Asymmetric Transformations Catalyzed by Chiral BINOL Alkaline Earth Metal Phosphate Complexes Sri Krishna Nimmagadda University of South Florida, [email protected]

Asymmetric Transformations Catalyzed by Chiral BINOL Alkaline Earth Metal Phosphate Complexes Sri Krishna Nimmagadda University of South Florida, Sri1@Mail.Usf.Edu

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10-26-2016 Asymmetric Transformations Catalyzed By Chiral BINOL Alkaline Earth Metal Phosphate Complexes Sri Krishna Nimmagadda University of South Florida, [email protected]

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Asymmetric Transformations Catalyzed By

Chiral BINOL Alkaline Earth Metal Phosphate Complexes

Sri Krishna Nimmagadda

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida

Major Professor: Jon Antilla, Ph.D. James Leahy, Ph.D. Wayne Guida, Ph.D. Jianfeng Cai, Ph.D.

Date of Approval: October 19, 2016.

Keywords: asymmetric catalysis, organocatalysis, chiral alkaline earth metal phosphate, oxazolidines, oxazinanes, hemiaminals, desymmetrization, dynamic kinetic resolution.

Acknowledgments

Firstly, I would like to thank my advisor Dr. Jon Antilla for giving me the opportunity to work under his supervision and pursue my dream. He is an exceptional mentor, constantly motivating me by giving suggestions personally and professionally and also believing in me to work independently on my own projects and his guidance in times of need. I’m grateful that he allowed me to do internship, which helped me not only to hone my skills in research but also enhanced my exposure in the field of organic chemistry. I’m always indebted to him for the guidance, exceptional support and being a good friend.

I would sincerely thank my committee members Dr. Wayne Guida, Dr. Jianfeng Cai, Dr. James

Leahy and Dr. Mark McLaughlin for their valuable insights during the meetings. I also like to express my gratitude to Dr. Mike Shi for his passion towards chemistry and allowing me to sit in his group meetings which really helped me to learn new chemistry and also kept me motivated.

I’m lucky to have very friendly colleagues in our lab, Dr. Guilong Li, Dr. Gajendrasingh Ingle,

Dr. Shawn Larson, Dr. Tao Liang, Dr. Youngran Ji, Dr. Susana Lopez, Trang and the undergraduates who worked with me Jalak, Ian, Karissa, and like to thank everyone who helped me directly or indirectly. Especially Dr. Pankaj Jain and Dr. Zuhui Zhang helped me during my early years of grad school by teaching lab skills, science discussions and patiently answering my questions.

I’m thankful for my friends outside lab Dr. Naga Duggirala, Dr. Srinivas Harinath, Dr.

Ramakanth, Dr. Padmini, Dr. Sridhar, Dr. Cyndi, Dr. Kurt, Dr. Praveen, Dr. Raghu, Dr. Xiaohan

Ye, Stephen Motika, Ankush Kanwar, Zachary Shultz, Robert Leon, Tirupathi Reddy for having fun during weekends playing tennis, pool and softball. It always feels good to have good friends especially when staying far away from family and I’m grateful to everyone.

Lastly, I would like to thank my parents, especially my dad who is a real role model for me since childhood for encouraging me in everything, giving me confidence during bad times and all his sacrifices. I would also like to thank my brother Pavan and sister Sarojini for being there all the time for me. I would also thank my family members Prasad, Raja Sree, Subrahmanyam, Durga

Prasad, Jaya Sree and Venu for their continuous support.

Table of Contents

List of Tables ...... iii

List of Figures ...... iv

List of Abbreviations ...... viii

Abstract ...... ix

1. Asymmetric reactions catalyzed by chiral alkaline earth metal complexes ...... 1 1.1 Chirality and asymmetric synthesis ...... 1 1.2 Chiral alkaline earth metal complexes ...... 2 1.3 Activation mode of alkaline earth metal complexes ...... 3 1.4 Complexes with chiral bissulfonamide type ligands ...... 4 1.5 Complexes with chiral BINOL type ligands ...... 4 1.5.1 Reactions catalyzed by BINOL derived calcium complexes ...... 6 1.5.2 Reactions catalyzed by BINOL derived barium complexes ...... 7 1.6 Complexes with chiral diol ligands...... 8 1.7 Complexes with chiral phosphoric acid ligands ...... 10 1.8 Complexes with chiral Bisoxazoline (Box) ligands...... 14 1.9 Complexes with chiral Pyridine Bisoxazoline (Pybox) ligands ...... 17 1.10 Conclusion ...... 19 1.11 References ...... 19

2. Asymmetric one-pot synthesis of 1,3-oxazolidines and 1,3-oxazinanes via hemiaminal intermediates ...... 22 2.1 Introduction ...... 22 2.2 1,3-oxazolidines as chiral auxiliaries ...... 23 2.3 1,3-oxazolidines as chiral ligands in asymmetric reactions ...... 24 2.4 Synthesis of chiral 1,3-oxazolidines ...... 25 2.4.1 Stereospecific synthetic methods ...... 25 2.4.2 Stereoselective synthetic methods ...... 27 2.5 Chiral BINOL phosphoric acids and alkaline earth metal phosphates ...... 28 2.6 Asymmetric one-pot synthesis of 1,3-oxazolidines ...... 32 2.7 Optimization of reaction conditions...... 34 2.8 Substrate scope for one-pot synthesis of chiral 1,3-oxazolidines ...... 36 2.9 Asymmetric one-pot synthesis of 1,3-oxazinanes ...... 37 2.10 Substrate scope for one-pot synthesis of chiral 1,3-oxazinanes ...... 39 2.11 Conclusion ...... 40 2.12 Experimental data ...... 40 2.13 References ...... 51 i

3. Desymmetrization of 4-substituted cyclohexanones: Enantioselective synthesis of novel axially chiral cyclohexylidene oximes ...... 55 3.1 Introduction ...... 55 3.2 Desymmetrization of cyclic ketones ...... 55 3.3 Desymmetrization reaction of cyclic ketones catalyzed by chiral BINOL phosphoric acid ...... 62 3.4 Desymmetrization of cyclic ketones to form axially chiral compounds...... 63 3.4.1 Synthesis of axially chiral cyclohexylidenes ...... 64 3.4.2 Synthesis of axially chiral cyclohexylidene oximes ...... 65 3.5 Optimization of reaction conditions for the asymmetric synthesis of cyclohexylidene oximes ...... 67 3.6 Substrate scope for the asymmetric synthesis of cyclohexylidene oxime ethers ...... 69 3.7 Conclusion ...... 72 3.8 Experimental data ...... 72 3.9 X-ray crystallography data ...... 83 3.10 References ...... 86

4. Dynamic Kinetic Resolution of 2-substituted cyclohexanones ...... 90 4.1 Introduction ...... 90 4.2 DKR by asymmetric transfer hydrogenation of 2-substituted cyclohexanones ...... 91 4.3 Optimization of reaction conditions for dynamic kinetic resolution of 2-substituted cyclohexanones ...... 94 4.4 Substrate scope for the DKR of 2-substituted cyclohexanones ...... 97 4.5 Conclusion ...... 97 4.6 Experimental data ...... 98 4.7 References ...... 106

Appendix I - HPLC and NMR data for Chapter 2 ...... 109

Appendix II - NMR and HPLC data for Chapter 3 ...... 143

Appendix III - NMR and HPLC data for Chapter 4 ...... 172

Appendix IV - Copyrights and Permissions ...... 191

List of Tables

Table 2.1 Optimization to find real catalyst ...... 31

Table 2.2 Trace element analysis by ICP-OES ...... 31

Table 2.3 Optimization of reaction conditions for alcohol addition to imines ...... 34

Table 2.4 Optimization of base mediated intramolecular cyclization ...... 35

Table 2.5 Optimization of reaction conditions...... 38

Table 2.6 Optimization of base mediated intramolecular cyclization ...... 38

Table 3.1 Optimization of reaction conditions...... 68

Table 3.2 Solvent and temperature screening ...... 69

Table 4.1 Optimization for DKR of 2-substituted cyclohexanones ...... 95

iii

List of Figures

Figure 1.1 Asparagine (1), Thalidomide (2)...... 2

Figure 1.2 Activation mode ...... 3

Figure 1.3 Asymmetric reactions catalyzed by chiral bissulfonamide alkaline earth metal complexes...... 5

Figure 1.4 Chiral BINOL derived alkaline earth metal complexes ...... 5

Figure 1.5 Calcium-BINOL complex catalyzed Morita-Baylis-Hillman reaction ...... 6

Figure 1.6 Asymmetric reactions catalyzed by calcium-BINOL complexes ...... 6

Figure 1.7 Asymmetric Aldol reaction catalyzed by barium-BINOL complex ...... 7

Figure 1.8 Friedel-Crafts type alkylation catalyzed by barium-BINOL complex ...... 8

Figure 1.9 Chiral calcium alkoxide catalyzed asymmetric aldol reaction ...... 8

Figure 1.10 Asymmetric Mannich reaction catalyzed by barium biphenolate ...... 9

Figure 1.11 Asymmetric reactions catalyzed by chiral barium and strontium alkoxide complexes ...... 9

Figure 1.12 Chiral BINOL derived alkaline earth metal phosphate complexes ...... 10

Figure 1.13 Asymmetric Mannich reaction catalyzed by calcium-BINOL phosphate complex...... 11

Figure 1.14 Asymmetric reactions catalyzed by calcium-VAPOL phosphate complexes ...... 11

Figure 1.15 Asymmetric synthesis of aziridines ...... 12

Figure 1.16 Asymmetric phosphination, Diels-Alder and hetero-Diels-Alder reactions catalyzed by metal-BINOL phosphate complexes ...... 12

Figure 1.17 Asymmetric carbonyl-ene reaction and Friedel-Crafts reaction catalyzed by calcium-BINOL phosphate complex ...... 13

Figure 1.18 Calcium-BINOL phosphate catalyzed asymmetric amination reactions ...... 14

Figure 1.19 Chiral bisoxazoline-calcium complexes ...... 14

Figure 1.20 Chiral Box-calcium complexes catalyzed asymmetric 1,4-addition and [3+2] cycloaddition reactions ...... 15

Figure 1.21 Asymmetric 1,4-addition and [3+2] cycloaddition reactions ...... 16

Figure 1.22 Chiral calcium-Pybox complexes ...... 17

Figure 1.23 Calcium-Pybox catalyzed asymmetric 1,4-addition and Mannich reactions ...... 17

Figure 1.24 Asymmetric 1,4-addition and Mannich reactions ...... 18

Figure 2.1 Polycyclic tetrahydroisoquinoline alkaloids ...... 22

Figure 2.2 Reactions with 1,3-oxazolidines as chiral auxiliaries ...... 23

Figure 2.3 Chiral 1,3-oxazolidine ligands ...... 24

Figure 2.4 Asymmetric allylic alkylation and Diels-Alder reactions ...... 24

Figure 2.5 Condensation of chiral aminoalcohols with aldehydes and ketones ...... 25

Figure 2.6 Double Michael addition reaction ...... 26

Figure 2.7 Formal cycloaddition of vinyl epoxides with imines ...... 26

Figure 2.8 Asymmetric oxyamination and formal cycloaddition reactions for stereoselective synthesis of chiral oxazolidines ...... 27

Figure 2.9 Chiral phosphoric acids...... 28

Figure 2.10 General synthetic scheme for the preparation of chiral BINOL phosphoric acid ...... 29

Figure 2.11 Asymmetric Mannich reactions catalyzed by chiral BINOL phosphoric acid ...... 30

Figure 2.12 Chiral BINOL metal phosphate complex ...... 32

Figure 2.13 Enantioselective addition of alcohols to imines...... 33

Figure 2.14 Retrosynthetic pathway ...... 33

Figure 2.15 Substrate scope for chiral 1,3-oxazolidines ...... 37

Figure 2.16 Substrate scope for one-pot synthesis of chiral 1,3-oxazinanes ...... 39

Figure 3.1 Tandem aminoxylation and O-N bond heterolysis of cyclohexanones ...... 56

Figure 3.2 Asymmetric aldol reaction of cyclohexanones with aldehydes ...... 56

Figure 3.3 Asymmetric intramolecular aldolization...... 57

Figure 3.4 Desymmetrization and intramolecular aldolization ...... 58

Figure 3.5 Enantioselective Friedländer condensation ...... 59

Figure 3.6 Asymmetric alkylation of cyclohexanones catalyzed by functionalized chiral ionic liquids (FCIL) ...... 59

Figure 3.7 Desymmetrization of cyclohexanones by asymmetric Michael addition ...... 60

Figure 3.8 Catalytic desymmetrizing asymmetric ring expansion ...... 61

Figure 3.9 Asymmetric Baeyer-Villiger oxidation ...... 61

Figure 3.10 Chiral BINOL phosphoric acid catalyzed Baeyer-Villiger oxidation...... 62

Figure 3.11 Catalytic enantioselective Fischer indolization ...... 63

Figure 3.12 Axially chiral compounds ...... 63

Figure 3.13 Asymmetric HWE reaction ...... 64

Figure 3.14 Asymmetric Peterson reaction ...... 65

Figure 3.15 First isolation of optically active cyclohexylidene oximes ...... 66

Figure 3.16 Enzyme catalyzed kinetic resolution of cyclohexylidene oxime ethers ...... 67

Figure 3.17 Substrate scope with different aryloxyamines ...... 70

Figure 3.18 Substrate scope with different 4-substituted cyclohexanones ...... 71

Figure 3.19 Synthesis of 4-aryl cyclohexanones……………………………………………...73

Figure 3.20 Synthesis of aryloxyamines………………………………………………………73

Figure 4.1 Dynamic Kinetic Resolution (DKR) process ...... 90

Figure 4.2 DKR of imines by asymmetric transfer hydrogenation ...... 91

Figure 4.3 Asymmetric reductive amination of α-branched ketones ...... 92

Figure 4.4 Asymmetric hydrogenation of aryl heterocycloalkyl ketones ...... 93

Figure 4.5 Asymmetric hydrogenation of α,α’-disubstituted cycloketones ...... 94

Figure 4.6 DKR of 2-phenyl cyclohexanone with phenoxyamine ...... 94

Figure 4.7 Substrate scope for the DKR of 2-substituted cyclohexanones ...... 96

Figure 4.8 Reductive cleavage and acylation ...... 97

vii

List of Abbreviations [α] specific rotation Ms methylsulfonyl (mesyl) Å angstrom(s) MTBE methyl tert-butyl ether Ac acetyl m/z mass-to-charge ratio anhyd anhydrous N normal (equivalents per liter) aq aqueous Ph phenyl Ar aryl ppm part(s) per million BINOL 1,1′-bi-2-naphthol Pr propyl Bn benzyl iPr isopropyl BOC, Boc tert-butoxycarbonyl py pyridine Bu, n-Bu normal (primary) butyl q quartet (spectral) s-Bu sec-butyl rt room temperature t-Bu tert-butyl s singlet (spectral) Bz benzoyl t triplet (spectral) °C degrees Celsius TBS tert-butyldimethylsilyl cat catalytic temp temperature Cy cyclohexyl Tf trifluoromethanesulfonyl (triflyl) δ chemical shift in parts per million TFA trifluoroacetic acid downfield from tetramethylsilane TFAA trifluoroacetic anhydride d day(s); doublet (spectral) THF tetrahydrofuran DCE 1,2-dichloroethane TIPS triisopropylsilyl DCM dichloromethane TMEDA N,N,N′,N′-tetramethyl- DMAP 4-(N,N-dimethylamino)pyridine 1,2-ethylenediamine DME 1,2-dimethoxyethane Tr triphenylmethyl (trityl) DMF dimethylformamide Ts para-toluenesulfonyl (tosyl) DMSO dimethyl sulfoxide dr diastereomer ratio equiv equivalent ee enantiomeric excess Et ethyl h hour(s) HPLC high-performance liquid chromatography HRMS high-resolution mass spectrometry Hz hertz J coupling constant (in NMR spectrometry) k kilo L liter(s) LDA lithium diisopropylamide μ micro m multiplet (spectral); meter(s); milli M molar (moles per liter); mega Me methyl MHz megahertz min minute(s) mM millimolar (millimoles per liter) mol mole(s) mp melting point

viii

Abstract

Small molecule hydrogen bond donors have emerged as versatile catalysts in asymmetric synthesis. Within this class, chiral BINOL phosphoric acid is regarded as one of the pioneer catalysts used in several asymmetric transformations. The ability of the catalyst to activate the substrates could be controlled in two different ways. (1) Dual activation/bifunctional activation of substrate by hydrogen bond interactions or ion pairing with phosphoric acid or (2) By forming chiral BINOL phosphate metal complex that could significantly alter the interactions in chiral space. In particular, chiral alkaline earth metal phosphate complexes have unique advantages as catalysts owing to the ubiquitous availability of alkaline earth metals, strong Brønsted basicity of their counterions, mild but significant Lewis acidity of the metal and their ability to coordinate at multiple reactive sites due to large ionic radius.

Chapter 1 summarizes the recent development of alkaline earth metal complexes in asymmetric catalysis. My thesis dissertation is focused on the application of chiral alkaline earth metal phosphate complexes in novel asymmetric reactions.

In Chapter 2, we disclosed an efficient asymmetric one-pot synthesis of chiral 1,3-oxazolidines and chiral 1,3-oxazinanes. Chiral oxazolidines and oxazinanes are widely used as auxiliaries in asymmetric transition metal catalysis and also key structural motifs in natural products with biological activities. We developed a new synthetic method for chiral 1,3-oxazolidines which follows the enantioselective addition of alcohols to imines catalyzed by chiral 3,3’-

(triisopropylphenyl)-derived BINOL magnesium phosphate to form hemiaminal intermediate,

ix which then undergoes mild base mediated intramolecular nucleophilic substitution to afford highly enantioselective 1,3-oxazolidines and 1,3-oxazinanes in good yields.

