1) 18(1) C(126) 9709(3) 5831(2) 8057(1) 26(1) C(127) 8175(2) 5508(2) 8037(1) 25(1) C(128) 9286(3) 4912(2) 8451(1) 27(1) O(13) 9468(2) 6764(1) 6552(1) 19(1) C(129) 10321(2) 6539(2) 6633(2) 24(1) C(130) 10728(3) 6981(2) 6956(2) 28(1) C(131) 10403(2) 7527(2) 6729(2) 26(1) C(132) 9493(2) 7386(1) 6602(2) 22(1) O(14) 7342(2) 5801(1) 6432(1) 20(1) C(133) 7296(3) 5190(2) 6348(2) 37(1) C(34A) 6373(5) 5079(5) 6216(4) 32(2) C(35A) 5947(7) 5470(4) 6604(4) 32(2) C(34B) 6366(10) 5027(9) 6431(16) 57(7) C(35B) 5853(14) 5559(8) 6402(17) 61(7) C(136) 6479(2) 6009(2) 6554(2) 32(1) Cl(21) 5333(1) 9044(1) 8100(1) 32(1) Cl(22) 1021(1) 3699(1) 8462(1) 26(1) Al(2) 3351(1) 6341(1) 8635(1) 14(1) O(21) 3811(2) 6771(1) 8137(1) 16(1) O(22) 2888(2) 5835(1) 8205(1) 15(1) N(21) 3819(2) 6851(1) 9171(1) 22(1) N(22) 2912(2) 5923(1) 9241(1) 17(1) C(201) 4170(2) 7278(1) 8127(1) 15(1) C(202) 4371(2) 7538(1) 7650(1) 16(1) C(203) 4728(2) 8080(1) 7659(1) 20(1) C(204) 4897(2) 8364(1) 8118(1) 22(1) C(205) 4736(2) 8113(1) 8581(1) 20(1) C(206) 4369(2) 7567(1) 8592(1) 17(1) C(207) 4204(2) 7323(2) 9092(1) 21(1) C(208) 3780(4) 6600(2) 9696(2) 51(2) C(209) 3878(3) 7007(2) 10146(1) 27(1) C(210) 3814(5) 6687(2) 10649(2) 67(2)

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x y z U(eq) C(211) 3135(4) 6274(2) 10685(2) 47(1) C(212) 2951(3) 5906(2) 10223(1) 33(1) C(213) 3055(4) 6227(2) 9731(1) 41(1) C(214) 2500(2) 5451(1) 9226(1) 19(1) C(215) 2276(2) 5142(1) 8765(1) 17(1) C(216) 1821(2) 4631(2) 8828(1) 20(1) C(217) 1606(2) 4325(1) 8402(1) 20(1) C(218) 1851(2) 4500(1) 7910(1) 19(1) C(219) 2297(2) 4999(1) 7832(1) 16(1) C(220) 2496(2) 5342(1) 8268(1) 16(1) C(221) 2559(2) 5183(1) 7286(1) 17(1) C(222) 3519(2) 5312(2) 7259(1) 22(1) C(223) 2036(3) 5710(1) 7139(1) 22(1) C(224) 2375(3) 4714(2) 6890(1) 24(1) C(225) 4209(2) 7224(2) 7139(1) 20(1) C(226) 4769(3) 6694(2) 7119(2) 27(1) C(227) 3272(2) 7058(2) 7090(1) 25(1) C(228) 4438(3) 7594(2) 6669(1) 31(1) O(23) 4434(2) 5891(1) 8697(1) 18(1) C(229) 5292(2) 6131(2) 8654(2) 26(1) C(30C) 5832(8) 5665(4) 8427(6) 42(3) C(31C) 5426(4) 5135(3) 8690(5) 32(2) C(30D) 5840(30) 5617(16) 8583(16) 32(6) C(31D) 5348(15) 5137(10) 8449(16) 28(6) C(232) 4496(2) 5270(1) 8667(2) 28(1) O(24) 2274(2) 6809(1) 8643(1) 20(1) C(233) 1428(2) 6577(2) 8531(2) 29(1) C(34C) 860(20) 7020(13) 8770(20) 30(8) C(35C) 1289(12) 7584(15) 8710(30) 42(8) C(34D) 802(9) 7049(5) 8638(7) 35(3) C(35D) 1325(6) 7567(5) 8503(7) 40(3) C(236) 2210(3) 7427(2) 8670(2) 42(1) Mn(1) 2548(1) 3898(1) 10364(1) 23(1) O(1) 1453(2) 3244(1) 9637(1) 39(1) O(2) 3755(2) 4623(1) 10954(1) 35(1) O(3) 2908(2) 2829(1) 10923(1) 37(1) O(4) 1057(3) 4519(2) 10784(2) 68(1) O(5) 3630(2) 4306(2) 9504(1) 40(1) C(1) 1870(3) 3498(2) 9917(1) 27(1) C(2) 3275(3) 4334(2) 10740(1) 26(1) C(3) 2778(3) 3249(2) 10710(2) 28(1) C(4) 1638(3) 4277(2) 10617(2) 40(1) C(5) 3193(3) 4139(2) 9832(1) 28(1) Mn(2A) 7032(2) 6167(1) 10067(1) 33(1)

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x y z U(eq) O(6A) 7737(5) 5007(2) 9905(3) 61(2) O(7A) 6220(6) 7311(3) 10077(3) 71(3) O(8A) 7814(12) 6278(7) 11095(4) 50(3) O(9A) 5314(8) 5648(6) 10047(5) 49(3) O(10A) 8105(7) 6575(4) 9190(3) 66(2) C(6A) 7470(6) 5456(3) 9972(3) 40(2) C(7A) 6545(6) 6869(3) 10080(4) 43(2) C(8A) 7502(10) 6236(6) 10687(4) 36(3) C(9A) 5986(10) 5862(10) 10036(9) 36(3) C(10A) 7671(8) 6412(5) 9528(3) 45(3) Mn(2B) 7145(2) 6226(1) 9868(1) 28(1) O(6B) 5493(9) 5725(8) 10217(5) 50(4) O(7B) 8661(7) 6696(4) 9302(4) 54(2) O(8B) 7443(5) 5121(3) 9348(3) 50(2) O(9B) 6179(5) 7250(3) 9536(4) 54(2) O(10B) 7871(17) 6294(11) 10913(5) 65(5) C(6B) 6144(10) 5925(11) 10110(9) 33(4) C(7B) 8069(7) 6513(5) 9527(5) 34(3) C(8B) 7339(6) 5559(4) 9548(4) 35(2) C(9B) 6572(6) 6847(4) 9664(4) 37(2) C(10B) 7597(12) 6272(8) 10494(5) 43(4) O(1S) 6000(3) 6500(2) 5390(2) 82(2) C(1S) 5833(4) 6214(3) 4918(2) 69(2) C(2S) 5729(3) 6693(2) 4529(2) 45(1) C(3S) 5493(4) 7204(2) 4840(2) 59(1) C(4S) 5443(4) 6969(4) 5385(2) 82(2) O(2S) 2937(4) 8974(2) 6889(2) 99(2) C(5S) 2212(4) 8555(2) 6849(3) 62(2) C(6S) 1933(6) 8375(3) 7318(3) 95(3) C(7S) 2418(5) 8629(3) 7685(3) 86(2) C(8S) 2853(5) 9133(2) 7469(3) 80(2) O(3S) 934(3) 6035(2) 9724(2) 75(1) C(9S) 331(5) 5688(4) 9513(3) 81(2) C(12S) 549(5) 6272(3) 10179(3) 92(3) C(10S) −117(6) 5402(3) 9942(2) 86(2) C(11S) −48(6) 5818(3) 10374(3) 94(3)

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Table 5.8 Bond lengths [Å] and angles [°] for 3b

