Attempted Azidation of Carbohydrate Secondary Alcohols Using Arylsulfonyl Azides

Home , Sodium azide, Triflate

Morgan Mayieka

Submitted in Partial Fulfilment of the Requirements

for the Degree of

Master of Science

in the

Chemistry

Program

YOUNGSTOWN STATE UNIVERSITY

August 2020

Attempted Azidation Of Carbohydrate Secondary Alcohols Using Arylsulfonyl Azides

Morgan Ongaga Mayieka

I hereby release this thesis to the public. I understand this thesis will be made available from the OhioLINK ETD Center and the Maag Library Circulation Desk for public access.

I also authorize the University or other individuals to make copies of this dissertation as needed for scholarly research.

Signature:

______

Morgan Ongaga Mayieka, Student Date

Approvals:

______

Dr. Peter Norris, Thesis Advisor Date

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Dr. John A. Jackson, Committee Member Date

______

Dr. Nina Stourman, Committee Member Date

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Dr. Salvatore A. Sanders, Dean of Graduate Studies Date Thesis Abstract

This thesis deals with an attempted “one-pot”azidation of carbohydrate secondary alcohols using arylsulfonyl azides. It also deals with the investigation of the reaction mechanism through which the attempted azidation process takes place. The results showed that the attempted azidation did not occur. Instead, the reactions led to the isolation of different sulfonate ester intermediates. A combination of steric (and stereoelectronic) problems were suspected to be the probable cause shutting down the substitution pathway.

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Acknowledgements

I would like to, most sincerely, thank Dr. Peter Norris for not only being my research advisor but also my mentor. Thank you for being so patient with me and making me realize my potential both in research and course work. I would also like to thank Dr. John Jackson for making me a better person in synthesis of organic compounds and for being in my thesis committee. I also thank Dr. Sherri Lovelace for the advice and encouragement.

I am also indebted to thank Dr. Chris Arnsten for the wonderful insight on Spartan

Molecular Modeling, Dr. Matthias Zeller for the X-ray crystal data, Dr. Caleb Tatebe for helping me draw crystal structures and Ray Hoff for teaching me how to use the NMR instrumentation.

I am grateful to the YSU chemistry department and the YSU graduate school for giving me a wonderful opportunity and financial support in my studies. I thank the entire YSU chemistry faculty especially Dr. Nina Stourman for being in my thesis committee and Dr.

Douglas Genna for the knowledge he imparted in me.

I am grateful to my colleagues in the Norris research group; Moffat, Angela, Haron and

Salam, for making my graduate experience enjoyable.

I would also like to thank my family and friends for being so supportive throughout this course.

Lastly, I would like to thank God for the gift of life and for seeing me through this entire process.

Table of Contents

Title Page...... …………………………………………………………………………. i

Signature Page…………………………………………………………………………… ii

Abstract.………………….…..…………………………………………………………. iii

Acknowledgements……………………………………………………………………... iv

Table of Contents…..……………………………………………………………………. v

List of Figures………………………………………………………………………...... vii

List of Tables……………………………………………………………………………. ix

List of Schemes……………………………………………………………………..……. x

List of Equations…………………………………………………………………………. x

Introduction

Azides…………………………………………………………………………………….. 1

Synthesis of Organic Azides…….……………………………………………………….. 3

Statement of Problem……...………………………………………………………...…… 8

Results and Discussion……………………………………………………………..…….. 9

Conclusion………………………………………………………………………………. 27

Experimental

Synthesis of p-nitrobenzenesulfonyl azide (2)…………………………………………. 27

Synthesis of o-nitrobenzenesulfonyl azide (4)…………………………………………. 28

Reaction of diacetone glucose with o-nitrobenzenesulfonyl azide (4)…………..……. 29

3-O-Sulfonate ester intermediate (6) from o-nitrobenzenesulfonyl chloride (3)………. 30

3-O-Sulfonate ester intermediate (6) from o-nitrobenzenesulfonyl chloride (3)………. 32

Side reaction product (8) from o-nitrobenzenesulfonyl chloride and nimethylamino- pyridine………………………………………………………………………………..... 33

3-O-Sulfonate Ester Intermediate (9) from p-nitrobenzenesulfonyl chloride…………... 34

1,2:5,6-di-o-isopropylidene-3-o-toluenesulfonyl-α-D-glucofuranose (11).…………….. 35

1,2:5,6-Di-O-isopropylidene-3-O-trifluoromethanesulfonyl-α-D-glucofuranose (12)..... 36

Attempted Synthesis of 1,2:5,6-Di-O-isopropylidene-3-azido-3-deoxy-α-D-allofuranose

(7)……………………………………………………………………………………...... 37

3-Deoxy-1,2:5,6-di-o-isopropylidene-α-D-erythrohex-3-enofuranose (13) from the

Tosylate (11)……………………………………………………………………………. 38 o-Nitrobenzenesulfonate ester (17)……………………………………………………... 39

Preparation of the azide anion…………………………………………………………... 40

References………………………………………………………………………………. 41

Appendix A

NMR and IR spectra data.………………………………………………………….….... 43

List of Figures

Figure 1 A general form of an organic azide……………………………………… 1

Figure 2 A β-glucosyl azide structure……………………… …………………….. 2

Figure 3 Zidovudine structure…….……………………………………………….. 2

Figure 4 Structures of DPPA, bis(p-nitrophenyl) phosphorazidate and bis(2,4-

dichlorophenyl) phosphate……………………………………………….. 5

Figure 5 Triphenylphosphine structure………….………………………………… 6

Figure 6 The structures of p-nitrobenzenesulfonyl azide and o-nitrobenzenesulfonyl

azide………………………………...……………………………………. 7

Figure 7 Diacetone D-glucose structure……………..…………………………….. 8

Figure 8 X-Ray crystal structure of 3-O-(2-nitrobenzenesulfonate) ester 6……... 13

