Borinic Acid-Catalyzed Regioselective Functionalization of Polyols

Caitlin Williamson

A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Chemistry University of Toronto

Caitlin Williamson

Master of Science

Department of Chemistry University of Toronto

2011 Abstract

The selective manipulation of hydroxyl groups in di- and polyols is a frequently encountered problem in organic synthesis. Such processes are often tedious and/or moderate yielding, and often necessitate multistep protection / deprotection sequences. Applying boron–diol interactions previously exploited in molecular recognition and based on methods previously developed in our research group, we have developed two classes of chemical transformations:

1. Regioselective sulfonylations of carbohydrate derivatives catalyzed by a borinic ester,

providing access to the corresponding mono-tosylates in high yields;

2. Selective monoalkylations and monosulfonylations of structurally diverse 1,2- and 1,3-

diol substrates.

Acknowledgments

First and foremost I would like to thank Professor Mark S. Taylor for accepting me into his research group and constantly giving me guidance. I would like to thank him for his patience whenever I felt the need to ask silly questions and for always displaying a willingness to help but at the same time trying to teach me to be more independent.

I would like to thank all of the members of the Taylor group. It has been wonderful working with you and getting to know you all over the past year. None of you ever hesitated to help whenever I asked and even sometimes offering assistance before I even had to ask. You provided an amazing and friendly working environment and made my time as the University of Toronto enjoyable and worthwhile. Specifically I would like to thank Christina, Doris, and Lina for helping whenever I had questions about sugar and functionalization chemistry or experimental set-ups. I would also like to thank Corey for always being there to get supplies down for me that were too high for me to reach.

Lastly, I would like to thank the entire staff of University of Toronto’s chemistry department for providing an amazing working environment. If all of you weren’t there to keep things running smoothly, completing my chemistry would have proved a lot more difficult and would not have been nearly as enjoyable.

iii

Table of Contents

Acknowledgments...... iii

Table of Contents...... iv

List of Abbreviations ...... vi

List of Tables ...... viii

List of Schemes ...... x

List of Figures...... xiii

List of Appendices ...... xiv

1 Boron-Diol Interactions...... 1 1.1 Use of Boronic Acids in Chemical Recognition of Carbohydrates ...... 1 1.2 Use of Borinic Acids in Functionalization of cis-Diols...... 3

2 Regioselective Sulfonylation of Polyols ...... 7 2.1 Introduction ...... 7 2.1.1 Regioselective Sulfonylation of Polyols...... 7 2.1.2 Regioselective Sulfonylation of Carbohydrate Derivatives...... 13 2.2 Results and Discussion ...... 18 2.2.1 Regioselective Sulfonylation of Carbohydrate Derivatives...... 18 2.2.2 Regioselective Sulfonylation of Polyols...... 22 2.3 Conclusion...... 25 2.4 Experimental...... 25 2.4.1 General...... 25 2.4.2 Procedure and Characterization Data for TBS-Protection of Carbohydrate Derivatives 26 2.4.3 Procedure and Characterization Data for Sulfonylation of Polyols...... 28

3 SN2 Reactions Using Carbohydrate Sulfonates...... 36 3.1 Introduction ...... 36 3.2 Results and Discussion ...... 37 3.3 Conclusion...... 40

4 Regioselective Deoxygenation of Carbohydrate Derivatives...... 41

4.1 Introduction ...... 41 4.2 Results and Discussion ...... 43 4.3 Conclusion...... 46 4.4 Experimental...... 46

5 Regioselective Alkylation of Polyols ...... 49 5.1 Introduction ...... 49 5.2 Results and Discussion ...... 53 5.3 Conclusion...... 60 5.4 Experimental...... 60

6 Competition Experiments to Study Selectivity of Functionalization...... 66 6.1 Functionalization of 1,2- and 1,3-Diols ...... 66 6.2 Functionalization of syn and anti 1,3-Diols ...... 68 6.3 Conclusions...... 71 6.4 Experimental...... 72 6.4.1 Procedure and Characterization Data for the Preparation of 1,3-Diols...... 72 6.4.2 Procedure and Characterization Data for Competition Experiments ...... 77

7 Regioselective Benzoylation of Diols...... 81 7.1 Conclusions...... 82 7.2 Experimental...... 82

8 Functionalization Using Epoxide Electrophiles...... 84 8.1 Conclusions...... 85

9 Conclusions...... 86

Appendix A NMR Spectra ...... 87

List of Abbreviations

Acac Acetylacetonate

AIBN Azobisisobutyronitrile

Bz Benzoyl

Bn Benzyl

Bu Butyl

Cat. Catalytic

COSY Correlation spectroscopy

DCE Dichloroethane

DCM Dichloromethane

DIPEA N.N-diisopropylethylamine

DMAP 4-Dimethylaminopyridine

DMF Dimethylformamide

DMSO Dimethyl sulfoxide

Equiv Equivalent

Et Ethyl

EtOAc Ethyl acetate

HRMS High resolution mass spectroscopy

Hz Hertz iPr Isopropyl

IR Infrared

FTIR Fourier transform infrared spectroscopy

HPLC High performance liquid chromatography

LDA Lithium diisopropylamide

Me Methyl

MW Microwave radiation

NMR Nuclear magnetic resonance spectroscopy

NOESY Nuclear Overhauser effect spectroscopy

Nu Nucleophile

PEMP Pentamethylpiperidine

Ph Phenyl

Rt Room temperature t-Bu tert-Butyl

TBAB Tetrabutylammonium bromide

TBAI Tetrabutylammonium iodide

TBS tert-Butyldimethylsilyl

THF Tetrahydrofuran

Tr Trityl

Ts Tosyl (p-toluenesulfonyl)

vii

List of Tables

Table 2.2.1 – Optimization of the Selective Tosylation of Isopropylthio-6-(tert- butyldimethylsilyloxy)-β-D-galactopyranoside...... 19

Table 2.2.2 – Catalyst Screen on Reaction Using Methyl-6-(tert-butyldimethylsilyloxy)-α-D- mannopyranoside ...... 20

Table 2.2.3 – Substrate Scope on 1 mmol Scale Using 2-Aminoethyl Diphenylborinate...... 21

Table 2.2.4 – Substrate Scope Using Previously Developed Tosylation Conditions ...... 23

Table 3.2.1 – Attempted Conditions for SN2 Reactions Using Tosylated Carbohydrate Derivatives ...... 38

Table 4.2.1 – Optimization of Regioselective Thiocarbonylation Using 2-Aminoethyl Diphenylborinate Catalyst ...... 44

Table 4.2.2 – Regioselective Thiocarbonylation Using Optimized Conditions ...... 45

Table 5.2.1 – Substrate Scope Using Previously Developed Benzylation Conditions...... 54

Table 5.2.2 – Evaluation of Halide Salt and Temperature Effects on Selective Benzylation of 1,2- cis-cyclohexanediol...... 57

Table 5.2.3 – Substrate Scope Using New Optimized Benzylation Conditions Using Halide Salt ...... 57

Table 5.2.4 – Evaluation of Catalyst Loading Effects on Selective Benzylation of 1,2-cis- cyclohexandiol ...... 59

Table 6.4.1 – Prepared Benzoates for Full Paper Using Lee’s Benzylation Conditions ...... 81

Table 7.2.1 – Regioselective Epoxide Ring-Opening of Styrene Oxide with β-Galactose Derivative...... 84

viii

Table 7.2.2 – Regioselective Epoxide Ring-Opening of Cyclohexene Oxide with Phenyl-1,2- Ethanediol ...... 85

List of Schemes

Scheme 1.2.1 – Borinic-Acid Catalyzed Direct Aldol Reaction ...... 4

Scheme 1.2.2 – Borinic Acid Catalyzed Regioselective Acylation of Carbohydrate Derivatives . 4

Scheme 1.2.3 – Regioselective Benzylation Catalyzed by 2-Aminoethyl Diphenylborinate...... 6

Scheme 1.2.4 – Regioselective Activation of Glycosyl Donors by a Borinic Acid Catalyst ...... 6

Scheme 2.1.1 – Tin-Mediated Functionalization of Diols...... 8

Scheme 2.1.2 – Tin-Mediated Selective Tosylation Using Dean-Stark Conditions...... 8

Scheme 2.1.3 – Tin Catalyzed Selective Tosylation of α-Chelatable Primary Alcohols...... 9

Scheme 2.1.4 – Tin Catalyzed Selective Tosylation of Internal Diols ...... 9

Scheme 2.1.5 – Selective Sulfonylation of 1,2-Diols using Recoverable Fluorous Tin Oxide.... 10

Scheme 2.1.6 – Selective Tosylation Using Iron Montmorillonite Clay...... 11

Scheme 2.1.7 – Silver Oxide Mediated Selective Monotosylation of Symmetrical Diols...... 11

Scheme 2.1.8 – Copper Catalyzed Selective Monotosylation of Meso-Vic-Diols ...... 12

Scheme 2.1.9 – Enantioselective Monotosylation of 1,3-Meso-Diols Using a Tetrapeptide Catalyst ...... 12

Scheme 2.1.10 – Tin-Mediated Monotosylation of Nucleosides...... 14

Scheme 2.1.11 – Production of Stannylene Acetal Coordinated to Anomeric Oxygen ...... 14

Scheme 2.1.12 – Tin-Mediated Monosulfonylation of Hexapyrannosides ...... 15

Scheme 2.1.13 – Tin-Mediated Monotosylation of Glucosides by Tsuda...... 15

Scheme 2.1.14 – Tin Catalyzed Monotosylation of Glycosides...... 16

Scheme 2.1.15 – Regioselective Protection of Sugar Molecules by Dimethyltin Dichloride ...... 17

Scheme 2.1.16 – Silver Oxide Mediated Tosylation of Monosaccarides...... 18

Scheme 3.1.1 – Typical SN2 Displacement Reaction of Sugar Tosylates Using NaN3 ...... 36

Scheme 3.1.2 – Typical SN2 Reaction of Tosylates Using Benzoate Anion ...... 37

Scheme 3.1.3 – Conversion of 3-Tosyl-galactose to 3-Benzoyl-gulose...... 37

Scheme 4.1.1 – Barton-McCombie Reaction ...... 42

Scheme 4.1.2 – Regioselective Thiocarbonylation Using a Petide Catalyst by Miller ...... 43

Scheme 4.1.3 – Radical Deoxygenation Using N-Heterocyclic Carbene Boranes...... 43

Scheme 5.1.1 – Monoalkylation of Symmetrial Diols Using a Polymer Support ...... 49

Scheme 5.1.2 – Monoalkylation Using Phase Transfer Conditions ...... 50

Scheme 5.1.3 – Monoalkylation Using Dibutyltin Oxide and Cesium Fluoride...... 50

Scheme 5.1.4 – Isopropylidene Ketal Opening Using Trimethylaluminum...... 51

Scheme 5.1.5 – Benzylation of 1,4-Butanediol Promoted by Sodium Hydroxide ...... 51

Scheme 5.1.6 – Selective Silver Oxide Mediated Monoprotection of Symmetrical Diols...... 52

Scheme 5.1.7 – Sodium Alkoxides and Dibromoalkanes Reacting to Produce Alkenyl Ethers .. 52

Scheme 5.1.8 – Regioselective Benzylation of 1,2-Propanediol Using Copper Catalyst...... 53

Scheme 5.1.9 – Monoalkylation of Diols Using Lewis Acid Catalyst ...... 53

Scheme 5.1.10 – Regioselective Benzylation Promoted by Silver Carbonate ...... 53

Scheme 6.2.1 – Aldol Reaction to Produce 3-Hydroxy-1-ketones...... 70

Scheme 6.2.2 – Production of syn-1,3-Diol from Hydroxyketone ...... 70

Scheme 6.2.3 – Production of anti-1,3-Diol from Hydroxyketone ...... 70

xii

List of Figures

Figure 1.1.1– Borinic Acid-Diol Complexation ...... 1

Figure 1.1.2 – Phenylboronic Acids Used by Shinkai for Saccharide Recognition ...... 2

Figure 1.1.3 – Boronic Acid Indicator Displacement by α-Hydroxycarboxylates...... 2

Figure 1.1.4 – Boronic Acid Used for Binding Studies with Sugars by Hall...... 3

Figure 1.2.1 – Proposed Reactivity of Borinic-Acid Activation of cis-Diols...... 3

Figure 1.2.2 – Proposed Mechanism for Acylation of Carbohydrates Using 2-Aminoethyl Diphenyl Borinate...... 5

Figure 6.1.1 – Benzylation Competition Experiment between meso- and (R,R)-Hydrobenzoin.. 66

Figure 6.1.2 – Tosylation Competition Experiment Between 1,3-Butanediol and 1,2-Propanediol ...... 67

Figure 6.1.3 - Tosylation Competition Experiment Between Diols and Primary Alcohols ...... 67

Figure 6.2.1 – syn and anti Conformation of the 1,3-diol-borinate Bound Complex...... 68

Figure 6.2.2 – Competition Experiment Between syn and anti 2,4-Pentanediol...... 69

Figure 6.2.3 – Benzylation Competition Experiment Between syn and anti 1,3-Phenyl-1,3- propanediol ...... 70

Figure 6.2.4 – Benzylation Competition Experiment Between 1-Phenyl-3-tert-butyl-1,3- propanediol ...... 71

xiii

List of Appendices

Appendix A NMR Spectra...... 87

xiv 1

1 Boron-Diol Interactions 1.1 Use of Boronic Acids in Chemical Recognition of Carbohydrates

The complexation that occurs between boronic acids and diol molecules is a thoroughly studied interaction (Figure 1.1.1)1 that has been widely used in chemical recognition of diols and carbohydrates.

Figure 1.1.1– Borinic Acid-Diol Complexation1

In 1994, Shinkai et al. reported saccharide recognition by amphiphilic diarylboronic acids. Skinkai compared selectivity of different bis-borinic acids towards monosaccharides in a monolayer system and in a two-phase solvent extraction. Binding constants, stoichiometry and lipophilicity were all determined for the series of phenyl and diphenyl boronic acids and their complexation with monosaccharides.2

1 (a) Lorand, J.P.; Edwards, J.O. J. Org. Chem. 1959, 24, 769-774. (b) Springsteen, G.; Wang, B. Tetrahedron 2002, 58, 5291-5300. 2 Ludwig, R.; Shiomi, Y.; Skinkai, S. Langmuir 1994, 10, 3195-3200.

Figure 1.1.2 – Phenylboronic Acids Used by Shinkai for Saccharide Recognition2

Anslyn et al. studied boronic acids in indicator-displacement assays with α-hydroxycarboxylates and other diol molecules. Anslyn developed a series of boronic acids, each with a neighbouring tertiary amino group, which could coordinate to the electron deficient boron atom to form a five- membered ring structure. Anslyn also developed several fluorescent indicators, which could enantioselectively complex the boronic acids causing fluorescence to “turn off”. α- Hydroxycarboxylates could then enantioselectively displace these indicators and the fluorescent change was used to determine enantioselectivities within experimental error.3

3 Figure 1.1.3 – Boronic Acid Indicator Displacement by α-Hydroxycarboxylates

Hall et al. then developed an improved class of boronic acids that could bind sugars in neutral water. Hall synthesized a series of phenylboronic acids with different ortho substituents. The association constants of these boronic acids with glycosides were measured to determine the best boronic acids for glycoside binding. ortho-Hydroxymethyl phenylboronic acid was shown to be superior to the dialkylamino analogues typically used. This boronic acid binds to hexopyranoside sugars through the 4.6-diol group, even under physiological conditions. Different forms of these boronic acids could be used in the design of oligomeric receptor sensors and could possibly be applied to the selective recognition of cell-surface glycoconjugates.4

3 Zhu, L.; Zhong, Z.; Anslyn, E.V. J. Am. Chem. Soc. 2005, 127, 4260-4269. 4 Dowlut, M.; Hall, D.G. J. Am. Chem. Soc. 2006, 128, 4226-4227.

Figure 1.1.4 – Boronic Acid Used for Binding Studies with Sugars by Hall4

These studies suggest that strong bonds are formed between boronic acids and diol motifs and possibly these bonds could be exploited in the regioselective catalysis of other diol motifs such as carbohydrate derivatives.

1.2 Use of Borinic Acids in Functionalization of cis-Diols

The complexation that occurs between boronic acids and diol moieties has been exploited in catalytic processes.5 More recently, the less used borinic acids have been used to activate cis-diol motifs and been applied to catalytic processes such as the functionalization of carbohydrate derivatives (Figure 1.2.1).

Figure 1.2.1 – Proposed Reactivity of Borinic-Acid Activation of cis-Diols

In 2009, our group described the use of diphenylborinic acid as a catalyst for the direct aldol reaction between pyruvic acids and aldehydes (Scheme 1.2.1). It was known previously that pyruvate could interact with boron and this was used as a basis for the catalytic aldol reaction. Several different boronic and borinic acids were tested in the reaction and arylborinic acids proved to be superior to arylboronic acids. Diphenylborinic acid was determined to be the optimum catalyst due to its good activity and availability. A broad range of pyruvic acids and aldehydes were tolerated by this catalyst, producing the direct aldol products in excellent yields (56-90%).6

5 (a) Oshima, K.; Aoyama, Y. J. Am. Chem. Soc. 1999, 121, 2315-2316. (b) Houston, T.A.; Wilkinson, B.L.; Blanchfield, J.T. Org. Lett. 2004, 6, 679-681. (c) Sakakura, A.; Ohkubo, T.; Yamashita, R.; Akakura, M.; Ishihara, K. Org. Lett. 2011, 13, 892-895. 6 Lee, D.; Newman, S.G.; Taylor, M.S. Org. Lett. 2009, 11, 5486-5489.

Scheme 1.2.1 – Borinic-Acid Catalyzed Direct Aldol Reaction6

Our group then reported regioselective acylation of carbohydrate derivatives. 2-Aminoethyl diphenylborinate coordinates with molecules having a cis-diol motif to selectively acylate one of the diols. In a carbohydrate derivative, the equatorial position on the diol is the one to be functionalized. This method of using 2-aminoethyl diphenylborinate as a catalyst for acylation was applied to many different carbohydrate derivatives and a few cyclic cis-diol molecules; all producing the regioselective acylated product in excellent yields (69-99%).7

Scheme 1.2.2 – Borinic Acid Catalyzed Regioselective Acylation of Carbohydrate Derivatives7

The proposed mechanism for this transition is displayed in figure 1.2.1. The 2-aminoethyl diphenylborinate acts as a precatalyst for the reaction. The free borinic acid then binds the cis- diol motif activating the equatorial position of the diol to electrophilic attack. Another carbohydrate then enters the cycle and binds the catalyst so that the functionalized carbohydrate leaves the cycle.

7 Lee, D.; Taylor, M.S. J. Am. Chem. Soc. 2011, 133, 3724-3727.

Figure 1.2.2 – Proposed Mechanism for Acylation of Carbohydrates Using 2-Aminoethyl Diphenyl Borinate

Our group has also reported the regioselective alkylation of carbohydrate derivatives catalyzed by a diarylborinic acid derivative. The optimized conditions were determined to be 10 mol% boron catalyst, 1.5 equiv alkyl halide, 1.1 equiv silver(I) oxide at 40 °C for 48 hours. A variety of carbohydrate derivatives were tested using several alkyl halides including benzyl bromides to produce the corresponding 3-O-alkylated products in excellent yields (63-99%) (Scheme 1.2.3).8

8 Chan, L.; Taylor, M.S. Org. Lett. 2011, 13, 3090-3093.

Scheme 1.2.3 – Regioselective Benzylation Catalyzed by 2-Aminoethyl Diphenylborinate8

The use of 2-aminoethyl diphenylborinate has more recently been reported to regioselectively activate glycosyl acceptors. Several glycosyl halides were reacted with different glycosyl acceptors with the use of silver oxide as a promoter to produce the corresponding regioselective disaccharides. As seen previously, the borinic acid reacts with the cis-diol motif of the glycosyl acceptor to allow electrophilic attack at the equatorial position. The resulting disaccharides were produced in excellent yields, ranging from 68-99%.9

Scheme 1.2.4 – Regioselective Activation of Glycosyl Donors by a Borinic Acid Catalyst9

The basis for the regioselectivity of these reactions was probed using computational experiments. The calculations were consistent with an electronic basis for the regioselectivity.7

We then proposed that the 2-aminoethyl diphenyl borinate could be used for the selective tosylation of carbohydrate derivatives and simple polyols, benzylation of polyols, and possibly the thiocarbonylation of carbohydrate derivatives.