In Chapter 3, we developed the first catalytic enantioselective desymmetrization process for the synthesis of novel axially chiral cyclohexylidene oxime ethers. Even though these molecules were found to be optically active in 1910, methods to synthesize these molecules are scarce. We have developed an efficient desymmetrization process of 4-phenyl cyclohexanones with phenoxyamines catalyzed by chiral BINOL strontium phosphate complex to afford highly enantioselective products. We then extended this methodology to the dynamic kinetic resolution of 2-substituted cyclohexanones to form chiral 2-substituted cyclohexyl oximes in good enantioselectivities, as demonstrated in Chapter 4. We further demonstrated the utility of these compounds by converting them to chiral 2-aryl cyclohexylamines which are important synthetic intermediates.

1 Asymmetric reactions catalyzed by chiral alkaline earth metal complexes

1.1 Chirality and asymmetric synthesis: Chirality is a property, which is derived from the Greek word “chiral” which in general means

“handedness”. Any molecule that is non-superimposable to its mirror image is known to be a

“chiral molecule” and the mirror images are called as “enantiomers”. Chiral molecules play a prominent role in biological systems, because all amino acids, proteins, carbohydrates, enzymes, etc. are chiral compounds.1 Although, enantiomers have same chemical structure, they will interact with the biological systems in different way in three-dimensional structures and exhibit different properties such as pharmacokinetics, metabolism, toxicology, etc. Piutti in 1886, first observed the notable taste difference in asparagines, in which the S-isomer is tasteless whereas the

R-isomer is sweet. The importance of chiral molecules in pharmaceutical compounds was realized in 1960’s when thalidomide racemate was prescribed for morning sickness. The research showed that R enantiomer of thalidomide has desired analgesic property, but S isomer caused teratogenesis, that led to defects in babies2.

Due to the prominence of chiral compounds in wide range of areas such as medicinal, biological and materials, the asymmetric synthesis of these compounds has been one of the major research interests in modern synthetic organic chemistry. The general asymmetric methods include chiral resolution of mixture of enantiomers, stereospecific synthesis (stoichiometric amount of chiral starting material is used) and asymmetric catalysis (chiral catalyst in used).

Asymmetric catalysis has significant advantages over other methods because small amount of chiral catalyst (as low as 1%) could produce excellent enantioselective products and also atom

1 economical. In 2001, the Noble Prize in Chemistry was awarded to three scientists, Dr. William

S. Knowles, Dr. K. Barry Sharpless and Dr. Ryoji Noyori for their contribution in the development of asymmetric synthesis3 and since then the field of asymmetric catalysis is ever-expanding to new horizons.

Figure 1.1 Asparagine (1), Thalidomide (2).

1.2 Chiral alkaline earth metal complexes: Many new and versatile methodologies have been discovered in the asymmetric synthesis of optically active compounds. Most of these reactions are driven by chiral metal catalysts and have achieved excellent enantioselective products in numerous asymmetric reactions.4 In modern synthetic organic chemistry, the development of environmentally benign synthetic methods has attracted major attention in the viewpoint of green chemistry. That means employing less harmful and less toxic catalysts, reagents, solvents and also to develop efficient chemical processes that generate less byproducts and curtail damage to the environment. In this regard, chiral complexes of alkaline earth metals Magnesium (Mg), Calcium (Ca), Strontium (Sr) and Barium (Ba) as efficient catalysts in asymmetric synthesis has gained recent attention.

Alkaline earth metals are ubiquitous in earth’s crust and show the follwoing characteristic features: (a) due to the low electronegativity, their counterions show strong Brønsted basicity (b) stable divalent oxidation state (c) they have large ionic radius, which will allow for multiple coordination sites and (d) they exhibit mild but significant Lewis acidity. Because of these chemical characteristics, by meticulous design of chiral environment around the alkaline earth metal they could serve as efficient stereoselective catalysts in asymmetric catalysis.5

1.3 Activation mode of alkaline earth metal complexes:

Figure 1.2 Activation mode

Three types of activation mode have been reported for the coordination of chiral alkaline earth metal complexes with substrates. In type I, the metal (M) forms complex with ligand through two covalent bonds. The advantage for this type is chiral environment is strictly controlled because of tight connection of ligand with metal. These complexes are formed with chiral anionic ligands.

In type II activation mode, the complex is formed with one covalent bond and one coordinate bond between metal and ligand in more than bidentate fashion. For these complexes, asymmetric environment is controlled based on the coordination of the free counter anion (Y) and also by using playing with different counter anions reactivity of the complex can be changed. The type III mode is deemed to be challenging to control the chiral environment, because metal and ligand are not bonded with covalent bonds. However, recent reports showed that alkaline earth metals have significant Lewis acidity to form complex with coordinative ligands and in addition, these

3 complexes are more stable to air and moisture compared to type I and type II complexes. Based on the different activation modes, several chiral ligands have been developed to form complexes with alkaline earth metals and applied as chiral catalysts in many important synthetic transformations. The following sections of this chapter have been divided based on the alkaline earth metal complexes formed with different chiral ligands and their applications in asymmetric synthesis.

1.4 Complexes with chiral bissulfonamide type ligands: Evans first developed the magnesium bissulfonamide complex prepared by treating chiral (S,

S)-bissulfonamide derived from 1,2-diphenylethylenediamine with dimethylmagnesium to catalyze the enantioselective amination of N-Acyloxazolidinones, 4 with di-tert-butyl azodicarboxylate as the electrophilic nitrogen source.6 Kobayashi7 et al. reported asymmetric 1,4- addition reactions of malonates, 6 with chalcones, 7 employing strontium metal complex yielding products with excellent enantioselectivities. The complex is formed by reacting chiral bissulfonamide ligand with strontium isopropoxide (Sr(OiPr)2). In addition, they also showed upon using Sr(HMDS)2 afforded more active catalyst. Furthermore, they reported asymmetric

Mannich reactions of sulfonylimidates, 9 with imines, 10 using this methodology. Reactions with chiral bissulfonamide ligand follow type I activation mode in which metal and ligand are connected with two covalent bonds in bidentate fashion (Figure 1.3).

1.5 Complexes with chiral BINOL type ligands: Chiral BINOL derivatives one of the versatile ligands used as catalysts in many asymmetric reactions. In these compounds, the ligand coordinates to the metal in bidentate fashion leading to the strict control of asymmetric environment. The BINOL derived alkaline earth metal complexes

4 show strong Brønsted basicities and also the coordination of metal to substrates can be controlled due to the significant Lewis acidity of the alkaline earth metals.

Figure 1.3 Asymmetric reactions catalyzed by chiral bissulfonamide alkaline earth metal complexes.

Figure 1.4 Chiral BINOL derived alkaline earth metal complexes.

1.5.1 Reactions catalyzed by BINOL derived calcium complexes: Yamada, reported asymmetric Morita-Baylis-Hillman reaction of cylopentenone, 15 with 3- phenylpropanal, 16 in presence of calcium complex of BINOL, 12a and tributylphosphine.8 The catalyst serves as Lewis acid catalyst to afford products with good yield and moderate enantioselectivity. (Figure 1.5).

Figure 1.5 Calcium-BINOL complex catalyzed Morita-Baylis-Hillman reaction.

Figure 1.6 Asymmetric reactions catalyzed by calcium-BINOL complexes.

Kumaraswamy et al. reported asymmetric Michael reaction of malonates and β-ketoesters to

α,β-unsaturated carbonyl compounds catalyzed by calcium BINOL complex. They also applied this methodology for asymmetric epoxidation of chalcones with tert-butyl hydroperoxide

(tBuOOH).9 (Figure 1.6)

1.5.2 Reactions catalyzed by BINOL derived barium complexes:

Figure 1.7 Asymmetric Aldol reaction catalyzed by barium-BINOL complex.

Shibasaki prepared barium complex of BINOL, 14 by treating two equivalents of BINOL monomethyl ether with barium alkoxide in which barium coordinates to two BINOL molecules in bidentate fashion. This complex was used in the asymmetric aldol reaction of ketones, 26 with aldehydes, 25 to give products with excellent yields and good enantioselectivities. They also reported asymmetric aldol-type reaction of β,γ-unsaturated esters, 29 to aldehydes, 28 to form

Morita-Baylis-Hillman type products, 30 after isomerization in high yields and excellent

7 enantioselectivities.10 Kobayashi reported 3,3’-disilyl-substituted BINOL derivative could also be used in aldol reaction to give products, 33 with moderate selectivity.11 (Figure 1.7)

Kobayashi et al. also reported asymmetric Friedel-Crafts type alkylation reaction of indoles with chalcone derivatives in presence of H8-BINOL derived barium complex to afford excellent

12 enantioselective products. In this the complex prepared by treating H8-BINOL derived ligand with Ba(HMDS)2 proved to be more active compared to the complex prepared from barium alkoxide. It was proposed in the mechanism that the acidic proton of indole was deprotonated by the chiral barium complex in the first step to form Barium-indole species. (Figure 1.8)

Figure 1.8 Friedel-Crafts type alkylation catalyzed by barium-BINOL complex.

1.6 Complexes with chiral diol ligands:

Figure 1.9 Chiral calcium alkoxide catalyzed asymmetric aldol reaction.

Noyori et al. reported asymmetric direct-type aldol reaction catalyzed by calcium-diolate

13 complex that was prepared from Ca(HMDS)2(thf)2 and chiral diol. By adding potassium

8 thiocyanate (KSCN) as additive enantioselectivity of the products, 39 was enhanced significantly.

(Figure 1.9)

Figure 1.10 Asymmetric Mannich reaction catalyzed by barium biphenolate

Figure 1.11 Asymmetric reactions catalyzed by chiral barium and strontium alkoxide complexes.

Shibasaki et al. developed chiral biphenol derived barium complex to catalyze asymmetric

Mannich reaction of imines, 41 with β,γ-unsaturated esters, 42. The Mannich products formed in

9 this reaction were isomerized to give aza-Morita-Baylis-Hillman type products, 43 in good enantioselectivities.14 (Figure 1.10)

Shibasaki et al. also discovered a novel chiral diol15 containing phosphine oxide group reacts with barium isopropoxide to form chiral complex that catalyze asymmetric Diels-Alder reaction.

The reaction of siloxydiene, 45 with fumarate, 46 affords 47 with high yield and excellent enantioselectivity. These products are precursor to the synthesis of optically active Tamiflu®.

They also reported asymmetric cyanation reaction of 49 catalyzed by strontium-diol chiral complex, to afford highly enantioselective quaternary carbon centered products, 50. (Figure 1.11)

1.7 Complexes with chiral phosphoric acid ligands:

Figure 1.12 Chiral BINOL derived alkaline earth metal phosphate complexes.

Since the discovery of chiral BINOL phosphoric acid (PA) in 2004 by Terada and Akiyama,

PA has been emerged as versatile catalyst in many asymmetric transformations yielding highly enantioselective products. Ishihara, first observed calcium complex of BINOL phosphoric acid,

52c could catalyze asymmetric Mannich reaction of imines with 1, 3-diketones to afford products,

57 with high yield and enantioselectivities.16 The catalyst is prepared by treating calcium methoxide with two equivalents of chiral BINOL phosphoric acid. (Figure 1.13)

Figure 1.13 Asymmetric Mannich reaction catalyzed by calcium-BINOL phosphate complex.

Figure 1.14 Asymmetric reactions catalyzed by calcium-VAPOL phosphate complexes.

Figure 1.15 Asymmetric synthesis of aziridines.

Figure 1.16 Asymmetric phosphination, Diels-Alder and hetero-Diels-Alder reactions catalyzed by metal-BINOL phosphate complexes.

Antilla et al. developed alkaline earth metal VAPOL phosphate complexes to efficiently catalyze asymmetric benzoyloxylation, chlorination and Michael reactions of 3-substituted oxindoles (Figure 1.14) and also asymmetric synthesis of aziridines to give highly enantioselective products (Figure 1.15).17 They also reported asymmetric catalytic reaction of chiral BINOL phosphate metal complexes applied to asymmetric phosphination of imines. Recently, they reported an elegant asymmetric Diels-Alder reaction and hetero-Diels-Alder reaction using

Danishefsky’s diene forming highly enantioselective and diastereoselective spirocyclic compounds in excellent yields. (Figure 1.16)

Figure 1.17 Asymmetric carbonyl-ene reaction and Friedel-Crafts reaction catalyzed by calcium-BINOL phosphate complex

Rueping et al. reported calcium-BINOL phosphate complex activation of diketoesters in asymmetric carbonyl-ene reaction and also in the Friedel-Crafts reaction of indoles to afford highly enantioselective quaternary hydroxyesters 79, 81 in excellent yields.18 (Figure 1.17) Masson reported efficient asymmetric bromination of enecarbamates catalyzed by calcium-BINOL phosphate complex using NBS in good yields and excellent enantioselectivities. Using similar catalyst they recently showed asymmetric addition of enamides to azodicarboxylates, two different

13 products were isolated by changing the workup procedure in high yields and excellent enantioselectivities.19 (Figure 1.18)

Figure 1.18 Calcium-BINOL phosphate catalyzed asymmetric amination reactions

1.8 Complexes with chiral Bisoxazoline (Box) ligands:

Figure 1.19 Chiral bisoxazoline-calcium complexes:

Figure 1.20 Chiral Box-calcium complexes catalyzed asymmetric 1,4-addition and [3+2] cycloaddition reactions.

Kobayashi et al. first developed calcium complexes of chiral bisoxazoline (Box) ligands.

Calcium alkoxide or amide deprotonates the acidic hydrogen of the methylene group tethering oxazolines forming an anionic bidentate complex that has rigid chiral environment. In these complexes the metal center acts as mild Lewis acidic site that helps in the coordination of the ligand and the Brønsted basicity of the overall complex can be controlled by changing the free

15 counterion. They reported an efficient asymmetric 1, 4-addition of Schiff bases of glycine derivatives, 93 with α, β-unsaturated esters, 92 for the synthesis of 4-substituted, 94 and 3- substituted, 97 glutamic acid derivatives in excellent enantioselectivities and diastereoselectivities.

For 3-substituted glutamic acid derivatives, the [3+2]-cylcoadduct was observed as major side product. They circumvent this problem by using tert-butyl phenylmethylene group Schiff base of

α-aminoester, 96 to get highly regioselective 1, 4-addition product. They further reported the asymmetric [3+2] cycloaddition reactions with high yields and excellent stereoselectivities.20

(Figure 1.20)

Kobayashi et al. have also reported similar Box-type ligand prepared from calcium chloride, and an external base. For this catalyst system, to improve the acidity of hydrongen on the methylene group, cyano group was introduced and 1,1,3,3-tetramethylguanidine (TMG) was used as external base. They showed this catalyst system also effectively catalyzes asymmetric 1, 4- addition and [3+2] cycloaddition reactions in high regio and stereoselectivities.21 (Figure 1.21)

Figure 1.21 Asymmetric 1,4-addition and [3+2] cycloaddition reactions

1.9 Complexes with chiral Pyridine Bisoxazoline (Pybox) ligands:

Figure 1.22 Chiral Calcium-Pybox complexes.

Figure 1.23 Calcium-Pybox catalyzed asymmetric 1,4-addition and Mannich reactions.

Kobayashi et al. has developed a novel stable complex prepared from calcium alkoxide and and a neutral coordinative ligand. Pyridinebisoxazoline (Pybox) is a versatile ligand with three nitrogen atoms coordinating to a Lewis acidic metal through coordinative bonds forming a stable complex and also providing chiral environment. They reported efficient asymmetric 1, 4-addition reactions of malonates to nitroalkenes and also acrylates catalyzed by chiral calcium-Pybox complex. The enantioselective of the reactions was enhanced in presence of aryl alcohol additive, which was presumed because of the steric bulkiness of calcium aryloxide formed. They also reported asymmetric Mannich reaction of malonates to imines with good enantioselectivities.22

(Figure 1.23)

Kobayashi et al. have further reported the application of Pybox-Calcium halide complexes in asymmetric catalytic 1,4-addition reactions and Mannich reactions to furnish products in good yields and excellent enantioselectivities.23

Figure 1.24 Asymmetric 1,4-addition and Mannich reactions

1.10 Conclusion: To conclude, recent asymmetric transformations catalyzed by chiral alkaline earth methal complexes have been summarized in this chapter. Alkaline earth metals have unique characteristics and have got increased attention due to their abundance, less toxicity, Brønsted basicity and mild Lewis acidity. The research in our lab is to focus on using alkaline earth metal phosphate complexes of chiral BINOL derivatives to develop enantioselective reactions and the results are shown in the next three chapters.

1.11 References 1. (a) Lin, G.-Q.; You, Q.-D.; Cheng, J.-F. Chiral Drugs: Chemistry and Biological Action, First

Edition, Wiley-VCH: Weinheim, 2011. (b) Nguyen, L. A.; He, H.; Pham-Huy, C. Int. J.

Biomed. Sci. 2006, 2, 85.

2. Rouhi, M. Thalidomide, Chem. Eng. News 2005, 83, 122.

3. (a) Borman, S. Asymmetric Catalysis Wins. Chemistry Nobel honors Knowles, Noyori,

Sharpless for chiral syntheses. Chem. Eng. News 2001, 79, 5.

4. (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds. Comprehensive Asymmetric Catalysis,

Springer: Heidelberg, 1999. (b) Ojima, I., Ed. Catalytic Asymmetric Synthesis, 3rd edn. Wiley,

Hoboken, 2010.

5. For reviews, see: (a)Kazmaier, U. Angew. Chem., Int. Ed. 2009, 48, 5790. (b) Kobayashi, S.

Matsubara, R. Chem.-Eur. J. 2009, 15, 10694. (c)Kobayashi, S.; Yamashita, Y. Acc. Chem.

Res. 2011, 44, 58. (d) Yamashita, Y.; Tsubogo, T.; Kobayashi, S. Chem. Sci. 2012, 3, 967. (e)

Yamashita, Y.; Tsubogo, T.; Kobayashi, S. Top Organomet. Chem., Springer, 2015.

6. Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452.

7. (a) Agostinho, M.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 2430. (b) Nguyen, H. V.;

Matsubara, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 5927.

8. Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165.

9. (a) Kumaraswamy, G.; Sastry, M. N. V.; Jena, N. Tetrahderon Lett. 2001, 42, 8515. (b)

Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Padmaja, M.; Markondaiah, B. Adv. Synth.

Catal. 2005, 347, 867. (c) Kumaraswamy, G.; Sastry, M. N. V.; Jena, N.; Kumar, K. R.;

Vairamani, M. Tetrahedron Asymmetry, 2003, 14, 3797.

10. (a) Yamada, Y. M.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 5561. (b) Yamaguchi, A.;

Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 10842.

11. Saito, S.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 8704.

12. Tsubogo, T.; Kano, Y.; Yamashita, Y.; Kobayashi, S. Chem. Asian J. 2010, 5, 1974.

13. Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamato, S.; Yamaguchi, K.; Shibasaki, M.; Noyori,

R. Tetrahedron Lett. 2001, 42, 4669.

14. Yamaguchi, A.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2007, 9, 338.

15. (a) Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M. Angew. Chem.

Int. Ed. 2009, 48, 1070. (b) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010,

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(b) Hatano, M.; Ishihara, K. Synthesis 2010, 3785.

17. (a) Zhang, Z.; Zheng, W.; Antilla, J. C. Angew. Chem. Int. Ed. 2011, 50, 1135. (b) Zheng, W.;

Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem. Soc. 2011, 133, 3339. (c) Larson, S. E.;

Li, G.; Rowland, G. B.; Junge, D.; Huang, R.; Woodcock, H. L.; Antilla, J. C. Org. Lett. 2011,

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18. Rueping, M.; Bootwicha, T.; Kambutong, S.; Sugiono, E. Chem. Asian J. 2012, 7, 1195.

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2 Asymmetric One-Pot Synthesis of 1, 3-Oxazolidines and 1, 3-Oxazinanes via Hemiaminal Intermediates

Note to the Reader: This chapter (Pages 22-54) has been previously published in Organic

Letters journal with citation Org. Lett., 2014, 16 (16), pp 4098–4101. DOI: 10.1021/ol501789c

2.1 Introduction Heterocyclic compounds are the cyclic compounds containing N, O, S etc. as part of the ring system. These compounds present in many natural products and exhibit a wide range of properties such as antibacterial, antiviral, anti-inflammatory, antimalarial, etc. More than 50% of the pharmaceutical compounds contain heterocyclic compounds in their structural unit. 1, 3- oxazolidines are a type of heterocyclic compounds which contain nitrogen and oxygen in a 5- membered cyclic ring. Chiral 1, 3-oxazolidines are key structural motifs that are present in many biologically active compounds and natural products.1 Polycyclic tetrahydroisoquinoline alkaloids such as Quinocarcin, 1 and Terazomine, 2 containing 1, 3-oxazolidine group exhibit antitumor activities.2 (Figure 2.1)

Figure 2.1 Polycyclic tetrahydroisoquinoline alkaloids.

2.2 1, 3-oxazolidines as chiral auxiliaries: Chiral 1, 3-oxazolidine moieties are also applied in asymmetric synthesis as chiral auxiliaries in many asymmetric transformations and as chiral ligands in asymmetric catalysis.3 Some representative examples4 Aldol reaction, Diels-Alder reaction and Grignard reaction in which 1,

3-oxazolidines act as chiral auxiliaries to yield highly diastereoselective products were shown in

Figure 2.2. They were also used as precursors in synthesis of many key intermediates and natural products.

Figure 2.2 Reactions with 1, 3-oxazolidines as chiral auxiliaries.

2.3 1, 3-oxazolidines as chiral ligands in asymmetric reactions:

Figure 2.3 Chiral 1, 3-oxazolidine ligands

Figure 2.4 Asymmetric allylic alkylation and Diels-Alder reactions.

Chiral 1, 3-oxazolidines have also been used as ligands (Figure 2.3) in several asymmetric reactions. Asymmetric alkylation, alkynylation of aldehydes and ketones with organozinc compounds were first reported with excellent enantioselectivities. Pyridinyloxazolidines, 13a, and

24 phosphino-oxazolidines, 13b-c, showed great utility as bidentate ligands in palladium-catalyzed asymmetric reactions with high yields and excellent enantioselectivities.5 (Figure 2.4)

2.4 Synthesis of chiral 1, 3-oxazolidines:

2.4.1 Stereospecific synthetic methods: Several methods have been reported for the synthesis of chiral 1, 3-oxazolidines owing to their growing importance in synthetic chemistry. The classical method for the preparation of these compounds is the condensation of chiral aminoalcohols with carbonyl compounds such as aldehydes or ketones. Starting from a variety of readily available chiral aminoalcohols, this method provides access to number of chiral oxazolidines. (Figure 2.5)

Figure 2.5 Condensation of chiral aminoalcohols with aldehydes and ketones.

Figure 2.6 Double Michael addition reaction.

In 2007, Kwon et al. developed asymmetric synthesis of oxazolidines by the asymmetric double Michael addition reaction of aminoalcohols to electron-deficient alkynes catalyzed by bisphosphine.6 They described that the intermediate phosphonium ion formed after first Michael addition was stabilized due to the presence of addition phosphine is bis(diphenylphosphine) derivative which led to the formation of oxazolidine product, 29 in high yields.

Figure 2.7 Formal cycloaddition of vinyl epoxides with imines.

Jarvo et al. reported the stereospecific synthesis of chiral oxazolidines by rhodium catalyzed the formal cycloaddition of vinyl epoxides with imines, by controlling the rates of isomerization of allylmetal intermediates. Starting with (R)-vinyl epoxide the reaction provides 32 with good yield and excellent enantioselectivity with the retention at stereogenic center from vinyl epoxide.7

(Figure 2.7)

2.4.2 Stereoselective synthetic methods:

Figure 2.8 Asymmetric oxyamination and formal cycloaddition reactions for stereoselective synthesis of chiral oxazolidines.

Yoon and co-workers reported the first enantioselective oxyamination of olefins catalyzed by chiral iron(II) bis(oxazoline) complex.8 They proposed the reaction proceeds through a kinetic resolution pathway in which one enantiomer of the racemic oxaziridine, 34 reacts first to form high diastereoselective and enantioselective products, 35. Jarvo et. al. reported the first catalytic

27 asymmetric synthesis of 1, 3-oxazolidines, by the palladium formal cycloaddition reaction of racemic vinyl epoxides with imines which proceeds through a dynamic kinetic resolution to yield products with high yields and good enantioselectivities7. Du et al. have also reported asymmetric formal cycloadditions of vinyl epoxide with imines catalyzed by rhodium with chiral sulfur/alkene ligand. This reaction also follows dynamic kinetic resolution process and they further applied this methodology to isatin imines, 40 to get highly enantioselective spirooxindole oxazolidines, 41 in good yields.9

2.5 Chiral BINOL phosphoric acids and alkaline earth metal phosphates:

Figure 2.9 Chiral phosphoric acids.

Over the last decade, chiral BINOL phosphoric acid has been emerged as one of the privileged

10 hydrogen-bond donor catalysts in many asymmetric transformations. The pKa of BINOL phosphoric acid is ranging 3 to 6 in DMSO,11 which exhibit considerable acidity to activate

28 substrates through hydrogen bonding. BINOL phosphoric acids are considered to be strong

Brønsted acids that activate electrophiles by protonation and lowering the LUMO to react with the nucleophile. With the chiral BINOL backbone and varying the steric groups on 3 and 3’ positions, the chiral environment can be controlled.

Figure 2.10 General synthetic scheme for the preparation of chiral BINOL phosphoric acid.

The versatility of these catalysts has been attributed to many features such as the strong

Brønsted acidity of (-OH), Lewis acidity of oxygen, steric controlling groups at 3, 3’ positions and mild reaction conditions for plethora of asymmetric reactions to yield excellent enantioselective products. Different structural variants of chiral phosphoric acids have been developed over the years and are applied to afford a wide range of highly enantioselective products. The general method for the synthesis of BINOL phosphoric acids is shown below. (Figure 2.10) The bromination of protected chiral BINOL, 44 with nBuLi and Br2 gives 45. Based on the steric

29 groups on 3, 3’ positions, 45 is subjected to Suzuki coupling or Kumada coupling to form 46.

Deprotection followed by phosphorylation yields chiral BINOL phosphoric acid 48.

The application of chiral phosphoric acids was first reported in 1971 as chiral resolving agents for amines.12 In 2004, Akiyama and Terada independently discovered catalytic asymmetric

Mannich reactions catalyzed by chiral BINOL phosphoric acid.13 The authors proposed the dual activation of imine and nucleophile with chiral phosphoric acid through hydrogen bonding yielding products with high enantioselectivity. Since then, several research groups has focused on development of tremendous asymmetric reactions catalyzed by chiral phosphoric acid.

Figure 2.11 Asymmetric Mannich reactions catalyzed by chiral BINOL phosphoric acid.

In 2010, Ishihara et. al. first discovered the metal contaminants while column chromatography purification of BINOL phosphoric acid. They reported that the metal contaminants present in the silica gel could replace the hydrogen in phosphoric acid –OH forming phosphate metal salts.

Optimization of the reaction conditions with various BINOL metal phosphates, they showed that

Calcium salt of phosphoric acid was the real catalyst to give 54 with 92% ee whereas pure acid of

BINOL phosphoric acid that was washed with 6N HCl gave only 27% ee. Later, List14 also confirmed this by comparing ICP-OES trace element analysis of BINOL phosphoric acid washed with HCl (Batch B) and another compound that was purified after column (Batch A). The data clearly shows the metal contamination for the compound purified after column chromatography

(Table 2.2)

Table 2.1 Optimization to find real catalyst:

Table 2.2. Trace Element Analysis by ICP-OES. (Values in ppm)

Batch Na K Mg Ca Al Si Fe Pd Zn A 6151 29 3590 7482 <5 560 15 7 5 B 16 13 20 83 20 725 9 <5 <5

Since this discovery, research groups have developed many metal complexes of BINOL phosphoric acid with Ca, Mg, Sr, Ba, Pd, Au, Sc, Ir, Cu, Ag, etc.10g Research in our group also focused on developing novel asymmetric reactions catalyzed by BINOL phosphoric acid and phosphate metal complexes. In particular, we are interested in catalytic asymmetric reactions of alkaline earth metal phosphate complexes. Compared to BINOL phosphoric acid, chiral BINOL phosphate complexes have advantages such as mild Lewis acidic site at the metal, Lewis basic site arising from P=O oxygen, and strong Brønsted basicity of the counterion owing to the low electronegativity of metal ions and multiple coordination sites due to large ionic radius of the metal. For selected reactions of chiral BINOL alkaline earth metal phosphate complexes see

Chapter 1, Section 1.7.

Figure 2.12 Chiral BINOL metal phosphate complex.

2.6 Asymmetric one-pot synthesis of 1, 3-oxazolidines: In 2008, our group disclosed enantioselective synthesis of chiral N,O-aminals by the asymmetric addition of alcohols to imines catalyzed by 3,3’-9-anthryl derived chiral BINOL phosphoric acid catalyst.15 (Figure 2.13) We envisioned to further apply this methodology for the asymmetric synthesis of chiral 1, 3-oxazolidines. We hypothesized, the hemiaminal intermediate obtained after initial alcohol addition to imines would undergo intramolecular cyclization through

32 nucleophilic substitution in 5-exo-tet manner, following the Baldwin’s rules16. (Figure 2.14)

Baldwin in 1976, reported some rules for the ring closure of organic compounds. These rules are designed based on the stereochemical requirements of the transition states for the ring closure of tetrahedral, trigonal, and diagonal carbons. Based on Baldwin rules 5-exo-tet ring closures is favored. In this case, since halogen is the leaving group, the geometry of the carbon bearing halogen is tetrahedral (tet), the number of atoms in the skeleton is 5 and the breaking of bond is exocyclic, so we propose this reaction will undergo ring closure in 5-exo-tet pathway.

Figure 2.13 Enantioselective addition of alcohols to imines.

Figure 2.14 Retrosynthetic pathway.

2.7 Optimization of reaction conditions: Table 2.3 Optimization of reaction conditions for alcohol addition to imines.

Inspired by the results of Ishihara and List, we started our investigation to find the real catalyst for the enantioselective addition of alcohols to imines. Interestingly, 9-anthryl derived BINOL phosphoric acid, P2 afforded product 3a with negligible enantioselectivity (Table 2.2, entry

1).This paved way for us to explore different alkali and alkaline earth metal BINOL phosphate complexes for this reaction. Ca[P2]2 also gave product with only 10% enatiomericexcess (ee) whereas Mg[P2]2 yielded product with high yield and excellent enantioselectivity (Table 2.2, entries 2-3). Upon using 3, 3’-triisopropyl derived BINOL phosphate complexes, we are delighted to get product 60a with 97% ee with Mg[P1]2. Ca, Li, Al, Zn and Sr complexes of BINOL 34 phosphate showed moderate selectivity (Table 2.2, entries 4-9). Based on the optimization data, clearly using Mg[P1]2 in ethyl acetate to imine, 58a and alcohol, 59 at room temperature in presence of molecular sieves gave hemiaminal intermediate, 60a in high yield and good enantioselectivity.

Table 2.4 Optimization of base mediated intramolecular cyclization.

A brief screening of bases for the intramolecular cyclization of 60a was performed and we observed that K3PO4, DBU, Cs2CO3 in ethyl acetate did not lead to the cyclized product 61a. By using the more reactive substrate 60b with bromide as the leaving group provided the desired transformation with bases DBU and KOtBu in good yields. But the highest enantioselectivity that 35 we observed for the preparation of 60b under the optimized conditions was 65% (Table 2.3, entries

5, 6). Interestingly, Cs2CO3 gave product 61a with retention in enantioselectivity and high yield

(Table 2.3, entry 7). Cesium salt with its large ionic radius, low degree of solvation and ion-pairing provided the balance in the reaction, which is not too strong base and not weak base either. To our delight, upon screening the solvents using 60a, using polar aprotic DMF showed better results to get product 61a. KOtBu showed little reduction in selectivity, whereas Cs2CO3 at 0°C produced

4a in high yield with retention of selectivity of 93% ee.

With the idea of combining these two steps to develop a one-pot reaction, we performed the intramolecular cyclization of 60a in ethyl acetate using Cs2CO3, but no occurrence of 61a was detected. Alternately, upon the addition of alcohol, 59 to imine, 58a in DMF and Mg[P1]2 afforded racemic 60a. From these observations, to make it one-pot synthesis, we decided to concentrate ethyl acetate after enantioselective addition of alcohol to imine and then add DMF and Cs2CO3 at

0 °C to yield 61a in high yield and retention of high enantioselectivity.

2.8 Substrate scope for one-pot synthesis of chiral 1, 3-oxazolidines: With the optimal conditions in hand, a broad range of chiral 1, 3-oxazolidines were prepared in one-pot using different imine substrates. The results were summarized in Figure 2.15.

Substrates with both electron-donating and electron-withdrawing groups at para position on the phenyl ring of imines had little effect on the enantioselectivity. Electron-withdrawing group at the meta position on the phenyl ring (61d) showed excellent enantioselectivity compared to electron- releasing methyl group (61i). Ortho substituted –CH3 group (61h) showed higher selectivity compared to meta (61i). This is attributed to different steric factors. The absolute configuration for all substrates was assigned in correlation with the HPLC data comparison of the product 60a that was reported in literature.

Figure 2.15 Substrate scope for chiral 1, 3-oxazolidines.

2.9 Asymmetric one-pot synthesis of 1, 3-oxazinanes: Based on the reaction design, we envisaged the possible synthesis of chiral 1, 3-oxazinanes17 using this methodology. The intramolecular cyclization would undergo in 6-exo-tet fashion which

37 is favored according to Baldwin’s rules. Mg[P1]2 catalyzed the addition of 3-chloropropanol, 62a and 3-bromopropanol, 62b to imines 58 with high enantioselectivity. (Table 2.4)

Table 2.5 Optimization of reaction conditions.

Table 2.6 Optimization for base mediated intramolecular cyclization.

For intramolecular cyclization in presence of Cs2CO3 base, slight drop in enantioselectivity was observed when chlorine was the leaving group (Table 2.5, entries 1, 2). We assumed because of the long reaction time in this case, the starting material or product is losing selectivity in basic medium. By changing the leaving group to better leaving group bromine, the reaction completes in 2 h by retaining the enantioselectivity (Table 2.5, entries 3, 4).

2.10 Substrate scope for one-pot synthesis of chiral 1, 3-oxazinanes:

Figure 2.16 Substrate scope for one-pot synthesis of chiral 1, 3-oxazinanes.

With the optimized conditions, we synthesized substrates of chiral 1, 3-oxazinanes with different substituents on the phenyl group in high yields and good enantioselectivities.

2.11 Conclusion: To summarize, we have developed a highly efficient 3, 3’-triisopropyl BINOL magnesium phosphate catalyzed one-pot synthesis of chiral 1, 3-oxazolidines and chiral 1, 3-oxazinanes. The products are formed with good enantioselectivities by the base mediated intramolecular 5-exo-tet and 6-exo-tet cyclization of hemiaminal intermediates formed by the enantioselective addition of alcohols to imines.

2.12 Experimental data: General considerations:

All reactions were carried out in flame-dried screw-cap test tubes with magnetic stirring. Ethyl acetate was dried over 4Å MS. Anhydrous N, N-dimethylformamide was purchased from commercial sources and transferred under Argon atmosphere. Alcohols were obtained commercially and purified under standard methods or dried over 4Å MS before use. Chiral (R)-

BINOL was purchased from commercial sources and used without further purification.