Cl(11)-C(104) 1.749(3) C(115)-C(120) 1.420(5) Cl(12)-C(117) 1.745(3) C(116)-H(116) 0.9300 Al(1)-O(11) 1.795(2) C(116)-C(117) 1.360(5) Al(1)-O(12) 1.791(2) C(117)-C(118) 1.397(5) Al(1)-N(11) 1.979(3) C(118)-H(118) 0.9300 Al(1)-N(12) 1.983(3) C(118)-C(119) 1.389(5) Al(1)-O(13) 2.020(3) C(119)-C(120) 1.428(4) Al(1)-O(14) 2.024(3) C(119)-C(121) 1.538(5) O(11)-C(101) 1.321(4) C(121)-C(122) 1.541(5) O(12)-C(120) 1.326(4) C(121)-C(123) 1.540(5) N(11)-C(107) 1.288(5) C(121)-C(124) 1.540(5) N(11)-C(108) 1.481(5) C(122)-H(12A) 0.9600 N(12)-C(113) 1.483(5) C(122)-H(12B) 0.9600 N(12)-C(114) 1.290(5) C(122)-H(12C) 0.9600 C(101)-C(102) 1.429(5) C(123)-H(12D) 0.9600 C(101)-C(106) 1.419(5) C(123)-H(12E) 0.9600 C(102)-C(103) 1.388(5) C(123)-H(12F) 0.9600 C(102)-C(125) 1.540(5) C(124)-H(12G) 0.9600 C(103)-H(103) 0.9300 C(124)-H(12H) 0.9600 C(103)-C(104) 1.399(5) C(124)-H(12I) 0.9600 C(104)-C(105) 1.363(5) C(125)-C(126) 1.541(5) C(105)-H(105) 0.9300 C(125)-C(127) 1.541(5) C(105)-C(106) 1.414(5) C(125)-C(128) 1.536(5) C(106)-C(107) 1.448(5) C(126)-H(12J) 0.9600 C(107)-H(107) 0.9300 C(126)-H(12K) 0.9600 C(108)-H(108) 0.9800 C(126)-H(12L) 0.9600 C(108)-C(109) 1.512(5) C(127)-H(12M) 0.9600 C(108)-C(113) 1.498(6) C(127)-H(12N) 0.9600 C(109)-H(10A) 0.9700 C(127)-H(12O) 0.9600 C(109)-H(10B) 0.9700 C(128)-H(12P) 0.9600 C(109)-C(110) 1.527(5) C(128)-H(12Q) 0.9600 C(110)-H(11A) 0.9700 C(128)-H(12R) 0.9600 C(110)-H(11B) 0.9700 O(13)-C(129) 1.453(4) C(110)-C(111) 1.473(7) O(13)-C(132) 1.470(4) C(111)-H(11C) 0.9700 C(129)-H(12S) 0.9700 C(111)-H(11D) 0.9700 C(129)-H(12T) 0.9700 C(111)-C(112) 1.531(6) C(129)-C(130) 1.482(5) C(112)-H(11E) 0.9700 C(130)-H(13A) 0.9700 C(112)-H(11F) 0.9700 C(130)-H(13B) 0.9700 C(112)-C(113) 1.532(5) C(130)-C(131) 1.502(5) C(113)-H(113) 0.9800 C(131)-H(13C) 0.9700 C(114)-H(114) 0.9300 C(131)-H(13D) 0.9700 C(114)-C(115) 1.441(5) C(131)-C(132) 1.503(5) C(115)-C(116) 1.410(5) C(132)-H(13E) 0.9700

244

C(132)-H(13F) 0.9700 C(204)-C(205) 1.365(5) O(14)-C(133) 1.457(4) C(205)-H(205) 0.9300 O(14)-C(136) 1.473(4) C(205)-C(206) 1.409(5) C(133)-H(13G) 0.9700 C(206)-C(207) 1.446(5) C(133)-H(13H) 0.9700 C(207)-H(207) 0.9300 C(133)-H(13I) 0.9700 C(208)-H(208) 0.9800 C(133)-H(13J) 0.9700 C(208)-C(209) 1.521(5) C(133)-C(34A) 1.510(10) C(208)-C(213) 1.438(7) C(133)-C(34B) 1.523(16) C(209)-H(20A) 0.9700 C(34A)-H(34E) 0.9700 C(209)-H(20B) 0.9700 C(34A)-H(34F) 0.9700 C(209)-C(210) 1.515(6) C(34A)-C(35A) 1.520(10) C(210)-H(21A) 0.9700 C(35A)-H(35E) 0.9700 C(210)-H(21B) 0.9700 C(35A)-H(35F) 0.9700 C(210)-C(211) 1.445(7) C(35A)-C(136) 1.524(9) C(211)-H(21C) 0.9700 C(34B)-H(34G) 0.9700 C(211)-H(21D) 0.9700 C(34B)-H(34H) 0.9700 C(211)-C(212) 1.511(5) C(34B)-C(35B) 1.490(19) C(212)-H(21E) 0.9700 C(35B)-H(35G) 0.9700 C(212)-H(21F) 0.9700 C(35B)-H(35H) 0.9700 C(212)-C(213) 1.494(5) C(35B)-C(136) 1.497(16) C(213)-H(213) 0.9800 C(136)-H(13K) 0.9700 C(214)-H(214) 0.9300 C(136)-H(13L) 0.9700 C(214)-C(215) 1.448(5) C(136)-H(13M) 0.9700 C(215)-C(216) 1.407(5) C(136)-H(13N) 0.9700 C(215)-C(220) 1.419(5) Cl(21)-C(204) 1.743(3) C(216)-H(216) 0.9300 Cl(22)-C(217) 1.743(3) C(216)-C(217) 1.366(5) Al(2)-O(21) 1.796(2) C(217)-C(218) 1.398(5) Al(2)-O(22) 1.788(2) C(218)-H(218) 0.9300 Al(2)-N(21) 1.982(3) C(218)-C(219) 1.382(5) Al(2)-N(22) 1.985(3) C(219)-C(220) 1.427(4) Al(2)-O(23) 2.007(3) C(219)-C(221) 1.542(4) Al(2)-O(24) 2.016(3) C(221)-C(222) 1.538(5) O(21)-C(201) 1.320(4) C(221)-C(223) 1.536(5) O(22)-C(220) 1.323(4) C(221)-C(224) 1.537(4) N(21)-C(207) 1.282(5) C(222)-H(22A) 0.9600 N(21)-C(208) 1.492(5) C(222)-H(22B) 0.9600 N(22)-C(213) 1.481(5) C(222)-H(22C) 0.9600 N(22)-C(214) 1.284(5) C(223)-H(22D) 0.9600 C(201)-C(202) 1.421(5) C(223)-H(22E) 0.9600 C(201)-C(206) 1.420(5) C(223)-H(22F) 0.9600 C(202)-C(203) 1.393(5) C(224)-H(22G) 0.9600 C(202)-C(225) 1.544(5) C(224)-H(22H) 0.9600 C(203)-H(203) 0.9300 C(224)-H(22I) 0.9600 C(203)-C(204) 1.396(5) C(225)-C(226) 1.526(5)

245

C(225)-C(227) 1.526(5) C(34C)-C(35C) 1.49(2) C(225)-C(228) 1.546(5) C(35C)-H(35A) 0.9700 C(226)-H(22J) 0.9600 C(35C)-H(35B) 0.9700 C(226)-H(22K) 0.9600 C(35C)-C(236) 1.493(18) C(226)-H(22L) 0.9600 C(34D)-H(34C) 0.9700 C(227)-H(22M) 0.9600 C(34D)-H(34D) 0.9700 C(227)-H(22N) 0.9600 C(34D)-C(35D) 1.510(10) C(227)-H(22O) 0.9600 C(35D)-H(35C) 0.9700 C(228)-H(22P) 0.9600 C(35D)-H(35D) 0.9700 C(228)-H(22Q) 0.9600 C(35D)-C(236) 1.490(9) C(228)-H(22R) 0.9600 C(236)-H(23I) 0.9700 O(23)-C(229) 1.462(4) C(236)-H(23J) 0.9700 O(23)-C(232) 1.468(4) C(236)-H(23K) 0.9700 C(229)-H(22S) 0.9700 C(236)-H(23L) 0.9700 C(229)-H(22T) 0.9700 Mn(1)-C(1) 1.835(4) C(229)-H(22U) 0.9700 Mn(1)-C(2) 1.820(4) C(229)-H(22V) 0.9700 Mn(1)-C(3) 1.811(4) C(229)-C(30C) 1.506(8) Mn(1)-C(4) 1.806(4) C(229)-C(30D) 1.498(19) Mn(1)-C(5) 1.807(4) C(30C)-H(30A) 0.9700 O(1)-C(1) 1.147(5) C(30C)-H(30B) 0.9700 O(2)-C(2) 1.158(5) C(30C)-C(31C) 1.559(15) O(3)-C(3) 1.151(5) C(31C)-H(31A) 0.9700 O(4)-C(4) 1.159(6) C(31C)-H(31B) 0.9700 O(5)-C(5) 1.161(5) C(31C)-C(232) 1.492(7) Mn(2A)-C(6A) 1.825(8) C(30D)-H(30C) 0.9700 Mn(2A)-C(7A) 1.822(8) C(30D)-H(30D) 0.9700 Mn(2A)-C(8A) 1.782(11) C(30D)-C(31D) 1.41(6) Mn(2A)-C(9A) 1.792(13) C(31D)-H(31C) 0.9700 Mn(2A)-C(10A) 1.817(10) C(31D)-H(31D) 0.9700 O(6A)-C(6A) 1.150(9) C(31D)-C(232) 1.484(16) O(7A)-C(7A) 1.157(9) C(232)-H(23A) 0.9700 O(8A)-C(8A) 1.175(13) C(232)-H(23B) 0.9700 O(9A)-C(9A) 1.167(14) C(232)-H(23C) 0.9700 O(10A)-C(10A) 1.177(12) C(232)-H(23D) 0.9700 Mn(2B)-C(6B) 1.833(13) O(24)-C(233) 1.464(4) Mn(2B)-C(7B) 1.828(12) O(24)-C(236) 1.460(4) Mn(2B)-C(8B) 1.804(8) C(233)-H(23E) 0.9700 Mn(2B)-C(9B) 1.797(9) C(233)-H(23F) 0.9700 Mn(2B)-C(10B) 1.782(13) C(233)-H(23G) 0.9700 O(6B)-C(6B) 1.159(15) C(233)-H(23H) 0.9700 O(7B)-C(7B) 1.179(13) C(233)-C(34C) 1.507(19) O(8B)-C(8B) 1.166(10) C(233)-C(34D) 1.509(9) O(9B)-C(9B) 1.178(11) C(34C)-H(34A) 0.9700 O(10B)-C(10B) 1.172(14) C(34C)-H(34B) 0.9700 O(1S)-C(1S) 1.428(8)