Figure 9 Structure of the suspected side product due to the side reaction between

DMAP and o-NBSCl…………………………………………………… 15

Figure 10 1H NMR spectrum of the attempted synthesis of 1,2:5,6-di-

-3-azido-3-deoxy- α-D-allofuranose 7………….………………………. 19

Figure 11 1H NMR spectrum of 1,2:5,6-di-O-isopropylidene-3- O-

trifluoromethanesulfonyl-α-D-glucofuranose 12……………………….. 19

Figure 12 1H NMR spectrum of 3-deoxy-1,2:5,6-di-o-isopropylidene-α-D-

erythrohex-3-enofuranose 13…………………………………………… 19

Figure 13 Minimized structure of 3-O-(2-nitrobenzenesulfonate) ester 6………… 23

Figure 14 1H NMR spectrum of p-nitrobenzenesulfonyl azide 2………………….. 44

vii

Figure 15 13C NMR spectrum of p-nitrobenzenesulfonyl azide 2……...………….. 45

Figure 16 1H NMR spectrum of o-nitrobenzenesulfonyl azide 4………………….. 46

Figure 17 13C NMR spectrum of o-nitrobenzenesulfonyl azide 4……...………….. 47

Figure 18 1H NMR spectrum of 3-O-Sulfonate ester intermediate 6……………… 48

Figure 19 13C NMR spectrum of 3-O-Sulfonate ester intermediate 6……….….… 49

Figure 20 1H NMR spectrum of attempted synthesis of

1,2:5,6-di-O-isopropylidene-3-azido-3-deoxy-α-D-allofuranose 7…….. 50

Figure 21 13C NMR spectrum of attempted synthesis of

1,2:5,6-di-O-isopropylidene-3-azido-3-deoxy-α-D-allofuranose 7…….. 51

Figure 22 1H NMR spectrum of side reaction product 8 …………………………. 52

Figure 23 13C NMR spectrum of side reaction product 8 …………………………. 53

Figure 24 1H NMR spectrum of 3-O-Sulfonate Ester Intermediate 9……………... 54

Figure 25 13C NMR spectrum of 3-O-Sulfonate Ester Intermediate 9……………... 55

Figure 26 1H NMR spectrum of 1,2:5,6-di-o-

isopropylidene-3-o-toluenesulfonyl-α-D-glucofuranose 11……………. 56

Figure 27 13C NMR spectrum of 1,2:5,6-di-o-

isopropylidene-3-o-toluenesulfonyl-α-D-glucofuranose 11……………. 57

Figure 28 1H NMR spectrum of 1,2:5,6-di-O-

isopropylidene-3-O-trifluoromethanesulfonyl-α-D-glucofuranose 12….. 58

Figure 29 13C NMR spectrum of 1,2:5,6-di-O-

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isopropylidene-3-O-trifluoromethanesulfonyl-α-D-glucofuranose 12….. 59

Figure 30 1H NMR spectrum of 3-deoxy-1,2:5,6-di-o-isopropylidene-α-

D-erythrohex-3-enofuranose 13………………………………………… 60

Figure 31 13C NMR spectrum of 3-deoxy-1,2:5,6-di-o-isopropylidene-α-

D-erythrohex-3-enofuranose 13………………………………………… 61

Figure 32 1H NMR spectrum of o-nitrobenzenesulfonate ester 17………………… 62

Figure 33 13C NMR spectrum of o-nitrobenzenesulfonate ester 17………………… 63

Figure 34 IR spectrum of ionic azide Scheme 7……………………………………. 64

Figure 35 IR spectrum showing the formation of an ionic azide…………………… 65

List of Tables

Table 1 List of conditions varied for the synthesis of 3-O-(2-

nitrobenzenesulfonate) ester from o-nitrobenzenesulfonyl chloride….... 14

Table 2 Duration of Spartan model energy minimization……………………….. 20

Table 3 Various angles within different sulfonate esters as calculated by the

Spartan molecular modeling software………………………...………… 21

Table 4 Spartan models of o-nitrosulfonate ester 6 intermediate synthesized…… 22

Table 5 Spartan models of p-nitrosulfonate ester 9 intermediate synthesized…… 24

Table 6 Spartan models of O-(trifluoromethyl)sulfonate ester 12

intermediate synthesized…………………………………………...…… 25

List of Schemes

Scheme 1 A classic nucleophilic substitution method of azidation…………...…...... 4

Scheme 2 The Mitsunobu method of azidation…………...…………………..…….. 5

Scheme 3 Attempted azide synthesis using p-ABSA………………..…...……….… 7

Scheme 4 Attempted azide synthesis using p-NBSA and o-NBSA………...…..…… 7

Scheme 5 Proposed azidation pathway……………………………………………… 8

Scheme 6 Attempted azidation using o-NBSA……………………………...... …… 11

Scheme 7 A suggested reaction mechanism in the generation of the intermediate… 12

List of Equations

Equation 1 The 1,3-dipolar cycloaddition reaction………………...…………...…..... 2

Equation 2 An alternative to DEAD in azide synthesis…………....…………..…….. 6

Equation 3 Synthesis of p-nitrobenzenesulfonyl azide………………..….....…….… 10

Equation 4 Synthesis of o-nitrobenzenesulfonyl azide……………………...….…… 10

Equation 5 Synthesis of 3-O-(2-nitrobenzenesulfonate) ester……………….……… 12

Equation 6 Attempted synthesis of side product 8…………………………...... …… 15

Equation 7 Synthesis of 3-O-(4-nitrobenzenesulfonate) ester………………………. 16

Equation 8 Synthesis of the tosylate ester intermediate 11………………………….. 16

Equation 9 Synthesis of the triflate ester intermediate 12……………….…………... 16

Equation 10 Attempted azidation of the triflate intermediate……………….………... 17

Equation 11 Synthesis of the alkene 13 from the tosylate intermediate 11…………... 18

Equation 12 Attempted azidation of diacetone D glucose using DPPA……………… 26

Equation 13 Conversion of tridecanol to the sulfonate ester intermediate 17………... 26

INTRODUCTION.