9 Gouliaras, C.; Lee, D.; Chan, L.; Taylor, M.S. J. Am. Chem. Soc. 2011, 133, 13926-13929.

2 Regioselective Sulfonylation of Polyols 2.1 Introduction

2.1.1 Regioselective Sulfonylation of Polyols

Selective functionalization of simple polyols has been of much interest in synthetic organic chemistry.10 Sulfonylation is a well-recognized method for the selective protection of alcohols11 and the conversion of alcohols to reactive electrophiles12. Typically sulfonylation is carried out using p-toluenesulfonyl chloride with pyridine or some other amine base, or a metal catalyst; however these conditions are not often regioselective. Conditions that allow for the selective sulfonylation of one hydroxyl group over another on the same molecule have been developed. Typically, regioselectivity has been obtained by using tin reagents such as dibutyltin oxide. Creation of the tin acetals allows for primary hydroxyl activation and temporary secondary hydroxyl protection simultaneously.13 Often stoichiometric amounts of these toxic tin reagents were required, therefore, developing catalytic regioselective sulfonylation methods became of particular interest.

Shanzer described the first regioselective sulfonylation of simple diols using a tin based reagent in 1980. He reacted 2,3-Butanediol with dibutyltin oxide, in stoichiometric amounts, to provide the desired stannoxane. The stannoxane was then reacted with either benzoyl chloride or tosyl chloride and subsequent hydrolysis gave the desired benzoate or tosylate, respectively (Scheme 2.1.1).13

10 David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-663. 11 Wuts, P.G.M.; Greene, T.W. Greene’s Protective Groups in Organic Synthesis; John Wiley and Sons, Inc.: NJ, 2007. 12 Tanabe, Y.; Yamamoto, H.; Yoshida, Y.; Miyawaki, T.; Utsumi, N. Bull. Chem. Soc. Jpn. 1995, 68, 297-300. 13 Shanzer, A. Tetrahedron Lett. 1980, 21, 221-222.

Scheme 2.1.1 – Tin-Mediated Functionalization of Diols13

In 1993, Ley et al. reported selective acylation, alkylation, and sulfonylation of diols with a dibutyltin dimethoxide catalyst using Dean-Stark conditions. Dibutyltin dimethoxide was a preferred reagent because it was commercially available as a stable liquid. Ley produced the tin acetal (stoichiometric amounts of tin reagent) in benzene, which could be easily removed; the tin acetal could then be reacted with an electrophile (either benzyl, benzoyl, or tosyl) (Scheme 2.1.2). The reaction resulted in high yields (70-98%) and high selectivity for the primary alcohol in all cases of both 1,2 and 1,3-diols. This method was also applied to sugars. When the 6 position of glucose was unprotected, the electrophile reacted there and when the 1, 4, and 6- positions of glucose were protected, functionalization occurred at the 2-position.14 Since this method used stoichiometric amounts of the toxic tin reagent, other catalytic methods were pursued.

Scheme 2.1.2 – Tin-Mediated Selective Tosylation Using Dean-Stark Conditions14

In 1999, in a report by Martinelli et al., the use of dibutyltin oxide to catalyze the selective sulfonylation of α-chelatable primary alcohols was first described. In previous reports, there was always the regeneration of stoichiometric amounts of toxic dibutyltin oxide that was only separable using column chromatography. Martinelli reported the primary selective sulfonylation of glycols using catalytic dibutyltin oxide in the presence of stoichiometric triethylamine (Scheme 2.1.3). Martinelli proposed that the stannylidene complex would lose its stability upon

14 Boons, G.; Castle, G.H.; Chase, J.A.; Grice, R.; Ley, S.V.; Pinel, C. Synlett 1993, 12, 913-914.

9 primary alcohol functionalization and that using excess triethylamine would enhance the turnover through competitive tin binding and neutralization of the HCl formed.15 Diols were then treated with tosyl chloride and triethylamine and 2 mol % dibutyltin oxide to produce the desired tosylates with excellent yields (86-99%) and regioselectivity.15

15 Scheme 2.1.3 – Tin Catalyzed Selective Tosylation of α-Chelatable Primary Alcohols

In 2000, Martinelli et al. extended this method to include internal 1,2-diols (Scheme 2.1.4). Previously, only the monosulfonylation of a terminal diol had been reported. A variety of symmetrical cis and trans cyclic and acyclic diols were used as substrates. The tosylates of the cis diols were produced in excellent yields (80-97%), while the yields were quite poor (32-73%) for those that contained a trans diol. The reactions of the trans diols were much slower than the cis diols. The proposed reason for this observation was that the cis-1,2-diol could more easily form the five-membered ring stannylene acetal.16

Scheme 2.1.4 – Tin Catalyzed Selective Tosylation of Internal Diols16

In a later report, Martinelli further studied the scope and mechanism of the dibutyltin catalyzed sulfonylation of α-chelatable alcohols. When using a trans-1,2-diol, some amount of epoxide was formed in the reaction which, along with the fact that the reaction was lower, lead to lower yields of the desired product.17

15 Martinelli, M.J.; Nayyar, N.K.; Moher, E.D.; Dhokte, U.P.; Pawlak, J.M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447-450. 16 Martinelli, M.J.; Vaidyanathan, R.; Khau, V.V. Tetrahedron Lett. 2000, 41, 3773-3776. 17 Martinelli, M.J.; Vaidyanathan, R.; Pawlak, J.M.; Nayyar, N.K.; Dhokte, U.P.; Doecke, C.W.; Zollars, L.M.H.; Moher, E.D.; Khau V.V.; Kpsmrlj, B. J. Am. Chem. Soc. 2002, 124, 3578-3585.

To further expand on Martinelli’s catalytic tin method, Curran et al. developed selective sulfonylation of 1,2-diols, and their derivatives, by recoverable fluorous tin oxide. Bibutyltin oxide was an effective reagent but the problem of having to remove it from solution, often by column chromatography, still remained. Fluorous tin reagents could be removed by fluorous- organic liquid-liquid or solid-liquid extractions if the appropriate alkylene spacers were used.

Curran prepared a fluorous analog of tin oxide, (CH2CH2C6F13)2SnO and subjected it to Martinelli’s tosylation conditions using 1-phenyl-1,2-ethanediol as a substrate and the desired tosylate was produced in 80% yield (Scheme 2.1.5). A variety of other 1,2-diols were tested, each with a terminal hydroxyl group that underwent tosylation selectively in good yield (70- 94%).18

Scheme 2.1.5 – Selective Sulfonylation of 1,2-Diols using Recoverable Fluorous Tin Oxide18

Moving away from tin oxide catalysts, Choudary et al. reported a montmorillonite clay catalyzed selective monotosylation of diols with p-toluenesulfonic acid (Scheme 2.1.6). Choudary first applied this method to alcohols but once seeing the selectivity with some of the substrates, moved on to explore the selectivity of diols using this method. Several different clay catalysts were all tested on the tosylation of cyclohexanol, with iron montmorillonite giving the highest yields. Several diols were tested, each producing the desired monotosylate in good yield (76- 94%). 1,2,3-Propanetriol was also used as a substrate and converted to the desired monotosylate in 50% yield. In cases where the diol had both a primary and secondary hydroxyl group, the primary hydroxyl group was always the one functionalized.19

18 Bucher, B.; Curran, D.P. Tetrahedron Lett. 2000, 41, 9617-9621. 19 Choudary, B.M.; Chowdari, N.S.; Kantam, M.L. Tetrahedron 2000, 56, 7291-7298.

Scheme 2.1.6 – Selective Tosylation Using Iron Montmorillonite Clay19

Bouzide and Sauve developed a silver(I) oxide mediated selective monotosylation of symmetrical diols. Using Bouzide’s previously developed method for the monotosylation of alcohols, selective tosylation of symmetrical diols was also accomplished. Several diols including 1,4-butanediol, 1,3-propanediol and 1,5-propanediol were tested under these conditions and the desired montosylates were produced in excellent yields (75-93%). When the amount of silver(I) oxide was doubled, the diol cyclized instead of producing the tosylate (Scheme 2.1.7). Polysubstituted cyclic ethers were then prepared by this method from the corresponding diols.20

Scheme 2.1.7 – Silver Oxide Mediated Selective Monotosylation of Symmetrical Diols20

In a further attempt to move away from tin-based catalysis methods, Onomura and Matsumura et al. reported a copper complex catalyzed asymmetric monosulfonylation of meso-vic-diols. Using a copper catalyst with a chiral ligand that selectively recognized a vic-diol, Onomura and Matsumura were able to develop an enantioselective sulfonylation of diols (Scheme 2.1.8). Using cis-1,2-cyclohexanediol as a model compound, they treated the substrate with tosyl chloride, copper(II) triflate and (R,R)-Ph-BOX and then experimented with different bases and solvents. They found that use of dichloromethane in conjunction with potassium carbonate gave both high yield (94%) and high enantioselectivity (97% ee). A variety of diol substrates were then tested under these conditions, all giving high yields (71 - >99%) and high enantioselectivity (93 - <99% ee). These conditions were extended to include both benzoylation and phenylcarbamolyation, with each method producing good yields and enantioselectivity.21

20 Bouzide, A.; Sauve, G. Org. Lett. 2002, 4, 2329-2332. 21 Demizu, Y.; Matsumoto, K.; Onomura,O.; Matsumura, Y. Tetrahedron Lett. 2007, 48, 7605-7609.

Scheme 2.1.8 – Copper Catalyzed Selective Monotosylation of Meso-Vic-Diols21

Miller et al. took a different approach to the regioselective sulfonylation and developed a method for enantioselective sulfonylation of 1,3-meso-diols mediated by a tetrapeptide catalyst (Scheme 2.1.9). Using 2,4,5-tribenzyl-myo-inositol as a test substrate and p-nitrobenzenesulfonyl chloride as a sulfonylation reagent, Miller developed enantioselective sulfonylation conditions using 5 mol% tetrapeptide catalyst 10 with sodium bicarbonate. Several different derivatives of myo- inositol as well as some acyclic 1,3-meso-diols were subjected to the reaction conditions and the desired nosylates were produced in good to excellent yields (40-76%) and enantioselectivities (50:50 to 97:3 er).22

Scheme 2.1.9 – Enantioselective Monotosylation of 1,3-Meso-Diols Using a Tetrapeptide Catalyst22

All of these methods produced the desired regioselective sulfonylation products in good yields; however, many of the higher yielding methods still require the use of toxic reagents, even if it is only in catalytic amounts. Developing a catalytic method that produces tosylates in high yields without the use of a toxic reagent is still a mounting interest in organic synthesis.

22 Fiori, K.W.; Puchlopek, A.L.A.; Miller, .J. Nature Chem. 2009, 1, 630-634.

2.1.2 Regioselective Sulfonylation of Carbohydrate Derivatives

Carbohydrates are very important molecules in biological processes.23 The synthesis and functionalization of carbohydrate molecules is a very time consuming process due to the large amount of protecting group manipulation that has to take place. Regioselective functionalization of a single hydroxyl group without protection of all other hydroxyl groups on a carbohydrate is of great interest in organic synthesis due to the fact that most carbohydrates each have at least four hydroxyl groups.24 Typically, enzymes have been used to mediate these functionalization processes; however, these enzymes are not always widely available.25 Given this fact, many other synthetic routes to selectively functionalize carbohydrate moieties have been pursued.

The tosyl group can be used as a protecting group, or for the preparation of an epoxide, on a glycoside ring.26 In a report by Moffatt et al. in 1974, organotin derivatives of nucleosides were used to selectively functionalize a single hydroxyl group on a nucleoside. 2’,3’-O- (dibutylstannylene) nucleosides were prepared by heating the nucleosides in methanol and adding stoichiometric amounts of dibutyltin oxide (Scheme 2.1.10). The stannylene derivatives of uridine, cytidine, and adenosine were easily prepared and crystallized in yields of 96, 91, and 70%, respectively. Moffat then found that each of these organotin derivatives could be reacted with electrophiles in methanol to selectively functionalize either the 2’- or 3’-positon. Acylation either took place at the 2’ or 3’ position depending on the nucleoside and alkylation could only be applied to the uridine stannylene where the 2’-position was selectively functionalized. Moffatt subjected each of the stannylene nucleosides to sulfonylation conditions using tosyl chloride and methanol. The 2’-O-p-toluenesulfonyl derivatives of uridine and adensosine were produced in yields of 62 and 70%, respectively. The reaction of 2’,3’-O-(dibutylstannylene)cytidine led to a complex mixture that was not easily isolated.27

23 Seeberger, P.H.; Werz, D.B. Nature 2007, 446, 1046-1051. 24 Wang, C.; Lee, J.; Luo, S.; Kulkarni, S.S.; Huang, Y.; Lee, C.; Chang, K.; Hung, S. Nature 2007, 446, 896-899. 25 Boltje, T.J.; Buskas, T.; Boons, G. Nature Chem. 2009, 1, 611-621. 26 Bear, H.H.; Astles, D.J.; Chin, H.C.; Siemsen, L. Can. J. Chem. 1985, 63, 432. 27 Wagner, D.; Verheyden, J.P.H.; Moffatt, J.G. J. Org. Chem. 1974, 39, 24-30.

Scheme 2.1.10 – Tin-Mediated Monotosylation of Nucleosides27

After Moffat’s report in 1974, Szmant et al. reported the selective 2-sulfonylation of methyl-α- D-hexapyranosides via dibutylstannylene derivatives. First, the methyl-4,6-O-benzylidene-2,3- O-dibutylstannylene-α-D-glucopyranoside was produced according to Scheme 2.1.11.

Scheme 2.1.11 – Production of Stannylene Acetal Coordinated to Anomeric Oxygen28

The glucopyranoside was then reacted with tosyl chloride in the presence of triethylamine to produce the 2-functionalized product in 70% yield (Scheme 2.1.12). Several other α-D- hexapyranoses were selectively functionalized at the 2-position using this method. Szmant then treated the unprotected methyl-α-D-glucopyranoside with stoichiometric amounts of dibutyltin oxide to produce the methyl-2,3-O-dibutylstannylene-α-D-glucopyranoside in quantitative yield. The unprotected glucopyranoside was reacted with tosyl chloride in the presence of triethylamine to produce the desired 2-sulfonate. This method was found to apply only to the α-anomer since the β−anomer tended to produce the 6-sulfonate. The difference in selectivity was suggested to be due to the fact that in the α-anomer, the tin could coordinate to the anomeric oxygen. The same conditions were also used to prepare 2-benzoylates and 2-myristates.28

28 Munavu, R.M.; Szmant, H.H. J. Org. Chem. 1976, 41, 1832-1836.

Scheme 2.1.12 – Tin-Mediated Monosulfonylation of Hexapyrannosides28

This is a widely applicable method and can even be applied to disaccharides;29,30 however, due to the toxicity of the dibutyltin oxide reagent, this method was not ideal.

Tsuda et al. extended on these results, treating unprotected and partially protected glycosides with dibutyltin oxide. The tosylation was carried out by treating various glycopyranosides with dibutyltin oxide in boiling methanol then reacting the tin glycoside with tosyl chloride. When using unprotected glycopyranosides, methyl-β-D-glucopyranoside (Scheme 2.1.13) and methyl- β-D-xylopyranoside gave the 6-O-tosyl and 4-O-tosyl derivatives, respectively, in excellent yields (92 and 100%). Methyl-α-D-galactopyranose, methyl-β-D-galactopyranose and methyl-α- D-mannopyranose selectively produced the 3-O-tosyl in 63, 78, and 65% yield, respectively. Methyl-α-D-glucopyranoside formed both the 2-O-tosyl and 6-O-tosyl (56:44) in 50% yield where as methyl-α-D-xylopyranoside formed the 2-O-tosyl and 4-O-tosyl (38:62) in 84% yield and methyl-α-L-arabinose formed the 3-O-tosyl and 4-O-tosyl (44:56) in 94% yield. Tsuda suggested the reasons for these differences to be the result of different conformers of the dibutyltin glycosides.31

Scheme 2.1.13 – Tin-Mediated Monotosylation of Glycosides by Tsuda31

29 Bazin, H. G.; Polat, T.; Linhardt, R.J. Carbohydr. Res. 1998, 309, 189-205. 30 Sofian, A.S.M.; Lee, C.K.; Linden, A. Carbohydr. Res. 2002, 337, 2377-2381. 31 Tsuda, Y.; Mishimura, M.; Kobayashi, T.; Sato, Y.; Kanemitsu, K. Chem. Pharm. Bull. 1991, 39, 2883-2887.

Martinelli further extended his work on the dibutyltin oxide catalyzed monotosylation of internal 16 diols to include carbohydrate examples. Both α- and β-methyl-D-xylopyranoside were tested using Martinelli’s dibutyltin oxide conditions. The α-xylopyranoside tosylate was produced in 70% yield with a 77:23 ratio of the 2-O-tosylate to 4-O-tosylate (Scheme 2.1.14), opposite to that 31 previously reported by Tsuda. The β-tosylate was only produced in 40% yield with a 90:10 ratio of the 4-O-tosylate to 2-O-tosylate, a result similar to that reported by Tsuda.31 Martinelli suggested the reason for the change in preferred functionality to be that with the α anomer, a five-membered intermediate is formed from tin coordination to the methoxy and 2-hydroxy groups thus tosylating at the 2 position. The 4-O-tosylate could be formed either from a six- membered ring stannylene intermediate or by an uncatalyzed reaction. Since five-membered rings are kinetically favoured over 6-membered rings, the 2-O-tosylate was the preferred product. The low yield for the β-anomer could be due to the trans ring formation, which, as seen with the symmetrical diols, is unfavourable.16 In a later report by Martinelli, additional support for this rationale was described.17

Scheme 2.1.14 – Tin Catalyzed Monotosylation of Glycosides16

Onomura et al. then developed a regioselective protection of sugars catalyzed by dimethyltin dichloride. First, several unprotected hexapyranoses were treated with benzoyl chloride in the presence of N,N-diisopropylethylamine and 0.05 equiv of dimethyltin dichloride to give selective benzoylation at the 2-, 3-, 4- or 6-position, depending upon the sugar substrate, with yields ranging from 72-91%. Methyl-α-glucopyrannose (Scheme 2.1.15) was benzoylated at the 2- position while methyl-α-galactopyranose, methyl-α-mannopyranose, and methyl-β-L- rhamnopyranoside were all benzoylated at the 3-position. The benzoates were then subjected to conditions for tosylation using tosyl chloride, N,N-diisopropylethylamine and catalytic dimethyltin dichloride. The 6-position was selectively tosylated in yields ranging from 65-88% with the exception of rhamnose (lacking a 6-hydroxyl group), which tosylated at the 2-position

17 in 50% yield. Methyl-α-glucopyranoside was then subjected to further conditions to selectively protect at the 3-position with a t-butoxycarbonylate group in 93% yield and was phosphorylated at the 4-position in 95% yield to produce the fully protected glycoside.32

Scheme 2.1.15 – Regioselective Protection of Sugar Molecules by Dimethyltin Dichloride32

Onomura then reacted the fully protected sugar at the tosylated 6-position in an SN2 reaction with sodium azide. The azide was then converted to an amine, which could be used in further reactions.32

Inspired by work by Bouzide and Sauve, Ye et al. reported a silver(I) mediated selective monoprotection of 2,3-diols in 4,6-O-benzylidene galactopyranosides and glucopyranosides. A solution of p-methylphenyl 4,6-O-benzylidene1-thio-β-D-glucopyranoside in dichloromethane was treated with silver(I) oxide and tosyl chloride in the presence of potassium iodide at room temperature, yielding the 3-monosulfonate ester in 97% yield (Scheme 2.1.16). The 2-substituted and 2,3-substituted products were not detected. Several other carbohydrates, such as galactopyranose and mannopyranose, were also subjected to this method. The β-anomer of the carbohydrate would produce the 3-functionalized product, where as the α-anomer would produce the 2-functionalized product. This method was also extended to include the acetylation and benzoylation of monosaccharides.33

32 Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.; Moriyama, N.; Onomura, O. Org. Lett. 2008, 10, 5075-5077. 33 Wang, H.; She, J.; Zhang, L.; Ye, X. J. Org. Chem. 2004, 69, 5774-5777.