246

O(1S)-C(4S) 1.408(9) O(12)-Al(1)-O(13) 91.34(11) C(1S)-H(1SA) 0.9700 O(12)-Al(1)-O(14) 92.47(11) C(1S)-H(1SB) 0.9700 N(11)-Al(1)-N(12) 81.73(12) C(1S)-C(2S) 1.525(7) N(11)-Al(1)-O(13) 86.37(12) C(2S)-H(2SA) 0.9700 N(11)-Al(1)-O(14) 89.56(12) C(2S)-H(2SB) 0.9700 N(12)-Al(1)-O(13) 90.32(12) C(2S)-C(3S) 1.495(7) N(12)-Al(1)-O(14) 87.28(13) C(3S)-H(3SA) 0.9700 O(13)-Al(1)-O(14) 175.53(11) C(3S)-H(3SB) 0.9700 C(101)-O(11)-Al(1) 133.2(2) C(3S)-C(4S) 1.526(8) C(120)-O(12)-Al(1) 133.8(2) C(4S)-H(4SA) 0.9700 C(107)-N(11)-Al(1) 125.4(2) C(4S)-H(4SB) 0.9700 C(107)-N(11)-C(108) 121.8(3) O(2S)-C(5S) 1.507(8) C(108)-N(11)-Al(1) 112.7(2) O(2S)-C(8S) 1.561(8) C(113)-N(12)-Al(1) 113.4(2) C(5S)-H(5SA) 0.9700 C(114)-N(12)-Al(1) 125.8(2) C(5S)-H(5SB) 0.9700 C(114)-N(12)-C(113) 120.3(3) C(5S)-C(6S) 1.363(9) O(11)-C(101)-C(102) 119.8(3) C(6S)-H(6SA) 0.9700 O(11)-C(101)-C(106) 120.6(3) C(6S)-H(6SB) 0.9700 C(106)-C(101)- 119.5(3) C(6S)-C(7S) 1.361(10) C(102) C(7S)-H(7SA) 0.9700 C(101)-C(102)- 120.8(3) C(7S)-H(7SB) 0.9700 C(125) C(7S)-C(8S) 1.481(9) C(103)-C(102)- 117.9(3) C(8S)-H(8SA) 0.9700 C(101) C(8S)-H(8SB) 0.9700 C(103)-C(102)- 121.2(3) O(3S)-C(9S) 1.364(7) C(125) O(3S)-C(12S) 1.442(7) C(102)-C(103)- 119.2 C(9S)-H(9SA) 0.9700 H(103) C(9S)-H(9SB) 0.9700 C(102)-C(103)- 121.6(3) C(9S)-C(10S) 1.482(9) C(104) C(12S)-H(12U) 0.9700 C(104)-C(103)- 119.2 C(12S)-H(12V) 0.9700 H(103) C(12S)-C(11S) 1.510(8) C(103)-C(104)- 118.5(3) C(10S)-H(10C) 0.9700 Cl(11) C(10S)-H(10D) 0.9700 C(105)-C(104)- 119.9(3) C(10S)-C(11S) 1.495(8) Cl(11) C(11S)-H(11G) 0.9700 C(105)-C(104)- 121.6(3) C(11S)-H(11H) 0.9700 C(103) O(11)-Al(1)-N(11) 91.52(12) C(104)-C(105)- 120.5 O(11)-Al(1)-N(12) 173.11(12) H(105) O(11)-Al(1)-O(13) 90.65(11) C(104)-C(105)- 118.9(3) O(11)-Al(1)-O(14) 91.29(11) C(106) O(12)-Al(1)-O(11) 95.67(11) C(106)-C(105)- 120.5 O(12)-Al(1)-N(11) 172.47(12) H(105) O(12)-Al(1)-N(12) 91.12(12) C(101)-C(106)- 123.1(3)

247

C(107) H(11C) C(105)-C(106)- 120.4(3) C(110)-C(111)- 108.8 C(101) H(11D) C(105)-C(106)- 116.6(3) C(110)-C(111)- 113.6(4) C(107) C(112) N(11)-C(107)-C(106) 124.4(3) H(11C)-C(111)- 107.7 N(11)-C(107)- 117.8 H(11D) H(107) C(112)-C(111)- 108.8 C(106)-C(107)- 117.8 H(11C) H(107) C(112)-C(111)- 108.8 N(11)-C(108)- 105.3 H(11D) H(108) C(111)-C(112)- 109.7 N(11)-C(108)-C(109) 117.8(3) H(11E) N(11)-C(108)-C(113) 106.8(3) C(111)-C(112)- 109.7 C(109)-C(108)- 105.3 H(11F) H(108) C(111)-C(112)- 109.7(3) C(113)-C(108)- 105.3 C(113) H(108) H(11E)-C(112)- 108.2 C(113)-C(108)- 115.2(4) H(11F) C(109) C(113)-C(112)- 109.7 C(108)-C(109)- 109.6 H(11E) H(10A) C(113)-C(112)- 109.7 C(108)-C(109)- 109.6 H(11F) H(10B) N(12)-C(113)-C(108) 106.1(3) C(108)-C(109)- 110.2(3) N(12)-C(113)-C(112) 116.1(3) C(110) N(12)-C(113)- 107.5 H(10A)-C(109)- 108.1 H(113) H(10B) C(108)-C(113)- 111.8(4) C(110)-C(109)- 109.6 C(112) H(10A) C(108)-C(113)- 107.5 C(110)-C(109)- 109.6 H(113) H(10B) C(112)-C(113)- 107.5 C(109)-C(110)- 108.7 H(113) H(11A) N(12)-C(114)- 117.4 C(109)-C(110)- 108.7 H(114) H(11B) N(12)-C(114)-C(115) 125.2(3) H(11A)-C(110)- 107.6 C(115)-C(114)- 117.4 H(11B) H(114) C(111)-C(110)- 114.2(4) C(116)-C(115)- 117.1(3) C(109) C(114) C(111)-C(110)- 108.7 C(116)-C(115)- 120.7(3) H(11A) C(120) C(111)-C(110)- 108.7 C(120)-C(115)- 122.2(3) H(11B) C(114) C(110)-C(111)- 108.8 C(115)-C(116)- 120.5

248

H(116) H(12A)-C(122)- 109.5 C(117)-C(116)- 119.1(3) H(12B) C(115) H(12A)-C(122)- 109.5 C(117)-C(116)- 120.5 H(12C) H(116) H(12B)-C(122)- 109.5 C(116)-C(117)- 120.5(3) H(12C) Cl(12) C(121)-C(123)- 109.5 C(116)-C(117)- 121.2(3) H(12D) C(118) C(121)-C(123)- 109.5 C(118)-C(117)- 118.3(3) H(12E) Cl(12) C(121)-C(123)- 109.5 C(117)-C(118)- 119.1 H(12F) H(118) H(12D)-C(123)- 109.5 C(119)-C(118)- 121.9(3) H(12E) C(117) H(12D)-C(123)- 109.5 C(119)-C(118)- 119.1 H(12F) H(118) H(12E)-C(123)- 109.5 C(118)-C(119)- 117.9(3) H(12F) C(120) C(121)-C(124)- 109.5 C(118)-C(119)- 121.0(3) H(12G) C(121) C(121)-C(124)- 109.5 C(120)-C(119)- 121.0(3) H(12H) C(121) C(121)-C(124)- 109.5 O(12)-C(120)-C(115) 121.0(3) H(12I) O(12)-C(120)-C(119) 119.9(3) H(12G)-C(124)- 109.5 C(115)-C(120)- 119.1(3) H(12H) C(119) H(12G)-C(124)- 109.5 C(119)-C(121)- 111.4(3) H(12I) C(122) H(12H)-C(124)- 109.5 C(119)-C(121)- 109.1(3) H(12I) C(123) C(102)-C(125)- 108.3(3) C(119)-C(121)- 111.7(3) C(126) C(124) C(102)-C(125)- 111.7(3) C(123)-C(121)- 109.8(3) C(127) C(122) C(127)-C(125)- 109.9(3) C(124)-C(121)- 107.1(3) C(126) C(122) C(128)-C(125)- 111.7(3) C(124)-C(121)- 107.7(3) C(102) C(123) C(128)-C(125)- 107.6(3) C(121)-C(122)- 109.5 C(126) H(12A) C(128)-C(125)- 107.5(3) C(121)-C(122)- 109.5 C(127) H(12B) C(125)-C(126)- 109.5 C(121)-C(122)- 109.5 H(12J) H(12C) C(125)-C(126)- 109.5