Substituted BINOL phosphoric acids H(P1),18 H(P2)19 were synthesized according to the literature

20 21 procedures. Ca(P1)2, Mg(P1)2 were prepared as the reported procedures. Thin layer chromatography was performed on Merck TLC plates (silica gel 60 F254). Flash column chromatography was performed with Merck silica gel (230-400 mesh). Enantiomeric excess (ee) was determined using a Varian Prostar HPLC with a 210 binary pump and a 335 diode array detector. Optical rotations were performed on a Rudolph Research Analytical Autopol IV polarimeter (λ 589) using a 700-μL cell with a path length of 1-dm. 1HNMR and 13C NMR were

40 recorded on Varian Inova-400 spectrometer with chemical shifts reported relative to

31 tetramethylsilane (TMS). PNMR was recorded on a Varian Inova-400 instrument with H3PO4 as an external standard. The HRMS data were measured on an Agilent 1100 LC/MS ESI/TOF mass spectrometer with electro-spray ionization. Compounds described in the literature were characterized by comparing their spectral data to the reported values.

21 Preparation of Catalyst, M[P1]n:

M[P1]n (M = Ca, Mg, Li, Al, Zn, Sr) were prepared by adding ‘H[P1] washed with HCl’ (10 mol%) and Ca(OMe)2 (5 mol%) or Mg(OtBu)2 (5 mol%) or Li(OiPr) (10 mol%) or Al(OiPr)3 (0.33 mol%) or Zn(OMe)2 (5 mol%) or Sr(OiPr)2 (5 mol%) into a flame dried reaction tube. Evacuate the tube and filled with Argon three times. Added 1 ml of dry dichloromethane and 1 ml of anhydrous methanol to the reaction tube. Stirred the reaction mixture at room temperature for 1 h. Solvent was concentrated, added 1 ml dichloromethane and concentrated again under reduced pressure to obtain the catalyst as pale yellow solid.

Mg[P1]2 Spectral data:

1H NMR (400MHz, DMSO): δ 7.96 (d, J = 7.9 Hz, 2H), 7.75 (s, 2H), 7.37 (t, J = 7.4 Hz, 2H),

7.25 (t, J = 7.5 Hz, 2H), 7.03 (m, 6H), 3.15 (d, J = 5.0 Hz, 1H), 3.00 – 2.85 (m, 3H), 2.63 – 2.51

(m, 2H), 1.26 (d, J = 6.7 Hz, 12H), 1.15 (d, J = 3.6 Hz, 12H), 1.06 (d, J = 6.7 Hz, 6H), 0.85 (d, J

31 = 6.7 Hz, 6H). P (400MHz, DMSO): δ 3.39. MS (MALDI) Calcd for C100H112MgO8P2

([M+H]+) m/z 1527.77 Found 1527.96.

N-Acyl imines (1a-k) were synthesized according to the literature procedure and purified by sublimation.22

General procedure for the preparation of chiral 1,3-Oxazolidines:

To a flame-dried reaction tube charged with 4Å molecular sieves 50mg (pre-activated in oven) was added N-benzoyl imine 58 (0.2 mmol), catalyst Mg[P1]2 (0.005 mmol), the tube was evacuated and filled with argon. Added anhydrous toluene (1.0 ml) followed by 2-chloro ethanol

59 (0.4 mmol) via oven-dried syringe to the reaction mixture. The reaction was stirred at room temperature for 24h. The completion of reaction was monitored by TLC and toluene (1.0 ml) was removed by rotovap. Added anhydrous dimethyl formamide to the reaction tube and cooled to 0

°C. Added Cs2CO3 (0.4 mmol) and the solution was allowed to stir at room temperature for 4h.

The crude product was purified by flash column chromatography (ethyl acetate : hexane) to get the pure 1, 3-oxazolidine product 61 and the enantiomeric excess was determined by chiral HPLC analysis.

(R)-phenyl(2-phenyloxazolidin-3-yl)methanone23

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 92% yield, 93% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 80:20, 1.0

20 1 mL/min), t r-major 9.36 min, t r-minor 15.53 min. [α] D= +140.7° (c =1.85, CHCl3). H NMR

st nd (400MHz, CDCl3): δ 3.50-4.50 (bm, 4H), 6.0 (bs, 1 rotamer), 6.5 (bs, 2 rotamer), 7.2-8.0 (bm,

13 10H). C NMR (400MHz, CDCl3): δ 48.31(broad peak), 66.66(broad peak), 89.35(broad peak),

126.70, 127.55, 128.30, 128.44, 128.80, 130.71, 135.80, 138.59, 169.58ppm. HRMS (ESI) calcd

+ for C16H15NO2 ([M+H] ) m/z 254.1103, found 254.1186.

(R)-(2-bromophenyl)oxazolidin-3-yl)(phenyl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 99% yield, 93% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 80:20, 1.0

20 1 mL/min), t r-major 11.72 min, t r-minor 14.71 min. [α] D= +162.5° (c =2.25, CHCl3). H NMR

st nd (400MHz, CDCl3): δ 3.50-4.50 (bm, 4H), 6.1 (bs, 1 rotamer), 6.5 (bs, 2 rotamer), 7.2-8.0 (bm,

13 9H). C NMR (400MHz, CDCl3): δ 48.20(broad peak), 66.82(broad peak), 88.91(broad peak),

122.88, 127.54, 130.90, 135.53, 137.71, 169.59ppm. HRMS (ESI) calcd for C16H14BrNO2

+ ([M+H] ) m/z 332.0208, found 332.0285.

(R)-(2-(4-fluorophenyl)oxazolidin-3-yl)(phenyl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 93% yield, 90% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 80:20, 1.0

20 1 mL/min), t r-major 9.80 min, t r-minor 14.04 min. [α] D= +162.2° (c =2.15, CHCl3). H NMR

st nd (400MHz, CDCl3): δ 3.50-4.50 (bm, 4H), 6.1 (bs, 1 rotamer), 6.5 (bs, 2 rotamer), 6.9-7.9 (bm,

13 9H). C NMR (400MHz, CDCl3): δ 48.42(broad peak), 66.87(broad peak), 89.12(broad peak),

115.43, 115.65, 127.77, 128.56, 128.82, 128.91, 134.72, 135.85, 161.91, 164.37, 169.78ppm.

+ HRMS (ESI) calcd for C16H14FNO2 ([M+H] ) m/z 272.1009, found 272.1090.

(R)-(2-(3-fluorophenyl)oxazolidin-3-yl)(phenyl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 94% yield, 97% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 90:10, 1.0

20 1 mL/min), t r-major 18.43 min, t r-minor 24.52 min. [α] D= +154.6° (c =1.25, CHCl3). H NMR

13 (400MHz, CDCl3): δ 3.50-4.50 (bm, 4H), 6.5(bs, 1H), 7.3-7.8 (bm, 9H). C NMR (400MHz,

CDCl3): δ 47.35(broad peak), 65.75(broad peak), 88.17(broad peak), 126.70, 127.41, 127.56,

+ 127.81, 130.07, 133.84, 134.75, 136.38, 168.80. HRMS (ESI) calcd for C16H14FNO2 ([M+H] ) m/z 272.1009, found 272.1087.

(R)-(2-(4-Chlorophenyl)oxazolidin-3-yl)(phenyl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 94% yield, 95% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 90:10, 1.0

20 1 mL/min), t r-major 13.65 min, t r-minor 21.19 min. [α] D= +173.9° (c =1.3, CHCl3). H NMR

13 (400MHz, CDCl3): δ 3.50-4.40 (bm, 4H), 6.20-6.75 (bs, 1H), 6.8-8.0 (bm, 9H). C NMR

(400MHz, CDCl3): δ 48.20(broad peak), 66.76(broad peak), 88.62(broad peak), 113.57, 113.79,

115.62, 115.83, 122.49, 122.51, 127.55, 128.36, 129.99, 130.07, 130.88, 161.57, 164.02, 169.64.

+ HRMS (ESI) calcd for C16H14ClNO2 ([M+H] ) m/z 288.0713, found 288.0794.

(R)-phenyl(2-(4-(trifluoromethyl)phenyl)oxazolidin-3-yl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 94% yield, 97% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 95:05, 1.0

20 1 mL/min), t r-major 25.23 min, t r-minor 26.96 min. [α] D= +152.4° (c =1.2, CHCl3). H NMR

13 (400MHz, CDCl3): δ 3.50-4.50 (bm, 4H), 6.20-6.75 (bs, 1H), 7.2-8.0 (bm, 9H). C NMR

(400MHz, CDCl3): δ 48.21(broad peak), 66.89(broad peak), 88.73(broad peak), 125.39, 127.22,

+ 127.55, 128.41, 131, 135.34, 142.52, 169.71ppm. HRMS (ESI) calcd for C17H14F3NO2 ([M+H] ) m/z 322.0977, found 322.1058.

(R)-phenyl(2-(p-tolyl)oxazolidin-3-yl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 97% yield, 90% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 85:15, 1.0

20 1 mL/min), t r-major 13.32 min, t r-minor 17.56 min. [α] D= +104.3° (c =1.0, CHCl3). H NMR

st nd (400MHz, CDCl3): δ 2.33(s, 3H), 3.50-4.50 (bm, 4H), 6.1 (bs, 1 rotamer), 6.5 (bs, 2 rotamer),

13 7.0-7.9 (bm, 9H). C NMR (400MHz, CDCl3): δ 21.19, 48.35(broad peak), 66.57(broad peak),

89.35(broad peak), 126.59, 127.51, 128.25, 129.12, 130.63, 135.62, 135.86, 138.61, 169.45ppm.

+ HRMS (ESI) calcd for C17H17NO2 ([M+H] ) m/z 268.1259, found 268.1336.

(R)-phenyl(2-(o-tolyl)oxazolidi-3-yl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 98% yield, 96% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 80:20, 1.0

20 1 mL/min), t r-major 8.27 min, t r-minor 10.72 min. [α] D= +78.151° (c =1.8, CHCl3). H NMR

st (400MHz, CDCl3): δ 2.0-2.7(bm, 3H), 3.50-4.50 (bm, 4H), 6.0-6.4 (bs, 1 rotamer), 6.4-6.8 (bs,

nd 13 st 2 rotamer), 7.0-7.9 (bm, 9H). C NMR (400MHz, CDCl3): δ 18.95, 45.17(broad peak, 1 rotomer), 48.95(broad peak, 2nd rotomer), 63.9(broad peak, 1st rotomer), 66.5(broad peak, 2nd rotomer), 88.02(broad peak), 125.85, 127.62, 128.28, 128.84, 130.95, 135.84, 136.88, 169.44

+ HRMS (ESI) calcd for C17H17NO2 ([M+H] ) m/z 268.1259, found 268.1336.

(R)-phenyl(2-(m-tolyl)oxazolidi-3-yl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 96% yield, 83% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 80:20, 1.0

20 1 mL/min), t r-major 7.60 min, t r-minor 10.03 min. [α] D= +103.7° (c =1.05, CHCl3). H NMR

st nd (400MHz, CDCl3): δ 2.33(s, 3H), 3.50-4.50 (bm, 4H), 5.8-6.3 (bs, 1 rotamer), 6.3-6.75 (bs, 2

13 rotamer), 7.0-7.9 (bm, 9H) C NMR (400MHz, CDCl3): δ 21.42, 48.38(broad peak), 66.62(broad peak), 89.39(broad peak), 123.67, 127.35, 128.26, 129.58, 135.82, 138.12, 138.46, 169.51. HRMS

+ (ESI) calcd for C17H17NO2 ([M+H] ) m/z 268.1259, found 268.1329.

(R)-(2-(naphthalen-1-yl)oxazolidin-3-yl)(phenyl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 94% yield, 96% ee. HPLC Analysis: Chiralcel OD-H (hexane:iPrOH = 90:10, 1.0

20 1 mL/min), t r-minor 22.39 min, t r-major 32.33 min. [α] D= -3.75° (c =1.9, CHCl3). H NMR (400MHz,

13 CDCl3): δ 3.50-4.50 (bm, 4H), 6.4-6.8(bm, 1H), 7.25-8.0 (bm, 12H). C NMR (400MHz,

CDCl3): δ(major rotamer) 48.63(broad peak), 66.44(broad peak), 89.12(broad peak), 124.07,

124.78, 125.95, 126.45, 128.37, 128.46, 128.62, 129.77, 130.79, 132.84, 134.13, 135.73, 170.01.

+ HRMS (ESI) calcd for C20H17NO2 ([M+H] ) m/z 304.1259, found 304.1342.

General procedure for the synthesis of chiral 1,3-Oxazinanes:

1,3-Oxazinanes were prepared according to the same procedure as described for the synthesis of chiral 1,3-Oxazolidines.

Analytical data:

(R)-phenyl(2-phenyl-1,3-oxazinan-3-yl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 92% yield, 95% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 85:15, 1.0

20 1 mL/min), t r-major 8.68 min, t r-minor 14.71 min. [α] D= +133.75° (c =0.45, CHCl3). H NMR

(400MHz, CDCl3): δ 1.39-1.46(m, 1H), 1.9-2.2(m, 1H), 3.0-3.25(m, 1H), 3.7-3.9(m, 2H), 4.45(br,

13 1H), 6.5(br, 1H), 7.3-7.7(m, 10H). C NMR (400MHz, CDCl3): δ 25.95, 37.54(broad peak),

60.86, 84.10(broad peak), 126.98, 127.02, 128.26, 128.65, 129.14, 130.21, 135.29, 136.21, 171.59.

+ HRMS (ESI) calcd for C17H17NO2 ([M+H] ) m/z 268.1332, found 268.1336.

(R)-(2-(3-fluorophenyl)-1,3-oxazinan-3-yl)(phenyl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 93% yield, 95% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 85:15, 1.0

20 1 mL/min), t r-major 9.44 min, t r-minor 19.63 min. [α] D= +103.7° (c =1.8, CHCl3). H NMR (400MHz,

CDCl3): δ 1.36-1.48(m, 1H), 1.9-2.2(m, 1H), 3.0-3.25(m, 1H), 3.7-3.9(m, 2H), 4.45(br, 1H),

13 6.5(br, 1H), 7.3-7.7(m, 9H). C NMR (400MHz, CDCl3): δ 24.99, 37.33(broad peak), 60.02,

82.48(broad peak), 126.07, 127.65, 127.82, 128.47, 129.47, 133.42, 133.99, 134.20, 170.66.

+ HRMS (ESI) calcd for C17H16FNO2 ([M+H] ) m/z 286.1165, found.

(R)-(2-(4-fluorophenyl)-1,3-oxazinan-3-yl)(phenyl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 96% yield, 91% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 90:10, 1.0

20 1 mL/min), t r-major 12.40 min, t r-minor 21.65 min. [α] D= +91.09° (c =2.1, CHCl3). H NMR

(400MHz, CDCl3): δ 1.36-1.48(m, 1H), 1.9-2.2(m, 1H), 3.0-3.25(m, 1H), 3.7-3.9(m, 2H), 4.45(br,

13 1H), 6.5(br, 1H), 7.05-7.20(m, 2H), 7.3-7.6(m, 7H). C NMR (400MHz, CDCl3): δ 25.89,

38.17(broad peak), 60.75, 83.34(broad peak), 115.90, 116.25, 126.85, 127.01, 128.78, 130.30,

+ 135.15, 160.70, 164.63, 171.53. HRMS (ESI) calcd for C17H16FNO2 ([M+H] ) m/z 286.1238, found 286.1246.

(R)-(2-(4-bromophenyl)-1,3-oxazinan-3-yl)(phenyl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 91% yield, 89% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 85:15, 1.0

20 1 mL/min), t r-major 9.63 min, t r-minor 21.44 min. [α] D= +76.7° (c =0.9, CHCl3). H NMR (400MHz,

CDCl3): δ 1.35-1.5(m, 1H), 1.9-2.2(m, 1H), 3.0-3.25(m, 1H), 3.7-3.9(m, 2H), 4.45(br, 1H), 6.5(br,

13 1H), 7.3-7.6(m, 9H). C NMR (400MHz, CDCl3): δ 24.97, 37.17(broad peak), 60.03,

82.60(broad peak), 121.59, 126.05, 127.82, 127.97, 129.47, 131.43, 134.14, 134.52, 170.66.

+ HRMS (ESI) calcd for C17H16BrNO2 ([M+H] ) m/z 346.0437, found 346.0442.

(R)-phenyl(2-(4-(trifluoromethyl)phenyl)1,3-oxazinan-3-yl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 85% yield, 80% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 85:15, 1.0

20 1 mL/min), t r-major 7.33 min, t r-minor 16.07 min. [α] D= +86.46° (c =1.95, CHCl3). H NMR

(400MHz, CDCl3): δ 1.36-1.48(m, 1H), 1.9-2.2(m, 1H), 3.0-3.25(m, 1H), 3.7-3.9(m, 2H), 4.45(br,

13 1H), 6.5(br, 1H), 7.3-7.8(m, 9H). C NMR (400MHz, CDCl3): δ 25.75, 37.69(broad peak), 61.07,

83.54(broad peak), 122.58, 125.26, 126.11, 127.46, 134.86, 140.53, 171.59. HRMS (ESI) calcd

+ for C18H16F3NO2 ([M+H] ) m/z 336.1206, found 336.1217.

(R)-(2-(4-methoxyphenyl)-1,3-oxazinan-3-yl)(phenyl)methanone

The product was obtained by flash column chromatography as viscous oil(hexane : ethyl acetate, 1:1) 85% yield, 80% ee. HPLC Analysis: Chiralcel AD-H (hexane:iPrOH = 85:15, 1.0

20 1 mL/min), t r-major 10.71 min, t r-minor 23.20 min. [α] D= +100.48° (c =0.45, CHCl3). H NMR

(400MHz, CDCl3): δ 1.36-1.48(m, 1H), 1.9-2.2(m, 1H), 3.0-3.25(m, 1H), 3.4-3.9(m, 5H), 4.45(br,

13 1H), 6.5(br, 1H), 6.7-7.0(m, 2H), 7.3-7.9(m, 7H). C NMR (400MHz, CDCl3): δ 25.98,

37.84(broad peak), 55.37, 60.60, 84.13(broad peak), 114.49, 126.96, 127.97, 128.30, 128.62,

+ 135.34, 159.58, 171.50. HRMS (ESI) calcd for C18H19NO3 ([M+H] ) m/z 298.1438, found

298.1454.