Scheme 2.1.16 – Silver Oxide Mediated Tosylation of Monosaccarides33

Many of these methods have been shown to work well for tosylation; however, a method that produces high yields without previous hydroxyl group protection or the use of toxic reagents is still desired. Due to this fact, catalytic regioselective sulfonylation of carbohydrate derivatives without the use of toxic reagents is still a developing field in organic synthesis.

2.2 Results and Discussion

2.2.1 Regioselective Sulfonylation of Carbohydrate Derivatives

Based on previous results from our laboratory,7 we investigated the use of a borinic acid to catalyze the regioselective sulfonylation of carbohydrate derivatives. Originally, conditions similar to those employed for benzoylation using 1.2 equiv tosyl chloride in place of benzoyl chloride and 1.5 equiv N,N-diisopropylethylamine, with 10 mol% 2-aminoethyl diphenylborinate in acetonitrile were applied to isopropylthiogalactose derivative 1a (0.2 mmol). The reaction was monitored by TLC and after 4 hours a large amount of starting material was still present. The reaction was continued to be monitored and after 48 hours, an aqueous work-up was applied and the crude product was purified by column chromatography. NMR confirmed that the desired 3- functionalized product 1b was formed in 81% yield. The conditions were then optimized.

The results of the optimization are displayed in Table 2.2.1. Typical solvents for tosylation reactions were employed (entries 1-6) with acetonitrile providing the best results. Increasing the quantity of tosyl chloride to 1.5 equivalents increased the yield (entry 4). N,N- Diisopropylethylamine worked well as base for this reaction, with better yields and selectivity than the use of silver(I) oxide, the promoter used in alkylation experiments8 (entry 9-10). When the reaction temperature was increased to 40°C the reaction was complete in just 24 hours as monitored by TLC (entry 8). Tosyl anhydride (entries 11-12) and tosyl imidazole (entry 13) were

19 investigated as tosylating agents but tosyl anhydride resulted in a complex mixture, and tosyl imidazole afforded no reaction.

Table 2.2.1 – Optimization of the Selective Tosylation of Isopropylthio-6-(tert- butyldimethylsilyloxy)-β-D-galactopyranoside

Entry Reagent Solvent Base Temperature Time Yield (°C) (%)a

1 p-TsCl (1.2 equiv) CH3CN DIPEA rt 48 h 81 2 p-TsCl (1.2 equiv) CH2Cl2 DIPEA rt 48 h 57 3 p-TsCl (1.2 equiv) THF DIPEA rt 48 h 73

4 p-TsCl (1.5 equiv) CH3CN DIPEA rt 48 h 84

5 p-TsCl (1.2 equiv) CH2Cl2 DIPEA 40 48 h 77 6 p-TsCl (1.2 equiv) THF DIPEA 40 48 h 53

7 p-TsCl (1.2 equiv) CH3CN DIPEA 40 48 h 66

8 p-TsCl (1.5 equiv) CH3CN DIPEA 40 24 h 92

9 p-TsCl (1.2 equiv) CH3CN Ag2O rt 24 h 16 10 p-TsCl (1.2 equiv) CH3CN Ag2O 40 24 h 18. 11 4-Ts-anhydride CH3CN DIPEA 40 24 h complex (1.5 equiv) mixture

12 p-Ts-imidazole CH3CN DIPEA rt 24 h N/R (1.5 equiv)

13 p-Ts-imidazole CH3CN DIPEA 40 24 h N/R (1.5 equiv) aYield determined using crude 1H NMR with mesitylene as internal standard

A halide additive method was also developed for the tosylation of carbohydrate derivatives. The halide additive method appeared to work well on a 0.2 mmol scale, but upon scale-up the yields decreased.

In order to address the possibility of improved yields, different borinic acid catalysts were screened in the tosylation reaction of 2a. 2-Aminoethyl diphenylborinate catalyst 7, 2-

20 aminoethyl di(4-methoxyphenyl)borinate catalyst 8, and 2-aminoethyl di(1,3- trifluoromethylphenyl)borinate 9 were tested in the reaction using the TBAB additive optimized conditions. The results are tabulated in Table 2.1.4. The unsubstituted phenyl borinate catalyst 7 produced the highest yield; however the selectivity was not optimum (7:1) (entry 1). The 1,3- trifluoromethylphenyl catalyst 9 did not react well and simply produced a complex reaction mixture (entry 3). The substituted methoxyphenyl catalyst 8 produced the best overall results with a yield of 84% and complete selectivity for the formation of 2b from 2a, with no formation of 2c detectable.

Table 2.2.2 – Catalyst Screen on Reaction Using Methyl-6-(tert-butyldimethylsilyloxy)-α-D- mannopyranoside

Entry Catalyst Product Yield (%)

1 2b + 2c 99 (7:1)

2 2b 84

3 2a + 2b + 2c complex mixture (SM present)

The reaction was then optimized at a 1mmol to determine the original conditions using 1.5 equiv tosyl chloride with 1.5 equiv N,N-diisopropylethylamine and 10mol% 2-aminoethyl diphenylborinate catalyst in acetonitrile for 48 hours at room temperature produced the highest yields with side products. The optimum conditions with the highest yields for scale-up of the tosylation were then applied to carbohydrates 1a-6a, 10a, and 11a. The results are displayed in

Table 2.2.5. All of the substrates were converted into the corresponding 3-O-tosylates in excellent yield except for 11a. The isopropylthiogalactose derivative 1a was converted to the corresponding tosylate in yield of 90%. In both alkylation and glycosylation using the 2- aminoethyl diphenylborinate catalyst with silver(I) oxide promoter, this substrate was not able to be used.8,9 Knowing that these conditions for tosylation are tolerable of these sulfur protecting groups is advantageous in that the sulfur group can be used for other transformations such as glycosylation.

In the case of anhydromannose 11a the equatorial position of the diol is in the 2-position. The 2- position is less favoured electronically as it is next to the electron withdrawing anomeric position. This could explain the fact that the yield is only 50% for 11b, much lower than that of all the other tosylates produced. Lower yields had also been observed for this substrate in other transformations in our lab.

Table 2.2.3 – Substrate Scope on 1 mmol Scale Using 2-Aminoethyl Diphenylborinate

Entry Substrate Product Yield (%)

1 90

1a 1b

2 85

2a 2b

3 >99

3a 3b

4 83

4a 4b

5 85

5a 5b

6 77

6a 6b

7 86

10a 10b

8 48

11a 11b

2.2.2 Regioselective Sulfonylation of Polyols

Since the tosylation of carbohydrate derivatives was a success, we wanted to explore the versatility of this reaction by seeing if it could be used to for tosylation of other di- and polyols. Since diols are found in many different biological molecules, selectively functionalizing one hydroxyl group over another is of particular interest in organic chemistry. The results of this study are summarized in Table 2.1.10.

The conditions previously developed for tosylation of carbohydrates, 1.5 equiv of tosyl chloride and 1.5 equiv N,N-diisopropylethylamine with 10 mol % 2-aminoethyl diphenylborinate in acetonitrile, were applied to polyols 12a-30a. The results are tabulated in Table 2.2.6. 1,2-Diol substrates 12a-14a produced the corresponding monotosylated products 12b-14b in excellent yields (81-97%). For 1,2-propanediol 12a, the primary hydroxyl group was selectively tosylated over the more sterically hindered secondary hydroxyl group. For 1,2-diol substrates 15a and 16a,

23 the corresponding tosylates were prepared in slightly lower yields of 72 and 63%, respectively. 1,3-Butanediol 16a was selectively functionalized at the primary position to produce tosylate 16b, which was in agreement with the results for substrate 12a.

Substrates 17a and 18a did not produce the desired products 17b and 18b. This is suspected to be because of epoxide formation since O-tosyl is an excellent leaving group for these substrates where the phenyl groups can stabilize a cation. Substrates 19a and 20a also did not produce the desired products 19b and 20b. This is possibly due to di- or tritosylation with a mixture of other products. To test the theory that longer chain alcohols may be able to selectively tosylate under our tosylation conditions, 1,4-butanediol and 1,6-hexanediol were subjected to the reaction conditions (entries 15 and 16). In the case for 1,4-butanediol, the reaction mixture was complex with multiple products formed. In the case of 1,6-hexanediol, both the mono- 27b and ditosylated versions of the product were formed in low yield.

Table 2.2.4 – Substrate Scope Using Previously Developed Tosylation Conditions

Entry Substrate Product Yield (%)

1 81

12a 12b

2 90

13a 13b

3 97

14a 14b

4 72

15a 15b

5 63

16a 16b

6 0

17a 17b

7 0

18a 18b

8 complex mixture

19a 19b

9 multiple inseparable products 20a 20b

10 complex mixture containing SM

21a 21b

11 complex mixture containing SM

22a 22b

12 complex mixture

23a 23b

13 22 + 10 regioisomer

24a 24b

14 complex mixture

25a 25b 15 complex mixture

26a 26b 16 28 + di-tosylate 27a 27b

Other, more “difficult” substrates were tried under the reaction conditions. These substrates were either sterically or electronically demanding and thus would be more difficult to selectively functionalize. Substrates 21a-25a were subjected to the reaction conditions; however none of the desired products 21b-25b were produced in good yield. Most of the reactions produced complex mixtures, inseparable reaction mixtures, except for carbohydrate 24a, which produced a mixture of regioisomers. The sterics demands for some of the substrates may have been too great, or the conditions may not be tolerable of a wide amount of functional groups (entries 10-12).

2.3 Conclusion

Several tosylated carbohydrate derivatives were prepared through the use of borinic acid catalysis. The method was optimized to be used on a 1mmol scale with the use of tosyl chloride as electrophile, and N,N-diisopropylethylamine as base in acetonitrile at room temperature for 48 hours. This method was also uniformly applied to simple diol molecules; however the reaction times were faster.

2.4 Experimental

2.4.1 General

General: Reactions were carried out without effort to exclude air or moisture, unless otherwise indicated. Stainless steel syringes were used to transfer air- and moisture-sensitive liquids. Flash chromatography was carried out using silica gel (Silicycle).

Materials: HPLC grade acetonitrile was dried and purified using a solvent purification system equipped with columns of activated alumina, under argon (Innovative Technology, Inc.). Deionized water was obtained from an in-house supply. All other reagents and solvents were purchased from Sigma-Aldrich, Caledon, Carbosynth or Alfa Aesar, and used without further purification.

1 13 Instrumentation: H and C NMR spectra were recorded in CDCl3 or CD3OD using a Bruker Advance III 400 MHz or Varian Mercury 400 MHz spectrometer, referenced to residual protium in the solvent. Spectral features are tabulated in the following order: chemical shift (δ, ppm); multiplicity (s-singlet, d-doublet, t-triplet, q-quartet, m-complex multiplet); coupling constants (J, Hz); number of protons; assignment. Assignments are based on analysis of coupling constants and COSY spectra. In cases of uncertain assignments, structural confirmation was secured through NOESY experiments. High-resolution mass spectra (HRMS) were obtained on a VS 70- 250S (double focusing) mass spectrometer at 70 eV. Infrared (IR) spectra were obtained on a Perkin-Elmer Spectrum 100 instrument equipped with a single-reflection diamond / ZnSe ATR accessory, either in the solid state or as neat liquids, as indicated. Spectral features are tabulated as follows: wavenumber (cm–1); intensity (s-strong, m-medium, w-weak, br-broad).

2.4.2 Procedure and Characterization Data for TBS-Protection of Carbohydrate Derivatives

General Procedure A : TBS-Protection of Primary Hydroxy Group

The glycoside substrate (1 equiv.) and tert-butyldimethylsilyl chloride (1.2 equiv.) were dissolved in pyridine (0.7 M). The flask was capped with a septum and stirred at room temperature overnight. The resulting mixture was diluted with dichloromethane, washed with water, and extracted several times with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography.

Isopropylthio-6-(tert-butyldimethylsilyloxy)-β-D-galactopyranoside (1a)

Synthesized according to general procedure A, from isopropyl-β-D-thiogalactopyranoside, 82% 7 yield, viscous colorless oil. Spectral data were in agreement with those previously reported ; Rf = 1 0.39 (EtOAc/Pentanes, 70:30); H NMR (400 MHz, CDCl3): δ 4.37 (d, J = 9.6 Hz, 1H, H-1), 4.07 (d, J = 2.8 Hz, 1H, H-4), 3.91-3.81 (m, 2H, H-6a and H-6b), 3.67 (dd, J = 9.2 Hz and 9.6

Hz, 1H, H-2), 3.57 (dd, J = 9.2 Hz and 2.8 Hz, 1H, H-3), 3.50 (dd, J = 5.2 Hz and 5.6 Hz, 1H, H-

5), 3.24-3.17 (m, 1H, CH(CH3)2), 2.99 (m, 1H, C3-OH), 2.95 (br s, 1H, C4-OH), 2.68 (br s, 1H,

C2-OH), 1.34 (d, J = 3.2 Hz, 3H, CH(CH3)2), 1.32 (d, J = 3.2 Hz, 3H, CH(CH3)2), 0.89 (s, 9H, 13 Si(C(CH3)3)(CH3)2), 0.08 (s, 6H, Si(C(CH3)3)(CH3)2); C NMR (100 MHz, CDCl3): δ 86.1, 78.4, 75.2, 70.9, 69.3, 63.0, 35.7, 26.1, 24.5, 24.3, 18.5, -5.2.

Methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside (2a).

Synthesized according to general procedure A, from methyl-α-D-mannopyranoside, 67% yield, 7 white solid. Spectral data were in agreement with those previously reported ; Rf = 0.33 1 (EtOAc/Pentanes, 80:20); H NMR (400 MHz, CDCl3): δ 4.61 (d, J = 1.6 Hz, 1H, H-1), 3.99 (dd, J = 11.2 Hz and 2 Hz, 1H, H-6a), 3.79-3.75 (m, 2H, H-2 and H-6b), 3.64 (dd, J = 8.8 Hz and 3.2

Hz, 1H, H-3), 3.56-3.46 (m, 2H, H-4 and H-5), 3.36 (s, 3H, OCH3), 0.92 (s, 9H, 13 Si(C(CH3)3)(CH3)2), 0.10 (s, 6H, Si(C(CH3)3)(CH3)2); C NMR (100 MHz, CDCl3): 102.7, 75.1, 72.8, 72.1, 68.9, 64.7, 55.1, 26.5, 19.3, -5.0.

Methyl-6-(tert-butyldimethylsilyloxy)-β-D-galactopyranoside (3a)

Synthesized according to general procedure A, from methyl-β-D-galactopyranoside, 90.1% 7 yield, white solid. Spectral data were in agreement with those previously reported ; Rf = 0.44 1 (EtOAc/Pentanes, 80:20); H NMR (400 MHz, CDCl3): δ 4.15 (d, J = 7.6, 1H, H-1), 4.02 (dd, J = 4.4 Hz and 4 Hz, 1H, H-4), 3.94-3.84 (m, 2H, H-6a and H-6b), 3.64 (dd, J = 7.6 Hz and 7.2

Hz, 1H, H-2), 3.58-3.55 (m, 1H, H-3), 3.54 (s, 3H, OCH3), 3.48 (dd, J = 5.2 Hz and 6 Hz, 1H,

H-5), 3.23 (d, J = 6.4 Hz, 1H, C3-OH), 3.10 (br s, 1H, C4-OH), 3.08 (d, J = 4 Hz, 1H, C2-OH), 13 0.90 (s, 9H, Si(C(CH3)3)(CH3)2), 0.09 (s, 6H, Si(C(CH3)3)(CH3)2); C NMR (100 MHz, CDCl3):

δ 104.2, 74.7, 74.0, 72.2, 69.1, 62.7, 57.2, 26.1, 18.5, -5.1.

Methyl-6-(tert-butyldimethylsilyloxy)-α-D-galactopyranoside (4a)

Synthesized according to general procedure A, from methyl-α-D-galactopyranoside, 20% yield, dried under vacuum to afford a white solid. Spectral data were in agreement with those

7 1 previously reported ; Rf = 0.26 (EtOAc/Pentanes, 80:20); H NMR (400 MHz, CDCl3): δ 4.81 (d, J = 3.6 Hz, 1H, H-1), 4.09 (dd, J = 3.2 Hz and 1.2 Hz, 1H, H-4), 3.90-3.84 (m, 3H, H-2, H-

6a, and H-6b), 3.76-3.73 (m, 2H, H-3 and H-5), 3.42 (s, 3H, OCH3), 3.23 (br s, 1H, C3-OH),

3.05 (br s, 1H, C4-OH), 2.45 (br s, 1H, C2-OH), 0.91 (s, 9H, Si(C(CH3)3)(CH3)2), 0.09 (s, 6H, 13 Si(C(CH3)3)(CH3)2); C NMR (100 MHz, CDCl3): δ 99.6, 71.5, 69.8, 68.8, 69.7, 63.3, 55.4, 25.9, 18.3, -5.4.

2.4.3 Procedure and Characterization Data for Sulfonylation of Polyols

General Procedure B : Borinic Acid-Catalyzed Selective Tosylation of Polyols

2-Aminoethyl diphenylborinate (10 mol %), p-toluenesulfonyl chloride (1.5 equiv) and the diol substrate (1 mmol) were dissolved in dry acetonitrile (5 mL). N,N-Diisopropylethylamine (1.5 equiv) was added in ambient atmosphere, and the resulting mixture was stirred at room temperature. After 48 hours (24 hours for small molecule substrates), the mixture was diluted with ethyl acetate, washed with water, and extracted several times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography on silica gel using the stated elutant system.

