Rhodium-Catalyzed Intermolecular Ketone Hydroacylation: Towards an Enantioselective and Diastereoselective Protocol

Lauren Elizabeth Longobardi

A thesis submitted in conformity with the requirements for the degree of Master of Science

Department of Chemistry University of Toronto

Lauren Elizabeth Longobardi

Master of Science

Department of Chemistry University of Toronto

2012

Abstract

The addition of an aldehyde C−H bond across a ketone functionality, formally a hydroacylation, has emerged as an atom-economical approach to the synthesis of esters.

While this is an efficient strategy for producing biologically-relevant materials, the field of transition metal-catalyzed ketone hydroacylation is currently limited to intramolecular systems.

The development of a new rhodium catalyst will be presented, and its application to intermolecular ketone hydroacylation will be discussed. Ester products were synthesized from unfunctionalized, aliphatic aldehydes and chelating ketones in excellent yields under relatively mild reaction conditions.

Efforts towards an asymmetric intermolecular ketone hydroacylation will be described, including the application of known chiral catalysts and the development of novel chiral phosphine ligands for asymmetric catalysis. Ester products were obtained in as high as 78% enantiomeric excess.

Acknowledgements

I am grateful to the Natural Sciences and Engineering Research Council of Canada for financially supporting my Master’s degree with a CGS-M scholarship. I would like to thank my supervisor, Prof. Vy M. Dong, for her encouragement and guidance over the past 12 months. She has continuously supported my project and my future career goals, and I am forever grateful to have had the opportunity to work with her. I want to acknowledge Mr. Wilmer Alkhas for helping to keep our lab running smoothly. On a more personal note, I would like to thank Wilmer for helping me to adjust to life in Toronto and for offering to help me out in any way possible. I am eternally grateful to my collaborator, Kevin G. M. Kou. He has helped me to learn from his wealth of knowledge and he has supported my creativity at every stage of this project, always with a smile on his face. Kevin, you’re an incredibly gifted chemist and a wonderful friend, and I will miss working with you. I need to acknowledge Christine M. Le, who has been an amazing lab mate, wonderful roommate, fierce competitor, and best friend to me for the past year. Thanks for all the love and laughs! To the rest of the Dong group: you’ve been amazing people to work with and I’ve thoroughly enjoyed getting to know each and every one of you. You’ve pushed me to learn and given me undying support, and I’m going to miss all of you. I wish you all the best of luck. Finally, I want to thank my parents, Paul Longobardi and Valerie Musgrave, my brother Patrick, and my aunt Mary, for always supporting my education and encouraging me to follow my dreams. When I think about family, you are the people who come to mind. Thanks for all the love and kindness, you mean the world to me.

iii

Table of Contents

Abstract ...... ii

Acknowledgements ...... iii

Table of Contents ...... iv

List of Tables ...... vii

List of Schemes ...... viii

List of Figures ...... x

List of Appendices ...... xi

List of Abbreviations ...... xii

Chapter 1: The Development of a Rhodium-Catalyzed Intermolecular Ketone

Hydroacylation ...... 1

1.1 Introduction ...... 1

1.1.1 The Discovery of Rhodium-Catalyzed Hydroacylation ...... 1

1.1.2 Intermolecular Hydroacylation and the Use of Chelating Substrates ...... 2

1.1.3 Aldehyde Hydroacylation ...... 4

1.1.4 Ketone Hydroacylation ...... 5

1.1.5 Challenges for an Intermolecular Ketone Hydroacylation ...... 8

1.1.6 Isolated Examples of Intermolecular Ketone Hydroacylation ...... 9

1.2 Research Goals ...... 10

1.3 Results and Discussion ...... 11

1.3.1 Isatin Synthesis ...... 11

1.3.2 Linear α–Ketoamide Synthesis ...... 11

1.3.3 Developing an Intermolecular Ketone Hydroacylation ...... 12

1.3.4 Catalysis at a Lower Rhodium Loading ...... 19

1.4 Conclusions and Future Work ...... 21

1.5 Experimental Procedures and Characterization Data ...... 21

1.5.1 General Considerations ...... 21

1.5.2 General Procedure for the Preparation of N-Substituted Isatins ...... 22

1.5.3 General Procedure for the Preparation of Linear α-Ketoamides ...... 22

1.5.4 General Procedure for Rhodium-Catalyzed Hydroacylation ...... 23

1.5.5 Characterization Data ...... 23

Chapter 2: Efforts Towards an Enantioselective and Diastereoselective Intermolecular

Ketone Hydroacylation ...... 34

2.1 Introduction ...... 34

2.1.1 Early Reports of Asymmetric Hydroacylation ...... 34

2.1.2 Recent Developments in Intermolecular Asymmetric Olefin Hydroacylation 35

2.1.3 Asymmetric Ketone Hydroacylation ...... 36

2.2 Research Goals ...... 37

2.3 Results and Discussion ...... 37

2.3.1 Enantioselective Rhodium-Catalyzed Intermolecular Ketone Hydroacylation

using Commercially Available Ligands ...... 37

2.3.2 Synthesis of Novel Bidentate Phosphine Ligands and Their Application to

Rhodium-Catalyzed Intermolecular Ketone Hydroacylation ...... 41

2.3.3 Efforts Towards a Diastereoselective Intermolecular Ketone Hydroacylation 46

2.4 Conclusions and Future Work ...... 50

2.5 Experimental Procedures and Characterization Data ...... 50

2.5.1 General Considerations ...... 50

2.5.2 General Procedure for Ditosylation of Diols ...... 51

2.5.3 General Procedure for the Preparation of Phosphine Ligands ...... 52

2.5.4 Procedure for the Preparation of Evans’ Auxiliary Substrate 2j ...... 52

2.5.5 General Procedure for Aldol Condensations ...... 53

2.5.6 General Procedure for Silyl-Protection of Alcohols ...... 53

2.5.7 Characterization Data ...... 54

Appendix A: NMR Spectra ...... 59

Appendix B: Chiral-SFC Traces ...... 84

List of Tables

Table 1.1: Achiral ligand screen for intermolecular isatin hydroacylation ...... 12

Table 1.2: Scope of isatins and linear α-ketoamides as hydroacylation substrates ...... 14

Table 1.3: Screen of aldehydes for intermolecular ketone hydroacylation ...... 16

Table 1.4: Screen of alternate directing groups for intermolecular ketone hydroacylation

...... 18

Table 1.5: Hydroacylation results at 5 mol% catalyst loading ...... 19

Table 2.1: Results for hydroacylation with [Rh(SL-J212)]BF4 ...... 39

Table 2.2: Results for hydroacylation with [Rh(BDPP)]BF4 ...... 40

Table 2.3: Results for hydroacylation of 2a using L1-4 as ligands ...... 44

Table 2.4: Results for hydroacylation of various ketone substrates using [Rh(L4)]BF4 .. 45

vii

List of Schemes

Scheme 1.1: Tsuji's report of decarbonylation using Wilkinson's complex ...... 1

Scheme 1.2: Suggs’ β-chelation strategy for the isolation of a stable rhodium-acyl species ...... 2

Scheme 1.3: Examples of transition metal-catalyzed inter- and intramolecular aldehyde hydroacylation ...... 5

Scheme 1.4: First example of a transition metal-catalyzed ketone hydroacylation, using a cationic Rh(I) source and (R)-DTBM-SEGPHOS ...... 6

Scheme 1.5: Proposed catalytic cycle for rhodium-catalyzed intramolecular ketone hydroacylation ...... 7

Scheme 1.6: Synthesis of benzoxazepinones and benzoxazecinones via rhodium- catalyzed intramolecular ketone hydroacylation ...... 7

Scheme 1.7: Synthesis of phthalides via rhodium-catalyzed intramolecular ketone hydroacylation ...... 8

Scheme 1.8: Competing hydroacylation and Tishchenko reaction pathways ...... 9

Scheme 1.9: Scheidt's NHC-catalyzed intermolecular ketone hydroacylation ...... 9

Scheme 1.10: Lu's NHC-catalyzed intermolecular ketone hydroacylation ...... 10

Scheme 1.11: Connon's intermolecular ketone hydroacylation ...... 10

Scheme 1.12: Procedure for the synthesis of N-substituted isatins ...... 11

Scheme 1.13: Synthesis of linear α-ketoamides ...... 11

Scheme 1.14: First generation conditions for rhodium-catalyzed intermolecular ketone hydroacylation ...... 13

viii

Scheme 2.1: Early enantioselective reports of 4-pentenal hydroacylation by Sakai and

Bosnich ...... 35

Scheme 2.2: Representative examples of stereoselective rhodium-catalyzed intermolecular olefin hydroacylation ...... 36

Scheme 2.3: Synthesis of P-chiral phosphine-borane ...... 42

Scheme 2.4: Syntheses of ligands L1-4 ...... 43

Scheme 2.5: Synthesis of α-ketoamide 2j ...... 46

Scheme 2.6: Synthesis of chiral substrates 2k and 2l ...... 47

Scheme 2.7: Synthesis of amino acid-derived 2m ...... 47

Scheme 2.8: Efforts towards the synthesis of a phenylpyruvic acid-derived chiral substrate ...... 48

Scheme 2.9: Synthesis of aldol product 2n and TMS protection yielding 2n’ ...... 49

Scheme 2.10: Synthesis of aldol product 2o and TBS protection yielding 2o’ ...... 49

List of Figures

Figure 1.1: Representative examples of chelation strategies for aldehyde substrates in intermolecular alkene/alkyne hydroacylation ...... 3

Figure 1.2: Representative examples of chelating alkenes for intermolecular olefin hydroacylation and their proposed binding to Rh(III) metal centres ...... 4

Figure 2.1: Josiphos ligand SL-J212 ...... 38

Figure 2.2: C2-symmetric BDPP ligand ...... 39

Figure 2.3: New ligand designs for ketone hydroacylation ...... 41

Figure 2.4: Chiral aldehyde 1l ...... 50

List of Appendices

Appendix A: NMR Spectra ...... 59

Appendix B: Chiral-SFC Traces ...... 84

List of Abbreviations

1H NMR proton NMR

13C NMR carbon-13 NMR

α alpha

δ chemical shift

µL microlitre

aq. aqueous

Ar aryl

BDPP (2S,4S)-(-)-2,4-Bis(diphenylphosphino)pentane

BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

Bn benzyl

br broad

C6D6 deuterated benzene

C7D8 deuterated toluene

Calcd. calculated

CDCl3 deuterated chloroform

COD 1,5-cyclooctadiene

conv. conversion

Cy cyclohexyl

d doublet

DABCO 1,4-diazabicyclo[2.2.2]octane

DBU 1,8-diazabicycloundec-7-ene

DCE 1,2-dichloroethane

xii

DCM dichloromethane

dcpe 1,2-bis(dicyclohexylphosphino)ethane

dcpp 1,3-bis(dicyclohexylphosphino)propane

dd doublet of doublets

DG directing group

DIPEA Di-iso-propylethylamine

DMF N,N-dimethylformamide

dppb 1,4-bis(diphenylphosphino)butane

dppe 1,2-bis(diphenylphosphino)ethane

dppf 1,1’-bis(diphenylphosphino)ferrocene

dppm bis(diphenylphosphino)methane

dppp 1,3-bis(diphenylphosphino)propane

dr diastereomeric ratio

ee enantiomeric excess

equiv. equivalents

ESI Electrospray Ionization

EtOAc ethyl acetate

g grams

GC-FID Gas chromatography-flame ionization detector

GC-MS Gas chromatography-mass spectrometry

h hours

HMDS hexamethyldisilazane

HRMS High Resolution Mass Spectrometry

xiii

Hz hertz

J coupling constant

LC-MS Liquid chromatography-mass spectrometry

LDA Lithium Di-iso-propylamide

M molarity

m multiplet mCPBA meta-chloroperbenzoic acid

Me methyl

MeOH methanol

mg milligram

MHz megahertz

min minutes

mL millilitre

mm millimetre

mmol millimole

nbd norbornadiene

nBu normal butyl

NHC N-heterocyclic carbene

nm nanometre

NMR Nuclear Magnetic Resonance

OAc acetate

OTf trifluoromethylsulfonate; triflate

OTMS trimethylsilyloxy

xiv

Ph phenyl

ppm parts per million

q quartet quant. quantitative recrys. recrystallize

rt room temperature

s singlet

sat. saturated

SFC Supercritical Fluid Chromatography

t triplet

TBS tert-butyldimethylsilyl temp. temperature

THF tetrahydrofuran

TLC thin layer chromatography

TMS tetramethylsilane

Chapter 1: The Development of a Rhodium-Catalyzed Intermolecular Ketone Hydroacylation 1.1 Introduction 1.1.1 The Discovery of Rhodium-Catalyzed Hydroacylation

Rhodium-catalyzed hydroacylation was inspired by an observation made by Tsuji in 1965. He reported that, upon treatment with a stoichiometric amount of Wilkinson’s complex, a variety of aldehydes undergo decarbonylation, producing a Rh−CO complex and the corresponding hydrocarbon (Scheme 1.1). 1 To rationalize this observed reactivity, he proposed that the aldehyde C−H bond underwent oxidative addition to the Rh(I) complex, followed by de-insertion of CO to the vacant cis coordination site on the metal. Subsequent reductive elimination of the hydrocarbon and hydride ligands generated the observed Rh−CO species. While not catalytic, this was the first report to recognize the oxidative addition of aldehyde C−H bonds across a Rh(I) centre.

O + [RhCl(PPh3)3] R H + [RhCl(CO)(PPh3)2] + PPh3 R H R = alkyl, aryl, vinyl Scheme 1.1: Tsuji's report of decarbonylation using Wilkinson's complex Since Tsuji’s decarbonylation experiments, there have been significant advancements in the field of hydroacylation. Sakai discovered that olefins could insert into acyl-rhodium-hydride species in an intramolecular fashion; using stoichiometric amounts of Wilkinson’s complex, he demonstrated the hydroacylation of 4-pentenals, generating cyclopentanones. 2 However, in addition to the cyclopentanone products, substantial amounts of cyclopropane byproducts were formed due to the competing decarbonylation reaction pathway. Following the work of Sakai, the hydroacylation of 4- pentenals was extensively explored,3 with Bosnich’s development of an achiral cationic

1 Tsuji, J.; Ono, K. Tetrahedron Lett. 1965, 6, 3969. 2 Sakai, K.; Ide, J.; Oda, O.; Nakamura, N. Tetrahedron Lett. 1972, 13, 1287. 3 Willis, M. C. Chem. Rev. 2010, 110, 725.