249

H(12K) C(130)-C(129)- 111.2 C(125)-C(126)- 109.5 H(12T) H(12L) C(129)-C(130)- 111.1 H(12J)-C(126)- 109.5 H(13A) H(12K) C(129)-C(130)- 111.1 H(12J)-C(126)- 109.5 H(13B) H(12L) C(129)-C(130)- 103.4(3) H(12K)-C(126)- 109.5 C(131) H(12L) H(13A)-C(130)- 109.1 C(125)-C(127)- 109.5 H(13B) H(12M) C(131)-C(130)- 111.1 C(125)-C(127)- 109.5 H(13A) H(12N) C(131)-C(130)- 111.1 C(125)-C(127)- 109.5 H(13B) H(12O) C(130)-C(131)- 111.2 H(12M)-C(127)- 109.5 H(13C) H(12N) C(130)-C(131)- 111.2 H(12M)-C(127)- 109.5 H(13D) H(12O) C(130)-C(131)- 102.6(3) H(12N)-C(127)- 109.5 C(132) H(12O) H(13C)-C(131)- 109.2 C(125)-C(128)- 109.5 H(13D) H(12P) C(132)-C(131)- 111.2 C(125)-C(128)- 109.5 H(13C) H(12Q) C(132)-C(131)- 111.2 C(125)-C(128)- 109.5 H(13D) H(12R) O(13)-C(132)-C(131) 105.4(3) H(12P)-C(128)- 109.5 O(13)-C(132)- 110.7 H(12Q) H(13E) H(12P)-C(128)- 109.5 O(13)-C(132)- 110.7 H(12R) H(13F) H(12Q)-C(128)- 109.5 C(131)-C(132)- 110.7 H(12R) H(13E) C(129)-O(13)-Al(1) 124.95(19) C(131)-C(132)- 110.7 C(129)-O(13)-C(132) 109.0(2) H(13F) C(132)-O(13)-Al(1) 125.0(2) H(13E)-C(132)- 108.8 O(13)-C(129)- 111.2 H(13F) H(12S) C(133)-O(14)-Al(1) 128.3(2) O(13)-C(129)- 111.2 C(133)-O(14)-C(136) 108.4(3) H(12T) C(136)-O(14)-Al(1) 122.2(2) O(13)-C(129)-C(130) 102.9(3) O(14)-C(133)- 110.8 H(12S)-C(129)- 109.1 H(13G) H(12T) O(14)-C(133)- 110.8 C(130)-C(129)- 111.2 H(13H) H(12S) O(14)-C(133)-H(13I) 110.5

250

O(14)-C(133)-H(13J) 110.5 H(34G)-C(34B)- 108.5 O(14)-C(133)- 104.6(5) H(34H) C(34A) C(35B)-C(34B)- 107.3(16) O(14)-C(133)- 105.9(10) C(133) C(34B) C(35B)-C(34B)- 110.3 H(13G)-C(133)- 108.9 H(34G) H(13H) C(35B)-C(34B)- 110.3 H(13I)-C(133)- 108.7 H(34H) H(13J) C(34B)-C(35B)- 111.1 C(34A)-C(133)- 110.8 H(35G) H(13G) C(34B)-C(35B)- 111.1 C(34A)-C(133)- 110.8 H(35H) H(13H) C(34B)-C(35B)- 103.2(17) C(34B)-C(133)- 110.5 C(136) H(13I) H(35G)-C(35B)- 109.1 C(34B)-C(133)- 110.5 H(35H) H(13J) C(136)-C(35B)- 111.1 C(133)-C(34A)- 111.9 H(35G) H(34E) C(136)-C(35B)- 111.1 C(133)-C(34A)- 111.9 H(35H) H(34F) O(14)-C(136)- 104.1(5) C(133)-C(34A)- 99.5(7) C(35A) C(35A) O(14)-C(136)- 108.0(10) H(34E)-C(34A)- 109.6 C(35B) H(34F) O(14)-C(136)- 110.9 C(35A)-C(34A)- 111.9 H(13K) H(34E) O(14)-C(136)- 110.9 C(35A)-C(34A)- 111.9 H(13L) H(34F) O(14)-C(136)- 110.1 C(34A)-C(35A)- 111.4 H(13M) H(35E) O(14)-C(136)- 110.1 C(34A)-C(35A)- 111.4 H(13N) H(35F) C(35A)-C(136)- 110.9 C(34A)-C(35A)- 102.0(7) H(13K) C(136) C(35A)-C(136)- 110.9 H(35E)-C(35A)- 109.2 H(13L) H(35F) C(35B)-C(136)- 110.1 C(136)-C(35A)- 111.4 H(13M) H(35E) C(35B)-C(136)- 110.1 C(136)-C(35A)- 111.4 H(13N) H(35F) H(13K)-C(136)- 109.0 C(133)-C(34B)- 110.3 H(13L) H(34G) H(13M)-C(136)- 108.4 C(133)-C(34B)- 110.3 H(13N) H(34H) O(21)-Al(2)-N(21) 91.09(12)

251

O(21)-Al(2)-N(22) 173.46(12) H(205) O(21)-Al(2)-O(23) 90.89(11) C(204)-C(205)- 119.1(3) O(21)-Al(2)-O(24) 92.08(11) C(206) O(22)-Al(2)-O(21) 94.99(11) C(206)-C(205)- 120.4 O(22)-Al(2)-N(21) 173.91(12) H(205) O(22)-Al(2)-N(22) 91.52(11) C(201)-C(206)- 122.5(3) O(22)-Al(2)-O(23) 92.44(11) C(207) O(22)-Al(2)-O(24) 91.81(11) C(205)-C(206)- 120.6(3) N(21)-Al(2)-N(22) 82.39(12) C(201) N(21)-Al(2)-O(23) 87.10(12) C(205)-C(206)- 116.8(3) N(21)-Al(2)-O(24) 88.32(12) C(207) N(22)-Al(2)-O(23) 88.16(11) N(21)-C(207)-C(206) 124.9(3) N(22)-Al(2)-O(24) 88.38(12) N(21)-C(207)- 117.5 O(23)-Al(2)-O(24) 174.59(11) H(207) C(201)-O(21)-Al(2) 133.9(2) C(206)-C(207)- 117.5 C(220)-O(22)-Al(2) 134.1(2) H(207) C(207)-N(21)-Al(2) 125.9(2) N(21)-C(208)- 104.9 C(207)-N(21)-C(208) 120.7(3) H(208) C(208)-N(21)-Al(2) 113.0(2) N(21)-C(208)-C(209) 116.8(3) C(213)-N(22)-Al(2) 113.2(2) C(209)-C(208)- 104.9 C(214)-N(22)-Al(2) 125.3(2) H(208) C(214)-N(22)-C(213) 121.4(3) C(213)-C(208)-N(21) 109.4(4) O(21)-C(201)-C(202) 119.9(3) C(213)-C(208)- 104.9 O(21)-C(201)-C(206) 120.7(3) H(208) C(206)-C(201)- 119.4(3) C(213)-C(208)- 114.6(4) C(202) C(209) C(201)-C(202)- 120.8(3) C(208)-C(209)- 109.6 C(225) H(20A) C(203)-C(202)- 117.9(3) C(208)-C(209)- 109.6 C(201) H(20B) C(203)-C(202)- 121.3(3) H(20A)-C(209)- 108.1 C(225) H(20B) C(202)-C(203)- 119.1 C(210)-C(209)- 110.2(3) H(203) C(208) C(202)-C(203)- 121.9(3) C(210)-C(209)- 109.6 C(204) H(20A) C(204)-C(203)- 119.1 C(210)-C(209)- 109.6 H(203) H(20B) C(203)-C(204)- 119.3(3) C(209)-C(210)- 108.2 Cl(21) H(21A) C(205)-C(204)- 119.7(3) C(209)-C(210)- 108.2 Cl(21) H(21B) C(205)-C(204)- 121.0(3) H(21A)-C(210)- 107.4 C(203) H(21B) C(204)-C(205)- 120.4 C(211)-C(210)- 116.2(4)