Azides

In the history of organic chemistry, many discoveries involving functional groups have been made, among them being organic azides. These azides are made of three nitrogen atoms bonded to an organic compound (Figure 1).

Figure 1: A general form of an organic azide.

The discovery of aryl azides, for instance, dates to 1864 when Peter Griess conducted an experiment involving arenediazonium perbromides and ammonia. The azide chemistry attracted more interest afterwards when Theodor Curtius, who specialized in the chemistry of nitrogen, entered the field. He is known to be the first scientist to have prepared diazo compounds. He also used silver azide to prepare alkyl azides.1

The wide applications of azides, which range from use in the pharmaceutical industry (in the discovery and synthesis of drugs) to applications in materials science makes them fall among the most useful functional groups ever discovered especially in synthetic chemistry. Figure 2 shows an example of an organic azide derived from a natural compound, in this case D-glucose.3

Figure 2: A -glucosyl azide structure.

Applications of organic azides include but are not limited to the synthesis of α- diazocarbonyls, amines, peptides, and heterocycles.4,5 The 1,3-dipolar cycloaddition reaction, for instance, is a unique character that is exhibited by azides in the formation of heterocyclic compounds. This takes place when azides react with unsaturated carbon- carbon or carbon-nitrogen bonded compounds according to Equation 1 below.6

Equation 1: 1,3-Dipolar cycloaddition reaction.

In the medical industry, azides have played an important role in the synthesis and discovery of drugs. For instance, zidovudine, (Figure 3), a drug for HIV/AIDS, contains the azide group.6

Figure 3: Zidovudine structure.

Synthesis of Organic Azides

The stability of organic azides when exposed to different conditions, and their diverse reactivity patterns, makes them one of the most important functional groups in chemistry. In the synthesis of organic azides, it is important to consider their explosive nature especially when exposed to heat, pressure, or both. Thus, the safest route is the one in which the reaction proceeds at room or lower temperature and pressure and gives a pure product hence reducing the need for any further purification processes. Various methods of azide preparation exist. The N3, N2 groups and nitrogen atoms can be inserted through substitution, diazo transfer and diazotization, respectively. On the other hand, some compounds such as triazines can be made to undergo cleavage giving rise to azides among other products.7

Azidation of alcohols is believed to proceed via a bimolecular nucleophilic substitution (SN2) pathway which gives rise to products with inverted configuration. The effectiveness of this pathway depends on several factors which include the leaving group effects and the solvation effects. The level of reactivity of a leaving group, for instance, directly influences the rate at which substitution occurs. p-Nitrobenzenesulfonate, for example is more reactive than p-toluenesulfonate. The pattern of the relative rates of reaction of some leaving groups is shown below.8

Triflates > p-Nitrobenzenesulfonate > p-Toluenesulfonate > Mesylates

The reactivity of primary alcohol substrates, on the other hand, is higher compared to the secondary and tertiary counterparts due to steric effects.

The classic nucleophilic substitution method of preparing azides has been considered of great importance. This proceeds via activation of the alcohols to convert them into better leaving groups such as tosylates, triflates, sulfonates or related compounds.

They then undergoe nucleophilic substitution by reaction with an azide nucleophile (e.g. a metal azide) according to the reaction scheme below (Scheme 1).9

Scheme 1: A classic nucleophilic substitution method of azidation.

The process in Scheme 1 above (where R is an alkyl, or aryl group, X is a halide,

OTs, etc.) involves two individual reactions and employs the use of environmentally unfriendly organic halides. The use of excess (and dangerous) azide salts is also a concern.10 Hence, there is a need to find a convenient way to directly synthesize azides from the corresponding alcohols in a single operation through an un-isolated intermediate.

From previous studies, the Mitsunobu displacement is ranked among the best methods of converting alcohols to azides.11 However, the hydrazoic acid used to generate the azide when mixed with diethyl azodicarboxylate (DEAD) for the hydroxyl group activation with triphenylphosphine is dangerous, besides DEAD being expensive. Also, the method gives a contaminated product which needs further purification by chromatography and/or distillation.

Modification of the Mitsunobu displacement can be done by using reagents such as diphenyl phosphoryl azide (DPPA),12 zinc azide/bispyridine complex,13 bis(p-nitrophenyl) phosphorazidate,14 bis(2,4-dichlorophenyl) phosphate with sodium azide,15 N-(p-toluene- 4

sulphonyl) imidazole with sodium azide, or triethylamine / tetrabutyl ammonium iodide16 among others.

Figure 4: Structures of DPPA, bis(p-nitrophenyl) phosphorazidate and bis(2,4-

dichlorophenyl) phosphate.

A useful alternative to the Mitsunobu method involves reacting alcohols with diphenyl phosphorazide (DPPA) as the source of the azide and 1,8-diazabicyclo [5.4.

0]undec-7-ene (DBU) as the base.17

Scheme 2: The Mitsunobu method of azidation.

This activation (Scheme 2) converts the alcohol into a good leaving group which then gets substituted by the azide from DPPA. This proceeds via an SN2 reaction which gives rise to an organic azide. However, DPPA is highly toxic and expensive.

Studies have shown that triphenylphosphonium anhydride trifluoromethane sulfonate can be used to replace the DPPA because it can be recycled when reacted with

trifluoromethanesulfonic anhydride (Tf2O). However, when this method is used with secondary alcohols, it leads to the generation of olefins through an elimination pathway.18

In a recent publication by Lee et al., carbon tetrabromide (CBr4), triphenylphosphine (PPh3), and sodium azide (NaN3) were used as an alternative to DEAD (Equation

2).19 However, the unreacted triphenylphosphine (Figure 5) and the triphenylphosphine- oxide byproduct are difficult to separate from the products.