Isopropylthio-6-(tert-butyldimethylsilyloxy)-3-O-(p-toluenesulfonyl)-β-D- galactopyranoside (1b)

Synthesized according to general procedure B, from isopropylthio-6-(tert- butyldimethylsilyloxy)-β-D-galactopyranoside, 90% yield, yellow gel; Rf = 0.80 -1 (Pentanes/EtOAc, 70:30); FTIR (νmax, neat, cm ) 3847 (br), 2927 (m), 2856 (m), 1733 (br), 1598 (w), 1463 (w), 1360 (m), 1249 (m), 1189 (w), 1175 (s), 1097 (s), 1046 (w), 972 (s), 886 (s), 837 1 (s), 779 (s), 669 (w); H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.4 Hz, 2H, ArH), 7.32 (d, J = 8.4 Hz, 2H, ArH), 4.45 (dd, J = 9.2 Hz and 3.2 Hz, 1H, H-3), 4.32 (d, J = 9.6 Hz, 1H, H-1), 4.16 (t, J = 3.2 Hz, 1H, H-4), 3.83-3.73 (m, 3H, H-6a, H-6b, and H-2), 3.43 (dd, J = 5.6 Hz and 5.2

Hz, 1H, H-5), 3.13 (m, 1H, CH(CH3)2), 3.76 (d, J = 4 Hz, 1H, C4-OH), 2.42 (s, 3H, CH3), 2.40

(d, J = 2.8 Hz, 1H, C2-OH), 1.29 (d, J = 6.8 Hz, 6H, CH(CH3)2), 0.86 (s, 9H, 13 Si(C(CH3)3)(CH3)2), 0.05 (s, 6H, Si(C(CH3)3)(CH3)2); C NMR (100 MHz, CDCl3): δ 145.1, 133.8, 129.9, 128.1, 86.1, 84.2, 77.9, 68.6, 67.7, 62.6, 35.6, 25.9, 24.2, 21.8, 18.3, -5.4; HRMS + m/z calcd for C22H38O7S2Si[M+NH4] : 524.21719. Found 524.21593.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(p-toluenesulfonyl)-α-D-mannopyranoside (2b)

Synthesized according to general procedure B, from methyl-6-(tert-butyldimethylsilyloxy)-α-D- mannopyranoside, 85% yield, pale yellow gel. Rf = 0.74 (Pentanes/EtOAc, 70:30); FTIR (νmax, neat, cm-1) 3424 (br), 2931 (m), 1856 (w), 1660 (w), 1598 (w), 1463 (w), 1357 (m), 1251 (w), 1174 (s), 1133 (w), 1095 (m), 1056 (s), 965 (s), 921 (w), 813 (s), 778 (s), 677(w); 1H NMR (400

MHz, CD3OD): δ 7.81 (d, J = 8.4 Hz, 2H, ArH), 7.38 (d, J = 8.4 Hz, 2H, ArH), 4.49 (d, J = 2 Hz, 1H, H-1), 4.43 (dd, J = 9.6 Hz and 3.6 Hz, 1H, H-3), 3.84-3.79 (m, 2H, H-2 and H-6a), 3.72-

3.66 (m, 2H, H-6b and H-4), 3.39 (m, 1H, H-5), 3.31 (s, 3H, OCH3), 0.88 (s, 9H, 13 Si(C(CH3)3)(CH3)2), 0.05 (s, 6H, Si(C(CH3)3)(CH3)2); C NMR (100 MHz, CD3OD): δ 146.2, 135.3, 130.8, 129.2, 102.3, 83.9, 75.0, 70.2, 65.6, 64.1, 55.1, 26.4, 21.6, 19.2, - 5.1; HRMS m/z + calcd for C20H34O8SSi[M+NH4] : 480.20874. Found 480.20845.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(p-toluenesulfonyl)-β-D-galactopyranoside (3b)

Synthesized according to general procedure B, from methyl-6-(tert-butyldimethylsilyloxy)-β-D- galactopyranoside, 99% yield, white solid; Rf = 0.61 (Pentanes/EtOAc, 60:40); FTIR (νmax, powder, cm-1) 3567 (m), 3427 (br), 2929 (m), 2877 (w), 2857 (m), 1734 (w), 1597 (w), 1451 (w), 1347 (s), 1260 (m), 1171 (s), 1130 (m), 1071 (s), 1027 (s), 991 (m), 960 (s), 938 (s), 890 (m), 1 850 (s), 817 (m), 771 (s), 708 (w), 671 (s); H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8.4 Hz, 2H, ArH), 7.31 (d, J = 8.4 Hz, 2H, ArH), 4.44 (dd, J = 9.6 Hz and 3.2 Hz, 1H, H-3), 4.16 (d, J = 7.6 Hz, 1H, H-1), 4.12 (dd, J = 3.2 Hz and 3.6 Hz, 1H, H-4), 3.85-3.81 (m, 3H, H-2, H-6a and H-

6b), 3.49 (s, 3H, OCH3), 3.45-3.43 (m, 1H, H-5), 2.83 (d, J = 4.4 Hz, 1H, C4-OH), 2.65 (d, J =

2.8 Hz, 1H, C2-OH), 2.14 (s, 3H, CH3), 0.85 (s, 9H, Si(C(CH3)3)(CH3)2), 0.04 (s, 6H, 13 Si(C(CH3)3)(CH3)2); C NMR (100 MHz, CDCl3): δ 145.1, 133.6, 129.9, 128.1, 103.9, 83.2, + 73.8, 69.1, 68.1, 62.2, 57.1, 25.9, 21.8, 18.3, -5.4; HRMS m/z calcd for C20H34O8SSi[M+NH4] : 480.20874. Found 480.20975.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(p-toluenesulfonyl)-α-D-galactopyranoside (4b)

Synthesized according to general procedure B, from methyl-6-(tert-butyldimethylsilyloxy)-α-D- galactopyranoside, 83% yield, white solid; Rf = 0.52 (Pentanes/EtOAc, 60:40); FTIR (νmax, powder, cm-1) 3514 (br), 2928 (m), 2171 (w), 1857 (m), 1597 (w), 1470 (w), 1360 (m), 1294 (w), 1252 (m), 1173 (s), 1146 (w), 1099 (s), 1084 (s), 1058 (s), 990 (w), 970 (s), 940 (m), 891 (m), 1 837 (s), 813 (s), 779 (s), 747 (m) 701 (w), 673 (w); H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.4 Hz, 2H, ArH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 4.81 (d, J = 4 Hz, 1H, H-1), 4.66 (dd, J = 10 Hz and 2.8 Hz, 1H, H-3), 4.23 (dd, J = 3.2 Hz and 2.8 Hz, 1H, H-4), 4.06 (td, J = 10 Hz and 4 Hz, 1H , H-2), 3.89-3.79 (m, 2H, H-6a and H-6b), 3.74 (dd, J = 5.6 Hz and 5.2 Hz, 1H, H-5), 3.41 (s,

3H, OCH3), 2.88 (d, J = 2.8 Hz, 1H, C4-OH), 2.45 (s, 3H, CH3), 1.91 (d, J = 10 Hz, 1H, C2-OH), 13 0.89 (s, 9H, Si(C(CH3)3)(CH3)2), 0.08 (s, 6H, Si(C(CH3)3)(CH3)2); C NMR (100 MHz, CDCl3): δ 145.3, 134.0, 130.1, 128.2, 99.9, 81.9, 69.8, 69.5, 67.0, 63.1, 55.7, 26.1, 22.0, 18.5, -5.2; + HRMS m/z calcd for C20H34O8SSi[M+NH4] : 480.20874. Found 480.20876.

Methyl-3-O-(p-toluenesulfonyl)-α-L-fucopyranoside (5b)

Synthesized according to general procedure B, from methyl-α-L-fucopyranoside, 85% yield, pale -1 yellow gel. Rf = 0.29 (EtOAc/Pentanes, 60:40); FTIR (νmax, neat, cm ) 3475 (br), 2938 (br), 1733 (m), 1598 (w), 1447 (w), 1355 (m), 1293 (w), 1243 (w), 1174 (s), 1135 (m), 1047 (s), 960 1 (m), 853 (s), 816 (m), 748 (m) 706 (w), 678 (w); H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8.4 Hz, 2H, ArH), 7.31 (d, J = 8.4 Hz, 2H, ArH), 4.73 (d, J = 4 Hz, 1H, H-1), 4.63 (dd, J = 10 Hz and 2.8 Hz, 1H, H-3), 4.01-3.95 (m, 2H, H-2 and H-4), 3.91 (q, J = 6.8 Hz, 1H, H-5), 3.37 (s,

3H, OCH3), 2.58 (s, 1H, C4-OH), 2.42 (s, 3H, CH3), 1.99 (s, 1H, C2-OH), 1.25 (d, J = 6.8 Hz, 13 3H, CHCH3); C NMR (100 MHz, CDCl3): δ 145.3, 133.7, 130.0, 128.2, 99.8, 82.2, 71.5, 66.6, + 65.8, 55.7, 21.9, 16.2; HRMS m/z calcd for C14H20O7S[M+NH4] : 350.12735. Found 350.12766.

Methyl-3-O-(p-toluenesulfonyl)-α-L-rhamnopyranoside (6b)

Synthesized according to general procedure B, from methyl-α-L-rhamnopyranoside, 77% yield, -1 pale yellow gel. Rf = 0.45 (EtOAc/Pentanes, 50:50); FTIR (νmax, neat, cm ) 3485 (br), 2937 (w), 1736 (m), 1598 (w), 1448 (w), 1355 (br), 1241 (m), 1174 (s), 1123 (w), 1095 (w), 1047 (s), 964 1 (s), 915 (m), 854 (s), 814 (m), 782 (m), 675 (m); H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8.4 Hz, 2H, ArH), 7.31 (d, J = 8.4 Hz, 2H, ArH), 4.62 (d, J = 1.2 Hz, 1H, H-1), 4.60 (dd, J = 9.22 Hz and 3.2 Hz, 1H, H-3), 3.98 (br s, 1H, H-2), 3.71-3.59 (m, 2H, H-4 and H-5), 3.32 (s, 3H, OCH3),

2.68 (br s, 1H, C2-OH), 2.52 (br s, 1H, C4-OH), 2.44 (s, 3H, CH3), 1.30 (d, J = 6 Hz, 3H,

13 CHCH3); C NMR (100 MHz, CDCl3): δ 145.5, 133.3, 130.2, 128.2, 100.6, 83.1, 70.4, 69.9, + 68.2, 55.1, 21.9, 17.8; HRMS m/z calcd for C14H20O7S[M+NH4] : 350.12735. Found 350.12807.

1,6-Anhydro-3-O-(p-toluenesulfonyl)-β-D-galactopyranoside (10b)

Synthesized according to general procedure B, from 1,6-Anhydro-β-D-galactopyranoside, 86% -1 yield, white solid; Rf = 0.59 (EtOAc/Pentanes, 80:20); FTIR (νmax, powder, cm ) 3469 (m), 3301 (m), 2926 (m), 2189 (w), 2105 (s), 1656 (m), 1597 (s), 1493 (w), 1455 (w), 1419 (w), 1368 (s), 1177 (s), 1131 (s), 1095 (m), 1056 (s), 997 (s), 926 (m), 854 (s), 807 (s), 768 (w), 706 (w), 657 1 (m); H NMR (400 MHz, CD3OD): δ 7.63 (d, J = 8.4 Hz, 2H, ArH), 7.20 (d, J = 8.4 Hz, 2H, ArH), 4.55 (s, 2H, H-6a and H-6b), 4.41 (dd, J = 4.8 Hz and 4.4 Hz, 1H, H-4), 4.16 (d, J = 7.2 Hz, 1H, H-1), 4.08 (dd, J = 4.8 Hz and 3.6 Hz, 1H, H-3), 3.53-3.50 (m, 1H, H-5), 3.39 (dd, J = 13 3.2 Hz and 1.6 Hz, 1H, H-2), 2.16 (s, 3H, CH3); C NMR (100 MHz, CD3OD): δ 147.1, 134.7, 131.4, 129.3, 103.2, 75.3, 74.1, 74.1, 71.6, 65.1, 21.8; HRMS m/z calcd for + C13H16O7S[M+NH4] : 334.09605. Found 334.09538.

1,6-Anhydro-3-O-(p-toluenesulfonyl)-β-D-mannopyranoside (11b)

Synthesized according to general procedure B, from 1,6-Anhydro-β-D-mannopyranoside, 47% -1 yield, white solid; Rf = 0.40 (EtOAc/Pentanes, 80:20); FTIR (νmax, powder, cm ) 3498 (br), 2972 (w), 2913 (w), 1596 (m), 1479 (w), 1410 (w), 1344 (s), 1273 (m), 1240 (m), 1170 (s), 1144 (m), 1123 (s), 1063 (m), 1047 (s), 999 (s), 972 (s), 908 (m), 863 (s), 812 (s), 727 (w), 684 (s), 1 658 (s); H NMR (400 MHz, CD3OD): δ 7.51 (d, J = 8 Hz, 2H, ArH), 7.10 (d, J = 8 Hz, 2H, ArH), 4.46 (s, 2H, H-6a and H-6b), 4.09-4.07 (m, 2H, H-4 and H-3), 3.90 (dd, J = 7.2 Hz and 1.6 Hz, 1H, H-1), 3.46-3.43 (m, 1H, H-5), 3.39 (dd, J = 3.6 Hz and 2 Hz, 1H, H-2), 2.10 (s, 3H, 13 CH3); C NMR (100 MHz, CD3OD):

δ 147.1, 134.9, 131.4, 129.3, 101.1, 77.8, 77.1, 74.4, 71.9, 66.3, 21.9; HRMS m/z calcd for + C13H16O7S[M+NH4] : 334.09605. Found 334.09583.

1-O-(p-toluenesulfonyl)-2-propanol (12b)

Synthesized according to general procedure B, from 1,2-propanediol, 81% yield, colourless oil. 34 Spectral data were in agreement with those previously reported . Rf = 0.37 (Pentanes/EtOAc, 1 70:30); H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 2H, ArH), 7.34 (d, J = 8.4 Hz, 2H,

ArH), 4.02-3.95 (m, 2H, CHOH and CH2OTs), 3.84 (dd, J = 10 Hz and 7.2 Hz, 1H, CH2OTs), 13 2.44 (s, 3H, CH3), 2.23 (br s, 1H, CHOH), 1.14 (d, J = 6.4 Hz, 3H, CHCH3); C NMR (100

MHz, CDCl3): δ 145.2, 132.7, 130.0, 128.0, 74.9, 65.6, 21.7, 18.6.

2-O-(p-toluenesulfonyl)-1-cyclopentanol (13b)

Synthesized according to general procedure A from 1,2-cyclopentanediol, 90% yield, colourless -1 oil. Rf = 0.26 (Pentanes/EtOAc, 70:30); FTIR (νmax, neat, cm ) 3508 (br), 2952 (br), 1598 (m), 1495 (w), 1449 (w), 1349 (s), 1173 (s), 1095 (s), 1025 (m), 976 (m), 905 (s), 876 (s), 815 (s), 706 1 (w), 669 (w); H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.4 Hz, 2H, ArH), 7.33 (d, J = 8.4 Hz,

2H, ArH), 4.67-4.63 (m, 1H, CHOTs), 4.12-4.08 (m, 1H, CHOH), 2.43 (s, 3H, CH3), 2.37 (br s, 1H, CHOH), 1.84-1.78 (m, 3H), 1.70-1.65 (m, 1H), 1.50-1.46 (m, 1H); 13C NMR (100 MHz,

CDCl3): δ 145.1, 133.7, 130.0, 127.9, 84.3, 72.8, 30.1, 27.9, 21.7, 18.9; HRMS m/z calcd for + C12H16O4S[M+NH4] : 274.11130. Found 274.11181.

2-O-(p-toluenesulfonyl)-1-cyclooctanol (14b)

34 Hudzthy et al. J. Org. Chem. 1992, 57, 5383-5394.

Synthesized according to general procedure A from 1,2-cyclooctanediol, 97% yield, colourless -1 gel; Rf = 0.38 (Pentanes/EtOAc, 80:20); FTIR (νmax, neat, cm ) 3537 (br), 1923 (m), 2858 (w), 1736 (w), 1598 (w), 1449 (w), 1352 (s), 1172 (s), 1127 (w), 1096 (m), 1043 (m), 1018 (w), 898 1 (s), 860 (m), 813 (s), 735 (w), 705 (w), 668 (s); H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.4 Hz, 2H, ArH), 4.76 (dt, J = 7.2 Hz and 2.8 Hz, 1H, CHOTs), 3.95-3.92 (m, 1H) 2.44 (s, 3H, 13 CH3), 2.36 (br s, 1H, CHOH), 2.07-2.02 (m,1H), 1.76-1.37 (m, 11H); C NMR (100 MHz,

CDCl3): δ 144.9, 134.1, 129.9, 127.8, 86.1, 71.8, 30.2, 28.2, 26.9, 25.5, 24.0, 21.8, 21.7; HRMS + m/z calcd for C15H22O4S[M+NH4] : 316.15825. Found 316.15816.

2-Benzyl-1,3-propanediol (15a)

Synthesized according to literature procedure from diethylmalonate and benzyl bromide. Spectral data were in agreement with literature values, 34% yield over two steps, white solid35; 1 Rf = 0.4 (EtOAc/Pentanes, 75:25); H NMR (400 MHz, CDCl3): δ 7.38-7.17 (m, 5H, PhH), 3.82

(dd, J = 7.6 Hz and 6.8 Hz, 2H, CH2OH), 3.70 (dd, J = 7.6 Hz and 6.8 Hz, 2H, CH2OH), 2.63 (d, 13 J = 7.6 Hz, 2H, CH2Ph), 2.10 (br s, 2H, OH), 2.07 (m, 1H, CH); C NMR (100 MHz, CDCl3): δ 140.0, 129.21, 128.7, 126.4, 65.9, 44.1, 34.5.

2-Benzyl-3-O-(p-toluenesulfonyl)-1-propanol (15b)

35 Lee, J.; Lee, J.; Kim, J.; Kim, S.Y.; Chun, M.W.; Cho, H.; Hwang, S.W.; Oh, U.; Park, Y.H.; Marquez, V. E.; Beheshti, M. et al. Bioorg. Med. Chem. 2001, 9, 19-32.

Synthesized according to general procedure B, from 2-benzyl-1,3-propanediol, 72% yield; -1 colourless gel; Rf = 0.68 (EtOAc/Pentanes, 50:50); FTIR (νmax, neat, cm ) 3448 (br), 2921 (br), 1705 (m), 1598 (m), 1495 (m), 1454 (m), 1354 (s), 1292 (w), 1211 (w), 1188 (m), 1173 (s), 1096 (m), 1039 (m), 947 (s), 831 (w), 813 (m), 743 (m), 702 (m), 666 (m); 1H NMR (400 MHz,

CDCl3): δ 7.77 (d, J = 8.4 Hz, 2H, ArH), 7.33 (d, J = 8.4 Hz, 2H, ArH), 7.21 (m, 3H, PhH), 7.06

(d, J = 8 Hz, 2H, PhH), 4.09 (dd, J = 9.6 Hz and 4.8 Hz, 1H, CH2OTs), 3.99 (dd, J = 9.6 Hz and

5.6 Hz, 1H, CH2OTs), 3.63 (dd, J = 11.2 Hz and 4.8 Hz, 1H, CH2OH), 3.54 (dd, J = 11.2 Hz and 13 6.4 Hz), 2.61 (m, 2H, CH2Ph), 2.44 (s, 3H, CH3), 2.101 (br m, 2H, CH and OH); C NMR (100

MHz, CDCl3): δ 145.1, 138.9, 132.8, 130.1, 129.1, 128.6, 128.0, 126.4, 69.8, 61.4, 42.6, 33.7, 21.8; HRMS m/z + calcd for C17H20O4S[M+NH4] : 338.14260. Found 338.14238.

4-O-(p-toluenesulfonyl)-2-butanol (16b)

Synthesized according to general procedure B, from 1,3-butanediol, 63% yield, colourless oil.

36,37 Spectral data were in agreement with those previously reported . Rf = 0.26 (Pentanes/EtOAc, 1 70:30); H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 2H, ArH), 7.32 (d, J = 8.4 Hz, 2H,

ArH), 4.25-4.19 (m, 1H, CH2OTs), 4.12-4.07 (m, 1H, CH2OTs), 3.94-3.89 (m, 1H, CHOH), 2.47

(s, 3H, CH3), 1.84-1.77 (m, 2H, CH2 and CHOH), 1.71-1.65 (m, 1H, CH2), 1.17 (d, J = 6.4 Hz, 13 3H, CHCH3); C NMR (100 MHz, CDCl3): δ 144.9, 133.1, 130.0, 127.9, 67.9, 64.2, 37.9, 23.7, 21.6.

36 Yoo, E.; Yoon, J.; Park Choo, H.-Y.; Pae, A.N.; Rhim, H.; Park, W.-K.; Kong, J-Y. Bioorg. Med. Chem. 2010, 18, 1665-1675. 37 Hintzer, K.; Koppenhoefer, B.; Schurig, V. J. Am. Chem. Soc. 1982, 47, 3850-3854.

