Selective Oxidative Glycosylation of Anomeric Stannanes

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STUDIES IN CARBOHYDRATE SYNTHESIS:

SELECTIVE OXIDATIVE GLYCOSYLATION OF ANOMERIC STANNANES,

SYNTHESIS OF RARE SUGARS FROM THE HEAD-TO-TAIL SWAPPING STRATEGY

TIANYI YANG

B.S., Sun Yat-sen University, 2012

M.S., University of Pittsburgh, 2013

A thesis submitted to the

Faculty of the Graduate School of the

University of Colorado in partial fulfillment

of the requirement for the degree of

Doctor of Philosophy

Department of Chemistry

2019

The enclosed thesis:

Studies in Carbohydrate Synthesis: Selective Oxidative Glycosylation of Anomeric Stannanes,

Synthesis of Rare Sugars from Head-to-Tail Swapping Strategy

written by Tianyi Yang

has been approved for the Department of Chemistry by

______Maciej A. Walczak

______David M. Walba

Date: ______

The final copy of this thesis has been examined by the signatories, and we find that both the

content and the form meet acceptable presentation standards of scholarly work in the above-

mentioned discipline

Yang, Tianyi (Ph.D., Chemistry) Studies in Carbohydrate Synthesis: Selective Oxidative Glycosylation of Anomeric Stannanes, Synthesis of Rare Sugars from Head-to-Tail Swapping Strategy Dissertation directed by Professor Maciej A. Walczak

Carbohydrates, one of the most important biomolecules that participate in a myriad of processes in the living organisms, have gained an increasing amount of focus in recent years. Yet, the research of carbohydrates is massively restrained by the accessibility of these complicated molecules. While the enzymatic/biochemical synthesis of carbohydrates is slowly evolving, the chemical synthesis remains the most efficient and universal method in preparing carbohydrates and glycoconjugates. Chapter 1 provides a general background of carbohydrate synthesis and outlines the current synthetic strategies of stereoselective glycosylation. Traditional glycosylations rely heavily on the substrate or reagent to achieve the stereochemical control, leading to a limited scope of applicability. Our solution to this old problem, however, concentrates on the anomeric nucleophiles – glycosyl stannanes, which enables a completely distinct mechanistic pathway and allows for exclusive stereochemical control with less dependence on the substrate structures and a broader scope of applications.

This dissertation encompasses three independent projects in the field of methodology development in carbohydrate synthesis based on glycosyl stannanes. The first project (Chapter 2) collects the reactions to prepare the stannanes at the anomeric position of common pyranoses, and reports studies in the optimization, derivatization and exploration of the existing methods to build a library of the readily available nucleophilic glycosyl donors. Major mechanistic pathways include the nucleophile/electrophilic displacement, epoxide opening and the carbene insertion. Upon the formation of the anomeric stannanes, the compatibility of different protecting groups and substituents is studied as well as various protecting/deprotecting conditions. We also discovered a general correlation in the 119Sn-13C coupling constants with the configuration of the anomeric stannanes, allowing for a rapid assignment of anomeric configuration of the complex saccharides.

Building on the successful establishment of the stannane synthesis, the second project (Chapter 3) summarizes our efforts in the discovery and development of highly stereoselective

iii oxidative glycosylation using hypervalent iodine reagents as the oxidants. This method couples a C2-OH stannane as the glycosyl donor with a carboxylate or an alcohol as the glycosyl acceptor, which results in an exclusive 1,2-trans selectivity with moderate to high yields. Unlike most of the established glycosylation methods, this reaction works at room temperature and allows the use of a glycosyl donor bearing free hydroxyl group without sacrificing the yield or selectivity. These features present a great advantage in orthogonal/sequential glycosylation and automated saccharide synthesis.

Having the different substitution patterns of anomeric stannanes also allowed us to investigate more advanced applications. The third project (Chapter 4) reports the synthesis of L- hexoses and rare D-hexoses from an unprecedented stereoretentive head(C1)-to-tail(C5) swapping strategy. The method is comprised of two key steps: the homologation of the C1 position and the oxidative cleavage of C5-C6. The homologation of the C1 position is achieved by a stereoretentive C-acyl glycosylation with the anomeric stannanes, adding a one-carbon unit that can be readily converted to hydroxymethyl (aldose), methyl (6-deoxyaldose) or ester (uronic acid) in a later stage. On the other hand, the C6 position is deprotected to reveal the free alcohol, which is converted to acyl azide to trigger the Curtius rearrangement resulting in the cleavage of C5-C6 and a new anomeric isocyanate. The isocyanate is subsequently hydrolyzed under acidic condition to provide the anomeric alcohol, concluding the reaction sequence. In contrast to the reported methods, our method takes advantage of the stereochemistry of C1 position and directly translate it to the new C5 position with high fidelity, paving a path to a great number of rare sugars and benefiting the research such as glycoprotein crystallography and natural product synthesis.

Taken together, the development of the efficient synthesis around the anomeric stannanes greatly enriched the chemical glycosylation repertoire and pioneered the stereoselective glycosylation with anomeric nucleophiles, representing a milestone in synthetic carbohydrate chemistry.

I dedicate this work to my family and friends. Thank you for always reminding me the world is a good place and worth fighting for.

Acknowledgements

Maciej Walczak, I cannot express the gratitude I owe you for the opportunities you enabled in my life!

People said I was brave to join your lab, but I think you were brave to accept a novice like me in your lab.

Your support especially in the last year of my journey here was of great importance to me. I have been lucky to be given a ticket to working in your lab as your enthusiasm for science is extremely inspiring and

I hope one day I can convey my love for science as you do.

Feng Zhu, thank you for always being helpful and available. Your presence in the lab changed the trajectory of my career in graduate school, so thank you for all you do.

Richard Shoemaker, I cannot say enough. Besides teaching me how to handle the complicated NMR experiments, you were always extremely helpful and willing to listen to my problems in detail. Thank you for your patience and kindness.

Walczak lab members and veterans, thank you for all the support you had to offer, especially when the experiments don’t work out. I found this is necessary for the growth of any researcher in an organic chemistry lab. Thank you for all the times you helped me, whether it came to new instruments or new reactions, helping with my teaching responsibilities, or even just turning off the heating plate for me – each sacrifice is truly appreciated.

I would like to gratefully acknowledge the National Institute of Health (NIH) and the National Science

Foundation (NSF) for funding under the following grants for the duration of my doctoral work: NIH

(OD/NIGMS, GM125284) and NSF (CAREER Award No. 1753225)

Chapter 1 ...... 1 Introduction: Carbohydrates and Glycosylation ...... 1 1.1 Carbohydrates – From Yesterday to Today...... 1 1.1.1 Glucose - the most common monosaccharide ...... 2 1.1.2 Defined Stereochemistry in Acetal Form ...... 2 1.2 Glycosylation Methods...... 5 1.2.1 Anomeric Effect vs Steric Effect ...... 5 1.2.2 Traditional Mechanistic Pathway for Glycosylation ...... 6 1.2.3 Stereoselective Glycosylation – Strategy and Examples ...... 8 Chapter 2 ...... 11 Synthesis and Characterization of Glycosyl Stannanes ...... 11 2.1.1 Nucleophilic replacement of anomeric leaving groups ...... 12 2.1.2 Electrophilic replacement with anomeric nucleophiles ...... 20 2.1.3 Carbene insertion ...... 28 2.2 Characterization of glycosyl tributylstannanes ...... 29 2.3 Functional Group Compatibility in Glycosyl Stannanes ...... 31 2.3.1 On the C2 position ...... 31 2.3.2 On the C6 position ...... 31 2.3.3 Preparation of the fully deprotected stannane ...... 33 Chapter 3 ...... 37 Oxidative Glycosylation of Anomeric Stannanes with Hypervalent Iodine Reagents ...... 37 3.1 Oxidative glycosylation with carboxylic acid nucleophiles ...... 37 3.2 Oxidative glycosylation with alcohol nucleophiles ...... 45 3.3 Mechanistic studies ...... 55 3.4 Attempts of Oxidative Glycosylation with retention of stereochemistry ...... 66 3.4.1 Summary of the current result ...... 66

3.4.2 Zn(OTf)2 catalyzed oxidative glycosylation ...... 67 3.4.3 Cu/Pd catalyzed oxidative glycosylation ...... 68 3.4.4 Cu(II) mediated oxidative glycosylation ...... 71 Chapter 4 ...... 80 Stereoselective Homologation of Anomeric Position Using Glycosyl Stannanes ...... 80 4.2 Stereoselective homologation with anomeric stannanes ...... 83 4.2.1 From the stereoselective acylation to homologation ...... 84 4.2.2 Development of the method ...... 86 4.2.3 Application to mono/disaccharide stannanes ...... 88

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4.3 Practical application of the stereoselective homologation ...... 90 4.3.1 Hydrolysis of the homologated product ...... 90 4.3.2 Synthesis of rare sugars from the head-to-tail swapping strategy ...... 91 4.3.3 Synthesis of nonoses from the sialic acid family ...... 99 Chapter 5 ...... 102 Conclusions ...... 102 Chapter 6 ...... 104 Experimentals ...... 104 References ...... 157

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Figures Figure 1.1 ...... 1 Figure 1.2 ...... 2 Figure 1.3 ...... 3 Figure 1.4 ...... 4 Figure 1.5 ...... 5 Figure 1.6...... 5 Figure 1.7 ...... 6 Figure 1.8 ...... 7 Figure 1.9 ...... 9 Figure 2.1 ...... 12 Figure 2.2 ...... 13 Figure 2.3 ...... 14 Figure 2.4 ...... 15 Figure 2.5 ...... 16 Figure 2.6 ...... 16 Figure 2.7 ...... 18 Figure 2.8 ...... 19 Figure 2.9 ...... 19 Figure 2.10 ...... 20 Figure 2.11 ...... 20 Figure 2.12 ...... 21 Figure 2.13 ...... 21 Figure 2.14 ...... 22 Figure 2.15 ...... 23 Figure 2.16 ...... 23 Figure 2.17 ...... 24 Figure 2.18 ...... 24 Figure 2.19 ...... 25 Figure 2.20 ...... 25 Figure 2.21 ...... 26 Figure 2.22 ...... 28 Figure 2.23 ...... 31 Figure 2.24 ...... 31

Figure 2.25 ...... 32 Figure 2.26 ...... 32 Figure 2.27 ...... 32 Figure 2.28 ...... 33 Figure 2.29 ...... 36 Figure 3.1 ...... 39 Figure 3.2 ...... 41 Figure 3.3 ...... 41 Figure 3.4 ...... 42 Figure 3.5 ...... 42 Figure 3.6 ...... 44 Figure 3.7 ...... 44 Figure 3.8 ...... 45 Figure 3.9 ...... 46 Figure 3.10 ...... 47 Figure 3.11 ...... 49 Figure 3.12 ...... 50 Figure 3.13 ...... 50 Figure 3.14 ...... 51 Figure 3.15 ...... 53 Figure 3.16 ...... 53 Figure 3.17 ...... 54 Figure 3.18 ...... 54 Figure 3.19 ...... 55 Figure 3.20 ...... 56 Figure 3.21 ...... 56 Figure 3.22 ...... 56 Figure 3.23 ...... 57 Figure 3.24 ...... 58 Figure 3.25 ...... 59 Figure 3.26 ...... 60 Figure 3.27 ...... 61 Figure 3.28 ...... 62 Figure 3.29 ...... 63 Figure 3.30 ...... 64

Figure 3.31 ...... 65 Figure 3.32 ...... 66 Figure 3.33 ...... 67 Figure 3.34 ...... 67 Figure 3.35 ...... 68 Figure 3.36 ...... 68 Figure 3.37 ...... 69 Figure 3.38 ...... 69 Figure 3.39 ...... 71 Figure 3.40 ...... 71 Figure 3.41 ...... 74 Figure 3.42 ...... 75 Figure 4.1 ...... 81 Figure 4.2 ...... 81 Figure 4.3 ...... 81 Figure 4.4 ...... 82 Figure 4.5 ...... 82 Figure 4.6 ...... 82 Figure 4.7 ...... 83 Figure 4.8 ...... 83 Figure 4.9 ...... 84 Figure 4.10 ...... 85 Figure 4.11 ...... 88 Figure 4.12 ...... 89 Figure 4.13 ...... 90 Figure 4.14 ...... 91 Figure 4.15 ...... 92 Figure 4.16 ...... 92 Figure 4.17 ...... 93 Figure 4.18 ...... 93 Figure 4.19 ...... 95 Figure 4.20 ...... 95 Figure 4.21 ...... 96 Figure 4.22 ...... 96 Figure 4.23 ...... 97

Figure 4.24 ...... 97 Figure 4.25 ...... 98 Figure 4.26 ...... 98 Figure 4.27 ...... 99 Figure 4.28 ...... 100 Figure 4.29 ...... 101

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Chapter 1

Introduction: Carbohydrates and Glycosylation

1.1 Carbohydrates – From Yesterday to Today

Carbohydrates are arguably the first type of bioorganic molecules chemists interacted with.

Well known as the energy source of living organisms (starch, glycogen and glucose) or the structural motif of cells (cellulose and D-ribose), carbohydrates for a long time were regarded as an important yet bland type of molecules. Unlike the other two types of biomolecules – proteins and nucleic acids, only recently have people sped up the research on carbohydrates.

Many more roles of carbohydrates have been identified especially at cell recognition.1 The complicated construction of polysaccharides made them a great carrier of biological information.

Only do they convey the physiological state of the cell, they also present the information to other cells, communicate and regulate them with exquisite precision.2

Figure 1.1. Carbohydrates in cell recognition

While cracking the “sugar code” can be exciting in many ways, the accurate assembly of monosaccharides to the linear or branched oligo and polysaccharides is acknowledged as one of the most challenging topics owing to the complexity of these molecules.3 For example, glucose, the most common monosaccharide, has 32 stereoisomers in its pyranose form. In every single stereoisomer, there are five hydroxy groups that can be potentially connected to other molecules, never mind the more complex poly saccharides.

Nevertheless, no matter how complex a carbohydrate molecule may look, the connectivity is still closely related to the reactivity. Thus, we shall start from a simple but important example

– D-glucose, to review the general reactivity in carbohydrate chemistry.

1.1.1 Glucose - the most common monosaccharide

In solution, glucose usually exists in its cyclic hemiacetal form with nearly all the groups on equatorial position on a saturated six-membered pyran ring. Only the configuration of one position (C1) is not defined because it is in equilibrium with the acyclic hydroxyaldehyde form:

Figure 1.2. Equilibrium of glucose in aqueous solution. The cyclic hemiacetal form (1-2ab) is preferred

Also because of the equilibrium, other ring sizes can be made but generally not as stable as the pyranose configuration.

1.1.2 Defined Stereochemistry in Acetal Form

Equilibrium with the acyclic form is absent when the hemiacetal is converted to acetal.

The bond formed in this process is glycosidic, and the process of forming a glycosidic bond is called glycosylation.

Figure 1.3. Glycosylation usually results in a mixture of anomers.

Glycosylation gives rise to two new stereoisomers with the C1 substituent on either the equatorial position or the axial position. An α-glycosidic bond is formed when C1 and C5 have the same stereochemistry, whereas a -glycosidic bond occurs when they have different stereochemistry. In common monosaccharides such as D-glucose, D-mannose, D-galactose and their derivatives, the two stereoisomers can also be named based on the spatial relationship to the

C5 substituent. If the C1 substituent is cis to the C5 substituent, the configuration is “”.

Otherwise if it is trans to the C5 substituent, the configuration is “α”.

On the other hand, the acetal product from the glycosylation is a polysaccharide/oligosaccharide when the R group is part of another carbohydrate chain, or a glycoside when the R group is from a non-sugar molecule. Furthermore, as long as the equilibration between the cyclic and acyclic forms is no longer available, the C1 substituent can be more than just an “OR” group in acetal. For example, N, S or C atoms can all be used to connect a saccharide and a non-sugar molecule at the C1 position, and eliminate the equilibration to the acyclic form, resulting in N-, S- or C-glycoside. These glycosides widely exist in nature and human body. Some examples are shown in Figure 1.4:

Figure 1.4. Some examples of natural and pharmaceutical glycosides4-9

Joining a molecule with a saccharide always yield two possible anomers, and unfortunately, the two products might behave very differently. For example, cellulose and starch are both polysaccharides of only D-glucose, but the D-glucose is connected by -glycosidic bonds in cellulose and by α-glycosidic bonds in starch.10 The physical and chemical properties are very distinct from each other, and humans do not have the appropriate enzymes to breakdown the - glycosidic bonds and hence cannot digest cellulose.

1.2 Glycosylation Methods

Controlling the stereochemistry or the α/ selectivity in glycosylation reactions has been one of the oldest and most challenging problems in synthetic carbohydrate chemistry. As shown in Figure 1.2, D-glucose in water (pH 7) consists of approximately a third of -glucose and two thirds of α-glucose.

When treated with acid in methanol, D-glucose is converted to the methyl glycoside with an exclusive α-configuration, which indicates a certain amount of intrinsic selectivity in these reactions. To understand the selectivity in the glycosylation process, a pair of effects that usually lead to opposite results need to be discussed – the anomeric effect and the steric effect.

Figure 1.5. Acid catalyzed glycosylation to form the methyl α-glycoside.

1.2.1 Anomeric Effect vs Steric Effect

The anomeric effect refers to the bonding interaction between the axial lone pair of pyranose oxygen and the *(C-X) of the C1 substituent.11 The bonding interaction that stabilizes the glycoside only exists when the C1 substituent is on the axial position. The anomeric position is a synonym for the C1 position:

Figure 1.6. Bonding interaction between the axial lone pair and the *(C-O) stabilizes the α-anomer.

Stirring the glucose in acidic methanol results in the formation of methyl glucoside. And the α-glucoside is formed exclusively. Since the acetal formation is under thermodynamic control, the α-glycoside is the thermodynamic product.12

Under the same condition, however, the -glycoside starts to form when the steric bulk of the alcohol increases. This is a consequence of the steric effect, which destabilizes the axial substituent due to the van der Waals repulsion. When a bulky group is attached to the anomeric position, the destabilizing steric effect increases significantly while the stabilizing anomeric effect remains roughly the same, resulting in the formation of more -glycoside. Therefore, the interplay between the anomeric effect and the steric effect determines the relative stability of the two anomers, which is highly dependent on the stereoelectronics of the specific R group.

1.2.2 Traditional Mechanistic Pathway for Glycosylation

Acid-catalyzed acetal formation is one of the most commonly used glycosylation methods.

In this reaction, the anomeric hydroxy group is first protonated in the acidic condition and becomes a good leaving group (1-7). A resonance-stabilized carbocation forms upon the departure of the leaving group, known as the oxocarbenium (1-8). The nucleophile (in this case it is an alcohol) attacks from either face of the planar oxocarbenium, leading to the formation of either

α- or -glycosides (1-9ab).

Figure 1.7. General mechanism of acid-catalyzed glycosylation.

The oxygen atom on the anomeric position can still get protonated, become a good leaving group (1-10ab), and dissociate from the glycoside to form oxocarbenium (1-8) again. The process repeats until the reaction is quenched, supposedly after the equilibrium is reached. Since the two anomers are interconverting in the reaction, the more stable product is formed in larger quantities, as in the case of methyl glycoside of glucose. This is a typical SN1 mechanism, where the thermodynamic product is formed preferably.

Figure 1.8. General mechanism of acid-catalyzed equilibration between the two anomers

Similar to how Brønsted acids activate the hydroxyl group, Lewis acids also activate leaving group to depart the anomeric position to form the oxocarbenium.13 The Lewis acid is usually selected based on the nature of the leaving group.

This mechanism, however, also raises two concerns. First, even though the more stable, thermodynamic product is formed, it is not necessarily the only product. In other words, the reaction always gives a mixture of both anomers in different amounts. If the equilibrium between the two anomers favors one side significantly, the reaction would give one major product. But if the two anomers are similar in energy, or the time needed for equilibration is too long, a good amount of both anomers will be present, making it hard to separate the anticipated product.

Second, the stability of the anomers are very substrate dependent. Hence, when the substrates are changed, the same method will potentially lead to very different outcomes. Moreover, the equilibrium is also dependent on the solvent, temperature and concentration of substrates, which further complicates the reaction.14

An alternative to the SN1 pathway is the stereospecific SN2 pathway. In a typical SN2-type glycosylation, a good leaving group is also installed at the anomeric position (e.g., halide, sulfonium, sulfonate), after which a nucleophile attacks from the back side and inverts the stereochemistry of the anomeric position. The glycoside formed thus has the opposite stereochemistry from the starting material.

Whether it is a reliable surrogate of SN1 glycosylation depends on a few factors. A good leaving group is needed because it must be replaced in the glycosylation. However, if it leaves before the nucleophile attacks, an oxocarbenium will arise and trigger the SN1 pathway. This happens when the nucleophile is not strong enough, or simply the leaving group is just too good.

Crich et al investigated the two mechanisms extensively and concluded that almost all the glycosylation methods thus far fall in somewhere between the two classical mechanisms.14 Other than the substrates, the pathway is also determined by the solvent, temperature, activating reagents, additives and so on. Therefore, it is of great importance and interest to find a glycosylation method that is less dependent on the factors mentioned above.

1.2.3 Stereoselective Glycosylation – Strategy and Examples

Of the commonly employed strategies for stereoselective O-glycosylation, the most widely applied methods capitalize on reactions of glycosyl donors in which the C2 position is capped with a carbonyl-based participating group.15-18 For example, activation of 2-O-acyl thioglycoside with an oxidant and triflate salt leads to the formation of the dioxolenium ion intermediate (1-12) which is quenched with an alcohol to provide glycoside (1-13) in high 1,2- trans selectivity.19

Figure 1.9. Two typical methods of stereoselective glycosylation: C2-neighboring group participation

and ring opening of glycal epoxide.

Other approaches based on a locked bicyclic conformation utilize acetal, carbonate, or carbamate groups introduced into the pyranose scaffold to amplify the differences of the energy barriers between two transition states.20-22 Ring opening reactions of glycal epoxides (1-14) in the presence of Lewis acid catalysts or bases provided a more direct solution to 1,2-trans configured glycosides (1-16).23 Primary alcohols and sterically unhindered secondary alcohols found the most success with this method,24 while some demanding glycosyl acceptors depend more on the pre-activation of hydroxyl group (e.g., as a stannyl ether) and the compatible Lewis acid to achieve good yield and stereoselectivity.25

Although these methods generate glycosides in a more selective way, the dependence is shifted more to the neighboring group and the electrophile scaffold. The mechanism itself has not changed, which still requires an electrophilic glycosyl donor (a leaving group on the anomeric position) to react with a nucleophilic glycosyl acceptor (alcohol or alkoxide) via an SN1 or SN2 pathway.

From the summary of current mainstream glycosylation reactions, it is clear that in order to overcome the dependence of substrates and develop a conceptually new glycosylation method,

9 a new mechanism can be engaged. The use of a configurationally stable anomeric nucleophile potentially solves the problem in stereochemical control in the glycosylation process. However, studies on anomeric nucleophiles are scarce compared to the research on anomeric electrophiles.

This thesis focuses on glycosyl stannanes as anomeric nucleophiles in glycosylation reactions.

Chapter 2

Synthesis and Characterization of Glycosyl Stannanes

Most topics in this dissertation involve the reactions with glycosyl stannanes. Glycosyl stannanes were selected as the focus of our research for several reasons. First, as anomeric nucleophiles, both α- and -stannanes are configurationally stable unlike other organometallic species that are only transient intermediates or require very low temperature to be stable.

Additionally, the synthesis of organostannanes was feasible and precedented in a few reports mostly as the stable precursor of the corresponding reactive organolithium species. Moreover, organostannanes are generally well-known substrates in many reactions such as the Stille coupling, electrophilic substitutions and radical reactions.

In this chapter, a broader spectrum of glycosyl stannane chemistry is described regarding the saccharide sources and the corresponding methods of preparation, the substitution groups on the carbohydrates, and the characterization of glycosyl stannanes. The stability and reactivity of the stannanes are discussed at the end of the chapter.

2.1 Preparation and Characterization of Glycosyl Stannanes

Three major pathways to install an organotin group on the anomeric position of a pyranose have been recognized. First, like the glycosylation reactions described earlier, a tributyltin-based nucleophile can replace a good leaving group on the anomeric position.26 Second, the anomeric position can serve as nucleophiles and replace a good leaving group on an electrophilic tributyltin

11 species, the most common being tributyltin chloride. Third, a non-polar concerted mechanism using an anomeric carbene to insert into the Sn-H bond also results in a glycosyl stannane.27 The three methods complement each other and provide the synthesis of a full scope of pyranosyl stannanes. In this section, we describe these common mechanisms and the design of these syntheses leading to the glycosyl stannanes.

Figure 2.1. Three mechanistic pathways to the anomeric stannanes

2.1.1 Nucleophilic replacement of anomeric leaving groups

Similar to the glycosylation reactions, it is preferred for the nucleophilic replacement of the anomeric group to be stereoselective, which means that one specific anomer is generated in this reaction with no or very small amounts of the epimer formed. The stereoselectivity usually comes from an SN2 process which reliably inverts the stereochemistry of the anomeric electrophile in the reaction. Due to the anomeric effect, the leaving groups on the anomeric position usually adopt the α-configuration. Hence the nucleophilic replacement is commonly used to generate the -stannanes. If a -configured leaving group is available, the corresponding α- stannane can be prepared in this fashion.

2.1.1.1 The Electrophiles

One of the most common electrophiles that results in a stereospecific, 1,2-trans outcome is the glycal epoxide. Glycosylation reactions with epoxide donors are well precedented.

Gin et al reported the stereoselective ring-opening glycosylation with in situ generated glucose/mannose epoxides.23,28 Yu et al. reported that ring-opening catalyzed by gold complex and good selectivity was observed with small alcohol nucleophiles.24

Figure 2.2. Glycal epoxides used in stereoselective glycosylation reactions.

Since the glycal epoxide decomposes readily on silica gel, it can be prepared either in situ or in high purity to avoid chromatography on silica. The method reported by Gin inevitably produces sulfide/thiophene in the reaction. However, with DMDO/acetone, the byproduct is only acetone which can be removed easily under vacuum.

In this reaction, DMDO is formed by oxidizing acetone with Oxone in a biphasic system that efficiently protects the substrate from over oxidation/decomposition. Saturated NaHCO3 (aq) is used to buffer the aqueous layer since bisulfate is produced during the oxidation which

13 increases the acidity of the solution. Without it, excess acid in the system decomposes the epoxide formed. When the protecting groups on glucal are all benzyl groups, the oxidation gives the α- epoxide as the major product in almost quantitative yield. The epoxide formed decomposes on silica gel but can be reliably characterized by NMR (in CDCl3).

Figure 2.3. Mechanistic details of glycal epoxidation: formation of DMDO and recovery of acetone.

The epoxide of mannose, however, cannot be directly made by epoxidation of glucal with

DMDO as the top face is blocked by the bulky benzyl groups. Recently Toshima and co-workers reported the decomposition of the mannose orthoacetate followed by elimination of TMSCl to give the mannose epoxide in moderate yield.29 The benefits of this method over Gin’s protocol are that the organic by-products are easy to remove, and the product epoxide can be recrystallized:

Figure 2.4. Toshima’s method of preparing mannose 1,2-epoxide (2-15).

Glycosyl halides, especially the glycosyl chlorides, are another electrophile stable enough to be separated and stored, and in some cases even purified on silica gel. The glycosyl halides adopt a stable α-configuration by virtue of anomeric effect. Hence, this configuration offers a great advantage in SN2 reactions since it provides the -stannane as the major product.

Two methods can be used to prepare the anomeric chloride. The first method uses the

30 anomeric alcohol with a chlorinating reagent such as SOCl2 or (COCl)2. The workup of the reaction is usually vacuum distillation to get rid of the solvents and chlorinating reagent. Even though SOCl2 and (COCl)2 have relatively low boiling points and can be removed in vacuo, it is usually necessary to use chloroform to dissolve the residue and rotovap again few times to ensure the residual chlorinating reagents will not consume the nucleophile in the following step. The resulting α-chloride is moisture sensitive and should be stored at low temperature free from any solvents.

Figure 2.5. Chlorination of the anomeric position using SOCl2.

The second method uses HCl as the chlorinating reagent in the presence of the C2-OH group. The specifics will be discussed in more detail in the next section.

2.1.1.2 The Nucleophiles

Tributyltin lithium is the most commonly used nucleophile. Traditionally, the tributyltin lithium is made fresh via reductive lithiation by treating the commercially available tributyltin chloride with finely cut lithium metal. The process can be accelerated by the addition of naphthalene as an electron transfer catalyst. In this case, lithium naphthalenide is formed first, giving a dark green solution in THF. The color fades upon addition of tributyltin chloride and reappears when the tributyltin chloride is fully consumed.

Figure 2.6. Preparation of Bu3SnLi with naphthalene as the catalyst.

It is worth noting that, the lithium rods taken directly from the commercial sources always have a layer of oxide on the surface. Depending on the batch and age of the bottle, the thickness of the oxide layer can vary. It is therefore advised that any oxide layer be removed before further

16 cutting and subjection to the reactions. The molecular weights of lithium and lithium oxide are quite different, and it was observed that the excess lithium oxide/nitride/hydroxide impurities generally lower the yield of the reaction with the tributyltin lithium.

One typical sign of the oxide layer hindering the reaction is the prolonged activation time.

When the lithium is high quality (with metallic luster) and is mixed with naphthalene in THF, the dark green color is fully generated within one minute under stirring. If the oxide layer is not removed, it takes significantly longer for the dark green color to appear. The reaction turns to the expected dark green color when any oxygen/moist is fully consumed, so the onset time can be used as a crude estimate of the tributyltin lithium reagent’s quality.

Other factors that also result in a prolonged activation time include using inadequately dried and deoxygenated solvent, and not setting up the reaction under an inert atmosphere. All these problems mentioned above lowers the quality of the lithium naphthalenide and subsequently, the tributyltin lithium. The look of the tributyltin lithium solution in THF is a turbid, dark brown as a mixed color of yellowish green and dark green while LiCl is insoluble in the mixture.

Depending on the level of impurity, the reaction can have green, yellow or orange color.

Ultimately, to ensure the quality of the tributyltin lithium reagent, the highest quality of lithium metal free from oxide layers should be used with adequately solvent, and the reaction should be set up strictly under an inert atmosphere.

An alternative method to prepare the tributyltin lithium takes advantage of the rapid proton exchange reaction between tributyltin hydride and a bulky base such as LDA. This reaction is finished within 15 minutes at low temperature (-78 ℃) and furnishes the reagent extremely high yield.

However, this approach generates the bulky conjugate acid, iPr2NH. This is still a potential proton source that could interfere with the further manipulations. As such, one might desire to lower the basicity and increase the nucleophilicity of the tributyltin lithium reagent, so a transmetallation step can be added to convert the tributyltin lithium into tributyltin Grignard reagent by treating with MeMgBr solution. However, the tributyltin Grignard reagent is not compatible with any proton source (including iPr2NH), therefore the tributyltin lithium reagent can only be made through reductive lithiation.

2.1.1.3 Preparation of glucosyl/galactosyl--stannanes and mannosyl-α-stannane

The ring-opening reaction of glycal epoxide is stereospecific and results only in the 1,2- trans configuration in the product. For this transformation, the tributyltin Grignard reagent was selected as the nucleophile, as the reagent has an advantage in the ring-opening of glycal epoxide where the Mg(II) coordinates with the epoxide oxygen and activates it, making the ring-opening a more facile process.

This method was applied to glucose epoxide (2-8) and galactose (2-24), where the corresponding α-epoxides were made in great yield and selectivity.31 The -stannane products bear C2-OH groups, which were further protected with benzyl group if needed32,33:

Figure 2.7. Preparation of -stannanes via epoxide opening.

This reaction worked equally well with the mannose epoxide, where the -epoxide (2-10) was opened to generate the α-stannane (2-27).

Figure 2.8. Preparation of α-stannanes via epoxide opening.