Equation 2: An alternative to DEAD in azide synthesis.

Figure 5: Triphenylphosphine structure.

Looking at how important organic azides are in synthetic chemistry, and the many disadvantages associated with the known methods of synthesizing them, which range from costs and toxicity of reagents to the difficulty in removing the byproducts, the Norris group has in the past years been looking at a new route which in a single operation will convert alcohols to azides using environmentally safe and cheaply available reagents.

p-Acetamidobenzenesulfonyl azide (p-ABSA), a nontoxic solid, was found to give the same results as DPPA when reacted with a mannofuranose-derived alcohol thereby providing a safer route using a one-pot synthesis (Scheme 3).20 6

Scheme 3: Attempted azide synthesis using p-ABSA.

The method, however, could not work with hindered secondary alcohols. Some of the secondary substrates often stopped at the intermediate sulfonate ester. In the more recent work of Hartranft,20 Dobosh,21 and Curry22 the use of p-NBSA or o-NBSA (Figure

6) lead to isolation of intermediates in some cases (Scheme 4).

Figure 6: The structures of o-nitrobenzenesulfonyl azide and p-nitrobenzenesulfonyl

azide.

Scheme 4: Attempted azide synthesis using p-NBSA and o-NBSA.

In the current research we used 1,2:5,6-di-O-isopropylidene--D-glucofuranose also known as diacetone glucose (Figure 7) as the starting material.

Figure 7. Diacetone D-Glucose structure.

The glucofuranose structure is a hindered secondary alcohol with a known starting configuration at C-3 bearing the OH. Once the 3-hydroxyl group gets converted into a suitable leaving group, the displacement reaction by the azide nucleophile in the azidation process should give a product whose configuration is inverted (Scheme 5). This could be used as proof that the process is occurring by an SN2 pathway.

Scheme 5: Proposed azidation pathway.

STATEMENT OF THE PROBLEM

The synthesis of azides has played an important role in organic chemistry. Azides exhibit a wide range of synthetic transformations to other equally useful organic

compounds whose applications range from the pharmaceutical industry to materials science. The traditional methods of azide synthesis involve the use of toxic and expensive materials. They also involve multiple steps which are tedious especially when it comes to purification of the product.

This research investigates a potentially efficient, safe, and cheap method of synthesizing azides from alcohols through a ‘one-pot’ process. A D-glucose-derived alcohol is used in the presence of a sulfonyl azide in an attempt to convert the alcohol into the corresponding azide. This involves the activation of the alcohol to a sulfonate ester and a potential subsequent substitution by an azide nucleophile. The method of azidation, which could proceed through standard bimolecular substitution replacement of sulfonic ester (SN2), will be investigated.

RESULTS AND DISCUSSION.

The major objective of this research was to study the potential for a one-pot activation/nucleophilic substitution on secondary alcohols. The primary focus was on a hindered glucose derivative that has, in the past, proven difficult to displace leaving groups from at C-3 of the furanose ring.

We began our research by synthesizing p-NBSA (2, Equation 3) from para- nitrobenzenesulfonyl chloride (1) and sodium azide using methanol as the solvent. The reaction was left to stir overnight at room temperature and upon consumption of the starting material (as thin layer chromatography analyses indicated). 1H NMR and 13C NMR spectra confirmed the successful synthesis of p-NBSA.

Equation 3: Synthesis of p-nitrobenzenesulfonyl azide.

The yellow crystals of p-NBSA were further purified by recrystallization from hot isopropanol before being used in the subsequent azidation reactions. Next, an additional azide transfer reagent, o-NBSA (4, Equation 4) was synthesized form ortho-nitrobenzenesulfonyl chloride (3) and sodium azide using acetone/water as the solvent.

Equation 4: Synthesis of o-nitrobenzenesulfonyl azide.

The reaction was left to stir overnight at room temperature and, upon consumption of the starting material (as thin layer chromatography analyses indicated), 1H NMR and

13C NMR spectra confirmed the successful synthesis of o-NBSA. The yellow crystals of o-NBSA were further purified by recrystallization from hot ethanol before being used in the subsequent azidation reactions.

Once the azide transfer reagents o-NBSA and p-NBSA had been prepared, the

“one-pot” azidation experiment with diacetone D-glucose was attempted (Scheme 6).

Scheme 6: Attempted azidation using o-NBSA.

After dissolving 5 in acetonitrile, o-NBSA and DBU were added and the reaction mixture was left to stir overnight. The IR spectra taken the following morning indicated a strong ionic azide absorption peak at 2022.04 cm-1. TLC (3:1 hexane : ethyl acetate) showed a UV-active spot within the reaction sample and an almost complete consumption of the starting material. The UV-active spot was suspected to be the sulfonate ester intermediate 6. This was later confirmed by the 1H NMR and 13C NMR data. After running for a week, the reaction did not give the expected carbohydrate azide product. The ionic azide nucleophile did not displace the leaving group; possibly because of steric and electronic interference from the neighboring 1,2-O-isopropylidene ring.

The following reaction mechanism (Scheme 7) was suggested in the generation of the sulfonate ester intermediate and the nucleophilic azide anion.

Scheme 7: A suggested reaction mechanism in the generation of the intermediate.

The next goal was to synthesize the sulfonate ester intermediate using different systems and methods to prove its structure. At first diacetone D-glucose (5) was reacted with o-nitrobenzenesulfonyl chloride in dry pyridine (Equation 5).

Equation 5: Synthesis of the 3-O-(2-nitrobenzenesulfonate) ester.