Rh(I) catalyst being a significant breakthrough.4 His highly reactive system allowed for catalyst loadings as low as 1 mol% rhodium and turnovers between 200 and 300. After the development of Bosnich’s catalyst, in 1992 Sakai reported the first highly enantioselective hydroacylation of 4-pentenals using a catalytic amount of his cationic Rh(I)-BINAP complex, isolating cyclopentanone products in >99% ee.5

1.1.2 Intermolecular Hydroacylation and the Use of Chelating Substrates

Recently, the field of olefin hydroacylation has expanded beyond 4-pentenal substrates to include studies on intermolecular systems. A frequently used approach to enable such a transformation has been the incorporation of chelating heteroatoms or π- systems into the starting materials.3 The purpose of the chelating substrate(s) is to occupy a vacant coordination site on the metal centre, promoting hydroacylation by suppressing decarbonylation. First demonstrated by Suggs,6 the use of β-chelating aldehydes was shown to be ideal for hydroacylation, seemingly because decarbonylation is disfavoured due to the four-membered rhodacycle that would ensue (Scheme 1.2).

PPh3 PPh3 N Cl benzene N Cl Rh Rh + PPh3 H reﬂux H PPh3 CO O Scheme 1.2: Suggs’ β-chelation strategy for the isolation of a stable rhodium-acyl species Inspired by Suggs’ strategy, there have been numerous reports on the use of β- chelating aldehydes for hydroacylation. Jun has used both phosphorus and nitrogen based chelating aldehydes,7 Breit has developed a bifunctional catalyst bearing both P- and N-

4 (a) Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 936. (b) Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 946. 5 (a) Fu, G. C. In Modern Rhodium-Catalyzed Reactions; Evans, P. A., Ed.; Wiley-VCH: New York, 2005; pp 79-91. (b) Wu, X. -M.; Funakoshi, K.; Sakai, K. Tetrahedron Lett. 1992, 33, 6331. 6 (a) Suggs, J. W. J. Am. Chem. Soc. 1978, 100, 640. (b) Suggs, J. W. J. Am. Chem. Soc. 1979, 101, 489. 7 (a) Lee, H.; Jun, C.-H. Bull. Korean Chem. Soc. 1995, 16, 66. (b) Lee, H.; Jun, C.-H. Bull. Korean Chem. Soc. 1995, 16, 1135. (c) Jun, C.-H.; Lee, D.-Y.; Lee, H.; Hong, J.-B. Angew. Chem. Int. Ed. 2000, 39, 3070.

donors,8 Willis has pioneered the use of sulfur-containing chelating aldehydes,9 and the groups of Miura, Bolm, Suemune, and Dong have employed oxygen-based chelation for intermolecular hydroacylation of alkenes and alkynes.10 Their respective catalyst systems are shown in Figure 1.1. While this strategy has been successful in achieving high yields and, in certain cases, high enantioselectivities of hydroacylation products, the need for a chelating aldehyde is an inherent limitation of these systems.

Me Me N Cl N N N N Rh O Ph2P Rh Rh Ph3P H R PPh H H R 3 Jun Suggs Breit

O O O

Rh H Rh H Rh H P S O Ph2 Me Miura, Suemune, Jun Willis Bolm, Dong Figure 1.1: Representative examples of chelation strategies for aldehyde substrates in intermolecular alkene/alkyne hydroacylation In addition to chelating aldehydes, there are several reports on the use of chelating olefins for intermolecular hydroacylation. Suemune and Bolm have used dienes as

8 Vautravers, N. R.; Regent, D. D.; Breit, B. Chem. Commun. 2011, 47, 6635. 9 For recent examples, see: (a) González-Rodríguez, C.; Pawley, R. J.; Chaplin, A. B.; Thompson, A. L.; Weller, A. S.; Willis, M. C. Angew. Chem. Int. Ed. 2011, 50,5134. (b) Lenden, P.; Entwistle, D. A.; Willis, M. C. Angew. Chem. Int. Ed. 2011, 50, 10657. (c) Poingdestre, S.-J.; Goodacre, J. D.; Weller, A. S.; Willis, M. C. Chem. Commun. 2012, 48, 6354. 10 (a) Kokubo, K.; Matsumasa, K.; Miura, M.; Nomura, M. J. Org. Chem. 1997, 62, 4564. (b) Kokubo, K.; Matsumasa, K.; Nishinaka, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1999, 72, 303. (c) Zhang, H.-J.; Bolm, C. Org. Lett. 2011, 13, 3900. (d) Tanaka, M.; Imai, M.; Yamamoto, Y.; Tanaka, K.; Shimowatari, M.; Nagumo, S.; Kawahara, N.; Suemune, H. Org. Lett. 2003, 5, 1365. (e) Phan, D. H. T.; Kou, K. G. M.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16354. (f) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16330. (g) Murphy, S. K.; Petrone, D. A.; Coulter, M. M.; Dong, V. M. Org. Lett. 2011, 13, 6216. (h) Murphy, S. K.; Coulter, M. M.; Dong, V. M. Chem. Sci. 2012, 3, 355.

substrates in combination with β-chelating aldehydes,11 Tanaka has used acrylamides with non-chelating aldehydes,12 Bolm has used enamides with chelating aldehydes,10c and Dong has used homo-allylic sulfides as well as allylic and homo-allylic phosphinites as hydroacylation substrates.10f-h Their respective systems are shown in Figure 1.2. Similar to chelating aldehydes, chelating olefins assist in promoting hydroacylation by occupying a vacant coordination site of the Rh(III) metal centre, suppressing decarbonylation. Despite these significant achievements in intermolecular olefin hydroacylation, the field is currently limited by the narrow scope of chelating substrates. O R O P O H H H Rh R1 P Rh Rh NR O O n R2 O O n = 0,1 PAr3 R1 NR3R3 Suemune, Bolm Tanaka Bolm

O O L Ph O O S Rh Rh H PPh 2 *PR3 H R O n Dong Dong n = 1,2 Figure 1.2: Representative examples of chelating alkenes for intermolecular olefin hydroacylation and their proposed binding to Rh(III) metal centres 1.1.3 Aldehyde Hydroacylation

Since Tsuji’s first report of the decarbonylation of aldehydes using Wilkinson’s complex, there has been a prominent focus on developing alkene and alkyne hydroacylation, however relatively few reports exist for the analogous reaction using substrates bearing carbonyl functionalities (Scheme 1.3). Bosnich reported the intramolecular aldehyde hydroacylation of butanedial using a cationic Rh(I) catalyst,

11 (a) see 10d. (b) Imai, M.; Tanaka, M.; Tanaka, K.; Yamamoto, Y.; Imai-Ogata, N.; Shimowatari, M.; Nagumo, S.; Kawahara, N.; Suemune, H. J. Org. Chem. 2004, 69, 1144. (c) Tanaka, K.; Tanaka, M.; Suemune, H. Tetrahedron Lett. 2005, 46, 6053. (d) Stemmler, R. T.; Bolm, C. Adv. Synth. Catal. 2007, 349, 1185. 12 (a) Tanaka, K.; Shibata, Y.; Suda, T.; Hagiwara, Y.; Hirano, M. Org. Lett. 2007, 9, 1215. (b) Shibata, Y.; Tanaka, K. J. Am. Chem. Soc. 2009, 131, 12552.

however analogous ketoaldehyde substrates were highly susceptible to decarbonylation, resulting in low yields of the desired lactone products. 13 Morimoto reported the intramolecular aldehyde hydroacylation of benzene-1,2-dicarboxaldehyde using a neutral Rh(I) catalyst,14 however only one substrate was presented and there was no mention of the catalyst’s activity in ketoaldehyde systems. Examples of intermolecular aldehyde hydroacylation include Yamamoto’s Ru(II)-catalyzed Tishchenko reaction 15 and Ogoshi’s Ni(0)-catalyzed homo- and crossed-Tishchenko reaction.16

Bosnich, Morimoto

O O + H [Rh(dcpe)S2] or [Rh(dppp)(COD)Cl] O S = acetone O H Yamamoto, Ogoshi

O RuH2(PPh3)4 O R H or R O R Ni(NHC) 2 equiv. Scheme 1.3: Examples of transition metal-catalyzed inter- and intramolecular aldehyde hydroacylation 1.1.4 Ketone Hydroacylation

Despite progress in catalyst development for aldehyde hydroacylation, until 200817 ketone hydroacylation remained a synthetic challenge as there were no improvements beyond Bosnich’s unsuccessful study on ketoaldehydes.13 Upon developing a chiral cationic Rh(I) catalyst, the Dong group reported the first high-yielding example of transition metal-catalyzed intramolecular ketone hydroacylation, using ketoaldehyde substrates to synthesize enantiopure lactones (Scheme 1.4). A key attribute to their substrates was the ether-oxygen, which was proposed to coordinate to the metal centre

13 Bergens, S. H.; Fairlie, D. P.; Bosnich, B. Organometallics 1990, 9, 566. 14 Fuji, K.; Morimoto, T.; Tsutsumi, K.; Kakiuchi, K. Chem. Commun. 2005, 3295. 15 (a) Horino, H.; Ito, T.; Yamamoto, A. Chem. Lett. 1978, 17. (b) Ozawa, F.; Yamagami, I.; Yamamoto, I. J. Organomet. Chem. 1994, 473, 265. 16 (a) Ogoshi, S.; Hoshimoto, Y.; Ohashi, M. Chem. Commun. 2010, 46, 3354. (b) Hoshimoto, Y.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2011, 133, 4668. 17 Shen, Z.; Khan, H. A. Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2916.

and suppress decarbonylation while promoting hydroacylation. The optimal ligand for this transformation was (R)-DTBM-SEGPHOS, a sterically demanding and moderately electron-rich bidentate phosphine.

O O O O PAr2 5 mol% [Rh(L)]BF4 L = H O H O PAr2 O DCM, rt Ph O O O Ph Ar = 3,5-t-Bu-4-OMeC6H2 (R)-DTBM-SEGPHOS

Scheme 1.4: First example of a transition metal-catalyzed ketone hydroacylation, using a cationic Rh(I) source and (R)-DTBM-SEGPHOS With this exciting contribution to the field of hydroacylation, the Dong group conducted mechanistic studies to further understand the transformation.18 Their proposed reaction mechanism is shown in Scheme 1.5. They concluded that insertion of the rhodium hydride into the ketone is the rate-limiting step, and that chelation of the ether- oxygen is crucial for this transformation; ineffective chelation can result in decarbonylation being the preferred pathway, rendering the catalyst inactive towards hydroacylation.

18 Shen, Z.; Dornan, P. K.; Khan, H. A.; Woo, T. K.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 1077.

H O O Me RhL + O O H Ph O P CO P O Rh H Rh * * H P L P O O Ph O C−H Bond O Activation Me Reductive Elimination + L O O H O CO O P Rh Decarbonylation P O * Rh P H * O Me P H O O Reductive + Ph Elmination Ph O Insertion Rate-limiting step P O * Rh H P O Ph Scheme 1.5: Proposed catalytic cycle for rhodium-catalyzed intramolecular ketone hydroacylation Extending their methodology to a larger class of substrates, the Dong group recently published a study in which they discovered that aryl sulfides and N-Me anilines can chelate to the metal centre and promote hydroacylation (Scheme 1.6).19 With aniline substrates they were able to synthesize seven- and eight-membered lactones, formally known as benzoxazepinones and benzoxazecinones, in 84-99% yield and 88-99% ee.

O 1-5 mol% O R [Rh((R)-DTBM-SEGPHOS)]BF O H O 4 H DCM, rt N R n n N Me Me n = 0,1 R = aryl, alkyl Scheme 1.6: Synthesis of benzoxazepinones and benzoxazecinones via rhodium- catalyzed intramolecular ketone hydroacylation

19 Khan, H. A.; Kou, K. G. M.; Dong, V. M. Chem. Sci. 2011, 2, 407.

In a continued effort towards developing ketone hydroacylation, the Dong group published a method for synthesizing five-membered lactones known as phthalides from ketoaldehydes.20 To enable this transformation without a chelating heteroatom, the use of a coordinating counter ion was essential for obtaining high yields of these naturally occurring compounds (Scheme 1.7).

O O 5 mol% [Rh(COD)Cl] P 2 tBu H 5 mol% DuanPhos O H H O 5 mol% AgNO3 P tBu toluene, 100 °C H R R R = aryl, alkyl >90% ee (S,S,R,R)-Duanphos

Scheme 1.7: Synthesis of phthalides via rhodium-catalyzed intramolecular ketone hydroacylation 1.1.5 Challenges for an Intermolecular Ketone Hydroacylation

An intermolecular ketone hydroacylation would be a highly valuable transformation, as it could be an alternate, atom-economical21 strategy for synthesizing esters, which are ubiquitous amongst biological architectures. While there are now reports of transition metal-catalyzed ketone hydroacylation, the transformation has solely been developed for intramolecular systems. The reason for this limitation can likely be attributed to two key challenges for the intermolecular system: the competing decarbonylation reaction pathway and the inherent reactivity of aldehydes. Decarbonylation is a challenge for any hydroacylation system,3 however it is assumed to be favoured in the presence of a coordinatively unsaturated rhodium complex.22 In an intermolecular system this unsaturated rhodium species can be formed much more readily, and thus decarbonylation becomes difficult to suppress. Another concern specific to intermolecular systems is the intrinsic reactivity of aldehydes. Due to their highly reactive nature, when attempting to couple a simple aldehyde and ketone via rhodium catalysis, the major product tends to be that from the

20 Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 15608. 21 Trost, B. M. Science 1991, 254, 1471. 22 Leung, J. C.; Krische, M. J. Chem. Sci. 2012, 3, 2202.

homo-coupled Tishchenko pathway between two molecules of the aldehyde rather than a cross-coupling of the aldehyde and ketone (Scheme 1.8). The Tishchenko pathway must therefore be suppressed to make intermolecular ketone hydroacylation a viable synthetic protocol.

O H hydroacylation Me O O [Rh(I)] not observed Ph O Me + H O H Me Me Tishchenko reaction H Ph O Ph

Scheme 1.8: Competing hydroacylation and Tishchenko reaction pathways 1.1.6 Isolated Examples of Intermolecular Ketone Hydroacylation

Despite inherent challenges with the transformation, there are isolated examples of intermolecular ketone hydroacylations. The first example was reported by the Scheidt group where they synthesized diester products from α-ketoesters and aldehydes using NHC organocatalysis (Scheme 1.9).23 While high-yielding, the transformation is limited to arylaldehydes, there was no discussion of an asymmetric variant of the reaction, and there has been no further development of this reaction.