3 SN2 Reactions Using Carbohydrate Sulfonates 3.1 Introduction

Manipulation of hydroxyl groups via a SN2 displacement reaction using appropriately activated derivatives is a very useful tool for introduction of different nucleophilic functional groups to carbohydrate frameworks.38 These reactions also result in inversion of configuration sometimes leading to completely different carbohydrate derivatives. Substitution reactions of carbohydrate derivatives are quite well known; however they are often difficult and require vigorous reaction 38 conditions. Sulfonates are an excellent leaving group for SN2 reaction mechanisms and thus are often used in SN2 displacement reactions to introduce oxygen, nitrogen, sulfur, or halogen centered nucleophiles to a sugar framework. Typical sulfonates used for these reactions are carbohydrate triflates or tosylates.38

A common SN2 displacement reaction of carbohydrate tosylates with a nitrogen-centered nucleophile uses the azide anion. These reactions generally have long reaction times and are done at high temperatures in DMF using sodium azide as a nucleophile.38

39 Scheme 3.1.1 – Typical SN2 Displacement Reaction of Sugar Tosylates Using NaN3

These reactions can often be done at lower temperatures when crown ether (15-crown-5) is used to activate the nucleophile by complexing the sodium and freeing the azide ion.32

Another common SN2 displacement reaction of carbohydrate tosylates is done using the benzoate anion. The benzoate anion is not nearly as reactive as the azide anion, so crown ether is often

38 Barton, D.H.R.; Ferreira, J.A.; Jaszberenyi, J.C. Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York,1997; pp 85-101. 39 Usui, T.; Takagi, Y.; Tsuchiya, T.; Umezawa, S. Carbohydr. Res. 1984, 130, 165.

used to activate the nucleophile by complexing its complementary cation. Similar to the SN2 reaction using the azide anion, the reaction typically takes place in DMF; however with the use of crown ether the temperatures required are often a lot lower.

40 Scheme 3.1.2 – Typical SN2 Reaction of Tosylates Using Benzoate Anion

The advantage of an oxygen-centered nucleophile is that unnatural sugars can be made from natural ones. For example, if galactopyranoside that was tosylated at the 3-position were to participate in an SN2 reaction with the benzoate anion, the product produced would be the unnatural sugar gulopyranoside protected at the 3-position.

Scheme 3.1.3 – Conversion of 3-Tosyl-galactose to 3-Benzoyl-gulose

There are also many different displacement reactions using halide anions, often using the tetrabutylammonium counterion. The reactions are similar to those already stated; DMF as solvent and typically high temperatures.38

3.2 Results and Discussion

The use of tosylates 1b, 3b, 5b, 6b, and 10b as substrates in SN2 displacement reactions was investigated. Tosylates have been known to react well in SN2 reactions with nucleophiles. It has been shown previously that sugar tosylates could react with sodium azide to product sugar azides, which could then be converted to their corresponding amines.32 The reaction of tosylates

40 Kim, S.; Augerl, D.; Yang, D.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 1786-1775.

1b, 3b, 5b, 6b, and 10b were investigated under similar reaction conditions. The reaction conditions are shown in Table 3.2.1.

Initial tests using tosylates 1b and 3b and the same conditions reported in literature failed to cause any sort of reaction32 (entries 1 and 2). The reaction was then heated to higher temperatures to see if it could be forced using heat, but once again no desired product was obtained, just starting material and some decomposition (entries 5 and 8). It was thought that the large TBS group on tosylates 1b and 3b could be inhibiting the attack of the nucleophile so tosylates 5b and 6b were then tested under the reaction conditions (entries 9 and 10). In this case, no desired product with a small amount of decomposition was also obtained. It was then thought that there was still too much sterics hindrance from the neighbouring functional groups, so tosylate 10b was tried in the reaction as a last resort (entry 14). Unfortunately, the results were still the same.

Table 3.2.1 – Attempted Conditions for SN2 Reactions Using Tosylated Carbohydrate Derivatives

Entry Substrate Product Nucleophile Temperature Time (h) (Additive) (°C)

3b 1 NaN3 50 24

1b 2 NaN3 50 24

3 5b KOBz reflux 4

4 3b KOBz reflux 4

5 3b 3f NaN3 80 24 6 3b 3g KOBz reflux 24

7 1b KOBz reflux 24

8 1b 1f NaN3 90 24

6b 9 NaN3 90 24

5b 10 NaN3 90 24

11 5b 5g Bu4NOBz 100 24 12 5b 5g KOBz (18-crown-6) 50 24

13 6b KOBz (18-crown-6) 50 24

10b 14 NaN3 80 24

10f

15 10b KOBz (18-crown-6) 80 24

10g

Substrates 1b, 3b, 5b, 6b, and 10b were also tested using the benzoate nucleophile. If either 2b or 3b could react via an SN2 mechanism with an oxygen-centered nucleophile, derivatives of the

40 corresponding unnatural carbohydrates altrose and gulose, respectively, with 3-position inverted stereochemistry could be produced. The reaction conditions are described Table 2.1.9.

The reactions were first carried out using potassium benzoate at reflux in DMF; however the crude reaction mixture showed no desired product and decomposition (entries 3, 4, 6 and 7). In order to be able to employ lower reaction temperatures, different benzoate salts (entry 11) were tested, but the reaction still failed. The addition of nucleophile activating agent was then tried in the reaction (entries 12, 13 and 15). 18-crown-6 should have complexed the potassium ion and allowed the free benzoate anion to participate in the reaction. 18-Crown-6 was added to the reaction and the reaction was done at lower temperatures; however the result was still the same with no product observed (entry 12). The reaction temperature was increased, but all that resulted was decomposition (entry 13 and 15).

3.3 Conclusion

The prepared carbohydrate tosylates were unable to be used in SN2 reactions using either azide or benzoate nucleophiles. Even at high temperatures or with crown ether additive, only starting material or decomposition was observed. Possibly the sterics in the tosylates leave them unfavourable to nucleophilic attack causing no reaction to take place.

4 Regioselective Deoxygenation of Carbohydrate Derivatives 4.1 Introduction

Deoxygenated sugars are a synthetically useful group of compounds. They are found in various antitumor compounds and other bioactive molecules.41 Numerous examples of thiocarbonylation as a prelude to the deoxygenation of carbohydrate derivatives have been reported41; however most of these methods are not highly regioselective. Typical methods for thiocarbonylation of carbohydrate derivatives involve treating the partially protected sugar with sodium hydride, imidazole, and carbon disulfide to produce the thiocarbonyl-protected carbohydrate.42 The development of a method for regioselective thiocarbonylation is important since it eliminates the use of multiple protecting groups. Regioselective thiocarbonylation, followed by deoxygenation by methods similar to the Barton-McCombie reaction has been thought of as an ideal way to provide access to these deoxygenated molecules.43

Barton and McCombie first reported their deoxygenation method in 1975. Condensation of the alcohol with imidoyl chloride methochloride gave an intermediate salt that could be converted to the thioester by reaction with hydrogen sulfide and pyridine. Using different thiocarbonyl reagents, several alcohols were converted to their corresponding thiocarbonylates, which could be radically deoxygenated using tributyltin hydride and AIBN (Scheme 4.1.1). This method of deoxygenation was also used on carbohydrate molecules; however, all hydroxyl groups but the one to be functionalized had to be protected beforehand.44

41 Barton, D.H.R.; Ferreira, J.A.; Jaszberenyi, J.C. Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York,1997; pp 151-172. 42 Sayal, A.K.; Purves, C.B. Can. J. Chem. 1956, 34, 426. 43 Sanchez-Rosello, M.; Puchlopek, A.L.A.; Morgan, A.J.; Miller, S.J. J. Org. Chem. 2008, 73, 1774-1782. 44 Barton, D.H.R.; McCombie, S.W. J. Chem. Soc., Perkin Trans. I 1975, 1574-1585.

Scheme 4.1.1 – Barton-McCombie Reaction44

Newer methods have been developed for thiocarbonylation. Most often DMAP is employed as catalyst45, often in the presence of pyridine46.

In a recent paper by Miller et al., regioselective thioformylation as a tool for regioselective deoxygenation of polyols was reported. Miller developed two peptide catalysts, of which one could direct thiocarbonylation at the 2-position and the other at the 3-position (Scheme 4.1.2). Pentamethylpiperidine was required as base since other amine bases would not form the thiocarbonylated product, instead the addition product of the amine to chlorothionoformate would form. Lewis acids such as iron(III) trichloride were found to increase yields and regioselectivity. This reaction was also applied to the β-glucoside with similar selectivity. The resulting thiocarbonylated derivatives were produced selectively in moderate yields (42-70%), and then subjected to deoxygenation conditions using tributyltin standard Barton-McCombie reaction conditions to produce the deoxygenated sugars in 70-72% yield.43

45 Rawal, V.H.; Newton, R.C.; Krishnamurthy, V. J. Org. Chem. 1990, 55, 5181-5183. 46 (a) Denmark, S.; Thorarensen, A. J. Org. Chem. 1994, 59, 5672-5680. (b) Rigby, J.H.; Mateo, M.E. Tetrahedron 1996, 52, 10569-10582. (c) Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem. Int. Ed. 2004, 43, 1559-1562.

Scheme 4.1.2 – Regioselective Thiocarbonylation Using a Peptide Catalyst by Miller43

Tributyltin hydride was not an ideal reagent for deoxygenation due to its toxic properties, so other methods have been developed for radical deoxygenation. In recent paper by Curran et al., radical deoxygenation of xanthates with N-heterocyclic carbene boranes was reported. These N- heterocyclic carbene boranes were easier reagents to work with because they were stable, easy to handle, and were easily prepared from common second-row elements. Using 1,3- dimethylimidazol-2-ylideneborane, a number of xanthate compounds were deoxygenated in moderate yields (48-81%) (Scheme 4.1.3).47

Scheme 4.1.3 – Radical Deoxygenation Using N-Heterocyclic Carbene Boranes47

A method for regioselective thiocarbonylation of unprotected carbohydrate derivatives is of particular interest in organic chemistry.43 Not many examples of regioselective deoxygenation of carbohydrates exist. Most involve the use of large amounts of protecting groups leading to several extra steps in a synthesis and low atom economy. A broadly applicable catalytic method that could regioselectively thiocarbonylate a carbohydrate derivative, which could then be radically deoxygenated using mild conditions, has yet to be developed.

4.2 Results and Discussion

Deoxygenated sugars are often used in biologically processes and thus are very valuable. Given this fact, we thought to undertake the study of selectively functionalizing carbohydrate derivatives with a thiocarbonyl group, which could then be radically deoxygenated to form the desired carbohydrate deoxygenated at the 3-position.

47 Ueng, S.; Fensterbank, L.; Lacote, E.; Malacria, M.; Curran, D.P. Org. Lett. 2010, 12, 3002-3005.

Our study began by using β-galactose derivative 3a and trying to convert it to the thiocarbonylated derivative 3e using similar conditions as those developed for tosylation. The results of the study are displayed in Table 4.2.1. The study began by applying conditions similar to tosylation, using 1.5 equivalents O-phenyl chlorothionoformate, 10 mol % 2-aminoethyl diphenylborinate and 2 equivalents N,N-diisopropylethylamine in acetonitrile for 24 h at room temperature (entry 1). Unfortunately, all that resulted was recovered starting material. Trying to increase the reaction time (entry 2) or increasing the temperature (entry 3) afforded similar results.

Miller and coworkers found that using a Lewis acid such as iron(III) trichloride and the use piperidine bases was necessary for the thiocarbonylation reaction.43 Several different bases including tetramethylpiperidine (entries 6 and 7) and pentamethylpiperidine (entry 9) were screened for the reaction as well as the addition of 15 mol% iron(III) trichloride (entries 6 and 9). No desired thiocarbonylated produce 3e was detectable in any case except for entry 9 which pentamethylpiperidine was employed in conjunction with iron(III) trichloride. A small amount of desired product (9%) was obtained. These were determined to be the optimal conditions for this reaction screen.

Table 4.2.1 – Optimization of Regioselective Thiocarbonylation Using 2-Aminoethyl Diphenylborinate Catalyst

Entry Base Additive Temperature Time Yield (2 equiv) (15 mol%) (°C) (h) (%) 1 DIPEA None rt 24 only SM 2 DIPEA None rt 48 only SM 3 DIPEA None 40 48 only SM

4 DIPEA FeCl3 rt 24 complex mixture 5 Ag2O None rt 24 complex mixture 6 TMP FeCl3 rt 24 <5%

7 TMP None rt 24 complex mixture

8 K2CO3 None rt 24 complex mixture

9 PEMP FeCl3 rt 24 9

Given the undesired results from trying the thiocarbonylation reaction screen on carbohydrate 3a, carbohydrates 4a-6a were tried under the determined optimal reaction conditions for 3a to see if improved results could be afforded. The results are described in Table 4.2.2. Once again the desired products 4e-6e were only able to be obtained in very low yields, with 4a producing the 2-functionalized regioisomer as well as the 3-fucntionalized.

Table 4.2.2 – Regioselective Thiocarbonylation Using Optimized Conditions

Entry Substrate Product Yield (%)

1 9

3a 3e

2 10 + 8 regioisomer

4a 4e

3 7

5a 5e

4 10

6e 4.3 Conclusion

Similar methods that were used for sulfonylation of carbohydrate derivatives using a borinic acid catalyst were unable to be applied to a thiocarbonyl electrophile. Low yields of product were obtained for some sugars; however more experimentation with different Lewis acids and other additives is still required.

4.4 Experimental

General Procedure C : Borinic Acid-Catalyzed Selective Thiocarboylation of Polyols

2-Aminoethyl diphenylborinate (10 mol %), iron(III) trichloride (15 mol %) and the diol substrate (0.2 mmol) were dissolved in dry acetonitrile (5 mL). Pentamethylpiperidine (2 equiv) and phenylchlorothionoformate (1.5 equiv) were added in ambient atmosphere, and the resulting mixture was stirred at room temperature. After 48 hours (24 hours for small molecule substrates), the mixture was diluted with ethyl acetate, washed with water, and extracted several times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography on silica gel using the stated elutant system.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-monothiocarbonyl-β-D-galactopyranoside (3e)

Synthesized according to general procedure C from methyl-6-(tert-butyldimethylsilyloxy)-β-D- 1 galactopyranoside, 9% yield, colourless gel; H NMR (400 MHz, CDCl3): δ 7.54-7.24 (m, 5H, PhH), 4.93 (dd, J = 7.2 Hz and 1.2 Hz, 1H), 4.57 (s, 1H, H-1), 4.29 (d, J = 7.2 Hz, 1H, H-2),

4.10-4.07 (m, 1H, H-4), 3.96-3.92 (m, 2H, H-6a and H-6b), 3.78-3.74 (m, 1H, H-5), 3.54 (s, 3H,

OCH3), 0.93 (s, 9H, Si(C(CH3)3)(CH3)2), 0.13 (s, 6H, Si(C(CH3)3)(CH3)2).

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-monothiocarbonyl-α-D-galactopyranoside (4e)

Synthesized according to general procedure C from methyl-6-(tert-butyldimethylsilyloxy)-α-D- 1 galactopyranoside, 10% yield, colourless gel; H NMR (400 MHz, CDCl3): δ 7.44-7.14 (m, 5H, PhH), 5.56 (dd, J = 10 Hz and 2.8 Hz, 1H, H-3), 4.92 (d, J = 4 Hz, 1H, H-1), 4.51 (ap s, 1H, H- 4), 4.13-4.11 (m, 1H, H-2), 3.96-3.93 (m, 2H, H-6a and H-6b), 3.84-3.80 (m, 1H, H-5), 3.47 (s,

3H, OCH3), 0.91 (s, 9H, Si(C(CH3)3)(CH3)2), 0.11 (s, 6H, Si(C(CH3)3)(CH3)2).

Methyl-3-O-monothiocarbonyl-α-L-fucopyranoside (5e)

Synthesize according to general procedure C from methyl-α-L-fucopyranoside, 7% yield, 1 colourless gel; H NMR (400 MHz, CDCl3): δ 7.42-7.12 (m, 5H, PhH), 5.17 (d, J = 2.8 Hz, 1H, H-1), 5.12 (dd, J = 6.8 Hz and 3.6 Hz, 1H, H-3), 4.91-4.75 (m, 3H, H-2, H-4, and H-5), 3.51 (s,

3H, OCH3), 1.32 (d, J = 6.8 Hz, 3H, CH3).

Methyl-3-O-monothiocarbonyl-α-L-rhamnopyranoside (6e)

Synthesized according to general procedure C from methyl-α-L-rhamnopyranoside, 10% yield, 1 colourless gel; H NMR (400 MHz, CDCl3): δ 7.45-7.14 (m, 5H, PhH), 4.98 (s, 1H, H-1), 4.89 (dd, J = 6.8 Hz and 7.2 Hz, 1H, H-3), 4.74 (d, J = 7.2 Hz, 1H, H-2), 3.78-3.74 (m, 1H, H-4),

3.58-3.55 (m, 1H, H-5), 3.43 (s, 3H, OCH3), 1.35 (d, J = 6.4 Hz, 3H, CH3).

5 Regioselective Alkylation of Polyols 5.1 Introduction

Another useful protecting group for alcohols is a benzyl ether. It has been widely used as a protecting group for alcohols as well as hydroxyl groups on carbohydrates. Benzyl ethers are good protecting groups due to the fact that they are stable, do not migrate, and are easily removed under mild reactions conditions.11 Typical benzylation conditions involve the use of benzyl bromide and a strong base such as sodium hydride in DMF48, THF49, or DMSO50; however, in these conditions, alkali-labile protecting groups are lost and the conditions cannot be applied to alcohols that are base sensitive.51 However these methods are not always regioselective and as stated previously, regioselective functionalization of diols is very important in organic synthesis.

One of the earlier approaches to selective functionalization of diols was the use of polymer supports. In 1973, Wong and Leznoff used polymer supports to prepare monoethers of symmetrical diols. An insoluble polymer containing acid chloride groups (P-C6H4-CH2OCl) was prepared and reacted with a variety of symmetrical diols in pyridine to give a resin in which one of the hydroxyl groups was attached to the polymer through an ester linkage. This was then reacted with trityl chloride or dihydropyran in pyridine to produce the desired alkyl ether. The polymer support was easily removed using acetic acid to give the desired monoalkylated alcohol (Scheme 5.1.1).52

Scheme 5.1.1 – Monoalkylation of Symmetrical Diols Using a Polymer Support52

48 Brimacombe, J.S. Methods Carbohydr. Chem. 1972, 6, 376. 49 Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett. 1976, 3535-3536. 50 Iwasige, T,; Saeki, H. Chem. Pharm. Bull. 1967, 15, 1803-1806. 51 Iverson, T.; Bundle, D.R. J. Chem. Soc. Chem. Comm. 1981, 1240-1241. 52 Wong, J.Y.; Leznoff, C.C. Can. J. Chem. 1973, 51, 2452-2456.

Phase transfer conditions have also been applied to monoalkylations. Sasson et al. reported the use benzyl chloride, 50%w KOH, and catalytic amounts of tetrabutylammonium bisulfate to monoalkylate primary, secondary, and tertiary diols (Scheme 5.1.2). 53

Scheme 5.1.2 – Monoalkylation Using Phase Transfer Conditions53

A common way to alkylate diols is to use dibutyltin oxide. In 1991, Ohno et al. reported the use of dibutyltin oxide with fluoride salts in the selective monoalkylation of acyclic diols. Several diols molecules were treated with dibutyltin oxide then subsequently with benzyl iodide with cesium fluoride to produce the corresponding monoalkylated diols (Scheme 5.1.3) in good yields 50-99% with good regioselectivities.54

Scheme 5.1.3 – Monoalkylation Using Dibutyltin Oxide and Cesium Fluoride54

A number of reports use selective ring opening of acetals as a way to monoalkylate diols. Barton et al. reported an efficient procedure for the regioselective monoprotection of 1,2-diols using acetals (Scheme 5.1.4). Several external 1,2-diols were converted to their isopropylidene ketals. These ketals were then ring opened using trimethylaluminum to produce the monoalkylated product at the 2-positon. Excellent regioselectivity was observed as well as good yield (73- 86%).55

53 De La Zerda, J.; Barak, G.; Sasson, Y. Tetrahedron 1989, 45, 1533-1536. 54 Nagashima, N.; Ohno, M. Chem. Pharm. Bull. 1991, 39, 1972-1982. 55 Barton, D.H.R.; Zhu, J. Tetrahedron 1992, 48, 8337-8346.