The reaction was left to stir overnight at room temperature. The analysis by TLC

(3:1 hexane : ethyl acetate) showed a complete consumption of the starting material after

72 h. 1H NMR and 13C NMR spectra of the product indicated the likelihood of a successful

3-O-(2-nitrobenzenesulfonate) ester 6. The identity of the product was further proved using

X-Ray crystallography (Figure 8).

Figure 8. X-Ray crystal structure of 3-O-(2-nitrobenzenesulfonate) ester 6.

Following the successful synthesis of the 3-O-(2-nitrobenzenesulfonate) ester 6 from o-nitrobenzenesulfonyl chloride and pyridine, other conditions (solvents and bases) were varied to compare the rates of reaction and yields (Table 1).

Table 1. List of conditions varied for the synthesis of 3-O-(2-nitrobenzenesulfonate) ester from o-nitrobenzenesulfonyl chloride.

Structure Name of base Solvent Temp. Time Yield of base (oC) (h) (%)

Pyridine Pyridine 75 24 89

1,8-Diazabicyclo[5.4. Acetonitrile 25 168 81

0]undec-7-ene

4-Dimethylaminopyridine DCM 75 96 64

4-Dimethylaminopyridine DCM 25 24 0

The reaction involving the use of 4-dimethylaminopyridine (DMAP) at room temperature did not give any significant sulfonate ester product. Instead the reaction had formed a precipitate. This outcome made us suspect the possibility of a side reaction between the base and o-NBSCl to give the product (8). To confirm this, the precipitate was

1 vacuum filtered and H NMR carried out using DMSO-d6 solvent since it could not

1 dissolve in CDCl3. The H NMR spectrum confirmed that a side product (8) had formed.

Figure 9. Structure of the suspected side product due to the

side reaction between DMAP and o-NBSCl.

To further support the above conclusion, DMAP and o-NBSCl were set up to react at room temperature without the alcohol according to Equation 6 below.

Equation 6: Attempted synthesis of the side product 8.

The reaction did not, however, give the expected product cleanly. This was evident from the 1H NMR which was complicated.

Having successfully synthesized the possible 3-O-(2-nitrobenzenesulfonate) ester intermediate 6, other intermediates that could be of great importance during the attempts to carry out the “one-pot” azidation of secondary alcohols via the bimolecular substitution

(SN2) reactions were synthesized. This could help compare the properties of various

leaving groups since this is an important factor that influences the rate of nucleophilic substitution either through direct displacement or via ionization routes. Equations 7, 8 and

9 show the various intermediates that were synthesized.

Equation 7: Synthesis of 3-O-(4-nitrobenzenesulfonate) ester 9.

Equation 8: Synthesis of the tosylate ester intermediate 11.

Equation 9: Synthesis of the triflate ester intermediate 12.

To synthesize alkyl azides, the bimolecular substitution (SN2) is usually used. This requires a strongly nucleophilic azide source. Previous studies have made use of sodium azide. In the Norris lab however, there has been a successful synthesis of azides using organic azide transfer agents.

Compounds 6, 9, 11, and 12, which translate to the 3-O-(2-nitrobenzenesulfonate) ester, 3-O-(4-nitrobenzenesulfonate) ester, tosylate, and triflate respectively were made to react with sodium azide in DMF at 140 °C. However, only the triflate showed some positive results despite the product mixture containing some of the starting material (Equation 10).

This was suspected to be due to the exceptional leaving group ability of triflate (Krel 29,000 x that of mesylate) and possibly the small size of the triflate which does not affect the shape of the furanose ring much (see below) and should not result in blocking the attack of the azide nucleophile.

Equation 10: Attempted azidation of the triflate intermediate 12.

On the account of the attempted azidation experiments above which failed to yield the anticipated azide products, we became interested in investigating the possible causes as to why the reactions were not going forward beyond the intermediates.

While knowing that triflate is a much better leaving group than any of the other sulfonate esters produced in this work, we wanted to also explore how the C-3 steric and electronic environments in the electrophile could contribute to the nucleophile not performing the required bimolecular displacement at C-3 of the diacetone D-glucose substrate. Alternative reaction pathways could lead to a possible bimolecular elimination of H-4.

We decided to synthesize 3-deoxy-1,2:5,6-di-o-isopropylidene-α-D-erythrohex-3- enofuranose (13), from the tosylate intermediate (11) (Equation 11). This could help us prove that indeed a bimolecular elimination reaction was part of the reaction taking place in our attempted azidation reaction (in Equation 10 above) by comparing the spectra of the products.

Equation 11: Synthesis of the alkene 13 from the tosylate intermediate 11.

We then compared the 1H NMR spectra of the 7, 12 and 13 (Figure 10). It was evident from the spectra that the attempted azidation experiment in Equation 11 above gave a mixture of products containing the alkene (13).

Figure 10. 1H NMR spectrum of the attempted synthesis of

1,2:5,6‑Di‑O‑isopropylidene‑3‑azido‑3‑deoxy‑α‑D‑allofuranose (7)

Figure 11. 1H NMR spectrum of 1,2:5,6‑Di‑O‑isopropylidene‑

3‑O‑trifluoromethanesulfonyl‑α‑D‑glucofuranose (12).

Figure 12. 1H NMR spectrum of 3-Deoxy-1,2:5,6-di-o-isopropylidene-α-D-erythrohex-

3-enofuranose (13).

Charles Hartranft, in his thesis, had found out that the para-amido group of p-

ABSA contributed to the possibility of an aryl substitution reaction where the azide nucleophile attacks the C-4 of the benzene ring instead of the C-3 of the D-glucose.21

Based on this, we set out to use the Spartan molecular modeling software to study the shape and steric properties of the sulfonate ester intermediates. The molecules were built in Spartan followed by energy minimization and calculations. To perform this, from the main Spartan menu, we chose setup, then calculations and we selected orbitals & energies. Once done, we then submitted the job. The calculations and minimization times are presented in Table 2.

Table 2: Duration of Spartan model energy minimization.