15 mol% Me N N Me I O O O N H Ar O + OMe Ar H Ph CO2Me DBU, DCM, 40 °C O Ph Scheme 1.9: Scheidt's NHC-catalyzed intermolecular ketone hydroacylation

More recently, the Lu group reported another example of an NHC-catalyzed intermolecular ketone hydroacylation, however their method differs from Scheidt’s method in that it uses N-benzyl isatins as ketone substrates (Scheme 1.10).24 They were able to isolate ester products in high yields, however good reactivity was only observed with arylaldehydes, and there was no discussion of an asymmetric transformation. Additionally, their system requires elevated temperatures and the use of a strong base for good reactivity.

23 Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558. 24 Du, D.; Lu, Y.; Jin, J.; Tang, W.; Lu, T. Tetrahedron 2011, 67, 7557.

10 mol% O N Cl O Ar O N N Mes O H O Ar H N 20 mol% KOtBu O Bn toluene, 100 °C N Bn Scheme 1.10: Lu's NHC-catalyzed intermolecular ketone hydroacylation Lastly, the Connon group recently reported a novel approach to intermolecular ketone hydroacylation.25 Using either selenide ions or thiolates as catalysts, they were able to isolate ester products in high yields under relatively mild conditions (Scheme 1.11). Their approach is unique in that it was inspired by enzymatic processes, however the transformation requires long reaction times (24-67 h) and the scope is limited to arylaldehydes and trifluoromethylketones.

cat. R-SH, RMgBr or O O cat. Ar2Se2, Bu2Mg O Ar + Ar H Ar CF3 THF, 65 °C, 24-67 h Ar O CF3 Scheme 1.11: Connon's intermolecular ketone hydroacylation While these isolated examples demonstrate the feasibility of an intermolecular ketone hydroacylation, a metal-catalyzed system has yet to be reported, and there have been no detailed efforts towards an asymmetric transformation.

1.2 Research Goals

In an effort to address the described challenge in hydroacylation, my co-worker Kevin Kou was inspired by the work of Tanaka where a Rh(I) catalyst enabled the intermolecular coupling of acrylamides with unfunctionalized aldehydes.12 To achieve this transformation Tanaka and co-workers developed a catalyst using a bidentate phosphine ligand with a cationic Rh(I) source; this catalyst enabled a hydroacylation using non-chelating aldehydes. Kevin envisioned a system in which a simple, unfunctionalized aldehyde could add across a chelating ketone using Rh(I) catalysts containing bidentate phosphine ligands. Goals of this project include establishing the first

25 (a) Cronin, L.; Manoni, F.; O’Connor, C. J.; Connon, S. J. Angew. Chem. Int. Ed. 2010, 49, 3045. (b) Curran, S. P.; Connon, S. J. Org. Lett. 2012, 14, 1074.

transition metal-catalyzed intermolecular ketone hydroacylation and developing the method to achieve intermolecular couplings of simple, aliphatic aldehydes with ketones composed of a variety of directing groups.

1.3 Results and Discussion 1.3.1 Isatin Synthesis

Our N-substituted isatin substrates, which contain the essential directing group for our transformation, are easily synthesized in one step from commercially available N-H isatins (Scheme 1.12).

O O NaH, R'−X R O R O DMF, 0 C rt N ° → N H R' R = H, 5-Me, R' = Me, Bn 5-OMe, 5-F Scheme 1.12: Procedure for the synthesis of N-substituted isatins Based on a literature procedure,30 the parent isatin was treated with NaH and the appropriate alkyl bromide or iodide at 0 °C, warming to rt over 14 h. The desired substrates were isolated in moderate to excellent yields following recrystallization in absolute ethanol.

1.3.2 Linear α–Ketoamide Synthesis

Our linear α–ketoamide substrates also contain the essential directing group for our intermolecular ketone hydroacylation and were easily synthesized in two steps from commercially available phenylglyoxylic acid (Scheme 1.13).

1) (COCl) , cat. DMF O 2 O R1 DCM, rt OH N R2 2) HNR1R2, Et3N O DCM, 0 °C→rt O HNR1R2 = HNMePh, morpholine, HNEt2 Scheme 1.13: Synthesis of linear α-ketoamides Using a modified literature procedure,33 we were able to synthesize α–ketoamides from N-methylaniline, morpholine, and diethylamine in excellent yields.

1.3.3 Developing an Intermolecular Ketone Hydroacylation

My co-worker Kevin discovered during preliminary screening of achiral ligands that bulky, electron-rich bidentate phosphines with cationic Rh(I) sources led to catalysts that could hydroacylate 1-benzylindoline-2,3-dione (2a) using hydrocinnamaldehyde (1a). He was pleased to observe reactivity with an isatin substrate as they are synthetically versatile compounds that are commonly used as raw materials for the production of valuable pharmaceuticals.26 Upon screening several ligands he discovered that the bulky aliphatic ligand dcpp was far superior to other simple bidentate phosphines, with the complete study shown in Table 1.1. Table 1.1: Achiral ligand screen for intermolecular isatin hydroacylation

O O Ph O 10 mol% [Rh(L)]BF O 4 H + O Ph H N 0.25 M DCE, 70 °C, 16 h O 1a Bn N 2a Bn 3aa Entry L Conversion to 3aa

1 Ph2P PPh2 <5% dppm

Ph2P 2 PPh2 <5% dppe

3 Ph2P PPh2 <5% dppp

Ph2P 4 PPh2 <5% dppb

Cy2P 5 PCy2 <5% dcpe

Cy P PCy 6 2 2 36% dcpp

26 Matos, M. A. R.; Miranda, M. S.; Morais, V. M. F.; Liebman, J. F. Org. Biomol. Chem. 2003, 1, 2566.

Following Kevin’s initial discovery of reactivity (Table 1.1, entry 6), we sought to explore other aldehydes and isatins to determine which substrates were most compatible with our catalyst. The first high-yielding hydroacylation was achieved using isobutyraldehyde (1b) and 1-benzyl-5-methylindoline-2,3-dione (2b), shown in Scheme 1.14.

Me O O O Me 10 mol% [Rh(dcpp)]BF4 Me O Me + H O Me H 0.25 M DCE N Me 80 °C, 18 h O Bn N 1b 2b 95% Bn 3bb Scheme 1.14: First generation conditions for rhodium-catalyzed intermolecular ketone hydroacylation Knowing that a proximal directing group on the ketone substrate was essential for reactivity, we tested other isatins as well as acyclic ketones with our catalyst. We discovered that both N-Me and N-Bn isatins were effective substrates, and electron- donating and electron-withdrawing substituents on the aryl backbone were well tolerated. We were pleased to observe that linear α-ketoamides were also compatible substrates, which have never before been used in hydroacylation, further demonstrating the utility of amides as directing groups. Our ketone study is summarized in Table 1.2, where we chose 1c as a representative aldehyde. At 10 mol% catalyst loading we observed excellent reactivity with all ketone substrates, isolating ester products 3ca-ch in very high yields.

Table 1.2: Scope of isatins and linear α-ketoamides as hydroacylation substrates

Me O O Me Me O 10 mol% [Rh(dcpp)]BF4 Me O Me + O H 0.25 M DCE, 70 °C, 4 h O Me H NR 1c NR 2 3 Entry Substrate Product Yield Me Me O O Me O 1 O H quant. N Bn O 2a N Bn 3ca Me Me O O Me Me O 2 O Me H quant. N Bn O 2b N Bn 3cb Me Me O O Me MeO O 3 O MeO H quant. N Bn O 2c N Bn 3cc Me Me O O Me F O 4 O F H 98% N Bn O 2d N Bn 3cd

Me Me O O Me O 5 O H 89% N Me O 2e N Me 3ce O Me O Ph Me Me Me N N 6 Ph Ph Me O Ph 99% O O 2f 3cf

O O Me O Ph O Me N N 7 Ph Me O 98% O O 2g 3cg

Me Me O Me O Ph Me N Me N Me 8 Ph Me O 91% O O 3ch 2h

To determine the scope of aldehydes that are compatible with our system, we tested a variety of commercially available aldehydes with linear α-ketoamide 2f. Hydroacylation of isatins is a known transformation, albeit using NHC catalysis, and we believe isatins are more susceptible to nucleophilic attack than linear α-ketoamides due to their characteristic degree of anti-aromaticity.26,27 We chose to use linear α-ketoamides for the aldehyde study as these substrates are unreported in hydroacylation literature, and we anticipated that they would be more challenging substrates than isatins due to their unstrained framework. We discovered that bulky aliphatic aldehydes are the most reactive substrates for our system; isobutyraldehyde (1b) gave high yields of

27 Matos, M. A. R.; Liebman, J. F. Experimental Thermochemistry of Heterocycles and Their Aromaticity: A Study of Nitrogen, Oxygen, and Sulfur Derivatives of Indane and Indene. In Topics in Heterocyclic Chemistry;1st Ed. Maes, B. U. W., Ed. Springer: Berlin / Heidelberg, 2008; vol. 5, pp 1-26.

hydroacylation products, as well as 3,3-dimethylbutanal (1c). Our complete aldehyde study is shown in Table 1.3. Table 1.3: Screen of aldehydes for intermolecular ketone hydroacylation

O O Ph O Me 10 mol% [Rh(dcpp)]BF4 Me + N N Ph Ph R O Ph R H 0.25 M DCE, 70 °C, 4 h O O 1 2f 3 Entry Aldehyde Product Yield O Ph O Me N 1 Ph O Ph 84%a Ph H 1a O 3af O O Ph Me Me Me N 2 H O Ph quant.a Me Me O 1b 3bf Me O Ph Me O Me Me Me N 3 Me O Ph quant. Me H 1c O 3cf Me O Ph Me O Me N 4 Me O Ph quant.b Me H 1d O 3df O O Ph Me N 5 H O Ph quant. O 1e 3ef O O Ph Me N 6 H O Ph 63%c O 1f 3ff O Ph O Me N 7 H O Ph <1% O 1g 3gf

O Ph O Me N 8 Me O Ph 30%b Me H 1h O 3hf O O Ph Me N 9 H O Ph <1% O 1i 3if O Ph O Me N Ph O Ph 10 Ph H <1% O 1j 3jf O O Ph Me Me Me N H O Ph 11 Me Me <1% Me Me O 1k 3kf Reaction conditions: 1 equiv. 2f, 2 equiv. aldehyde.28 a: 16 h b: 8 h c: 18 h

Our investigation of various aldehydes revealed that bulkier substrates are preferred, including aldehydes 1b-e; however, too much steric hindrance (1k, entry 11) impedes all reactivity. Enal 1j (entry 10) and benzaldehyde 1i (entry 9) are inactive with our system, and long chain alkylaldehydes like 1h (entry 8) show low reactivity. Despite these limitations we were pleased with the scope of this reaction, as it is complimentary to previously reported intermolecular ketone hydroacylations,23-25 which are limited to arylaldehydes. In an effort to determine the efficacy of other directing groups at promoting ketone hydroacylation, we tested 2-pyridyl-substituted ketones, due to their precedence in the Suggs, Jun, and Breit catalysts (Figure 1.1),6-8 as well as α-ketoesters, due to their excellent reactivity in the Scheidt system (Scheme 1.9). Results are shown in Table 1.4.

28 Two equivalents of aldehyde were used due to its anticipated volatility

Table 1.4: Screen of alternate directing groups for intermolecular ketone hydroacylation

O O O [Rh(dcpp)]BF4 + DG R O R H R' 0.25 M DCE, DG 70 °C, 24 h 1 R' Entry Aldehyde Substrate Conv. to Product

1 1b O <1% N N 2 1c <1%

3 1b O <1% N 4 1c <1%

5 1b O <1% N Me 6 1c <1%

7 1b O 50% OMe 8 1c Ph >90% O

We chose to test three commercially available pyridyl-substituted ketones, shown in entries 1-6. However, pyridine directing groups were unsuccessful with our catalyst system (entries 1-6), with no hydroacylation products observed and full recovery of the ketone starting materials. We believe that this may be due to the inherent s-trans conformation of these substrates,29 whereas the s-cis conformation is required to direct hydroacylation across the ketone. To our surprise, when we subjected 2-benzoylpyridine and aldehyde 1c (entry 6) to the same catalyst at 110 °C for 24 h, we saw a small amount of the hydroacylation product by 1H NMR, and confirmed by LC-MS analysis. This was an interesting discovery because it demonstrates that pyridyl-substituted ketones can be feasible substrates in hydroacylation, however this transformation requires further investigation, and likely a more active catalyst.

29 Le Fèvre, R. J. W.; Stiles, P. J. J. Chem. Soc. B, 1966, 420.

We chose to test aldehydes 1b and 1c with one commercially available α-ketoester (entries 7 and 8), which was a substrate used in Scheidt’s hydroacylation chemistry.23 After 24 h at 70 °C, 50% conversion to the corresponding ester product was observed with aldehyde 1b (entry 7), and near full conversion was observed with aldehyde 1c (entry 8). Unfortunately, we were unable to purify the ester products to homogeneity by silica gel chromatography. Efforts directed at purifying the corresponding products are ongoing; we hope to determine a more efficient isolation method to extend our methodology to this class of substrates.

1.3.4 Catalysis at a Lower Rhodium Loading

We were pleased to observe that a range of alkylaldehydes were compatible for intermolecular ketone hydroacylation, as well as a large class of linear α-ketoamides and isatins. Our system is efficient and high yielding, however we were interested in studying the effect of the catalyst loading. With rhodium being a costly transition metal, there is a significant demand for systems that offer very low loadings. We decided to test our ketone substrates with aldehyde 1c at 5 mol% catalyst loading. Results are shown in Table 1.5. Table 1.5: Hydroacylation results at 5 mol% catalyst loading

Me O O Me Me O 5 mol% [Rh(dcpp)]BF4 Me O Me + O O 0.25 M DCE, 70 °C, 17 h Me H NR 1c NR 2 3 Entry Substrate Product Yield Me Me O O Me O 1 O H 81% N Bn O 2a N Bn 3ca

Me Me O O Me Me O 2 O Me H 75% N Bn O 2b N Bn 3cb Me Me O O Me MeO O 3 O MeO H 80% N Bn O 2c N Bn 3cc Me Me O O Me F O 4 O F H 47% N Bn O 2d N Bn 3cd Me Me O O Me O 5 O H 80% N Me O 2e N Me 3ce O Me O Ph Me Me Me N N 6 Ph Ph Me O Ph quant. O O 2f 3cf

O O Me O Ph O Me N N 7 Ph Me O 73% O O 2g 3cg

We were pleased to observe that ester 3cf was isolated in quantitative yield after 17 h at 70 °C (entry 6), consistent with our results at 10 mol% catalyst loading. However the

isolation of other hydroacylation products were not comparable, with yields typically 20- 25% lower than when a 10 mol% catalyst loading was used. We hope to further pursue these studies and determine the cause for this decrease in isolated yield; we believe that there may be formation of an inactive Rh−CO species, and so further optimization is required.