Scheme 5.1.4 – Isopropylidene Ketal Opening Using Trimethylaluminum55

In 1996, Bessodes et al. reported the monobenzylation of 1,n-diols (n = 3-9) using benzyl bromide, sodium hydroxide and catalytic amounts of crown ether in THF at 0°C (Scheme 5.1.5). The 1,n-diols were converted to the corresponding monobenzylated products in excellent yields (82-91%) with only small amounts of dibenzylated product observed (9-18%). It was found in most cases that higher temperatures and using either potassium or lithium hydroxide increased the amount of dibenzylated product.56

Scheme 5.1.5 – Benzylation of 1,4-Butanediol Promoted by Sodium Hydroxide56

Bouzide and Sauve developed a silver(I) oxide mediated monoprotection of symmetrical diols. A variety of primary and secondary symmetrical diols were reacted with benzyl bromide in the presence of silver(I) oxide at room temperature to produce the corresponding monobenzylated product in excellent yield (70-93%) with only small amounts of the dibenzylated product observed (3-16%) (Scheme 5.1.6). The reactions of oligoethane diols proceeded much faster than aliphatic diols. Bouzide also found that the monoprotection of secondary alcohols gave better yields and selectivity. Bouzide and Sauve tried to apply this method to unsymmetrical diols; however, when 1,2-propanediol was reacted, the 1-benzylated product was formed over the 2- benzylated product in only a 2:1 ratio. In order to explain this result, it was suggested that there is complexation of the diol’s oxygen with the silver atom in the mechanism.57

56 Bessodes, M.; Boukarim, C. Synlett 1996, 11, 1119-1120. 57 Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945-5948.

Scheme 5.1.6 – Selective Silver Oxide Mediated Monoprotection of Symmetrical Diols57

Joshi et al, reported the use of sodium alkoxides of diols reacting with dibromoalkanes to produce the corresponding alkenyl ethers (Scheme 5.1.7). The initially formed monobromo ether that results from the reaction of the sodium alkoxide and dibromoalkane goes through intramolecular dehydrohalogenation to form the corresponding alkenyl ether. Several chiral 1,2-, 1,3-, and 1,4-diols were subjected to the reaction conditions producing the desired alkenyl ethers in moderate to excellent yields (32-90%).58

Scheme 5.1.7 – Sodium Alkoxides and Dibromoalkanes Reacting to Produce Alkenyl Ethers58

Sirkecioglu et al. reported a method for the benzylation of alcohols using bis[acetylacetonato]copper as a catalyst. The reaction was screened using this copper catalyst with benzyl bromide with primary and secondary alcohols without solvent to produce the corresponding benzyl ethers in 62-94% yield. Further studies showed that in a diol, either mono- or bisbenzylation was possible depending on the stoichiometry of the benzyl bromide reagent. When only one equivalent of benzyl bromide was used, only one hydroxyl group was functionalized in good yield (70-90%) and when two equivalents were used, both hydroxyl groups could be functionalized (70-85%). Primary alcohols were selectively protected over secondary alcohols (Scheme 5.1.8).59

58 Jha, S.C.; Joshi, N.N. J. Org. Chem. 2002, 67, 3897-3899. 59 Sirkecioglu, O.; Karliga, B.; Talinli, N. Tetrahedron Lett. 2003, 44, 8483-8385.

Scheme 5.1.8 – Regioselective Benzylation of 1,2-Propanediol Using Copper Catalyst59

In 2009, Onomura et al. reported a regioselective catalytic monoalkylation of 1,2-diols using Lewis acid catalysts (Scheme 5.1.9). A borinic acid catalyst was used in conjunction with potassium carbonate and an alkyl halide to selectively alkylate several different diols in excellent yields (64-99%). The alkylation also proved to be exclusively selective for 1,2- or 1,3-diols versus an alcohol.60

Scheme 5.1.9 – Monoalkylation of Diols Using Lewis Acid Catalyst60

More recently, Malik et al. reported benzylation of diols promoted by silver carbonate. 1,2- Propanediol was selectively benzylated at the 1-position in 80% yield (Scheme 5.1.10).61

Scheme 5.1.10 – Regioselective Benzylation Promoted by Silver Carbonate61

Each of these methods was proven effective for benzylation under certain conditions; however, mild conditions that can easily be applied to both carbohydrate derivatives and diol molecules have yet to be developed. Our conditions produced excellent yields on carbohydrate derivatives but its versatility to be expanded to simple polyol molecules had yet to be explored.

5.2 Results and Discussion

Alkylation of carbohydrate derivatives has been of particular interest in our research group. To expand on the functionalization of small polyol molecules using the 2-aminoethyl

60 Maki, T.; Ushijima, N.; Matsumura, Y.; Onomura, O. Tetrahedron Lett. 2009, 50, 1466-1468. 61 Malik, S.; Dixit, V.A.; Bharatam, P.V.; Kartha, K.P.R. Carbohydr. Res. 2010, 345, 559-564.

54 diphenylborinate catalyst and to expand on the alkylation of carbohydrate derivatives, selective benzylation of small polyol molecules was examined. We first began by using the alkylation conditions8 previously reported from our group. The alkylation conditions using benzyl bromide and silver(I) oxide in acetonitrile were applied to polyol molecules 13a-25a and 28a-31a. The results are displayed in Table 5.2.1.

Table 5.2.1 – Substrate Scope Using Previously Developed Benzylation Conditions

Entry Substrate Product Yield (%)

1 63

13a 13d

2 83

14a 14d

3 97

15a 15d

4 47

16a 16d

5 83

17a 17d

6 79

18a 18d

7 complex mixture

19a 19d

8 complex mixture

20a 20d

9 complex mixture

21a 21b

10 complex mixture containing SM

22a 22b

11 complex mixture

23a 23b

12 6 + regioisomer

24a 24b

13 complex mixture

25a 25b

14 59

28a 28d

15 88

29a 29d

16 51 + complex mixture

30a 30d

17 15 + complex mixture

31a 31d

In general, substrates that were problematic for borinic acid-catalyzed monosulfonylation also resulted in low yields of monoalkylated products. The exceptions are substrates 5a and 6a, which produced the corresponding benzylated products 5d and 6d in excellent yields. In this case, an O-benzyl group is not a good leaving group, so epoxide formation does not take place and the reaction can proceed smoothly.

Substrates 30a and 31a were also tested under the benzylation conditions. These substrates were not tested using the conditions for tosylation, as it is known that elimination often takes place due to tosylate being a good leaving group. Substrate 30a gave the desired benzylation product 30d in moderate yield (51%), while 31a gave a complex reaction mixture and only a small amount of product 31d (15%). These low yields could be due to the fact that the substrates were not favoured electronically or the ketone group could interfere with catalyst binding and selectivity.

Overall the yields for the benzylated products were generally low (15-83%) with the exception of substrate 15a, which produced the benzylated product 15d in an excellent yield of 97%. Given these results, we wanted to increase yields of the benzylated products. It has recently been determined in our lab that halide catalysis could be used with the 2-aminoethyl diphenylborinate catalyst and potassium carbonate in acetonitrile to benzylate carbohydrate derivatives. An iodide salt could cause exchange of bromide with iodide to create a more reactive alkylating agent. Cis- 1,2-cyclohexanediol 28a was chosen as a model substrate to be used in the optimization of the halide salt catalyzed reaction to produce benzylated product 28d. Several reaction conditions were attempted and the consumption of starting material was monitored by TLC. The results of the optimization are shown in Table 5.2.2.

Table 5.2.2 – Evaluation of Halide Salt and Temperature Effects on Selective Benzylation of 1,2-cis-cyclohexanediol

Entry Halide Salt Time Temperature (°C) Yield (%)a 1 KI 24 h rt 62 2 TBAI 24 h rt 65 3 KI 24 h 40 78 4 TBAI 24 h 40 >99 5 KI 24 h 60 >99 6 TBAI 24 h 60 >99 7 KI 24 h 80 89 8 TBAI 24 h 80 mixture aYield determined using crude 1H NMR with mesitylene as internal standard

The optimum conditions for benzylation catalyzed by 2-aminoethyl diphenylborinate and a halide salt were determined to be 1 equivalent of potassium iodide as the halide salt and 1.1 equivalent potassium carbonate in acetonitrile at 60°C for 24 hours. These conditions produced benzylated product 28d from cis-1,2-cyclohexanediol 28a in excellent yield of >99%. Using TBAI, roughly the same yield could be obtained at only 40°C, however byproducts were evident by crude NMR. At temperatures higher than 60°C, the yield of 28d did not increase; it appeared that some decomposition took place. These optimized reaction conditions that were developed for the conversion of substrate 28a to benzylated product 28d were then applied to polyol substrates 12a-18a, 29a and 32a. The results are tabulated in Table 5.2.3.

Table 5.2.3 – Substrate Scope Using New Optimized Benzylation Conditions Using Halide Salt

Entry Substrate Product Yield (%)

1 77

12a 12d

2 93

13a 13d

3 99

14a 14d

4 >99

15a 15d

5 95

16a 16d

6 93

17a 17d

7 85

18a 18d

8 >99

28a 28d

9 88

29a 29d

10 90

32a 32d

Substrates 12a-18a, 28a, 29a, and 32a all produced the corresponding benzylated products 12d- 18d, 28d, 29d and 32d in excellent yields (77 - >99%). All products were easily separated through column chromatography except 12d, which yielded product in >99% yield, however part of the yield was due to an inseparable regioisomer. The halide salt conditions using potassium iodide produced yields largely superior to those recorded previously using the silver(I) oxide promoted conditions that had been used for alkylation of carbohydrate derivates.8

Throughout the optimization process, 10 mol % of the 2-aminoethyl diphenylborinate catalyst was used, but it was of interest to determine the amount of catalyst required to complete the transformation in excellent yield over 24 hours. The results of the catalyst-loading screen for the preparation of 28d are shown in Table 5.2.4.

Table 5.2.4 – Evaluation of Catalyst Loading Effects on Selective Benzylation of 1,2-cis- cyclohexandiol

Entry Mol % Catalyst Yield (%)a 1 0 14 2 0.5 90 3 2 97 4 5 95 5 10 96 aYield determined using crude 1H NMR with mesitylene as internal standard

Without any catalyst the reaction is very low yielding, only 14% product visible by 1H NMR of the crude product (entry 1). With as low was 0.5 mol% of the 2-aminoethyl diphenylborinate catalyst, an excellent yield of 90% was observed (entry 2). The reaction appeared to have reached optimum performance when using 2 mol% catalyst where 97% yield was observed (entry 3). The yield slightly decreased when using 5 and 10 mol% catalyst, however the difference could be due to systematic error in using mesitylene as internal standard in crude 1H NMR to determine yields.

5.3 Conclusion

The borinic acid catalyzed alkylation method promoted by silver (I) oxide proved to be not very versatile when being applied to simple diol molecules. A borinic acid catalyzed alkylation system using halide catalysis was then developed. The benzylation of simple diols was completed in excellent yields using as little as 2 mol % 2-aminoethyl diphenylborinate catalyst.

5.4 Experimental

General Procedure D: Borinic Acid-Catalyzed Selective Alkylation of Polyols

The polyol substrate (1 equiv), 2-aminoethyl diphenylborinate 2a (10 mol %), potassium iodide (1.0 equiv) and potassium carbonate (1.1 equiv) were dissolved (potassium carbonate does not dissolve) in dry acetonitrile (0.2 M). Benzyl bromide (1.5 equiv) was then added in ambient atmosphere and the resulting mixture was stirred for 24 hr at 60 °C. The resulting mixture was diluted with ethyl acetate, washed with water, and extracted several times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography on silica gel using the stated elutent system.

1-O-Benzyl-2-propanol (12d)

Synthesized according to general procedure D from 1,2-propanediol, 77% yield plus 22% regio-

62 isomer, colourless oil; Spectral data were in agreement with those previously reported . Rf = 1 0.47 (Pentanes/EtOAc, 80:20); H NMR (400 MHz, CDCl3): δ 7.37-7.34 (m, 5H, PhH), 4.56 (s,

2H, OCH2Ph), 4.03-3.97 (m, 1H, CHOH), 3.47 (dd, J = 9.2 Hz and 3.2 Hz, 1H, CH2OBn), 3.29

(dd, J = 9.2 Hz and 8 Hz, 1H, CH2OBn), 2.50 (br s, 1H, CHOH), 1.15 (d, J = 6.4 Hz, 3H, 13 CHCH3); C NMR (100 MHz, CDCl3): δ 138.1, 128.6, 127.9, 127.8, 75.9, 73.4, 66.6, 18.7.

2-O-Benzyl-1-cyclopentanol (13d)

Synthesized according to general procedure D from 1,2-propanediol, 93% yield, colourless oil. 63 Spectral data were in agreement with those previously reported . Rf = 0.62 (Pentanes/EtOAc, 1 80:20); H NMR (400 MHz, CDCl3): δ 7.37-7.30 (m, 5H, PhH), 4.62 (d, J = 12 Hz, 1H,

OCH2Ph), 4.54 (d, J = 11.6 Hz, 1H, OCH2Ph), 4.11-4.09 (m, 1H, CHOH), 3.84-3.79 (m, 1H, CHOBn), 2.54 (d, J = 4 Hz, 1H, CHOH), 1.86-1.74 (m, 5H), 1.51-1.47 (m, 1H); 13C NMR (100

MHz, CDCl3): δ 138.2, 128.5, 127.8, 127.7, 81.5, 72.3, 71.6, 31.2, 28.0, 19.7.

2-O-Benzyl-1-cyclooctanol (14d)

Synthesized according to general procedure D from 1,2-cyclooctanediol, 99% yield, colourless -1 gel; Rf = 0.71 (Pentanes/EtOAc, 80:20); FTIR (νmax, neat, cm ) 3423 (br), 2918 (s), 1855 (m), 1605 (w), 1496 (w), 1453 (m), 1363 (m), 1275 (m), 1205 (m), 1063 (s), 1027 (s), 970 (w), 815 1 (w), 748 (s), 697 (s); H NMR (400 MHz, CDCl3): δ 7.34-7.29 (m, 5H, PhH), 4.62 (d, J = 12 Hz,

1H, OCH2Ph), 4.50 (d, J = 11.6 Hz, 1H, OCH2Ph), 3.96-3.93 (m, 1H, CHOH), 3.63-3.60 (m, 1H, 13 CHOBn), 2.49 (br s, 1H, CHOH), 2.04-1.36 (m, 12H); C NMR (100 MHz, CDCl3): δ 138.6,

62 Brunsveld, L. ; Zhang, H. ; Glasbeek. M. ; Vekemans, J.A. ; Meijer, E.W. J. Am. Chem. Soc. 2000, 122, 6175- 6182. 63 Fujioka, H. ; Nagatomi, Y, ; Kitagawa, H. ; Kita, Y. J. Am. Chem. Soc. 1997, 119, 12016-12017.

128.5, 127.7, 127.7, 80.9, 71.6, 70.9, 29.6, 26.9, 26.7, 25.6, 25.5, 22.6; HRMS m/z calcd for + C15H22O2[M+NH4] : 252.19635. Found 252.19588.

2-Benzyl-3-O-benzyl-1-propanol (15d)

Synthesized according to general procedure D from 2-benzyl-1,3-propanediol, >99% yield, -1 colourless gel; Rf = 0.66 (EtOAc/Pentanes, 50:50); FTIR (νmax, neat, cm ) 3371 (br), 3027 (w), 2856 (br), 1735 (br), 1603 (w), 1495 (m), 1453 (s), 1364 (m), 1244 (m), 1206 (w), 1028 (br), 910 1 (w), 737 (s), 698 (s); H NMR (400 MHz, CDCl3): δ 7.38-7.17 (m, 10H, ArH), 4.51 (d, J = 6 Hz,

2H, OCH2Ph), 3.76 (dd, J = 11.2 Hz and 4 Hz, 1H, CH2OH), 3.68-3.59 (m, 2H, CH2OBn and

CH2OH), 3.50 (dd, J = 9.2 Hz and 6.4 Hz, 1H, CH2OBn), 2.68 (d, J = 7.6 Hz, 2H, CH2Ph), 2.52 13 (br s, 1H, CH2OH), 2.16 (m, 1H, CH). C NMR (100 MHz, CDCl3): δ 140.2, 138.2, 129.3, 128.7, 128.6, 127.9, 127.8, 126.2, 73.6, 73.0, 65.5, 42.8, 34.7; HRMS m/z + calcd for C17H20O2[M+H] : 257.15534. Found 257.15415.

4-O-Benzyl-2-butanol (16d)

Synthesized according to general procedure D from 1,3-butanediol, 95% yield, colourless oil. 64 Spectral data were in agreement with those preciously reported . Rf = 0.45 (Pentanes/EtOAc, 1 70:30); H NMR (400 MHz, CDCl3): δ 7.37-7.27 (m, 5H, PhH), 4.52 (s, 2H, OCH2Ph), 4.03-3.99

(m, 1H, CHOH), 3.73-3.61 (m, 2H, CH2OBn), 2.89 (d, J = 3.2 Hz, CHOH), 1.78-1.71 (m, 2H, 13 CH2), 1.20 (d, J = 6 Hz, 3H, CHCH3); C NMR (100 MHz, CDCl3): δ 138.1, 128.5, 127.8, 127.7, 73.4, 69.2, 67.6, 38.2, 23.4.

64 Cadot, C. ; Dalko, P.I. ; Cossy, J. ; Ollivier, C, ; Chuard, R. ; Renaud, P. J. Org. Chem. 2002, 67, 7193-7202.

(R,R)-2-Benzyloxy-1,2-diphenylethanol (17d)

Synthesized according to general procedure D from (R,R)-(+)-hydrobenzoin, 93% yield, -1 colourless gel; Rf = 0.66 (Pentanes/EtOAc, 90:10); FTIR (νmax, neat, cm ) 3672 (w), 3551 (br), 3061 (w), 3030 (m), 2867 (br), 1736 (m), 1603 (w), 1495 (m), 1453 (s), 1387 (m), 1343 (w), 1243 (m), 1195 (s), 1070 (br), 1024 (s), 913 (m), 848 (m), 766 (s), 736 (m), 697 (s), 657 (w); 1H

NMR (400 MHz, CDCl3): δ 7.39-7.36 (m, 5H, ArH), 7.35 (m, 3H, PhH), 7.33-7-31 (m, 3H,

PhH), 7.26-7.03 (m, 4H, PhH), 4.76 (d, J = 8 Hz, 1H, OCH2Ph), 4.55 (d, J = 11.2 Hz, 1H, 13 CHOH), 4.37 (dd, J = 11.6 Hz and 9.2 Hz, 2H, OCH2Ph and CHOBn), 3.56 (br s, 1H, OH); C

NMR (100 MHz, CDCl3): δ 139.2, 137.8, 137.6, 128.6, 128.2, 128.2, 128.1, 128.0, 127.9, 127.7, + 127.7, 127.3, 87.1, 78.7, 70.9; HRMS m/z calcd for C21H20O2[M+NH4] : 322.18070. Found 322.18101. meso-2-Benzyloxy-1,2-diphenylethanol (18d)

Synthesized according to general procedure D from meso-hydrobenzoin, 85% yield, white solid. 65 Spectral data were in agreement with those previously reported . Rf = 0.55 (Pentanes/EtOAc, 1 80:20); H NMR (400 MHz, CDCl3): δ 7.35-7.22 (m, 13H, PhH), 7.15-7.12 (m, 2H, PhH), 4.93

(d, J = 6 Hz, 1H, CHOH), 4.52 (dd, J = 12 Hz and 6 Hz, 2H, OCH2Ph and CHOBn), 4.27 (d, J = 13 12 Hz, 1H, OCH2Ph), 2.33 (br s, 1H, CHOH); C NMR (100 MHz, CDCl3): δ 140.5, 138.1, 137.7, 128.4, 128.3, 128.2, 128.2, 127.9, 127.7, 127.6, 127.2, 127.2, 85.1, 77.1, 70.8.