Sulfonate Ester Molecule Duration (Minutes)

Tosylate 133 p-Nitro 137

Triflate 143 o-Nitro 149

Having found minimum energy conformations of each molecule we then generated both the dihedral angles (between H-1 & H-2 and H-2 & H-3) and the angle between H-3 and the leaving group (Table 3).

Table 3: Various angles within different sulfonate esters as calculated by the Spartan molecular modeling software.

Dihedral (X°)

(H-3, C-3, R) H-1 and H-2 H-2 and H-3 Molecule (X°)

Tosylate 104.51 28.55 156.88

p-Nitro 110.32 21.06 81.66

o-Nitro 109.70 29.00 154.21

Triflate 110.95 22.18 80.94

For an SN2 reaction to occur, the nucleophile must approach the C-3 at an angle of

180° from the leaving group (backside attack). As evident from the Spartan models, the prevailing shape of some of the molecules suggested that the substitution possibly could not occur. The o-nitrosulfonate ester for instance could apparently not allow any substitution because of the preferred orientation of the o-nitro group and the close alignment of the adjacent 1,2-O-isopropylidene ring (Table 4).

Table 4: Spartan models of o-nitrosulfonate ester 6 intermediate synthesized.

o-nitro derivative (side) o-nitro derivative (side) with H

Looking at model 6C (Table 4) it appears that the sulfonate ester group is actually in an equatorial position, which means that the required C-3 to OSO2R anti-bond is tucked underneath the furanose ring. This suggests that nucleophilic attack will be unlikely from underneath the furanose cycle (see the red arrow in Figure 10) through a combination of steric and stereoelectronic effects. Not only is the position of the anti-bond inaccessible,

the O1-O2 isopropylidene group possibly blocks approach from below and the O-2 lone pairs could also repel the incoming nucleophile anion.

Figure 13. Minimized structure of 3-O-(2-nitrobenzenesulfonate) ester 6.

In the minimized structure of the p-nitrobenzenesulfonate ester 9 (Table 5), there is a noticeable change in shape at C-3 of furanose ring. Looking at the side-on view 9C, the leaving group now seems to be closer to an axial position on the furanose ring, which might be because of the nitro group now being further away at the 4-position. This opens up C-3 since the required anti-bond should now be more accessible from underneath, however substitution did not happen under the conditions attempted.

Table 5: Spartan models of p-nitrosulfonate ester 9 intermediate synthesized. p-nitro derivative (front) p-nitro derivative (front) with H

p-nitro derivative (side) p-nitro derivative (side) with H

For the triflate (12) the model was similar to the p-nitrobenzenesulfonate model

(Table 6) with the leaving group being close to an axial position. This opens up attack at the anti-bond from underneath and the isopropylidene is not blocking like it does in the o- nitrobenzenesulfonate derivative.

Table 6: Spartan models of O-(trifluoromethyl)sulfonate ester 12 intermediate synthesized. triflate derivative (front) triflate derivative (front) with H

triflate derivative (side) triflate derivative (side) with H

As the azidation reactions with diacetone glucose were unsuccessful, we further synthesized various other compounds both for practice and to compare their reactivities 25

under different conditions. This could help us draw valid conclusions in our reactions involving azidation of secondary alcohols.

In an attempt to investigate the reaction of diacetone D-glucose and diphenyl phosphoryl azide (Equation 12), the intermediate (14) and azide were not identified. The

1H NMR was complicated which made us conclude that the reaction was not successful.

Equation 12: Attempted azidation of diacetone D glucose using DPPA.

Experiments involving unhindered primary alcohols were also carried out. The reaction between tridecanol (15) and o-nitrobenzenesulfonyl chloride (Equation 14), for instance, successfully gave a sulfonate ester product 17 (Equation 13).

Equation 13.

CONCLUSION

The attempted azidation of secondary alcohols, particularly diacetone glucose, was not successful. According to the experiments that were carried out in this research, it was confirmed that the attempted azidation stopped at the sulfonate ester intermediates. Efforts to advance the reactions to the substitution product have been shown here and previously to be either slow, diverted to other alternative reaction pathways (bimolecular elimination of H-4 or a nucleophilic aryl substitution on the leaving group) or could not work at all. It is important to note that the NMR spectrum of the product mixture from the triflate intermediate showed numerous chemical shifts, however the shifts indicated the formation of the bimolecular elimination product instead. The nature of the attached groups in terms of their electronic properties and their steric bulk likely contributed to this problem. The leaving group abilities were well-understood but, in this system, it could well be a combination of steric and stereoelectronic problems that were shutting down the substitution pathway. For example, the conformation of the substrate might not allow backside attack, and the lone pairs on O at

C-2 could be repelling nucleophiles.

EXPERIMENTAL

Synthesis of p-Nitrobenzenesulfonyl Azide (2).

In a 250 mL round bottom flask fitted with a rubber septum and magnetic stir bar, p-nitrobenzenesulfonyl chloride (5.0 g, 22.6 mmol) was dissolved in methanol (100 mL). 27

Sodium azide (2.9 g, 45.1 mmol) was then added to the solution and the reaction was left to stir overnight. Upon consumption of the starting material as thin layer chromatography

(3:1 hexane : ethyl acetate) analyses indicated, methanol was removed under vacuum and an aqueous work up was performed by partitioning the solid between de-ionized water (50 mL) and ethyl acetate (3 x 50 mL). The organic layer was dried using anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The crude product was a yellowish solid which was later recrystallized from hot isopropanol giving 3.53 g of sulfonyl azide 2, 71% yield.

1 H NMR (400 MHz, CDCl3, ppm): 8.48 (2H, d, J =8.78 Hz), 8.18 (2H, d, J = 8.78 Hz).

13 C NMR (100 MHz, CDCl3, ppm): 151.22, 143.74, 128.94, 124.98.

Melting Point: 97-100 °C.