1.4 Conclusions and Future Work

We were able to successfully design an achiral catalyst system for the intermolecular hydroacylation of isatins, linear α-ketoamides, and α-ketoesters with simple aliphatic aldehydes. This was enabled through the use of a cationic Rh(I) precursor and dcpp, a bulky, electron-rich bidentate phosphine. Preliminary results suggest that catalyst loadings as low as 5 mol% may be feasible, however further optimization is required to ameliorate isolated yields. Future directions for this project include exploring other directing groups to make our transformation more general.

1.5 Experimental Procedures and Characterization Data 1.5.1 General Considerations

Commercial reagents were purchased from Sigma Aldrich, Strem, Alfa Aesar, Acros and Solvias and used without further purification. All reactions were carried out in a nitrogen-filled glovebox unless otherwise indicated. Solvents used in rhodium- catalyzed hydroacylations were first distilled over calcium hydride, degassed by three freeze-pump-thaw cycles and stored in a glove box. Other solvents were dried through two columns of activated alumina. Reactions were monitored using thin-layer chromatography (TLC) on EMD Silica Gel 60 F254 plates or by LC-MS. Visualization of the developed plates was performed under UV light (254 nm) or KMnO4 stain. Column chromatography was performed with Silicycle Silia-P Flash Silica Gel using glass columns. Preparative-TLC was performed with 0.5 mm EMD Silica Gel 60 F254 plates. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. 1H and 13C NMR spectra were recorded on a Varian Mercury 300, Varian Mercury 400, or Bruker 400. NMR spectra were internally referenced to the residual solvent signal or TMS. Data for 1H NMR are reported as follows: chemical shift (δ ppm),

multiplicity (s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant (Hz), integration. Data for 13C NMR are reported in terms of chemical shift (δ ppm). High resolution mass spectra (HRMS) were obtained on a micromass 70S-250 spectrometer (EI) or an ABI/Sciex Qstar Mass Spectrometer (ESI).

1.5.2 General Procedure for the Preparation of N-Substituted Isatins

Following a literature procedure,30 20.4 mmol (1.0 equiv.) isatin was added to a flame-dried round bottom flask equipped with a magnetic stir bar. 51 mL of DMF was added to the flask, which was then cooled to 0 °C under N2(g). To the reaction mixture was added 24.5 mmol (1.2 equiv.) NaH in small portions; the reaction became a thick purple suspension. This mixture was stirred for 30 min at 0 °C, after which 22.4 mmol (1.1 equiv.) benzyl bromide was added dropwise to the reaction over 2 min. The reaction was allowed to slowly warm to rt, and was monitored by TLC and LC-MS. Once completed, the reaction was quenched with distilled H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the solvent was removed in vacuo. The recovered solid was purified by recrystallization in absolute ethanol. *For N-Me isatins, methyl iodide was used in place of benzyl bromide.

1.5.3 General Procedure for the Preparation of Linear α-Ketoamides

5.9 mmol (1.0 equiv.) benzoylformic acid and 12 mL DCM were added to a flame-dried round bottom flask equipped with a magnetic stir bar. This solution was stirred under N2(g) for 2 min followed by the addition of 5.9 mmol (1.0 equiv.) oxalyl chloride in one portion. The colourless solution was stirred at rt for 10 min, followed by addition of one drop of dry DMF. The solution turned yellow and bubbled, and was stirred at rt under N2(g) for 1 h. The solution was then cooled to 0 °C, and 703 µL (1.1 equiv.) of N-methylaniline was added dropwise to the reaction mixture. 1.23 mL (1.5 equiv.) of Et3N was then added to the reaction; effervescence was observed and a precipitate formed. The suspension was allowed to warm to rt over 14 h, after which it was diluted with distilled water and extracted with DCM. The combined organic layers were washed with brine and dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude yellow oil was purified by flash column chromatography.

1.5.4 General Procedure for Rhodium-Catalyzed Hydroacylation

In a nitrogen-filled glove box, 0.01 mmol (10 mol%) ligand was dissolved in 100

µL of DCM and transferred to a vial containing 0.01 mmol (10 mol%) [Rh(nbd)2]BF4, followed by an additional 100 µL DCM rinse, which was added to the catalyst mixture. The resulting pre-catalyst mixture was transferred to a 25 mL Schlenk tube equipped with a magnetic stir bar, followed by an additional 200 µL DCM rinse, which was added to the Schlenk tube. The tube was sealed and removed from the glovebox. The solution was degassed twice, after which the atmosphere was replaced with H2(g) and the reaction stirred at rt for 15 min. The solvent was then removed under reduced pressure and the vessel was refilled with H2(g). In the glovebox, 0.1 mmol (1.0 equiv.) ketone substrate was dissolved in 200 µL DCE, to which 0.2 mmol (2.0 equiv.) aldehyde was added. The resulting solution was transferred to the 25 mL Schlenk tube containing the catalyst, and the vial was rinsed with an additional 2x100 µL DCE, which was added to the Schlenk tube. The tube was sealed and heated to the indicated temperature for the indicated time period. The crude reaction mixture was directly purified by preparative TLC.

1.5.5 Characterization Data

O N Bn 2a 1-benzylindoline-2,3-dione (2a): Synthesized according to general procedure for the preparation of N-substituted isatins, the product was isolated as orange crystals (3.979 g, 1 82%). H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 7.2, 1,2 Hz, 1H), 7.48 (td, J = 7.8, 1.2 Hz, 1H), 7.36-7.30 (m, 5H), 7.09 (td, J = 7.5, 0.9 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 4.94 (s, 2H). Characterization data matched that in the literature.30

30 Vyas, D. J.; Fröhlich, R.; Oestreich, M. J. Org. Chem. 2010, 75, 6720.

O Me O N Bn 2b 1-benzyl-5-methylindoline-2,3-dione (2b): Synthesized according to general procedure for the preparation of N-substituted isatins, the product was isolated as maroon crystals 1 (3.640 g, 78%). H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.36-7.28 (m, 6H), 6.66 (d, J = 8 Hz, 1H), 4.91 (s, 2H), 2.30 (s, 3H). Characterization data matched that in the literature.30

O MeO O N Bn 2c 1-benzyl-5-methoxyindoline-2,3-dione (2c): Synthesized according to general procedure for the preparation of N-substituted isatins, the product was isolated as dark purple 1 crystals (3.710 g, 82%). H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m, 5H), 7.15 (d, J = 2.4 Hz), 7.02 (dd, J = 8.4, 2.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 4.90 (s, 2H), 3.77 (s, 3H). Characterization data matched that in the literature.30

O F O N Bn 2d 1-benzyl-5-fluoroindoline-2,3-dione (2d): Synthesized according to general procedure for the preparation of N-substituted isatins, the product was isolated as a dark red solid 1 (2.208 g, 57%). H NMR (400 MHz, CDCl3) δ 7.37-7.31(m, 6H), 7.19 (td, J = 8.6, 2.7 Hz, 1H), 6.72 (dd, J = 8.6, 3.6 Hz, 1H), 4.93 (s, 2H). Characterization data matched that in the literature.30

O N Me 2e 1-methylindoline-2,3-dione (2e): Synthesized according to general procedure for the preparation of N-substituted isatins, the product was isolated as orange crystals (259 mg, 1 47%). H NMR (400 MHz, CDCl3) δ 7.63-7.59 (m, 2H), 7.15-7.11 (m, 1H), 6.91-6.88 (m, 1H), 3.26 (s, 3H). Characterization data matched that in the literature.31

O Me N Ph Ph O 2f N-methyl-2-oxo-N,2-diphenylacetamide (2f): Synthesized according to general procedure for the preparation of linear α-ketoamides, the product was isolated as a white solid 1 (2.844 g, 95%). H NMR (400 MHz, CDCl3) δ 7.87-7.84 (m, 2H), 7.59-7.55 (m, 1H), 7.46-7.42 (m, 2H), 7.24-7.21 (m, 3H), 7.15-7.12 (m, 2H), 3.49 (s, 3H). Characterization data matched that in the literature.32

O O N Ph O 2g 1-morpholino-2-phenylethane-1,2-dione (2g): Synthesized according to general procedure for the preparation of linear α-ketoamides, the product was isolated as a white 1 solid (1.23 g, 84%). H NMR (400 MHz, CDCl3) δ 7.97-7.95 (m, 2H), 7.68-7.64 (m, 1H), 7.54-7.51 (m, 2H), 3.80 (s, 4H), 3.67-3.64 (m, 2H), 3.40-3.37 (m, 2H). Characterization data matched that in the literature.33

31 Tang, B.-X.; Song, R.-J.; Wu, C.-Y.; Liu, Y.; Zhou, M.-B.; Wei, W.-T.; Deng, G.-B.; Yin, D.-L.; Li, J.-H. J. Am. Chem. Soc. 2010, 132, 8900. 32 Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am. Chem. Soc. 2010, 132, 7266. 33 Liu, J.; Zhang, R.; Wang, S.; Sun, W.; Xia, C. Org. Lett. 2009, 11, 1321.

Me O N Me Ph O 2h N,N-diethyl-2-oxo-2-phenylacetamide (2h): Synthesized according to general procedure for the preparation of linear α-ketoamides, the product was isolated as a yellow oil (1.220 1 g, 89%). H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 3.57 (q, J = 7.2 Hz, 2H), 3.25 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). Characterization data matched that in the literature.32

O Me O N Me 2i 1,5-dimethylindoline-2,3-dione (2i): Synthesized according to general procedure for the preparation of N-substituted isatins, the product was isolated as a red crystals (2.826 g, 1 87%). H NMR (400 MHz, CDCl3) δ 7.42-7.39 (m, 2H), 6.78 (m, 1H), 3.23 (s, 3H), 2.34 (s, 3H). Characterization data matched that in the literature.31

O Ph O H O N Bn 3aa 1-benzyl-2-oxoindolin-3-yl 3-phenylpropanoate (3aa): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was isolated as a yellow oil 1 (13 mg, 36%). H NMR (400 MHz, CDCl3) δ 7.33-7.19 (m, 12H), 7.00-6.96 (m, 1H), 6.70-6.68 (m, 1H), 6.03 (s, 1H), 4.90 (s, 2H), 3.04-3.00 (m, 2H), 2.83-2.75 (m, 2H). 13 1 C{ H} NMR (101 MHz, CDCl3) δ 172.4, 172.2, 143.7, 140.1, 135.3, 130.2, 129.0, 128.7, 128.4, 127.9, 127.4, 126.5, 125.6, 124.4, 123.2, 109.6, 70.1, 44.1, 35.6, 31.0. + + HRMS (ESI) Calcd. for [C24H22NO3] ([M+H] ) 372.1606, found 372.1594.

Me O

Me O Me H O N Bn 3bb 1-benzyl-5-methyl-2-oxoindolin-3-yl isobutyrate (3bb): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was isolated as a colourless 1 oil (28 mg, 95%). H NMR (400 MHz, CDCl3) δ 7.32-7.26 (m, 5H), 7.13 (s, 1H), 7.02- 6.99 (m, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.00 (s, 1H), 4.92 (d, J = 15.7 Hz, 1H), 4.86 (d, J = 15.7 Hz, 1H), 2.73 (hept, J = 7.0 Hz, 1H), 2.27 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H), 1.24 13 1 (d, J = 7.0 Hz, 3H). C{ H} NMR (101 MHz, CDCl3) δ 176.5, 172.5, 141.3, 135.5, 132.9, 130.4, 128.9, 127.8, 127.4, 126.2, 124.7, 109.4, 70.0, 44.1, 33.9, 21.1, 19.1, 19.0. + + HRMS (ESI) Calcd. for [C20H22NO3] ([M+H] ) 324.1594, found 324.1604.

Me Me O Me O H O N Bn 3ca 1-benzyl-2-oxoindolin-3-yl 3,3-dimethylbutanoate (3ca): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was isolated as a 1 yellow oil (34 mg, >99%). H NMR (400 MHz, CDCl3) δ 7.34-7.19 (m, 7H), 7.04-7.00 (m, 1H), 6.70 (d, J = 8 Hz, 1H), 6.05 (s, 1H), 4.94 (d, J = 15.6 Hz, 1H), 4.88 (d, J = 15.6 13 1 Hz, 1H), 2.36 (s, 2H), 1.08 (s, 9H). C{ H} NMR (101 MHz, CDCl3) δ 172.6, 171.6, 143.7, 135.4, 130.2, 129.0, 129.0, 127.9, 127.5, 127.5, 125.6, 124.7, 123.1, 109.6, 69.8, + + 47.6, 44.1, 31.2, 29.8. HRMS (ESI) Calcd. for [C21H24NO3] ([M+H] ) 338.1756, found 338.1762.

Me Me O Me O Me H O N Bn 3cb 1-benzyl-5-methyl-2-oxoindolin-3-yl 3,3-dimethylbutanoate (3cb): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was 1 isolated as a yellow oil (36 mg, >99%). H NMR (400 MHz, CDCl3) δ 7.32-7.25 (m, 5H), 7.16 (s, 1H), 7.02-6.99 (m, 1H), 6.58 (d, J = 8 Hz, 1H), 6.04 (s, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 2.36 (s, 2H), 2.27 (s, 3H), 1.09 (s, 9H). 13C{1H} NMR

(101 MHz, CDCl3) δ 172.5, 171.7, 141.3, 135.5, 132.8, 130.4, 128.9, 127.8, 127.4, 127.4,

126.4, 124.7, 109.4, 69.9, 47.7, 44.1, 31.2, 29.8, 21.1. HRMS (ESI) Calcd. for [C22H- + + 26NO3] ([M+H] ) 352.1907, found 352.1896.