2.1.1.4 Preparation of C2-deoxy/acetamido -stannanes

A characteristic feature of the epoxide-opening reaction to prepare the glycosyl stannanes is the resulting hydroxyl group on C2 position. Consequently, if C2-OH group is not a desirable feature in the product, it is not suitable to use epoxide opening to prepare the stannane. In such cases, the anomeric chlorides can be used as substrates.

However, it was observed that the α-chloride undergoes a competing E2 reaction pathway that gives the olefin product (2-30) instead of the anomeric stannanes (2-31). In glucose and galactose, the problem is more pronounced due to the perfect alignment of C2-H and C1-Cl in the antiperiplanar fashion. Additionally, the C2-alkoxy group increases the acidity of the C2-H, making it more susceptible to reaction with bases. Therefore, in the cases mentioned above an epoxide would be preferred to glycosyl halide.

Figure 2.9. The competing mechanisms in the nucleophilic replacement of anomeric chloride.

The difficulties are avoided, however, when the C2 position lacks a substituent. When this is the case, the glycosyl halide is an advantageous electrophile. The α-chloride derived from the

C2-deoxy anomeric alcohol is attacked by tributyltin lithium to give the -stannanes (2-32) in good yield. The competing E2 reaction is less pronounced due to the reduced acidity of C2 protons when an OH or OR group is absent on C2 position. When the reaction is run on large scale, the glucal generated from the E2 pathway can also be recycled to the α-chloride (2-21) easily.

Figure 2.10. Preparation of C2-deoxy -stannanes via nucleophilic replacement of chloride.

Effects of other substituents on C2 requires additional consideration. In N- acetylglucosamine (GlcNAc), the C2 position bears the acidic amide group, which consumes the tributyltin lithium. Therefore, excess tributyltin lithium (3 equivalents) is used in this reaction and gives the -stannane (2-33) in good yield. However, one of the major observed side-products is the oxazoline (2-34) formed from the acetamido group attacking C1, possibly through an SN1 mechanism.34

Figure 2.11. Preparation of C2-acetamido -stannanes via nucleophilic replacement of chloride.

2.1.2 Electrophilic replacement with anomeric nucleophiles

2.1.2.1 The Anomeric Nucleophiles

Assuming an anomeric carbanion attacks tributyltin chloride to produce the corresponding anomeric stannane, this carbanion species must be made first. When the C2 position is protected with ether or ester functional group (2-35), the whole group readily falls off as an alkoxide or a carboxylate when C1 is anionic.

Figure 2.12. C2-OR (R = alkyl) metallic reagents readily eliminates to form a glycal.

This leaves only a few choices for the C2 substituents. First, the C2-deoxy sugar where no substituent/leaving group is present on the C2 position (2-37). Second, any OH or NH group on C2 position can be deprotonated to form the anion prior to the electrophilic replacement, as these cannot be eliminated under such conditions.

Figure 2.13. Anomeric metal reagents (Li, MgX) that are stable at low temperatures.

Aside from considering the substituents at the C2 position, these anomeric nucleophiles are made primarily through the reductive lithiation. Because the anomeric α-halide (2-21) undergoes rapid elimination fast (the undesired side reaction to 2-41 and 2-7), the rate of reductive lithiation must be superior to the elimination to avoid self-consumption of starting materials. This

21 prohibits the direct use of lithium metal, since the reaction only proceeds on the surface of the metal and is thus too slow to outcompete the elimination pathway. Instead, lithium naphthalenide, as mentioned earlier, is used in this case in stoichiometric amounts.

Figure 2.14. Side reactions in the formation of anomeric lithium reagents.

The concentration of lithium naphthalenide is critical to the success of the reaction.

Insufficient amounts of lithium naphthalenide leave space for self-consumption shown above, while excess lithium naphthalenide competes with the anomeric nucleophile to react with the electrophile, tributyltin chloride in the subsequent step. Therefore, it is worthwhile to determine the exact concentration of the lithium naphthalenide by titration before the addition to the anomeric chloride.

However, as discussed before, the quality of the lithium naphthalenide is affected by several factors including the quality of the lithium metal, the quality of the solvent and human operations. It was also observed that the solvent evaporates overnight under a N2 atmosphere, consequently changing the volume and concentration of the solution. Hence, a titration of the lithium naphthalenide before use can minimize the difference between batches of the reagents.

The titration protocol is adapted from the work of Secrettas et al.35 A solution of 1,1’- diphenylethylene reacts with lithium naphthalenide to produce a dianion with a bloody red color,

22 which is quenched by a solution of isopropanol in toluene that turns the color back to yellow. The concentration of lithium naphthalenide is determined by the amount of isopropanol solution used.

Figure 2.15. Reactions used in the titration of lithium naphthalenide solution.

It is worth noting that the anomeric anion produced from the reductive lithiation does not have a stable configuration at room temperature. At –78 ℃, the equilibrium between the two anionic anomers is very slow. Therefore, in theory the reaction can be run at –78 ℃. However, in practice, it is preferred to set up the reaction at -100 ℃ to prevent the temperature from rising too much upon addition of the materials.36

2.1.2.2 Preparation of the C2-deoxy α-stannane

The anomeric chloride, prepared as described earlier, undergoes reductive lithiation at -

100 ℃. The lithiation process was allowed to proceed for 15 minutes, before addition of tributyltin chloride. The reaction was then slowly warmed up to room temperature to allow full conversion to the α-stannane product.

Figure 2.16. Preparation of C2-deoxy α-stannanes from the anomeric lithium reagent.

2.1.2.3 Preparation of the C2-hydroxy/acetamido α-stannane

Generating the anomeric chloride of glucose and galactose requires preservation of the

C2-OH group. This was first achieved by treating the 1,2-diol with HCl in anhydrous ether. HCl gas was bubbled slowly into ether, and the speed of bubbling increased significantly when the solution became saturated with HCl. However, this reaction takes hours to days depending on the structure and the concentration of HCl. Subsequently, saturated HCl solution in diethyl ether was replaced by commercially available 4 M HCl solution in dioxane.

Figure 2.17. Preparation of the α-chloride from the glucose 1,2-diol (2-46).

It was also found that the glycal epoxide undergoes ring opening upon treatment with HCl

(4 M in dioxane) to produce the α-chloride. This approach is more advantageous compared to reacting with the diol since it is significantly faster, and the use of the 1,2-diol requires significantly more purification (chromatography) and the use of a very toxic reagent, OsO4.

Figure 2.18. Preparation of the α-chloride from the glucal epoxide (2-8).

Preparation of the α-stannane from the α-chloride with C2-substituent is straightforward.

The anomeric chloride is first treated by n-BuLi to deprotonate the C2-OH, followed by reductive lithiation with lithium naphthalenide. The rest of the procedure is the same as the C2-deoxy

24 stannane. This method also applies to the glucosamine-derived stannane where a C2-NHAc was present.

Figure 2.19. Preparation of the C2-OH and C2-NHAc α-stannanes.

The C2-OH group can be further alkylated once the stannane is installed.

2.1.2.4 The intramolecular delivery of tributyltin to form α-stannane

The intramolecular delivery of silyl groups has precedent, and this transformation can be achieved in carbohydrate substrates by depositing the silyl group on the C2 position as a temporary silyl ether, followed by generation of the the anomeric carbanion to trigger a retro-

[1,4]-Brook rearrangement.37

Figure 2.20. Retro-[1,4]-Brook reaction produces the anomeric α-silane (2-56).

The trimethylsilyl group was successfully delivered from the C2-O to the C1 position intramolecularly, and it was a suprafacial migration that resulted in the formation of the α-silane

25 product. From this, it was envisioned that the α-stannane can be formed in a similar fashion via a temporary stannyl ether on C2 and lithiation of the anomeric position to trigger the rearrangement.

There are a few advantages over previous methods if this reaction works as planned: 1) the starting material, the anomeric sulfide, is easier to prepare in bulk and is more shelf-stable; 2) the reaction is theoretically faster since it is intramolecular; 3) the potential of intramolecular delivery from C6-OH to result in -stannane; 4) the possibility of doing intramolecular delivery to prepare some substrates which are hard to access such as furanosyl stannanes.

Figure 2.21. Designed stanna-retro-Brook reactions to prepare the anomeric stannanes.

When attempting to reproduce the results from the protocol to make the anomeric silanes, it was observed that the time it took for reductive lithiation to occur on sulfide was significantly longer compared to the corresponding chlorides. Additionally, it was hard to gauge the endpoint of the reaction since the product silane could potentially undergo lithiation itself. Therefore, to enhance the rate of the reaction, the sulfide was oxidized to the sulfone with mCPBA.

Additionally, sodium naphthalenide was used instead of lithium naphthalenide to reduce the sulfone to the anomeric carbanion.

To further optimize the yield of the stannane, more reaction conditions were screened including the base and the time to generate the stannyl ether (Table 2.1, Condition 1), and the

26 amount of alkali metal used to form the anomeric anion (Table 2.1, Condition 2). Unfortunately, the yield of the reaction was not satisfactory.

Table 2.1. Condition screening for stanna-retro-[1,4]-Brook reactions.

Entry Condition 1 Condition 2 Yield

1 KHMDS, then Bu3SnCl, 1 h 2.1 eq NaC10H8 10%

2 KHMDS, then Bu3SnCl, 4 h 2.1 eq NaC10H8 12%

3 Bu3SnCl, then KHMDS, 4 h 2.1 eq NaC10H8 NR

4 Bu3SnCl 3.2 eq NaC10H8 NR

5 KHMDS, then Bu3SnCl, 1 day 2.1 eq NaC10H8 26%

6 KHMDS, then Bu3SnCl, 1 day 2.1 eq LiC10H8 8%

7 KHMDS, then Bu3SnCl, 1 day 3.2 eq NaC10H8 29%

8 KH, then Bu3SnCl, 1 day 2.1 eq NaC10H8 32%

KHMDS was used as the base in the first step in making the stannyl ether, as the use of

BuLi resulted in elimination product only. However, the HMDS generated in this process potentially consumes the sodium naphthalenide in the second step. Hence, potassium hydride (KH) was also tested since the conjugate acid is molecular hydrogen, but the yield is very similar. The main challenge in optimizing this reaction stems from the formation of the stannyl ether. The conversion from alcohol to stannyl ether is hard to quantify since the stannyl ether is very labile compare to alkyl/silyl ethers and cannot be separated. Danishefsky reported refluxing

27 bis(tributyltin)ether with alcohol to generate the stannyl ether in situ, but this method was unsuccessful in our case.

2.1.3 Carbene insertion

Some glycosyl stannanes are hard to prepare through the polar mechanisms. For example, the -mannosyl stannane could not be made from treating the α-chloride with tributyltin lithium potentially because the SN2 process is significantly hampered by the C2-axial substituent.

Lithiation of the α-chloride however, requires the deprotonation of the C2-OH first, which directly results in the formation of mannose epoxide.

Carbene insertion to tributyltin hydride can be used when polar mechanism does not give the anticipated product. While the mechanism does not involve reactive species such as carbanions, the limits on the C2 substituents are less. The carbene is formed in situ from the diazirine precursor made from the simple building blocks in multiple steps:38

Figure 2.22. Preparation of α- and -mannosyl stannanes via carbene insertion.

Despite the advantage of making the stannanes which is hard to obtain from other methods, the carbene insertion sequence bears a few shortcomings: 1) the reaction is not stereoselective, which always generates a mixture of anomers; 2) the yield is only suboptimal, and the reaction

28 was hard to scale up; 3) the preparation of the carbene precursor is more tedious.27 Therefore, this method is used only when the stannane is highly desirable and no other routes are developed to this specific product.

2.2 Characterization of glycosyl tributylstannanes

Glycosyl stannanes can be easily characterized with NMR. In addition, since the two isotopes of tin: 117Sn and 119Sn are both NMR active spin ½ nuclei with the natural abundance of

7.68% and 8.59%, these isotopes couple with 1H and 13C and the patterns show on the corresponding NMR spectra.39 Another isotope 115Sn which is also NMR active only has a natural abundance of 0.34% so it is usually ignored. For example, in the 1H NMR spectrum, the anomeric peak shows from 3 – 4 ppm as a doublet with a coupling constant of 6 – 8 Hz for the -anomers and 2 – 4 Hz for the α-anomers. On both sides of the doublet are the satellite peaks where 117Sn and 119Sn couple and split the proton signal (2J).

In the 13C NMR, the Sn-C coupling is more pronounced since the there are four carbons directly connected to the tin atom so there are one-bond coupling constants (1J). The two satellite peaks corresponding to 117Sn and 119Sn are outstanding for the methylene carbons from the n- butyl group directly connected to the tin because all three butyl groups are equivalent. The numbers can be measured accurately and show a clear trend in both α-stannanes and -stannanes

(Table 2.2). The 117Sn-13C coupling constants in α-stannanes are greater than 305 Hz and the

119Sn-13C coupling constants in α-stannanes are greater than 319 Hz. In comparison, the 117Sn-13C and 119Sn-13C coupling constants in -stannanes are smaller than 305 Hz and 319 Hz, respectively.

This trend in 1J(Sn-C) coupling constant is helpful in the determination the configuration of anomeric stannanes, especially the ones that are not reported before.

Table 2.2. The 1J coupling constants between Sn and C on the n-butyl groups

Saccharide C2 substituent 1J(117Sn-13C)/Hz 1J(119Sn-13C)/Hz α α-Glcp OH 298.2 312.1

α-Glcp OBn 293.5 307.0

α-Glcp OH 294.8 308.4

α-Glcp OBn 293.8 307.4

α-GlcNAcp NHAc 304.3 318.3

α-dGlcp H 284.4 297.7

 -Glcp OH 311.9 326.4

-Glcp OBn 310.9 325.3

-Glcp OH 311.5 325.8

-Glcp OBn 310.1 324.6

-GlcNAcp NHAc 313.6 327.3

-dGlcp H 306.8 320.6

-Arap OBn 308.1 322.4

-D-Quip OH 311.1 325.6

α α-Glcp OH 292.7 305.6

α-Glcp OH 290.5 303.9

α-dGlcp H 283.4 294.5

 -Glcp OH 311.4 325.9

-Glcp OH 309.9 324.5

-dGlcp H 308.6 323.0

2.3 Functional Group Compatibility in Glycosyl Stannanes

2.3.1 On the C2 position

It is common that the C2 position is alkylated to remove the proton source. Common protecting group include benzyl group, methyl group, methoxymethyl group and 2- naphthylmethyl group. Acetamido group is also compatible since it was present in the stannane of N-acetylglucosamine.

Figure 2.23. Alkylation of the C2-OH stannanes.

However, when the oxygen on C2 position is acylated, the compound is unstable and eliminates to form the glycal, potentially from a six-membered ring intermediate.

Figure 2.24. Product from the acylation of the C2-OH stannanes is unstable and decomposes to glycal.

2.3.2 On the C6 position

Usually a silyl group is installed on the C6 position prior to the installation of the tributyltin group. Deprotection of the silyl group exposes the hydroxyl group on C6 which can be converted to other functional groups.

Figure 2.25. Synthesis of the C6-OH stannanes.

The tolerance of functional groups on C6 position is higher than C2 position since it is farther away from the anomeric center.

Figure 2.26. Acylation of the C6-OH stannanes is feasible and the products are stable.

The C6-OH group can also be converted to halides, then replaced by other nucleophiles:

Figure 2.27. Conversion of C6-OH in glycosyl stannanes to other functional groups.

The halide undergoes E2 reaction with tBuOK, however, the double bond migrates to C4-

C5 in the ring rather than locating at C5-C6:

Figure 2.28. Elimination of C6-iodide results in the internal alkene rather than the external alkene.

2.3.3 Preparation of the fully deprotected stannane

Protecting groups are often necessary in synthetic carbohydrate chemistry to provide the regioselectivity and avoid undesired side-reactions.40 However, the additional protection and deprotection reactions lower the step economy and complicate the syntheses. The anomeric stannanes as nucleophilic glycosyl donors are mostly protected with benzyl groups. It was envisioned that these benzyl groups can be removed to expose the alcohols and the stannanes which are free from any protecting groups and could also undergo certain reactions like the fully protected stannanes.

Hydrogenation catalyzed by palladium or platinum on activated charcoal is the most commonly used method to remove benzyl groups. However, only one group reported the successful deprotection of 2-deoxy -stannane.41 Yet, attempts to reproduce the result from that protocol failed to generate the product.

Table 2.3. Condition screening for global deprotection of O-benzylated stannanes

H source Catalyst Solvent Pressure Temp. Outcome

Et3SiH Pd/C, 10% wt. MeOH Atmp. 23 ℃ N. R.

H2 Pd/C, 5% wt. MeOH Atmp. 23 ℃ N. R.

H2 Pd/C, 5% wt. MeOH 200 psi 23 ℃ N. R.

(1 equiv)

H2 Pd/C, 5% wt. MeOH 200 psi 60 ℃ Decomp.

H2 Pd/C, 5% wt. MeOH 200 psi 23 ℃ N. R.

H2 Pd/C, 5% wt. EtOAc Atmp. 23 ℃ N. R.

H2 Pd(OH)2/C MeOH/EtOAc Atmp. 23 ℃ N. R.

More conditions were screened and under forcing conditions where the pressure and temperature were both raised, the starting material stannane decomposed. Otherwise, the starting material remained intact. In addition, DDQ which is usually used to remove PMB group was also tested, and the reaction did not progress. Interestingly, the anomeric stannane was not oxidized by DDQ, either.

Birch reduction is a less used method to deprotect benzyl groups. It is a well-known procedure to dearomatize benzene.42 In a preliminary test, Birch reduction successfully deprotected all the benzyl groups in extremely high conversion. The method was further optimized in terms of the temperature, reaction time, and details at quenching.

Table 2.4. Condition screening for the work-up in the global deprotection of O-benzylated stannanes

Conditions Workup Outcome

-78 ℃, 15 min NH4Cl, then EtOH 20% yield, SM left

-78 ℃, 30 min iPrOH <10% yield + Destannylated pdt

-78 ℃, 30 min MeOH Destannylated pdt

-78 ℃, 60 min, with tBuOH NH4Cl Destannylated pdt

-78 ℃ to -35 ℃, 60 min NH4Cl Destannylated pdt

o -78 ℃ to -35 ℃, 2 h NH4Cl at - 78 C 80% yield

Since excess of sodium was used, quenching the reaction with alcoholic solvents all resulted in low yield, possibly from the generation of sodium alkoxide in the reaction which decomposed the stannane. The solvent of the reaction is liquid ammonia and solid ammonium chloride was used to neutralize the extra basic contents. It was observed that the reaction boiled vigorously when solid ammonium chloride was added at a higher temperature and the excess of heat potentially decomposed the compound as well. The best result was obtained when ammonium chloride was added slowly at -78 ℃.

It is worth noting that the it takes a couple of hours to evaporate all the ammonia, and certain solvents can be used to accelerate the process such as hexanes. It is not advised to add any halogenated solvents to the system since the residual sodium can react explosively with halogenated solvents.

This optimized condition was applied to other benzylated glycosyl stannanes and resulted in moderate to good yields:

Figure 2.29. Products and yields from the global deprotection of O-benzylated stannanes.

In conclusion, the synthesis of anomeric stannanes derived from various hexose scaffolds are reported, and the compatibility with common protecting groups is explored. The global deprotection of benzyl groups in the presence of stannanes is achieved with Birch reduction. This work laid a solid foundation for the methodology development with anomeric stannanes such as in the stereoselective C-glycosylation and O-glycosylation.

Chapter 3

Oxidative Glycosylation of Anomeric Stannanes with Hypervalent Iodine Reagents

Stereoselective chemical synthesis of saccharides and glycosides is one of the most studied topics in carbohydrate research due to the need for well-defined glycan probes for biological and pharmaceutical research. The majority of chemical glycosylation reactions accomplish high stereoselectivity through the neighboring group participation of C2 substituents.

Usually, the substrates must be fully protected in order to avoid unwanted side-reactions wherein the protection-deprotection sequence lowers the synthetic efficiency. Moreover, successful reaction conditions are usually harsh, frequently requiring low temperatures to control reactivity and anhydrous environments.14

Given the observed stereospecific reactivity of anomeric stannanes, it was hypothesized that an oxidative glycosylation could couple the stannane and an alcohol to form a glycosidic linkage. More importantly, through a coupling reaction similar to the Chan-Lam-Evans reaction43-

45, the traditional glycosylation mechanism could be avoided which lowers the requirements on the protecting groups and reaction conditions. In this chapter, we introduce the Lewis acid catalyzed oxidative glycosylation with carboxylic acids and alcohols using hypervalent iodine reagents as the oxidant, to generate saccharides and glycosides efficiently and stereoselectively under very mild conditions.46

3.1 Oxidative glycosylation with carboxylic acid nucleophiles

The screening started with proper oxidants that could produce the O-glycosides. Based on the Chan-Lam-Evans coupling conditions, Cu(II) is usually engaged in the catalytic cycle. Also,

37 from our previous studies in C-glycosylation, an additional fluoride source was included as it is known to facilitate reactions that involve stannanes. Therefore, the standard design of the reaction included Cu(OAc)2 (2 equiv) and KF (4 equiv), along with cyclohexanol (CyOH) as the glycosyl acceptor. Oxidants (2 equiv) included AgOTf, SelectFluor, and PIDA. Since excess Cu(OAc)2 was used in this reaction and Cu(II) itself can be an oxidant, other basic additives including

NaHCO3, Et3N, and pyridine were used. The reactions were carried out in sealed tubes and the temperature was set slightly above the boiling point of the solvent (1,4-dioxane).

Table 3.1. Condition screening of the oxidants for the oxidative glycosylation.

Entry Additives Outcome

1 - N. R.

2 AgOTf Starting material decomposed

3 Et3N N. R.

4 NaHCO3 N. R.

5 SelectFluor Starting material decomposed

6 PIDA Two major products

7 pyridine N. R.

From the result, only when PIDA was used, the stannane was converted to two major products. While LC-MS analysis of the crude mixture did not show the molecular weight of

38 cyclohexyl glycoside, further examination with 1H NMR revealed that the two major products were the glucal and the anomeric acetate:

Figure 3.1. Actual oxidative glycosylation product was the anomeric acetate.

It is assumed that the CyOH did not participate in the reaction. Instead, the source of acetate is either Cu(OAc)2 or PIDA. Thus, is was postulated that PIDA oxidized the stannane without the assistance of copper. To validate this hypothesis, some control experiments were carried out in the absence of CyOH:

Table 3.2. Control experiments of oxidative glycosylation with PIDA/Cu(OAc)2.

Entry Conditions Outcome

1 PIDA N. R.

2 PIDA, KF N. R.

3 PIDA, KF, Cu(OAc)2 30% Acetate (α: = 1:3.0) + 11% Glucal

It was shown that only when Cu(OAc)2 was present could the reaction proceed and PIDA alone cannot oxidize the stannane to the corresponding acetate. Since the copper in this scheme bears an acetate, an acetate-free copper source was elected to determine whether or not PIDA was the acetate source:

Table 3.3. Condition screening of copper source for oxidative glycosylation with PIDA.

Entry Additives Outcome (3-3:3-4)

1 Cu(OAc)2 1:0.31

2 CuCl 1:1.34

3 CuBr 1:1.85

4 CuI 1:1.29

5 CuCN N. R.

6 CuTC 1:0.72

7 CuO N. R.

8 CuBr2 SM decomposed

9 Cu(OTf)2 SM decomposed

From the table it is shown that Cu(I) species such as CuCl, CuBr, CuI and CuTC all yielded the product, proving that the acetate group is provided by PIDA instead of the copper source. In the case of CuO (entry 7), low solubility in organic solvents prevented the reaction from taking place. On the other hand, regarding entries 8 and 9 with CuBr2 and Cu(OTf)2 respectively, it was reasoned that these copper species are too Lewis acidic, which potentially caused decomposition of the stannane starting material.

At this point, it was to our interest if the acetate on the PIDA oxidant could be exchanged for different groups, allowing for a variety of different carboxylates to be delivered into the anomeric position. Therefore, a different phenyliodonium dicarboxylate was prepared:

Figure 3.2. Preparation of other phenyliodonium dicarboxylate from PIDA.

PIDA and benzoic acid (BzOH) were mixed in xylenes, and the reaction mixture was distilled under reduced pressure to remove the acetic acid and force the equilibrium to the generate the product. When the solvent was fully distilled, the residue was collected and further dried under vacuum. The powdered product is phenyliodonium dibenzoate (PIDB), which was subjected to the standard protocol:

Figure 3.3. PIDB reacts with anomeric stannane and made the corresponding benzoate.

In this reaction, molecular sieves were used to ensure the anhydrous condition, and the

CyOH was removed since it did not participate in the reaction. The mixture of toluene and dioxane was used to increase the yield of the product while suppressing the glycal byproduct. The anomeric benzoate was indeed produced as a mixture of anomers with an α: ratio of 1:3.8 with the  anomer as the major product. This result agrees with the initial reaction conditions employing PIDA. When the -stannane was used in the starting material, the -carboxylate was

41 generated as the major product. More data and analysis on this phenomenon will be discussed in the last section of the chapter.

On the other hand, the glycosylation of partially-protected and unprotected saccharides is of great importance given the operational simplicity and synthetic efficiency.40 Since it is confirmed that the anomeric acylation was highly selective for β anomer under conditons using

PIDA, we sought to investigate further with the C2-OH stannanes.

Hypervalent iodine reagents are known to oxidize alcohols to aldehydes and sometimes carboxylic acids.47 It was to our interest to investigate whether or not a hydroxyl group could survive the developed set of reaction conditions since only the glycosyl carboxylate was observed so far. Therefore, the C2-OH stannane was subjected to the same reaction condition:

Figure 3.4. C2-OH glucosyl stannane undergoes oxidative glycosylation with exclusive  selectivity.

From the crude NMR, only the  anomer was obtained in each case. This exclusive selectivity was soon observed when the α anomer was used, which suggested some common intermediate(s) in the reaction process.

Figure 3.5. The C2-OH α-glucosyl stannane yields only the -glycoside.

The reaction conditions were further optimized, and it was found that CuCl (2 equiv) always gave better yield compared to other Cu(I) halide (2 equiv), and the mixed solvent system of toluene and dioxane provided little elimination products and maintained the good yield:

Table 3.4. Condition optimization of the oxidative glycosylation with PIDA

Entry Cu source PhI(OAc)2 Solvent Yield

1 CuCl 2 equiv PhMe 45% 2 CuBr 2 equiv PhMe -

3 CuI 2 equiv PhMe -

4 CuCl 2 equiv dioxane 56%

5 CuCl 2 equiv PhMe-dioxane 77%

6 CuCl 2 equiv PhMe-dioxane 58%

7 CuCl 2 equiv THF -

8 CuCl 2 equiv (CH2Cl)2 -

To demonstrate the versatility of the reaction, several phenyliodonium dicarboxylates were prepared and utilized in the reaction:

Figure 3.6. Different phenyliodonium dicarboxylates yield the glucosyl carboxylate with  selectivity.

It was found that aromatic (3-12), heteroaromatic (3-14), aliphatic (3-13, 3-15), and complex ester groups (3-16, 3-17) could be installed at the anomeric position using the corresponding phenyliodonium dicarboxylate in high selectivities. To further probe the generality of this reaction, we applied the optimized conditions from Table 3.4 to reactions forming anomeric acetates.

Figure 3.7. Different C2-OH stannanes undergo oxidative glycosylation with PIDA.

D-arabinose (3-20), D-lactose (3-21) and N-acetyl-D-glucosamine (3-22) derived stannanes can all undergo the oxidative glycosylation with PIDA to give the corresponding glycosyl acetates. Moreover, the configuration of the starting material has no bearing on the

44 stereochemical outcome of the reactions, as shown in the example of glucose and N-acetyl-D- glucosamine examples even though the yield was slightly diminished.

In contrast, when the C2-OH is absent such as in 2-deoxyglycose or C2-protected stannanes, the reaction generated a mixture of anomers, indicating that the hydroxyl group on C2 position is crucial for the stereoselectivity in this process.

3.2 Oxidative glycosylation with alcohol nucleophiles

The stereoselective synthesis of anomeric ester was a serendipitous find in the quest for the oxidative glycosylation with CyOH. The original question, how to couple the glycosyl stannane with alcohols remains unknown. From the collective results it was clear that: 1) simple alcohols survive the reaction condition; 2) when PIDA and CyOH were both present, the reaction only couples the acetate to the stannane. Therefore, we reasoned that if the presence of carboxylate and other potential nucleophiles can be completely removed from the reaction, the hypervalent iodine reagent would have a chance to deliver an alkoxide to the anomeric position.

Iodosobenzene is such a reagent that does not bear intrinsic nucleophiles. It is a polymeric hypervalent iodine reagent with an empirical formula of PhIO or (PhIO)n. It can be prepared from hydrolyzing PIDA under basic conditions:48

Figure 3.8. Preparation of PhIO from PIDA.

However, PhIO does not oxidize the glycosyl stannanes nor couple it with any alcohols.

In fact, it does not dissolve in most organic solvents such as diethyl ether, chloroform, dichloromethane and THF. In most solvents, it only gives a turbid suspension upon stirring. It was reported that Lewis acids such as Zn(OTf)2, Zn(NTf2)2, and BF3-Et2O can activate hypervalent iodine reagents.49 For example, Li et al. reported the computational study on how

50 Zn(NTf2)2 activated the Togni’s reagent in an ionic pathway.

In an initial NMR experiment, -stannane was dissolved in CDCl3 (1 mL) with one drop of MeOH. To the solution was added PhIO, and the mixture was vortexed for 1 min. The 1H NMR did not show any changes and the PhIO was not dissolved. Then 10% Zn(OTf)2 was introduced to the NMR tube and the reaction mixture was vortexed for 10 sec. The PhIO dissolved immediately on vortexing. The process time was 3-5 min in total, and the 1H NMR showed the conversion was complete (>99%). A new anomeric proton peak corresponding to a -O-glycoside appeared together with aromatic peaks from iodobenzene:

Figure 3.9. Zn(OTf)2 catalyzes the oxidative glycosylation with PIDA.

From the crude NMR data, the reaction was finished within three to five minutes. Only the -glycoside was observed and the α-glycoside was not present at all, indicating a highly stereoselective reaction. The reaction was then performed on a larger scale with CyOH as the alcohol nucleophile. Chloroform was again used as the solvent. Several control experiments were performed at the same time:

Figure 3.10. Both α- and -glucosyl stannanes undergo oxidative glycosylation with PhIO to afford the

same -glycoside (3-25). In the absence of alcohol, the C1-C2 cleaved compound (3-26) was the major

product.

The reaction between -stannane and CyOH is slower compared to the reaction with

MeOH since CyOH is a secondary alcohol that is more sterically hindered. When allowed to react overnight, the reaction gives the -glycoside in 83% yield. Similar to the anomeric ester synthesis, the α-stannane underwent this condition and produced the -glycoside in 71% yield. Interestingly, when CyOH was absent, the oxidative cleavage of C1-C2 was observed, giving an acyclic compound in almost quantitative yield. Careful examination of the crude NMR in the other two reactions revealed the presence of the same compound, indicating that oxidative cleavage is a common side-reaction of this process.

On the other hand, in the absence of Zn(OTf)2, the reaction did not take place. CyOH does not get oxidized by PhIO even in the presence of Zn(OTf)2. When the stannane was stirred in a suspension of Zn(OTf)2 in chloroform, the stannane decomposes very slowly (<5% in 12 h).

Since Zn(OTf)2 was not the only Lewis acid known to activate hypervalent iodine reagents, a number of different Lewis acids were screened in the reaction (Table 3.4).

Table 3.4. Condition screening of the Lewis acids for the oxidative glycosylation with PhIO

Entry Catalyst Yield dr

1 ZnCl2 <1% ND

2 KOTf <1% ND

3 NaOTf <1% ND

4 BF3-Et2O <1% ND

5 Tf2NH (10 mol%) 35% Only β

6 TfOH (10 mol%) 65% Only β

7 Cu(OTf)2 60% Only β

8 Zn(OTf)2 86% Only β

9 AgOTf 31% Only β

10 Sc(OTf)3 80% Only β

11 Zn(NTf2)2 31% Only β

12 Y(OTf)3 80% Only β

While ZnCl2 did not enable the reaction, BF3-Et2O completely decomposed the stannane without producing the glycoside. Sc(OTf)3 and Y(OTf)3 showed similar results compared to

Zn(OTf)2. Other catalysts also enabled the reaction but at a significantly slower rate. From the

48 difference between ZnCl2 and Zn(OTf)2, it was inferred that triflate might play an important role in the glycosylation. However, alkaline metal triflate resulted in no reaction even under forcing conditions (100 °C, 24 h). Catalyst loadings of Zn(OTf)2 as low as 1% could promote the conversion of 3-8 into 3-25, although after 2 days the anomeric nucleophile was not fully consumed indicating that the rate of the reaction could be increased by simply adding more catalyst.