65 Schuster, C. ; Broeker, J. ; Knollmueller, M, ; Gaertner, P. Tetrahedron : Asymmetry. 2005, 16, 2631-2647.

2-O-Benzyl-1-cyclohexanol (28d)

Synthesized according to general procedure D from 1,2-cyclohexanediol, >99% yield, colourless 63 gel. Spectral data were in agreement with those previously reported . Rf = 0.6 (Pentanes/EtOAc, 1 80:20); H NMR (400 MHz, CDCl3): δ 7.36-7.25 (m, 5H, PhH), 4.60 (d, J = 12 Hz, 1H,

OCH2Ph), 4.52 (d, J = 12 Hz, 1H, OCH2Ph), 3.87-3.85 (m, 1H, CHOH), 3.53-3.49 (m, 1H, CHOBn), 2.31 (br s, 1H, CHOH), 1.85-1.79 (m, 2H), 1.65-1.51 (m, 4H), 1.31-1.27 (m, 2H); 13C

NMR (100 MHz, CDCl3): δ 138.7, 128.5, 127.7, 127.6, 78.2, 70.2, 68.8, 30.5, 26.6, 22.2, 21.3.

1-Phenyl-2-O-benzyl-1-ethanol (29d)

Synthesized according to general procedure D from 1-phenyl-1,2-ethanediol, 88% yield, 66 colourless gel. Spectral data were in agreement with those previously reported . Rf = 0.33 1 (Pentanes/EtOAc, 90:10); H NMR (400 MHz, CDCl3): δ 7.40-7.29 (m, 10H, PhH), 4.95 (d, J =

8.8 Hz, 1H, CHOH), 4.61 (s, 2H, OCH2Ph), 3.65 (dd, J = 10 Hz and 3.2 Hz, 1H, CH2OBn), 3.52 13 (t, J = 9.2 Hz, 1H, CH2OBn), 2.89 (s, 1H, CHOH); C NMR (100 MHz, CDCl3): δ 140.2, 137.8, 128.6, 128.4, 128.0, 127.9, 127.9, 126.2, 75.9, 73.5, 72.9.

3-O-Benzylpinanediol (32d)

Synthesized according to general procedure D from pinanediol, 90% yield, yellow gel. Spectral

66 Molinaro, C. ; Jamison, T. Angew. Chem. Int. Ed. 2005, 44, 129-132.

67 1 data were in agreement with those previously reported . Rf = 0.75 (Pentanes/EtOAc, 90:10); H

NMR (CDCl3, 400 MHz, ppm): 7.38–7.29 (m, 5H, PhH); 4.71 (d, J = 11.6 Hz, 1H, OCH2Ph);

4.61 (d, J = 11.6 Hz, 1H, OCH2Ph); 3.76 (dd, J = 9.0 Hz and 5.1 Hz, 1H, CHOBn); 2.45–2.34 (m, 1H); 2.27–2.14 (m, 1H); 1.97 (t, 5.7 Hz, 1H); 1.95–1.89 (m, 1H); 1.78 (ddd, J = 13.6 Hz, 5.0

Hz and 2.4 Hz, 1H); 1.45 (d, J = 10.5 Hz, 1H); 1.27 (s, 3H, CH3); 1.26 (s, 3H, CH3); 0.89 (s, 3H, 13 CH3); C NMR (100 MHz, CDCl3): δ 138.1, 128.6, 128.1, 127.9, 76.4, 73.5, 72.3, 54.1, 40.5, 38.5, 35.5, 30.9, 28.4, 28.1, 24.5.

67 Pinheiro, S. ; Goncalves, C.B.S.S. ; de Lima, M.B. ; de Farias, F.M.C. Tetrahedron : Asymmetry. 2000, 11, 3495-3502.

6 Competition Experiments to Study Selectivity of Functionalization 6.1 Functionalization of 1,2- and 1,3-Diols

Competition experiments were completed as a first step towards applying this mode of catalyst to more complex polyols (polyketide natural products, etc.) Many natural products contain both 1,2- and 1,3-diols as well as syn and anti diols, so these were the chosen systems that were investigated.

First a competition experiment between meso-hydrobenzoin 18a and (R,R)-hydrobenzoin 17a was employed. The result is described in Figure 6.1.1. As expected, the favoured product was 17d formed from the benzylation of 17a in a 6:1 ratio over 18d. In the case of 18a, to bind the borinate catalyst, the phenyl rings would have to eclipse one another.

Figure 6.1.1 – Benzylation Competition Experiment between meso- and (R,R)-Hydrobenzoin

The next selectivity to study was the selectivity of 1,2- between 1,3-diols. 1,3-Butanediol 16a and 1,3-propanediol 12a were subjected to reaction conditions to determine which would bind 2- aminoethyl diphenylborinate better and thus react faster producing more of the tosylated product. The result is displayed in Figure 6.1.2. The reaction was analyzed by both crude 1H NMR and through isolation, producing the same result; that 12d is formed from 1,3-propanediol where as 15d from 1,3-butandiol is not. This result suggest that the binding of 2-aminoethyl diphenylborinate to 1,2-diols is faster and much more favourable than the binding of 1,3-diols.

Figure 6.1.2 – Tosylation Competition Experiment Between 1,3-Butanediol and 1,2-Propanediol

Since it appeared that the 2-aminoethyl diphenylborinate catalyst strongly preferred the 1,2-diol to the 1,3-diol, we then sought to investigate the selectivity of the tosylation reaction of diols versus primary alcohols. 1,3-Butanediol was set against 1-butanol and 1,2-propanediol was set against 1-propanol in tosylation competition experiments. The reaction resulting reaction mixtures were then analyzed using their crude 1H NMR mixtures. The results are displayed in Figure 6.1.3.

Figure 6.1.3 - Tosylation Competition Experiment Between Diols and Primary Alcohols

In both of the competition experiments, it was evident that the diol was strongly favoured in the reaction over the primary alcohol. The competition reaction between the 1,2-diol and primary alcohol was more strongly favoured towards the diol as compared to the reaction between the

1,3-diol and primary alcohol. This could be due to the fact that the 2-aminoethyl diphenylborinate binds the 1,2-diol making it more active towards electrophilic attack than the primary alcohol.

6.2 Functionalization of syn and anti 1,3-Diols

Since the selectivity of 1,2-, and 1,3- diols had been determined, we then set to determine if there was any selectivity between syn and anti 1,3-diols. One would expect the syn diol to be faster in the reaction due to the fact that the R groups on the 1- and 3-positions would be in equatorial positions and in the anti diol, one R group would be axial and one equatorial, making it less favoured (Figure 6.2.1).

Figure 6.2.1 – syn and anti Conformation of the 1,3-diol-borinate Bound Complex

2,4-Pentanediol was chosen as a model substrate for the competition between syn and anti 1,3- diols. 2,4-Pentanediol 33a was purchased commercially as a mixture of the syn and anti stereoisomers and the exact ratio of the mixture was determined using 1H NMR. 2,4-Pentanediol was subjected to reaction conditions for benzylation, tosylation, and benzoylation and the crude reaction mixture was analyzed using 1H NMR. The results are shown in Figure 6.2.2.

Figure 6.2.2 – Competition Experiment Between syn and anti 2,4-Pentanediol

There appeared to be little or no selectivity for the syn stereoisomer over the anti stereoisomer of the 1,3-diol. This was perplexing, but it was thought that methyl was not sufficiently sterically demanding to result in high selectivity. The syn and anti stereoisomers of 1,3-phenyl-1,3- propanediol were then targeted, which having phenyl as a much larger R group, would hopefully display some selectivity for one of the two stereoisomers.

1,3-Diols were prepared by first producing the desired 3-hydroxy-1-ketone through a simple aldol reaction of a ketone with benzaldehyde.

Scheme 6.2.1 – Aldol Reaction to Produce 3-Hydroxy-1-ketones

The hydroxyketone produced was then selectively reduced to either give the syn or anti product depending upon the reagents used. In order to produce the syn product, the hydroxyketone was first treated with BEt2OMe and then NaBH4.

Scheme 6.2.2 – Production of syn-1,3-Diol from Hydroxyketone

To produce the anti-diol, the hydroxyketone was treated with tetramethylammonium triacetoxyborohydride as a reducing agent.

Scheme 6.2.3 – Production of anti-1,3-Diol from 3-Hydroxy-1-ketone

The resultant syn and anti-1,3-diols were then pitted against one another in competition experiments.

Figure 6.2.3 – Benzylation Competition Experiment Between syn and anti 1,3-Phenyl-1,3- propanediol

The prepared syn and anti 1,3-phenyl-1,3-propanediol stereoisomers were subjected to benzylation competition reaction conditions. The results in shown in Figure 6.2.3. By using 1H NMR analysis confirmed by purification and isolation using column chromatography, the syn stereoisomer was strongly favoured over the anti in a 4.8:1 ratio. Given this expected result, the selectivity of the benzylation reaction for certain stereoisomers was probed further.

Figure 6.2.4 – Benzylation Competition Experiment Between 1-Phenyl-3-tert-butyl-1,3- propanediol

The selectivity for syn or anti stereoisomers was then probed using unsymmetrical 1,3-diol 35a. Syn diol 35a’ and anti diol 35a’’ were subjected to the benzylation competition reaction conditions and the result is displayed in Figure 6.2.4. Once again, the syn stereoisomer was favoured over the anti stereoisomer in a 4.8:1 ratio. It was also interesting to note that the unsymmetrical 1,3-diol selectively benzylated at the carbon that is attached to the phenyl group rather than the one attached to the tert-butyl group, likely due to sterics reasons.

6.3 Conclusions

1,2-Diols were the preferred substrate for the borinic acid catalyzed system. From the hydrobenzoin experiments, it can be determined that sterics within the substrate molecule have a large effect of the preference of substrate binding. 1,2 and 1,3-diols are both preferred over primary alcohols. Syn diols are preferred over anti diols in both competition experiments using different 1,3-diols. Whether the 1,3-diol is symmetrical or unsymmetrical, the syn orientation is always preferred.

6.4 Experimental

6.4.1 Procedure and Characterization Data for the Preparation of 1,3- Diols

General Procedure E : Preparation of 1-hydroxy-3-ketones68

Butyllithium (1.1 equiv, 1.6 M in hexanes) was added to a stirred solution of diisopropylamine (1.2 equiv) in dry THF (25 mL) and the reaction was stirred for 15 minutes at 0°C. The reaction was then cooled to -78°C and propiophenone (10 mmol) in dry THF (5 mL) was added dropwise and the reaction was stirred for 30 minutes. Benzaldehyde (1.2 equiv) in dry THF (5 mL) was added dropwise and the reaction mixture was stirred for 30 mins at -78°C. The reaction was quenched with saturated ammonium chloride (12.5 mL) and extracted with EtOAc three times.

The combined extracts were dried using MgSO4, filtered, and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel using the stated elutent system.

General Procedure F : Preparation of 1,3-syn-Diols68

1,3-Hydroxyketone substrate (1 mmol) was dissolved in THF (8 mL) and MeOH (2 mL) at - 78°C under argon. Diethylmethoxyborane (1.1 equiv, 1 M in THF) was added dropwise and the resulting mixture was stirred for 30 minutes. Sodium borohydride (1.1 mmol) was then added and the resulting mixture was stirred overnight at -78°C. Acetic Acid (1 mL) was then added to quench the reaction. The resulting mixture was diluted with EtOAc, washed with sodium bicarbonate, and extracted 3 times using EtOAc. The extracts were combined, dried using

MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel using the stated elutent system.

General Procedure G : Preparation of 1,3-anti-Diols69

Tetramethylammonium triacetoxyborohydride (8 equiv) was dissolved in 4.5 mL dry acetonitrile. 4.5 mL of acetic acid was then added and the mixture was stirred at room

68 Aftab, T.; Carter, C.; Christlieb, M.; Hart, J.; Nelson, A. J. Chem. Soc., Perkin Trans. 1 2000, 711. 69 Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.

73 temperature for 30 minutes under argon. The mixture was then cooled to -40°C and a solution of 1,3-hydroxyketone (1 mmol) in 1.5 mL acetonitrile was then added. The reaction was stirred at - 40°C overnight. A solution of potassium tartrate was prepared by dissolving tartaric acid and potassium hydroxide in water and added to quench the reaction mixture. The reaction was then allowed to slowly warm to room temperature. The mixture was then diluted with DCM, washed with sodium bicarbonate and extracted three times with DCM. The extracts were combined, dried using MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel using the stated elutent system.

1,3-phenyl-3-hydroxypropanone

Synthesized according to general procedure E from acetophenone and benzaldehyde, 85% yield, 70 yellow gel. Spectral data were in agreement with those previously reported. Rf = 0.31 1 (Pentanes/EtOAc, 100:10); H NMR (400 MHz, CDCl3): δ 7.96 (m, 2H, PhH), 7.58-7.26 (m, 8H, 13 PhH), 5.35 (dd, J = 4.8 and 4.4 Hz, 1H, CHOH), 3.38 (dd, J = 4.8 and 4.4 Hz, 2H. CH2); C

NMR (100 MHz, CDCl3): δ 200.2, 143.1, 136.6, 133.7, 128.7, 128.6, 128.2, 127.7, 125.8, 70.1, 47.5.

1,3-phenyl-syn-2-methyl-3-hydroxypropanone

Synthesized according to general procedure E from propiophenone and benzaldehyde, white 71 solid. Spectral data were in agreement with those previously reported. Rf = 0.43 1 (Pentanes/EtOAc, 100:10); H NMR (400 MHz, CDCl3): δ 7.95-7.92 (m, 2H, PhH), 7.59-7.25

70 Xu, H.; Liu, Y.; Fu, Y.; Wu, Y. Org. Lett. 2006, 8, 3449-3451. 71 Mei, Y.; Dissanayake, P.; Allen, M.J. J. Am. Chem. Soc. 2010, 132, 12871-12873.

(m, 8H, PhH), 5.25 (d, J = 3.2 Hz, 1H, CHOH), 3.71 (m, 1H, CHCH3), 1.18 (d, J = 6.8 Hz, 3H, 13 CHCH3); C NMR (100 MHz, CDCl3): δ 205.8, 141.9, 135.8, 133.7, 128.9, 128.6, 128.4, 127.4, 126.1, 73.2, 47.1, 11.3.

1,3-phenyl-anti-2-methyl-3-hydroxypropanone

Synthesized according to general procedure E from propiophenone and benzaldehyde, colourless 72 gel. Spectral data were in agreement with those previously reported. Rf = 0.34 1 (Pentanes/EtOAc, 100:10); H NMR (400 MHz, CDCl3): δ 7.99-7.96 (m, 2H, PhH), 7.61-7.27

(m, 8H, PhH), 5.01 (d, J = 8 Hz, 1H, CHOH), 3.87-3.82 (m, 1H, CHCH3), 1.07 (d, J = 7.2 Hz, 13 3H, CHCH3); C NMR (100 MHz, CDCl3): δ 205.1, 142.3, 136.8, 133.8, 130.3, 128.7, 128.5, 128.1, 126.8, 76.9, 48.1, 15.8.

5-Hydroxy-2,2-dimethyl-5-phenyl-pentan-3-one

Synthesized according to general procedure E from 3,3-dimethyl-butan-2-one and benzaldehyde, 73 yellow gel. Spectral data were in agreement with those previously reported. Rf = 0.48 1 (Pentanes/EtOAc, 100:10); H NMR (400 MHz, CDCl3): δ 7.38-7.25 (m, 5H, PhH), 5.14 (m, 1H, 13 CHOH), 2.88 (dd, J = 4.4 Hz and 2.8 Hz, 2H, CH2), 1.12 (s, 9H, CH3); C NMR (100 MHz,

CDCl3): δ 216.9, 143.0, 128.5, 127.6, 125.7, 70.2, 45.5, 44.5, 26.2.

1,3-Phenyl-syn-1,3-propanediol (34a’)

72 Ohtsuka, Y.; Koyasu, K.; Ikeno, T.; Yamada, T. Org. Lett. 2001, 3, 2543-2546. 73 Chopade, P.R.; Davis, T.A.; Prasad, E.; Flowers, R.A. Org. Lett. 2004, 6, 2685-2688.

Synthesized according to general procedure F from 1,3-phenyl-3-hydroxypropanone, 50% yield, 74 colourless gel. Spectral data are in agreement with those previously reported. Rf = 0.25 1 (Pentanes/EtOAc, 80:20); H NMR (400 MHz, CDCl3): δ 7.38-7.25 (m, 10H, PhH), 4.98 (dd, J = 10 Hz and 2.8 Hz, 2H, CHOH), 3.38 (br s, 2H, CHOH), 2.17 (dd, J = 10 Hz and 14.8 Hz, 1H, 13 CH2), 1.95 (dd, J = 14.8 Hz and 2.8 Hz, 1H, CH2); C NMR (100 MHz, CDCl3): δ 144.2, 128.6, 127.7, 125.8, 75.1, 47.7.

1,3-Phenyl-anti-1,3-propanediol (34a’’)

Synthesized according to general procedure G from 1,3-phenyl-3-hydroxypropanone, 69% yield, 75 white solid. Spectral data were in agreement with those previously reported. Rf = 0.19 1 (Pentanes/EtOAc, 80:20); H NMR (400 MHz, CDCl3): δ 7.36-7.26 (m, 10H, PhH), 4.97 (dd, J = 13 6 Hz and 5.6 Hz, 2H, CHOH), 2.61 (br s, 2H, CHOH), 2.17 (dd, J = 6 Hz and 5.6 Hz, CH2); C

NMR (100 MHz, CDCl3): δ 144.3, 128.6, 127.6, 125.7, 71.9, 46.6.

2,2-Dimethyl-5-phenyl-syn-3,5-pentanediol (35a’)

Synthesized according to general procedure F from 5-hydroxy-2,2-dimethyl-5-phenyl-pentan-3- 76 one, 38%, white solid. Spectral data were in agreement with those previously reported. Rf =

74 Ravikumar, K.S.; Sinha, S.; Chandrasekaran, S. J. Org. Chem. 1999, 64, 5841-5844. 75 Lotz, M.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed. 2002, 41, 4708-4711.

1 0.28 (Pentanes/EtOAc, 80:20); H NMR (400 MHz, CDCl3): δ 7.39-7.28 (m, 5H, PhH), 4.91 (dd, J = 9.6 Hz and 2.8 Hz, 1H, CHPh), 3.61 (dd, J = 10 Hz and 2 Hz, 1H, CHOH), 2.37 (br s, 2H, 13 CHOH), 1.29-1.73 (m, 2H, CH2), 0.89 (s, 9H, CH3); C NMR (100 MHz, CDCl3): δ 144.9, 128.6, 127.7, 125.8, 81.0, 75.9, 40.1, 25.6, 25.4.

2,2-Dimethyl-5-phenyl-anti-3,5-pentanediol (35a’’)

Synthesized according to general procedure G from 5-hydroxy-2,2-dimethyl-5-phenyl-pentan-3- 76 one, 86%, white solid. Spectral data were in agreement with those previously reported. Rf = 1 0.41 (Pentanes/EtOAc, 80:20); H NMR (400 MHz, CDCl3): δ 7.39-7.25 (m, 5H, PhH), 5.08 (dd, J = 7.2 Hz and 3.2 Hz, 1H, CHPh), 3.51 (dd, J = 10.8 Hz and 2.4 Hz, 1H, CHOH), 1.91-1.78 (m, 13 2H, CH2), 0.87 (s, 9H, CH3); C NMR (100 MHz, CDCl3): δ 144.9, 128.5, 127.3, 125.6, 76.4, 72.0, 39.4, 34.8, 25.6.