2.13 References:

1. Ii, K.; Ichikawa, S.; Al-Dabbagh, B.; Bouhss, A.; Matsuda, A. J. Med. Chem. 2010, 53, 3793. 2. (a) Williams, R. M.; Glinka, T.; Flanagan, M. E.; Gallegos, R.; Coffman, H.; Pei, D. J. Am.

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Yoon, J. K.; Lee, S. J.; Kim, Y. M.; Jin, M. J. Bull. Korean Chem. Soc. 2003, 24, 1239. (e)

Nakano, H.; Okuyama, Y.; Suzuki, Y.; Fujita, R.; Kabuto, C. Chem. Commun. 2002, 1146. (f)

Nakano, H.; Takahashi, K.; Okuyama, Y.; Senoo, C.; Tsugawa, N.; Suzuki, Y.; Fujita, R.;

Sasaki, K.; Kabuto, C. J. Org. Chem. 2004, 69, 7092.

6. Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12928.

7. Shaghafi, M. B.; Grote, R. E.; Jarvo, E. R. Org. Lett. 2011, 13, 5188.

8. Williamson, K. S.; Yoon, T. P. J. Am. Chem. Soc. 2012, 134, 12370.

9. Liu, Z.; Feng, X.; Du, H. Org. Lett. 2012, 14, 3154.

10. For selected reviews see: (a) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348,

999. (b) Akiyama, T. Chem. Rev. 2007, 107, 5744. (c) Doyle, A. D.; Jacobsen, E. N. Chem.

Rev. 2007, 107, 5713. (d) Terada, M. Synthesis 2010, 1929. (e) Kampen, D.; Reisinger, C. M.;

List. B. Top. Curr. Chem. 2010, 291, 395. (f) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem.

Soc. Rev. 2011, 40, 4539. (g) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014,

114, 9047.

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A. C. Chem. Eur. J. 2011, 17, 8524. (b) Kaupmees, K.; Tolstoluzhsky, N.; Raja, S.; Rueping,

M.; Leito, I. Angew. Chem. Int. Ed. 2013, 52, 11569.

12. (a) Jacques, J.; Fouquey, C.; viterbo, R. Tetrahedron Lett. 1971, 4617. (b) Arnold, W.; Daly,

J. J.; Imhof, R.; Kyburz, E. Tetrahedron Lett. 1983, 24, 343. (c) Wilen, S. H.; qi, J. Z.; Williard,

P. G. J. Org. Chem. 1991, 56, 485.

13. (a) Itoh, J.; Yokota, K.; Fuchibe, K.; Akiyama, T. Angew. Chem. Int. Ed. 2004, 43, 1566. (b)

Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.

14. Klussman, M.; Ratjen, L.; Hoffmann, S.; Wakchaure, V.; Gooddard, R.; List, B. Synlett 2010,

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16. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.

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K.; Sakamoto, M.; Fujita, T. Tetrahedron Lett. 2001, 42, 4837. (b) Groth, T.; Meldal, M. J.

Comb. Chem. 2001, 3, 34. (c) Diness, F.; Beyer, J.; Meldal, M. QSAR Comb. Sci. 2004, 23,

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3080.

3 Desymmetrization of 4-substituted cyclohexanones: Enantioselective synthesis of novel axially chiral cyclohexylidene oximes

3.1 Introduction Desymmetrization is the stereochemical modification of a molecule that results in the loss of one or more elements of symmetry such as center of inversion, mirror plane or rotational axis.

One of the major advantages of desymmetrization is the formation of chiral compounds with multiple stereocenters from meso or prochiral starting materials in one step. Recently, enantioselective desymmetrization reactions have gained much attention for the synthesis of chiral molecules.1 The most common type of desymmetrization reactions are enzyme catalyzed transformations.2 Several versatile transition metal catalyzed and non-metal catalyzed desymmetrization reactions of meso compounds such as epoxides, anhydrides, diols, aziridines, etc have been reported.3

3.2 Desymmetrization of cyclic ketones: Over the last decade, the asymmetric desymmetrization of meso-cyclohexanones has seen tremendous progress owing to the formation of contiguous stereocenters on the cylic ring through a single transformation. Since the breakthrough discovery of L-proline catalyzed asymmetric aldol reaction by List, Lerner and Barbas in 2000,4 L-proline and its derivatives were used as efficient organocatalysts in several key synthetic transformations involving ketones as substrates. Barbas reported elegant synthesis of α-hydroxy ketones through asymmetric desymmetrization of highly substituted cyclohexanones via L-proline catalyzed tandem aminoxylation/O-N bond heterolysis.5

The products are formed with very high enantio- and diastereoselectivities and good yields. (Figure

3.1) In the first step, enamine intermediate generated in situ reacts with nitrosobenzene to form α- aminoxy ketone, which will react with excess nitrosobenzene, followed by rearrangement affords

3 with good yield and excellent enantioselectivity.

Figure 3.1 Tandem aminoxylation and O-N bond heterolysis of cyclohexanones.

Figure 3.2 Asymmetric aldol reaction of cyclohexanones with aldehydes.

Desymmetrization of cyclohexanone compounds via aldol reaction is one of the first reactions that was highly explored. Gong et al. reported the enantioselective desymmetrization of 4- substituted cyclohexanones via organocatalytic direct aldol reaction with aldehydes.6 The reaction was catalyzed by 4-hydroxy-prolinamide derivative, 7 to generate products, 6 with three chiral centers in high enantio- and diastereoselectivities. Consequently, Rios and Moyano et al. disclosed that proline, 8 also could catalyze this reaction with thiourea, 9 as co-catalyst. The role of thiourea was assumed to form hydrogen bonding with the proline carboxylic acid, thereby enhancing the

Brønsted acidity to activate the aldehyde carbonyl group through hydrogen bonding.7 Bolm et al. reported the same reaction catalyzed by L-proline under solvent free conditions using Ball Mill to yield high enantioselective products.8 (Figure 3.2)

Figure 3.3 Asymmetric intramolecular aldolization.

Iwabuchi et al. reported an efficient enantioselective synthesis of bicyclic ketones, by the asymmetric intramolecular aldolization of σ-symmetric substrates. Intramolecular aldolization of

10 catalyzed by L-proline gave endo bicyclo compounds, 11 and 12 with excellent diastereoselectivity and good enantioselectivity.9 (Figure 3.3)

Bonjoch developed an interesting microwave-assisted intramolecular aldol reaction for the enantioselective synthesis of 2-azabicyclo[3.3.1]nonanes with good yield and moderate enantioselectivity.10 The products are formed via proline catalyzed desymmetrization of prochiral

4-N-protected aminocyclohexanone, 13 through intramolecular aldol cyclization generated bicyclic products. (Figure 3.4)

Figure 3.4 Desymmetrization and intramolecular aldolization.

Siedel in 2010, reported the first catalytic enantioselective Friedländer condensation reaction.

The synthesis of highly enantioselective quinoline substrates was achieved by the desymmetrization of 4-substituted cyclohexanone with O-aminobenzaldehydes. The products, 17 formed serve as precursors to tacrine analogues which show activity towards the treatment of cognitive disorders such as Alzheimer’s disease.11 (Figure 3.5)

Cheng and co-workers disclosed functionalized chiral ionic liquids catalyzed asymmetric α- alkylation of 4-substituted cyclohexanones with secondary alcohols, which can form stable carbocations.12 The bromide ion in FCIL was found to be effective to give high enantioselective

58 products compared to BF4- and PF6- counterparts. The alcohols that form more stable carbocations gave better yields and good enantioselective products. (Figure 3.6)

Figure 3.5 Enantioselective Friedländer condensation.

Figure 3.6 Asymmetric alkylation of cyclohexanones catalyzed by functionalized chiral ionic liquids (FCIL).

Xiao et al. reported highly stereoselective desymmetrization of meso-cyclic ketones by

Michael addition to nitrostyrenes catalyzed by novel bifunctional catalyst.13 The catalyst with pyrrolidine backbone and O-phenyl amide linkage provide dual hydrogen bonding with nitro group, thus affording Michael adducts with very high enantio- and diastereoselectivities. Recently,

Chen et al. has developed Michael addition of ketones to vinyl sulfones. The desired products are

59 obtained with high enantioselectivities by using either camphor-derived pyrrolidine, 25 or cinchonidine-derived amine, 26 as catalyst.14 (Figure 3.7)

Figure 3.7 Desymmetrization of cyclohexanones by asymmetric Michael addition.

Maruoka et al. discovered an excellent bis-aluminium Lewis acid catalyzed ring expansion reaction of substituted cyclohexanones with α-substituted α-diazo acetates to yield quaternary carbon centered seven membered carbocyclic products in high yield and excellent enantioselectivities.15 The catalyst was prepared by mixing 3, 3’-bis(trimethylsilyl)-BINOL, (S)-

30 and Me3Al in 1:2 ratio for 1 h. A wide range of substrates of cyclohexanones with different substituents were prepared with high diastereo- and enantioselectivities. (Figure 3.8)

Figure 3.8 Catalytic desymmetrizing asymmetric ring expansion.

Baeyer-Villiger oxidation is one of the very old and valuable reaction for the synthesis of lactones from cyclohexanones. Feng et al. disclosed an efficient synthesis of highly enantioselective γ- and ε-lactones from the desymmetrization of cyclobutanones and cyclohexanones.16 The reaction was catalyzed by chiral N, N’-dioxide-Sc(III) complex to furnish lactones 32 and 33 with excellent enantioselectivities. (Figure 3.9)

Figure 3.9 Asymmetric Baeyer-Villiger Oxidation

3.3 Desymmetrization reactions of cyclic ketones catalyzed by chiral BINOL phosphoric acid:

Figure 3.10 Chiral BINOL phosphoric acid catalyzed Baeyer-Villiger Oxidation.

Ding and coworkers, disclosed the first chiral Brønsted acid catalyzed desymmetrization of 3- substituted cyclobutanones by asymmetric Baeyer-Villiger oxidation with aqueous H2O2. The mechanistic investigations suggest that the reaction proceeds in a two-step concerted mechanism.

The catalyst coordinates both carbonyl oxygen and peroxide in a bifunctional activation mode, there by enhances the dissociation of –OH group from the Criegee intermediate. The products were formed with excellent yield and good enantioselectivities.17 (Figure 3.10)

List et al. in 2011, developed an elegant asymmetric Fischer indolization reaction catalyzed by chiral SPINOL derived phosphoric acid.18 The desymmetrization of protected hydrazones, 35 which are prepared from condensation with 4-substituted cyclohexanones, occurs via [3,3]- sigmatropic rearrangement in presence of catalytic amount of phosphoric acid and Amberlite

CG50 resin to give highly enantioselective products. The resin functions as a quenching agent for

62 the ammonia byproduct that was produced in the reaction, without hindering the catalytic activity.

The chiral indole product was further functionalized to the formal synthesis of (S)-Ramatroban.

Figure 3.11 Catalytic enantioselective Fischer indolization.

3.4 Desymmetrization of cyclic ketones to form axially chiral compounds: Axially chiral compounds, also referred as Atropisomers, exhibit unique chirality due to the non-coplanar arrangement of groups about an imaginary axis. Usually, the axial chirality in a molecule arises due to the restricted rotation of a single bond or double bond.19 Following are the different types of axially chiral compounds that are found to exist so far.

Figure 3.12 Axially chiral compounds.

Axially chiral compounds attracted much attention over the last two decades owing to their importance in asymmetric catalysis as chiral ligands and also occurrence in natural products.20

Tremendous research advances has been made in the synthesis of axially chiral biaryl, allenes and sprianes.21 The axially chiral cyclohexylidenes and cyclohexylidene oximes are generally synthesized by employing the desymmetrization of cyclohexanones strategy in various asymmetric reactions.

3.4.1 Synthesis of axially chiral cyclohexylidenes:

Figure 3.13 Asymmetric HWE reaction.

Denmark et al. in 1992, first reported the synthesis of chiral cyclohexylidenes by asymmetric

Horner-Wadsworth-Emmons (HWE) reaction employing scalemic phosphonamidates, (cis)-38 as chiral auxiliaries.22 Reaction of Lithium salt of the phoshpnamidate anion, 38, with 4-substituted cyclohexanones afford 39 as single adduct. The phosphorous moiety was activated under mild basic conditions for the formation of oxaphosphenate, which results in the formation of chiral

64 cyclohexylidenes, 40 with high yield and moderate enantioselectivity. Tomioka et al. developed asymmetric HWE reaction of phosphonates, 41 with substituted cyclohexanones catalyzed by external chiral ligand, 42. In presence of chiral ligand 42, gave (S)-cis-alcohol, 43a and (R)- trans-alcohol, 43b in a separable diastereomeric mixture in 89% and 5% yields respectively.

Upon heating 43a in presence of propionic acid and sodium acetate gave (S)-cyclohexylidene product, 44 in high yield and good enantioselectivity.23 (Figure 3.13)

Figure 3.14 Asymmetric Peterson reaction.

Tomioka also reported asymmetric Peterson reaction employing the chiral external ligand strategy, using 46 as chiral ligand the reaction of α-trimethylsilanylacetate with substituted cyclohexanones furnished desymmetric cyclohexylidene products, 47 in excellent yields and good enantioselectivities.24 (Figure 3.14)

3.4.2 Synthesis of axially chiral cyclohexylidene oximes: Since the discovery of cyclohexylidene oximes show optical activity in 1910,25 Toda and Akai were first to successfully isolate these chiral compounds by the diastereomeric resolution with

49.26 By keeping the solution of racemic 48 and chiral 49 at room temperature, a diastereomeric compound containing 1:1 ratio of 48:49 was formed as colorless needles. By treating this with

65 allyl amine, optically pure cyclohexylidene oxime, 50 was formed with 79% ee. Benzoylation of chiral oxime was performed using benzoyl chloride in presence of pyridine. Since the oxime, 50 was not stable on HPLC column, the enantioselectivity of 50a was determined using chiral HPLC and assigned to 50 analogously. To show the application of these compounds, in presence of 85%

H2SO4 the diastereomeric compound (48:49) undergoes Beckmann rearrangement to form lactam,

51 with 58% yield and 80% enantiomeric excess. (Figure 3.15)

Figure 3.15. First isolation of optically active cyclohexylidene oximes.

Hoshino et al. in 2004, disclosed kinetic resolution of cyclohexylidene oxime esters by transesterification catalyzed by lipase.27 They observed that the use of 5-phenyl valeryl group as ester is key in getting high enantioselectivity. By using using oxime acetates afforded products with low enantioselectivities. The transesterification of 52 proceeded smoothly in presence of lipase and the oxime ester 54 was obtained with 93% enantiomeric excess. These are the only two 66 methods reported for the synthesis of chiral cyclohexylidene oximes and the development of novel methodology is highly desired.

Figure 3.16 Enzyme catalyzed kinetic resolution of cyclohexylidene oxime esters.

3.5 Optimization of reaction conditions for the asymmetric synthesis of cyclohexylidene oximes: Our investigation started with the reaction of phenoxyamine, 58 with 4-phenyl cyclohexanone,

59 in presence of chiral BINOL phosphoric acid and phosphate complexes. We did not observe the desired benzofuran product, 61 but instead full conversion of starting materials to the condensed product oxime, 60 was observed, surprisingly with 54% enantioselectivity (Table 3.1, entry 3). Screening of different catalysts showed Mg(P1)2 at room temperature afforded cyclohexylidene oximes with slight increase in enantioselectivity with 62% ee (Table 3.1, entry

6).

Table 3.1 Optimization of reaction conditions.

Our efforts to further improve the enantioselectivity by optimizing the solvent and temperature with Mg(P1)2 as catalyst were not successful (Table 3.2, entries 1 – 7). To our delight, we observed strontium phosphate complex of P1, Sr(P1)2 at -78 °C proved to be the ideal conditions to afford 60 with 91% ee (Table 3.2, entry 8). Surprisingly, this reaction can also be catalyzed by P1 with slight less enantioselective products (Table 3.2, entry 9).

Table 3.2 Solvent and temperature screening.

3.6 Substrate scope for the asymmetric synthesis of cyclohexylidene oxime ethers: A wide range of chiral cyclohexylidene oxime ether substrates were synthesized using this methodology. All substrates are well-tolerated with substituents on the phenyl ring of phenoxyamine. Disubstituted phenyl substrates showed slight increase in enantioselectivity due to the steric factors (60d, 60e). The absolute configuration for 60b was observed to be ‘R’ based on the X-ray crystal structure and all other compounds were assigned analogously.

Figure 3.17. Substrate scope with different aryloxyamines.

We then used 3,5-dimethylphenyloxy amine to react with different substrates of 4-substituted cyclohexanones. Electron-releasing groups on para position of the phenyl ring of cyclohexanone afforded products with high enantioselectivities (60f, 60g, 60h) compared to electron-withdrawing groups (60k, 60l). Even the alkyl groups at 4-position of cyclohexanone afforded products with good enantioselectivities and excellent yields (60m, 60n).

Figure 3.18. Substrate scope with different 4-substituted cyclohexanones.

3.7 Conclusion: To conclude, we have developed the first catalytic asymmetric synthesis of novel axially chiral cyclohexylidene oxime ethers by the desymmetrization of 4-substituted cyclohexanones, catalyzed by chiral BINOL strontium phosphate to furnish products with excellent yields and good enantioselectivities.

3.8 Experimental data: General Considerations:

All reactions were carried out in flame-dried screw-cap test tubes with magnetic stirring. All anhydrous solvents were purchased from commercial sources and used under Argon atmosphere.

Chiral (R)-BINOL was purchased from commercial sources and used without further purification.