With the optimized condition, different alcohols and glycosyl stannanes were subjected to the reaction. It was found that small alcohol nucleophiles gave consistently high yields and 1,2- trans selectivities.

Figure 3.11. C2-OH stannanes react with small alcohols using PhIO as the oxidant with exclusive 

selectivity.

However, when sterically hindered glycosyl nucleophiles were used, the reaction was so stagnant that the side reaction, oxidative cleavage of C1-C2, was the major pathway while the glycosidic bond formation was not observed:

Figure 3.12. Oxidative cleavage of C1-C2 was observed (3-26) when bulky alcohol 3-37 was used.

Prolonged reaction time and harsher conditions (higher catalyst loading, higher temperature) only resulted in more oxidative decomposition of the starting material. The C1-C2 elimination product was also observed under these conditions. The glycosyl acceptor remained intact in the reaction. Switching solvents in the condition only altered the ratio of the side products and resulted in no glycoside formation.

One observation was that PhIO remained heterogeneous, which did not happen when reacting with smaller alcohols. It was hypothesized that the reaction was hindered by the poor solubility of PhIO, and a soluble version of PhIO could improve the efficiency of the reaction.

Hydroxy(tosyloxy)iodobenzene, HTIB, or Koser’s reagent is another well-known

51 hypervalent iodine reagent. It can be prepared from stirring PIDA and TsOH·H2O in acetonitrile,

52 or oxidize iodobenzene with mCPBA in the presence of TsOH·H2O:

Figure 3.13. Preparation of HTIB from PIDA or iodobenzene (3-39)

Swapping PhIO with HTIB in the reaction condition lead to the formation of a glycosidic bond in moderate yield (47%) while the major side products remained the same. Further optimization of the solvent, catalyst load, stannane/oxidant ratio, and the concentration of the reaction boosted the yield of the reaction to 89%. This was accomplished by addition of the stannane and oxidant in three batches:

Figure 3.14. C2-OH stannane reacts with C6-OH using HTIB

Table 3.5. Condition screening for oxidative glycosylation with HTIB

Zn loading HTIB Concentration Isolated Yield (mol %) (equiv) (M)

30% 1 0.025 M 38%

30% 2 0.025 M 30%

5% 1 0.025 M 49%

5% 2 0.025 M 21%

5% 1 0.0125 M 34%

30% 1 0.0125 M 5%

5% 1 0.025 M 48% (add Koser’s in 3 portions)

89% (add Koser’s & stannane in 3 5% 3 0.025 M portions, 3 eq in total)

From Table 3.6, the optimal solvents for this transformation are chlorinated solvents such as CHCl3 or DCE. Coordinating solvents (THF, MeCN) result only in low yields (<10%) potentially because they participate in the stabilization of the oxonium intermediate or they lower the Lewis acidity of the Zn(OTf)2 and shut down the reaction.

Table 3.6. Condition screening of solvents for oxidative glycosylation with HTIB

Entry Solvent Outcome

1 Chloroform 49%

2 DCM 30%

3 Acetone SM decomposed

4 MeCN No reaction, SM remained

5 Toluene 27%

6 DCE 40%

7 THF 9%

The optimized method was applied to other saccharide acceptors, and the result is shown below:

Figure 3.15. C6-OH acceptors undergo oxidative glycosylation with HTIB as the oxidant

Moving forward to more hindered, secondary carbohydrate alcohols, the yield of oxidative glycosylation with HTIB was significantly decreased. The oxidative cleavage to 3-26 was observed again:

Figure 3.16. Oxidative cleavage of C1-C2 was observed (3-26) when the bulky alcohol 3-53 was used

It was postulated that the increase of the steric bulk of the nucleophile can be compensated by increasing the strength of the oxidants. Therefore, a few derivatives from HTIB with additional electron withdrawing groups have been prepared with the following method:

Figure 3.17. Derivatives of HTIB prepared by oxidizing iodobenzene (3-55) with mCPBA in the

presence of arylsulfonic acid

It was found that when R1 is 3,5-bis(trifluomethyl) (3-57), the yield of the reaction was significantly increased, while other substitution patterns all led to only trace amount of improvement. Therefore, this activated Koser’s reagent was chosen for the substrates that were hard to couple to the glycosyl stannanes:

Figure 3.18. Secondary carbohydrate alcohols undergo oxidative glycosylation with C2-OH stannanes

with exclusive  selectivity

It was shown that more hindered secondary carbohydrate alcohols including C2-OH, C3-

OH and C4-OH can all react with the anomeric stannane under this condition, affording the glycosides 3-58, 3-59, and 3-54 respectively. More importantly, all these reactions only yielded the  glycosides selectively.

3.3 Mechanistic studies

The oxidative glycosylation provides a powerful tool to make 1,2-trans glycosides in a mild condition. Meanwhile, the intrinsic directing group on C2 position also opened a new pathway which needs more mechanistic insight.

Two important features of this oxidative glycosylation method are that: (1) the reaction requires the C2-OH group to proceed, and (2) it results in exclusive  selectivity in the product regardless of the configuration of the starting material. These observations point to an intermediate which only leads to the 1,2-trans glycoside.

The most common pathway that provides to the  selectivity or 1,2-trans selectivity in glycosylation involves a glycal epoxide as the intermediate. Since the C2-OH group is necessary for the reaction, it was assumed that the anomeric stannane was oxidized and became a good leaving group (in 3-60), which left the molecule with the assistance of C2-OH and resulted in the formation of an epoxide (3-61). The epoxide underwent ring opening to give the 1,2-trans product

(3-62).

Figure 3.19. Proposed mechanistic pathway via the glycal epoxide

Moreover, it was precedented that tributyl tin activated alcohol (3-65) served as the nucleophile to open a glycal epoxide under the catalysis of Lewis acid.25

Figure 3.20. Premade stannyl ether (3-67) opened the epoxide (3-61) under Lewis acid catalysis

While a silyl ether is usually used as the protecting group of alcohols, a stannyl ether activates the alcohol and makes it a softer nucleophile. Dibutyltin oxide is commonly used in carbohydrate chemistry to activate diols and induce regioselectivity53:

Figure 3.21. Dibutyltin oxide used in regioselective benzylation of diol system53

Taken together, the hypothesis was that the glycal epoxide was the intermediate in the oxidative glycosylation reaction. Since the glucal epoxide can be obtained from the glucal and it is a stable compound, it was prepared and subjected to the reaction condition:

Figure 3.22. Glucal epoxide (3-61) reacts with HTIB and tributyltin ether (3-71)

Glycal epoxide underwent oxidative cleavage when no alcohol or stannylated alcohol was present. When a premade tributyltin methoxide (tributyltin activated methanol) was used, the epoxide opened readily under catalysis by Zn(OTf)2, and the same  selectivity was observed.

The yield was slightly diminished compared to the initial reaction where MeOH and PhIO were used.

The greatest difference, however, is the kinetics of the two reactions: while the reaction using the stannane, MeOH and PhIO was finished within five minutes, the epoxide opening reaction with premade stannyl ether was significantly slower. It is worth noting that the time needed for epoxide opening with tributyltin methoxide varies depending on the quality of the reagent. The reagent from a fresh bottle of Sigma-Aldrich opened approximately 50% of the epoxide in 30 min, and the reaction was completed in 1.5 h. The reagent taken from an older bottle can take up to 6 h and the starting material stannane still remained.

Figure 3.23. Partial 1H NMR spectra of the reaction between 3-61 and 3-71

Assuming that the formation of the epoxide was the rate determining step of the reaction, the ring opening process would be faster than the direct oxidative glycosylation with hypervalent iodine reagents. This does not agree with the observation. On the other hand, if the ring opening reaction was the rate determining step, the two reactions would have similar rate which also does not agree with the observation.

Moreover, the lifetime of epoxide under the reaction condition is long enough that the epoxide should be observed from monitoring the 1H NMR, yet the characteristic proton peaks from the epoxide were never observed in the reaction with stannanes, PhIO and alcohol.

Although the theory of C2-OH stabilizing the oxocarbenium seems feasible, several reports suggested otherwise. Schmidt reported a glycosylation of 2-hydroxy-1-acetimidates resulting in a mixture of anomers.54 Similar results were reported by Baker in reactions of 2- hydroxy-1-thioglycosides.55

Figure 3.24. Glycosyl donors bearing C2-OH also yields a mixture of anomers in glycosylation

Therefore, the intermediate that lead to the exclusive  selectivity must be some other species instead of the glycal epoxide. To elucidate the detailed process of the reaction, a low temperature NMR (LT-NMR) experiment was performed. Since dichloromethane has a lower freezing point compared to chloroform and had similar performance in the reaction, CD2Cl2 was

58 selected as the solvent in the reaction. The following reactions were set up at -78 ℃ in N2 flushed

NMR tubes:

Figure 3.25. Low-temperature NMR experiments designed for mechanistic studies

The first two reactions using the α- and -stannanes at the low temperature in the absence of alcohol nucleophiles were set up to probe the common intermediate, supposedly an electrophilic species. Since the α-triflate was proved to be the active intermediate in multiple reports directing the formation of the  glycoside, the third reaction was set up as a standard to generate the reactive α-triflate intermediate.

Figure 3.26. Partial 1H NMR spectra of the C2-OH -stannane reacting in the absence of nucleophiles

from -80 ℃ to 20 ℃

From the LT-NMR spectra of the first reaction (Figure 3.26), two major peaks can be seen at the region around 6 ppm. The dd peak at 6.4 ppm belonged to the H1 in the glucal, likely generated from the Lewis acid promoted elimination. Another peak was a doublet found at 5.9 ppm with a coupling constant of 3.5 Hz, which is a typical anomeric proton signal for the α configuration.

Figure 3.27. Partial 1H NMR spectra of the C2-OH α-stannane reacting in the absence of nucleophiles

from -80 ℃ to 20 ℃

From the LT-NMR spectra of the second reaction (Figure 3.27), the same peaks were seen at the region around 6 ppm. The dd peak at 6.40 ppm, though less intense, belonged to the

H1 of the glucal. Another peak was also a doublet found around 5.92 – 5.95 ppm with the same coupling constant of 3.5 Hz, which is a typical anomeric proton signal for the α configuration. It

61 is notable that at 0 ℃, the intensity of the α intermediate remained the same. Although significantly decayed, the doublet at 5.94 ppm still could be seen at 20 ℃ in both cases. Hence, the intermediate is stable at 0 ℃ and starts to decompose above 0 ℃.

Figure 3.28. Partial 1H NMR spectra of the preparation of anomeric α-triflate -80 ℃ to 20 ℃

It is well established that the anomeric proton of α-triflate intermediate shows from 6.07 ppm – 6.50 ppm in the 1H NMR.56 The NMR spectra (Figure 3.28) results showing above are zoomed in to this region to show detail. From the LT-NMR spectra of the third reaction, the appearance of the spectra was quite distinct from the first two. The endpoint of the progression

62 showed the peak for the glucal H1 as well. At low temperature, a doublet peak was found at 6.38 ppm with a coupling constant of 3.5 Hz, which corresponded to the α-triflate anomeric proton.

However, this doublet was significantly deformed at -50 ℃. At -40 ℃, the intensity of the peak significantly went down. The peak completely disappeared at -20 ℃. This observation of chemical shift, coupling constant and stability agrees with the previous reported NMR data of the

α-triflates.

Therefore, it can be concluded from this experiment that: 1) α-triflate is not likely to be the active intermediate in this oxidative glycosylation; 2) the reaction does have an intermediate with α configuration; 3) the intermediate is the same regardless of the configuration of stannanes used.

Since the nucleophilic species present in the reaction medium were very limited, the two major possibilities that remained were an anomeric iodonium species and anomeric tosylate:

Figure 3.29. Proposed reactive intermediates of oxidative glycosylation with HTIB

It was hypothesized that the chemical shift of the anomeric proton in the anomeric iodonium/tosylate intermediate will change based on the substituent (Ph- or TsO-). The synthesis of tailored Koser’s reagent was shown before in the context of optimizing the oxidants (Figure

3.16). When R1 affects the chemical shifts of the intermediate anomeric proton, the intermediate is likely to be the anomeric iodonium. But if R2 affects the chemical shifts of the intermediate anomeric proton and R1 does not, the intermediate is likely to be the anomeric tosylate/sulfonate.

Indeed, only R2 affects the chemical shifts of the anomeric proton in the α-intermediate.

Moreover, the anomeric tosylate is reported by Bennett and co-workers,57 and the chemical shift and stability agrees with our finding.

In conclusion, the following mechanism is proposed: The C2-OH first reacts with the hypervalent iodine reagent which brings the hypervalent iodine reagent to the proximity of the stannane. The oxidation takes place which delivers the hypervalent iodine to the anomeric position, which is unstable and undergoes reductive elimination rapidly to form the anomeric tosylate. The tosylate reacts with the stannyl ether activated alcohol to produce the 1,2-trans glycoside as the final product.

Figure 3.30. Proposed mechanism based on the control studies

To further prove the intermediacy of the α-sulfonate, the C2-OH mannose stannane was subjected to the reaction condition:

Figure 3.31. Oxidative glycosylation of C2-OH mannosyl stannane gives a mixture of anomers

The reaction produced a mixture of anomers with the α-mannoside as the major product.

This result can be explained by the α-sulfonate intermediate (3-81):

Figure 3.32. Proposed mechanism for the generation of both anomers in the oxidative glycosylation of

C2-OH mannosyl stannane (3-79) assuming that the α-sulfonate (3-81) is the reactive intermediate

The α-sulfonate intermediate can undergo nucleophilic attack by the nucleophiles, but the conformation is not preferred because of the axial group on C2 position (3-81a). It is more likely that the C2 hydroxyl group facilitates the departure of the sulfonate and stabilizes the oxocarbenium by forming the mannose epoxide (3-83), which undergoes nucleophilc attack to form the 1,2-trans product (3-84a).

Comparing this result versus the exclusive selectivity in other stannanes, it seems that the stereochemical outcome cannot be simply described as 1,2-trans selective, and the -selectivity cannot be simply applied to substrates such as mannose and rhamnose. In retrospect, the formation of the glycal epoxide is potentially faster with a C2-axial hydroxyl group (3-82) compared to the

C2-equatorial hydroxyl group (3-86):

Figure 3.33. Comparison of the epoxide formation in glucose and mannose scaffolds.

3.4 Attempts of Oxidative Glycosylation with retention of stereochemistry

3.4.1 Summary of the current result

The oxidative glycosylation of anomeric stannanes with hypervalent iodine reagents catalyzed by Zn(OTf)2 results in -glycosides exclusively. Through mechanistic studies, it is demonstrated that the reactive intermediate leading to the -glycosides is likely to be the α- sulfonate. Despite the high selectivity of this reaction, the anticipated retention of the stereochemistry was not observed, which indicates that the reaction may not proceed via a Chan-

Lam-Evans coupling mechanism.

Consequently, the reaction only proceeds with the  selectivity. As a result, aside from developing this method, multiple reactions were attempted or developed preliminarily in efforts to achieve the retention of stereochemistry. These attempts include: 1) Lewis acid catalyzed oxidative glycosylation, 2) Cu(II) mediated oxidation of stannanes, and 3) Pd-catalyzed oxidation of stannanes.

3.4.2 Zn(OTf)2 catalyzed oxidative glycosylation

Even though Zn(OTf)2 catalyzes the reaction between the stannanes and with PhIO or

HTIB, when PIDA and other phenyliodonium dicarboxylates were used, the reaction yields a mixture of anomers:

Figure 3.34. Oxidative glycosylation of C2-OH stannanes with PIDA/PIDB and Zn(OTf)2 gave a

mixture of anomers.

The combinations of PhIO and different nucleophiles were tested under these conditions.

It was found that most nitrogen nucleophiles including TMSN3, PhCONH2 and MsNH2. Phenol type of nucleophiles decompose under these conditions. However, using PhIO and BzOH as the substitute of PIDB, the reaction generated a mixture of anomers albeit in low yield, and the rest was the C1-C2 oxidized product:

Figure 3.35. Oxidative glycosylation of C2-OH stannanes with PhIO/carboxylic acid and Zn(OTf)2 gave

a mixture of anomers.

Sodium salt of the carboxylate or additional amine base did not result in any glycosylation.

It is possible that the anomeric ester is activated by the Lewis acid and undergoes equilibration between the two anomers. If the α-sulfonate is the active intermediate in these reactions as well, the -ester is the primary product and it slowly equilibrates to the more stable

α-ester.

It is also worth to noting that Zn(OTf)2 does not catalyze the reaction with the stannane made from N-acetylglycosamine (3-87). It is possible that the acetamido group interferes with the

Lewis acid or hypervalent iodine reagents, leading to different outcome other than glycosylation.

Figure 3.36. No reaction was observed mixing C2-NHAc stannanes with PIDA/Zn(OTf)2

When the phenyliodonium dicarboxylate is used as the oxidant, half of the carboxylate will not participate in the reaction theoretically. To reduce the amount of carboxylate used, the derivatives from 2-iodosobenzoic acid (3-88) was used. However, the reaction did not result in any glycosylation products:

Figure 3.37. No reaction was observed replacing PIDA with 3-88

3.4.3 Cu/Pd catalyzed oxidative glycosylation

When PIDA was used in the presence of copper species, the anomeric acetate was be formed from the oxidative glycosylation. This reaction is stereoselective when the C2 position bears a hydroxyl or an acetamido group. Otherwise, a mixture of anomers are resulted. Following this line, a couple of oxidants were subjected to this condition hoping to generate the corresponding glycoside (3-89) and anomeric azide (3-90), but no reaction was observed.

Figure 3.38. No reaction was observed replacing PIDA with 3-89 and 3-90.

It is worth noting that with the addition of 5 mol% Pd(OAc)2 together with the CuCl and

KF, the anomeric stannane reacts with alcohol to give the corresponding glycoside rather than the anomeric acetate (α:β = 0.67:1 to 1.12:1), Pd(OAc)2 alone cannot oxidize the anomeric stannane.

Figure 3.39. Oxidative glycosylation in the presence of Pd catalyst enables the formation of cyclohexyl

glycoside (3-2) over the anomeric acetate (3-3)

Table 3.7. Condition screening of oxidants for Pd-catalyzed oxidative glycosylation.

Entry Oxidant Yield

1 PhI(OAc)2 56%

2 (PhIO)n 41%

3 AgOTf 25%

4 Ag2CO3 9%

5 AgOAc 12%

6 Benzoquinone 15%

7 DDQ 31%

8 CAN 28%

Other oxidants instead of PIDA were subjected in this reaction condition and the yield varies (Table 3.7). From the results above, the glycosides were formed in low to moderate yields, but it was always a mixture of anomers that resulted. This is a common observation when the C2 position lacks the hydroxyl group. It was hypothesized that the reaction went through a complex where the transition metal (Pd or Cu) was attached to the anomeric center. This complex is not stable enough to maintain the configuration and is under equilibrium with its anomer. Therefore, multiple ligands were tested to increase the stability of the reactive intermediate, thus improve the selectivity of the reaction. The stannane from C2-deoxy glucose was used in the reaction:

Figure 3.40. Oxidative glycosylation of C2-deoxy stannanes under different conditions

From the result shown in Table 3.7, it was found that the ligands tested in this condition all led to suboptimal selectivity and the yields were between 50% - 80%. And it was unclear whether changing ligands would improve the diastereoselectivity of the reaction.

3.4.4 Cu(II) mediated oxidative glycosylation

It was first discovered that Cu(OAc)2 in the presence of PIDA and KF could oxidize the anomeric stannane to the anomeric acetate where the acetate installed was from PIDA. In contrast to PIDA which cannot oxidized the anomeric stannanes without Cu(OAc)2 or CuX (X = Cl, Br,

I), stoichiometric amount of Cu(OAc)2 does oxidize the anomeric stannane to acetate as well.

Figure 3.41. Stoichiometric amount of Cu(OAc)2 oxidizes the anomeric stannane to the acetate.

Table 3.7. Condition screening of oxidants for Pd-catalyzed oxidative glycosylation.

Oxidants (2 eq.) Pd source (5%) Ligand (10%) Ratio(a:b)

PhI(DMM) Pd(OAc)2 - 0.87:1

PhI(DMM) Pd(OAc)2 Quinaldic acid 0.61:1

PhI(DMM) Pd(OAc)2 DavePhos 0.89:1

PhI(DMM) Pd(OAc)2 JackiePhos 0.70:1

PIDA CNN-pincer - 1.01:1

PhI(DMM) Pd(OAc)2 Picolinic acid 0.62:1

PhI(DMM) Pd(OAc)2 PyBOX 0.82:1

PhI(DMM) Pd(OAc)2 3-acetaminopyridone 1.25:1

PhI(DMM) Pd(OAc)2 3,3’-carbonyl-2,2’- 0.75:1

bipyridine

PhI(DMM) Pd(OAc)2 Picolinic acid 0.62:1

PhI(DMM) Pd(OAc)2 4-nitropicolinic acid 0.55:1

PhI(DMM) Pd(OAc)2 4-hydroxypicolinic acid 0.80:1

PhI(DMM) Pd(OAc)2 Pyrimidin-2-acetic acid 0.99:1

Therefore, it was envisioned that a soluble Cu(II) species whose counterion is not or only weakly nucleophilic can oxidize the glycosyl stannanes to glycosides in the presence of an alcohol.

A few Cu(II) species were tested:

Table 3.8. Condition screening of copper(II) source for Cu-mediated oxidative glycosylation

Entry Conditions 3-94 3-4 3-93

1 2.5 eq Cu(OTf)2, 4 eq KF, 4Å MS 73% 5% -

2 2.5 eq Cu(NO3)2-3H2O, 4 eq KF, 4Å 30% 6% -

3 2.5 eq Cu(NO3)2-3H2O, 4Å MS 41% 5% -

4 2.5 eq CuBr2, 4Å MS 16% - 57% (1.05:1)

5 2.5 eq CuBr2, 4 eq KF, 4Å MS 6% 3% 80% (0.73:1)

6 2.5 eq CuCl2-2H2O, 4 eq KF, 4Å MS 14% 2% 76% (0.96:1)

From Table 3.8, it was shown that one major product that was seen in these reactions was the C2-C3 olefinated glycoside (3-94). It was thought that this product was from a glycal isomerization reaction from 3-4 catalyzed by the Lewis acidic Cu(II) species (Figure 3.41).

It was rationalized from the results that the Cu(II) species cannot be excessively Lewis acidic because it promotes the elimination of stannane and potentially triggers the isomerization as well. However, it must be reactive enough to oxidize the anomeric stannanes. From the results it was shown that copper (II) bromide was a good choice since it provided a good yield of the glycosides with only small amounts of side-products. Copper(II) chloride gave comparable yields as well but was not chosen because the anhydrous CuCl2 was hard to obtain and store.

Figure 3.42. Proposed mechanism of Lewis acid catalyzed isomerization of glycal. Lewis acid activates the C3-alkoxy group (3-95) to leave and forms the conjugated oxocarbenium species (3-96). The alcohol

attacks the more electron-positive anomeric position to form the kinetic product 3-97.

In addition, different alcohols and additives were tested in this reaction:

Table 3.9. Condition screening of additives and nucleophiles for Cu-mediated oxidative glycosylation

Entry R Additive 3-97 3-98

1 - 4 eq KF - -

2 Ph 4 eq KF - 41% (0.33:1)

3 C6-OH 4 eq KF - -

4 iBu 4 eq KF, 3 eq TTBP 7% 40% (0.86:1)

5 iBu 4 eq KF, 2 eq pyAlk 5% 12% (0.91:1)

6 - 4 eq KF, 2 eq pyAlk, PIDA - -

i 7 Bu 0.05 eq Pd(OAc)2, 4 eq KF, PIDA, 7% -

pyAlk

The results were shown in Table 3.9. It was found that in the absence of alcohols the reaction barely proceeded (Entry 1). Unlike the condition with hypervalent iodine, phenol

74 survives this reaction and produced a mixture of phenyl glycoside anomers (Entry 2). When the bulky alcohol was used such as the C6-OH from glucose, the reaction did not proceed (Entry 3).

Additional base (TTBP) slightly lowered the yield of the reaction but changed the α/ ratio significantly (Entry 4). This is also observed when a ligand (pyAlk) was used in stoichiometric amounts (Entry 5 and 6). Trace amount of Pd(OAc)2 changed the reaction pathway and only generated a small amount of glycosyl acetate instead of the isobutyl glycosides (Entry

7).

In Chan-Lam-Evans reaction, it is often not necessary to use stoichiometric amount of

Cu(II) as oxidants. Instead, the reduced Cu(I) product in solution is oxidized rapidly by the aerobic oxygen. Therefore, it is common to use catalytic amount of copper species under aerobic conditions. For example, Batey et al reported the coupling between organotrifluoroboronates and aliphatic alcohols under aerobic conditions:58

Figure 3.43. Proposed mechanism of Lewis acid catalyzed isomerization of glycal

The aerobic oxidation with catalytic amount of copper species was also attempted in the oxidative glycosylation:

Table 3.10. Condition screening for catalytic aerobic oxidative glycosylation

Entry Cat. Additives Yield Ratio (α:)

1 1 eq CuBr2 O2(backfill) 60% 1:1.33

2 1 eq CuBr2 O2(active purging) 35% 1:1.50

3 0.05 eq CuBr2 O2(active purging) 9% Not detectable

4 0.05 eq Cu2Br2 O2(backfill) - -

5 0.05 eq CuCl O2(backfill) - -

6 0.05 eq IPrCuCl O2(backfill) - -

7 0.05 eq Cu-TMEDA O2(backfill) - -

8 0.05 eq CuBr2 O2(backfill), 0.05 eq 5% Not detectable

TEMPO

Stoichiometrically, two equivalents of Cu(II) are needed to fully oxidize the stannane to the corresponding glycoside. It was found that the aerobic conditions only resulted in low yield in Table 3.10. In the Cu(I) species, the reaction all resulted in no reaction. To conclude, it is still possible to use aerobic oxygen as the source of oxidant, but the condition must be further developed.

Since the reaction generates a mixture of anomers, it was envisioned that with ligands stabilizing the transition metal center, the selectivity can be improved (similar to the

76 aforementioned Pd/Cu condition). A few ligands were subjected to the reaction condition with

CuBr2:

Table 3.11. Condition screening of ligands for Cu-mediated oxidative glycosylation

Entry Cu source Ligand Yield ()

1 CuBr2 2,2’-bipyridyl 11%

2 CuBr2 4,4’-di-tert-butyl-2,2’-bipyridyl SM recovered

3 CuBr2 Phenanthroline SM recovered

4 CuBr2 8-hydroxylquinoline 12%

5 Cu(acac)2 - SM recovered

6 CuBr2 TEMPO SM recovered

From the results in Table 3.11, when 2,2’-bipyridyl and 8-hydroxyquinoline were used, only the -glycoside was observed. However, all the ligands lowered the yield, and some stopped the reaction. It is potentially because the ligands stabilized the copper and slowed down the disproportionation of Cu(II) to the reactive Cu(III), shutting down the reaction.

The solvent effect was also investigated. To ensure the reaction is free of moisture, extra molecular sieves were used:

Table 3.12. Condition screening of solvents for Cu-mediated oxidative glycosylation

Entry Solvent Yield Ratio (α:)

1 Toluene 63% 1:1.3

2 iBuOH 59% 1:0.85

3 Dioxane 33% 1:0.85

4 MeCN 69% 1:1.5

5 DMF N.R. -

6 DMSO N.R. -

From Table 3.12, acetonitrile and toluene showed similar yields and selectivity (Entry 1 and 2). Isobutanol and dioxane somehow lowered the yield and resulted in more of the α- glycoside (Entry 3 and 4). High boiling solvent such as DMF and DMSO did not result in any glycosylation potentially because the solvent caged up the copper center (Entry 5 and 6).

Since the extrinsic ligands did not significantly improve the selectivity, the stannanes with coordinating groups on C2 were subjected to the reaction condition. It was shown in Table 3.13 that, when the C2 position bears a MOM group or an acetamido group, the reaction shows an exclusive  selectivity (Entry 1, 2 and 3) which is absent when C2 position bears a benzyl group

(Entry 4 and 5). However, when C2-OMOM mannose stannane was used instead of the glucose

78 stannane, the reaction yielded a mixture of anomers. Therefore, the details of neighboring group participation must be scrutinized before more comments are made.

Table 3.13. Effects of neighboring group on C2 on Cu-mediated oxidative glycosylation

Entry R Anomeric Conf. Ratio Yield

1 OMOM  Only  58%

2 NHAc α Only  47%

3 NHAc  Only  64%

4 OBn α α: = 2.3:1 51%

5 OBn  α: = 1:1.3 63%

Chapter 4

Stereoselective Homologation of Anomeric Position Using Glycosyl Stannanes

Homologation on the reducing end of aldoses dates back to Kiliani-Fischer synthesis in the 1900s.

By adding one carbon on the reducing end, a chain-elongated product is obtained. This provides a convenient route to synthesize hexoses from pentoses, or heptoses from hexoses. Since the carbohydrate substrate itself is usually chiral, the homologation reaction achieves a certain level of diastereoselectivity.

The two basic strategies involved in the traditional homologation reactions are the nucleophilic and the electrophilic replacements of the anomeric center with C1 synthons matching the polarity of the anomeric center. In this chapter, the reported homologation reactions on the anomeric position is discussed and an alternative pathway to reach the same goal with higher precision with stereochemical control is described. We also demonstrate the versatility of the method by showing that the homologated hexoses can be further derivatized into two classes of highly important sugar with much higher values.

4.1 A collection of homologation reactions on anomeric carbon

The Kiliani-Fischer synthesis shown below represents the classical way of homologation using a nucleophile to add to the aldoses. Kiliani showed that a cyanohydrin (4-2) is formed when

L-arabinose (4-1) is treated with HCN. Following this chain elongation, Fischer was able to prepare the hexoses using hydrolysis and reduction with sodium amalgam. The product was a mixture of L-mannose (4-5) and L-glucose (4-6), which are the C2-epimers of each other due to the lack of stereoselectivity in cyanohydrin formation.

Figure 4.1. Fischer-Kiliani synthesis of L-mannose and L-glucose

An improved version of this sequence was published shortly after by Sowden and Fischer using nitromethane instead of cyanide. A Nef reaction was used to convert the nitro group directly to a carbonyl.

Figure 4.2. Sowden-Fischer synthesis of L-mannose and L-glucose

In the pyranose form, the anomeric position can be made electrophilic by forming a lactone (4-8), forming an epoxide from glucal (4-9) or installing a good leaving group (4-10).

Figure 4.3. Three methods to introduce a nucleophile to the anomeric position

The nucleophilic replacement of cyanide has been reported by multiple groups, and the stereochemistry is usually directed by the neighboring group on C2 position:59-61:

Figure 4.4. Nucleophilic replacement on the anomeric position with cyanide

The epoxide opening with carbon-based nucleophiles was reported by multiple groups.

One of the common strategies of homologation is to react difurylzinc or trifurylaluminum with the epoxide, and then oxidize the furan ring to the carboxylic acid afterward:62,63

Figure 4.5. Formation of the glycosyl furan and the glycosyl carboxylic acid

Carbanions at the anomeric position can also be prepared from the anomeric stannane or anomeric halide. Reacting the carbanion species with electrophiles at low temperatures provides the homologated products.64

Figure 4.6. Anomeric lithium reagents as the nucleophiles in homologation reactions

Transition metals including manganese, iron, cobalt and rhodium have been reported to catalyze the homologation of the anomeric acetate using the metal carbonyl complexes.65 These reactions usually generate the glycosyl methanol and its derivatives, sometimes with good α/ selectivity. This selectivity however, is very substrate dependent:

Figure 4.7. Transition metal carbonyl complex (dicobalt octacarbonyl in this figure) mediated

homologation reactions on the anomeric position

Falck et al reported that a C2-MOM protected anomeric stannane undergoes cross- coupling reaction with chlorothioformate to produce the corresponding glycosyl thioester.31

However, the performance of this method is highly dependent on the substituent of C2 position.