252

C(209) C(214) C(211)-C(210)- 108.2 C(216)-C(215)- 120.9(3) H(21A) C(220) C(211)-C(210)- 108.2 C(220)-C(215)- 122.0(3) H(21B) C(214) C(210)-C(211)- 107.8 C(215)-C(216)- 120.7 H(21C) H(216) C(210)-C(211)- 107.8 C(217)-C(216)- 118.6(3) H(21D) C(215) C(210)-C(211)- 118.2(4) C(217)-C(216)- 120.7 C(212) H(216) H(21C)-C(211)- 107.1 C(216)-C(217)- 120.1(3) H(21D) Cl(22) C(212)-C(211)- 107.8 C(216)-C(217)- 121.5(3) H(21C) C(218) C(212)-C(211)- 107.8 C(218)-C(217)- 118.4(3) H(21D) Cl(22) C(211)-C(212)- 109.2 C(217)-C(218)- 119.2 H(21E) H(218) C(211)-C(212)- 109.2 C(219)-C(218)- 121.6(3) H(21F) C(217) H(21E)-C(212)- 107.9 C(219)-C(218)- 119.2 H(21F) H(218) C(213)-C(212)- 111.9(3) C(218)-C(219)- 118.3(3) C(211) C(220) C(213)-C(212)- 109.2 C(218)-C(219)- 120.6(3) H(21E) C(221) C(213)-C(212)- 109.2 C(220)-C(219)- 121.2(3) H(21F) C(221) N(22)-C(213)-C(212) 118.5(3) O(22)-C(220)-C(215) 121.1(3) N(22)-C(213)- 102.5 O(22)-C(220)-C(219) 119.9(3) H(213) C(215)-C(220)- 119.0(3) C(208)-C(213)-N(22) 111.1(3) C(219) C(208)-C(213)- 116.6(4) C(222)-C(221)- 110.9(3) C(212) C(219) C(208)-C(213)- 102.5 C(223)-C(221)- 108.3(3) H(213) C(219) C(212)-C(213)- 102.5 C(223)-C(221)- 110.6(3) H(213) C(222) N(22)-C(214)- 117.2 C(223)-C(221)- 108.3(3) H(214) C(224) N(22)-C(214)-C(215) 125.6(3) C(224)-C(221)- 111.6(3) C(215)-C(214)- 117.2 C(219) H(214) C(224)-C(221)- 107.1(3) C(216)-C(215)- 117.1(3) C(222)

253

C(221)-C(222)- 109.5 C(226) H(22A) C(227)-C(225)- 107.5(3) C(221)-C(222)- 109.5 C(228) H(22B) C(225)-C(226)- 109.5 C(221)-C(222)- 109.5 H(22J) H(22C) C(225)-C(226)- 109.5 H(22A)-C(222)- 109.5 H(22K) H(22B) C(225)-C(226)- 109.5 H(22A)-C(222)- 109.5 H(22L) H(22C) H(22J)-C(226)- 109.5 H(22B)-C(222)- 109.5 H(22K) H(22C) H(22J)-C(226)- 109.5 C(221)-C(223)- 109.5 H(22L) H(22D) H(22K)-C(226)- 109.5 C(221)-C(223)- 109.5 H(22L) H(22E) C(225)-C(227)- 109.5 C(221)-C(223)- 109.5 H(22M) H(22F) C(225)-C(227)- 109.5 H(22D)-C(223)- 109.5 H(22N) H(22E) C(225)-C(227)- 109.5 H(22D)-C(223)- 109.5 H(22O) H(22F) H(22M)-C(227)- 109.5 H(22E)-C(223)- 109.5 H(22N) H(22F) H(22M)-C(227)- 109.5 C(221)-C(224)- 109.5 H(22O) H(22G) H(22N)-C(227)- 109.5 C(221)-C(224)- 109.5 H(22O) H(22H) C(225)-C(228)- 109.5 C(221)-C(224)- 109.5 H(22P) H(22I) C(225)-C(228)- 109.5 H(22G)-C(224)- 109.5 H(22Q) H(22H) C(225)-C(228)- 109.5 H(22G)-C(224)- 109.5 H(22R) H(22I) H(22P)-C(228)- 109.5 H(22H)-C(224)- 109.5 H(22Q) H(22I) H(22P)-C(228)- 109.5 C(202)-C(225)- 112.0(3) H(22R) C(228) H(22Q)-C(228)- 109.5 C(226)-C(225)- 109.0(3) H(22R) C(202) C(229)-O(23)-Al(2) 124.64(19) C(226)-C(225)- 107.5(3) C(229)-O(23)-C(232) 108.7(3) C(228) C(232)-O(23)-Al(2) 125.2(2) C(227)-C(225)- 110.7(3) O(23)-C(229)- 110.7 C(202) H(22S) C(227)-C(225)- 110.1(3) O(23)-C(229)- 110.7

254

H(22T) C(229)-C(30D)- 109.4 O(23)-C(229)- 111.1 H(30C) H(22U) C(229)-C(30D)- 109.4 O(23)-C(229)- 111.1 H(30D) H(22V) H(30C)-C(30D)- 108.0 O(23)-C(229)- 105.4(6) H(30D) C(30C) C(31D)-C(30D)- 111(3) O(23)-C(229)- 103(2) C(229) C(30D) C(31D)-C(30D)- 109.4 H(22S)-C(229)- 108.8 H(30C) H(22T) C(31D)-C(30D)- 109.4 H(22U)-C(229)- 109.1 H(30D) H(22V) C(30D)-C(31D)- 111.1 C(30C)-C(229)- 110.7 H(31C) H(22S) C(30D)-C(31D)- 111.1 C(30C)-C(229)- 110.7 H(31D) H(22T) C(30D)-C(31D)- 103(2) C(30D)-C(229)- 111.1 C(232) H(22U) H(31C)-C(31D)- 109.0 C(30D)-C(229)- 111.1 H(31D) H(22V) C(232)-C(31D)- 111.1 C(229)-C(30C)- 111.7 H(31C) H(30A) C(232)-C(31D)- 111.1 C(229)-C(30C)- 111.7 H(31D) H(30B) O(23)-C(232)- 105.9(4) C(229)-C(30C)- 100.4(8) C(31C) C(31C) O(23)-C(232)- 106.7(10) H(30A)-C(30C)- 109.5 C(31D) H(30B) O(23)-C(232)- 110.6 C(31C)-C(30C)- 111.7 H(23A) H(30A) O(23)-C(232)- 110.6 C(31C)-C(30C)- 111.7 H(23B) H(30B) O(23)-C(232)- 110.4 C(30C)-C(31C)- 111.3 H(23C) H(31A) O(23)-C(232)- 110.4 C(30C)-C(31C)- 111.3 H(23D) H(31B) C(31C)-C(232)- 110.6 H(31A)-C(31C)- 109.2 H(23A) H(31B) C(31C)-C(232)- 110.6 C(232)-C(31C)- 102.2(7) H(23B) C(30C) C(31D)-C(232)- 110.4 C(232)-C(31C)- 111.3 H(23C) H(31A) C(31D)-C(232)- 110.4 C(232)-C(31C)- 111.3 H(23D) H(31B) H(23A)-C(232)- 108.7

255

H(23B) H(35B) H(23C)-C(232)- 108.6 H(35A)-C(35C)- 109.1 H(23D) H(35B) C(233)-O(24)-Al(2) 123.5(2) C(236)-C(35C)- 103(2) C(236)-O(24)-Al(2) 127.1(2) C(34C) C(236)-O(24)-C(233) 108.6(3) C(236)-C(35C)- 111.2 O(24)-C(233)- 111.6 H(35A) H(23E) C(236)-C(35C)- 111.2 O(24)-C(233)- 111.6 H(35B) H(23F) C(233)-C(34D)- 111.5 O(24)-C(233)- 110.5 H(34C) H(23G) C(233)-C(34D)- 111.5 O(24)-C(233)- 110.5 H(34D) H(23H) C(233)-C(34D)- 101.4(9) O(24)-C(233)- 100.9(17) C(35D) C(34C) H(34C)-C(34D)- 109.3 O(24)-C(233)- 106.1(7) H(34D) C(34D) C(35D)-C(34D)- 111.5 H(23E)-C(233)- 109.4 H(34C) H(23F) C(35D)-C(34D)- 111.5 H(23G)-C(233)- 108.7 H(34D) H(23H) C(34D)-C(35D)- 110.7 C(34C)-C(233)- 111.6 H(35C) H(23E) C(34D)-C(35D)- 110.7 C(34C)-C(233)- 111.6 H(35D) H(23F) H(35C)-C(35D)- 108.8 C(34D)-C(233)- 110.5 H(35D) H(23G) C(236)-C(35D)- 105.0(8) C(34D)-C(233)- 110.5 C(34D) H(23H) C(236)-C(35D)- 110.7 C(233)-C(34C)- 110.1 H(35C) H(34A) C(236)-C(35D)- 110.7 C(233)-C(34C)- 110.1 H(35D) H(34B) O(24)-C(236)- 108.4(14) H(34A)-C(34C)- 108.5 C(35C) H(34B) O(24)-C(236)- 105.7(6) C(35C)-C(34C)- 108(2) C(35D) C(233) O(24)-C(236)-H(23I) 110.0 C(35C)-C(34C)- 110.1 O(24)-C(236)-H(23J) 110.0 H(34A) O(24)-C(236)- 110.6 C(35C)-C(34C)- 110.1 H(23K) H(34B) O(24)-C(236)- 110.6 C(34C)-C(35C)- 111.2 H(23L) H(35A) C(35C)-C(236)- 110.0 C(34C)-C(35C)- 111.2 H(23I)