Me Me O Me O MeO H O N Bn 3cc 1-benzyl-5-methoxy-2-oxoindolin-3-yl 3,3-dimethylbutanoate (3cc): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was 1 isolated as a yellow oil (37 mg, >99%). H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 5H), 6.97-6.96 (m, 1H), 6.73 (ddd, J = 8.4, 2.4, 0.8 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.02 (s, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.86 (d, J = 15.6 Hz, 1H), 3.73 (s, 3H), 2.37 (s, 2H), 1.09 13 1 (s, 9H). C{ H} NMR (101 MHz, CDCl3) δ 172.3, 171.6, 156.3, 137.0, 135.5, 128.9, 127.8, 127.4, 127.4, 125.9, 114.8, 112.7, 110.1, 70.1, 55.9, 47.6, 44.2, 31.3, 29.8. HRMS + + (ESI) Calcd. for [C22H26NO4] ([M+H] ) 368.1856, found 368.1848.

Me Me O Me O F H O N Bn 3cd 1-benzyl-5-fluoro-2-oxoindolin-3-yl 3,3-dimethylbutanoate (3cd): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was isolated as a 1 yellow oil (35 mg, 98%). H NMR (400 MHz, CDCl3) δ 7.36-7.26 (m, 5H), 7.09 (ddd, J = 7.6, 2.8, 1.2 Hz, 1H), 6.94-6.89 (m, 1H), 6.61 (dd, J = 8.8, 4 Hz, 1H), 5.98 (s, 1H), 4.92 (d, J = 16 Hz, 1H), 4.88 (d, J = 16 Hz, 1H), 2.37 (s, 2H), 1.08 (s, 9H). 13C{1H} NMR

(101 MHz, CDCl3) δ 172.3 (d, J = 0.9 Hz), 171.5, 159.3 (d, J = 243.0 Hz), 139.6 (d, J = 2.1 Hz), 135.1, 129.0, 128.0, 127.4, 126.2 (d, J = 8.4 Hz), 116.5 (d, J = 23.5 Hz), 113.7 (d, J = 25.4 Hz), 110.3 (d, J = 8.0 Hz), 69.8 (d, J = 1.7 Hz), 47.5, 44.3, 31.3, 29.8. 19 1 + F{ H} NMR (377 MHz, CDCl3) δ –120.6. HRMS (ESI) Calcd. for [C21H23FNO3] ([M+H]+) 356.1662, found 356.1671.

Me Me O Me O H O N Me 3ce 1-methyl-2-oxoindolin-3-yl 3,3-dimethylbutanoate (3ce): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was isolated as a 1 colourless oil (23 mg, 89%). H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 2H), 7.08-7.04 (m, 1H), 6.84-6.82 (m, 1H), 5.97 (s, 1H), 3.21 (s, 3H), 2.34 (s, 2H), 1.06 (s, 9H). 13C{1H}

NMR (101 MHz, CDCl3) δ 172.4, 171.7, 144.7, 130.3, 125.6, 124.8, 123.1, 108.6, 69.7, + + 47.6, 31.2, 29.8, 26.5. HRMS (ESI) Calcd. for [C15H20NO3] ([M+H] ) 262.1437, found 262.1432.

Me O Ph Me Me N Me O Ph O 3cf 2-(methyl(phenyl)amino)-2-oxo-1-phenylethyl 3,3-dimethylbutanoate (3cf): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was 1 isolated as a colourless oil (36 mg, >99%). H NMR (400 MHz, CDCl3) δ 7.37-7.04 (m, 10H), 5.83 (s, 1H), 3.24 (s, 3H), 2.31 (d, J = 13.4 Hz, 1H), 2.25 (d, J = 13.4 Hz, 1H), 1.07 13 1 (s, 9H). C{ H} NMR (101 MHz, CDCl3) δ 172.2, 168.2, 142.6, 134.4, 129.7, 129.0,

128.7, 128.5, 128.4, 128.3, 73.7, 47.8, 38.0, 31.1, 29.8. HRMS (ESI) Calcd. for [C21H- + + 26NO3] ([M+H] ) 340.1907, found 340.1920.

Me O Ph O Me N Me O O 3cg 2-morpholino-2-oxo-1-phenylethyl 3,3-dimethylbutanoate (3cg): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was isolated as a 1 white solid (31 mg, 98%). H NMR (400 MHz, CDCl3) δ 7.44-7.38 (m, 5H), 6.21 (s, 1H), 3.66-3.22 (m, 8H), 2.34 (d, J = 13.6 Hz, 1H), 2.30 (d, J = 13.6 Hz, 1H), 1.05 (s, 9H). 13 1 C{ H} NMR (101 MHz, CDCl3) δ 172.0, 166.7, 134.3, 129.4, 129.2, 129.2, 128.4, 73.0, + + 66.8, 66.2, 47.7, 46.0, 42.8, 31.1, 29.7. HRMS (ESI) Calcd. for [C18H26NO4] ([M+H] ) 320.1856, found 320.1856.

Me Me O Ph Me N Me Me O O 3ch 2-(diethylamino)-2-oxo-1-phenylethyl 3,3-dimethylbutanoate (3ch): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was 1 isolated as a yellow oil (28 mg, 91%). H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 2H), 7.38-7.36 (m, 3H), 6.16 (s, 1H), 3.56-3.47 (m, 1H), 3.35-3.14 (m, 3H), 2.34-2.26 (m, 2H), 13 1 1.10-1.04 (m, 15H). C{ H} NMR (101 MHz, CDCl3) δ 172.1, 167.1, 134.9, 129.2,

129.0, 128.7, 73.2, 47.8, 41.6, 40.8, 31.1, 29.7, 13.8, 12.8. HRMS (ESI) Calcd. for + + [C18H27NO3Na] ([M+Na] ) 328.1884, found 328.1883.

O Ph Me N Ph O Ph O 3af 2-(methyl(phenyl)amino)-2-oxo-1-phenylethyl 3-phenylpropanoate (3af): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was 1 isolated as a colourless oil (31 mg, 84%). H NMR (400 MHz, CDCl3) δ 7.36-7.04 (m, 15H), 5.86 (s, 1H), 3.26 (s, 3H), 3.05-2.93 (m, 2H), 2.83-2.64 (m, 2H). 13C{1H} NMR

(101 MHz, CDCl3) δ 172.8, 168.2, 142.4, 140.5, 134.1, 129.8, 129.2, 128.7, 128.6, 128.5, + 128.4, 128.3, 126.3, 74.0, 38.0, 35.6, 30.9. HRMS (ESI) Calcd. for [C24H24NO3] ([M+H]+) 374.1750, found 374.1742.

O Ph Me Me N O Ph Me O 3bf 2-(methyl(phenyl)amino)-2-oxo-1-phenylethyl isobutyrate (3bf): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was isolated as a 1 colourless oil (35 mg, >99%). H NMR (400 MHz, CDCl3) δ 7.37-7.04 (m, 10H), 5.82 (s, 1H), 3.24 (s, 3H), 2.71-2.61 (m, 1H), 1.27 (d, J = 7.2 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H). 13 1 C{ H} NMR (101 MHz, CDCl3) δ 177.1, 168.3, 142.5, 134.3, 129.7, 129.1, 128.7, + 128.5, 128.4, 128.3, 73.7, 38.0, 33.8, 19.1, 18.8. HRMS (ESI) Calcd. for [C19H21NO3Na] ([M+Na]+) 334.1413, found 334.1428.

Me O Ph Me N Me O Ph O 3df 2-(methyl(phenyl)amino)-2-oxo-1-phenylethyl 3-methylbutanoate (3df): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was

1 isolated as a yellow oil (33 mg, >99%). H NMR (400 MHz, CDCl3) δ 7.37-7.05 (m, 10H), 5.84 (s, 1H), 3.24 (s, 3H), 2.36-2.12 (m, 3H), 0.99-0.97 (m, 6H). 13C{1H} NMR

(101 MHz, CDCl3) δ 173.0, 168.2, 142.5, 134.3, 129.7, 129.1, 128.7, 128.5, 128.4, 128.3, + + 73.7, 43.1, 38.0, 25.8, 22.6, 22.5. HRMS (ESI) Calcd. for [C20H23NO3Na] ([M+Na] ) 348.1565, found 348.1570.

O Ph Me N O Ph O 3ef 2-(methyl(phenyl)amino)-2-oxo-1-phenylethyl cyclohexanecarboxylate (3ef): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the 1 product was isolated as a faint yellow oil (35 mg, 99%). H NMR (400 MHz, CDCl3) δ 7.35-7.04 (m, 10H), 5.82 (s, 1H), 3.24 (s, 3H), 2.41 (tt, J = 11.2, 3.6 Hz, 1H), 2.09-2.05 (m, 1H), 1.91-1.87 (m, 1H), 1.80-1.71 (m, 2H), 1.64-1.63 (m, 1H), 1.52-1.44 (m, 2H), 13 1 1.30-1.22 (m, 3H). ). C{ H} NMR (101 MHz, CDCl3) δ 176.1, 168.3, 142.6, 134.4, 129.8, 129.1, 128.7, 128.6, 128.4, 128.3, 73.6, 42.9, 38.0, 29.2, 28.9, 25.9, 25.6, 25.5. + + HRMS (ESI) Calcd. for [C22H26NO3] ([M+H] ) 352.1913, found 352.1919.

O Ph Me N O Ph O 3ff 2-(methyl(phenyl)amino)-2-oxo-1-phenylethyl cyclopentanecarboxylate (3ff): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the 1 product was isolated as a faint yellow oil (18 mg, 50%). H NMR (400 MHz, CDCl3) δ 7.36-7.04 (m, 10H), 5.82 (s, 1H), 3.24 (s, 3H), 2.84 (quintet, J = 8 Hz, 1H), 1.99-1.94 (m, 2H), 1.88-1.82 (m, 2H), 1.76-1.66 (m, 2H), 1.62-1.52 (m, 2H). 13C{1H} NMR (101 MHz,

CDCl3) δ 176.8, 168.4, 142.6, 134.4, 129.8, 129.1, 128.7, 128.6, 128.4, 128.3, 73.7, 43.6, + + 38.0, 30.2, 29.9, 26.0. HRMS (ESI) Calcd. for [C21H24NO3] ([M+H] ) 338.1756, found 338.1753.

O Ph Me N Me O Ph O 3hf 2-(methyl(phenyl)amino)-2-oxo-1-phenylethyl hexanoate (3hf): Synthesized according to general procedure for rhodium-catalyzed hydroacylation, the product was isolated as a 1 yellow oil (10 mg, 30%). H NMR (400 MHz, CDCl3) δ 7.36-7.04 (m, 10H), 5,84 (s, 1H), 3.25 (s, 3H), 2.49-2.31 (m, 2H), 1.67-1.62 (m, 2H), 1.32-1.30 (m, 4H), 0.89-0.86 (m, 3H). 13 1 C{ H} NMR (101 MHz, CDCl3) δ 173.8, 168.3, 142.5, 134.2, 129.8, 129.1, 128.7, 128.6, 128.4, 128.3, 73.8, 38.0, 34.1, 31.4, 24.6, 22.4, 14.0. HRMS (ESI) Calcd. for + + [C21H25NO3Na] ([M+Na] ) 362.1728, found 362.1726.

Chapter 2: Efforts Towards an Enantioselective and Diastereoselective Intermolecular Ketone Hydroacylation

2.1 Introduction 2.1.1 Early Reports of Asymmetric Hydroacylation

Since the discovery of hydroacylation, there have been extensive studies conducted to better understand and develop the reaction (see Chapter 1). One attractive feature of the transformation is that it is amenable to enantioselective addition of the aldehyde across the unit of unsaturation. Because there is a demand for enantiopure products in drug development and medicinal chemistry, there is a large interest in stereoselective hydroacylation protocols. The first highly enantioselective hydroacylation was reported by Sakai in 1992, using a Rh(I)-BINAP system for 4-pentenal substrates (Scheme 2.1).5b In 1994 Bosnich further developed that same transformation, broadening the scope of the reaction and examining the effect of other chiral ligands. He concluded that the Rh(I)-BINAP catalyst could only induce high enantioselectivities in cyclopentanone products when the 4- pentenal substrates contained bulky substituents on the alkene moiety. 34 He later determined that for more difficult 4-pentenal substrates bearing small alkyl substituents on the alkene, BINAP could be substituted for Me-DUPHOS and high enantioselectivities could be achieved (Scheme 2.1).35

34 Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821. 35 (a) Barnhart, R.W.; McMorran, D.A.; Bosnich, B. Inorg. Chim. Acta. 1997, 263, 1. (b) Barnhart, R.W.; McMorran, D. A.; Bosnich, B. Chem. Commun. 1997, 589.

Me P O O Me PPh2 [Rh(L*)]+ H L* = PPh2 Me P Me R R (S)-BINAP R = small, L* = Me-DUPHOS (S,S)-Me-DUPHOS R = large, L* = BINAP Scheme 2.1: Early enantioselective reports of 4-pentenal hydroacylation by Sakai and Bosnich 2.1.2 Recent Developments in Intermolecular Asymmetric Olefin Hydroacylation

Complimentary to developments in enantioselective intramolecular olefin hydroacylation, there are now many reports of enantioselective intermolecular olefin hydroacylation using chiral ligands to achieve enantioinduction (Scheme 2.2). Willis used a neutral Rh(I)/Me-DUPHOS catalyst (shown in Scheme 2.1) to synthesize β,γ- unsaturated ketones from 2-methylthiobenzaldehyde and allenes,36 and Tanaka used a cationic Rh(I)/QuinoxP* catalyst for the intermolecular hydroacylation of acrylamides with unfunctionalized aldehydes.12b The Dong group used a neutral Rh(I)/SIPHOS-PE catalyst to achieve hydroacylation of homoallylic sulfides with salicylaldehydes,10f and they used a ligand from the Josiphos family, SL-J009, in combination with a neutral Rh(I) source to enable the desymmetrization of cyclopropenes.10e These representative examples demonstrate how, depending on the nature of the substrates and their ability to chelate to the metal centre, chiral monodentate or bidentate phosphine ligands can be used to achieve a highly enantioselective transformation.