When the C2 position bears a methyl or benzyl ether, the reaction results in decomposition of the stannane or very low yield of adducts. Only the -anomer was reported, and it is unknown whether this method applies to the α-anomer as well.

Figure 4.8. Palladium catalyzed homologation reported by Falck et al.

4.2 Stereoselective homologation with anomeric stannanes

Transition metal catalyzed homologation on C(sp2) center with carbon monoxide is well precedented. Despite the lack of control in stereoselectivity, CO insertion is feasible in the anomeric position as shown in the examples mentioned above. Nonetheless, the reported method is limited to the -C-glycoside and the yield varies significantly when different monosaccharides

83 are used. On the other hand, while the work of Falck is very intriguing, the method remains underdeveloped due to the limited substrate scope.

Recently, our group developed the Stille coupling of anomeric stannanes with aryl halide or thioester to produce the corresponding C-glycosides, which effectively showed the efficiency of transition metal catalyzed coupling reactions on the pyranose scaffold. The highlight of this method is that the reaction takes place on a C(sp3) center with the retention of stereochemistry, a feature that is hard to achieve with conventional methods.

In this section a special case of anomeric acylation is reported, where a selenothiocarbonate is used as the acyl donor to install a one-carbon unit on the pyranoses resulting in the homologation of the anomeric position. Next, the mechanism of the reaction is discussed followed by some applications of this method.

4.2.1 From the stereoselective acylation to homologation

While acylation on C(sp2) centers is well-known and widely used in industry, stereoselective acylation on C(sp3) center is much less explored. Falck’s report was one of the early stereoselective acylation reactions. Biscoe et al reported this Stille coupling reaction on alkylcarbastannatranes (4-27) which represents a versatile strategy of acylating the asymmetric

C(sp3) center.66 Changing the acyl donor and/or the organometallics usually can alter the stereochemical outcome, making the method an appealing approach for asymmetric synthesis.67

Figure 4.9. Palladium catalyzed acylation of alkylcarbastannnatrances reported by Biscoe et al.

It was envisioned that this strategy can be utilized on a carbohydrate scaffold. The asymmetric C-glycosylation was developed to introduce C-acyl groups to the anomeric position:

Figure 4.10. Palladium catalyzed acylation of glycosyl stsannanes with stereoretention

While the acylation of the glycosyl stannane is accomplished,68 we continued to seek more possibilities where a one-carbon unit could be installed on the anomeric position. Based on the conditions developed for the C-acyl glycosylation, we set out to find suitable electrophiles for the one-carbon homologation reactions.

4.2.2 Development of the method

First, the electrophiles were prepared and screened under similar condition to the acylation method:

Table 4.1. Condition screening of acylating reagent for palladium catalyzed homologation reactions.

Entry Coupling reagent Yield

1 PhSCO2Me N. D.

2 PhSCO2Ph N. D.

3 PhSCO2Bn N. D.

4 PhSeCOSiPr 87%

5 ClCO2Bn N. D.

6 Boc2O N. D.

It was found that the selenoformate thioester is the only species that can be coupled with the anomeric stannanes, resulting in the anomeric thioester in exclusive  selectivity. The other thioformates and chloroformate all failed to couple with the stannane.

Therefore, the selenoformate thioester was chosen as the coupling partner. The catalysts and solvents were briefly screened to further optimize the already high yield from the previous conditions:

Table 4.2. Condition screening of ligands and solvents for palladium catalyzed homologation reactions.

b Entry Ligand Pd2(dba)3 CuCl Solvent Yield

1 JackiePhos - 200% 1,4-Dioxane N.D.

2 JackiePhos 7.5% - 1,4-Dioxane trace

3 JackiePhos (1 d) 7.5% 200% 1,4-Dioxane 34%

4 JackiePhos (2 d) 7.5% 200% 1,4-Dioxane 51%

5 JackiePhos (4 d) 7.5% 200% 1,4-Dioxane 87%

6 JackiePhos 7.5% 200% Toluene 64%

7 BrettPhos 7.5% 200% 1,4-Dioxane 23%

8 tBuBrettPhos 7.5% 200% 1,4-Dioxane 16%

9 P(OEt)3 7.5% 200% 1,4-Dioxane 18%

The coupling reaction failed to generate the anomeric thioester when either Pd2(dba)3 or

CuCl were absent. Under reflux, the yield in toluene was slightly diminished compared to 1,4- dioxane. But the reaction required four days to achieve the yield of 87%. Ligands other than

JackiePhos all led to lower yield. Therefore, the initial condition was still the most efficient among all the reactions screened.

Throughout the screening process, the Se-glycoside was observed as a common byproduct. A potential mechanism for the generation of the Se-glycoside is below with the ring substituents hidden:

Figure 4.11. Proposed mechanism of palladium catalyzed homologation reactions

It was hypothesized that diphenyl diselenide is needed for the generation of the Se- glycoside. The reaction readily generates benzeneselenol or its derivatives, which undergo rapid oxidation to the diselenide. The selenoformate thioester in storage also slowly undergoes hydrolysis to produce benzeneselenol, which further builds up the diselenide in the starting material. The diselenide shows a characteristic bright yellow color which can be used as an indicator of the quality of the starting material. A pure batch of the selenoformate thioester is colorless to very light yellow with a freezing point lower than -20 ℃. If the reagent shows a bright yellow color or freezes in the -20 ℃ freezer, then the quality of the reagent is questionable. Since it is hard to judge the reagent quality from 1H NMR, the visual clues are important in evaluating the grade of reagents.

4.2.3 Application to mono/disaccharide stannanes

Upon optimization of the method, various reactions were run to probe the effect of the C2 substituents have on the coupling reaction as reported by other groups. Hence, a few stannanes were subjected to the optimized conditions:

Figure 4.12. Homologations of various glycosyl stannanes

It was observed that the reaction proceeded with stereoretention, meaning that the configuration of the starting material stannanes translate to the thioester products. Furthermore, substituents on C2 position do not have an obvious effect on the performance of the reaction.

When α-stannanes were used, the yields were slightly lowered but the selectivity was not compromised.

To further investigate the compatibility of common protecting groups of synthetic carbohydrate chemistry, a few glycosyl stannanes bearing C2 and C6-substitution groups are prepared and subjected to the reaction condition:

Figure 4.13. Compatibility of protecting groups in the Pd-catalyzed homologation reaction

Common protecting groups such as acetate, pivalate, levulinate, 2-naphthyl and silyl ethers are compatible with the reaction condition, providing more versatility in late stage modification of the substrates.

4.3 Practical application of the stereoselective homologation

Thioesters are very versatile functional groups that can be converted easily to other important functional groups. For example, thioesters undergo hydrolysis or alcoholysis to give the corresponding carboxylic acid or ester, respectively. They can also be reduced under certain conditions to afford the glycosyl aldehyde or methanol. Further transformation can thus be implemented in later stages. In this section, first the hydrolysis of the thioesters to the corresponding glycosyl carboxylic acids is shown. Then, two comprehensive schemes centered around this homologation to produce rare hexoses such as L-glucose and L-idose, and nonoses from the sialic acid family are disclosed.

4.3.1 Hydrolysis of the homologated product

The glycosyl thioesters were hydrolyzed using LiOH-H2O in a mixed solvent system of

THF:MeOH:H2O. The reaction typically finished in three hours, and purification over silica gel furnished the glycosyl carboxylic acid while removing the thiolate byproduct. The yield of the reaction was 95% to quantitative. Therefore, homologation of the glycosyl stannane and subsequent hydrolysis can be done in tandem. Figure 4.12 shows the overall conversion to the carboxylic acids:

Figure 4.14. Tandem homologation-hydrolysis of various glycosyl stannanes.

4.3.2 Synthesis of rare sugars from the head-to-tail swapping strategy

Take the coupling product 4-59 as an example. Once this C1-homologated product is reduced to an alcohol (4-73) and the C6 position is deprotected, the product diol 4-74 is an achiral

C2-symmetric molecule belonging to the Cs point group, and it has a mirror plane in the middle of the molecule (C3-O). The two hydroxyl groups are enantiotopic, meaning that if the reaction sequence is reversed on the opposite hydroxyl groups, the enantiomer of 4-59 will be produced

(4-75):

Figure 4.15. Introduction of plane symmetry from the anomeric homologation

This intrinsic property of the product provides a possibility of a head-to-tail swap between the original C1 and C5. If the bond between C5 and C6 can be cleaved in the homologated product, the resulting product will also be a hexose where the order of the carbon backbone from C1 to C5 will be fully reversed (Figure. 4.14) Figure 4.16. The head-to-tail (C1-C5)

swapping strategy to synthesize rare sugars

Albeit an appealing strategy, similar schemes have rarely been reported due to the lack of methods for stereoselective homologation.

As mentioned earlier, Li et al reported the silyloxymethylation on the anomeric acetate 4-19,

92 which was carried on further to produce the C6-carboxylic acid 4-77. Oxidative cleavage of C5-

C6 on 4-77 by lead tetraacetate afforded the L-glucose acetate 4-78.69

Figure 4.17. Synthesis of L-glucose reported by Li and coworkers

The group further manipulated the functional groups on the L-glucose scaffold and derived it to L-mannose and L-galactose. The synthesis however, is quite limited on the silyloxymethylation because only one example was done successfully in the report and the yield is suboptimal.

Figure 4.18. Large scale syntheses of L-glucose reported by Jenkinson group and Izumori groups. The

route from 4-79 to 4-80 was shared in the scheme

The other example focused on the large scale synthesis of L-glucose was shown by

Jenkinson and coworkers.70 The D-glucoheptonate was obtained from the traditional Kiliani

93 synthesis, which was protected with acetonide and selectively deprotected to expose the terminal diol 4-80. Reduction of the ester and oxidative cleavage of the terminal C-C bond afforded hydroxyaldehyde 4-81, which undergoes hydrolysis in acidic condition to produce the L-glucose.

This method took advantage of the easily accessible D-glucoheptonate and is very industrially applicable. Later, the Izumori group showed that the same intermediate 4-80 can be repurposed to generate D-gulose by inverting the reducing and non-reducing ends, generating the

D-gulose from the sequence.71

The methods mentioned above are useful when the target can be converted from the L- glucose. Otherwise, the stereoselective homologation will be the first obstacle researchers have to face if the head-to-tail strategy is desired. By using our method demonstrated in this chapter, a thioester can be installed in a stereoselective fashion to extend the reducing end of the hexose, thus bridging the gap in this strategy.

There are two major advantages compared to the reported methods. First, viable substrates are no longer restricted to only glucose. Instead, other common monosaccharides building blocks such as galactose and mannose can be used. Second, α-stannanes can be exploited as the starting materials which, in theory provides access to idose and altrose from glucose and mannose, respectively.

The C6-OTBDPS protected stannane was used in this synthesis because the silyl group provided an easy handle for the later stage manipulation (C5-C6 cleavage). Once the homologation on the anomeric position is finished, the resulting thioester can be conveniently converted into an alcohol/ether (4-86), an ester (4-84), or a methyl group (4-88), which later leads to the aldose (4-87), the uronic acid/uronate (4-85), and the 6-deoxyaldose (4-89) respectively.

Figure 4.19. Versatile conversion of the thioester to other functional groups

The second part of the head-to-tail inversion is the cleavage of C5-C6. Deprotection of the TBDPS group worked well when the thioester was converted to the ether or methyl group.

When a methyl formate was present on C1, deprotection of silyl ether with TBAF/THF resulted in the decomposition of the ester. Additional acetic acid was used to inhibit the decomposition of the ester.

Then Parikh-Doering oxidation of the resulting alcohol (4-90) provided the aldehyde (4-

91) in good yield.

Figure 4.20. Parikh-Doering oxidation of C6-OH

At first, attempts were made to prepare the formate from the aldehyde using Baeyer-

Villiger oxidation with mCPBA as the oxidant. Under the normal condition with mCPBA in DCM, the reaction yielded only the carboxylic acid (4-93) instead of the formate (4-92).

Figure 4.21. Baeyer-Villiger oxidation of C6-CHO affords the corresponding carboxylic acid instead of

the formate

It was reported by Horn et al that purified mCPBA oxidizes the aldehyde to a formate rather than a carboxylic acid.72 Also, the same group proposed that the pure mCPBA can be added in a solution of Et2O to increase the performance of the oxidant. The two conditions were tested on a very similar substrate, methyl α-galactoside (4-94):

Figure 4.22. Attempts of Baeyer-Villiger reaction with purified mCPBA

The conversion to the aldehyde (4-95) was again successful. However, in both conditions, the only observed product was the carboxylic acid (4-96). More specifically, the crude 1H NMR showed no new anomeric proton corresponding to the formate.

In sum, purification of mCPBA did not change the selectivity in this reaction. It is well known that aliphatic aldehydes undergo oxidation to carboxylic acids with mCPBA, whereas aromatic aldehydes can be oxidized to formates under basic conditions and further hydrolyzed to phenols, also known as the Dakin oxidation. Though sporadic cases are reported where mCPBA oxidizes aliphatic aldehydes to the corresponding formates, the reaction requires further investigation.

Since the direct oxidative cleavage failed to insert an oxygen atom to C5-C6, it was envisioned that a Curtius rearrangement from the carboxylic acid product (4-97) can be used to convert the carboxylic acid into an isocyanate group (4-99), which can be hydrolyzed to an amino group or a hemiaminal (4-100). The amino group at the new anomeric position can be further hydrolyzed to form the anomeric alcohol as the final product (4-101).

Figure 4.23. Proposed reaction sequence to cleave C5-C6 via Curtius rearrangement

Although the carboxylic acid was obtained as a by-product from the two-step procedure via the aldehyde intermediate, it can also be prepared conveniently with PIDA/TEMPO.

To probe the reactivity of the acyl azide and isocyanate, a derivative from methyl α- glucoside (4-102) was used:

Figure 4.24. C5-C6 cleavage on a model system

The reaction was monitored by TLC and crude NMR to ensure full conversion of the starting material. According to the NMR, the acyl azide (4-103) was formed quantitatively and refluxing in toluene generated isocyante (4-104). Acidic hydrolysis yielded the symmetric dialdehyde (4-105) as the final product, which proved that the feasibility of hydrolysis.

To increase the accountability of the reaction sequence, the isocyanate was trapped with tBuOH to form a Boc-amide, which can be separated and purified:

Figure 4.25. Conversion of the C5-carboxylic acid to C5-NHBoc via Curtius rearrangement

The reaction sequence consists of six to eight steps depending on the specific substrate.

Shown below are the products obtained from these reaction sequence, together with the scheme in details:

Figure 4.26. Syntheses of rare L-sugars from the head-to-tail swapping strategy

Figure 4.27. Detailed scheme of the head-to-tail swapping strategy

More examples are currently being prepared. Meanwhile, it was also found that the primary alcohol on C5 position is directly oxidized to the anomeric acetate by lead tetraacetate, which shortens the synthesis by two steps.73

4.3.3 Synthesis of nonoses from the sialic acid family

Sialic acid, or N-acetylneuraminic acid, represents a family of ketononoses which are all monosaccharides featuring a nine-carbon backbone. The molecules in this family are widely distributed especially on the cell surface playing important roles in the cell recognition process.

The biosynthesis of these molecules is well studied, while the chemical synthesis of these molecules is far behind. Even though the synthesis of some molecules in this family is reported, the construction of these molecules is still notoriously difficult and tedious.7474,75

Take N-acetylneuraminic acid (Neu5Ac) as an example. Even though the biosynthetic precursor of Neu5Ac is mannosamine, the substitution pattern on the pyran backbone is extremely similar to that of glucosamine:

Figure 4.28. Comparison of the structure of Neu5Ac and GlcNAc

From the structure three major distinctions can be seen between GlcNAc and Neu5Ac.

First a three-carbon chain is added to the anomeric position of GlcNAc. The original C4-OH on

GlcNAc is moved to C5 and the primary alcohol on C6 is oxidized to the carboxylic acid. Similar patterns can be seen between 2-keto-3-deoxynonic acid (Kda) to glucose.

With the reliable method of homologation at the anomeric position discussed previously, it was envisioned that these molecules can be made from the corresponding stannanes of glucosamine and glucose. The retrosynthetic analysis is shown below:

100

Figure 4.29. Retrosynthetic analysis of N-acetylneuraminic acid (Neu5Ac), legionaminic acid (Leg)

and 2-keto-3-deoxynonoic acid (Kda).

The synthesis is currently still in progress. Because the isomerization of the hydroxyl group is well precedented before, the major goal of the synthesis is to construct the chiral centers on the three-carbon tail.

101

Chapter 5

Conclusions

Through the development of chemical glycosylation, the mechanistic pathway follows the mainstream of nucleophilic replacement where the nucleophilic glycosyl acceptor reacts with the electrophilic anomeric center of the glycosyl donor. Numerous strategies of stereoselective glycosylation have evolved around this classical reaction model. However, the scarcity of a novel strategy which is less dependent or not dependent on the substrate to achieve the selectivity calls for exploration into new methods of glycosylation.

Glycosyl stannanes, as anomeric nucleophiles, provide a novel approach toward solving this old problem. While traditionally used as the stable precursors for the corresponding glycosyl lithium reagents, the glycosyl stannanes can be excellent glycosyl donors themselves. Successful

C-glycosylation with stereoretention demonstrated the potential of the stannanes as substrates in transition metal catalyzed glycosylations.

In this dissertation, the syntheses of glycosyl stannanes were first summarized and presented with a particular focus on the underlying mechanisms. From understanding the preparation of these molecules, new glycosyl stannanes from other carbohydrate scaffolds and those bearing alternative functional groups were made and characterized. The characterization of glycosyl stannanes revealed several features and trends in the NMR spectra, which should serve as the foundation for further study of these novel anomeric nucleophiles.

Oxidative glycosylation reactions using the anomeric stannanes branched out in several directions, the most successful of which was the glycosylation using C2-OH stannanes. Utilizing

102 hypervalent iodine reagents as the oxidants, exclusive  selectivity was observed in most cases.

The nucleophiles varied from carboxylates to complicated carbohydrate alcohols. Preliminary mechanistic studies proved the intermediacy of the anomeric sulfonate, indicating a traditional

SN2 pathway of the reaction. To unleash the full potential of this method, the reaction conditions must be further investigated to identify a mechanistically distinct pathway of glycosylation.

Additionally, a stereoretentive homologation using a selenoformate thioester was presented. This reaction enabled efficient synthesis that translates the configuration of the starting material stannane to the anomeric thioester product, an anomeric thioester. Through this method, three individual derivatization routes were developed: direct hydrolysis, synthesis of rare sugars, and synthesis of nonoses from the sialic acid family. The latter two were previously limited by the lack of stereoselective synthetic tools.

In conclusion, the dissertation summarized the preparation of glycosyl stannanes and some of their applications in synthetic carbohydrate chemistry. These efforts show the promise of using anomeric nucleophiles such as the glycosyl stannanes in glycosylation. While chemistry of glycosyl stannanes requires further development in order to see their widespread use, alternative anomeric nucleophiles including the anomeric boron and silicon species have emerged as attractive targets with less environmental impacts involved compared to tributyltin. This work highlights a very promising field and largely uncharted territory in chemical glycosylations, especially in O/N-glycosylations.

103

Chapter 6

Experimentals

(3,4,6-Tri-O-benzyl-β-D-glucopyranosyl)tri-n-butylstannane (2-22). To a solution of tri-O- benzyl-glucal (3.00 g, 7.21 mmol) in a cooled (0 °C), vigorously stirring biphasic solution of

® DCM (60 mL), saturated aq. NaHCO3 (100 mL), and acetone (6 mL), a solution of Oxone (17.75 g, 28.83 mmol) in H2O (70 mL) was added dropwise over 15 min. The mixture was stirred for

0.5 h at 0 °C, then for 2 h at rt. The organic phase was then separated, and the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were dried (Na2SO3) and concentrated to afford the crude epoxide as a white solid. This material was dissolved in anhydrous and degassed THF (70 mL), cooled to -20 °C (ice salt bath) followed by the addition of a solution of MeMgSnBu3 (3.57 g, 10.8 mmol) in THF. The solution was stirred at -20 °C for

® 2 h, quenched with saturated aq. NH4Cl (20 mL), filtered through Celite and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 (3 × 50 mL), and the combined organic layers were dried (Na2SO4), concentrated, and purified by flash column chromatography

26 on SiO2 (Hexanes/EtOAc, 1:0 then 20:1) to afford 1 (3.13 g, 60%) as a light yellow oil:[훼]퐷 = -

1.8 (c = 1.00, CHCl3); IR (ATR) ν = 3029, 2920, 2359, 1580, 1452, 1359, 1043, 871, 731, 694,

-1 1 597 cm ; H NMR (300 MHz, CDCl3) δ 7.41-7.27 (m, 15H), 5.00 (d, J = 11.4 Hz, 1H), 4.85 (d,

J = 10.9 Hz, 1H), 4.77 (d, J = 11.4 Hz, 1H), 4.70 (d, J = 8.9 Hz, 1H), 4.66 (d, J = 10.1 Hz, 1H),

4.58 (d, J = 12.3 Hz, 1H), 3.81-3.70 (m, 3H), 3.64 (t, J = 9.3 Hz, 1H), 3.47 (d, J = 10.8 Hz, 1H),

3.41 (d, J = 8.8 Hz, 1H), 3.35-3.32 (m, 1H), 2.10 (d, J = 3.2 Hz, 1H), 1.66-1.48 (m, 6H), 1.34 (m,

104

13 6H), 1.09-0.97 (m, 6H), 0.90 (t, J = 7.2 Hz, 1H); C NMR (75 MHz, CDCl3) δ 138.8 (2), 138.4,

128.8, 128.6, 128.4, 128.1, 128.0 (2), 127.9, 127.6, 127.5, 89.2, 83.6, 79.0, 75.7, 75.5, 75.0, 74.2,

+ 73.6, 69.6, 29.2, 27.6, 13.9, 9.1; FT-HRMS (ESI) calcd for C39H56O5SnNa [M + Na] : 747.3042, found 747.3052.

(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)tri-n-butylstannane (2-23). A solution of 2-22

(600 mg, 0.828 mmol) in anhydrous THF (5 mL) was cooled to 0 °C, and a solution of KHMDS

(6.22 mL, 1.24 mmol, 0.5 M in PhMe) was added. The solution was stirred for at 0 °C for 15 min and benzyl bromide (0.197 mL, 1.66 mmol) was added. The resulting solution was stirred at 0 °C for 0.5 h then at rt for 24 h, concentrated and directly purified by column chromatography on SiO2

25 (Hexanes:EtOAc, 1:0 then 20:1) to yield 2-23 (660 mg, 98%) as a light yellow oil: [훼]퐷 = -4.3°

(c = 0.42, CHCl3); IR (ATR) ν = 3029, 2919, 2858, 2360, 1480, 1452, 1358, 1207, 1066, 872,

-1 1 730, 694 cm ; H NMR (300 MHz, CDCl3) δ 7.38-7.23 (m, 20H), 5.07 (d, J = 11.1 Hz, 1H), 4.96

(d, J = 10.9 Hz, 1H), 4.85 (d, J = 10.8 Hz, 1H), 4.84 (d, J = 10.9 Hz, 1H), 4.54-4.69 (m, 4H),

3.78-3.61 (m, 5H), 3.52 (d, J = 10.8 Hz, 1H), 3.32-3.27 (m, 1H), 1.40-1.30 (m, 6H), 1.33-1.21 (m,

13 6H), 1.08-0.87 (m, 6H), 0.85 (t, J = 7.3 Hz, 9H); C NMR (75 MHz, CDCl3) δ 138.8, 138.7,

138.7, 138.5, 128.6, 128.5, 128.4, 128.4, 128.0, 127.9, 127.9, 127.8, 127.8, 127.7, 127.6, 127.6,

127.5, 89.7, 83.4, 81.8, 79.4, 77.2, 75.5, 75.2, 74.8, 74.5, 73.6, 72.3, 69.6, 29.2, 27.6, 13.8, 9.2;

+ FT-HRMS (ESI) calcd for C46H62O5SnNa [M + Na] : 837.3511, found 837.3509.

105

(3,4,6-Tri-O-benzyl--D-galactopyranosyl)tri-n-butylstannane (2-25). To a solution of tri-O- benzyl-D-galactal (1.04 g, 2.50 mmol) in a cooled (0 °C), vigorously stirring biphasic solution of

® CH2Cl2 (20 mL), saturated aq. NaHCO3 (33 mL), and acetone (2 mL), a solution of Oxone (6.16 g, 10 mmol) in H2O (25 mL) was added dropwise over 15 min. The reaction mixture was stirred at 0 °C for 0.5 h then at rt for 2 h, the organic phase was separated, and extracted with CH2Cl2 (2 x 20 mL). The combined organic layers were dried (Na2SO3) and concentrated to afford the epoxide as a white solid. The crude epoxide was dissolved in anhydrous and degassed THF (30 mL), cooled to -20 °C (ice salt bath), and a solution of MeMgSnBu3 (1.24 g, 3.75 mmol) in THF was added. The reaction was stirred at -20 °C for 2 h, quenched with H2O (30 mL), filtered twice through Celite®, and the organic phase was separated. The aqueous phase was extracted with

CH2Cl2 (3 × 20 mL), and the combined organic layers were dried (Na2SO4), concentrated, and purified by column chromatography on SiO2 (Hexanes:EtOAc, 1:0 then 20:1) to afford 2-25 (1.10

23 g 61%) as a light yellow oil: [훼]퐷 = +4.9 (c = 1.00, CHCl3); IR (ATR) ν = 3029, 2918, 2857,

-1 1 2359, 1453, 1358, 1207, 1064, 574, 731, 694, 595 cm ; H NMR (300 MHz, CDCl3) δ 7.38-7.27

(m, 15H), 4.89 (d, J = 11.7 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.54-

4.49 (m, 2H), 4.45 (d, J = 11.8 Hz, 1H), 4.24-4.17 (m, 1H), 4.05-4.04 (m, 1H), 3.62-3.52 (m, 2H),

3.48-3.40 (m, 2H), 3.34-3.30 (m, 1H), 2.22 (dd, J = 2.6, 1.9 Hz, 1H), 1.65-1.40 (m, 6H), 1.36-

13 1.24 (m, 6H), 1.06-0.91 (m, 6H), 0.87 (t, J = 7.2 Hz, 9H); C NMR (75 MHz, CDCl3) δ 139.2,

138.3, 138.2, 128.7, 128.5, 128.3, 128.0 (3), 127.8, 127.7, 127.4, 86.6, 81.3, 76.2, 74.5, 73.7, 73.6,

+ 71.7, 70.3, 69.4, 29.2, 27.5, 13.9, 9.1; FT-HRMS (ESI) calcd for C39H56O5SnNa [M + Na] :

747.3042, found 747.3043.

(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)tri-n-butylstannane (2-26). A solution of 2-25

(600 mg, 0.828 mmol) in anhydrous THF (5 mL) was cooled to 0 °C, and a solution of KHMDS

106

26 (Hexanes:EtOAc, 1:0 then 20:1) to yield 2-26 (660 mg, 97%) as a light yellow oil: [훼]퐷 = +3.2

(c = 1.00, CHCl3); IR (ATR) ν = 3029, 2918, 1857, 2359, 1452, 1358, 1206, 1089, 871, 731, 694.

-1 1 596 cm ; H NMR (300 MHz, CDCl3) δ 7.56 – 7.07 (m, 20H), 5.14 (d, J = 11.1 Hz, 1H), 5.01 (d,

J = 11.8 Hz, 1H), 4.80 (d, J = 11.5 Hz, 1H), 4.69 – 4.58 (m, 3H), 4.52 (d, J = 11.8 Hz, 1H), 4.45

(d, J = 11.8 Hz, 1H), 4.16 (dd, J = 10.9, 8.9 Hz, 1H), 4.06 (dd, J = 2.9, 1.1 Hz, 1H), 3.64 – 3.55

(m, 3H), 3.50 (d, J = 11.0 Hz, 1H), 3.46 – 3.40 (m, 1H), 1.56 – 1.41 (m, 6H), 1.35 – 1.21 (m, 6H),

13 0.98 – 0.78 (m, 15H); C NMR (75 MHz, CDCl3) δ 139.3, 138.9, 138.4, 138.2, 128.4 (2), 128.1

(2), 127.8, 127.7, 127.6 (3), 127.5, 127.3, 127.2, 87.4, 80.8, 77.9, 75.1, 74.6, 74.4, 74.3, 73.5,

+ 71.7, 69.4, 29.1, 28.9, 27.4, 13.7, 9.1; FT-HRMS (ESI) calcd for C46H62O5SnNa [M + Na] :

837.3511, found 837.3518.

(3,4,6-Tri-O-benzyl-2-deoxy-β-D-glucopyranosyl)tri-n-butylstannane (2-32). To a cold (0 ℃)

i solution of Pr2NH (0.80 mL, 5.7 mmol) in anhydrous and degassed THF (10 mL), n-BuLi (3.13 mL, 5.00 mmol, 1.6 M in hexanes) was added. The reaction mixture was stirred at 0 °C for 5 min,

Bu3SnH (1.32 mL, 1.45 g, 5.00 mmol) was added and the reaction was left to stir at 0 °C for 20 min. In a separate flask, a solution of 3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl chloride 2-

21 (1.18 g, 2.60 mmol) in anh. THF (10 mL) was cooled to 0 ℃ and the stannane reagent (11.89 mL, 3.9 mmol) was added at 0 ℃ over 20 min. The reaction was stirred at 0 ° for 1.5 h, quenched with H2O (50 mL) and extracted with Et2O. The combined organic layers were dried (MgSO4),

107 concentrated, and purified by column chromatography on SiO2 (Hexanes:EtOAc, 1:0 to 10:1) to

26 afford 2-32 (1.04 g, 56%) as a colorless oil: [훼]퐷 = -9.1 (c = 1.00, CHCl3); IR (ATR) ν = 2851,

-1 1 1746, 1452, 1358, 1095, 875, 730, 694, 595 cm ; H NMR (400 MHz, CD3Cl) δ 7.39 – 7.29 (m,

15H), 4.90 (d, J = 10.8 Hz, 1H), 4.67 (d, J = 12.0 Hz, 2H), 4.62 (d, J = 11.2 Hz, 2H), 4.54 (d, J =

12.3 Hz, 1H), 3.71 – 3.67 (m, 2H), 3.62 (dd, J = 13.3, 1.8 Hz, 1H), 3.58 – 3.50 (m, 1H), 3.47 (t,

J = 9.0 Hz, 1H), 3.26 – 3.16 (m, 1H), 2.12 (ddd, J = 13.1, 5.0, 2.0 Hz, 1H), 1.89 – 1.75 (m, 1H),

13 1.58 – 1.39 (m, 6H), 1.37 – 1.05 (m, 6H), 1.02 – 0.71 (m, 15H); C NMR (101 MHz, CDCl3) δ

139.0 (2), 138.89, 128.5 (2), 128.4, 128.2, 127.8, 127.7, 127.7, 127.6, 127.4, 83.2, 83.0, 79.3,

75.3, 73.5, 71.7, 70.8, 70.1, 37.1, 29.2, 27.6, 13.9, 8.7; FT-HRMS (ESI) calcd for C39H56O4SnNa

[M + Na]+: 731.3093, found 731.3102.

(2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-glucopyranosyl)tri-n-butylstannane (2-33).

To a suspension of N-acetyl-3,4,6-tri-O-benzyl-D-glucosamine 2-18 (387 mg, 0.790 mmol) in

CHCl3 (4 mL) and toluene (2 mL), SOCl2 (2 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 30 min and concentrated to afford the anomeric

i chloride 2-19 as a yellow solid residue. To a cooled (-78 ℃) solution of Pr2NH (0.35 mL, 2.5 mmol) in anh. THF (1.5 mL) n-BuLi (2.00 mL, 2.40 mmol, 1.2 M in hexane) was added dropwise.