256

C(35C)-C(236)- 110.0 O(6A)-C(6A)- 178.9(9) H(23J) Mn(2A) C(35D)-C(236)- 110.6 O(7A)-C(7A)- 178.1(9) H(23K) Mn(2A) C(35D)-C(236)- 110.6 O(8A)-C(8A)- 179.6(16) H(23L) Mn(2A) H(23I)-C(236)- 108.4 O(9A)-C(9A)- 175.7(19) H(23J) Mn(2A) H(23K)-C(236)- 108.7 O(10A)-C(10A)- 177.9(11) H(23L) Mn(2A) C(2)-Mn(1)-C(1) 173.21(17) C(7B)-Mn(2B)- 171.0(9) C(3)-Mn(1)-C(1) 89.91(17) C(6B) C(3)-Mn(1)-C(2) 94.73(18) C(8B)-Mn(2B)- 88.1(9) C(4)-Mn(1)-C(1) 91.6(2) C(6B) C(4)-Mn(1)-C(2) 91.1(2) C(8B)-Mn(2B)- 88.0(5) C(4)-Mn(1)-C(3) 113.0(2) C(7B) C(4)-Mn(1)-C(5) 124.5(2) C(9B)-Mn(2B)- 89.3(9) C(5)-Mn(1)-C(1) 89.95(17) C(6B) C(5)-Mn(1)-C(2) 83.39(17) C(9B)-Mn(2B)- 87.2(5) C(5)-Mn(1)-C(3) 122.39(18) C(7B) O(1)-C(1)-Mn(1) 179.3(4) C(9B)-Mn(2B)- 131.0(5) O(2)-C(2)-Mn(1) 176.2(3) C(8B) O(3)-C(3)-Mn(1) 178.1(4) C(10B)-Mn(2B)- 92.8(9) O(4)-C(4)-Mn(1) 179.5(5) C(6B) O(5)-C(5)-Mn(1) 177.1(4) C(10B)-Mn(2B)- 96.1(7) C(7A)-Mn(2A)- 172.8(4) C(7B) C(6A) C(10B)-Mn(2B)- 114.2(7) C(8A)-Mn(2A)- 92.9(5) C(8B) C(6A) C(10B)-Mn(2B)- 114.8(7) C(8A)-Mn(2A)- 94.2(5) C(9B) C(7A) O(6B)-C(6B)- 173.7(19) C(8A)-Mn(2A)- 117.1(9) Mn(2B) C(9A) O(7B)-C(7B)- 179.2(12) C(8A)-Mn(2A)- 116.3(6) Mn(2B) C(10A) O(8B)-C(8B)- 178.1(9) C(9A)-Mn(2A)- 88.3(8) Mn(2B) C(6A) O(9B)-C(9B)- 178.3(10) C(9A)-Mn(2A)- 88.9(9) Mn(2B) C(7A) O(10B)-C(10B)- 177.7(19) C(9A)-Mn(2A)- 126.7(8) Mn(2B) C(10A) C(4S)-O(1S)-C(1S) 104.4(4) C(10A)-Mn(2A)- 88.9(5) O(1S)-C(1S)-H(1SA) 110.9 C(6A) O(1S)-C(1S)-H(1SB) 110.9 C(10A)-Mn(2A)- 87.5(5) O(1S)-C(1S)-C(2S) 104.1(5) C(7A) H(1SA)-C(1S)- 109.0

257

H(1SB) C(8S)-C(7S)-H(7SB) 109.7 C(2S)-C(1S)-H(1SA) 110.9 O(2S)-C(8S)-H(8SA) 111.3 C(2S)-C(1S)-H(1SB) 110.9 O(2S)-C(8S)-H(8SB) 111.3 C(1S)-C(2S)-H(2SA) 110.7 C(7S)-C(8S)-O(2S) 102.4(5) C(1S)-C(2S)-H(2SB) 110.7 C(7S)-C(8S)-H(8SA) 111.3 H(2SA)-C(2S)- 108.8 C(7S)-C(8S)-H(8SB) 111.3 H(2SB) H(8SA)-C(8S)- 109.2 C(3S)-C(2S)-C(1S) 105.2(5) H(8SB) C(3S)-C(2S)-H(2SA) 110.7 C(9S)-O(3S)-C(12S) 105.8(5) C(3S)-C(2S)-H(2SB) 110.7 O(3S)-C(9S)-H(9SA) 110.3 C(2S)-C(3S)-H(3SA) 111.1 O(3S)-C(9S)-H(9SB) 110.3 C(2S)-C(3S)-H(3SB) 111.1 O(3S)-C(9S)-C(10S) 107.3(5) C(2S)-C(3S)-C(4S) 103.1(5) H(9SA)-C(9S)- 108.5 H(3SA)-C(3S)- 109.1 H(9SB) H(3SB) C(10S)-C(9S)- 110.3 C(4S)-C(3S)-H(3SA) 111.1 H(9SA) C(4S)-C(3S)-H(3SB) 111.1 C(10S)-C(9S)- 110.3 O(1S)-C(4S)-C(3S) 105.1(5) H(9SB) O(1S)-C(4S)-H(4SA) 110.7 O(3S)-C(12S)- 110.7 O(1S)-C(4S)-H(4SB) 110.7 H(12U) C(3S)-C(4S)-H(4SA) 110.7 O(3S)-C(12S)- 110.7 C(3S)-C(4S)-H(4SB) 110.7 H(12V) H(4SA)-C(4S)- 108.8 O(3S)-C(12S)- 105.2(5) H(4SB) C(11S) C(5S)-O(2S)-C(8S) 99.2(5) H(12U)-C(12S)- 108.8 O(2S)-C(5S)-H(5SA) 109.1 H(12V) O(2S)-C(5S)-H(5SB) 109.1 C(11S)-C(12S)- 110.7 H(5SA)-C(5S)- 107.8 H(12U) H(5SB) C(11S)-C(12S)- 110.7 C(6S)-C(5S)-O(2S) 112.6(6) H(12V) C(6S)-C(5S)-H(5SA) 109.1 C(9S)-C(10S)- 111.0 C(6S)-C(5S)-H(5SB) 109.1 H(10C) C(5S)-C(6S)-H(6SA) 110.0 C(9S)-C(10S)- 111.0 C(5S)-C(6S)-H(6SB) 110.0 H(10D) H(6SA)-C(6S)- 108.4 C(9S)-C(10S)- 103.6(5) H(6SB) C(11S) C(7S)-C(6S)-C(5S) 108.3(6) H(10C)-C(10S)- 109.0 C(7S)-C(6S)-H(6SA) 110.0 H(10D) C(7S)-C(6S)-H(6SB) 110.0 C(11S)-C(10S)- 111.0 C(6S)-C(7S)-H(7SA) 109.7 H(10C) C(6S)-C(7S)-H(7SB) 109.7 C(11S)-C(10S)- 111.0 C(6S)-C(7S)-C(8S) 109.9(6) H(10D) H(7SA)-C(7S)- 108.2 C(12S)-C(11S)- 110.8 H(7SB) H(11G) C(8S)-C(7S)-H(7SA) 109.7 C(12S)-C(11S)- 110.8

258

H(11H) H(11H) C(10S)-C(11S)- 104.8(5) H(11G)-C(11S)- 108.9 C(12S) H(11H) C(10S)-C(11S)- 110.8 Symmetry transformations used to H(11G) generate equivalent atoms. C(10S)-C(11S)- 110.8

Table 5.9 Anisotropic displacement parameters (Å2x103) for 3b. The anisotropic displacement factor exponent takes the form: −2π2[h2 a*2U11+ ... + 2 h k a* b* U12]