Synthesis of o-Nitrobenzenesulfonyl Azide (4).

In a 250 mL round bottom flask fitted with a rubber septum and a magnetic stir bar, a solution of 2-nitrobenzenesulfonyl chloride (4.56 g, 20.6 mmol) in acetone (20 mL) was added into a solution of sodium azide (1.95 g, 30.0 mmol) in water (10 mL) dropwise over

1 h at 0°C. The reaction mixture was warmed up to room temperature and left to stir overnight. thin layer chromatography (3:1 hexane : ethyl acetate) was used to monitor the 28

progress of the reaction. When TLC analyses showed complete consumption of the starting material, the solvent was removed under reduced pressure and the reaction mixture was extracted using ethyl acetate (3 x 50 mL). The combined organic extract was dried over anhydrous magnesium sulfate, filtered under gravity, and concentrated under reduced pressure. The crude product was recrystallized from hot ethanol giving o- nitrobenzenesulfonyl azide 4 as yellow crystals (3.47 g, 76%).

1 H NMR (400 MHz, CDCl3, ppm): 8.20 (1H, d, J = 8.06 Hz) 7.94-7.83 (3H, m).

13 C NMR (100 MHz, CDCl3, ppm): 147.73, 135.85, 133.18, 132.56, 131.73, 125.43.

Melting Point: 59-62 °C.

Reaction of Diacetone Glucose with o-Nitrobenzenesulfonyl Azide (4).

In a 25 mL round bottom flask fitted with a rubber septum and magnetic stir bar

1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (0.260g ,1.0 mmol) was dissolved in acetonitrile (3 mL). o-Nitrobenzenesulfonyl azide (o-NBSA) (0.228 g, 1.0 mmol) was added to the solution followed by the addition of 1,8-diazabicyclo[5.4. 0]undec-7-ene

(DBU) (0.16 mL, 1.1 mmol). The reaction was left to stir overnight at room temperature.

TLC (3:1 hexane : ethyl acetate) showed a UV-active spot on the reaction sample and an

almost complete consumption of the starting material. IR scans showed an azide anion signal at 2020.28 cm-1. The reaction was left to run for a week after which aqueous work up was done by first evaporating the acetonitrile solvent under vacuum, then extracting using ethyl acetate (3 x 25 mL). The combined organic extract was dried over anhydrous magnesium sulfate, filtered under gravity, and evaporating it under reduced pressure to give 0.36 g of 3-O-sulfonate ester intermediate 6, 81% yield.

1 H NMR (400 MHz, CDCl3, ppm): 8.19 (1H, d, J = 7.67 Hz) 7.88-7.74 (3H, m), 5.98 (1H, d, J = 3.58 Hz), 5.01 (1H, d, J = 2.78 Hz), 4.87 (1H, d, J = 3.60 Hz), 4.29-4.24 (1H, m),

4.08 (1H, dd, J = 8.55 Hz, 2.81 Hz), 4.00 (1H, dd, J = 8.77 Hz, 6.20 Hz), 3.93 (1H, dd, J =

8.84 Hz, 4.28 Hz), 1.50 (3H, s), 1.33 (3H, s), 1.13 (3H, s), 1.01 (3H, s).

13 C NMR (100 MHz, CDCl3, ppm): 134.79, 132.08, 131.81, 129.70, 125.05, 112.73,

109.01, 105.18, 84.21, 83.53, 79.90, 71.90, 67.23, 26.63, 26.24, 24.62.

Melting Point: 83-87 °C.

3-O-Sulfonate Ester Intermediate (6) from o-Nitrobenzenesulfonyl Chloride (3).

In a 3-neck round bottom flask 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose

(0.52 g, 2.0 mmol) was dissolved in pyridine (3 mL). o-Nitrobenzenesulfonyl chloride

(0.44 g, 1.9 mmol) was dissolved in pyridine (3 mL) in a separate vial and dropped into the diacetone D-glucose solution at 0 °C. The reaction was left to stir as temperature adjusted to room temperature. TLC (3:1 hexane : ethyl acetate) analyses were carried out at intervals. After 48 h, the reaction was run at elevated temperature (75 °C) for 24 h. From the TLC analysis, the starting material was fully consumed after running the reaction for

72 h. The reaction mixture was poured into ice water and left to sit for 30 min. Extraction was then done using ethyl acetate (3 x 25 mL). The combined organic extract was washed with 5% sulfuric acid (3 x 10 mL). It was then washed with distilled water (3 x 10 mL), dried over anhydrous magnesium sulfate, filtered under gravity and the solvent was removed under reduced pressure giving 0.39 g of 3-O-sulfonate ester intermediate 6, 89% yield.

1 H NMR (400 MHz, CDCl3, ppm): 8.20 (1H, d, J = 7.91 Hz) 7.92-7.82 (3H, m), 5.94 (1H, d, J = 3.59 Hz), 4.54 (1H, d, J = 3.60 Hz), 4.37-4.32 (1H, m), 4.17 (1H, dd, J = 8.60 Hz,

6.24 Hz), 4.07 (1H, dd, J = 7.70 Hz, 2.67 Hz), 3.99 (1H, dd, J = 8.63 Hz, 5.31 Hz), 1.50

(3H, s), 1.44 (3H, s), 1.37 (3H, s), 1.32 (3H, s).

13 C NMR (100 MHz, CDCl3, ppm): 147.74, 135.80, 133.15, 132.59, 131.74, 125.43,

111.82, 109.64, 105.25, 85.08, 81.09, 75.06, 73.35, 67.59, 26.83, 26.77, 26.17, 25.14.

Melting Point: 83-87 °C.

3-O-Sulfonate Ester Intermediate (6) from o-Nitrobenzenesulfonyl Chloride (3).