28 29 30 H(P1) was synthesized according to the literature procedure. Ca(P1)2, Mg(P1)2, Sr(P1)2 were prepared as the reported procedures. Thin layer chromatography was performed on Merck TLC plates (silica gel 60 F254). Flash column chromatography was performed with Merck silica gel

(230-400 mesh). Enantiomeric excess (ee) was determined using Agilent 1260 infinity HPLC equipped with quaternary pump and Diode-Array detector. Optical rotations were performed on a Rudolph Research Analytical Autopol IV polarimeter (λ 589) using a 700-μL cell with a path length of 1-dm. 1HNMR and 13C NMR were recorded on Varian Inova-400 spectrometer and

Varian-500 spectrometer with chemical shifts reported relative to tetramethylsilane (TMS) in

CDCl3 solvent. The HRMS data were measured on an Agilent 1100 LC/MS ESI/TOF mass spectrometer with electro-spray ionization. Compounds described in the literature were characterized by comparing their spectral data to the reported values.

Experimental Section:

Synthesis of 4-aryl cyclohexanones:

All 4-aryl cyclohexanones 59f-59l were synthesized using the following scheme reported by

List31 and confirmed by comparison of the spectral data.

Figure 3.19 Synthesis of 4-aryl cyclohexanones.

59a, 59m, 59n were purchased from commercial sources and used without purification.

Synthesis of aryloxyamines:

Aryloxyamines 58a-58d32 and 58e33 were prepared following the literature procedure and confirmed by comparison of spectral data.

Figure 3.20 Synthesis of aryloxyamines.

General procedure for the preparation of chiral 4-substituted cyclohexylidene oxime ethers, 60:

To a flame-dried reaction tube charged with 4Å molecular sieves 50 mg (pre-activated in oven) was added 4-phenyl cyclohexanone 59 (0.22 mmol), catalyst Sr[P1]2 (5 mol%), the tube was evacuated and filled with argon. Added anhydrous dichloromethane (1.0 mL) and cooled the reaction mixture to -78 °C. Added O-phenylhydroxylamine 58 (0.15 mmol) to the reaction mixture at -78 °C and stirred the reaction at the same temperature for 2 h. After completion of reaction

(monitored by TLC) the reaction mixture was directly added on silica gel column and purified by flash chromatography (1:10, ether : hexane) to get the pure product 60.

All racemic substrates were synthesized following the general procedure using diphenyl phosphate (5 mol%) as catalyst at room temperature.

(R,Z)-4-phenylcyclohexan-1-one O-phenyloxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as viscous oil. Yield: 98%, ee: 91%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 98:2,

20 1 1.0 mL/min), t r-major 9.2 min, t r-minor 7.82 min. [α] D= -9.6 (c = 2.7, CHCl3). H NMR (500

MHz; CDCl3): δ 7.25-7.21 (m, 4H), 7.15-7.11 (m, 5H), 6.91 (m, 1H), 3.57-3.52 (m, 1H), 2.74 (tt,

J = 12.2, 3.3 Hz, 1H), 2.64 (m, J = 2.2 Hz, 1H), 2.28 (td, J = 13.8, 4.9 Hz, 1H), 2.10-1.94 (m, 3H),

13 1.74-1.59 (m, 2H). C NMR (126 MHz; CDCl3): δ 163.0, 159.8, 145.9, 129.6, 128.9, 127.1,

+ 126.8, 122.1, 115.0, 44.0, 34.5, 33.4, 32.4, 26.1. HRMS (ESI) calcd for C18H19NO ([M+H] ) m/z

266.1467, found 266.1542.

(R,Z)-4-phenylcyclohexan-1-one O-(4-bromophenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as viscous oil. Yield: 96%, ee: 91%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 98:2,

20 1 1.0 mL/min), t r-major 7.65 min, t r-minor 8.16 min. [α] D= -8.4 (c = 0.8, CHCl3). H NMR (400

MHz; CDCl3): δ 7.42-7.38 (m, 2H), 7.34-7.30 (m, 2H), 7.24-7.21 (m, 3H), 7.11-7.07 (m, 2H),

3.61-3.56 (m, 1H), 2.84 (tt, J = 12.1, 3.3 Hz, 1H), 2.70 (m, J = 2.2 Hz, 1H), 2.36 (td, J = 13.8, 4.9

13 Hz, 1H), 2.21-2.02 (m, 3H), 1.83-1.67 (m, 2H). C NMR (126 MHz; CDCl3): δ 163.4, 158.9,

145.7, 132.4, 128.9, 127.0, 126.8, 116.6, 114.1, 43.9, 34.4, 33.3, 32.2, 26.1. HRMS (ESI) calcd

+ for C18H18BrNO ([M+H] ) m/z 344.0572, found 344.0643.

(R,Z)-4-phenylcyclohexan-1-one O-(p-tolyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as viscous oil. Yield: 99%, ee: 84%. HPLC Analysis: Chiralcel AD-H (Hexane:Isopropanol 98:2,

20 1 1.0 mL/min), t r-major 4.62 min, t r-minor 5.15 min. [α] D= -6.3 (c = 0.11, CHCl3). H NMR (400 75

MHz; CDCl3): δ 7.34-7.30 (m, 2H), 7.24-7.21 (m, 3H), 7.13-7.08 (m, 4H), 3.65-3.60 (m, 1H),

2.83 (tt, J = 12.1, 3.3 Hz, 1H), 2.71 (m, J = 2.2 Hz, 1H), 2.40-2.32 (m, 4H), 2.20-2.02 (m, 3H),

13 1.84-1.68 (m, 2H). C NMR (126 MHz; CDCl3): δ 162.3, 157.5, 145.7, 131.2, 129.8, 128.7,

+ 126.9, 126.5, 114.7, 43.8, 34.3, 33.2, 32.1, 25.8, 20.8. HRMS (ESI) calcd for C19H21NO ([M+H] ) m/z 280.1623, found 280.17.

(R,Z)-4-phenylcyclohexan-1-one O-(3,5-dimethylphenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as viscous oil. Yield: 98%, ee: 93%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 98:2,

20 1 1.0 mL/min), t r-major 7.55 min, t r-minor 7.18 min. [α] D= -8.1 (c = 2.2, CHCl3). H NMR (500

MHz; CDCl3): δ 7.25-7.22 (m, 2H), 7.16-7.12 (m, 3H), 6.76 (s, 2H), 6.57 (s, 1H), 3.53 (m, J = 2.1

Hz, 1H), 2.74 (tt, J = 12.2, 3.3 Hz, 1H), 2.64 (m, J = 2.2 Hz, 1H), 2.28 (td, J = 13.8, 4.9 Hz, 1H),

13 2.23 (s, 6H), 2.10-1.93 (m, 3H), 1.66 (m, J = 4.2 Hz, 2H). C NMR (126 MHz; CDCl3): δ 162.32,

159.39, 145.51, 138.98, 128.49, 126.70, 126.36, 123.49, 112.23, 43.62, 34.12, 33.02, 31.96, 25.64,

+ 21.42. HRMS (ESI) calcd for C20H23NO ([M+H] ) m/z 294.178, found 294.1856.

(R,Z)-4-phenylcyclohexan-1-one O-(2,4-dinitrophenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as yellow solid. Yield: 94%, ee: 94%. HPLC Analysis: Chiralcel AD-H (Hexane:Isopropanol 98:2,

20 1 1.0 mL/min), t r-major 17.53 min, t r-minor 16.65 min. [α] D= -33.02 (c = 2.2, CHCl3). H NMR (500

MHz; CDCl3): δ 8.89 (d, J = 2.7 Hz, 1H), 8.43 (dd, J = 9.4, 2.8 Hz, 1H), 8.01 (d, J = 9.4 Hz, 1H),

7.33 (t, J = 7.6 Hz, 2H), 7.25-7.22 (m, 3H), 3.70-3.66 (m, 1H), 2.88 (tt, J = 12.2, 3.2 Hz, 1H), 2.77

(m, J = 2.2 Hz, 1H), 2.44 (td, J = 13.8, 5.0 Hz, 1H), 2.26-2.17 (m, 3H), 1.85-1.73 (m, 2H). 13C

NMR (126 MHz; CDCl3): δ 168.3, 157.8, 144.8, 140.6, 136.0, 129.5, 128.8, 126.80, 126.78, 122.2,

+ 117.3, 43.4, 34.1, 33.0, 31.7, 27.1. HRMS (ESI) calcd for C18H17N3O5 ([M+Na] ) m/z 378.1168, found 378.1221.

(R,Z)-4-(p-tolyl)cyclohexan-1-one O-(3,5-dimethylphenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 98%, ee: 90%. HPLC Analysis: Chiralcel AD-H (Hexane:Isopropanol 98:2, 1.0

20 1 mL/min), t r-major 4.32 min, t r-minor 4.98 min. [α] D= -2.5 (c = 1.55, CHCl3). H NMR (500 MHz;

CDCl3): δ 7.16-7.12 (m, 4H), 6.85 (s, 2H), 6.67 (s, 1H), 3.64-3.60 (m, 1H), 2.81 (tt, J = 12.1, 3.3

Hz, 1H), 2.73 (m, J = 2.2 Hz, 1H), 2.38 (m, 1H), 2.35 (s, 3H), 2.33 (s, 6H), 2.18-2.02 (m, 3H),

13 1.82-1.67 (m, 2H). C NMR (126 MHz; CDCl3): δ 162.7, 159.7, 142.8, 139.3, 136.2, 129.5,

126.9, 123.8, 112.5, 43.5, 34.5, 33.4, 32.3, 26.0, 21.7, 21.3. HRMS (ESI) calcd for C21H25NO

+ ([M+H] ) m/z 308.1936, found 308.2025.

(R,Z)-4-(4-methoxyphenyl)cyclohexan-1-one O-(3,5-dimethylphenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 99%, ee: 86%. HPLC Analysis: Chiralcel AD-H (Hexane:Isopropanol 98:2, 1.0

20 1 mL/min), t r-major 6.34 min, t r-minor 7.75 min. [α] D= -3.06 (c = 4, CHCl3). H NMR (400 MHz;

CDCl3): δ 7.19-7.16 (m, 2H), 6.91-6.88 (m, 4H), 6.68 (s, 1H), 3.82 (s, 3H), 3.63 (m, 1H), 2.84-

2.73 (m, 2H), 2.41-2.37 (m, 1H), 2.35 (s, 6H), 2.18-2.03 (m, 3H), 1.78-1.67 (m, 2H). 13C NMR

(101 MHz; CDCl3): δ 162.7, 159.7, 158.4, 139.3, 138.0, 127.9, 123.8, 114.2, 112.6, 55.5, 43.1,

+ 34.7, 33.6, 32.3, 26.0, 21.7. HRMS (ESI) calcd for C21H25NO2 ([M+H] ) m/z 324.1885, found

324.1972.

(R,Z)-4-(4-(tert-butyl)phenyl)cyclohexan-1-one O-(3,5-dimethylphenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 99%, ee: 86%. HPLC Analysis: Chiralcel AD-H (Hexane:Isopropanol 98:2, 1.0

20 1 mL/min), t r-major 3.61 min, t r-minor 4.48 min. [α] D= -4.23 (c = 4.3, CHCl3). H NMR (400 MHz;

CDCl3): δ 7.38 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H), 6.88 (s, 2H), 6.69 (s, 1H), 3.64 (m,

1H), 2.87-2.73 (m, 2H), 2.42-2.38 (m, 7H), 2.21-2.03 (m, 3H), 1.81-1.71 (m, 2H), 1.36 (s, 9H).

13 C NMR (101 MHz; CDCl3): δ 162.7, 159.7, 149.4, 142.7, 139.2, 126.6, 125.6, 123.7, 112.5, 43.3,

+ 34.63, 34.44, 33.3, 32.3, 31.6, 25.9, 21.7. HRMS (ESI) calcd for C24H31NO ([M+H] ) m/z

350.2406, found 350.2490.

(R,Z)-4-(naphthalen-1-yl)cyclohexan-1-one O-(3,5-dimethylphenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 97%, ee: 85%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 98:2, 1.0

20 1 mL/min), t r-major 14.13 min, t r-minor 15.36 min. [α] D= +23.98 (c = 3, CHCl3). H NMR (400

MHz; CDCl3): δ 8.18 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.62-

7.38 (m, 4H), 6.91 (s, 2H), 6.70 (s, 1H), 3.70 (m, 2H), 2.85 (m, 1H), 2.54 (td, J = 13.6, 4.2 Hz,

13 1H), 2.36-2.17 (m, 9H), 1.98-1.80 (m, 2H). C NMR (101 MHz; CDCl3): δ 162.6, 159.8, 141.6,

139.3, 134.3, 131.5, 129.4, 127.2, 126.3, 125.94, 125.76, 123.9, 123.1, 122.6, 112.6, 38.7, 34.0,

+ 32.9, 32.6, 26.3, 21.8. HRMS (ESI) calcd for C24H25NO ([M+H] ) m/z 344.1936, found 344.2014.

(R,Z)-4-(3,5-dimethylphenyl)cyclohexan-1-one O-(3,5-dimethylphenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as gummy liquid. Yield: 98%, ee: 89%. HPLC Analysis: Chiralcel AD-H (Hexane:Isopropanol 98:2,

20 1 1.0 mL/min), t r-major 3.84 min, t r-minor 4.43 min. [α] D= -3.4 (c = 3.6, CHCl3). H NMR (500

MHz; CDCl3): δ 6.87 (m, 5H), 6.67 (s, 1H), 3.62 (m, J = 2.0 Hz, 1H), 2.81-2.71 (m, 2H), 2.40-

13 2.33 (m, 13H), 2.18-2.01 (m, 3H), 1.83-1.68 (m, 2H). C NMR (126 MHz; CDCl3): δ 162.6,

159.6, 145.7, 139.1, 138.1, 128.2, 124.7, 123.6, 112.4, 43.7, 34.3, 33.2, 32.2, 25.9, 21.6. HRMS

+ (ESI) calcd for C22H27NO ([M+H] ) m/z 322.2093, found 322.2173.

(R,Z)-4-(4-(trifluoromethyl)phenyl)cyclohexan-1-one O-(3,5-dimethylphenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as yellow solid. Yield: 98%, ee: 83%. HPLC Analysis: Chiralcel AD-H (Hexane:Isopropanol 98:2,

20 1 1.0 mL/min), t r-major 5.39 min, t r-minor 6.38 min. [α] D= -3.5 (c = 3.5, CHCl3). H NMR (500

MHz; CDCl3): δ 7.59 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.88 (s, 2H), 6.69 (s, 1H),

3.68-3.65 (m, 1H), 2.90 (tt, J = 12.1, 3.0 Hz, 1H), 2.77 (m, J = 2.1 Hz, 1H), 2.43-2.30 (m, 7H),

13 2.20-2.04 (m, 3H), 1.84-1.68 (m, 2H). C NMR (126 MHz; CDCl3): δ 162.1, 159.8, 149.9, 129.2,

129.0, 127.5, 125.86, 125.83, 124.0, 123.5, 112.6, 43.9, 34.2, 33.1, 32.2, 25.8, 21.8. HRMS (ESI)

+ calcd for C21H22F3NO ([M+H] ) m/z 362.1653, found 362.1742.

(R,Z)-4-(4-chlorophenyl)cyclohexan-1-one O-(3,5-dimethylphenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as gummy liquid. Yield: 98%, ee: 76%. HPLC Analysis: Chiralcel AD-H (Hexane:Isopropanol 99:1,

20 1 1.0 mL/min), t r-major 5.6 min, t r-minor 6.98 min. [α] D= -4.08 (c = 5.8, CHCl3). H NMR (500

MHz; CDCl3): δ 7.30-7.28 (m, 2H), 7.17-7.15 (m, 2H), 6.85 (s, 2H), 6.67 (s, 1H), 3.64-3.60 (m,

1H), 2.81 (m, J = 3.8 Hz, 1H), 2.73 (m, J = 2.2 Hz, 1H), 2.37 (m, 7H), 2.16-2.01 (m, 3H), 1.78-

13 1.64 (m, 2H). C NMR (126 MHz; CDCl3): δ 162.1, 159.5, 144.1, 139.1, 132.1, 128.7, 128.2,

+ 123.7, 112.4, 43.2, 34.2, 33.1, 32.0, 25.7, 21.6. HRMS (ESI) calcd for C20H22ClNO ([M+H] ) m/z

328.139, found 328.1464.

(R,Z)-4-methylcyclohexan-1-one O-phenyl oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 98%, ee: 80%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 99:1, 1.0

20 1 mL/min), t r-major 5.12 min, t r-minor 4.44 min. [α] D= -2.5 (c = 0.6, CHCl3). H NMR (500 MHz;

CDCl3): δ 7.31-7.26 (m, 2H), 7.18-7.15 (m, 2H), 6.97 (tt, J = 7.3, 1.1 Hz, 1H), 3.43-3.38 (m, 1H),

2.55 (m, J = 1.6 Hz, 1H), 2.20 (td, J = 13.5, 4.9 Hz, 1H), 1.99-1.85 (m, 3H), 1.73-1.66 (m, 1H),

13 1.28-1.14 (m, 2H), 0.97 (d, J = 6.6 Hz, 3H). C NMR (126 MHz; CDCl3): δ 163.6, 159.5, 129.2,

+ 121.6, 114.5, 35.0, 33.8, 31.9, 31.5, 25.2, 21.5. HRMS (ESI) calcd for C13H17NO ([M+H] ) m/z

204.131, found 204.139.

(R,Z)-4-ethylcyclohexan-1-one O-phenyl oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 98%, ee: 92%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 99:1, 1.0

20 1 mL/min), t r-major 4.91 min, t r-minor 4.31 min. [α] D= -2.9 (c = 0.4, CHCl3). H NMR (500 MHz;

CDCl3): δ 7.30-7.26 (m, 2H), 7.17-7.13 (m, 2H), 6.98-6.95 (m, 1H), 3.43-3.38 (m, 1H), 2.56 (m,

J = 1.7 Hz, 1H), 2.19 (m, J = 4.9 Hz, 1H), 2.02-1.91 (m, 3H), 1.44 (m, J = 3.7 Hz, 1H), 1.30 (m,

13 2H), 1.25-1.14 (m, 2H), 0.91 (q, J = 9.0 Hz, 3H). C NMR (126 MHz; CDCl3): δ 164.1, 159.7,

129.3, 121.7, 114.7, 38.7, 32.7, 31.65, 31.57, 28.9, 25.4, 11.8. HRMS (ESI) calcd for C14H19NO

+ ([M+H] ) m/z 218.1467, found 218.1549.