After 2 min, Bu3SnH (0.68 mL, 2.50 mmol) was added dropwise, the reaction mixture was stirred at -78 °C for 30 min, and a solution of the anomeric chloride in anh. THF (6 mL) was added to this solution at -78 °C. The reaction was then stirred at -78 °C for another 2 h and quenched with

108 saturated aq. NH4Cl (1 mL). The reaction mixture was allowed to warm up to room temperature and partitioned between water and CH2Cl2. The organic layer was dried (Na2SO4), concentrated, and the residue was purified by column chromatography on SiO2 (Hexanes:EtOAc, 1:0 to 5:1) to

23 afford 2-33 (198 mg, 33%) as a yellow syrup: [훼]퐷 = +17.6 (c 1.00, CHCl3); IR (ATR): 3286,

-1 1 3036, 2919, 2860, 1648, 1542, 1454, 1365, 1085, 740 cm ; H NMR (500 MHz, CDCl3) δ 7.42-

7.26 (m, 15H), 4.88 (d, J = 11.7 Hz, 1H), 4.85-4.81 (m, 2H), 4.66 (d, J = 11.4 Hz, 2H), 4.64 (d, J

= 12.3 Hz, 1H), 4.56 (d, J = 12.3 Hz, 1H), 4.17 (dt, J = 11.7, 9.5 Hz, 1H), 3.66 (dd, J = 9.7, 8.9

Hz, 1H), 3.47 (d, J = 11.7 Hz, 1H), 3.42 (t, J = 9.2 Hz, 1H), 3.27 (ddd, J = 9.8, 4.2, 2.1 Hz, 1H),

13 1.56-1.41 (m, 6H), 1.37-1.21 (m, 6H), 0.99-0.80 (m, 15H); C NMR (101 MHz, CDCl3) δ 9.3,

13.9, 23.7, 27.6, 29.3, 54.8, 69.6, 73.6, 74.8, 75.0, 75.1, 79.5, 83.6, 85.6, 127.5 (2), 127.9 (2),

128.2, 128.4 (2), 128.6 (2), 128.7, 138.4, 138.8 (2), 169.6; IR (ATR): 3286, 3036, 2919, 2860,

-1 + 1648, 1542, 1454, 1365, 1085, 740 cm ; HRMS (ESI) calculated for C41H59NNaO5Sn [M + Na] :

788.3307, found 788.3308.

(3,4,6-Tri-O-benzyl-2-deoxy-α-D-glucopyranosyl)tri-n-butylstannane (2-45). To a flask containing 3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl chloride 2-21 (0.587 g, 1.30 mmol), anh./degassed THF (11 mL) was added under a nitrogen atmosphere followed by stirring at -

100 °C. Then, freshly prepared lithium naphthalenide solution (1 M in THF, 4.55 mL, 4.55 mmol) was added quickly and the reaction was stirred for 15 min, followed by the addition of tributyltin chloride (1.23 mL, 4.55 mmol). The reaction mixture was allowed to slowly warm up to rt. The reaction mixture was quenched with H2O (25 mL), extracted with Et2O, dried (MgSO4), and concentrated. The residue was purified by column chromatography on SiO2 (Hexanes:EtOAc, 1:0

109

25 then 5:1) to afford 2-45 (370 mg, 42%) as a colorless oil: [훼]퐷 = +77.8 (c = 0.083, CHCl3); IR

(ATR) ν = 3029, 2920, 2858, 2359, 1453, 1359, 1201, 1086, 1016, 907, 731, 694, 594 cm-1;1H

NMR (400 MHz, CDCl3) δ 7.43 – 7.24 (m, 15H), 4.97 (d, J = 11.1 Hz, 1H), 4.75 (d, J = 11.9 Hz,

1H), 4.68(d, J =11.89 Hz, 1H) , 4.66 (d, J = 12.3 Hz, 2H), 4.60 (d, J = 11.1 Hz, 1H), 4.57 (t, J =

4.16 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 3.78 (dd, J = 10.4, 4.2 Hz, 1H), 3.71 (dd, J = 10.3, 2.2

Hz, 1H), 3.66 – 3.57 (m, 1H), 3.58 (t, J = 8.5 Hz, 1H) 3.22 (dt, J = 6.9, 2.1 Hz, 1H), 2.24 (dd, J

= 7.0, 3.8 Hz, 2H), 1.57 – 1.45 (m, 6H), 1.39 – 1.29 (m, 9H), 0.99 – 0.87 (m, 12H); 13C NMR

(101 MHz, CDCl3) δ 138.9, 138.7, 138.4, 80.9, 79.3, 78.8, 74.9, 73.6, 72.0, 71.4, 69.5, 36.3, 29.3,

+ 27.6, 13.8, 10.1; FT-HRMS (ESI) calcd for C39H56O4SnNa [M + Na] : 731.3093, found 731.3109.

(3,4,6-Tri-O-benzyl-α-D-glucopyranosyl)tri-n-butylstannane (2-50). To a flask charged with

2-8 (1.00 g, 2.31 mmol) was added 4 M HCl in dioxane (30 mL). The resulting solution was stirred for 12 h and concentrated to give 3,4,6-tri-O-benzyl-α-D-glucopyranosyl chloride (2-47) as a light yellow oil which was directly submitted to the following step. The solution of 2-47 (422 mg, 0.900 mmol) in anh/degassed THF (9 mL) was cooled to -100 ℃, treated with n-BuLi (0.771 mL, 1.08 mmol, 1.4 M in hexane) and then immediately with a solution of lithium naphthalenide

(1.98 mL, 1.98 mmol, 1 M in THF). The dark reaction mixture was stirred at -100 ℃ for 15 min, tributyltin chloride (0.732 mL, 2.7 mmol) was added and the resulting light yellow mixture was stirred at -100 ℃ for 1 h. The reaction mixture was then allowed to warm up to rt over 1 h, quenched with H2O (10 mL), extracted with CH2Cl2, dried (Na2SO4), and concentrated. The resultant residue was purified by chromatography on SiO2 (Hexanes:EtOAc, 1:0 then 10:1, then

110

26 5:1) to afford 2-50 (313 mg, 48%) as a clear oil: [훼]퐷 = +59.8 (c = 1.00, CHCl3); IR (ATR) ν =

3301, 3029, 2919, 2857, 1453, 1357, 1206, 1070, 864, 731, 694, 596 cm-1; 1H NMR (300 MHz,

CDCl3) δ 7.37 – 7.19 (m, 15H), 4.85 (d, J = 11.6 Hz, 1H), 4.75 (d, J = 11.1 Hz, 1H), 4.67 (d, J =

11.7 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H),4.57 (J = 8.31, 2.4 Hz, 1H), 4.51 (d, J = 12.1 Hz, 1H),

3.95 (ddd, J = 7.3, 6.0, 4.5 Hz, 1H), 3.78 (dd, J = 10.4, 4.5 Hz, 1H), 3.68 (dd, J = 10.4, 2.9 Hz,

1H), 3.62 (t, J = 7.7 Hz, 1H), 3.43 (t, J = 7.7 Hz, 1H), 3.37 (ddd, J = 7.6, 4.4, 2.9 Hz, 1H), 2.47

(d, J = 4.5 Hz, 1H), 1.57-1.42 (m, 6H), 1.31 (h, J = 7.1 Hz, 6H), 0.90 (q, J = 7.6, 7.1 Hz, 25H);13C

NMR (75 MHz, CDCl3) δ 138.7, 138.3, 128.8, 128.5 (2), 128.0, 128.0, 127.9, 127.9, 127.9, 127.7,

83.9, 78.3, 77.4, 75.7, 74.6, 74.1, 73.7, 68.8, 29.3, 27.6, 13.9, 10.4; FT-HRMS (ESI) calcd for

+ C39H56O5SnNa [M + Na] : 747.3042, found 747.3048.

(2,3,4-Tri-O-benzyl-b-D-glucopyranosyl)tri-n-butylstannane (2-74). A solution of (3,4-di-O- benzyl-6-O-tert-butyldiphenylsilyl- -D-glucopyranosyl)tri-n-butylstannan 2-73 (385 mg, 0.487 mmol) in anh. THF (5 mL) was cooled to 0 °C, and a solution of KHMDS (0.97 mL, 0.97 mmol,

1.0 M in THF) was added. The solution was stirred at 0 °C for 0.5 h, BnBr (0.128 mL, 1.08 mmol) was added, and the resulting solution was stirred for additional 0.5 h at 0 °C and then for 4 h at rt. The reaction was concentrated and directly purified by column chromatography on SiO2

(Hexanes:EtOAc, 1:0 then 50:1) to yield the intermediate. Under N2, the intermediate (65.9 mg,

0.100 mmol) and anh. THF (2 mL) were successively added into a flame dried flask. The mixture was cooled to 0°C for 30 min followed by the addition of TBAF (0.11 mL, 0.11 mmol, 1.0 M in

111

THF). The reaction mixture was warmed up to rt and stirred overnight. Purification by column chromatography on SiO2 (Hexanes:EtOAc, 10:1) afforded 2-74 (52.0 mg, 82%) as a colorless oil:

25 [훼]퐷 = -5.04 (c = 0.50, CHCl3); IR (ATR) = 2920, 2866, 2360, 1593, 1469, 1441, 1361, 1269,

-1 1 1098, 786, 738, 698 cm ; H NMR (300 MHz, CDCl3) δ 7.23 - 7.23 (m, 15H), 5.07 (d, J = 11.2

Hz, 1H), 4.96 (d, J = 10.9 Hz, 1H), 4.90 - 4.83 (m, 2H), 4.65 (dd, J = 11.0, 6.4 Hz, 2H), 3.83 (ddd,

J = 11.6, 6.2, 2.8 Hz, 1H), 3.77 - 3.50 (m, 5H), 3.23 (ddd, J = 9.5, 5.0, 2.8 Hz, 1H), 1.87 - 1.82

(m, 1H), 1.56 - 1.43 (m, 6H), 1.33 - 1.21 (m, 6H), 1.01 - 0.79 (m, 15H); 13C NMR (75 MHz,

CDCl3) δ 138.6, 138.5, 138.2, 128.6 (2), 128.4, 128.1, 128.0, 127.8 (2), 127.6, 127.5, 89.4, 82.8,

81.7, 79.3, 75.5, 75.3, 74.7, 74.5, 62.8, 29.3, 27.5, 13.8, 9.2; HRMS (ESI) m/z calcd for

+ C39H56O5SnNa [M + Na] 747.3042, found 747.3052.

(6-O-Benzoyl-2,3,4-tri-O-benzyl--D-glycopyranosyl)tri-n-butylstannane (2-75). To a solution of (2,3,4-tri-O-benzyl--D-glycopyranosyl)tri-n-butylstannane 2-74 (144.7 mg, 0.200 mmol) in 6 mL Pyridine was added Bz2O (90.5mg, 0.400 mmol) and DMAP (2.4 mg, 0.020mmol) at room temperature. After stirring overnight, H2O was added to the reaction mixture, extracted with EtOAc (3 × 10ml) and dried with Na2SO4. The product was afforded after chromatographic

23 purification on SiO2 (Hexanes:EtOAc, 10:1) 2-75 (136.1 mg, 80%) as a colorless liquid: [훼]퐷 =

-1 1 +7.2 (c = 1.00, CHCl3); IR (ATR) ν = 2919, 1721, 1453, 1270, 1066, 875, 695, 599 cm ; H

NMR (300 MHz, CDCl3) δ 8.08 - 8.03 (m, 2H), 7.61 - 7.53 (m, 1H), 7.50 - 7.39 (m, 2H), 7.37 -

112

7.26 (m, 15H), 5.09 (d, J = 11.1 Hz, 1H), 4.97 (d, J = 10.7 Hz, 1H), 4.92 (d, J = 10.8 Hz, 1H),

4.89 (d, J = 10.8 Hz, 1H), , 4.68 (d, J = 11.1 Hz, 1H),4.65 (d, J = 10.8 Hz, 1H), 4.59 (dd, J = 11.8,

2.1 Hz, 1H), 4.40 (dd, J = 11.8, 4.9 Hz, 1H), 3.84 - 3.52 (m, 4H), 3.47 (ddd, J = 9.4, 5.0, 2.0 Hz,

13 1H), 1.59 - 1.29 (m, 6H), 1.28 - 1.14 (m, 6H), 1.02 - 0.74 (m, 15H); C NMR (75 MHz, CDCl3)

δ 166.4, 138.5, 138.4, 138.0, 133.1, 130.3, 129.8, 128.7, 128.4 (2), 128.1 (2), 128.0, 127.9, 127.6,

127.5, 89.6, 81.9, 80.8, 79.3, 75.7, 75.4, 74.7, 74.6, 64.2, 29.2, 27.5, 13.8, 9.2; HRMS (ESI) m/z

+ calcd for C46H60O6SnNa [M + Na] 851.3304, found 851.3320.

(2,3,4-Tri-O-benzyl-6-O-levulinyl--D-glucopyranosyl)tri-n-butylstannane (2-76). To the solution of (2,3,4-tri-O-benzyl-β-D-glucopyranosyl)tri-n-butylstannane 2-74 (201 mg, 0.28 mmol) and levulinic acid (LevOH, 80.0 mg, 0.69 mmol) in dry DCM (4 mL) was added N,N’- diisopropylcarbodiimide (DIC, 0.1 mL, 0.6 mmol) followed by DMAP (4 mg, 0.03 mmol). The resulting mixture was allowed to stir at room temperature overnight, concentrated, and purified by silica-gel column chromatography (Hexanes, Hexane:EtOAc 20:1) to afford 2-76 (210 mg,

1 93%) as a colorless oil: H NMR (500 MHz, CDCl3) δ 7.49 - 7.19 (m, 15H), 5.07 (d, J = 11.1 Hz,

1H), 4.96 (d, J = 10.9 Hz, 1H), 4.89 (dd, J = 10.9, 9.2 Hz, 2H), 4.64 (dd, J = 24.5, 11.0 Hz, 1H),

4.33 (dd, J = 11.7, 2.1 Hz, 1H), 4.17 (dd, J = 11.7, 5.4 Hz, 1H), 3.78 - 3.65 (m, 2H), 3.56 - 3.46

(m, 2H), 3.35 (ddd, J = 9.8, 5.5, 2.1 Hz, 1H), 2.75 (td, J = 6.7, 2.7 Hz, 2H), 2.59 (t, J = 6.7 Hz,

2H), 2.20 (s, 3H), 1.57 - 1.41 (m, 6H), 1.34 - 1.22 (m, 6H), 0.97 - 0.83 (m, 15H); 13C NMR (126

MHz, CDCl3) δ 206.5, 172.6, 138.5, 138.5, 138.0, 128.6, 128.6, 128.4, 128.1, 128.0, 127.8, 127.8,

127.6, 127.5, 89.5, 81.7, 80.6, 79.2, 75.5, 75.3, 74.6, 74.5, 64.1, 38.0, 30.0, 29.1, 28.0, 27.5, 13.8,

+ 9.2; C44H62NaO7SnNa [M + Na] : 844.6722, found 844.6729.

113

(2,3,4-Tri-O-benzyl-6-deoxy-6-iodo--D-glucopyranosyl)tri-n-butylstannane (2-77). To a solution of iodine (251 mg, 0.990 mmol) in anh. DCM (5.0 mL) was added PPh3 (525 mg, 1.00 mmol) at 0 oC. Imidazole (270 mg, 3.97 mmol) was then added in one portion and the mixture was stirred at 0 oC for another 0.5 h. To this reaction mixture a solution of (2,3,4-tri-O-benzyl--

D-glucopyranosyl)tri-n-butylstannane 2-74 (204 mg, 0.28 mmol) in DCM (3.0 mL) was added dropwise, and the resulting solution was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated and purified by column chromatography on SiO2 (DCM:Hexanes, 1:5)

23 to yield iodide 2-77 (166 mg, 71%) as a colorless oil: [훼]퐷 = -2.0 (c = 1.00, CHCl3); IR (ATR) n

= 3028, 2923, 2853, 1719, 1600, 1494, 1451, 1359, 1268, 1205, 1093, 1025, 906, 805, 733, 695

-1 1 cm ; H NMR (500 MHz, CDCl3) δ 7.43 - 7.27 (m, 15H), 5.11 (d, J = 11.1 Hz, 1H), 5.03 - 4.95

(m, 2H), 4.91 (d, J = 10.9 Hz, 1H), 4.80 (d, J = 10.9 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 3.79

(dd, J = 10.9, 8.5 Hz, 1H), 3.73 (t, J = 8.6 Hz, 1H), 3.63 (d, J = 10.9 Hz, 1H), 3.51 (dd, J = 10.5,

2.7 Hz, 1H), 3.46 (t, J = 9.0 Hz, 1H), 3.33 (dd, J = 10.5, 5.8 Hz, 1H), 2.95 (ddd, J = 8.8, 5.8, 2.6

Hz, 1H), 1.62 - 1.48 (m, 6H), 1.37 - 1.29 (m, 6H), 1.04 - 0.87 (m, 15H); 13C NMR (126 MHz,

CDCl3) δ 138.4 (2), 138.1, 128.7, 128.6, 128.4, 128.0 (2), 127.8, 127.6, 127.4, 89.1, 81.8, 75.6,

75.6, 74.5, 74.3, 29.2, 27.6, 13.9, 9.3, 7.9; HRMS (ESI) m/z calcd for C39H55IO4Sn 857.2059, found 857.2120.

(6-Azido-2,3,4-tri-O-benzyl-6-deoxy--D-glucopyranosyl)tri-n-butylstannane (2-78). A mixture of (2,3,4-tri-O-benzyl-6-deoxy-6-iodo--D-glucopyranosyl)tri-n-butylstannane 2-77

(70.0 mg, 0.084 mmol), NaN3 (24 mg, 0.34 mmol) in anh. DMF (1 mL) was stirred at 110 °C for

114

10 h. The resulting mixture was diluted with EtOAc and washed with water and brine, dried

(Na2SO4), concentrated, and purified by column chromatography on SiO2 (DCM:Hexanes, 1:1)

25 to yield 2-78 (41.0 mg, 65%) as a colorless oil:[훼]퐷 = +12.7 (c = 0.50, CHCl3); IR (ATR) n =

3030, 2919, 2858, 2099, 1453, 1359, 1284, 1209, 1076, 907, 860, 729, 695, 594 cm-1; 1H NMR

(400 MHz, CDCl3) δ 7.41 - 7.27 (m, 15H), 5.10 (d, J = 11.1 Hz, 1H), 4.96 (d, J = 10.9 Hz, 1H),

4.94 - 4.87 (m, 2H), 4.69 (d, J = 11.1 Hz, 1H), 4.65 (d, J = 10.9 Hz, 1H), 3.78 (dd, J = 11.1, 8.4

Hz, 1H), 3.68 (t, J = 8.7 Hz, 1H), 3.61 - 3.54 (m, 2H), 3.51 (dd, J = 13.0, 2.3 Hz, 1H), 3.34 (ddd,

J = 9.4, 4.9, 2.3 Hz, 1H), 3.22 (dd, J = 13.1, 5.0 Hz, 1H), 1.60 - 1.41 (m, 6H), 1.30 (h, J = 7.3 Hz,

13 6H), 1.03 - 0.85 (m, 15H); C NMR (101 MHz, CDCl3) δ 138.5, 138.1, 128.6 (2), 128.4, 128.0

(2), 127.8, 127.6, 127.5, 89.4, 82.2, 81.7, 79.6, 75.5, 75.4, 74.6, 74.6, 51.8, 29.2, 27.5, 13.8, 9.1;

+ HRMS (ESI) m/z calcd for C39H55N3O4SnNa [M + Na] 772.3107, found 772.3124.

(2,3,4-Tri-O-benzyl-4,5-dehydro-6-deoxy--D-glucopyranosyl)tri-n-butylstannane (2-80).

To a solution of (2,3,4-tri-O-benzyl-6-deoxy-6-iodo--D-glucopyranosyl)tri-n-butylstannane 2-

77 (105 mg, 0.120 mmol) in anh. THF under N2 atmosphere was added solid tBuOK (135 mg,

1.20 mmol) in one portion. The resulting suspension was stirred at rt for 6 h then quenched with water. The mixture was extracted with DCM, and the combined organic layers were dried

(Na2SO4)) concentrated, and purified by column chromatography on SiO2 (DCM:Hexanes, 1:5)

25 to yield 2-80 (55.0 mg, 62%) as a colorless oil: [훼]퐷 = +39.2 (c = 0.05, CHCl3); IR (ATR) n =

-1 1 2855, 2360, 1740, 1606, 1455, 1208, 1093, 765, 668 cm ; H NMR (400 MHz, CDCl3) δ 7.40 -

115

7.26 (m, 15H), 4.72 - 4.46 (m, 7H), 4.02 (s, 1H), 3.71 (t, J = 2.1 Hz, 1H), 1.82 (s, 3H), 1.46 - 1.34

13 (m, 6H), 1.23 (dq, J = 14.3, 7.2 Hz, 6H), 0.90 - 0.79 (m, 15H); C NMR (101 MHz, CDCl3) δ

146.2, 138.6, 138.4, 138.2, 130.5, 128.5, 128.4 (2), 128.2, 128.1, 128.0, 127.8 (2), 127.7, 76.5,

74.2, 71.5, 71.4, 71.1, 70.5, 29.1, 27.6, 14.5, 13.9, 11.0; HRMS (ESI) m/z calcd for C39H54O4SnNa

[M + Na]+ 729.2936, found 729.2972.

Tri-n-butyl-(β-D-glucopyranosyl)stannane (2-81). Freshly cut sodium (0.580 g, 25.2 mmol) was added to liquid NH3 (ca. 40 mL) at -78 ℃ followed by a solution of 2-23 (83.0 mg, 0.110 mmol) in anhydrous dioxane (2 mL). This dark blue reaction mixture was stirred under reflux (-

34 ℃) for 2 h, cooled to -78 °C and solid NH4Cl was added portion-wise until the color disappeared. The resulting suspension was allowed to warm up to rt, the residue was washed with

EtOAc, filtered, and concentrated. Purification by column chromatography on SiO2 (CH2Cl2 then

24 EtOAc) to afford 2-81 (40.0 mg, 80%) as a colorless oil: [훼]퐷 = -30.0 (c = 1.00, CHCl3); IR

(ATR) ν = 3350, 2921, 2858, 1458, 1375, 1248, 1068, 1014, 873, 690, 596, 504 cm-1; 1H NMR

(300 MHz, CDCl3) δ 4.55 (br, 1H), 4.30 (br, 1H), 3.86 – 3.66 (m, 2H), 3.69 – 3.54 (m, 1H), 3.55

– 3.43 (m, 3H), 3.44 – 3.32 (m, 1H), 3.14 (dt, J = 9.2, 3.5 Hz, 1H), 2.47 (t, J = 5.9 Hz, 1H), 1.91

116

(s, 1H), 1.63 – 1.41 (m, 6H), 1.40 – 1.23 (m, 6H), 1.03 – 0.84 (m, 15H); 13C NMR (75 MHz,

CDCl3) δ 9.1, 13.9, 27.5, 29.3, 62.8, 71.1, 74.1, 75.8, 77.6, 80.7, 82.7; HRMS (ESI) calculated

+ for C18H38O5Sn [M + Na] 477.1633, found 477.1631.

Tri-n-butyl-(α-D-glucopyranosyl)stannane (2-84). Freshly cut sodium (0.550 g, 23.9 mmol) was added to liquid NH3 (ca. 40 mL) at -78 ℃ followed by a solution of 2-50 (0.220 g, 0.270 mmol) in anhydrous dioxane (2 mL). This dark blue reaction mixture was stirred under reflux (-

34 ℃) for 2 h, cooled to -78 ℃ and solid NH4Cl was added portion-wise until the color disappeared. The resulting suspension was allowed to warm up to rt, the residue was washed with

EtOAc, filtered, and concentrated. Purification by column chromatography on SiO2 (CH2Cl2 then

24 EtOAc) afford 2-84 (78.0 mg, 84%) as a colorless oil: [훼]퐷 = +51.1 (c = 1.00, CHCl3); IR (ATR)

-1 1 ν = 3337, 2921, 2860, 1459, 1286, 1064, 1021, 863, 662 cm ; H NMR (500 MHz, CD3CN) δ

4.46 (d, J = 7.1 Hz, 1H), 3.75 (ddd, J = 8.3, 7.0, 3.2 Hz, 1H), 3.68 (ddd, J = 11.7, 6.3, 3.0 Hz,

1H), 3.55 (dt, J = 11.7, 5.8 Hz, 1H), 3.48 (d, J = 3.4 Hz, 1H), 3.35 (d, J = 3.8 Hz, 1H), 3.28 (d, J

= 4.3 Hz, 1H), 3.22-3.10 (m, 2H), 2.90 (ddd, J = 8.7, 5.4, 3.0 Hz, 1H), 2.66 (t, J = 6.3 Hz, 1H),

13 1.65-1.40 (m, 6H), 1.39-1.24 (m, 6H), 1.00-0.76 (m, 15H); C NMR (101 MHz, CD3CN) δ 11.1,

14.0, 28.2, 29.9, 63.2, 71.9, 73.7, 78.9, 79.1, 81.4; HRMS (ESI) calculated for C18H38O5Sn [M +

Na]+ 477.1633, found 477.1629.

Tri-n-butyl-(β-D-galactopyranosyl)stannane (2-85). Freshly cut sodium (0.549 g, 23.9 mmol) was added to liquid NH3 (ca. 40 mL) at -78 ℃ followed by a solution of 2-26 (202 mg, 0.279 mmol) in anhydrous dioxane (2 mL). This dark blue reaction mixture was stirred under reflux (-

34 ℃) for 2 h, was cooled to -78 ℃ and solid NH4Cl was added portion-wise until the color disappeared. The resulting suspension was allowed to warm up to rt, the residue was washed with

EtOAc, filtered, and concentrated. Purification by column chromatography on SiO2 (CH2Cl2 then

117

25 EtOAc) to afford 2-85 (92 mg, 73%) as a colorless oil: [훼]퐷 = -18.4 (c = 0.075, CHCl3); IR (ATR)

ν = 3385, 2923, 2863, 1713, 1460, 1376, 1252, 1083, 1047, 972, 753, 696, 663, 597 cm-1; 1H

NMR (500 MHz, CD3CN) δ 3.83-3.78 (br, 1H), 3.68 (t, J = 10.0 Hz, 1H), 3.62-3.49 (m, 2H), 3.33

(d, J = 11.1 Hz, 1H), 3.28-3.15 (m, 3H), 3.04 (br, 1H), 2.95 (br, 1H), 2.67 (br, 1H), 1.64-1.44 (m,

13 6H), 1.31 (h, J = 7.3 Hz, 6H), 0.98-0.82 (m, 15H); C NMR (101 MHz, CD3CN) δ 9.5, 14.0,

+ 28.1, 29.8, 62.8, 70.8, 72.1, 76.8, 77.7, 83.4; HRMS (ESI) calculated for C18H38O5Sn [M + Na]

477.1633, found 477.1638.

Tri-n-butyl-(α-D-galactopyranosyl)stannane (2-86). Freshly cut sodium (0.357 g, 15.1 mmol) was added to liquid NH3 (ca. 40 mL) at -78 ℃ followed by a solution of (2,3,4,6-tetra-O-benzyl-

α-D-galactopyranosyl)tri-n-butylstannane (119 mg, 0.164 mmol) in anhydrous dioxane (2 mL).

This dark blue reaction mixture was stirred under reflux (-34 ℃) for 2 h, was cooled to -78 ℃ and solid NH4Cl was added portion-wise until the color disappeared. The resulting suspension was allowed to warm up to rt, the residue was washed with EtOAc, filtered, and concentrated.

Purification by column chromatography on SiO2 (CH2Cl2 then EtOAc) to afford 2-86 (45 mg,

25 60%) as a colorless oil: [훼]퐷 = +68.5 (c = 1.00, CHCl3); IR (ATR) ν = 3394, 2921, 2859, 1457,

-1 1 1375, 1069, 960, 873, 750, 662 cm ; H NMR (500 MHz, CD3CN) δ 4.49 (d, J = 7.1 Hz, 1H),

4.00 (ddd, J = 8.7, 7.0, 3.3 Hz, 1H), 3.80 (ddd, J = 4.6, 3.4, 1.2 Hz, 1H), 3.71 -3.53 (m, 2H), 3.42

(d, J = 3.5 Hz, 1H), 3.23-3.15 (m, 2H), 3.11 (td, J = 5.9, 1.2 Hz, 1H), 2.99 (d, J = 4.4 Hz, 1H),

2.80 (dd, J = 6.9, 5.1 Hz, 1H), 1.58-1.46 (m, 6H), 1.32 (h, J = 7.3 Hz, 6H), 0.96 – 0.84 (m, 15H);

13 C NMR (75 MHz, CD3CN) δ 11.2, 14.0, 28.2, 29.9, 62.7, 70.1, 71.0, 75.5, 79.0, 80.1; IR (ATR):

3394, 2921, 2859, 1457, 1375, 1069, 960, 873, 750, 662 cm-1; HRMS (ESI) calculated for

+ C18H38O5Sn [M + Na] 477.1633, found 477.1632.

118

Tri-n-butyl-(2-deoxy-β-D-glucopyranosyl)stannane (2-87). Freshly cut sodium (0.547 g, 23.8 mmol) was added to liquid NH3 (ca. 40 mL) at -78 ℃ followed by a solution of 2-32 (209 mg,

0.295 mmol) in anhydrous dioxane (2 mL). This dark blue reaction mixture was stirred under reflux (-34 ℃) for 2 h, cooled to -78 °C and solid NH4Cl was added portion-wise until the color disappeared. The resulting suspension was allowed to warm up to rt, the residue was washed with

EtOAc, filtered, and concentrated. Purification by column chromatography on SiO2 (CH2Cl2 then

24 EtOAc) to afford 2-87 (64.0 mg, 50%) as a colorless oil: [훼]퐷 = -9.2 (c = 0.65, CHCl3); IR (ATR)

ν = 3354, 2920, 2867, 1459, 1375, 1251, 1200, 1048, 870, 658, 593 cm-1; 1H NMR (500 MHz,

CDCl3) δ 4.00 (br, 1H), 3.76 (m, 3H), 3.56 (m, 1H), 3.51 (br, 1H), 3.38 (t, J = 9.0 Hz, 1H), 3.08

(dt, J = 9.3, 3.9 Hz, 1H), 2.42 (br, 1H), 2.01 (ddd, J = 13.1, 5.0, 2.0 Hz, 1H), 1.81 (td, J = 13.3,

13 10.8 Hz, 1H), 1.49 (m, 6H), 1.37 – 1.23 (m, 6H), 0.89 (m, 15H); C NMR (101 MHz, CDCl3) δ

8.7, 13.9, 27.5, 29.2, 38.9, 63.0, 71.2, 73.4, 74.6, 82.2; HRMS (ESI) calculated for C18H38O4Sn

[M + Na]+ 461.16834 found 461.1681.