U11 U22 U33 U23 U13 U12 Cl(11) 35(1) 14(1) 32(1) −1(1) −2(1) 10(1) Cl(12) 29(1) 15(1) 31(1) 4(1) 5(1) 9(1) Al(1) 15(1) 12(1) 16(1) 0(1) 1(1) 2(1) O(11) 20(1) 12(1) 18(1) 0(1) 0(1) 4(1) O(12) 17(1) 11(1) 17(1) 0(1) 0(1) 3(1) N(11) 22(2) 17(1) 18(1) 1(1) 2(1) 4(1) N(12) 30(2) 19(1) 20(2) 0(1) 0(1) 7(1) C(101) 12(2) 12(2) 24(2) 0(1) 1(1) 1(1) C(102) 15(2) 16(2) 23(2) −1(1) −2(1) −3(1) C(103) 22(2) 15(2) 22(2) 1(1) −2(1) 1(1) C(104) 19(2) 10(2) 35(2) −1(1) −2(2) 2(1) C(105) 21(2) 15(2) 24(2) −5(1) 2(1) 2(1) C(106) 17(2) 13(2) 24(2) 0(1) −2(1) 1(1) C(107) 20(2) 20(2) 18(2) −3(1) 4(1) 2(1) C(108) 49(3) 35(2) 24(2) 6(2) 7(2) 17(2) C(109) 33(2) 24(2) 22(2) 0(1) 6(2) 6(2) C(110) 63(3) 49(3) 23(2) 5(2) 16(2) 25(2) C(111) 83(4) 48(3) 25(2) 3(2) 6(2) 21(3) C(112) 45(2) 23(2) 20(2) 1(1) 3(2) 12(2) C(113) 46(3) 34(2) 26(2) 2(2) 2(2) 10(2) C(114) 22(2) 21(2) 19(2) 4(1) 1(1) 5(1) C(115) 13(2) 15(2) 21(2) 1(1) 1(1) 0(1) C(116) 16(2) 16(2) 21(2) 5(1) 2(1) 1(1) C(117) 15(2) 13(2) 30(2) 5(1) 4(1) 3(1) C(118) 17(2) 14(2) 23(2) −1(1) 5(1) 2(1) C(119) 16(2) 13(2) 21(2) 0(1) 2(1) −1(1) C(120) 12(2) 12(1) 22(2) 0(1) 2(1) 0(1) C(121) 20(2) 16(2) 20(2) −1(1) 3(1) 1(1) C(122) 22(2) 21(2) 23(2) −2(1) −1(1) −2(1) C(123) 19(2) 24(2) 25(2) 5(1) 2(1) −4(1) C(124) 42(2) 27(2) 22(2) −1(2) 1(2) 12(2) C(125) 21(2) 15(2) 18(2) 0(1) −2(1) 0(1) C(126) 33(2) 22(2) 24(2) −4(1) 0(2) −6(2)

259

U11 U22 U33 U23 U13 U12 C(127) 22(2) 29(2) 24(2) −2(2) 2(2) 6(2) C(128) 37(2) 23(2) 22(2) 3(1) 1(2) 7(2) O(13) 18(1) 11(1) 27(1) −2(1) 1(1) 2(1) C(129) 16(2) 19(2) 38(2) 3(2) 0(2) 3(1) C(130) 21(2) 28(2) 34(2) 1(2) −4(2) −3(2) C(131) 22(2) 21(2) 36(2) −4(2) 4(2) −2(1) C(132) 25(2) 12(2) 31(2) −1(1) 2(2) 0(1) O(14) 18(1) 19(1) 24(1) −5(1) 1(1) −1(1) C(133) 23(2) 20(2) 68(3) −8(2) 7(2) −5(2) C(34A) 27(4) 20(4) 49(5) −9(4) 3(3) −5(3) C(35A) 19(4) 28(4) 48(5) −8(3) 3(3) −1(3) C(34B) 30(7) 38(8) 104(19) 11(11) −3(10) −12(6) C(35B) 26(7) 45(9) 110(19) −12(11) −17(11) −2(6) C(136) 17(2) 28(2) 50(2) −9(2) 3(2) 0(2) Cl(21) 42(1) 15(1) 37(1) −4(1) 13(1) −12(1) Cl(22) 31(1) 15(1) 32(1) 4(1) −4(1) −10(1) Al(2) 17(1) 11(1) 13(1) 0(1) 0(1) −2(1) O(21) 23(1) 11(1) 15(1) 0(1) 0(1) −4(1) O(22) 16(1) 12(1) 16(1) 0(1) 0(1) −4(1) N(21) 33(2) 18(1) 15(1) −1(1) 0(1) −8(1) N(22) 20(2) 16(1) 15(1) −1(1) −1(1) −2(1) C(201) 12(2) 13(1) 20(2) −1(1) −2(1) 1(1) C(202) 14(2) 14(2) 21(2) −1(1) 0(1) 3(1) C(203) 21(2) 16(2) 24(2) 1(1) 6(1) −1(1) C(204) 23(2) 12(2) 30(2) −2(1) 5(2) −5(1) C(205) 20(2) 16(2) 24(2) −6(1) 3(1) −5(1) C(206) 19(2) 13(2) 18(2) −1(1) 0(1) −2(1) C(207) 29(2) 19(2) 15(2) −5(1) −1(1) −4(1) C(208) 95(4) 42(3) 17(2) 1(2) 4(2) −37(3) C(209) 40(2) 22(2) 18(2) −5(1) −2(2) −8(2) C(210) 127(6) 56(3) 18(2) −6(2) 0(3) −45(4) C(211) 81(4) 45(3) 14(2) −3(2) 3(2) −26(3) C(212) 58(3) 26(2) 16(2) −1(1) 4(2) −13(2) C(213) 72(3) 36(2) 15(2) −2(2) 0(2) −27(2) C(214) 21(2) 19(2) 16(2) 3(1) 4(1) 2(1) C(215) 19(2) 14(2) 19(2) 0(1) 0(1) −3(1) C(216) 23(2) 17(2) 21(2) 4(1) 1(1) −2(1) C(217) 22(2) 9(2) 30(2) 3(1) −3(2) −3(1) C(218) 20(2) 14(2) 22(2) −1(1) −7(1) 0(1) C(219) 16(2) 12(2) 19(2) 1(1) −3(1) 1(1) C(220) 14(2) 12(1) 20(2) 1(1) 0(1) 0(1) C(221) 20(2) 14(2) 17(2) −3(1) 2(1) −2(1) C(222) 21(2) 25(2) 19(2) −6(1) 4(1) −3(1) C(223) 30(2) 18(2) 18(2) 1(1) −5(1) 2(1)

260

U11 U22 U33 U23 U13 U12 C(224) 30(2) 18(2) 23(2) −4(1) −4(2) −3(1) C(225) 22(2) 21(2) 15(2) 1(1) 1(1) −2(1) C(226) 28(2) 27(2) 26(2) −8(2) 0(2) 3(2) C(227) 25(2) 28(2) 22(2) 2(1) −6(2) −5(2) C(228) 45(3) 31(2) 17(2) 3(2) 4(2) −13(2) O(23) 17(1) 12(1) 24(1) 2(1) 1(1) −2(1) C(229) 16(2) 20(2) 43(2) 6(2) 0(2) −4(1) C(30C) 24(3) 23(3) 79(8) 12(4) 21(5) 2(2) C(31C) 28(3) 20(2) 49(5) 10(3) 1(3) 1(2) C(30D) 23(8) 35(9) 38(16) 17(10) −4(10) 9(7) C(31D) 35(9) 16(7) 33(14) 11(9) 10(9) 12(6) C(232) 25(2) 13(2) 45(2) 5(2) 1(2) 1(1) O(24) 19(1) 14(1) 28(1) −1(1) 1(1) −1(1) C(233) 18(2) 23(2) 46(2) −4(2) −1(2) −1(1) C(34C) 16(9) 26(9) 48(18) −6(9) 10(11) −1(6) C(35C) 21(8) 22(8) 80(20) −11(14) 4(11) 4(6) C(34D) 27(4) 27(3) 52(8) −5(4) 0(4) 5(3) C(35D) 31(3) 24(3) 64(7) 3(4) 5(3) 5(3) C(236) 29(2) 13(2) 85(4) 2(2) 3(2) 4(2) Mn(1) 22(1) 29(1) 18(1) 1(1) −1(1) 2(1) O(1) 39(2) 45(2) 33(2) −1(1) −8(1) −7(1) O(2) 31(2) 43(2) 30(2) −4(1) 1(1) −5(1) O(3) 42(2) 38(2) 31(2) 8(1) −2(1) 4(1) O(4) 41(2) 99(3) 62(2) −28(2) −2(2) 28(2) O(5) 38(2) 58(2) 23(2) 9(1) 1(1) −8(2) C(1) 26(2) 32(2) 24(2) 6(2) −1(2) 3(2) C(2) 22(2) 35(2) 22(2) 3(2) 2(2) 3(2) C(3) 26(2) 36(2) 23(2) 2(2) −2(2) 2(2) C(4) 31(2) 51(3) 38(2) −8(2) −3(2) 11(2) C(5) 29(2) 33(2) 22(2) 2(2) −4(2) −1(2) Mn(2A) 52(1) 24(1) 24(1) −1(1) −9(1) 8(1) O(6A) 63(5) 26(3) 95(6) −10(3) 4(4) 10(3) O(7A) 90(6) 32(3) 90(6) 0(3) −20(5) 20(3) O(8A) 72(6) 36(4) 41(6) −10(5) −27(6) 13(4) O(9A) 54(5) 36(4) 57(7) 8(5) −12(4) 12(3) O(10A) 95(8) 62(5) 41(4) 15(4) 10(4) 0(5) C(6A) 44(5) 32(4) 44(5) −8(3) −4(4) −3(3) C(7A) 55(6) 29(4) 45(5) −1(3) −14(4) 7(3) C(8A) 49(6) 28(5) 30(6) −5(5) −16(5) 11(4) C(9A) 53(6) 30(5) 25(7) −4(4) −18(6) 10(5) C(10A) 66(8) 42(5) 28(4) 2(3) −7(5) −5(5) Mn(2B) 27(1) 28(1) 28(1) −6(1) −8(1) 6(1) O(6B) 46(7) 56(8) 50(9) 24(7) 22(6) 17(5) O(7B) 51(5) 36(4) 73(6) −3(4) 11(5) −7(4)