36 Osborne, J. D.; Randell-Sly, H. E.; Currie, S. G.; Cowley, A. R.; Willis, M. C. J. Am. Chem. Soc. 2008, 130, 17232.

Willis SMe O SMe O R 10 mol% [Rh(Me-DUPHOS)]ClO 2 4 R H + 2 R1 R3 R1 R3 >90% ee Tanaka R2 O R2 O 5 mol% [Rh(QuinoxP*)]BF4 + NR3R4 NR3R4 R1 R1 H O O R1 = alkyl 96-99% ee Dong OH O 2.5 mol% [Rh(COD)Cl]2 OH O 5 mol% SIPHOS-PE SPh H + SPh Me >90% ee Dong OH O 2.5 mol% [Rh(COD)Cl]2 O H Ph Ph Me 5 mol% SL-J009 HO Me H +

>90% ee

Ph O P(t-Bu) N N Me Cy P 2 P N 2 Fe Me O P P Me Me tBu Ph tBu Me (R,R)-QuinoxP* (R)-SIPHOS-PE SL-J009

Scheme 2.2: Representative examples of stereoselective rhodium-catalyzed intermolecular olefin hydroacylation 2.1.3 Asymmetric Ketone Hydroacylation

The Dong group has reported several examples of enantioselective intramolecular ketone hydroacylation.17-19 Using Rh(I) catalysts with chiral phosphine ligands they have been able to synthesize 7-membered lactones (Scheme 1.4), phthalides natural products (Scheme 1.7), and novel benzoxazepinones and benzoxazecinones (Scheme 1.6) via intramolecular ketone hydroacylation. However, to date there are no reports of an

asymmetric intermolecular ketone hydroacylation; limited reports of intermolecular ketone hydroacylations are racemic syntheses (see Chapter 1).

2.2 Research Goals

Recognizing the underdeveloped area of asymmetric intermolecular ketone hydroacylation, we wanted to modify our achiral catalyst and incorporate chiral ligands, with the goal being the efficient synthesis of chiral esters. We were interested in testing commercially available chiral ligands, however, we also wanted to explore ligand design to develop unique phosphine scaffolds for our desired transformation. We also hoped to explore a diastereoselective protocol, using chiral building blocks to induce a stereoselective hydroacylation with our previously developed [Rh(dcpp)]BF4 catalyst.

2.3 Results and Discussion 2.3.1 Enantioselective Rhodium-Catalyzed Intermolecular Ketone Hydroacylation using Commercially Available Ligands

In collaboration with Kevin Kou, we tested several chiral phosphine ligands that have previously been used in hydroacylation chemistry. We wanted to test BINAP-based ligands, QuinoxP* from Tanaka’s intermolecular hydroacylation of acrylamides (Scheme 2.2), and Josiphos ligands. Cationic Rh(I) sources containing monodentate phosphine ligands were unreactive with our achiral hydroacylation system (which we anticipated due to our non-chelating aldehyde substrates), and so chiral monodentate phosphine ligands were not investigated. Disappointingly, most chiral bidentate ligands in combination with [Rh(nbd)2]BF4 were unsuccessful catalysts, giving very low conversion to hydroacylation products and ees < 20%; however, we observed one promising result with SL-J212 (Figure 2.1), a member of the Josiphos family. SL-J212 is C1-symmetric, it is composed of one bulky, electron-rich phosphine and one electron-poor phosphine, and it was the only ligand of its kind to show promising reactivity and enantioselectivity in intermolecular ketone hydroacylation.

O P(t-Bu)2 P Fe Me O SL-J212

Figure 2.1: Josiphos ligand SL-J212 We originally observed promising results when aldehyde 1a and isatin 2i were treated with [Rh(SL-J212)]BF4, shown in Table 2.1. At 50 °C we were able to isolate 3ai in 94% yield and 47% ee (entry 1). We hypothesized that the elevated reaction temperature may be impeding enantioinduction, and so we repeated the reaction at 20 °C, this time isolating 3ai in 70% yield and 68% ee (entry 4). We also wanted to investigate how the use of excess aldehyde affects the outcome of the reaction: it appears as though 1.5 equiv. is optimal for both yield and ee (entry 3), whereby increasing the amount of aldehyde to 3 equiv. and 5 equiv. (entries 5 and 6) results in successively lower yields and lower ees. We believe that the aldehyde may be playing a pivotal role in intermediates of the catalytic cycle due to its profound effect on the enantioselectivity of the reaction, and we hope to conduct stoichiometric studies to better understand the mechanism of this transformation.

Table 2.1: Results for hydroacylation with [Rh(SL-J212)]BF4

O O Ph O Me O 10 mol% [Rh(SL-J212)]BF4 + O Me H Ph H N 0.25 M DCE 1a O Me N 2i Me 3ai Entry equiv. aldehyde Temp. (°C) Reaction time (h) Yield (%) ee (%) 1 2 50 20 94 47 2 1 20 8 63 70 3 1.5 20 8 75 70 4 2 20 8 70 68 5 3 20 8 62 64 6 5 20 8 44 58 7 2 0 8 32 41

While we were pleased to see that [Rh(SL-J212)]BF4 could induce enantioselectivities up to 70%, we were not able to achieve higher ees with this catalyst system. Repeating the reaction at 0 °C resulted in a lower yield (32%) and lower ee (41%) (entry 7). We then decided to try other classes of chiral ligands that had previously been used in intramolecular ketone hydroacylations. One such ligand that showed promising results was BDPP, a C2-symmetric bidentate ligand with phosphine donors that are π-electron withdrawing. The ligand structure is shown in Figure 2.2.

Me Me

Ph2P PPh2 (S,S)-BDPP

Figure 2.2: C2-symmetric BDPP ligand We discovered that, when using BDPP as a ligand, the rhodium catalyst showed reactivity with linear α-ketoamide substrates and bulkier aliphatic aldehydes 1b and 1c.

Results from our [Rh(BDPP)]BF4 catalyst system are shown in Table 2.2.

Table 2.2: Results for hydroacylation with [Rh(BDPP)]BF4

O O Ph O Me 10 mol% [Rh(BDPP)]BF Me N 4 N + Ph Ph R O Ph R H 0.25 M DCE O O 1 2f 3 Temp. Time Yield ee Entry Aldehyde Product (°C) (h) (%) (%)

O O Ph Me Me Me N 1 H O Ph 30 24 22 78 Me Me O 1b 3bf O O Ph Me Me Me N 2 H O Ph 30 72 35 77 Me Me O 1b 3bf O O Ph Me Me Me N 3 H O Ph 50 24 26 46 Me Me O 1b 3bf Me O Ph Me O Me Me Me N 4 Me O Ph 30 72 69 57 Me H 1c O 3cf Me O Ph Me O Me Me Me N 5 Me O Ph 50 48 84 59 Me H 1c O 3cf

We were pleased to observe that, after 24 h at 30 °C, ester 3bf could be isolated in 78% ee (entry 1), however the yield was a mere 22%. The reaction was repeated with an extended reaction time (72 h) and while we were pleased to see that the ee did not decrease, there was little improvement to the overall yield (entry 2). When the temperature of the reaction was increased to 50 °C for 24 h the yield did not improve significantly, and the ee dropped to 46% (entry 3).

When hydroacylation was attempted with aldehyde 1c at 30 °C for 72 h, ester 3cf was isolated in 69% yield, an improvement over couplings with 1b, however the ee was only 57% (entry 4). Heating the reaction to 50 °C further improved the yield, with 3cf isolated in 84%, however the ee remained essentially the same (entry 5). The consistency in the ee may be due to the increased reaction time at 30 °C, which may have contributed to racemization of the product.

2.3.2 Synthesis of Novel Bidentate Phosphine Ligands and Their Application to Rhodium-Catalyzed Intermolecular Ketone Hydroacylation

After screening several commercially available phosphine ligands we were unable to develop a system that was both high yielding and highly enantioselective. We thus decided to develop novel phosphine ligands based on scaffolds that showed promising results in hydroacylation. In an effort to design a chiral ligand that had the reactivity of dcpp with the enantioselectivity of BDPP, we proposed several new phosphines for our transformation. Structures are shown in Figure 2.3

Me Me Me Me Me Me tBu Me tBu Me tBu Me P P P P P P Cy2P PCy2 Me tBu Me tBu Me tBu L1 L2 L3 L4

Figure 2.3: New ligand designs for ketone hydroacylation One feature that we were interested in incorporating into our ligand designs was the P-chiral phosphine found in QuinoxP* (Scheme 2.2). Kevin Kou conducted the synthesis of the chiral phosphine found in L2-4; his route and results are shown in Scheme 2.3.37

37 Oohara, N.; Imamoto, T. Bull. Chem. Soc. Jpn. 2002, 75, 1359.

Me Me Me LiAlH Me BH THF Me 4 Me 3⋅ Me 1) nBuLi Me BH3 BH3 THF Me P 2) MeI Me P Me PCl2 butyl diglyme Me PH2 -78 °C 0 °C to rt H H Me H 80% >99% 89% Me Me Me Me BH Me Me Me Me P 3 Me Me Me triphosgene Me H Me BH3 quinoline, toluene O Cl nBuLi O P Me OH 0 °C to 60 °C tBu 86% O 100% O Me Me Me BH recrys. 3x BH KOH 3 3 Me hexanes P O P Me CH3CN/MeOH/H2O H tBu 20% tBu 77% >95% dr O Scheme 2.3: Synthesis of P-chiral phosphine-borane The reasoning behind the design of L1 is that it maintains the chiral backbone of BDPP but is contains the bulky, electron-rich phosphines that are found in dcpp. This ligand has been previously synthesized by Livinghouse and co-workers,38 however there are no reported applications of the ligand in transition metal catalysis. Ligands L2 and L3 are diastereoisomers, synthesized from different commercially available diols. They maintain the chiral backbone of BDPP, however these ligands contain the electron-rich chiral phosphine donors found in QuinoxP* (Scheme 2.2). L4 has the flexible, achiral backbone of dcpp but is P-chiral. The achiral synthesis of the diphosphonium bromide salt of L4 has been reported,39 however there are no reported applications of this ligand in transition metal catalysis. Syntheses of these ligands are shown in Scheme 2.4.

38 McKinstry, L.; Livinghouse, T. Tetrahedron 1995, 51, 7655. 39 Yaowu, S. Bisphosphonium salt and process for producing the same. US patent 2004/0138504, July 15, 2004.

1) nBuLi Me Me Me Me THF, -78 °C DABCO Cy2PH−BH3 Cy P PCy Cy P PCy 2 2 toluene, 80 C 2 2 2) OTs OTs ° L1 BH3 BH3 Me Me (R,R)-OTs Me Me Me Me BH 1) nBuLi tBu Me tBu Me 3 THF, -78 C DABCO Me ° P P P P P H3B BH3 H tBu 2) OTs OTs toluene, 80 °C Me tBu Me L2 tBu Me Me Me Me Me Me 1) nBuLi BH tBu Me tBu Me 3 THF, -78 °C P P DABCO P P P Me H3B BH3 H 2) OTs OTs toluene, 80 °C tBu Me tBu Me L3 tBu Me Me (S,S)-OTs 1) nBuLi BH3 tBu Me tBu Me Me THF, -78 °C P P DABCO P P P H B BH H tBu 2) 3 3 toluene, 80 °C Me tBu Me L4 tBu Br Br Scheme 2.4: Syntheses of ligands L1-4 Given that ligands L1-3 are based on the BDPP scaffold, we decided to first test these ligands with substrate 2f and aldehydes 1b and 1c, which were consistently the most reactive coupling partners. Results from these experiments are shown in Table 2.3.

The [Rh(L1)]BF4 catalyst was more reactive than [Rh(BDPP)]BF4, improving the isolated yield of 3bf to 93% (entry 1). This supported our hypothesis that using bulkier, more electron-rich phosphines with cationic Rh(I) sources leads to highly reactive catalysts for ketone hydroacylation. However, we observed only trace enantioinduction with the [Rh(L1)]BF4 catalyst. We believe that the planar phenyl substituents on the phosphines of BDPP are an important feature for enantioselectivity.

The [Rh(L2)]BF4 catalyst showed excellent reactivity with aldehyde 1c and ketone 2f at 30 and 50 °C (entries 4 and 5), as well as with aldehyde 1b at 50 °C (entry 3), however ees were modest; the best result was 52% (entry 2), which is not an improvement over the BDPP catalyst system. The [Rh(L3)]BF4 catalyst, which is a diastereomer of L2, appeared to have improved reactivity to [Rh(L2)]BF4, isolating 3bf

in 67% yield after 20 h at 30 °C (entry 6), however the ee was 38%, lower than the analogous reaction with the L2 catalyst system (entry 2). Table 2.3: Results for hydroacylation of 2a using L1-4 as ligands

O O Ph O Me 10 mol% [Rh(L)]BF Me N 4 N + Ph Ph R O Ph R H 0.25 M DCE O O 1 2f 3 Temp. Time Yield ee Entry Aldehyde Product L (°C) (h) (%) (%)

O O Ph Me Me Me N 1 H O Ph L1 30 45 93 4 Me Me O 1b 3bf O O Ph Me Me Me N 2 H O Ph L2 30 24 19 52 Me Me O 1b 3bf O O Ph Me Me Me N 3 H O Ph L2 50 24 86 37 Me Me O 1b 3bf Me O Ph Me O Me Me Me N 4 Me O Ph L2 30 12 99 50 Me H 1c O 3cf Me O Ph Me O Me Me Me N 5 Me O Ph L2 50 12 >99 39 Me H 1c O 3cf O O Ph Me Me Me N 6 H O Ph L3 30 20 67 38 Me Me O 1b 3bf

O O Ph Me Me Me N 7 H O Ph L4 30 24 88 63 Me Me O 1b 3bf

[Rh(L4)]BF4 was the most promising catalyst for hydroacylation, with 3bf isolated in 88% yield and 63% ee (entry 7), however the enantioselectivity was lower than when

[Rh(BDPP)]BF4 was used as the catalyst. L4 is based on the dcpp ligand scaffold, and so we tested the [Rh(L4)]BF4 catalyst with a series of other ketone substrates that had shown good reactivity with our [Rh(dcpp)]BF4 catalyst; results are shown in Table 2.4.

Table 2.4: Results for hydroacylation of various ketone substrates using [Rh(L4)]BF4

O O O 10 mol% [Rh(L4)]BF4 Me Me + DG O H 0.25 M DCE, R Me DG Me 2 30 °C R 1b 3 Time Yield ee Entry Ketone Product (h) (%) (%)

Me O O Me Me O 1 O Me 18 86 40 N O Bn N 2b Bn 3bb Me O O Me Me O 2 O Me 18 87 40 N O Me N 2i Me 3bi

O O O Ph O N Me N 3 Ph O 45 36 60 O Me O 2g 3bg

We were pleased to discover that the [Rh(L4)]BF4 catalyst showed excellent reactivity with isatin substrates (entries 1 and 2), however enantioselectivities were only modest (40%). We also subjected linear α-ketoamide 2g and aldehyde 1b to our

[Rh(L4)]BF4 catalyst (entry 3), and while this led to improved enantioselectivity (60%) the reaction was sluggish, isolating 3bg in 36% yield after 45 h. Despite being much more reactive, the ability of [Rh(L4)]BF4 to induce enantioselectivity in hydroacylation was consistently inferior to that of [Rh(BDPP)]BF4.