Tri-n-butyl-(2-deoxy-α-D-glucopyranosyl)stannane (2-88). Freshly cut sodium (0.580 g, 25.2 mmol) was added to liquid NH3 (ca. 40 mL) at -78 ℃ followed by a solution of (3,4,6-tri-O- benzyl-2-deoxy-α-D-glucopyranosyl)tri-n-butylstannane (203 mg, 0.287 mmol) in anhydrous dioxane (2 mL). This dark blue reaction mixture was stirred under reflux (-34 ℃) for 2 h, cooled to -78 °C and solid NH4Cl was added portion-wise until the color disappeared. The resulting suspension was allowed to warm up to rt, the residue was washed with EtOAc, filtered, and concentrated. Purification by column chromatography on SiO2 (CH2Cl2 then EtOAc) to afford 2-

25 88 (66.0 mg, 53%) as a colorless oil: [훼]퐷 = +36.6 (c = 0.50, CHCl3); IR (ATR) ν = 3354, 2920,

-1 1 2857, 1459, 1375, 1251, 1200, 1048, 870, 658, 593, 503 cm ; H NMR (500 MHz, CD3CN) δ

4.47 (dd, J = 4.4, 3.4 Hz, 1H), 3.68 (ddd, J = 11.6, 6.2, 3.1 Hz, 1H), 3.56 (dt, J = 11.5, 5.7 Hz,

119

1H), 3.40 (qd, J = 8.4, 3.8 Hz, 1H), 3.30 (d, J = 4.4 Hz, 1H), 3.17 (d, J = 4.3 Hz, 1H), 3.08 (td, J

= 8.9, 4.0 Hz, 1H), 2.90 (ddd, J = 9.0, 5.5, 3.1 Hz, 1H), 2.65 (t, J = 6.2 Hz, 1H), 2.01 – 1.96 (m,

2H), 1.59 – 1.44 (m, 6H), 1.39 – 1.25 (m, 7H), 0.99 – 0.91 (m, 6H), 0.89 (t, J = 7.3 Hz, 9H); 13C

NMR (101 MHz, CD3CN) δ 10.7, 13.9, 28.2, 29.8, 39.5, 63.4, 73.1, 73.7, 74.2, 81.5; HRMS (ESI)

+ calculated for C18H38O4Sn [M + Na] 461.1684, found 461.1686.

3,4,6-Tri-O-benzyl--D-glucopyranosyl acetate (3-9). According to the general protocol A,

(3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), freshly activated 4Å MS, PIDA (64.4 mg, 0.200 mmol), CuCl (19.8 mg, 0.200 mmol), KF (23.2 mg,

0.400 mmol), anh. toluene (1.00 mL), and anh. 1,4-dioxane (1.00 mL) were successively added into a vial. The reaction mixture was stirred at 110 °C for 12 h and afforded after chromatographic

24 purification on SiO2 (Hexanes:EtOAc, 3:1) 3-9 (37.9 mg, 77%) as a colorless oil: []퐷 = +24.0

- (c = 1.00, CHCl3); IR (ATR)  = 3471, 3030, 2925, 1741, 1454, 1365, 1279, 1075, 735, 698 cm

1 1 ; H NMR (400 MHz, CDCl3) δ 7.37 - 7.27 (m, 13H), 7.18 - 7.14 (m, 2H), 5.50 (d, J = 8.0 Hz,

1H), 4.91 (d, J = 11.4 Hz, 1H), 4.84 - 4.78 (m, 2H), 4.64 (d, J = 12.1 Hz, 1H), 4.54 (d, J = 10.8

Hz, 1H), 4.48 (d, J = 12.1 Hz, 1H), 3.80 - 3.69 (m, 3H), 3.65 (td, J = 8.5, 8.1, 2.5 Hz, 1H), 3.63 -

13 3.55 (m, 2H), 2.14 (s, 3H); C NMR (101 MHz, CDCl3) δ 169.5, 138.3, 137.8, 128.6, 128.4,

120

128.4, 128.0, 127.9, 127.8, 127.7, 94.0, 84.5, 77.1, 75.6, 75.3, 74.9, 73.5, 72.9, 68.0, 21.1; HRMS

+ (ESI) m/z calcd for C29H32O7Na [M + Na] 515.2046, found 515.2050.

3,4,6-Tri-O-benzyl--D-glucopyranosyl benzoate (3-10). According to the general protocol A,

(3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 10 (72.4 mg, 0.100 mmol), freshly activated 4Å MS, phenyliodonium dibenzoate (83.0 mg, 0.200 mmol), CuCl (19.8 mg, 0.200 mmol), KF (23.2 mg, 0.400 mmol), anh. toluene (1.00 mL), and anh. 1,4-dioxane (1.00 mL) were successively added into a vial. The reaction mixture was stirred at 110 °C for 12 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 4:1) 15 (25.0 mg, 45%) as a

24 colorless oil: []퐷 = -197.0 (c = 1.00, CHCl3); IR (ATR)  = 3463, 3029, 2929, 2855, 1728, 1495,

-1 1 1451, 1360, 1107, 1049, 732 cm ; H NMR (500 MHz, CDCl3) δ 8.11 (dd, J = 8.3, 1.4 Hz, 1H),

7.60 - 7.56 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.40 - 7.29 (m, 15H), 5.78 (d, J = 8.1 Hz, 1H), 4.91

(d, J = 11.5 Hz, 1H), 4.77 (d, J = 11.7 Hz, 1H), 4.67 (d, J = 11.5 Hz, 1H), 4.61 (d, J = 11.7 Hz,

1H), 4.50 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 11.8 Hz, 1H), 4.26 (ddd, J = 10.2, 8.1, 2.5 Hz, 1H),

4.10 - 4.07 (m, 1H), 3.87 - 3.83 (m, 1H), 3.74 - 3.67 (m, 1H), 3.64 (dd, J = 9.1, 5.3 Hz, 1H), 3.57

13 (dd, J = 9.7, 2.8 Hz, 1H), 2.31 (d, J = 2.6 Hz, 1H); C NMR (101 MHz, CDCl3) δ 165.3, 137.8,

133.6, 130.3, 128.8, 128.6, 128.5, 128.4, 128.4, 128.2, 128.0, 127.9, 127.9, 95.1, 82.4, 74.9, 74.5,

+ 73.7, 72.4, 72.3, 70.1, 67.9; HRMS (ESI) m/z calcd for C34H34O7Na [M + Na] 577.2202, found

577.2216.

121

3,4,6-Tri-O-benzyl--D-glucopyranosyl pivalate (3-13). According to the general protocol A,

(3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), freshly activated 4Å MS, phenyliodonium dipivalate S1 (75.0 mg, 0.202 mmol), CuCl (19.8 mg, 0.200 mmol), KF (23.2 mg, 0.400 mmol), anh. toluene (1.00 mL), and anh. 1,4-dioxane (1.00 mL) were successively added into a vial. The reaction mixture was stirred at 110 °C for 12 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 5:1) 3-13 (25.0 mg, 64%) as a

24 colorless oil: []퐷 = +27.8 (c = 1.00, CHCl3); IR (ATR)  = 3490, 3080, 2924, 2889, 1736, 1603,

-1 1 1453, 1267, 1072, 737 cm ; H NMR (500 MHz, CDCl3) δ 7.39 - 7.29 (m, 15H), 5.49 (d, J = 8.1

Hz, 1H), 4.88 (d, J = 11.5 Hz, 1H), 4.74 (d, J = 11.8 Hz, 1H), 4.66 (d, J = 11.5 Hz, 1H), 4.57 (d,

J = 11.8 Hz, 1H), 4.50 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.08 (dd, J = 9.7, 8.1 Hz,

1H), 4.04 (dd, J = 3.0, 1.1 Hz, 1H), 3.76 (ddd, J = 7.9, 5.2, 1.1 Hz, 1H), 3.68 (t, J = 8.5 Hz, 1H),

3.62 (dd, J = 9.0, 5.2 Hz, 1H), 3.49 (dd, J = 9.8, 2.9 Hz, 1H), 2.22 (s, 1H), 1.24 (s, 9H); 13C NMR

(101 MHz, CDCl3) δ 177.1, 138.3, 137.7, 128.6, 128.4, 128.3, 128.3, 128.0, 128.0, 127.9, 127.7,

127.7, 94.4, 82.2, 74.7, 74.3, 73.5, 72.2, 72.2, 69.9, 67.7, 38.8, 26.9; HRMS (ESI) m/z calcd for

+ C32H38O7Na [M + Na] 557.2515, found 557.2517.

122

3,4,6-Tri-O-benzyl--D-glucopyranosyl furoate (3-14). According to the general protocol A,

(3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), freshly activated 4 Å MS, phenyliodonium difuroate S2 (79.2 mg, 0.200 mmol), CuCl (19.8 mg, 0.200 mmol), KF (23.2 mg, 0.400 mmol), anh. toluene (1.00 mL), and anh. 1,4-dioxane (1.00 mL) were successively added into a vial. The reaction mixture was stirred at 110 °C for 12 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 5:1) 3-14 (25.0 mg, 64%) as a

24 colorless oil: []퐷 = +12.4 (c = 1.00, CHCl3); IR (ATR)  = 3466, 3029, 2921, 1730, 1576, 1471,

-1 1 1360, 1293, 1178, 1067, 927 cm ; H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 1.7 Hz, 1H), 7.37

- 7.27 (m, 14H), 7.20 - 7.15 (m, 2H), 6.52 (dd, J = 3.5, 1.7 Hz, 1H), 5.73 (d, J = 8.0 Hz, 1H), 4.92

(d, J = 11.4 Hz, 1H), 4.88 - 4.79 (m, 2H), 4.62 (d, J = 12.1 Hz, 1H), 4.57 (d, J = 10.8 Hz, 1H),

4.49 (d, J = 12.1 Hz, 1H), 3.85 - 3.72 (m, 4H), 3.69 - 3.61 (m, 2H), 2.26 (d, J = 3.2 Hz, 1H); 13C

NMR (101 MHz, CDCl3) δ 157.1, 147.2, 143.8, 138.5, 138.0, 137.9, 128.8, 128.6, 128.5, 128.1,

128.1, 128.1, 128.0, 127.9, 119.7, 112.2, 94.5, 84.5, 77.4, 75.9, 75.5, 75.1, 73.7, 73.1, 68.2;

+ HRMS (ESI) m/z calcd for C32H32O8Na [M + Na] 567.1995, found 567.2001.

3,4,6-Tri-O-benzyl--D-glucopyranosyl palmitate (3-15). According to the general protocol A,

(3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), freshly activated 4Å MS, phenyliodonium dipalmate S4 (137 mg, 0.200 mmol), CuCl (19.8 mg, 0.200 mmol), KF (23.2 mg, 0.400 mmol), anh. toluene (1.00 mL), and anh. 1,4-dioxane (1.00 mL) were successively added into a vial. The reaction mixture was stirred at 110 °C for 12 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 10:1) 3-15 (56.6 mg, 82%) as a

24 colorless oil: []퐷 = -14.8 (c = 1.00, CHCl3); IR (ATR)  = 3467, 2923, 2853, 1729, 1616, 1454,

-1 1 1361, 1272, 1070, 711 cm ; H NMR (500 MHz, CDCl3) δ 7.39 - 7.28 (m, 13H), 7.20 - 7.15 (m,

2H), 5.53 (d, J = 8.0 Hz, 1H), 4.92 (d, J = 11.4 Hz, 1H), 4.87 - 4.80 (m, 2H), 4.66 (d, J = 12.1 Hz,

123

1H), 4.57 (d, J = 10.8 Hz, 1H), 4.51 (d, J = 12.1 Hz, 1H), 3.80 - 3.72 (m, 3H), 3.69 - 3.65 (m,

1H), 3.64 - 3.57 (m, 2H), 2.41 (t, J = 7.6 Hz, 2H), 1.65 (p, J = 7.5, 2H), 1.35 - 1.19 (m, 24H), 0.90

13 (t, J = 6.9 Hz, 3H); C NMR (101 MHz, CDCl3) δ 172.6, 138.5, 138.0, 138.0, 128.8, 128.6, 128.5,

128.1, 128.1, 128.1, 128.1, 128.0, 127.9, 94.0, 84.7, 77.3, 75.8, 75.5, 75.1, 73.7, 73.2, 68.2, 34.3,

32.1, 29.8, 29.8, 29.8, 29.6, 29.5, 29.4, 29.2, 24.7, 22.9, 14.3; HRMS (ESI) m/z calcd for

+ C43H60O7Na [M + Na] 711.4236, found 711.4233.

3,4,6-Tri-O-benzyl--D-glucopyranosyl S-(4-isobutylphenyl)propionate (3-16). According to the general protocol A, (3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg,

0.100 mmol), freshly activated 4Å MS, phenyliodonium bis(ibuprofen) S3 (116 mg, 0.200 mmol),

CuCl (19.8 mg, 0.200 mmol), KF (23.2 mg, 0.400 mmol), anh. toluene (1.00 mL), and anh. 1,4- dioxane (1.00 mL) were successively added into a vial. The reaction mixture was stirred at 110 °C for 12 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 10:1) 3-16

24 (49.8 mg, 78%) as a colorless oil: []퐷 = +34.8 (c = 1.00, CHCl3); IR (ATR)  = 3458, 3030,

-1 1 2922, 1751, 1453, 1363, 1269, 1069, 737 cm ; H NMR (500 MHz, CDCl3) δ 7.38 - 7.29 (m,

13H), 7.24 -7.21 (d, J = 8.2 Hz, 2H), 7.19 (dd, J = 7.4, 2.0 Hz, 2H), 7.10 - 7.07 (d, J = 8.2 Hz,

2H), 5.51 (d, J = 7.8 Hz, 1H), 4.89 (d, J = 11.4 Hz, 1H), 4.83 - 4.78 (m, 2H), 4.60 - 4.54 (m, 2H),

4.46 (d, J = 12.1 Hz, 1H), 3.80 (q, J = 7.2 Hz, 1H), 3.75 - 3.69 (m, 3H), 3.65 (td, J = 8.3, 7.9, 2.3

Hz, 1H), 3.62 - 3.56 (m, 2H), 2.43 (d, J = 7.2 Hz, 2H), 2.04 (d, J = 3.2 Hz, 1H), 1.83 (dp, J = 13.5,

13 6.7 Hz, 1H), 1.54 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.6 Hz, 6H); C NMR (101 MHz, CDCl3) δ

173.3, 140.7, 138.3, 138.0, 137.9, 136.9, 129.3, 128.6, 128.4, 128.3, 127.9, 127.9, 127.8, 127.6,

127.2, 94.3, 84.2, 76.7, 75.9, 75.2, 74.8, 73.5, 73.0, 68.0, 45.1, 45.0, 30.1, 22.4, 18.5; HRMS (ESI)

+ m/z calcd for C40H46O7Na [M + Na] 641.3141, found 641.3144.

124

3,4,6-Tri-O-benzyl--D-glucopyranosyl S-(6-methoxynaphthyl)propionate (3-17).

According to the general protocol A, (3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane

3-8 (72.4 mg, 0.100 mmol), freshly activated 4Å MS, phenyliodonium bis(naproxen) (126 mg,

0.200 mmol), CuCl (19.8 mg, 0.200 mmol), KF (23.2 mg, 0.400 mmol), anh. toluene (1.00 mL), and anh. 1,4-dioxane (1.00 mL) were successively added into a vial. The reaction mixture was stirred at 110 °C for 12 h and afforded after chromatographic purification on SiO2

24 (Hexanes:EtOAc, 7:1) 3-17 (49.8 mg, 78%) as a light yellow oil: [푎]퐷 = +46.8 (c = 1.00, CHCl3);

IR (ATR)  = 3410, 3030, 2925, 1731, 1605, 1453, 1360, 1266, 1065, 739 cm-1; 1H NMR (400

MHz, CDCl3) δ 7.69 - 7.64 (m, 3H), 7.40 (dd, J = 8.5, 1.8 Hz, 1H), 7.36 - 7.27 (m, 8H), 7.26 -

7.19 (m, 3H), 7.21 - 7.13 (m, 4H), 7.14 - 7.05 (m, 2H), 5.54 (d, J = 7.5 Hz, 1H), 4.87 (d, J = 11.4

Hz, 1H), 4.81 - 4.73 (m, 2H), 4.55 (d, J = 10.9 Hz, 1H), 4.43 (d, J = 12.1 Hz, 1H), 4.33 (d, J =

12.1 Hz, 1H), 3.98 - 3.87 (m, 4H), 3.71 - 3.52 (m, 6H), 2.10 (s, 1H), 1.61 (d, J = 7.2 Hz, 3H); 13C

NMR (101 MHz, CDCl3) δ 173.3, 157.6, 138.3, 137.9, 137.8, 134.8, 133.7, 129.3, 128.9, 128.6,

128.4, 128.2, 127.9, 127.9, 127.9, 127.8, 127.8, 127.5, 127.1, 126.2, 126.1, 118.9, 105.5, 94.2,

84.1, 75.9, 75.1, 74.7, 73.4, 72.7, 68.0, 55.3, 45.4, 29.7, 18.6; HRMS (ESI) m/z calcd for

C41H42O8Na [M + Na]+ 685.2777, found 685.2785.

125

3,4-Di-O-benzyl--D-arabinopyranosyl acetate (3-20). (3,4-Di-O-benzyl--D-arabinosyl)tri- n-butylstannane (60.3 mg, 0.100 mmol), freshly activated 4Å MS, PIDA (64.4 mg, 0.200 mmol),

24 (22.7 mg, 61%) as a colorless oil: []퐷 = -34.8 (c = 1.00, CHCl3); IR (ATR)  = 3462, 3029,

-1 1 2923, 1743, 1602, 1453, 1366, 1228, 1085, 1050, 738 cm ; H NMR (500 MHz, CDCl3) δ 7.45

- 7.29 (m, 10H), 5.47 (d, J = 7.7 Hz, 1H), 4.77 (d, J = 12.3 Hz, 1H), 4.67 (d, J = 12.2 Hz, 1H),

4.62 (d, J = 12.2 Hz, 1H), 4.52 (d, J = 11.8 Hz, 1H), 4.16 - 4.07 (m, 2H), 3.78 (s, 1H), 3.51 - 3.46

13 (m, 2H), 2.35 (br, 1H), 2.17 (s, 3H); C NMR (101 MHz, CDCl3) δ 169.8, 137.7, 137.5, 128.6,

128.4, 128.4, 128.0, 128.0, 127.8, 127.8, 94.6, 80.2, 71.7, 71.3, 71.1, 69.3, 64.1, 29.7; HRMS

+ (ESI) m/z calcd for C21H24O6Na [M + Na] 395.1471, found 395.1465.

(2,3,4,6-tetra-O-benzyl--D-galactopyranosyl-(1→4)-3,6-di-O-benzyl--D-glucopyanosyl acetate (3-21). [2,3,4,6-Tetra-O-benzyl--D-galactopyranosyl-(1→4)-3,6-di-O-benzyl--D- glucopyranosyl]tri-n-butylstannane (115.6 mg, 0.100 mmol), freshly activated 4Å MS, PIDA

(64.4 mg, 0.200 mmol), CuCl (19.8 mg, 0.200 mmol), KF (23.2 mg, 0.400 mmol), anh. toluene

(1.00 mL), and anh. 1,4-dioxane (1.00 mL) were successively added into a vial. The reaction

126 mixture was stirred at 110 °C for 12 h and afforded after chromatographic purification on SiO2

24 (Hexanes:EtOAc, 1:1) 3-21 (51.8 mg, 56%) as a colorless oil: []퐷 = +24.6 (c = 1.00, CHCl3);

IR (ATR)  = 3460, 3029, 2919, 2869, 1754, 1500, 1453, 1225, 1071, 736 cm-1; 1H NMR (500

MHz, CDCl3) δ 7.37 - 7.27 (m, 20H), 7.24 - 7.19 (m, 10H), 5.52 (d, J = 8.1 Hz, 1H), 5.14 (d, J =

11.1 Hz, 1H), 4.96 (d, J = 11.6 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 4.76 - 4.70 (m, 2H), 4.69 (d,

J = 11.9 Hz, 1H), 4.62 (d, J = 11.1 Hz, 1H), 4.59 - 4.50 (m, 2H), 4.40 - 4.35 (m, 2H), 4.33 (d, J =

12.0 Hz, 1H), 4.29 (d, J = 11.8 Hz, 1H), 4.06 (t, J = 9.3 Hz, 1H), 3.90 (d, J = 3.0 Hz, 1H), 3.84

(dd, J = 11.0, 3.1 Hz, 1H), 3.74 (dd, J = 9.7, 7.7 Hz, 1H), 3.63 - 3.56 (m, 2H), 3.54 (t, J = 8.6 Hz,

1H), 3.51 - 3.46 (m, 2H), 3.43 (dd, J = 9.1, 5.2 Hz, 1H), 3.37 - 3.30 (m, 2H), 2.36 (d, J = 2.4 Hz,

13 1H), 2.13 (s, 3H); C NMR (101 MHz, CDCl3) δ 169.8, 139.1, 138.8, 138.7, 138.6, 138.1, 128.5,

128.5, 128.4, 128.4, 128.4, 128.3, 128.1, 128.0, 128.0, 127.9, 127.7, 127.7, 127.5, 127.5, 102.8,

93.9, 82.9, 82.4, 79.9, 76.1, 75.5, 75.4, 75.0, 74.7, 73.7, 73.6, 73.3, 73.1, 72.7, 72.0, 68.3, 67.6,

+ 21.3; HRMS (ESI) m/z calcd for C56H60O12Na [M + Na] 947.3983, found 947.3972.

2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl acetate (3-22). (2-Acetamido-

3,4,6-tri-O-benzyl-2-deoxy--D-glucosyl)tri-n-butylstannane1 (76.5 mg, 0.100 mmol), freshly activated 4Å MS, PIDA (64.4 mg, 0.200 mmol), CuCl (19.8 mg, 0.200 mmol), KF (23.2 mg,

0.400 mmol), anh. toluene (1.00 mL), and anh. 1,4-dioxane (1.00 mL) were successively added into a vial. The reaction mixture was stirred at 110 °C for 12 h and afforded after chromatographic

24 purification on SiO2 (Hexanes:EtOAc, 2:1) 3-22 (22.7 mg, 73%) as a colorless oil: []퐷 = +75.7

(c = 1.00, CHCl3); IR (ATR)  = 3297, 3030, 2918, 1751, 1654, 1544, 1452, 1372, 1273, 1224,

-1 1 1126, 1027, 941 cm ; H NMR (400 MHz, CDCl3) δ 7.39 - 7.25 (m, 13H), 7.21 - 7.15 (m, 2H),

6.12 (d, J = 3.6 Hz, 1H), 4.91 - 4.84 (m, 2H), 4.80 (d, J = 10.6 Hz, 1H), 4.67 - 4.59 (m, 2H), 4.57

(d, J = 10.5 Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 4.31 (ddd, J = 10.7, 8.6, 3.5 Hz, 1H), 3.86 (dd, J

127

= 9.9, 8.6 Hz, 1H), 3.82 - 3.74 (m, 2H), 3.73 - 3.61 (m, 2H), 2.05 (s, 3H), 1.77 (s, 3H); 13C NMR

(101 MHz, CDCl3) δ 170.0, 169.1, 138.3, 138.0, 137.9, 128.8, 128.7, 128.5, 128.4, 128.3, 128.2,

128.1, 128.0, 127.8, 91.8, 79.1, 76.8, 75.3, 74.7, 73.7, 73.5, 68.2, 51.5, 23.3, 21.0; HRMS (ESI)

+ m/z calcd for C31H35NO7Na [M + Na] 556.2311, found 556.2323.

Methyl 3,4,6-tri-O-benzyl--D-glucopyranoside (3-24). According to the general protocol B,

(3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), methanol (8.00 l, 0.200 mmol), Zn(OTf)2 (7.30 mg, 0.020 mmol), iodosobenzene (66.0 mg,

0.300 mmol), freshly activated 4Å MS and anh. CHCl3 (1.00 mL) were successively added into a vial. The reaction mixture was stirred at room temperature for 24 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 3:1) 3-24 (40.0 mg, 86%) as a colorless

1 oil: H NMR (300 MHz, CDCl3) δ 7.44 - 7.28 (m, 13H), 7.24 - 7.17 (m, 2H), 4.97 (d, J = 11.3

Hz, 1H), 4.89 (d, J = 11.3 Hz, 1H), 4.87 (d, J = 10.8 Hz, 1H), 4.67 (d, J = 12.2 Hz, 1H), 4.63 -

4.54 (m, 2H), 4.22 (d, J = 7.2 Hz, 1H), 3.88 -3.71 (m, 2H), 3.61 - 3.68 (m, 2H), 3.60 (s, 3H),3.58

13 - 3.46 (m, 2H), 2.58 (d, J = 1.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 138.7, 138.2, 138.1, 128.5

(2), 128.4, 128.0 (2), 127.9, 127.8 (2), 127.7, 103.8, 84.6, 77.7, 75.2, 75.1, 74.7, 73.6, 68.9, 57.2.

128

Cyclohexyl 3,4,6-tri-O-benzyl--D-glucopyranoside (3-25). According to the general protocol

B, (3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), cyclohexanol (20.8 l, 0.200 mmol), Zn(OTf)2 (7.30 mg, 0.020 mmol), iodosobenzene (44.0 mg,

0.200 mmol), freshly activated 4Å MS and anh. CHCl3 (1.00 mL) were successively added into a vial. The reaction mixture was stirred at room temperature for 24 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 5:1) 3-25 (45.9 mg, 86%) as a colorless

24 oil: []퐷 = -8.0 (c = 1.00, CHCl3); IR (ATR)  = 3463, 3029, 2929, 2855, 1728, 1495, 1451,

-1 1 1360, 1107, 1049, 732 cm ; H NMR (300 MHz, CDCl3) δ 7.43 - 7.29 (m, 13H), 7.24 - 7.19 (m,

2H), 4.98 (d, J = 11.3 Hz, 1H), 4.87 (d, J = 10.9 Hz, 1H), 4.85 (d, J = 11.3 Hz, 1H), 4.64 (d, J =

12.2 Hz, 1H), 4.61 - 4.54 (m, 2H), 4.38 (d, J = 7.2 Hz, 1H), 3.81 - 3.65 (m, 3H), 3.64 - 3.47 (m,

4H), 2.36 (d, J = 1.9 Hz, 1H), 2.09 - 1.90 (m, 2H), 1.77 (m, 2H), 1.61 - 1.16 (m, 6H); 13C NMR

(75 MHz, CDCl3) δ 138.9, 138.4, 138.3, 128.5 (2), 128.4, 128.1, 128.0, 127.9, 127.8, 127.7 (2),

101.2, 84.8, 77.8, 77.7, 75.3, 75.2, 75.1, 74.9, 73.5, 69.2, 33.8, 32.1, 25.7, 24.3, 24.2; HRMS (ESI)

+ m/z calcd for C33H40O6Na [M + Na] 555.2717, found 555.2722.

2,3,5-tri-O-benzyl-4-O-formyl-D-arabinose (3-26). To a solution of 3,4,6-tri-O-benzyl--D- glucose (45.0 mg, 0.100 mmol) in anh. CHCl3 (2.00 mL) was added iodosobenzene (23.0 mg,

0.104 mmol). The mixture was allowed to stir vigorously at room temperature for 4 h. The

129 resulting suspension was filtered through Celite and concentrated under vacuum to affored 3-26

23 (43.3 mg, 97%) as a colorless oil: []퐷 = -20.9 (c = 1.00, CHCl3); IR (ATR) = 3067, 3033, 2929,

-1 1 2873, 1730, 1499, 1458, 1175, 1104, 1033, 743, 702 cm ; H NMR (500 MHz, CDCl3) δ 9.65 (d,

J = 1.2 Hz, 1H), 7.85 (s, 1H), 7.37 - 7.27 (m, 13H), 7.22 - 7.16 (m, 2H), 5.30 (ddd, J = 7.4, 4.4,

3.0 Hz, 1H), 4.72 (d, J = 11.8 Hz, 1H), 4.56 - 4.43 (m, 5H), 4.23 (dd, J = 7.4, 3.1 Hz, 1H), 3.92

(dd, J = 3.1, 1.3 Hz, 1H), 3.81 (dd, J = 11.1, 2.9 Hz, 1H), 3.76 (dd, J = 11.1, 4.6 Hz, 1H); 13C

NMR (126 MHz, CDCl3) δ 203.1, 160.0, 137.6, 137.1, 136.5, 128.9, 128.8, 128.6 (2), 128.5,

128.4, 128.3, 128.0 (2), 82.5, 76.7, 74.4, 73.6, 73.5, 71.5, 67.7; HRMS (ESI) m/z calcd for

+ C27H28O6Na [M + Na] 471.1783, found 471.1781.

130

Benzyl 3,4,6-tri-O-benzyl--D-glucopyranoside (3-30). (3,4,6-Tri-O-benzyl--D- glucopyranosyl)tri-n-butylstannane 3-8 (144.8 mg, 0.200 mmol), benzyl alcohol (10.8 mg, 0.100 mmol), Zn(OTf)2 (7.30 mg, 0.020 mmol), iodosobenzene (66.0 mg,0.300 mmol), freshly activated 4Å MS and anh. CHCl3 (1.00 mL) were successively added into a vial. The reaction mixture was stirred at room temperature for 24 h and afforded after chromatographic purification

24 on SiO2 (Hexanes:EtOAc, 5:1) 3-30 (33.0 mg, 61%) as a colorless oil: []퐷 = -20.3 (c = 0.50,

-1 1 CHCl3); IR (ATR) = 3454, 3030, 2866, 2359, 1496, 1453, 1360, 1208, 1110, 1061, 735 cm ; H

NMR (300 MHz, CDCl3) δ 7.42 - 7.27 (m, 18H), 7.19 (dt, J = 6.5, 2.5 Hz, 2H), 4.96 (d, J = 11.7

Hz, 1H), 4.93 (d, J = 11.2 Hz, 1H), 4.85 (d, J = 10.8 Hz, 1H), 4.83 (d, J = 11.3 Hz, 1H), 4.65 (d,

J = 12.2 Hz, 1H), 4.64 (d, J = 11.8 Hz, 1H), 4.57 (d, J = 12.2 Hz, 1H), 4.56 (d, J = 10.8 Hz, 1H),

4.37 (d, J = 7.0 Hz, 1H), 3.86 - 3.69 (m, 2H), 3.69 - 3.55 (m, 3H), 3.52 - 3.42 (m, 1H), 2.32 (d, J

13 = 1.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 138.8, 138.3, 138.3, 137.3, 128.6, 128.6, 128.5,

128.5, 128.3, 128.1, 128.1, 128.1, 127.9, 127.9, 127.8, 127.8, 101.8, 84.7, 77.7, 75.4, 75.3, 75.1,

+ 74.9, 73.7, 71.2, 69.1; HRMS (ESI) m/z calcd for C34H36O6Na [M + Na] 563.2404, found

563.2401.

131

Isopropyl 3,4,6-tri-O-benzyl--D-glucopyranoside (3-31). (3,4,6-Tri-O-benzyl--D- glucopyranosyl)tri-n-butylstannane 3-8 (144.8 mg, 0.200 mmol), isopropanol (7.70 l, 0.100 mmol), Zn(OTf)2 (7.30 mg, 0.020 mmol), iodosobenzene (66.0 mg, 0.300 mmol), freshly activated 4Å MS and anh. CHCl3 (1.00 mL) were successively added into a vial. The reaction mixture was stirred at room temperature for 24 h and afforded after chromatographic purification

24 on SiO2 (Hexanes:EtOAc, 5:1) 3-31 (37.4 mg, 76%) as a colorless oil: []퐷 = -12.3 (c = 1.00,

CHCl3); IR (ATR)  = 3447, 3031, 2927, 2868, 1725, 1483, 1453, 1360, 1167, 1099, 738, 698

-1 1 cm ; H NMR (300 MHz, CDCl3) δ 7.42 - 7.27 (m, 13H), 7.20 - 7.17 (m, 2H), 4.95 (d, J = 11.3

Hz, 1H), 4.84 (d, J = 10.8 Hz, 1H); 4.83 (d, J = 11.3 Hz, 1H), 4.62 (d, J = 12.3 Hz, 1H), 4.58 -

4.51 (m, 2H), 4.31 (d, J = 7.4 Hz, 1H), 4.02 (p, J = 6.2 Hz, 1H), 3.79 - 3.44 (m, 6H), 2.28 (d, J =

13 1.8 Hz, 1H), 1.29 (d, J = 6.2 Hz, 3H), 1.20 (d, J = 6.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ

138.9, 138.4, 138.3, 128.6, 128.5, 128.5, 128.1, 128.1, 127.9, 127.8, 127.7, 101.3, 84.8, 77.8, 75.3,

75.2, 75.2, 74.9, 73.6, 72.1, 69.2, 23.7, 22.2. Characterization data matched the literature report.4

N-(tert-Butoxycarbonyl)-O-(3,4,6-tri-O-benzyl--D-glucopyranosyl)-L-serine methyl ester

(3-32). (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (144.8 mg, 0.200 mmol), methyl (tert-butoxycarbonyl)-D-serine (21.9 mg, 0.100 mmol), Zn(OTf)2 (7.30 mg, 0.020 mmol), iodosobenzene (66.0 mg, 0.300 mmol), freshly activated 4Å MS and anh. CHCl3 (1.00 mL) were successively added into a vial. The reaction mixture was stirred at room temperature for 24 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 3:1) 3-32 (54.1 mg, 83%)

24 as a colorless foam: []퐷 = +5.1 (c = 0.50, CHCl3); IR (ATR)  = 3419, 2868, 1713, 1497, 1453,

-1 1 1364, 1211, 1161, 1058, 737, 698 cm ; H NMR (300 MHz, CDCl3) δ 7.38 - 7.27 (m, 13H), 7.20

- 7.14 (m, 2H), 5.56 - 5.48 (m, 1H), 4.96 (d, J = 11.3 Hz, 1H), 4.90 - 4.77 (m, 2H), 4.64 - 4.50

132

(m, 4H), 4.28 (d, J = 7.2 Hz, 1H), 4.20 (dd, J = 10.8, 5.0 Hz, 1H), 3.88 (dd, J = 10.8, 3.4 Hz, 1H),

13 3.75 (s, 3H), 3.71 - 3.41 (m, 6H), 2.96 (s, 1H), 1.45 (s, 9H); C NMR (75 MHz, CDCl3) δ 170.6,

155.9, 138.8, 138.2 (2), 128.6, 128.5 (2), 128.1 (2), 128.0, 127.9, 127.8 (2), 103.9, 84.6, 77.4,

75.3 (2), 75.2, 74.7, 73.7, 70.7, 68.9, 54.3, 52.8, 28.5; HRMS (ESI) m/z calcd for C36H45NO10Na

[M + Na]+ 674.2936, found 674.2947.