1,3-Phenyl-syn-2-methyl-anti-1,3-propanediol

Synthesized according to general procedure G from 1,3-phenyl-anti-2-methyl-3- hydroxypropanone, 71% yield, colourless gel. Spectral data were in agreement with those

77 1 previously reported. Rf = 0.38 (Pentanes/EtOAc, 80:20); H NMR (400 MHz, CDCl3): δ 7.38- 7.26 (m, 10H, PhH), 5.03 (d, J = 2.4 Hz, 1H, CHOH), 4.7 (d, J = 6.8 Hz, 1H, CHOH), 2.7 (br s, 13 2H, CHOH), 2.21-2.17 (m, 1H, CHCH3), 0.75 (d, J = 7.2 Hz, 3H, CHCH3); C NMR (100 MHz,

CDCl3): δ 143.6, 142.7, 128.6, 128.1, 127.7, 127.1, 126.4, 126.1, 77.98, 74.5, 46.0, 11.4.

76 Chan, T.H.; Nwe, K.T. J. Org. Chem. 1992, 57, 6107-6111. 77 Vicario, J.L.; Badia, D.; Dominguez, E.; Rodriguez, M.; Carrillo, L. J. Org. Chem. 2000, 65, 3754-3760.

1,3-Phenyl-syn-2-methyl-syn-1,3-propanediol

Synthesized according to general procedure F from 1,3-phenyl-syn-2-methyl-3- hydroxypropanone, 49% yield, white solid. Spectral data were in agreement with those

77 1 previously reported. Rf = 0.50 (Pentanes/EtOAc, 80:20); H NMR (400 MHz, CDCl3): δ 7.39- 7.26 (m, 10H, PhH), 5.16 (d, J = 3.2 Hz, 2H, CHOH), 2.41 (br s, 2H, CHOH), 2.06 (m, 1H, 13 CHCH3), 0.74 (d, J = 7.2 Hz, 3H, CHCH3); C NMR (100 MHz, CDCl3): δ 143.4, 128.4, 127.3, 125.7, 78.0, 47.0, 4.8.

6.4.2 Procedure and Characterization Data for Competition Experiments

General Procedure for Benzylation Competition Experiments

To a 2-dram vial equipped with a stir bar were added diphenylborinic acid (10 mol %), two diol substrates (0.2 mmol each) and acetonitrile (2 mL). To the resulting mixture were added benzyl bromide (0.2 mmol), potassium iodide (0.2 mmol), and potassium carbonate (0.2 mmol). The vial was capped in ambient atmosphere and stirred at 40°C. After 24 hours, the reaction was quenched by addition of 50 µL methanol, diluted in ethyl acetate, washed with water, and extracted with ethyl acetate. The extracts were then concentrated in vacuo. The resulting reside 1 was dissolved using CDCl3 or C6D6 and analyzed by H NMR.

General Procedure for Tosylation Competition Experiments

To a 2-dram vial equipped with a stir bar were added diphenylborinic acid (10 mol %), two diols substrates (0.2 mmol each) and acetonitrile (2 mL). To the resulting mixture were added tosyl chloride (0.2 mmol), and N,N-Diisopropylethylamine (0.2 mmol). The vial was capped in ambient atmosphere and stirred at room temperature. After 24 hours, the reaction was quenched by addition of 50 µL methanol, diluted in ethyl acetate, washed with water, and extracted with ethyl acetate. The extracts were then concentrated in vacuo. The resulting reside was dissolved 1 using CDCl3 and analyzed by H NMR.

1,3-Phenyl-syn-3-O-benzyl-1-propanol (34d’)

Synthesized according to general procedure D from 1,3-phenyl-syn-1,3-propanediol, 54% yield, -1 colourless gel; Rf = 0.37 (Pentanes/EtOAc, 90:10); ); FTIR (νmax, neat, cm ) 3196 (br), 3063 (w), 3028 (m), 2922 (w), 2886 (br), 1602 (w), 1493 (m), 1452 (m), 1416 (w), 1397 (w), 1371 (w), 1351 (m), 1284 (w), 1251 (w), 1227 (w), 1197 (w), 1102 (s), 1084 (s), 1058 (s), 1038 (s), 1026 (s), 945 (m), 910 (w), 844 (w), 824 (w), 770 (m), 748 (m), 733 (s), 694 (s); 1H NMR (400

MHz, CDCl3): δ 7.40-7.24 (m, 15H, PhH), 4.95 (dd, J = 9.6 Hz and 3.2 Hz, 1H, CHOH), 4.68

(dd, J = 10 Hz and 3.2 Hz, 1H, CHOBn), 4.51 (d, J = 11.6 Hz, 1H, CH2Ph), 4.31 (d, J = 11.6 Hz, 13 1H, CH2Ph), 2.36-2.27 (m, 1H, CH2), 1.98-1.94 (m, 1H, CH2); C NMR (100 MHz, CDCl3): δ 144.4, 141.4, 137.8, 128.8, 128.7, 128.5, 128.3, 128.2, 128.2, 128.1, 127.5, 126.8, 125.9, 82.1, + 74.1, 70.7, 48.0; HRMS m/z calcd for C22H22O2[M+NH4] : 336.19635. Found 336.19817.

1,3-Phenyl-anti-3-O-benzyl-1-propanol (34d’’)

Synthesized according to general procedure D from 1,3-phenyl-anti-1,3-propanediol, 71% yield, -1 colourless gel; Rf = 0.61 (Pentanes/EtOAc, 90:10); FTIR (νmax, neat, cm ) 3205 (br), 3027 (m), 2925 (m), 1886 (m), 1602 (w), 1493 (m), 1450 (s), 1416 (m), 1397 (m), 1284 (w), 1226 (m), 1196 (m), 1102 (s), 1084 (s), 1058 (s), 1026 (s), 1000 (w), 945 (s), 910 (m), 901 (w), 870 (w), 1 843 (w), 770 (m), 747 (m), 733 (s), 694 (s); H NMR (400 MHz, CDCl3): δ 7.42-7.25 (m, 15H, PhH), 5.04 (dd, J = 8 Hz and 2.8 Hz, 1H, CHOH), 4.63 (dd, J = 9.2 Hz and 3.2 Hz, 1H,

CHOBn), 4.50 (d, J = 11.6 Hz, 1H, CH2Ph), 4.28 (d, J = 11.6 Hz, 1H, CH2Ph), 2.31-2.24 (m, 1H, 13 CH2), 2.13-2.07 (m, 1H, CH2); C NMR (100 MHz, CDCl3): δ 144.5, 141.6, 138.1, 128.7, 128.6, 128.4, 128.0, 127.9, 127.8, 127.2, 126.6, 125.6, 78.8, 71.2, 70.9, 46.9; HRMS m/z calcd + for C22H22O2[M+NH4] : 336.19635. Found 336.19766.

1,3-Phenyl-syn-2-methyl-syn-3-O-benzylpropanol

Synthesized according to general procedure D from 1,3-phenyl-syn-2-methyl-syn-1,3- 1 propanediol, 20% yield, yellow gel; Rf = 0.53 (Pentanes/EtOAc, 95:5); H NMR (400 MHz,

CDCl3): δ 7.39-7.30 (m, 15H, PhH), 4.97 (d, J = 2.8 Hz, 1H, CHOH), 4.71 (d, J = 4 Hz, 1H,

CHOBn), 4.57 (d, J = 11.6 Hz, 1H, OCH2Ph), 4.31 (d, J = 11.6 Hz, 1H, OCH2Ph), 2.05-2.00 (m,

1H, CHCH3), 0.83 (d, J = 7.2 Hz, CHCH3).

1,3-Phenyl-syn-2-methyl-anti-3-O-benzylpropanol

Synthesized according to general procedure D from 1,3-phenyl-syn-2-methyl-anti-1,3- 1 propanediol, 20% yield, yellow gel; Rf = 0.58 (Pentanes/EtOAc, 95:5); H NMR (400 MHz,

CDCl3): δ 7.41-7.24 (m, 30H, PhH), 5.13 (d, J = 2 Hz, 1H, CHOH), 4.73 (d, J = 2.8 Hz, 1H,

CHOBn), 4.70 (d, J = 6.8 Hz, 1H, CHOH), 4.57-4.50 (m, 2H, OCH2Ph), 4.36 (d, J = 7.2 Hz, 1H,

CHOBn), 4.27 (d, J = 11.6 Hz, 2H, OCH2Ph), 2.23-2.14 (m, 2H, CHCH3), 0.77 (d, J = 7.2 Hz,

3H, CHCH3), 0.68 (d, J = 7.2 Hz, 3H, CHCH3).

2,2-Dimethyl-5-phenyl-syn-5-O-benzyl-3-pentanol (35d’)

Synthesized according to general procedure D from 2,2-dimethyl-5-phenyl-syn-3,5-pentanediol, 1 44% yield, colourless gel; Rf = 0.64 (Pentanes/EtOAc, 95:5); H NMR (400 MHz, CDCl3): δ 7.41-7.28 (m, 10H, PhH), 4.60 (dd, J = 9.6 Hz and 4 Hz, 1H, CHOBn), 4.44 (d, J = 11.2 Hz,

1H, OCH2Ph), 4.30 (d, J = 11.2 Hz, 1H, OCH2Ph), 3.79 (d, J = 1.2 Hz, 1H, CHOH), 3.47 (dd, J

= 11.6 Hz and 3.2 Hz, 1H. CHOH), 1.93-1.80 (m, 2H, CH2), 0.88 (s, 9H, CH3).

2,2-Dimethyl-5-phenyl-anti-5-O-benzyl-3-pentanol (35d’’)

Synthesized according to general procedure D from 2,2-dimethyl-5-phenyl-anti-3,5-pentanediol, 1 11% yield, colourless gel; Rf = 0.53 (Pentanes/EtOAc, 95:5); H NMR (400 MHz, CDCl3): δ 7.40-7.29 (m, 10H, PhH), 4.69 (dd, J = 8.4 Hz and 3.2 Hz, 1H, CHOBn), 4.54 (d, J = 12 Hz,

1H, OCH2Ph), 4.30 (d, J = 12 Hz, 1H, OCH2Ph), 3.57 (dd, J = 10 Hz and 2 Hz, 1H, CHOH),

1.95-1.88 (m, 1H, CH2), 1.71-1.64 (m, 1H, CH2), 0.86 (s, 9H, CH3).

7 Regioselective Benzoylation of Diols

As a side experiment and for completion of a substrate table for a full paper on functionalization of small polyol molecules using 2-aminoethyl diphenylborinate, several benzoate-functionalized polyols were also produced. The results are displayed in Table 7.1.1. Similar results to tosylation experiments were obtained using the benzylation conditions with substrates 17a and 18a, affording no product likely due to complicated reaction involving epoxide formation. The yields might also be lower than tosylation for some substrates such as 15a because the reaction time is much shorter, only 4 hours compared to 24 hours for tosylation.

Table 6.4.1 – Prepared Benzoates for Full Paper Using Lee’s Benzylation Conditions7

Entry Substrate Product Yield (%)

1 97

12a 12i

4 47

15a 15i

5 80

16a 16i

6 no desired product

17a 17i

7 no desired product

18a 18i

7.1 Conclusions

The borinic acid-catalyzed benzoylation system previously applied to carbohydrate derivatives is easily applicable to a variety of simple diols. The shorter reaction time lowers the yield for some substrates that would take longer time to react.

7.2 Experimental

General Procedure H: Borinic Acid-Catalyzed Selective Acylation of Polyols

2-Aminoethyl diphenylborinate 4a (10 mol %) and the diol substrate (1 mmol) were dissolved in dry acetonitrile (5 mL). N,N-Diisopropylethylamine (1.2–2.0 mmol) and benzoyl chloride (1.2– 2.0 mmol) were added in ambient atmosphere, and the resulting mixture was stirred at room temperature. After 4 hours, the mixture was diluted with ethyl acetate, washed with water, and extracted several times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography on silica gel using the stated elutant system.

1-O-Benzoyl-2-propanol (12i)

Synthesized according to general procedure H from 1,2-propanediol, 97% yield, colourless oil. 78 Spectral data were in agreement with those previously reported . Rf = 0.51 (Pentanes/EtOAc, 1 70:30); H NMR (400 MHz, CDCl3): δ 8.05 (dd, J = 6.4 Hz and 2Hz, 2H, PhH), 7.56 (td, J = 7.6 Hz and 2 Hz, 1H, PhH), 7.43 (dd, J = 7.6 Hz and 6.4 Hz, 2H, PhH), 4.33 (d, J = 8 Hz, 1H,

CH2OTs), 4.18 (m, 2H, CH2OTs and CHOH), 2.29 (br s, 1H, CHOH), 1.28 (d, J = 6 Hz, 3H, 13 CHCH3); C NMR (100 MHz, CDCl3): δ 166.7, 133.2, 129.9, 129.7, 128.5, 70.1, 66.3, 19.4.

2-Benzyl-3-O-benzoyl-1-propanol (15i)

78 Kaluzna et al. Tetrahedron : Asymmetry. 2005, 16, 3682-3689.

Synthesized according to general procedure H from 2-benzyl-1,3-propanediol, 47% yield, 79 colourless gel. Spectral data were in agreement with those previously reported . Rf = 0.52 1 (Pentanes/EtOAc, 70:30); H NMR (400 MHz, CDCl3): δ 8.05 (dd, J = 8 Hz and 1.2 Hz, 2H, PhH), 7.56 (td, J = 7.2 Hz and 1.2 Hz, 1H, PhH), 7.45 (td, J = 8 Hz and 7.2 Hz, 2H, PhH), 7.33-

7.22 (m, 5H, ArH), 4.45 (dd, J = 11.2 Hz and 4.4 Hz, 1H, CH2OBz), 4.34 (dd, J = 11.2 Hz and

6.4 Hz, 1H, CH2OBz), 3.69 (dd, J = 11.2 Hz and 4.8 Hz, 1H, CH2OH), 3.61 (dd, J = 11.2 Hz and

8 Hz, 1H, CH2OH), 2.78-2.74 (m, 2H, CH2Ph), 2.29-2.25 (m, 1H, CH), 2.07 (br s, 1H, CH2OH); 13 C NMR (100 MHz, CDCl3): δ 167.1, 139.3, 133.1, 129.9, 129.6, 129.1, 128.5, 128.4, 126.3, 64.2, 62.1, 42.8, 34.4.

4-O-benzoyl-2-butanol (16i)

Synthesized according to general procedure H from 1,3-butanediol, 80% yield, colourless oil. 80 Spectral data were in agreement with those previously reported . Rf = 0.49 (Pentanes/EtOAc, 1 70:30); H NMR (400 MHz, CDCl3): δ 8.02 (dd, J = 6.4 Hz and 1.6 Hz, 2H, PhH), 7.54 (td, J = 7.6 Hz and 1.6 Hz, 1H, PhH), 7.42 (td, J = 7.6 Hz and 6.4 Hz, 2H, PhH), 4.61-4.54 (m, 1H,

CH2OTs), 4.41-4.35 (m, 1H, CH2OTs), 3.99-3.94 (m, 1H, CHOH), 2.18 (br s, 1H, CHOH), 1.93- 13 1.81 (m, 2H, CH2), 1.26 (d, J = 6.4 Hz, CHCH3); C NMR (100 MHz, CDCl3): δ 167.1, 133.1, 130.2, 129.7, 128.5, 64.9, 62.3, 38.3, 23.7.

79 Trost, B.M. ; Malhotra, S. ; Mino, T. ; Rajapaksa, N.S. Chem. Eur. J. 2008, 14, 7648-7657. 80 Trost, B.M. ; Verhoeven, T.R. J. Am. Chem. Soc. 1980, 102, 4743-4763.

8 Functionalization Using Epoxide Electrophiles

We then wanted to explore other possible electrophiles that could be applied using the 2- aminoethyl diphenylborinate catalyst. We were particularly interested to see if it was possible to open an epoxide under similar conditions for other functionalizations using our 2-aminoethyl diphenylborinate catalyst.

First the reaction of 3a with styrene oxide to produce the desired functionalized product 3h was attempted. The reaction was screened in acetonitrile using the carbohydrate substrate 3a with 10 mol % 2-aminoethyl diphenylborinate catalyst and 1.5 equiv of styrene oxide with 10 mol % of a Lewis acid to activate the epoxide. The results of testing different Lewis acids in the reaction conditions at room temperature for 24 h are tabulated in Table 7.2.1.

Table 7.2.1 – Regioselective Epoxide Ring-Opening of Styrene Oxide with β-Galactose Derivative

Entry Lewis Acid Temperature (°C) Time Yield 1 MgOTf rt 24 h only SM 2 ScOTf rt 24 h only SM 3 SmOTf rt 24 h only SM 4 AgOTf rt 24 h only SM 5 LaOTf rt 24 h only SM 6 YbOTf rt 24 h only SM 7 ZnOTf rt 24 h only SM

To our disappointment, no reaction took place using any of the conditions with starting material still left in the reaction mixture. It was thought that carbohydrate 3a was too difficult a substrate and that styrene oxide was too difficult of an electrophile. This lead to the reaction screen of a simpler substrate, phenyl-1,2-ethanediol 29a, reacting with cyclohexene oxide. The same

85 reactions conditions as mentioned previously were used and different Lewis acids were tested in the reaction to activate the epoxide. The results are displayed in Table 7.2.2.

Table 7.2.2 – Regioselective Epoxide Ring-Opening of Cyclohexene Oxide with Phenyl-1,2- Ethanediol

Once again, the reaction afforded none of the functionalized product and only starting material remained in the reaction mixture. Since there appeared to be no activation by the 2-aminoethyl diphenylborinate catalyst toward an epoxide electrophile, this project was abandoned as well.

8.1 Conclusions

The borinic-acid catalyzed functionalization system previously applied to tosylation, benzylation and benzoylation was unable to be applied to epoxide electrophiles. Both difficult and simple substrates and epoxide electrophiles were tested with a variety of Lewis acids, but no reaction was shown to take place.

9 Conclusions

Regioselective borinic acid-catalysis of polyols is reported. Borinic acid catalysis was found to be an adaptable system that could be used to activate polyols to both benzyl and tosyl electrophiles. The developed methods are mild and do not involve the use of stoichiometric amounts of toxic reagents making them more attractive than previous methods. Regioselective tosylation of carbohydrate derivatives using tosyl chloride and 2-aminoethyl diphenylborinate catalyst was achieved in excellent yields. This method was able to further extended to 1,2- and 1,3-diol substrates.

A silver(I) oxide mediated benzylation of 1,2- and 1,3-diols was attempted; however, the reaction afforded low to moderate yields. A regioselective halide-salt assisted borinic acid- catalyzed system for benzylation of 1,2- and 1,3-diols was then developed, which could produce the desired benzyl ethers in good to excellent yields. The catalyst could be used in amounts as small as 2 mol% without diminishing yields.

Competition experiments demonstrated the strong selectivity of the 2-aminoethyl diphenylborinate-catalyzed systems for certain substrates. The catalyst was completely selective for 1,2-diols over both 1,3-diols and primary alcohols. Some selectivity was also experienced for 1,3-diols over primary alcohols. In a diol system, it was always the least substituted diol that became functionalized. In 1,3-diol systems, the catalyst was selective for syn- over anti-1,3- diols.

Although versatile, the 2-aminoethyl diphenylborinate catalysis method could not be applied to either thiocarbonyl or epoxide electrophiles using the tested conditions. More investigation into the systems and further optimization using different additives is required if the borinic acid catalyzed system is to be applied to either of these electrophiles.

Appendix A NMR Spectra

100

101

102

103

104

105