2.3.3 Efforts Towards a Diastereoselective Intermolecular Ketone Hydroacylation

With our dcpp catalyst system demonstrating very good reactivity for intermolecular ketone hydroacylation, we wanted to explore chiral substrates that could induce diastereoselectivity in our reaction. The first substrate that we were interested in testing was synthesized by modifying our general procedure for linear α-ketoamides to incorporate an Evans auxiliary (Scheme 2.5).

O O 1) nBuLi O O THF, -78 °C HN O N 2) O Ph Cl O Ph Ph O 2j 63% Scheme 2.5: Synthesis of α-ketoamide 2j We were able to synthesize 2j in 63% overall yield, and we tested the substrate with aldehydes 1a, 1b, and 1c at 80 °C and 110 °C using our [Rh(dcpp)]BF4 catalyst, however we never observed reactivity with this substrate, and saw full recovery of the starting material. We believe that the electronic properties of 2j are such that it cannot efficiently coordinate to the metal centre to promote hydroacylation. In an effort to maintain similar electronics but incorporate a chiral centre in the ketone substrate, we synthesized two linear α-ketoamides, 2k and 2l, from commercially available (R)-(+)-α-methylbenzylamine (Scheme 2.6).

Me O O O (COCl)2, cat. DMF H N Ph H OH Cl 2 N Ph Ph Ph Ph DCM, rt Et3N, DCM, 0 °C O O O Me 93% (over two steps) 2k O NaH, MeI Me N Ph Ph DMF, 0 °C→rt O Me 94% 2l

Scheme 2.6: Synthesis of chiral substrates 2k and 2l Linear α-ketoamides 2k and 2l were isolated in high yields, and were tested with aldehydes 1a, 1b, and 1c at 80 °C using [Rh(dcpp)]BF4 as the catalyst. Substrate 2k was never observed to undergo hydroacylation, and by 1H NMR the crude reaction mixtures contained some starting material as well as unidentifiable decomposition products. From these experimental observations we believe that the presence of a free N−H bond is detrimental to our catalyst. Substrate 2l only showed reactivity with aldehyde 1c, isolating the corresponding ester product in 76% yield, however the material was an inseparable mixture of diastereomers, with a 1:1.5 dr. We believe that the chiral centre is too far from the site of hydroacylation to induce any significant diastereoselectivity. The final chiral linear α-ketoamide substrate that we synthesized was derived from L-valine. We hypothesized that the bulky isopropyl group may be better at inducing diastereoselectivity in our hydroacylation. The synthesis is shown in Scheme 2.7.

OMe O O H2N O O (COCl) , cat. DMF H OH 2 Cl O N Ph Ph Ph OMe DCM, rt Et3N, DCM, 0 °C O O O 86% (over two steps) 2m

Scheme 2.7: Synthesis of amino acid-derived 2m We were able to isolate substrate 2m in 86% overall yield, and tested it with aldehydes 1a, 1b, and 1c using our [Rh(dcpp)]BF4 catalyst at 80 °C, however this substrate was unreactive with our system. We did not observe any reactivity under

standard conditions, leading us to believe that the methyl ester may be coordinating to the metal centre, impeding our desired hydroacylation reactivity, or that the free N−H bond is problematic for our catalyst. We then decided to incorporate a chiral substituent on the ketone, since chiral substituents on the amide were unsuccessful at inducing any appreciable diastereoselectivity. To synthesize such a ketone, we explored aldol chemistry as a method for generating an α-chiral centre. Preliminary efforts for synthesizing a chiral substrate stemmed from commercially available phenylpyruvic acid (Scheme 2.8).

PhCHO, Bu2BOTf DIPEA, DCM -78 °C→0 °C

Me Ph O O N O (COCl) , cat. DMF Me PhCHO,LiHMDS OH 2 Cl H N Ph DCM, rt Et N, DCM THF, -78 °C Ph O Ph O 3 Ph O 0 °C→rt 63% (over two steps) PhCHO, NaOH EtOH/H2O 0 °C

Scheme 2.8: Efforts towards the synthesis of a phenylpyruvic acid-derived chiral substrate Unfortunately, all of our efforts towards an aldol reaction with phenylpyruvic acid- derived substrates were unsuccessful. We tried boron, lithium, and sodium enolates, however we never observed any product formation. We also synthesized a silicon enolate for a Mukaiyama aldol reaction, however that too was unsuccessful in a 1,2-addition with benzaldehyde. We concluded that the enolate of the α-ketoamide is too stable to undergo 1,2-additions. We then decided to synthesize a substrate derived from 2-oxobutyric acid (Scheme 2.9). We hypothesized that, upon treatment with a strong base, the subsequent enolate would be highly reactive and should undergo the desired aldol reaction.

Me Ph O O N O (COCl)2, cat. DMF H Me OH Cl N Ph DCM, rt Et3N, DCM Me O Me O 0 °C→rt Me O 75% (over two steps) 1) PhCHO OH O TMSOTf TMSO O LDA, -78 °C Me 2,6-lutidine Me N N Ph Ph Ph Ph 2) HCl DCM Me O -78 C Me O 95% ° 2n 60% 2n'

Scheme 2.9: Synthesis of aldol product 2n and TMS protection yielding 2n’ When a lithium enolate was used, and the reaction was quenched with HCl at −78 °C, the aldol product 2n was obtained in 95% yield, however, this was an inseparable mixture of diastereomers. We protected 2n with a TMS group, hoping that it would then be possible to separate the diastereomers, however when we isolated the product 2n’ we were still unable to separate the stereoisomers. Nevertheless, we tested the mixture with our achiral dcpp catalyst and aldehydes 1a, 1b, and 1c at 80 °C, however we only observed elimination of the OTMS group to form the α,β-unsaturated enone, thus indicating that the TMS-protected alcohol is labile under our reaction conditions. To rectify the issues with substrate 2n’, we used an aliphatic aldehyde for the aldol reaction to discourage elimination, and protected the alcohol with a TBS group, anticipating that it would be more stable than the TMS group under our hydroacylation conditions. The synthesis is shown in Scheme 2.10.

O 1) CH3CH2CHO OH O TBSOTf TBSO O Me Me Me N LDA, -78 °C Me N 2,6-lutidine Me N Ph 2) HCl Ph DCM Ph Me O 61% Me O -78 °C Me O 73% 2o 2o'

Scheme 2.10: Synthesis of aldol product 2o and TBS protection yielding 2o’ We were able to synthesize aldol product 2o in 61% yield and TBS-protected 2o’ in a 46% overall yield, however we were not able to separate the diastereomers of either substrate. We subjected the TBS-protected mixture of diastereomers to hydroacylation conditions with our dcpp catalyst and aldehydes 1a, 1b, and 1c at 80 °C, however the substrate was unreactive, with recovery of starting material. We concluded that the

complexity of these substrates is interfering with the catalyst and inhibiting reactivity, perhaps through coordination of the β-oxygen atom. We briefly explored the idea of using a chiral aldehyde to induce diastereoselectivity in hydroacylation, and we chose to use aldehyde 1l (Figure 2.4) that had been synthesized by Dr. I-Hon Chen, a postdoctoral fellow in the Dong group. This aldehyde showed poor reactivity with isatins and linear α-ketoamides using our standard hydroacylation catalyst, and purification by silica gel was unsuccessful, thus we were unable to isolate the reaction products.

O H O 1l

Figure 2.4: Chiral aldehyde 1l 2.4 Conclusions and Future Work

We were able to demonstrate the first enantioselective intermolecular ketone hydroacylation using Rh(I) catalysts with Josiphos and BDPP ligands, with ees as high as 78%. We synthesized novel bidentate phosphine ligands that show promise in improving reactivity and enantioselectivity of intermolecular ketone hydroacylations. Future directions for this project include additional ligand syntheses in an attempt to improve the enantioselectivity of intermolecular ketone hydroacylations, and developing additional chiral substrates for a diastereoselective hydroacylation. We also hope to conduct stoichiometric studies with our catalysts to better understand the reaction mechanism and the role of the aldehyde in enantioinduction.

2.5 Experimental Procedures and Characterization Data

2.5.1 General Considerations

Commercial reagents were purchased from Sigma Aldrich, Strem, Alfa Aesar, Acros and Solvias and used without further purification. All reactions were carried out under an inert atmosphere (N2(g) or Ar(g)). Solvents used in rhodium-catalyzed hydroacylations were first distilled and then degassed by three freeze-pump-thaw cycles

before being taken into a glove box. Other solvents were dried through two columns of activated alumina. Reactions were monitored using thin-layer chromatography (TLC) on EMD Silica Gel 60 F254 plates or by 1H NMR spectroscopy. Visualization of the developed plates was performed under UV light (254 nm) or KMnO4 stain. Column chromatography was performed with Silicycle Silia-P Flash Silica Gel using glass columns. Preparative-TLC was performed with 0.5 mm EMD Silica Gel 60 F254 plates. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. 1H and 13C NMR spectra were recorded on a Varian Mercury 300, Varian Mercury 400, or Bruker 400. NMR spectra were internally referenced to the residual solvent signal or TMS. Data for 1H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant (Hz), integration. Data for 13C NMR are reported in terms of chemical shift (δ ppm). High resolution mass spectra (HRMS) were obtained on a micromass 70S-250 spectrometer (EI) or an ABI/Sciex Qstar Mass Spectrometer (ESI). Enantiomeric excesses (ees) were ascertained on an Agilent 1200

Series HPLC using supercritical CO2 generated by an Aurora SFC system. Specific SFC columns and conditions can be found in Appendix B.

2.5.2 General Procedure for Ditosylation of Diols

To a flame-dried round bottom flask was added 1.000 g (9.60 mmol, 1.0 equiv.) (S,S)-2,4-pentanediol and 7.322 g (38.4 mmol, 4.0 equiv.) dry tosyl chloride. The vessel was purged with Ar(g) for 5 min while cooling to 0 °C, followed by the addition of 7.5 mL of anhydrous pyridine to the flask. The resulting yellow solution was allowed to warm to rt over 24 h. After 24 h the reaction was not complete (by TLC and LC-MS analyses), and so another 1.830 g (9.60 mmol, 1.0 equiv.) tosyl chloride was added to the solution. The reaction continued to stir at rt, and after another 24 h the reaction was quenched with ice cold distilled H2O. The resulting solution was extracted three times in DCM. The combined organic fractions were washed with 1 M HCl, then sat. NaHCO3, and then brine. The organic layer was dried over Na2SO4, and the solvent was removed in vacuo, recovering a yellow oil. The crude material was purified by flash column chromatography (20% EtOAc in hexanes) and a crystalline white solid was isolated (2.304 g, 58%).

2.5.3 General Procedure for the Preparation of Phosphine Ligands

To a flame-dried round bottom flask was added 720 mg (2.2 equiv.) of phosphine- borane adduct (Scheme 2.3) dissolved in 5 mL dry THF, followed by an additional 5 mL

THF rinse. The reaction was cooled to -78 °C under N2(g), after which 3.85 mL (2.2 equiv.) nBuLi (2.5 M in hexanes) was added, dropwise. The reaction was stirred for ~10 min. In a separate oven-dried round bottom flask was added 1,3-dibromopropane (or appropriate ditosylate) and 3 mL dry DMF. This solution was added dropwise to the phosphine mixture at -78 °C, followed by an additional 3 mL DMF rinse. The reaction was stirred at -78 °C for 30 min, then warmed to 0 °C over 30 min, and then was allowed to warm to rt over 21 h. The adduct was extracted in diethyl ether with 10% HCl. The combined organic layers were washed twice with distilled H2O and once with brine. The organic layers were dried over Na2SO4, filtered, and the solvent was removed in vacuo. The material was purified by flash column chromatography (20% EtOAc/hexanes) and isolated in 99% yield (760 mg). The purified adduct was added to a flame-dried Schlenk tube, followed by 488 mg

(3 equiv.) DABCO. The vessel was flushed with Ar(g) followed by the addition of 9 mL dry toluene. The vessel was sealed and heated to 80 °C for 24 hours, after which the toluene was removed in vacuo. The crude material was brought into the glovebox, dissolved in dry pentane and filtered through a plug of silica. The solvent was removed in vacuo, isolating the pure ligand L4 in 42% yield.

2.5.4 Procedure for the Preparation of Evans’ Auxiliary Substrate 2j

1.3 mmol (1.0 equiv.) benzoylformic acid was added to a flame-dried round bottom flask equipped with a magnetic stir bar, and was dissolved in 3 mL dry DCM. This solution was stirred under N2(g) for 2 min followed by the addition of 1.3 mmol (1.0 equiv.) oxalyl chloride in one portion. The colourless solution was stirred for 10 min followed by one drop of dry DMF. The solution turned yellow, bubbled, and was stirred at room temperature under N2(g) for 1 h, after which the DCM was removed in vacuo, recovering a yellow oil. This material was carried forward without any further purification.

To a flame-dried round bottom flask equipped with a magnetic stir bar was added 1.2 mmol (1.0 equiv.) (S)-4-benzyl-2-oxazolidinone followed by 5 mL dry THF. The resulting solution was cooled to -78 °C under N2(g) after which 1.3 mmol (1.1 equiv.) nBuLi (2.5 M in hexanes) was added dropwise to the solution. The reaction stirred at -78 °C for 30 min, followed by addition of the acid chloride dissolved in 1 mL dry THF over 10 min. The reaction stirred at -78 °C and was allowed to warm to rt over 17 h, after which it was extracted in DCM with 1M HCl, then brine. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude yellow oil was purified by flash column chromatography, and isolated in 63% yield.

2.5.5 General Procedure for Aldol Condensations

To a flame-dried round bottom flask was added 5 mL dry THF, which was cooled to -78 °C under N2(g). Once cooled, 628 µL (1.2 equiv.) LDA (2.0 M in THF) was added to the vessel. In a separate flame-dried round bottom flask was added 200 mg (1.0 equiv.)

α-ketoamide. The vessel was evacuated for ~10 min, then refilled with N2(g), after which 5 mL dry THF was added. The solution containing the substrate was added in one portion to the solution of LDA; the resulting mixture continued to stir at -78 °C. After 20 min 160 µL (1.5 equiv.) benzaldehyde was added to the reaction in one portion. The reaction stirred at -78 °C for 5 min after which 1 M HCl was added to quench the reaction. The solution was allowed to warm to rt, after which it was diluted with sat. NaHCO3 and extracted with diethyl ether. The combined organic layers were washed with brine and dried over Na2SO4. The solution was filtered and solvent removed in vacuo. The crude material was purified by flash column chromatography to give the product as an inseparable 1:1.5 mixture of diastereomers.