O-(3,4,6-Tri-O-benzyl--D-glucopyranosyl)cholesterol (3-33). (3,4,6-Tri-O-benzy--D- glucopyranosyl)tri-n-butylstannane 3-8 (144.8 mg, 0.200 mmol), cholesterol (38.7 mg, 0.100 mmol), Zn(OTf)2 (36.5 mg, 0.100 mmol), iodosobenzene (66.0 mg, 0.300 mmol), freshly activated 4Å MS and anh. CHCl3 (1.00 mL) were successively added into a vial. The reaction mixture was stirred at room temperature for 48 h and afforded after chromatographic purification

25 on SiO2 (Hexanes:EtOAc, 8:1) 3-33 (56.7 mg, 68%) as a colorless foam: [푎]퐷 = -13.2 (c = 1.00,

-1 1 CHCl3); IR (ATR)  = 3460, 3029, 2933, 2863, 1453, 1362, 1110, 1060, 732, 696 cm ; H NMR

(300 MHz, CDCl3) δ 7.42 - 7.27 (m, 13H), 7.23 - 7.17 (m, 2H), 5.36 (dt, J = 5.9, 1.7 Hz, 1H),

4.95 (d, J = 11.3 Hz, 1H), 4.85 (d, J = 10.9 Hz, 1H), 4.84 (d, J = 11.3 Hz, 1H), 4.61 (d, J = 12.2

Hz, 1H), 4.58 - 4.52 (m, 2H), 4.36 (d, J = 7.3 Hz, 1H), 3.79 - 3.64 (m, 2H), 3.64 - 3.44 (m, 5H),

2.41 - 2.32 (m, 1H), 2.30 (d, J = 1.9 Hz, 1H), 2.28 - 2.22 (m, 1H), 2.01 (tq, J = 9.5, 2.9, 2.5 Hz,

3H), 1.92 - 1.77 (m, 2H), 1.72 - 1.58 (m, 2H), 1.58 - 0.99 (m, 22H), 0.93 (d, J = 6.4 Hz, 3H), 0.89

13 (d, J = 1.3 Hz, 3H), 0.87 (d, J = 1.3 Hz, 3H), 0.69 (s, 3H); C NMR (75 MHz, CDCl3) δ 140.5,

138.9, 138.4, 138.3, 128.6, 128.5 (2), 128.1 (2), 127.9 (2), 127.8, 127.7, 122.2, 101.4, 84.8, 79.3,

77.8, 75.3, 75.2, 75.1, 74.9, 73.6, 69.2, 56.9, 56.3, 50.3, 42.5, 39.9, 39.7, 39.1, 37.4, 36.9, 36.3,

35.9, 32.1, 32.0, 29.9, 28.4, 28.2, 24.4, 24.0, 23.0, 22.7, 21.2, 19.5, 18.9, 12.0.

Cyclohexyl 3,4,6-tri-O-benzyl--D-galactopyranoside (3-34). (3,4,6-Tri-O-benzyl--D- galactopyranosyl)tri-n-butylstannane (144.8 mg, 0.200 mmol), cyclohexanol (10.4 l, 0.100

133 mmol), Zn(OTf)2 (7.30 mg, 0.020 mmol), iodosobenzene (66.0 mg, 0.300 mmol), freshly activated 4Å MS, and anh. CHCl3 (1.00 mL) were successively added into a vial. The reaction mixture was stirred at room temperature for 24 h and afforded after chromatographic purification

24 on SiO2 (Hexanes:EtOAc, 8:1) 3-34 (38.4 mg, 72%) as a colorless liquid: []퐷 = -3.4 (c = 0.30,

-1 1 CHCl3); IR (ATR)  = 3469, 3029, 2930, 2856, 1495, 1452, 1364, 1075, 1070, 735, 697 cm ; H

NMR (300 MHz, CDCl3) δ 7.41 - 7.26 (m, 15H), 4.89 (d, J = 11.6 Hz, 1H), 4.72 (s, 2H), 4.62 (d,

J = 11.7 Hz, 1H), 4.51 - 4.40 (m, 2H), 4.32 (d, J = 7.7 Hz, 1H), 3.99 - 3.88 (m, 2H), 3.69 - 3.52

(m, 4H), 3.44 (dd, J = 9.8, 2.9 Hz, 1H), 2.30 (d, J = 1.9 Hz, 1H), 1.94 (t, J = 11.9 Hz, 2H), 1.72

13 (t, J = 5.7 Hz, 2H), 1.53 - 1.12 (m, 6H); C NMR (75 MHz, CDCl3) δ 138.7, 138.4, 138.1, 128.6

(2), 128.5, 128.3, 128.0, 127.9, 127.8 (2), 127.7, 101.7, 82.2, 74.7, 74.0, 73.7, 73.3, 72.7, 71.6,

+ 69.1, 33.7, 32.0, 25.7, 24.4, 24.2; HRMS (ESI) m/z calcd for C33H40O6Na [M + Na] 555.2717, found 555.2717.

Cyclohexyl 3,4-di-O-benzyl--D-arabinopyranoside (3-35). (3,4-Di-O-benzyl--D- arabinosyl)tri-n-butylstannane (120.7 mg, 0.200 mmol), cyclohexanol (10.4 l, 0.1 mmol),

Zn(OTf)2 (7.30 mg, 0.020 mmol), iodosobenzene (66.0 mg, 0.300 mmol), freshly activated 4Å

MS, and anh. CHCl3 (1.00 mL) were successively added into a vial. The reaction mixture was stirred at room temperature for 24 h and afforded after chromatographic purification on SiO2

23 (Hexanes:EtOAc, 5:1) 3-35 (23.5 mg, 57%) as a colorless foam:[]퐷 = -10.8 (c = 0.50, CHCl3);

IR (ATR)  = 3466, 2927, 2855, 1727, 1452, 1363, 1253, 1093, 735, 698 cm-1; 1H NMR (300

MHz, CDCl3) δ 7.42 - 7.27 (m, 10H), 4.78 (d, J = 12.6 Hz, 1H), 4.69 - 4.59 (m, 3H), 4.26 (d, J =

7.6 Hz, 1H), 4.05 (dd, J = 12.9, 2.2 Hz, 1H), 3.94 (ddd, J = 9.4, 7.5, 1.8 Hz, 1H), 3.72 - 3.60 (m,

2H), 3.40 (dd, J = 9.6, 3.3 Hz, 1H), 3.28 (dd, J = 12.9, 1.2 Hz, 1H), 2.32 (d, J = 2.0 Hz, 1H), 1.95

13 (s, 2H), 1.74 (s, 2H), 1.45 - 1.16 (m, 6H); C NMR (75 MHz, CDCl3) δ 138.4, 128.6, 128.5,

134

128.1, 127.8 (3), 101.9, 80.5, 77.3, 72.2, 72.0, 71.5, 71.3, 63.9, 33.8, 32.0, 25.7, 24.4, 24.3; HRMS

+ (ESI) m/z calcd for C25H32O5Na [M + Na] 435.2142, found 435.2144.

Cyclohexyl 2,3,4,6-tetra-O-benzyl--D-galactopyranosyl-(1→4)-3,6-di-O-benzyl--D- glucopyranoside (3-36). [2,3,4,6-Tetra-O-benzyl--D-galactopyranosyl-(1→4)-3,6-di-O- benzyl--D-glucopyranosyl]tri-n-butylstannane (231.2 mg, 0.200 mmol), cyclohexanol (10.4 l,

0.100 mmol), Zn(OTf)2 (7.30 mg, 0.020 mmol), iodosobenzene (66.0 mg, 0.300 mmol), freshly activated 4Å MS, and anh. CHCl3 (1.00 mL) were successively added into a vial. The reaction mixture was stirred at room temperature for 24 h and afforded after chromatographic purification

24 on SiO2 (Hexanes:EtOAc, 5:1) 3-36 (68.5 mg, 71%) as a colorless foam:[]퐷 = -1.1 (c = 0.40,

- CHCl3); IR (ATR)  = 3453, 3029, 2928, 2856, 1495, 1452, 1361, 1207, 1060, 731, 704, 462 cm

1 1 ; H NMR (300 MHz, CDCl3) δ 7.41 - 7.16 (m, 30H), 5.05 (d, J = 11.2 Hz, 1H), 4.97 (d, J = 11.5

Hz, 1H), 4.83 (d, J = 11.2 Hz, 1H), 4.81 - 4.66 (m, 4H), 4.61 - 4.33 (m, 6H), 4.27 (d, J = 11.7 Hz,

1H), 3.97 - 3.86 (m, 2H), 3.84 - 3.72 (m, 3H), 3.71 - 3.35 (m, 8H), 2.36 (s, 1H), 2.02 - 1.91 (m,

13 2H), 1.78 - 1.63 (m, 2H), 1.55 - 1.14 (m, 6H); C NMR (75 MHz, CDCl3) δ 139.3, 139.1, 138.9,

138.6 (2), 138.1, 128.5 (2), 128.4, 128.3 (2), 128.0 (2), 127.9, 127.8, 127.7, 127.6, 127.5 (2),

127.4, 103.0, 101.1, 83.0, 82.7, 80.1, 77.8, 75.6, 75.4, 74.8, 74.7, 73.8, 73.7, 73.6, 73.2, 72.7, 68.6,

+ 68.3, 33.8, 32.2, 25.7, 24.4, 24.3; HRMS (ESI) m/z calcd for C60H68O11Na [M + Na] 987.4654, found 987.4666.

135

Methyl 3,4,6-tri-O-benzyl--D-glucopyranosyl-(1→6)-2,3,4-tri-O-methyl-α-D- glucopyranoside (3-41). (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), methyl 2,3,4-tri-O-methyl-α-D-glucopyranoside6 (23.6 mg, 0.100 mmol),

Zn(OTf)2 (1.83 mg, 0.005 mmol), hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol), freshly activated 4Å MS and anh. CH2Cl2 (4.00 mL) were successively added into a vial. After stirring at room temperature for 12 h, (3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane1 3-8

(72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred for an additional 12h. (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-

8 (72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic purification on SiO2

25 (Hexanes:EtOAc, 1:1.5) 3-41 (53.5 mg, 80%) as a colorless liquid: []퐷 = +43.2 (c = 1.00,

-1 1 CHCl3); IR (ATR)  = 3461, 2904, 1494, 1452, 1359, 1081, 1045, 908, 734, 697 cm ; H NMR

136

(300 MHz, CDCl3) δ 7.40 - 7.28 (m, 13H), 7.18 (dt, J = 6.5, 2.3 Hz, 2H), 4.96 (d, J = 11.2 Hz,

1H), 4.90 - 4.79 (m, 3H), 4.62 (d, J = 12.2 Hz, 1H), 4.55 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 10.9

Hz, 1H), 4.38 - 4.30 (m, 1H), 4.22 - 4.13 (m, 1H), 3.78 - 3.67 (m, 4H), 3.63 (s, 3H), 3.61 - 3.57

(m, 3H), 3.55 (s, 3H), 3.53 - 3.49 (m, 2H), 3.51 (s, 3H), 3.42 (s, 3H), 3.21 (dd, J = 9.6, 3.6 Hz,

13 1H), 3.13 (t, J = 9.2 Hz, 1H), 2.68 (s, 1H); C NMR (75 MHz, CDCl3) δ 138.8, 138.3, 138.2,

128.5 (3), 128.1, 128.0, 127.9, 127.8 (2), 127.7, 103.7, 97.5, 84.7, 83.5, 81.8, 80.0, 75.5, 75.3,

75.2, 74.7, 73.6, 69.8, 69.1 (2), 61.0, 60.6, 59.1, 55.4; HRMS (ESI) m/z calcd for C37H48O11Na

[M + Na]+ 691.3089, found 591.3091.

Methyl 3,4,6-tri-O-benzyl--D-glucopyranosyl-(1→6)-2,3,4-tri-O-benzyl-α-D- glucopyranoside (3-42). (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside7 (46.5 mg, 0.100 mmol),

(72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred for an additional 12 h. (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-

8 (72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic purification on SiO2

ퟐퟒ (Hexanes:EtOAc, 3:1) 3-42 (76.3 mg, 85%) as a colorless liquid: []푫 = +12.8 (c = 0.10, CHCl3);

IR (ATR)  = 3454, 3029, 2902, 1483, 1453, 1359, 1050, 911, 735, 697, 462 cm-1; 1H NMR (300

MHz, CDCl3) δ 7.40 - 7.26 (m, 28H), 7.22 - 7.14 (m, 2H), 5.00 (d, J = 10.9 Hz, 1H), 4.93 (d, J =

11.2 Hz, 1H), 4.91 (d, J = 11.1 Hz, 1H), 4.86 - 4.77 (m, 4H), 4.72 - 4.50 (m, 6H), 4.29 - 4.21 (m,

137

1H), 4.16 (dd, J = 11.0, 2.2 Hz, 1H), 4.02 (t, J = 9.2 Hz, 1H), 3.84 (ddd, J = 10.1, 5.2, 2.1 Hz,

1H), 3.79 - 3.63 (m, 3H), 3.62 - 3.44 (m, 6H), 3.39 (s, 3H), 2.49 (d, J = 1.4 Hz, 1H); 13C NMR

(75 MHz, CDCl3) δ 138.8 (2), 138.4, 138.3, 138.2, 128.6 (2), 128.5 (2), 128.3, 128.1 (2), 128.0,

127.9(3), 127.8(2), 127.7 (2), 103.6, 98.2, 84.6, 82.1, 79.9, 78.2, 77.6, 75.9, 75.5, 75.2, 75.1 (2),

74.6, 73.6, 73.5, 70.0, 69.1, 68.9, 55.4; HRMS (ESI) m/z calcd for C55H60O11Na [M + Na]+

919.4028, found 919.4021.

Methyl 3,4,6-tri-O-benzyl--D-glucopyranosyl-(1→6)-2,3,4-tri-O-acetyl-α-D- glucopyranoside (3-45). (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), methyl 2,3,4-tri-O-acetyl-α-D-glucopyranoside8 (32.0 mg, 0.100 mmol),

(72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred for an additional 12h. (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-

8 (72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic purification on SiO2

24 (Hexanes:EtOAc, 1:1) 3-45 (67.0 mg, 89%) as a colorless foam: []퐷 = +24.7 (c = 1.00, CHCl3);

IR (ATR)  = 3491, 3067, 3033, 2925, 2869, 1752, 1499, 1458, 1372, 1231, 1048, 743, 702 cm-

1 1 ; H NMR (500 MHz, CDCl3) δ 7.41 – 7.29 (m, 13H), 7.14 (dd, J = 7.4, 2.1 Hz, 2H), 5.15 (dd, J

= 10.3, 9.3 Hz, 1H), 5.06 (d, J = 2.7 Hz, 1H), 4.97 (d, J = 3.6 Hz, 1H), 4.87 (d, J = 11.0 Hz, 1H),

4.84 – 4.79 (m, 3H), 4.62 (d, J = 12.0 Hz, 1H), 4.54 – 4.46 (m, 2H), 4.26 (d, J = 9.6 Hz, 2H), 4.23

(dd, J = 7.6, 4.8 Hz, 1H), 4.09 (dd, J = 12.4, 2.5 Hz, 1H), 3.94 – 3.85 (m, 2H), 3.76 (dd, J = 10.6,

138

2.9 Hz, 1H), 3.70 – 3.64 (m, 4H), 3.40 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 1.91 (d, J

13 = 8.6 Hz, 1H); C NMR (126 MHz, CDCl3) δ 170.9, 170.4, 170.2, 138.7, 138.4, 138.0, 128.6,

128.5 (4), 128.1, 128.0, 127.9 (2), 127.8 (3), 100.2, 96.9, 82.8, 75.6 (2), 75.0, 73.8, 72.9, 72.2,

+ 71.4, 70.4, 67.4, 55.5, 21.2, 21.1, 20.9; HRMS (ESI) m/z calcd for C40H48O14Na [M + Na]

775.2942, found 775.2939.

Methyl 3,4,6-tri-O-benzyl--D-glucopyranosyl-(1→6)-2,3,4-tri-O-benzoyl-α-D- glucopyranoside (3-46). (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), methyl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside9 (50.7 mg, 0.100 mmol),

Zn(OTf)2 (1.83 mg, 0.005 mmol), hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol), freshly activated 4 Å MS and anh. CH2Cl2 (4.00 mL) were successively added into a vial. After stirring at room temperature for 12 h, (3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8

(72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred for additional 12 h. (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8

(72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic purification on SiO2

24 (Hexanes:EtOAc, 2:1) 3-46 (56.3 mg, 60%) as a colorless foam: []퐷 = +34.4 (c = 0.20, CHCl3);

IR (ATR)  = 3521, 3030, 2919, 1724, 1601, 1451, 1359, 1260, 1103, 1065, 707, 484 cm-1; 1H

NMR (300 MHz, CDCl3) δ 8.01 -7.76 (m, 4H), 7.90 - 7.81 (m, 2H), 7.59 - 7.48 (m, 2H), 7.47 -

7.27 (m, 20H), 7.17 (dt, J = 6.4, 2.3 Hz, 2H), 6.19 (ddd, J = 11.3, 9.7, 1.6 Hz, 1H), 5.82 (t, J =

9.9 Hz, 1H), 5.33 - 5.26 (m, 2H), 5.08 (d, J = 11.2 Hz, 1H), 4.85 (d, J = 10.8 Hz, 1H), 4.81 (d, J

= 11.2 Hz, 1H), 4.68 - 4.44 (m, 4H), 4.30 - 4.16 (m, 3H), 3.79 - 3.53 (m, 6H), 3.48 (s, 3H), 3.27

13 (d, J = 1.7 Hz, 1H); C NMR (75 MHz, CDCl3) δ 166.1, 165.9 (2), 139.0, 138.3 (2), 133.8, 133.5,

139

133.2, 130.2, 130.1, 129.8, 129.3, 129.2, 128.8, 128.6 (2) , 128.5 (3), 128.4, 128.2, 128.1, 127.8,

127.7, 103.4, 97.3, 84.8, 77.4, 75.5, 75.3, 75.2 (2), 73.5, 72.2, 70.6, 69.3, 69.0, 68.4, 67.9, 55.9;

+ HRMS (ESI) m/z calcd for C55H54O14Na [M + Na] 961.3406, found 961.3408.

Methyl 2,3,4,6-tetra-O-benzyl--D-galactopyranosyl-(1→4)-3,6-di-O-benzyl--D- glucopyranosyl-(1→6)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (3-50). [2,3,4,6-Tetra-O- benzyl--D-galactopyranosyl-(1→4)-3,6-di-O-benzyl--D-glucopyranosyl]tri-n-butylstannane

(115.6 mg, 0.100 mmol), methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside7 (46.5 mg, 0.100 mmol), Zn(OTf)2 (1.83 mg, 0.005 mmol), hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol), freshly activated 4 Å MS and anh. CH2Cl2 (4.00 mL) were successively added into a vial. After stirring at room temperature for 12 h, [2,3,4,6-tetra-O-benzyl--D-galactopyranosyl-(1→4)-3,6- di-O-benzyl--D-glucopyranosyl]tri-n-butylstannane (115.6 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred for an additional

12h. [2,3,4,6-tetra-O-benzyl--D-galactopyranosyl-(1→4)-3,6-di-O-benzyl--D-glucopyranosyl] tri-n-butylstannane (115.6 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic

24 purification on SiO2 (Hexanes:EtOAc, 1.5:1) 3-50 (83.8 mg, 63%) as a colorless liquid: []퐷 =

+15.3 (c = 1.00, CHCl3); IR (ATR)  = 3461, 3029, 2865, 1602, 1495, 1452, 1360, 1207, 1048,

-1 1 908, 731, 695 cm ; H NMR (300 MHz, CDCl3) δ 7.47 - 7.17 (m, 45H), 5.09 (d, J = 11.1 Hz,

1H), 5.01 (dd, J = 11.1, 5.9 Hz, 2H), 4.93 (d, J = 11.0 Hz, 1H), 4.91 - 4.79 (m, 4H), 4.79 - 4.62

(m, 6H), 4.59 (d, J = 11.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.48 (d, J = 7.6 Hz, 1H), 4.40 (d, J

= 12.0 Hz, 2H), 4.30 (dd, J = 9.7, 2.0 Hz, 2H), 4.15 (dd, J = 11.0, 2.0 Hz, 1H), 4.09 - 3.90 (m,

140

3H), 3.89 - 3.63 (m, 6H), 3.63 - 3.43 (m, 6H), 3.41 (s, 3H), 3.44 - 3.35 (m, 2H), 2.51 (s, 1H); 13C

13 NMR (75 MHz, CDCl3) C NMR (75 MHz, CDCl3) δ 139.1, 138.9 (2), 138.6 (2), 138.5, 138.2,

138.1, 128.6 (2), 128.5, 128.5 (3), 128.3 (2), 128.2 (2), 128.1, 128.0 (2), 127.9 (2), 127.8 (2),

127.7 (2), 127.6, 127.5 (2), 127.4 (2), 103.5, 102.9, 98.2, 82.9, 82.6, 82.2, 80.1, 79.9, 78.0, 76.3,

75.9, 75.8, 75.4, 75.1, 74.8, 73.7, 73.6, 73.5, 73.4, 73.2, 72.7, 70.8, 70.0, 68.6, 68.4, 68.3, 62.0,

+ 55.4; HRMS (ESI) m/z calcd for C82H88O16Na [M + Na] 1351.5965, found 1351.5945.

Methyl 3,4,6-tri-O-benzyl--D-glucopyranosyl-(1→6)-2,3,4-tri-O-benzyl-α-D- galactopyranoside (3-49). (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8

(72.4 mg, 0.100 mmol), methyl 2,3,4-tri-O-benzoyl-α-D-galactopyranoside (46.5 mg, 0.100 mmol), Zn(OTf)2 (1.83 mg, 0.005 mmol), hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol), freshly activated 4 Å MS and anh. CH2Cl2 (4.00 mL) were successively added into a vial. After stirring at room temperature for 12 h, (3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n- butylstannane 3-8 (72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred for an additional 12 h. (3,4,6-Tri-O-benzyl--D- glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc,

24 2:1) 3-49 (73.6 mg, 82%) as a colorless foam: []퐷 = +18.1 (c = 1.00, CHCl3); IR (ATR)  =

3454, 3063, 3033, 2906, 1499, 1458, 1357, 1096, 1048, 739, 702 cm-1; 1H NMR (500 MHz,

Chloroform-d) δ 7.41 – 7.28 (m, 28H), 7.16 – 7.12 (m, 2H), 4.94 (t, J = 11.2 Hz, 2H), 4.88 – 4.81

(m, 4H), 4.73 (d, J = 11.8 Hz, 1H), 4.73 – 4.67 (m, 2H), 4.65 (d, J = 11.4 Hz, 1H), 4.57 (d, J =

12.1 Hz, 1H), 4.52 (d, J = 10.8 Hz, 1H), 4.47 (d, J = 12.1 Hz, 1H), 4.28 (d, J = 7.6 Hz, 1H), 4.04

141

(dd, J = 10.0, 3.6 Hz, 1H), 3.96 – 3.91 (m, 2H), 3.88 – 3.84 (m, 2H), 3.76 – 3.69 (m, 3H), 3.67 –

3.62 (m, 1H), 3.56 (t, J = 8.9 Hz, 1H), 3.50 (dd, J = 9.1, 7.6 Hz, 1H), 3.45 (ddd, J = 9.8, 4.0, 2.3

Hz, 1H), 3.39 (s, 3H); 13C NMR (126 MHz, Chloroform-d) δ 138.9, 138.7, 138.5, 138.2, 138.1,

128.6, 128.5 (2), 128.4 (2), 128.3, 128.2, 128.1, 128.0, 127.9 (3), 127.8 (2), 127.7 (2), 127.6,

103.5, 98.9, 84.5, 79.1, 76.4, 75.2 (2), 75.1, 75.0, 74.7, 73.7, 73.6, 73.5, 70.0, 69.7, 68.8, 55.6;

+ HRMS (ESI) m/z calcd for C55H60O11Na [M + Na] 919.4033, found 919.4026.

Methyl 3,4,6-tri-O-benzyl--D-galactopyranosyl-(1→6)-2,3,4-tri-O-benzyl-α-D- glucopyranoside (3-50). (3,4,6-Tri-O-benzyl--D-galactopyranosyl)tri-n-butylstannane (72.4 mg, 0.100 mmol), methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside7 (46.5 mg, 0.1 mmol),

Zn(OTf)2 (1.83 mg, 0.005 mmol), hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol), freshly activated 4Å MS, and anh. CH2Cl2 (4.00 mL) were successively added into a vial. After stirring at room temperature for 12 h, (3,4,6-tri-O-benzyl--D-galactopyranosyl)tri-n-butylstannane (72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred for an additional 12h. (3,4,6-tri-O-benzyl--D-galactopyranosyl)tri-n-butylstannane (72.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic purification on SiO2

24 (Hexanes:EtOAc, 2:1) 3-50 (60.1 mg, 67%) as a colorless oil: []퐷 = +12.9 (c = 0.50, CHCl3);

IR (ATR)  = 3458, 3029, 2912, 1495, 1453, 1360, 1067, 909, 733, 696, 461 cm-1; 1H NMR (300

MHz, CDCl3) δ 7.43 - 7.19 (m, 30H), 4.98 (d, J = 10.9 Hz, 1H), 4.89 (d, J = 11.4 Hz, 1H), 4.88

(d, J = 11.0 Hz, 1H), 4.84 - 4.75 (m, 2H), 4.74 - 4.54 (m, 6H), 4.50 - 4.38 (m, 2H), 4.23 (d, J =

7.7 Hz, 1H), 4.12 (dd, J = 11.0, 2.2 Hz, 1H), 4.06 - 3.90 (m, 3H), 3.82 (ddd, J = 10.1, 5.3, 2.1 Hz,

1H), 3.72 - 3.46 (m, 6H), 3.41 (dd, J = 9.8, 2.8 Hz, 1H), 3.37 (s, 3H), 2.52 (s, 1H); 13C NMR (75

142

MHz, CDCl3) δ 138.9, 138.8, 138.5, 138.3, 138.2, 138.0, 128.6 (3), 128.5 (2), 128.3 (2), 128.1

(2), 128.0 (2), 127.9, 127.8, 127.7 (2), 127.6, 104.2, 98.1, 82.2, 82.0, 79.9, 78.2, 75.9, 75.1, 74.7,

73.9, 73.7, 73.5, 73.2, 72.5, 71.1, 70.0, 68.7, 68.6, 55.4; HRMS (ESI) m/z calcd for C55H60O11Na

[M + Na]+ 919.4028, found 919.4022.

Methyl 3,4-di-O-benzyl--D-arabinopyranosyl-(1→6)-2,3,4-tri-O-benzyl-α-D- glucopyranoside (3-51). (3,4-Di-O-benzyl--D-arabinosyl)tri-n-butylstannane (60.4 mg, 0.100 mmol), methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (46.5 mg, 0.100 mmol), Zn(OTf)2 (1.83 mg, 0.005 mmol), hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol), freshly activated 4Å

MS and anh. CH2Cl2 (4.00 mL) were successively added into a vial. After stirring at room temperature for 12 h, (3,4-di-O-benzyl--D-arabinosyl)tri-n-butylstannane (60.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred for an additional 12h. (3,4-di-O-benzyl--D-arabinosyl)tri-n-butylstannane (60.4 mg, 0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc,

23 1.5:1) 3-51 (55.9 mg, 72%) as a colorless liquid: []퐷 = -12.3 (c = 0.40, CHCl3); IR (ATR) =

-1 1 3454, 3020, 2910, 1491, 1452, 1364, 1062, 910, 735, 696, 463, cm ; H NMR (300 MHz, CDCl3)

δ 7.43 - 7.27 (m, 25H), 4.99 (d, J = 10.9 Hz, 1H), 4.85 (dd, J = 10.9, 8.8 Hz, 2H), 4.76 (d, J = 8.8

Hz, 1H), 4.74 - 4.57 (m, 7H), 4.27 (d, J = 7.4 Hz, 1H), 4.15 (dd, J = 11.5, 4.2 Hz, 1H), 4.08 - 3.93

(m, 3H), 3.81 (dd, J = 11.4, 2.0 Hz, 1H), 3.77 - 3.66 (m, 2H), 3.66 - 3.58 (m, 1H), 3.55 (dd, J =

9.6, 3.5 Hz, 1H), 3.44 - 3.34 (m, 1H), 3.38 (s, 3H), 3.28 (dd, J = 13.0, 1.2 Hz, 1H), 2.57 (s, 1H);

13 C NMR (75 MHz, CDCl3) δ 138.9, 138.6, 138.3 (2), 128.6, 128.5 (3), 128.2, 128.1, 128.0 (3) ,

143

127.8, 127.7 (2), 103.8, 98.3, 82.2, 80.3, 80.1, 77.6, 75.8, 75.1, 73.6, 72.2, 72.0, 71.4, 71.0, 70.1,

+ 67.4, 63.7, 55.4; HRMS (ESI) m/z calcd for C47H52O10Na [M + Na] 799.3453, found 799.3459.

Methyl 3,4-di-O-benzyl-6-deoxy--D-glucopyranosyl-(1→6)-2,3,4-tri-O-methyl-α-D- glucopyranoside (3-52). (3,4-Di-O-benzyl--D-quinovopyranosyl)tri-n-butylstannane (61.7 mg,

7 0.100 mmol), methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (46.5 mg, 0.100 mmol), Zn(OTf)2

(1.83 mg, 0.005 mmol), hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol), freshly activated

4Å MS, and anh. CH2Cl2 (4.00 mL) were successively added into a vial. After stirring at room temperature for 12 h, (3,4-di-O-benzyl--D-quinovopyranosyl)tri-n-butylstannane (61.7 mg,

0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred for an additional 12h. (3,4-Di-O-benzyl--D-quinovopyranosyl)tri-n-butylstannane (61.7 mg,

0.100 mmol) and hydroxy(tosyloxy)iodobenzene (39.2 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic purification on SiO2

23 (Hexanes:EtOAc, 2:1) 3-52 (41.9 mg, 53%) as a colorless liquid: []퐷 = -23.0 (c = 0.25, CHCl3);

IR (ATR)  = 3433, 2924, 2359, 1731, 1453, 1453, 1361, 1069, 736, 698 cm-1; 1H NMR (300

MHz, CDCl3) δ 7.41 - 7.26 (m, 25H), 4.99 (d, J = 10.7 Hz, 1H), 4.94 - 4.75 (m, 7H), 4.71 - 4.53

(m, 4H), 3.99 (t, J = 9.2 Hz, 1H), 3.89 (d, J = 10.7 Hz, 1H), 3.77 (dd, J = 9.6, 6.1 Hz, 2H), 3.65

(d, J = 6.8 Hz, 2H), 3.52 (td, J = 10.2, 9.7, 4.6 Hz, 2H), 3.42 (d, J = 9.5 Hz, 1H), 3.36 (s, 3H),

3.10 (t, J = 9.0 Hz, 1H), 2.04 (d, J = 7.8 Hz, 1H), 1.23 (d, J = 6.3 Hz, 3H); 13C NMR (75 MHz,

CDCl3) δ 138.8 (2), 138.4, 138.3, 138.2, 128.7, 128.6 (3), 128.3, 128.2, 128.1 (2), 128.0, 127.8

(2), 99.1, 98.1, 83.5, 83.1, 82.2, 80.1, 78.2, 76.0, 75.5, 75.4, 75.2, 73.7, 73.5, 70.2, 67.4, 67.3,

+ 55.4, 17.9; HRMS (ESI) m/z calcd for C48H54O10Na [M + Na] 813.3609, found 813.3616.