3.9 X-ray Crystallography data: The X-ray diffraction data for compound 60b were measured on Bruker D8 Venture PHOTON

100 CMOS system equipped with a Cu Kα INCOATEC ImuS micro-focus source (λ = 1.54178

Å). Indexing was performed using APEX234 (Difference Vectors method). Data integration and reduction were performed using SaintPlus 6.01.35 Absorption correction was performed by multi- scan method implemented in SADABS.36 Space group was determined using XPREP implemented in APEX334. Structure was solved using SHELXS-97 (direct methods) and refined using SHELXL-201537 (full-matrix least-squares on F2) through OLEX2 interface program.38 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms of –CH, –CH2, groups were placed in geometrically calculated positions and were included in the refinement process using riding model with isotropic thermal parameters: Uiso(H) = 1.2Ueq(-CH,-CH2). Crystal data and refinement conditions are shown in Table 1. Asymmetric unit contains two crystallographically independent molecules. Some of observed residual density peaks close to Br atoms could potentially come from sample contamination by second isomer sharing the same site in the crystal lattice, however low occupancy (<5%) precludes the possibility of further modeling of disorder.

ORTEP diagram of 60b deposited in CCDC with number CCDC 1491317.

Table 1 Crystal data and structure refinement for 60b. Identification code 60b Empirical formula C18H18BrNO Formula weight 344.24 Temperature/K 99.97 Crystal system monoclinic Space group P21 a/Å 8.6817(3) b/Å 6.3668(2) c/Å 28.2219(9) α/° 90 β/° 97.2250(17) γ/° 90 Volume/Å3 1547.57(9) Z 4 3 ρcalcg/cm 1.477 μ/mm-1 3.595 F(000) 704.0 Crystal size/mm3 0.09 × 0.06 × 0.01 Radiation CuKα (λ = 1.54178) 2Θ range for data collection/° 6.314 to 138.99 Index ranges -9 ≤ h ≤ 10, -7 ≤ k ≤ 7, -34 ≤ l ≤ 34 Reflections collected 15510 Independent reflections 5403 [Rint = 0.0834, Rsigma = 0.0867] Data/restraints/parameters 5403/1/379 Goodness-of-fit on F2 1.038 Final R indexes [I>=2σ (I)] R1 = 0.0590, wR2 = 0.1366 Final R indexes [all data] R1 = 0.0738, wR2 = 0.1449 Largest diff. peak/hole / e Å-3 1.48/-0.57 Flack parameter 0.027(17)

3.10 References: 1. For reviews see: (a) Willis, M. C. J. Chem. Soc., Perkin Trans. 1, 1999, 1765. (b) Hoveyda, A.

H.; Schrock, R. R. Chem. -Eur. J. 2001, 7, 945. (c) Trost, B. M.; Crawley, M. L. Chem. Rev.

2003, 103, 2921. (d) Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313.

(e) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683.

2. (a) Drauz, K.; Waldmann, H. Enzyme Catalysis in Organic Synthesis: A Comprehensive

Handbook, Vol I-III, 2nd ed., VCH, Weinheim, 2002. (b) Faber, K. Biotransformations in

Organic Chemistry, 4th ed., Springer, Berlin, 2000. (c) Reetz, M. T.; Brunner, B.; Schneider,

T.; Schultz, F.; Clouthier, C. M.; Kayser, M. M. Angew. Chem. Int. Ed. 2004, 43, 4075.

3. (a) Nugent, W. A. J. Am. Chem. Soc. 1998, 120, 7139. (b) Mizuta, S.; Tsuzuki, T.; Fujimoto,

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H.; Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028. (d) Lewis, C. A.; Sculimbrene,

B. R.; Xu, Y.; Miller, S. J. Org. Lett. 2005, 7, 3021. (e) Zhou, J.; Wakchaure, V.; Kraft, P.;

List, B. Angew. Chem. Int. Ed. 2008, 47, 7656. (f) Della Sala, G.; Lattanzi, A. Org. Lett. 2009,

11, 3330. (g) Mori, K.; Katoh, T.; Suzuki, T.; Noji, T.; Yamanaka, M.; Akiyama, T. Angew.

Chem. Int. Ed. 2009, 48, 9652. (h) De, C. K.; Seidel, D. J. Am. Chem. Soc. 2011, 133, 14538.

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You, S.-L. Org. Lett. 2011, 13, 5192. (k) Lee, J. Y.; You, Y. S.; Kang, S. H. J. Am. Chem. Soc.

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9. Itagaki, N.; Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org. Lett. 2005, 7, 4185.

10. Diaba, F.; Bonjoch, J. Org. Biomol. Chem. 2009, 7, 2517.

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13. Chen, J.-R.; Lai, Y.-Y.; Lu, H.-H.; Wang, X.-F.; Xiao, W.-J. Tetrahedron, 2009, 65, 9238.

14. Chen, Y. M.; Lee, P.-H.; Lin, J.; Chen, K. Eur. J. Org. Chem. 2013, 2699.

15. Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 8834.

16. Zhou, L.; Liu, X.; Ji, J.; Zhang, Y.; Hu, X.; Lin, L.; Feng, X. J. Am. Chem. Soc. 2012, 134,

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17. (a) Xu, S.; Wang, Z.; Zhang, X.; Zhang, X.; Ding, K. Angew. Chem. Int. Ed. 2008, 47, 2840.

(b) Xu, S.; Wang, Z.; Li, Y.; Zhang, X.; Wang, H.; Ding, K. Chem. Eur. J. 2010, 16, 3021.

18. Müller, S.; Webber, M. J.; List, B. J. Am. Chem. Soc. 2011, 133, 18534.

19. (a) Eilel, E. L., Wilen, S. H. Stereochemistry of Carbon Compounds; McGraw-Hill Book

Company, Inc: New York, 1994, Chapter 14. (b) Cahn, R. S.; Ingold, C.; Prelog, V. Angew.

Chem. Int. Ed. 1966, 5, 385.

20. (a) “Biaryl in Nature”: Bringmann, G.; Günther, C.; Ochse, M.; Schupp, O.; Tasler, S. Progress

in the Chemistry of Organic Natural Products, 82, Springer, Vienna, 2001. (b) Williams, D.

H.; Bardsley, B. Angew. Chem. Int. Ed. 1999, 38, 1172. (c) Hoffmann-Röder, Krause, N.

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Sivaguru, J. Chem. Rev. 2015, 115, 11239.

21. For recent reviews on: Biaryls: (a) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert,

F. Chem. Soc. Rev. 2015, 44, 3418. Allenes: (b) Yu, S.; Ma, S. Angew. Chem. Int. Ed. 2012,

51, 3074. (c) Ye, J.; Ma, S. Org. Chem. Front. 2014, 1, 1210. Spiranes: (d) Rios, R. Chem.

Soc. Rev. 2012, 41, 1060. (e) Franz, A. K.; Hanhan, N. V.; Ball-Jones, N. R. ACS Catal. 2013,

3, 540.

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24. Iguchi, M.; Tomioka, K. Org. Lett. 2002, 4, 4329.

25. Mills, W. H.; Bain, A. M. J. Chem. Soc. 1910, 97, 1866.

26. Toda, F.; Akai, H. J. Org. Chem. 1990, 55, 4973.

27. Murakata, M.; Imai, M.; Tamura, M.; Hoshino, O. Tetrahedron: Asymmetry, 1994, 5, 2019.

28. For synthesis of diol, see: (a) Zhu, S. S.; Cefalo, D. R.; La, D. S.; Jamieson, J. Y.; Davis, W.

M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1999, 121, 8251. For synthesis of

phosphoric acid, see: (b) Klussmann, M.; Hoffmann, S.; Wakchaure, V.; Goddard, R.; List, B.

Synlett 2010, 14, 2189. (c) Liu, W.; Chen, X.; Gong, L. Org. Lett. 2008, 10, 5357.

29. Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew Chem. Int. Ed. 2010, 49, 3823.

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13, 2054. (b) Nimmagadda, S. K.; Zhang, Z.; Antilla, J. C. Org. Lett. 2014, 16, 4098.

31. Müller, S.; Webber, M. J.; List, B. J. Am. Chem. Soc. 2011, 133, 18534.

32. Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. Org. Lett. 2001, 3, 139.

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Kürti, L.; Falck, J. R. Science, 2014, 343, 61.

34. Bruker (2016). APEX3 Bruker AXS Inc., Madison, Wisconsin, USA.

35. Bruker (2016) SAINT Data Reduction Software.

36. Sheldrick, G. M. (1996). SADABS. Program for Empirical Absorption Correction. University

of Gottingen, Germany.

37. (a) Sheldrick, G.M. (1997) SHELXL-97. Program for the Refinement of Crystal. (b) Sheldrick,

G.M. (1990) Acta Cryst. A46, 467-473. (c) Sheldrick, G. M. (2008). Acta Cryst. A64, 112-

122.

38. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H., OLEX2: A

complete structure solution, refinement and analysis program (2009). J. Appl. Cryst., 42, 339-

341.

4 Dynamic Kinetic Resolution of 2-substituted cyclohexanones

4.1 Introduction: Dynamic Kinetic Resolution (DKR) process is one of the prominent methods to get enantiopure compounds from racemic substrates. The DKR process proceeds in combination with the kinetic resolution step, in which the in situ racemization or equilibration of the substrate occurs.

This follows the Curtin-Hammett kinetic conditions, in which the two enantiomers of the substrate are induced to equilibrate or racemize at a rate faster than the rate of slow-reacting enantiomer with the chiral reagent. For an efficient DKR process, the rate of racemization of the substrates has to be faster than the rate of the both resolution steps (fast and slow). Also, the rate of resolution for one enantiomer has to be faster than that of the other enantiomer. (Figure 4.1) Several DKR processes has been developed based on asymmetric enzyme catalysis, transition metal catalysis and recently organocatalytic methodologies.1 The DKR process has been applied in numerous asymmetric transformations involving α-substituted ketones, α-substituted keto esters and amides,

α-substituted imine derivates etc., to afford chiral products with 100% theoretical yield and excellent enantioselectivity.

Figure 4.1 Dynamic Kinetic Resolution (DKR) process.

4.2 DKR by asymmetric transfer hydrogenation of 2-substituted cyclohexanones: Lassaletta and co-workers first reported the asymmetric transfer hydrogenation of 2-substituted

2 cyclic imines by DKR. In presence of Ru(II) catalyst, (R,R)-1 and HCO2H/Et3N azeotropic mixture used as hydrogen source, the bicyclic imines (3) were reduced to give cis-4 with high yield and enantioselectivities. They also showed that 2-substituted cyclicimines, 5 undergo transfer hydrogenation in presence of Ir(III) catalyst, (S,S)-2 to give cis-6 products with moderate yield and enantioselecitivities.

Figure 4.2 DKR of imines by asymmetric transfer hydrogenation.

In 2010, List et al. published an efficient organocatalytic asymmetric reductive amination of

2-substituted cyclohexanones, 7 with p-anisdine, 8 and Hantzsch ester, 9 catalyzed by chiral

BINOL phosphoric acid.3 The reaction proceeds with the in situ formation of imine followed by reduction with Hantzsch ester via dynamic kinetic resolution to furnish products, 10 with good yields and high diastereo- and enantioselectivities. The reaction also works with 2-substituted

91 cyclopentanones. They further applied this methodology in the synthesis of perindopril, a long- acting ACE inhibitor3b.

Figure 4.3 Asymmetric reductive amination of α-branched ketones.

In 2011, Ohkuma et al. reported an asymmetric hydrogenation of aryl heterocycloalkyl ketones catalyzed by (S,R)-15 through dynamic kinetic resolution process.4 The diastereoselectivity of the reaction was essentially controlled by the catalyst via metal chelation with carbonyl oxygen and the X group present in the heterocycle in 13 and 14. Under these conditions, syn alcohols, 16 and

17 were produced with high diastereo- and enantioselectivities with excellent yields. The authors also showed the synthesis of (S,S)-reboxetine succinate using this methodology, which is a selective norepinephrine uptake inhibitor. (Figure 4.4)

Figure 4.4 Asymmetric hydrogenation of aryl heterocycloalkyl ketones.

Recently, Zhou et al. reported ruthenium (II) catalyzed asymmetric hydrogenation of α-aryl cyclohexanones, 20 to furnish syn diols with excellent enantio- and diastereoselectivity and good yields. They applied this methodology in the synthesis of molecules such as (-)-α-lycorane, (-)-

CP55940 and tetrahydrocannabinol derivatives that are biologically active.5 They further showed the application of this methodology in the asymmetric hydrogenation of α,α’-disubstituted cycloketones, 22 resulting in the formation of chiral diols with three continuous stereocenters, 23 in single step.6 The compounds with five membered ring only gave moderate enantioselectivity upto 75% ee, while six and seven membered rings showed high enantioselectivities. The authors noted that both aryl and ester groups were necessary to afford highly enantioselective products.

(Figure 4.5)

Figure 4.5 Asymmetric hydrogenation of α,α’-disubstituted cycloketones.

4.3 Optimization of reaction conditions for dynamic kinetic resolution of 2-substituted cyclohexanones. Based on our observation and results from desymmetrization of 4-substituted cyclohexanones, we investigated dynamic kinetic resolution of 2-substituted cyclohexanones using the same methodology. Our initial reactions with phenoxy amine with 2-phenyl cyclohexanone in presence of Sr(P1)2 under identical conditions gave negligible enantioselectivity.

Figure 4.6 DKR of 2-phenyl cyclohexanone with phenoxyamine.

From our observation, the use of different O-protecting group effects the enantioselectivity of the product significantly. Upon using O-(2,4-dinitrophenyl)hydroxylamine in dichloromethane at

-78 °C in presence of Mg(P1)2 gave product with 38% ee (Table 4.1, entry 3). Changing the solvent to toluene provided excellent enantioselectivity with moderate yield. Screening the optimal temperature for the reaction showed, the yield and enantioselectivity are

Table 4.1 Optimization for DKR of 2-substituted cyclohexanones.

95 inversely proportional. At low temperatures high enantioselectivity was observed but with low yield (Table 4.1, entries 6 – 10). This was attributed to the probable decomposition of 27 in the reaction conditions to 2, 4-dinitrophenol. Interestingly, chiral BINOL phosphoric acid, P1 also could catalyze the dynamic kinetic resolution process with good yield and enatioselectivity.

Figure 4.7 Substrate scope for the DKR of 2-substituted cyclohexanones.

4.4 Substrate scope for the DKR of 2-substituted cyclohexanones: With the optimal conditions, a wide range of substrates are screened using this methodology.

Both electron releasing and with-drawing groups on the phenyl group of cyclohexanones are tolerated providing good enantioselectivities with moderate yields. This method not only works with aryl groups, but also for methyl and chloro groups at the 2-position of the cyclohexanone to furnish products with excellent yields.

Figure 4.8 Reductive cleavage and acylation.

To further extend the utility of this reaction, the oxime ether was reduced to amines in presence

7 of 3 eq. of BH3.THF in THF at room temperature. The crude amine intermediate obtained was subjected to acylation conditions without purification resulting in the formation of cis-29 product with 66% yield and 83% ee. The NMR and HPLC data of the acylated amine obtained, cis-29 are in correlation with the literature data8 reported previously and the configuration for the 2- substituted chiral cyclohexanone oxime ethers were assigned analogously.

4.5 Conclusion: In conclusion, we have developed a novel asymmetric dynamic kinetic resolution process of

α-branched cyclohexanones to give 2-substituted cyclohexanone oxime ethers in good yield and

97 enantioselectivities. Furthermore, we showed the utility of these compounds in the synthesis of chiral syn-2-phenyl cyclohexylamines which are useful synthetic intermediates with excellent diastereoselectivity and good enantioselectivity.

4.6 Experimental data: General considerations:

All reactions were carried out in flame-dried screw-cap test tubes with magnetic stirring. All anhydrous solvents were purchased from commercial sources and used under Argon atmosphere.

Chiral (R)-BINOL was purchased from commercial sources and used without further purification.

9 10 11 H(P1) was synthesized according to the literature procedure. Ca(P1)2, Mg(P1)2, Sr(P1)2 were prepared as the reported procedures. Thin layer chromatography was performed on Merck TLC plates (silica gel 60 F254). Flash column chromatography was performed with Merck silica gel

(230-400 mesh). Enantiomeric excess (ee) was determined using a Agilent 1260 infinity HPLC equipped with quaternary pump and Diode-Array detector. Optical rotations were performed on a Rudolph Research Analytical Autopol IV polarimeter (λ 589) using a 700-μL cell with a path length of 1-dm. 1HNMR and 13C NMR were recorded on Varian Inova-400 spectrometer and

Varian-500 spectrometer with chemical shifts reported relative to tetramethylsilane (TMS) in

Synthesis of 2-aryl cyclohexanones:

Compounds 25b-25f12 were prepared following the literature procedure and confirmed by comparison of spectral data. 25a, 25g, 25h were purchased from commercial sources.

General procedure for the preparation of 2-substituted cyclohexanone oxime ethers, 6:

To a flame-dried reaction tube charged with 4Å molecular sieves 20 mg (pre-activated in oven) was added 2-phenyl cyclohexanone 25a (0.05 mmol), catalyst P1 (5 mol%), the tube was evacuated and filled with argon. Added dry toluene (1.0 ml) and cooled the reaction mixture to -

78 °C. Added O-(2,4-dinitrophenyl)hydroxylamine 27 (0.07 mmol) to the reaction mixture at -78

°C and stirred the reaction mixture at -78 °C to -65 °C for 20 h. After completion of reaction

(monitored by TLC) the reaction mixture was directly added on silica gel column and purified by flash chromatography (1:10, ether : hexane) to get the pure product 28.

In the synthesis of racemic substrates upon using diphenylphosphate as catalyst E-oxime was observed as major isomer, whereas using P1 at rt gave Z-oxime as major isomer. In order to have

99 clear comparison between racemic and chiral substrates for HPLC, all racemic substrates were prepared using P1 (5 mol%) in dichloromethane at rt.