2.5.6 General Procedure for Silyl-Protection of Alcohols

To a flame-dried round bottom flask was added 75 mg (1.0 equiv.) Aldol product

2o followed by 2 mL dry DCM. The solution was cooled to 0 °C under N2(g), and 36 µL (1.5 equiv.) 2,6-lutidine was added. The reaction was stirred for ~10 min followed by dropwise addition of 53 µL (1.1 equiv.) TBSOTf. The reaction continued to stir at 0 °C for 2 h, after which the solution was diluted with sat. NaHCO3 and extracted with DCM.

The combined organic layers were washed with brine and dried over Na2SO4. The solution was filtered and solvent removed in vacuo, isolating a yellow oil. The crude material was purified by flash column chromatography, however the diastereomers were inseparable.

2.5.7 Characterization Data

Me Me

TsO OTs (S,S,)-OTs (2S,4S)-pentane-2,4-diyl bis(4-methylbenzenesulfonate) ((S,S)-OTs): Synthesized according to general procedure for ditosylation of diols, the product was isolated in 58% 1 yield (2.304 g). H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8 Hz, 4H), 7.34 (d, J = 8 Hz, 4H), 4.71 (sextet, J = 6.4 Hz, 2H), 2.45 (s, 6H), 1.88 (t, J = 6 Hz, 2H), 1.23 (d, J = 6.4 13 1 Hz, 6H). C{ H} NMR (101 MHz, CDCl3) δ 144.8, 134.5, 130.0, 127.9, 76.9, 44.1, 21.8, + + 21.5. HRMS (ESI) Calcd. for [C19H28NO6S2] ([M+H] ) 430.1358, found 430.1357.

Me Me

Cy2P PCy2 L1 (2S,4S)-pentane-2,4-diylbis(dicyclohexylphosphine) (L1): Synthesized according to general procedure for the preparation of phosphine ligands, the product was spilt and an 1 isolated yield was unattained. H NMR (400 MHz, CDCl3) δ 2.25-1.50 (m, 27H), 1.46- 31 0.74 (m, 27H); P NMR (162 MHz, CDCl3) δ 10.8 (s). Characterization data matched that in the literature.38

Me Me tBu Me P P

Me tBu L2

(SP,SP)-(2S,4S)-pentane-2,4-diylbis(tert-butyl(methyl)phosphine) (L2): Synthesized according to general procedure for the preparation of phosphine ligands, the product was isolated as a colourless oil.40

Me Me tBu Me P P

Me tBu L3

(SP,SP)-(2R,4R)-pentane-2,4-diylbis(tert-butyl(methyl)phosphine) (L3): Synthesized according to general procedure for the preparation of phosphine ligands, the product was 1 isolated as a colourless oil. H NMR (400 MHz, C6D6) δ 1.89-1.85 (m 1H), 1.75-1.68 (m, 1H), 1.04 (d, J = 11 Hz, 9H), 0.99-0.95 (m, 3H), 0.83 (d, J = 4Hz, 3H). 13C{1H} NMR

(101 MHz, C6D6) δ 44.0 (t, J = 26 Hz), 30.2, 28.3 (d, J = 16 Hz), 28.2 (d, J = 14 Hz), 25.8 (dd, J = 19, 14 Hz), 15.9 (d, J = 4 Hz), 3.8 (d, J = 25 Hz). δ 31P{1H} NMR (162 41 MHz, C6D6) δ -1.31.

tBu Me P P

Me tBu L4

(SP,SP)1,3-bis(tert-butyl(methyl)phosphino)propane (L4): Synthesized according to general procedure for the preparation of phosphine ligands, the product was isolated as a 1 colourless oil (150 mg, 42%). H NMR (400 MHz, C7D8) δ 1.36-1.17 (m, 4H), 1.03-0.95 (m, 2H), 0.70 (s, 9H), 0.67 (s, 9H), 0.52 (d, J = 3.2 Hz, 6H). 13C{1H} NMR (101 MHz,

C7D8) δ 28.2 (dd, J = 17.9, 11.9 Hz), 27.4 (d, J = 13.8 Hz), 27.3 (d, J = 11.6 Hz), 24.8 (t,

40 Full characterization of L2 was not completed due to low yielding purification and low enantioselectivity of hydroacylation products. 41 Yield was not recorded due to the small scale of the reaction. A mass spectrum was not recorded due to the innate air sensitivity of L3

31 1 J = 18.5 Hz), 7.7 (d, 22 Hz). P{ H} NMR (162 MHz, C7D8) δ -17.5. HRMS (ESI) + + Calcd. for [C13H31P2] ([M+H] ) 249.1901, found 249.1901.

O Ph O Me N O Me O 3bg 2-morpholino-2-oxo-1-phenylethyl isobutyrate (3bg): Synthesized according to general procedure for rhodium-catalyzed hydroacylation (Chapter 1), the product was isolated as 1 a white solid (11 mg, 36%). H NMR (400 MHz, CDCl3) δ 7.44-7.39 (m, 5H), 6.20 (s, 1H), 3.64-3.25 (m, 8H), 2.69 (heptet, J = 7.0 Hz, 1H), 1.26 (d, J = 7.0 Hz, 3H), 1.19 (d, J 13 1 = 6.9 Hz, 3H). C{ H} NMR (101 MHz, CDCl3) δ 176.9, 166.8, 134.3, 129.5, 129.2, 128.3, 73.0, 66.9, 66.2, 46.0, 42.8, 33.9, 19.1, 18.9. HRMS (ESI) Calcd. for + + [C16H22NO4] ([M+H] ) 292.1543, found 292.1552.

Me O

Me O Me O N Me 3bi 1,5-dimethyl-2-oxoindolin-3-yl isobutyrate (3bi): Synthesized according to general procedure for rhodium-catalyzed hydroacylation (Chapter 1), the product was isolated as 1 a colourless oil (22 mg, 87%). H NMR (400 MHz, CDCl3) δ 7.15-7.13 (m, 2H), 6.72 (d, J = 8 Hz, 1H), 5.92 (s, 1H), 3.19 (s, 3H), 2.70 (m, 1H), 2.31 (s, 3H), 1.23 (m, 6H). 13 1 C{ H} NMR (101 MHz, CDCl3) δ 176.6, 172.4, 142.2, 132.9, 130.5, 126.2, 124.8, + 108.3, 69.9, 33.9, 26.5, 21.1, 19.1, 19.0. HRMS (ESI) Calcd. for [C14H17NO3Na] ([M+Na]+) 270.1100, found 270.1112.

O O O N

O Ph 2j (S)-1-(4-benzyl-2-oxooxazolidin-3-yl)-2-phenylethane-1,2-dione (2j): Synthesized according to procedure for the preparation of Evans’ auxiliary substrate 2j, the product 1 was isolated as a white solid (236 mg, 63%). H NMR (400 MHz, CDCl3) δ 7.90-7.88 (m, 2H), 7.68-7.64 (m, 1H), 7.55-7.51 (m, 2H), 7.41-7.28 (m, 5H), 4.85-4.79 (m, 1H), 4.44- 4.40 (m, 1H), 4.34 (dd, J = 9.3, 3.5 Hz, 1H), 3.55 (dd, J = 13.6, 3.6 Hz, 1H), 2.99 (dd, J = 13 1 13.5, 9.4 Hz, 1H). C{ H} NMR (100 MHz, CDCl3) δ 187.7, 166.8, 153.1, 134.9, 134.5,

132.6, 129.6, 29.5, 129.3, 129.2, 127.9, 68.3, 54.3, 37.8. HRMS (ESI) Calcd. For [C18H- + + 16NO4] ([M+H] ) 310.10793, found 310.10849.

O H N Ph Ph O Me 2k (R)-2-oxo-2-phenyl-N-(1-phenylethyl)acetamide (2k): Synthesized according to general procedure for the preparation of linear α-ketoamides (Chapter 1) the product was isolated 1 as a yellow solid (1.392 g, 93%). H NMR (400 MHz, CDCl3) δ 8.36-8.33 (m, 2H), 7.64- 7.60 (m, 1H), 7.49-7.45 (m, 2H), 7.38-7.24 (m, 5H), 5.23-5.16 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H). Characterization data matched that in the literature.42

O Me N Ph Ph O Me 2l (R)-N-methyl-2-oxo-2-phenyl-N-(1-phenylethyl)acetamide (2l): Synthesized according to general procedure for the preparation of N-substituted isatins (Chapter 1) from linear α- ketoamide 2k, the product was isolated as a colourless oil (493 mg, 94%). 1H NMR (400

42 Takeuchi, Y.; Itoh, N.; Satoh, T.; Koizumi, T.; Yamaguchi, K. J. Org. Chem. 1993, 58, 1812.

MHz, CDCl3) δ 8.05-8.02 (m, 1H), 7.97-7.94 (m, 1H), 7.69-7.62 (m, 1H), 7.57-7.52 (m, 2H), 7.41-7.26 (m, 5H), 6.13 (q, J = 7.2 Hz, 0.5H), 4.90 (q, J = 7.2 Hz, 0.5H), 2.80 (s, 1.5H), 2.62 (s, 1.5H), 1.65 (d, J = 7.2 Hz, 1.5H), 1.60 (d, J = 6.8 Hz, 1.5H). 13C{1H}

NMR (100 MHz, CDCl3) δ 191.9, 191.6, 167.4, 167.2, 139.2, 138.5, 134.9, 134.8, 133.5, 133.3, 129.9, 129.7, 129.2, 129.2, 128.9, 128.8,128.2, 128.0, 127.6, 127.3, 55.7, 50.4, + + 29.6, 26.6, 16.9, 15.5. HRMS (ESI) Calcd. for [C17H21N2O2] ([M+NH4] ) 285.1603, found 285.1600.

O O H N Ph OMe O 2m (S)-methyl 3-methyl-2-(2-oxo-2-phenylacetamido)butanoate (2m): Synthesized according to general procedure for linear α-ketoamides (Chapter 1) the product was isolated as a 1 colourless oil (865 mg, 86%). H NMR (300 MHz, CDCl3) δ 8.34-8.31 (m, 2H), 7.66- 7.60 (m, 1H), 7.52-7.45 (m, 3H), 4.61 (dd, J = 9.1, 5.0 Hz, 1H), 3.78 (s, 3H), 2.33-2.24 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H). Characterization data matched that in the literature.43

43 Müller, E.; Péczely, G.; Skoda-Földes, R.; Takács, E.; Kokotos, G.; Bellis, E.; Kollár, L. Tetrahedron 2005, 61, 797.

Appendix A: NMR Spectra

Appendix B: Chiral-SFC Traces

O Ph O Me H O N Me 3ch (±) CHIRALCEL OD-H SFC (4.6 x 100 mm), 9:1 CO2:MeOH, 3 mL/min, 254 nm, tR1=1.8 min, tR2=2.4 min

[Rh(SL-J212)]BF4, 2 equiv. aldehyde, 50 °C, 20 h (Table 2.1, entry 1)

[Rh(SL-J212)]BF4, 1 equiv. aldehyde, 20 °C, 8 h (Table 2.1, entry 2)

[Rh(SL-J212)]BF4, 1.5 equiv. aldehyde, 20 °C, 8 h (Table 2.1, entry 3)

[Rh(SL-J212)]BF4, 2 equiv. aldehyde, 20 °C, 8 h (Table 2.1, entry 4)

[Rh(SL-J212)]BF4, 3 equiv. aldehyde, 20 °C, 8 h (Table 2.1, entry 5)

[Rh(SL-J212)]BF4, 5 equiv. aldehyde, 20 °C, 8 h (Table 2.1, entry 6)

[Rh(SL-J212)]BF4, 2 equiv. aldehyde, 0 °C, 8 h (Table 2.1, entry 7)

O Ph Me Me N O Ph Me O 3aa (±) CHIRALPAK IC (4.6 x 250 mm), 9:1 CO2:MeOH, 3 mL/min, 254 nm, tR1=1.9 min, tR2=2.0 min

[Rh(BDPP)]BF4, 30 °C, 24 h (Table 2.2, entry 1)

[Rh(BDPP)]BF4, 30 °C, 72 h (Table 2.2, entry 2)

[Rh(BDPP)]BF4, 50 °C, 24 h (Table 2.2, entry 3)

[Rh(L1)]BF4, 30 °C, 45 h (Table 2.3, entry 1)

[Rh(L2)]BF4, 30 °C, 24 h (Table 2.3, entry 2)

[Rh(L2)]BF4, 50 °C, 24 h (Table 2.3, entry 3)

[Rh(L3)]BF4, 30 °C, 20 h (Table 2.3, entry 6)

[Rh(L4)]BF4, 30 °C, 24 h (Table 2.3, entry 7)

Me O Ph Me Me N Me O Ph O 3ba (±) CHIRALPAK IC (4.6 x 250 mm), 9:1 CO2:MeOH, 3 mL/min, 254 nm, tR1=1.8 min, tR2=2.0 min

[Rh(BDPP)]BF4, 30 °C, 72 h (Table 2.2, entry 4)

[Rh(BDPP)]BF4, 50 °C, 48 h (Table 2.2, entry 5)

[Rh(L2)]BF4, 30 °C, 12 h (Table 2.3, entry 4)

[Rh(L2)]BF4, 50 °C, 12 h (Table 2.3, entry 5)

O Ph O Me N O Me O 3ab (±) CHIRALPAK IC (4.6 x 250 mm), 9:1 CO2:MeOH, 3 mL/min, 254 nm, tR1=2.2 min, tR2=2.5 min

[Rh(L4)]BF4, 30 °C, 45 h (Table 2.4, entry 1)

Me O

Me O Me O N Bn 3ae (±) CHIRALPAK IC (4.6 x 250 mm), 9:1 CO2:MeOH, 3 mL/min, 254 nm, tR1=3.5 min, tR2=4.1 min

[Rh(L4)]BF4, 30 °C, 18 h (Table 2.4, entry 2)

Me O

Me O Me O N Me 3ah (±) CHIRALPAK AD-H SFC (4.6 x 100 mm), 19:1 CO2:MeOH, 3 mL/min, 254 nm, tR1=1.1 min, tR2=1.5 min

[Rh(L4)]BF4, 30 °C, 18 h (Table 2.4, entry 3)