144

Methyl 3,4,6-tri-O-benzyl--D-glucopyranosyl-(1→4)-2,3,6-tri-O-benzyl-α-D- glucopyranoside (3-54). (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (46.5 mg, 0.100 mmol),

Zn(OTf)2 (1.83 mg, 0.005 mmol), 3,5-bis(trifluoromethyl)-1-hydroxy(tosyloxy)iodobenzene 3-

57 (52.8 mg, 0.100 mmol), freshly activated 4 Å MS and anh. CH2Cl2 (4.00 mL) were successively added into a vial. After stirring at room temperature for 12 h, (3,4,6-tri-O-benzyl--

D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol), 3,5-bis(trifluoromethyl)-1- hydroxy(tosyloxy)iodobenzene 3-57 (52.8 mg, 0.100 mmol) were added and stirred for an additional 12h. (3,4,6-tri-O- benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol) and 3,5-bis(trifluoromethyl)-1-hydroxy(tosyloxy)iodobenzene 3-57 (52.8 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic

24 purification on SiO2 (Hexanes:EtOAc, 3:1) 3-54 (76.0 mg, 85%) as a colorless liquid: []퐷 =

+14.6 (c = 1.00, CHCl3); IR (ATR)  = 3480, 3067, 3033, 2925, 2869, 1499, 1458, 1365, 1111,

-1 1 1055, 739, 702 cm ; H NMR (500 MHz, CDCl3) δ 7.39 – 7.27 (m, 28H), 7.15 (dd, J = 7.3, 2.2

Hz, 2H), 5.03 (d, J = 11.4 Hz, 1H), 4.92 – 4.87 (m, 2H), 4.83 – 4.76 (m, 2H), 4.74 (d, J = 12.2

145

Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.61 – 4.49 (m, 5H), 4.44 (d, J = 12.1 Hz, 1H), 4.40 (d, J =

12.1 Hz, 1H), 4.01 – 3.96 (m, 3H), 3.80 (td, J = 6.5, 3.0 Hz, 1H), 3.67 (dd, J = 11.2, 2.3 Hz, 1H),

3.63 – 3.58 (m, 1H), 3.52 – 3.41 (m, 4H), 3.37 (s, 3H), 3.22 (ddd, J = 9.9, 3.8, 2.3 Hz, 1H), 2.06

13 (s, 1H); C NMR (126 MHz, CDCl3) δ 139.4, 138.9, 138.4, 138.3, 138.2, 137.5, 129.7, 128.7,

128.6, 128.5 (4), 128.4, 128.3, 128.2 (2), 128.1, 128.0 (3), 127.8 (3), 127.6, 127.2 (2), 127.1,

103.3, 98.3, 84.5, 81.1, 79.6, 77.0, 75.7, 75.3, 75.2, 75.1, 75.0, 73.9, 73.6, 73.4, 69.6, 68.8, 68.6,

+ 55.4; HRMS (ESI) m/z calcd for C55H60O11Na [M + Na] 919.4033, found 919.4020.

Methyl 3,4,6-tri-O-benzyl--D-glucopyranosyl-(1→2)-3,4,6-tri-O-benzyl--D- glucopyranoside (3-58). (3,4,6-Tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 10 (72.4 mg, 0.100 mmol), methyl 3,4,6-tri-O-benzyl--D-glucopyranoside (46.5 mg, 0.100 mmol),

Zn(OTf)2 (1.8 mg, 0.005 mmol), 3,5-bis(trifluoromethyl)-1-hydroxy(tosyloxy)iodobenzene 3-57

(52.8 mg, 0.100 mmol), freshly activated 4 Å MS and anh. CH2Cl2 (4.00 mL) were successively added into a vial. After stirring at room temperature for 12 h, (3,4,6-tri-O-benzyl--D- glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol) and 3,5-bis(trifluoromethyl)-1- hydroxy(tosyloxy)iodobenzene 3-57 (52.8 mg, 0.100 mmol) were added and stirred for an additional 12h. (3,4,6-tri-O-benzyl--D-glucopyranosyl)tri-n-butylstannane 3-8 (72.4 mg, 0.100 mmol) and 3,5-bis(trifluoromethyl)-1-hydroxy(tosyloxy)iodobenzene 3-57 (52.8 mg, 0.100 mmol) were added and stirred at room temperature for 12 h and afforded after chromatographic

24 purification on SiO2 (Hexanes:EtOAc, 2:1) 3-58 (53.0 mg, 59%) as a colorless oil: []퐷 = -0.9

(c = 1.00, CHCl3); IR (ATR)  = 3473, 3067, 3033, 2903, 2869, 1499, 1458, 1365, 1067, 739,

-1 1 702 cm ; H NMR (500 MHz, CDCl3) δ 7.40 – 7.27 (m, 26H), 7.22 – 7.15 (m, 4H), 4.95 (d, J =

10.7 Hz, 1H), 4.90 – 4.82 (m, 3H), 4.82 (d, J = 10.8 Hz, 1H), 4.73 (d, J = 11.1 Hz, 1H), 4.68 –

146

4.57 (m, 3H), 4.57 (d, J = 12.2 Hz, 0H), 4.55 – 4.49 (m, 3H), 4.36 (d, J = 7.6 Hz, 1H), 3.79 – 3.70

(m, 5H), 3.68 – 3.60 (m, 3H), 3.57 – 3.53 (m, 1H), 3.52 (s, 3H), 3.53 – 3.44 (m, 3H), 3.03 (d, J =

13 2.2 Hz, 1H); C NMR (126 MHz, CDCl3) δ 138.9, 138.3, 138.2, 137.8 (2), 128.7, 128.6, 128.5

(3), 128.4, 128.3, 128.2, 128.1, 128.0 (2), 127.9 (2), 127.8 (2), 127.7, 127.6, 104.1, 103.7, 84.3,

84.1, 81.3, 78.5, 76.3, 76.2, 75.6, 75.1, 75.0 (2), 74.9, 73.6, 73.5, 69.1, 68.7, 57.6; HRMS (ESI)

+ m/z calcd for C55H60O11Na [M + Na] 919.4033, found 919.4037.

Phenyliodonium dipivalate (S1). A mixture of PIDA (0.010 mmol, 1.00 equiv.) and pivalic acid

(0.020 mmol, 2.00 equiv.) was stirred in m-xylene (5 mL) at 80 °C for 5 min. The solvent was then distilled off under vacuum at this temperature to afford S1 as white solid, which was used directly in the next step without further purification: mp 99-102 oC; IR (ATR)  = 3078, 2981,

2873, 1704, 1644, 1555, 1480, 1398, 1286, 1168, 996, 892, 750, 605 cm-1; 1H NMR (500 MHz,

13 CDCl3) δ 8.03 - 7.98 (m, 2H), 7.58 - 7.52 (m, 1H), 7.51 - 7.44 (m, 2H), 1.17 - 1.05 (m, 18H). C

NMR (126 MHz, CDCl3) δ 183.7, 134.4, 131.4, 130.7, 122.2, 39.1, 27.9.

Phenyliodonium difuroate (S2). A mixture of PIDA (0.010 mmol, 1.00 equiv.) and furan-2- carboxylic acid (0.020 mmol, 2.00 equiv.) was stirred in m-xylene (5 mL) at 80 °C for 5 min. The

147 solvent was then distilled off under vacuum at this temperature to afford S2 as light solid, which was used directly in the next step without further purification: mp 104-107 oC; IR (ATR)  =

3136, 3051, 1630, 1564, 1469, 1389, 1308, 1228, 1113, 1011, 931, 882, 805, 727 cm-1; 1H NMR

(300 MHz, CDCl3) δ 8.30 - 8.19 (m, 2H), 7.66 - 7.57 (m, 1H), 7.56 - 7.51 (m, 2H), 7.50 (dd, J =

1.7, 0.9 Hz, 2H), 7.06 (dd, J = 3.5, 0.9 Hz, 2H), 6.44 (dd, J = 3.5, 1.8 Hz, 2H). 13C NMR (126

MHz, CDCl3) δ 146.1, 137.6, 135.2, 132.2, 131.3, 130.4, 118.2, 112.4, 111.9.

Phenyliodonium bis(ibuprofen) (S3). A mixture of PIDA (0.010 mmol, 1.00 equiv.) and (S)-2-

(4-isobutylphenyl)propanoic acid (0.020 mmol, 2.00 equiv.) was stirred in m-xylene (5 mL) at

80 °C for 5 min. The solvent was then distilled off under vacuum at this temperature to afford S3 as white oil, which was used directly in the next step without further purification: IR (ATR)  =

3055, 2969, 2873, 1707, 1689, 1610, 1417, 1271, 1231, 854, 735 cm-1; 1H NMR (300 MHz,

CDCl3) δ 7.79 (dd, J = 8.5, 1.2 Hz, 2H), 7.53 – 7.45 (m, 1H), 7.40 – 7.28 (m, 2H), 7.11 (d, J =

8.0 Hz, 4H), 7.03 (d, J = 8.3 Hz, 4H), 3.65 (q, J = 7.1 Hz, 2H), 2.44 (d, J = 7.2 Hz, 3H), 1.84

(sept, J = 6.8 Hz, 2H), 1.41 (d, J = 7.1 Hz, 6H), 0.90 (d, J = 6.6 Hz, 12H). 13C NMR (101 MHz,

CDCl3) δ 179.2, 140.3, 138.4, 134.3, 131.4, 130.7, 129.2, 127.2, 122.1, 45.2, 45.1, 30.3, 22.5,

19.1.

148

Phenyliodonium dipalmate (S4). A mixture of PIDA (0.010 mmol, 1.00 equiv.) and pivalic acid

-1 1 2851, 1704, 1659, 1473, 1376, 1312, 1204, 1186, 743, 720 cm ; H NMR (500 MHz, CDCl3) δ

8.03 - 7.98 (m, 2H), 7.58 - 7.52 (m, 1H), 7.51 - 7.44 (m, 2H), 1.17 - 1.05 (m, 18H). 13C NMR

1 (126 MHz, CDCl3) δ 183.7, 134.4, 131.4, 130.7, 122.2, 39.1, 27.9. H NMR (500 MHz, CDCl3)

δ 8.07 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 2.24 (t, J = 7.5 Hz,

4H), 1.53 (m, 4H), 1.24 (d, J = 13.8 Hz, 48H), 0.87 (t, J = 6.8 Hz, 6H). 13C NMR (126 MHz,

CDCl3) δ 179.1, 135.0, 131.7, 131.0, 121.9, 34.2, 32.1, 29.8, 29.8, 29.8, 29.7, 29.6, 29.5, 29.4,

29.4, 25.8, 22.8, 14.3.

S-Isopropyl (2,3,4,5-tetra-O-benzyl--D-glucopyranosyl)thioformate (4-34). To a mixture of

(2,3,4,6-tetra-O-benzyl--D-glycopyranosyl)tri-n-butylstannane 4-31 (81.4 mg, 0.100 mmol), S- isopropyl Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg,

0.0075 mmol), JackiePhos (23.9 mg, 0.030 mmol), and CuCl (20.0 mg, 0.200 mmol) were added in 1,4-dioxane (2.00 mL). The reaction mixture was heated under N2 at 110 ºC for 96 h and

149 afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 20:1) 4-34 (54.5 mg, 87%)

24 as a colorless oil: [훼]퐷 = +19.1 (c = 0.20, CHCl3); IR (ATR)  = 3030, 2923, 1684, 1604, 1453,

-1 1 1361, 1278, 1095, 1028, 735, 697 cm ; H NMR (300 MHz, CDCl3) δ 7.41 - 7.26 (m, 18H), 7.22

- 7.15 (m, 2H), 4.95 - 4.79 (m, 3H), 4.76 - 4.52 (m, 5H), 3.94 (d, J = 8.9 Hz, 1H), 3.84 - 3.63 (m,

6H), 3.52 (ddd, J = 9.1, 3.6, 2.4 Hz, 1H), 1.37 (d, J = 3.6 Hz, 1H), 1.34 (d, J = 3.5 Hz, 1H); 13C

NMR (75 MHz, CDCl3) δ 197.0, 138.6, 138.4, 138.1, 137.9, 128.6, 128.5 (2), 128.4, 128.1, 128.0,

127.9 (2), 127.8 (2), 127.7, 86.4, 83.7, 80.5, 79.6, 77.8, 75.8, 75.3, 75.2, 73.6, 68.8, 34.5, 23.0 (2);

+ HRMS (ESI) m/z calcd for C38H42O6Li [M + Li] 633.2857, found 633.2881.

S-Isopropyl (2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl)thioformate (4-44). To a mixture of (2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl)tri-n-butylstannane (81.4 mg, 0.100 mmol), S- isopropyl Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg,

150

0.0075 mmol), JackiePhos (23.9 mg, 0.030 mmol), and CuCl (20.0 mg, 0.200 mmol) were added in 1,4-dioxane (2.00 mL). The reaction mixture was heated under N2 at 110 ºC for 96 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 10:1) 4-44 (36.4 mg, 58%)

24 as a colorless oil: [훼]퐷 = +23.3 (c = 1.00, CHCl3); IR (ATR)  = 3029, 2924, 1674, 1453, 1366,

1246, 1090, 918, 734, 697, 607 cm-1; 1H NMR (300 MHz,CDCl3) δ 7.35 - 7.17 (m, 20H), 4.60 -

4.47 (m, 8H), 4.44 (d, J = 11.8 Hz, 1H), 4.39 (d, J = 2.9 Hz, 1H), 4.08 (dd, J = 5.3, 2.8 Hz, 1H),

4.03 (dd, J = 5.2, 2.9 Hz, 1H), 3.96 (dd, J = 11.7, 8.2 Hz, 1H), 3.80 - 3.62 (m, 3H), 1.34 (d, J =

13 3.5 Hz, 3H), 1.32 (d, J = 3.4 Hz, 3H); C NMR (75 MHz, CDCl3) δ 200.1, 138.7, 138.3, 137.9,

128.5 (2), 128.2, 128.0, 127.9, 127.8 (2), 127.7, 127.6 (2), 76.6, 75.4, 75.2, 73.9, 73.5, 73.2, 73.0,

+ 72.3, 65.7, 33.9, 23.0, 22.9; HRMS (ESI) m/z calcd for C38H42O6Li [M + Li] 633.2857, found

633.2870.

S-Isopropyl (2,3,4,6-tetra-O-benzyl--D-galactopyranosyl)thioformate (4-45). To a mixture of (2,3,4,6-Tetra-O-benzyl- -D-galactopyranosyl)tri-n-butylstannane (81.4 mg, 0.100 mmol), S- isopropyl Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg,

24 as a colorless oil: [훼]퐷 = +4.3 (c = 1.00, CHCl3); IR (ATR)  = 3029, 2921, 2864, 1682, 1453,

-1 1 1362, 1208, 1093, 991, 909, 733, 696, 609 cm ; H NMR (300 MHz, CDCl3) δ 7.39 - 7.28 (m,

20H), 4.99 (d, J = 11.8 Hz, 1H), 4.84 - 4.60 (m, 5H), 4.54 - 4.40 (m, 2H), 4.19 (t, J = 9.5 Hz, 1H),

3.98 (d, J = 2.8 Hz, 1H), 3.89 (d, J = 9.5 Hz, 1H), 3.78 - 3.56 (m, 5H), 1.35 (d, J = 3.0 Hz, 3H),

13 1.33 (d, J = 3.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 196.8, 138.9, 138.4, 138.3, 138.0, 128.6,

151

128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.6 (2), 84.2, 84.0, 77.8, 76.9, 75.5, 74.6, 73.7, 72.8,

+ 68.7, 34.4, 23.0, 23.0; HRMS (ESI) m/z calcd for C38H42O6Li [M + Li] 633.2857, found

633.2889.

S-Isopropyl (3,4,6-tri-O-benzyl-2-deoxy- -D-glucopyranosyl)thioformate (4-46). To a mixture of (3,4,6-tri-O-benzyl-2-deoxy- -D-glucopyranosyl)tri-n-butylstannane (70.8 mg, 0.100 mmol), S-isopropyl Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg, 0.0075 mmol), JackiePhos (23.9 mg, 0.030 mmol), and CuCl (20.0 mg, 0.200 mmol) were added in 1,4-dioxane (2.00 mL). The reaction mixture was heated under N2 at 110 ºC for 96 h and afforded after chromatographic purification on SiO2 (Hexanes:Et3N, 1:0 to 50:1) 4-46 (42.0 mg,

22 81%) as a colorless oil: []퐷 = +34.9 (c 1.00, CHCl3); IR (ATR)  = 3089, 3067, 3033, 2966,

2929, 2869, 1678, 1499, 1458, 1368, 1305, 1111, 1033, 739, 702 cm-1; 1H NMR (500 MHz,

CDCl3) δ 7.43 – 7.39 (m, 2H), 7.37 – 7.27 (m, 11H), 7.22 (dd, J = 7.6, 1.8 Hz, 2H), 4.91 (d, J =

10.8 Hz, 1H), 4.75 – 4.68 (m, 2H), 4.65 (d, J = 12.5 Hz, 1H), 4.64 – 4.56 (m, 2H), 3.96 (dd, J =

12.0, 2.3 Hz, 1H), 3.80 (dd, J = 11.2, 2.0 Hz, 1H), 3.76 (dd, J = 11.2, 4.3 Hz, 1H), 3.70 (ddd, J =

11.3, 8.3, 4.9 Hz, 1H), 3.64 (sept, J = 6.9 Hz, 1H), 3.54 (dd, J = 9.7, 8.3 Hz, 1H), 3.49 (ddd, J =

9.7, 4.3, 2.0 Hz, 1H), 2.56 (ddd, J = 12.8, 5.0, 2.3 Hz, 1H), 1.60 (q, J = 11.8 Hz, 1H), 1.34 (d, J

13 = 6.9 Hz, 3H), 1.33 (d, J = 6.9 Hz, 3H); C NMR (101 MHz, CDCl3) δ 200.3, 138.6, 138.4, 138.3,

128.6, 128.5 (2), 128.2, 127.9 (2), 127.8, 127.7, 80.5, 80.4, 79.6, 77.9, 75.3, 73.5, 71.5, 69.1, 34.3,

+ + 33.7, 23.1, 23.0; HRMS (ESI) m/z calcd for C31H36O5SNa [M + Na] 543.2176, found 543.2181.

S-Isopropyl (2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl)thiocarboxylate

(4-47). To a mixture of (2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl)tri-n-

152 butylstannane (76.4 mg, 0.100 mmol), S-isopropyl Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg, 0.0075 mmol), JackiePhos (23.9 mg, 0.030 mmol), and

CuCl (20.0 mg, 0.200 mmol) were added 1,4-dioxane (2.00 mL). The reaction mixture was heated under N2 at 110 ºC for 96 h and afforded after chromatographic purification on SiO2

22 (Hexanes:EtOAc, 10:1 to 2:1) 4-47 (32.1 mg, 56%) as a colorless oil: []퐷 = +18.5 (c 1.00,

CHCl3); IR (ATR)  = 3350, 3063, 3033, 2959, 2929, 2866, 1681, 1659, 1536, 1502, 1458, 1376,

-1 1 1130, 1104, 1067, 1033 cm ; H NMR (500 MHz, CDCl3) δ 7.37 – 7.27 (m, 13H), 7.20 (dd, J =

7.5, 1.9 Hz, 2H), 6.27 (d, J = 9.8 Hz, 1H), 4.68 (d, J = 11.8 Hz, 1H), 4.65 (d, J = 11.8 Hz, 1H),

4.63 – 4.55 (m, 3H), 4.54 (d, J = 12.0 Hz, 1H), 4.51 (d, J = 12.2 Hz, 1H), 4.47 (d, J = 3.7 Hz, 1H),

4.08 (q, J = 5.2 Hz, 1H), 3.80 (dd, J = 10.5, 5.5 Hz, 1H), 3.74 – 3.69 (m, 2H), 3.66 (t, J = 5.4 Hz,

1H), 3.62 (sept, J = 6.9 Hz, 1H), 1.79 (s, 3H), 1.29 (d, J = 6.9 Hz, 3H), 1.28 (d, J = 6.9 Hz, 3H);

13 C NMR (75 MHz, CDCl3) δ 200.5, 169.7, 138.1, 137.9, 137.7, 131.7, 129.3, 128.7, 128.6, 128.2,

128.1 (2), 128.0, 127.9, 76.8, 76.6, 76.1, 75.4, 73.6, 73.5 (2), 67.8, 48.9, 34.2, 23.4, 23.1, 22.9;

+ + HRMS (ESI) m/z calcd for C33H39NO6SNa [M + Na] 600.2390, found 600.2396.

S-Isopropyl [2,3,4,6-tetra-O-benzyl-D-galactopyranosyl- -(1→4)-2,3,6-tri-O-benzyl-D- - glucopyranosyl]thiocarboxylate (4-48). [2,3,4,6-tetra-O-benzyl-D-galactopyranosyl- -(1→4)-

2,3,6-tri-O-benzyl-D- -glucopyranosyl]tri-n-butylstannane (125 mg, 0.100 mmol), S-isopropyl

Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg, 0.0075 mmol),

JackiePhos (23.9 mg, 0.030 mmol), and CuCl (20.0 mg, 0.200 mmol) were added in 1,4-dioxane

(2.00 mL). The reaction mixture was heated under N2 at 110 ºC for 96 h and afforded after chromatographic purification on SiO2 (Hexanes:EtOAc, 20:1 to 5:1) 4-53 (79.6 mg, 75%) as a

25 colorless oil: []퐷 = +0.80 (c 1.00, CHCl3); IR (ATR) ṽ = 3089, 3061, 2904, 1680, 1494, 1452,

153

-1 1 1359, 1081, 1045, 908, 734, 697 cm ; H NMR (300 MHz, CDCl3) δ 7.39 – 7.23 (m, 15H), 4.75

– 4.48 (m, 6H), 4.26 – 4.16 (m, 2H), 4.12 (d, J = 5.1 Hz, 1H), 3.88 (dt, J = 6.7, 3.0 Hz, 1H), 3.74

13 (dd, J = 6.3, 2.8 Hz, 1H), 3.60 (dd, J = 11.5, 3.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 201.0,

138.8, 138.3, 138.2, 128.5 (3), 128.1, 128.0, 127.9, 127.8 (2), 127.7, 103.7, 97.5, 84.7, 83.5, 81.8,

80.0, 75.5, 75.3, 75.2, 74.7, 73.6, 69.8, 69.1 (2), 61.0, 60.6, 59.1, 55.4, 34.3, 23.2, 23.1; HRMS

+ + (ESI) m/z calcd for C65H70O11SNa [M + Na] 1081.4531, found 1081.4512.

S-Isopropyl (2,3,4-tri-O-benzyl--D-fucopyranosyl)thiocarboxylate (4-49). To a mixture of

(2,3,4-tri-O-benzyl--D-fucopyranosyl)tri-n-butylstannane (70.8 mg, 0.100 mmol), S-isopropyl

Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg, 0.0075 mmol),

JackiePhos (23.9 mg, 0.030 mmol), and CuCl (20.0 mg, 0.200 mmol) were added in 1,4-dioxane

(2.00 mL). The reaction mixture was heated under N2 at 110 ºC for 96 h and afforded after chromatographic purification on SiO2 (Hexanes:Et3N, 1:0 to 50:1) 4-49 (40.5 mg, 78%) as a

22 colorless oil: []퐷 = -3.4 (c 1.00, CHCl3); IR (ATR) ṽ = 3089, 3067, 3033, 2966, 2933, 2869,

-1 1 1685, 1499, 1458, 1387, 1361, 1212, 1108, 1070, 1033, 1003 cm ; H NMR (300 MHz, CDCl3)

δ 7.42 – 7.27 (m, 15H), 5.02 (d, J = 11.9 Hz, 1H), 4.79 (d, J = 10.4 Hz, 1H), 4.75 – 4.69 (m, 3H),

4.64 (d, J = 10.4 Hz, 1H), 4.16 (t, J = 9.2 Hz, 1H), 3.85 (d, J = 9.5 Hz, 1H), 3.69 (sept, J = 6.9

Hz, 1H), 3.64 – 3.57 (m, 2H), 3.52 (q, J = 6.4 Hz, 1H), 1.33 (d, J = 6.9 Hz, 3H), 1.32 (d, J = 6.9

13 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H); C NMR (75 MHz, CDCl3) δ 197.0, 138.8, 138.5, 138.4, 128.6,

128.4 (2), 128.3, 128.2, 127.8 (2), 127.7, 127.6, 84.4 (2), 76.9, 76.5, 75.5, 75.3, 74.6, 73.0, 34.4,

+ + 23.1, 23.0, 17.4; HRMS (ESI) m/z calcd for C31H36O5SNa [M + Na] 543.2176, found 543.2184.

S-Isopropyl (2,3,4-tri-O-benzyl--D-arabinopyranosyl)thiocarboxylate (4-50). To a mixture of (2,3,4-tri-O-benzyl--D-arabinopyranosyl)tri-n-butylstannane (70.8 mg, 0.100 mmol), S-

154 isopropyl Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg,

22 80%) as a colorless oil: []퐷 = +0.88 (c 1.00, CHCl3); IR (ATR) ṽ = 3067, 3033, 2966, 2899,

-1 1 2869, 1681, 1499, 1458, 1365, 1134, 1097, 1063, 1030 cm ; H NMR (300 MHz, CDCl3) δ 7.40

– 7.27 (m, 15H), 4.72 – 4.64 (m, 3H), 4.63 – 4.57 (m, 2H), 4.54 (d, J = 12.1 Hz, 1H), 4.31 (dd, J

= 7.0, 5.8 Hz, 1H), 4.25 (dd, J = 11.8, 6.2 Hz, 1H), 4.04 (d, J = 5.8 Hz, 1H), 3.86 (dt, J = 6.0, 2.9

Hz, 1H), 3.69 (dd, J = 7.0, 2.8 Hz, 1H), 3.64 (sept, J = 6.9 Hz, 1H), 3.55 (dd, J = 11.8, 2.9 Hz,

13 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.28 (d, J = 6.9 Hz, 2H); C NMR (75 MHz, CDCl3) δ 198.1,

138.3, 138.2, 138.0, 128.5 (2), 128.4, 128.1, 127.9 (2), 127.8 (2), 127.7, 82.4, 77.7, 76.0, 74.1,

+ + 72.0, 71.9, 71.3, 64.8, 34.2, 23.1, 22.9; HRMS (ESI) m/z calcd for C30H34O5SNa [M + Na]

529.2020, found 529.2018.

S-Isopropyl (3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl)thiocarboxylate (4-53). To a mixture of (3,4,6-tri-O-benzyl-2-deoxy-α-D-glucopyranosyl)tri-n-butylstannane (70.8 mg, 0.100 mmol), S-isopropyl Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg, 0.0075 mmol), JackiePhos (23.9 mg, 0.030 mmol), and CuCl (20.0 mg, 0.200 mmol) were added in 1,4-dioxane (2.00 mL). The reaction mixture was heated under N2 at 110 ºC for 96 h and afforded after chromatographic purification on SiO2 (Hexanes:Et3N, 1:0 to 50:1) 4-53 (33.9 mg,

22 65%) as a colorless oil: []퐷 = +36.1 (c 1.00, CHCl3); IR (ATR)  = 3089, 3067, 3033, 2966,

-1 1 2929, 2869, 1681, 1499, 1458, 1368, 1208, 1104, 1044, 936 cm ; H NMR (500 MHz, CDCl3) δ

7.39 – 7.24 (m, 13H), 7.16 (dd, J = 7.4, 2.0 Hz, 2H), 4.84 (d, J = 10.7 Hz, 1H), 4.70 (d, J = 11.9,

155

1H), 4.69 (d, J = 11.9, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.52 – 4.48 (m,

2H), 3.85 – 3.77 (m, 2H), 3.77 – 3.71 (m, 1H), 3.67 – 3.55 (m, 3H), 2.72 (ddd, J = 13.2, 4.3, 2.5

Hz, 1H), 1.83 (ddd, J = 13.4, 10.5, 6.2 Hz, 1H), 1.30 (d, J = 6.9 Hz, 3H), 1.29 (d, J = 7.0 Hz, 3H);

13 C NMR (101 MHz, CDCl3) δ 201.4, 138.5, 138.4, 138.2, 128.6, 128.5, 128.1 (2), 127.9, 127.8

(2), 79.1, 77.7, 77.2, 75.8, 75.0, 73.6, 71.7, 68.8, 34.3, 30.5, 23.2, 23.1; HRMS (ESI) m/z calcd

+ + for C31H36O5SNa [M + Na] 543.2176, found 543.2181.

S-Isopropyl (2-acetamido-3,4,6-tri-O-benzyl-2-deoxy--D-glucopyranosyl)thiocarboxylate

(4-54). To the mixture of (2-acetamido-3,4,6-tri-O-benzyl-2-deoxy--D-galactopyranosyl)tri-n- butylstannane (81.3 mg, 0.100 mmol), S-isopropyl Se-phenyl carbonoselenothioate 4-33 (77.8 mg, 0.300 mmol), Pd2(dba)3 (6.87 mg, 0.0075 mmol), JackiePhos (23.9 mg, 0.030 mmol), and

CuCl (20.0 mg, 0.200 mmol) were added in 1,4-dioxane (2.00 mL). The reaction mixture was heated under N2 at 110 ºC for 96 h and afforded after chromatographic purification on SiO2

25 (Hexanes:EtOAc, 2:1) 4-54 (33.0 mg, 57%) as a colorless oil: []퐷 = +36.5 (c 1.00, CHCl3); IR

(ATR)  = 3357, 3301, 3067, 3093, 3033, 2962, 2899, 2869, 1689, 1659, 1536, 1458, 1372, 1316,

-1 1 1138, 1097, 1071 cm ; H NMR (400 MHz, CDCl3) δ 7.43 – 7.27 (m, 13H), 7.25 – 7.18 (m, 2H),

5.17 (d, J = 8.3 Hz, 1H), 4.83 (t, J = 11.7 Hz, 2H), 4.73 – 4.56 (m, 4H), 3.98 (d, J = 10.0 Hz, 1H),

3.92 (td, J = 9.7, 8.3 Hz, 1H), 3.80 (t, J = 9.1 Hz, 1H), 3.76 (d, J = 3.2 Hz, 2H), 3.69 (t, J = 9.1

Hz, 1H), 3.63 – 3.51 (m, 2H), 1.82 (s, 3H), 1.30 (d, J = 6.1 Hz, 3H), 1.29 (d, J = 6.1 Hz, 3H); 13C

NMR (101 MHz, CDCl3) δ 197.8, 170.3, 138.4 (2), 138.0, 128.7, 128.6, 128.5, 128.3, 128.2,

128.0 (2), 127.9, 127.7, 82.3, 82.2, 79.5, 78.4, 75.1, 74.8, 73.6, 68.7, 54.1, 34.0, 23.6, 22.9 (2);

+ + HRMS (ESI) m/z calcd for C33H39NO6SNa [M + Na] 600.2390, found 600.2391.

156

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