(R,Z)-2-phenylcyclohexan-1-one O-(2,4-dinitrophenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 86%, ee: 88%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 99:1, 1.0

20 1 mL/min), t r-major 18.81 min, t r-minor 16.47 min. [α] D= +276.42 (c = 1.1, CHCl3). H NMR (500

MHz; CDCl3): δ 8.88 (d, J = 2.8 Hz, 1H), 8.44 (dd, J = 9.4, 2.8 Hz, 1H), 8.05 (d, J = 9.4 Hz, 1H),

7.38-7.26 (m, 4H), 7.24-7.23 (m, 1H), 5.01 (d, J = 4.9 Hz, 1H), 2.59-2.48 (m, 2H), 2.33 (m, 1H),

2.05 (m, 1H), 1.97-1.90 (m, 1H), 1.75-1.68 (m, 2H), 1.67-1.61 (m, 1H). 13C NMR (126 MHz;

CDCl3): δ 170.8, 157.9, 140.8, 138.4, 136.2, 129.7, 129.2, 127.5, 127.1, 122.4, 117.7, 39.8, 29.7,

+ 29.4, 27.1, 21.0. HRMS (ESI) calcd for C18H17N3O5 ([M+Na] ) m/z 378.1168, found 378.1050.

(R,Z)-2-(p-tolyl)cyclohexan-1-one O-(2,4-dinitrophenyl) oxime

100

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 84%, ee: 84%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 99:1, 1.0

20 1 mL/min), t r-major 14.55 min, t r-minor 13.28 min. [α] D= +222.9 (c = 1.3, CHCl3). H NMR (500

MHz; CDCl3): δ 8.87 (d, J = 2.7 Hz, 1H), 8.43 (dd, J = 9.4, 2.8 Hz, 1H), 8.05 (d, J = 9.4 Hz, 1H),

7.18-7.13 (m, 4H), 4.97 (d, J = 4.6 Hz, 1H), 2.56 (m, 1H), 2.48 (m, J = 2.8 Hz, 1H), 2.37-2.30 (m,

4H), 2.04 (m, J = 2.5 Hz, 1H), 1.91 (m, J = 5.7 Hz, 1H), 1.71 (m, 2H), 1.66-1.59 (m, 1H). 13C

NMR (126 MHz; CDCl3): δ 171.0, 158.0, 140.8, 136.8, 135.3, 129.9, 129.7, 128.2, 127.4, 122.4,

+ 117.7, 39.5, 29.8, 29.4, 27.2, 21.3, 21.1. HRMS (ESI) calcd for C19H19N3O5 ([M+Na] ) m/z

392.1325, found 392.1212.

(R,Z)-2-(m-tolyl)cyclohexan-1-one O-(2,4-dinitrophenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 83%, ee: 82%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 99:1, 0.7

20 1 mL/min), t r-major 18.41 min, t r-minor 17.3 min. [α] D= +233.5 (c = 0.5, CHCl3). H NMR (500

MHz; CDCl3): δ 8.87 (d, J = 2.7 Hz, 1H), 8.43 (dd, J = 9.4, 2.7 Hz, 1H), 8.04 (d, J = 9.4 Hz, 1H),

7.23-7.20 (m, 1H), 7.07-7.04 (m, 3H), 4.96 (d, J = 4.4 Hz, 1H), 2.56 (dd, J = 14.3, 0.7 Hz, 1H),

2.48 (dt, J = 14.5, 2.2 Hz, 1H), 2.37-2.31 (m, 4H), 2.04 (m, J = 2.6 Hz, 1H), 1.91 (m, J = 5.7 Hz,

13 1H), 1.71 (m, 2H), 1.66-1.60 (m, 1H). C NMR (126 MHz; CDCl3): δ 170.8, 157.8, 140.7, 138.8,

101

138.3, 129.5, 129.0, 128.2, 127.8, 124.4, 122.3, 117.6, 39.7, 29.8, 29.4, 27.1, 21.8, 21.0. HRMS

+ (ESI) calcd for C19H19N3O5 ([M+Na] ) m/z 392.1325, found 392.1223.

(R,Z)-2-(3,5-dimethylphenyl)cyclohexan-1-one O-(2,4-dinitrophenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as liquid. Yield: 79%, ee: 82%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 99:1, 0.7

20 1 mL/min), t r-major 14.48 min, t r-minor 14.00 min. [α] D= +236.38 (c = 0.6, CHCl3). H NMR (500

MHz; CDCl3): δ 8.87 (d, J = 2.7 Hz, 1H), 8.43 (dd, J = 9.4, 2.8 Hz, 1H), 8.05 (d, J = 9.4 Hz, 1H),

6.87 (d, J = 7.8 Hz, 3H), 4.92 (d, J = 4.3 Hz, 1H), 2.58-2.55 (m, 1H), 2.49-2.45 (m, 1H), 2.39-2.33

(m, 1H), 2.29 (s, 6H), 2.04 (m, 1H), 1.89 (m, J = 5.6 Hz, 1H), 1.73-1.68 (m, 2H), 1.63 (t, J = 8.2

13 Hz, 1H). C NMR (126 MHz; CDCl3): δ 171.0, 157.9, 140.8, 138.7, 138.3, 129.6, 128.7, 125.3,

+ 122.4, 117.7, 39.8, 29.9, 29.5, 27.2, 21.8, 21.1. HRMS (ESI) calcd for C20H21N3O5 ([M+Na] ) m/z 406.1481, found 406.1365.

102

(R,Z)-2-(4-bromophenyl)cyclohexan-1-one O-(2,4-dinitrophenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as gummy liquid. Yield: 66%, ee: 90%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 99:1,

20 1 1.0 mL/min), t r-major 20.84 min, t r-minor 19.94 min. [α] D= +239.3 (c = 1.4, CHCl3). H NMR

(500 MHz; CDCl3): δ 8.88 (d, J = 2.8 Hz, 1H), 8.44 (dd, J = 9.4, 2.7 Hz, 1H), 8.04 (d, J = 9.4 Hz,

1H), 7.46 (d, J = 8.6 Hz, 2H), 7.15 (dd, J = 8.6, 0.7 Hz, 2H), 4.94 (d, J = 4.5 Hz, 1H), 2.61-2.57

(m, 1H), 2.46-2.42 (m, 1H), 2.28 (m, 1H), 2.05 (m, J = 2.3 Hz, 1H), 1.97-1.90 (m, 1H), 1.73-1.61

13 (m, 3H). C NMR (126 MHz; CDCl3): δ 170.1, 157.7, 141.0, 137.5, 132.3, 130.2, 129.7, 129.3,

+ 122.4, 121.1, 117.6, 39.4, 29.7, 29.4, 26.9, 21.0. HRMS (ESI) calcd for C18H16BrN3O5 ([M+Na] ) m/z 458.0273, found 458.0151.

(R,Z)-2-(4-chlorophenyl)cyclohexan-1-one O-(2,4-dinitrophenyl) oxime

103

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as solid. Yield: 68%, ee: 90%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 99:1, 1.0

20 1 mL/min), t r-major 19.72 min, t r-minor 19.10 min. [α] D= +232.6 (c = 1.3, CHCl3). H NMR (500

MHz; CDCl3): δ 8.88 (d, J = 2.8 Hz, 1H), 8.44 (dd, J = 9.4, 2.8 Hz, 1H), 8.04 (d, J = 9.4 Hz, 1H),

7.35-7.29 (m, 2H), 7.23-7.20 (m, 2H), 4.96 (d, J = 4.6 Hz, 1H), 2.59 (m, 1H), 2.49-2.42 (m, 1H),

2.32-2.25 (m, 1H), 2.16-2.13 (m, 1H), 2.05 (m, J = 2.3 Hz, 1H), 1.97-1.90 (m, 1H), 1.74-1.68 (m,

13 2H). C NMR (126 MHz; CDCl3): δ 170.2, 157.7, 141.0, 136.9, 136.2, 133.0, 129.7, 129.4, 129.0,

+ 122.5, 117.7, 39.3, 29.7, 29.4, 27.0, 21.0. HRMS (ESI) calcd for C18H16ClN3O5 ([M+Na] ) m/z

412.0778, found 412.0676.

(R,Z)-2-chlorocyclohexan-1-one O-(2,4-dinitrophenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as solid. Yield: 56%, ee: 90%. HPLC Analysis: Chiralcel AD-H (Hexane:Isopropanol 99:1, 1.0

20 1 mL/min), t r-major 11.85 min, t r-minor 15.11 min. [α] D= +36.4 (c = 0.8, CHCl3). H NMR (500

MHz; CDCl3): δ 8.92 (d, J = 2.7 Hz, 1H), 8.44 (dd, J = 9.4, 2.7 Hz, 1H), 7.97 (d, J = 9.4 Hz, 1H),

5.74 (s, 1H), 2.78 (td, J = 14.1, 5.1 Hz, 1H), 2.53 (m, 1H), 2.28-2.24 (m, 1H), 2.10-2.04 (m, 1H),

13 1.97 (m, J = 2.7 Hz, 2H), 1.74-1.71 (m, 2H). C NMR (126 MHz; CDCl3): δ 166.9, 165.6, 157.2,

141.3, 129.8, 122.5, 117.5, 48.8, 34.2, 27.5, 26.5, 19.6.

104

(R,Z)-2-methylcyclohexan-1-one O-(2,4-dinitrophenyl) oxime

The product was obtained by flash column chromatography (diethyl ether: hexane, 1:10) as mixture of diastereomers as solid. Yield: 77%, ee: 94%. HPLC Analysis for major diastereomer:

Chiralcel OJ-H (Hexane:Isopropanol 99:1, 0.7 mL/min), t r-major 35.78 min, t r-minor 35.00 min.

20 1 [α] D= +24.35 (c = 2.2, CHCl3). H NMR (500 MHz; CDCl3): δ 8.87 (d, J = 2.8 Hz, 1H), 8.41

(m, J = 9.4, 3.5, 2.8 Hz, 1H), 7.97 (m, J = 9.4, 3.1 Hz, 1H), 3.30-3.25 (m, 1H), 2.55-2.45 (m, 1H),

2.37 (m, J = 14.0, 5.3 Hz, 1H), 2.25-2.19 (m, 1H), 2.04-1.98 (m, 1H), 1.93-1.80 (m, 1H), 1.73-

13 1.63 (m, 2H), 1.55-1.41 (m, 1H), 1.25-1.21 (m, 3H). C NMR (126 MHz; CDCl3): δ 172.9,

172.0, 158.12, 157.93, 140.4, 136.0, 129.47, 129.45, 122.2, 117.34, 117.31, 37.8, 35.8, 31.8, 29.6,

+ 28.0, 26.71, 26.62, 26.44, 24.4, 20.1, 16.85, 16.82. HRMS (ESI) calcd for C13H15N3O5 ([M+H] ) m/z 294.1012, found 294.1087.

Synthesis of cis-N-((1R,2R)-2-phenylcyclohexyl)acetamide, 7:7, 8

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In a flame-dried reaction tube dissolved 28a (0.03 mmol) in 1 mL of dry tetrahydrofuran (THF) under Ar atmosphere and cooled to 0 °C. Added BH3. THF (0.08 mmol) and stirred the reaction mixture at rt until full conversion of starting material (monitored by TLC). Quenched the reaction mass with water (1 mL) and extracted with diethyl ether (2 mL). The pH of aqueous layer was adjusted to alkaline using 1M NaOH solution and extracted with diethyl ether (2 mL) three times.

The combined organic layer was washed with brine (2 mL), treated with Na2SO4, filtered and concentrated to give crude reduced product (1R,2R)-2-phenylcyclohexylamine. The crude (1R,

2R)-2-phenylcyclohexylamine was dissolved in diethylether (1 mL), added trimethylamine (0.07 mmol) followed by acetic anhydride (0.07 mmol) and stirred at room temperature for 4 h.

Quenched with sat. NaHCO3 solution (1 mL) and extracted with diethylether (2 mL) three times.

The organic layer was treated with Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC to give pure cis-29 as white solid.

Yield: 66%, ee: 82%. HPLC Analysis: Chiralcel OD-H (Hexane:Isopropanol 92:8, 0.8

20 1 mL/min), t r-major 10.69 min, t r-minor 16.63 min. [α] D = -16 (c = 0.2, CHCl3). H NMR (500 MHz;

CDCl3): δ 7.31-7.28 (m, 2H), 7.21 (m, 3H), 5.37 (s, 1H), 4.39 (m, 1H), 2.96 (dt, J = 12.1, 3.7 Hz,

1H), 2.01 (m, J = 2.6 Hz, 1H), 1.94-1.88 (m, 2H), 1.79 (s, 3H), 1.71-1.62 (m, 3H), 1.45-1.39 (m,

13 2H). C NMR (126 MHz; CDCl3): δ 169.7, 143.2, 128.7, 127.7, 126.9, 50.0, 45.0, 31.2, 26.3,

+ 25.8, 23.9, 21.3. HRMS (ESI) calcd for C14H19NO ([M+H] ) m/z 218.1467, found 218.1541.

4.7 References: 1. For recent reviews, see: (a) Pámies, O.; Bäckvall, J.-E. Chem. Rev. 2003, 103, 3247. (b)

Pellissier, H. Tetrahedron 2003, 59, 8291. (c) Vedejs, E.; Jure, M. Angew. Chem. Int. Ed.

2005, 44, 3974. (d) Pellissier, H. Tetrahedron 2008, 64, 1563. (e) Pellissier, H. Tetrahedron

2011, 67, 3769. (f) Pellissier, H. In Chirality from Dynamic Kinetic Resolution; Royal

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Society of Chemistry: Cambridge, UK, 2011; (g) Rachwalski, M.; Vermue, N.; Rutjes, F.

P. J. T. Chem. Soc. Rev. 2013, 42, 9268. (h) Verho, O.; Bäckvall, J.-E. J. Am. Chem. Soc.

2015, 137, 3996. (i) Applegate, G. A.; Berkowitz, D. B. Adv. Synth. Catal. 2015, 357, 1619.

(j) Diaz-Rodriguez, A.; Lavendera, I.; Gotor, V. Curr. Org. Chem. 2015, 2, 192. (k)

Pellissier, H. Tetrahedron 2016, 72, 3133. (l) Echeverria, P.-G.; Ayad, T.; Phansavath, P.;

Ratovelomanana-Vidal, V. Synthesis, 2016, 48, 2523.

2. Ros, A.; Magriz, A.; Dietrich, H.; Ford, M.; Fernández, R.; Lassaletta, J. M. Adv. Synth.

Catal. 2005, 347, 1917.

3. (a) Wakchaure, V. N.; Zhou, J.; Hoffmann, S.; List, B. Angew. Chem. Int. Ed. 2010, 49,

4612. (b) Dubuffet, T.; Lecouve, J.-P. WO 103969, 2004.

4. Akashi, M.; Arai, N.; Inoue, T.; Ohkuma, T. Adv. Synth. Catal. 2011, 353, 1955.

5. (a) Cheng, L.-J.; Xie, J.-H.; Chen, Y.; Wang, L.-X.; Zhou, Q.-L. Adv. Synth. Catal. 2012,

354, 1105. (b) Li, G.; Xie, J.-H.; Hou, J.; Zhu, S.-F.; Zhou, Q.-L. Adv. Synth. Catal. 2013,

355, 1597. (c) Cheng, L.-J.; Xie, J.-H.; Chen, Y.; Wang, L.-X.; Zhou, Q.-L. Org. Lett.

2013, 15, 764. (d) Cheng, J.-Q.; Xie, J.-H.; Bao, D.-H.; Zhou, Q.-L. Org. Lett. 2012, 14,

2714.

6. Liu, C.; Xie, J.-H.; Li, Y.-L.; Chen, J.-Q.; Zhou, Q.-L. Angew. Chem. Int. Ed. 2013, 52,

593.

7. Huang, X.; Ortiz-Marciales, M.; Huang, K.; Stepanenko, V.; Merced, F. G.; Ayala, A. M.;

Correa, W.; De Jesús, M. Org. Lett. 2007, 9, 1793.

8. (a) T. Hayashi, T. Senda, M. Ogasawara, J. Am. Chem. Soc. 2000, 122, 10716. (c) J.

González-Sabín, V. Gotor, F. Rebolledo, Tetrahedron: Asymmetry, 2005, 16, 3070.

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9. For synthesis of diol, see: (a) Zhu, S. S.; Cefalo, D. R.; La, D. S.; Jamieson, J. Y.; Davis,

W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1999, 121, 8251. For synthesis

of phosphoric acid, see: (b) Klussmann, M.; Hoffmann, S.; Wakchaure, V.; Goddard, R.;

List, B. Synlett 2010, 14, 2189. (c) Liu, W.; Chen, X.; Gong, L. Org. Lett. 2008, 10, 5357.

10. Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew Chem. Int. Ed. 2010, 49, 3823.

11. (a) Ingle, G. K.; Liang, Y.; Mormino, M.; Li, G.; Fronczek, F. R.; Antilla, J. C. Org. Lett.

2011, 13, 2054. (b) Nimmagadda, S. K.; Zhang, Z.; Antilla, J. C. Org. Lett. 2014, 16, 4098.

12. (a) S. M. Ceccarelli, S. Jolidon, E. Pinard, A. W. Thomas, US2005/154001 A1, 2005, 8.

(b) X. Yang, R. J. Phipps, D. F. Toste, J. Am. Chem. Soc. 2014, 136, 5225. (c) E. Pinard,

S. M. Ceccarelli, H. Stalder, D. Alberati, Bioorg. Med. Chem. Lett. 2006, 16, 349. (d) S.

D. Meyer, S. L. Schreiber, J. Org. Chem. 1994, 59, 7549.

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Appendix I HPLC and NMR data for Chapter 2

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NMR and HPLC data for Chapter 3.

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NMR and HPLC data for Chapter 4.

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Appendix IV

Copyrights and Permissions

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