261

U11 U22 U33 U23 U13 U12 O(8B) 50(5) 34(4) 66(5) −13(3) 18(4) −1(3) O(9B) 41(5) 41(4) 80(6) 7(4) −5(4) 9(3) O(10B) 84(9) 66(8) 46(8) −22(9) −28(9) 29(7) C(6B) 37(6) 45(10) 18(8) 11(7) −1(6) 21(5) C(7B) 31(5) 25(5) 46(7) −4(4) −10(5) −1(4) C(8B) 30(5) 31(4) 44(6) −6(4) 6(4) −4(4) C(9B) 30(5) 33(4) 50(6) 3(4) 4(4) 1(4) C(10B) 53(8) 36(6) 38(7) −9(7) −12(6) 12(5) O(1S) 52(3) 140(4) 53(2) 29(3) −18(2) −25(3) C(1S) 54(4) 70(4) 83(4) 29(3) −11(3) −10(3) C(2S) 39(3) 54(3) 42(3) 7(2) −11(2) −6(2) C(3S) 42(3) 60(3) 76(4) −5(3) 10(3) −12(3) C(4S) 40(3) 150(7) 57(3) −30(4) 3(3) −32(4) O(2S) 112(4) 75(3) 110(4) −13(3) 15(3) 1(3) C(5S) 56(3) 39(3) 93(4) −3(3) −14(3) 14(2) C(6S) 101(6) 85(5) 100(5) −51(4) 62(5) −44(4) C(7S) 67(4) 97(5) 95(5) 30(4) 22(4) 38(4) C(8S) 99(5) 43(3) 99(5) −23(3) -47(4) 17(3) O(3S) 66(3) 98(3) 61(2) −35(2) 29(2) −32(2) C(9S) 65(4) 112(6) 66(4) −42(4) 12(3) −33(4) C(12S) 79(5) 78(4) 118(6) −59(4) 55(4) −43(4) C(10S) 136(7) 64(4) 59(4) −19(3) 14(4) −44(4) C(11S) 122(7) 95(5) 64(4) −38(4) 48(4) −55(5)

Table 5.10 Hydrogen coordinates (x104) and isotropic displacement parameters (Å2x103) for 3b

x y z U(eq) H(103) 9757 4291 7757 23 H(105) 9941 4356 6224 24 H(107) 9562 5176 5760 23 H(108) 9424 6445 5523 43 H(10A) 8944 5473 4975 32 H(10B) 9882 5686 5066 32 H(11A) 9688 6458 4545 54 H(11B) 9338 5937 4236 54 H(11C) 7977 6187 4398 62 H(11D) 8451 6719 4175 62 H(11E) 7575 6965 4889 35 H(11F) 8531 7134 4985 35 H(113) 7724 6146 5377 42 H(114) 7385 7345 5616 25

262

x y z U(eq) H(116) 6724 8135 6000 21 H(118) 6684 8334 7524 22 H(12A) 8546 6936 7704 33 H(12B) 8505 7123 8282 33 H(12C) 8741 7568 7857 33 H(12D) 6304 6965 7973 34 H(12E) 7033 6719 8320 34 H(12F) 7009 6575 7732 34 H(12G) 7546 8184 8205 46 H(12H) 7392 7704 8612 46 H(12I) 6634 7921 8271 46 H(12J) 10291 5703 8068 39 H(12K) 9576 6029 8369 39 H(12L) 9634 6082 7770 39 H(12M) 8052 5772 7766 37 H(12N) 8081 5688 8363 37 H(12O) 7806 5184 8007 37 H(12P) 8943 4577 8415 41 H(12Q) 9145 5100 8767 41 H(12R) 9878 4809 8453 41 H(12S) 10621 6494 6310 29 H(12T) 10303 6176 6809 29 H(13A) 11345 6959 6935 33 H(13B) 10556 6944 7312 33 H(13C) 10722 7630 6424 31 H(13D) 10436 7835 6976 31 H(13E) 9114 7512 6873 27 H(13F) 9323 7566 6283 27 H(13G) 7461 4984 6655 44 H(13H) 7667 5076 6068 44 H(13I) 7661 4991 6589 44 H(13J) 7475 5096 6002 44 H(34E) 6217 4685 6270 39 H(34F) 6241 5187 5866 39 H(35E) 5978 5315 6948 38 H(35F) 5355 5539 6516 38 H(34G) 6183 4761 6168 69 H(34H) 6295 4849 6764 69 H(35G) 5375 5547 6638 73 H(35H) 5641 5622 6057 73 H(13K) 6263 6250 6281 38 H(13L) 6479 6223 6873 38 H(13M) 6364 6357 6367 38 H(13N) 6432 6088 6919 38

263

x y z U(eq) H(203) 4858 8258 7349 24 H(205) 4868 8300 8886 24 H(207) 4391 7525 9377 25 H(208) 4277 6348 9717 62 H(20A) 4427 7196 10125 32 H(20B) 3435 7295 10130 32 H(21A) 4351 6494 10708 81 H(21B) 3740 6962 10923 81 H(21C) 2615 6475 10772 56 H(21D) 3264 6024 10971 56 H(21E) 3336 5583 10223 40 H(21F) 2373 5763 10245 40 H(213) 2575 6494 9742 49 H(214) 2332 5295 9538 23 H(216) 1670 4504 9154 24 H(218) 1709 4276 7629 23 H(22A) 3835 4987 7376 32 H(22B) 3648 5632 7473 32 H(22C) 3675 5396 6911 32 H(22D) 2114 6000 7394 32 H(22E) 1442 5611 7120 32 H(22F) 2224 5850 6812 32 H(22G) 2554 4839 6556 35 H(22H) 1775 4634 6885 35 H(22I) 2683 4376 6983 35 H(22J) 4674 6497 6802 40 H(22K) 4628 6449 7401 40 H(22L) 5358 6803 7143 40 H(22M) 3180 6872 6766 37 H(22N) 2924 7393 7108 37 H(22O) 3121 6805 7364 37 H(22P) 5032 7693 6682 47 H(22Q) 4100 7935 6673 47 H(22R) 4324 7386 6359 47 H(22S) 5507 6241 8989 32 H(22T) 5291 6462 8432 32 H(22U) 5448 6337 8963 32 H(22V) 5335 6384 8361 32 H(30A) 6428 5707 8518 50 H(30B) 5777 5648 8056 50 H(31A) 5556 4789 8503 39 H(31B) 5619 5096 9042 39 H(30C) 6259 5690 8315 38 H(30D) 6151 5540 8899 38

264

x y z U(eq) H(31C) 5581 4794 8600 34 H(31D) 5318 5092 8080 34 H(23A) 4250 5132 8349 33 H(23B) 4197 5095 8952 33 H(23C) 4049 5119 8449 33 H(23D) 4438 5103 9006 33 H(23E) 1348 6207 8688 35 H(23F) 1329 6548 8165 35 H(23G) 1311 6251 8749 35 H(23H) 1392 6458 8175 35 H(34A) 309 7023 8609 36 H(34B) 785 6937 9136 36 H(35A) 1093 7774 8401 51 H(35B) 1186 7828 9003 51 H(34C) 630 7054 8996 42 H(34D) 299 7018 8423 42 H(35C) 1306 7639 8136 47 H(35D) 1114 7900 8683 47 H(23I) 2457 7596 8364 51 H(23J) 2518 7568 8966 51 H(23K) 2624 7604 8443 51 H(23L) 2310 7560 9017 51 H(1SA) 5317 5988 4941 83 H(1SB) 6305 5968 4825 83 H(2SA) 6257 6758 4344 54 H(2SB) 5283 6604 4284 54 H(3SA) 4948 7358 4731 71 H(3SB) 5925 7497 4813 71 H(4SA) 5623 7253 5633 99 H(4SB) 4865 6852 5467 99 H(5SA) 1742 8731 6667 75 H(5SB) 2399 8229 6651 75 H(6SA) 1338 8477 7364 114 H(6SB) 1984 7965 7343 114 H(7SA) 2840 8362 7813 104 H(7SB) 2060 8743 7971 104 H(8SA) 3409 9190 7625 96 H(8SB) 2513 9474 7514 96 H(9SA) 599 5409 9291 97 H(9SB) -69 5909 9311 97 H(12U) 237 6616 10097 110 H(12V) 980 6360 10434 110 H(10C) 158 5045 10029 104 H(10D) −709 5329 9856 104

265

x y z U(eq) H(11G) 183 5637 10679 112 H(11H) −602 5977 10457 112

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