In a 100 mL round bottom flask 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose

(0.26 g, 1.0 mmol) was mixed with o-nitrobenzenesulfonyl chloride (0.265 g, 1.2 mmol).

4-Dimethylaminopyridine (DMAP) (0.146 g, 1.2 mmol) was added into the flask followed by the addition of dichloromethane (7 mL). The reaction was left to stir as TLC (3:1 hexane

: ethyl acetate) analysis were periodically carried out. After 72 h, the reaction was heated at 75 °C for 24 h. From the TLC plates, the starting material was almost fully consumed after running the reaction for 4 days. The reaction was poured into ice water and left to sit for 30 min. Extraction was then done using ethyl acetate (3 x 25 mL). The combined organic extract was washed with 5% sulfuric acid (3 x 10 mL). It was then washed with deionized water (3 x 10 mL), dried over anhydrous magnesium sulfate, filtered under gravity and the solvent removed under reduced pressure giving a thick sticky solid which was recrystallized from hot ethanol to give white crystals 3-O-sulfonate ester intermediate

6 (0.28 g, 64%).

1 H NMR (400 MHz, CDCl3, ppm): 8.28 (1H, dd, J = 7.88 Hz, 1.14 Hz), 8.22 (1H, dd, J =

7.79 Hz, 1.31 Hz) 7.91-7.77 (3H, m), 6.00 (1H, d, J = 3.61 Hz), 4.90 (1H, d, J = 3.62 Hz),

4.32-4.27 (1H, m), 4.09 (1H, dd, J = 8.64 Hz, 2.91 Hz), 4.02 (1H, dd, J = 8.91 Hz, 6.15 32

Hz), 3.95 (1H, dd, J = 8.90 Hz, 4.17 Hz), 1.52 (3H, s), 1.35 (3H, s), 1.13 (3H, s), 1.02 (3H, s).

13 C NMR (100 MHz, CDCl3, ppm): 147.74, 135.80, 133.15, 132.59, 131.74, 125.43,

111.82, 109.64, 105.25, 85.08, 81.09, 75.06, 73.35, 67.59, 26.83, 26.77, 26.17, 25.14.

Melting Point: 83-87 °C.

Side Reaction Product (8) from o-Nitrobenzenesulfonyl Chloride and

Dimethylaminopyridine.

In a 100 mL round bottom flask 1,2,5,6-di-O-isopropylidene-α-D-glucofuranose

(1.3 g, 5.0 mmol) was mixed with o-nitrobenzenesulfonyl chloride (1.66 g, 7.2 mmol). 4-

Dimethylaminopyridine (DMAP) (0.915 g, 7.5 mmol) was then added into the flask followed by the addition of dichloromethane (15 mL). The reaction was left to stir at room temperature as TLC (3:1 hexane : ethyl acetate) analyses were periodically carried out.

After 3 h, the reaction mixture had formed a precipitate which was believed to be due to the side reaction. Further dichloromethane (5 mL) was added and the reaction was left to stir overnight. The precipitate was vacuum filtered and 1HNMR carried out using DMSO- d6 solvent.

1H NMR (400 MHz, DMSO-d6, ppm): 8.20 (1H, d, J = 6.78 Hz), 7.68 (1H, d, J = 7.74 Hz

Hz) 7.59-7.50 (1H, m), 3.18 (6H, s).

13 C NMR (100 MHz, CDCl3, ppm): 154.24, 149.74, 149.43, 135.70, 132.97, 132.50,

131.54, 125.27, 106.56, 38.85.

Melting Point: 106-109 °C.

3-O-Sulfonate Ester Intermediate (9) from p-Nitrobenzenesulfonyl Chloride.

In a 25 mL round bottom flask 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose

(0.26 g, 1.0 mmol) was dissolved in pyridine (1 mL, 12.0 mmol). p-Nitrobenzenesulfonyl chloride (0.33 g, 1.5 mmol) was also dissolved in pyridine in a separate vial and then added dropwise into the reaction mixture at 0 °C. The reaction was left to stir as the temperature adjusted to room temperature. After 4h, TLC (1:3 hexane : ethyl acetate) indicated the starting material still present. The concentration of the p-nitrobenzenesulfonylchloride was doubled, and the temperature was increased to 65 °C, and left to run for another 1 h 30 min after which TLC indicated complete consumption of the starting material. The reaction was poured into ice water and then extraction was done using ethyl acetate (3 x 10 mL). This was followed by an acid work up with 5% sulfuric acid (3 x 10 mL) and then the organic

layer was washed with de-ionized water (3 x 10 mL). The extract was dried using anhydrous magnesium sulfate, gravity filtered, and evaporated to yield an off-white product. The product was recrystallized from hot ethanol giving white crystals of the 3-O- sulfonate ester intermediate (0.19 g, 43%).

1 H NMR (400 MHz, CDCl3, ppm): 8.38 (2H, d, J = 8.62 Hz), 8.17 (2H, d, J = 8.63 Hz),

5.94 (1H, d, J = 3.60 Hz), 4.87 (1H, d, J = 2.62 Hz), 4.86 (1H, d, J = 3.66 Hz), 4.04-3.90

(4H, m), 1.49 (3H, s), 1.33 (3H, s), 1.18 (3H, s), 1.10 (3H, s).

13 C NMR (100 MHz, CDCl3, ppm): 151.03, 141.45, 129.77, 124.13, 112.78, 109.32,

105.11, 83.44, 83.99, 79.70, 71.67, 67.29, 26.69, 26.56, 26.20, 24.91.

Melting Point: 101-105 °C.

1,2:5,6‑di‑o‑isopropylidene‑3‑o‑toluenesulfonyl‑α‑D‑glucofuranose (11).

1,2:5,6-Di-O-isopropylidene-α-D-glucofuranose (2.6 g, 10.0 mmol) was dissolved in pyridine (5 mL) and p-toluenesulfonylchloride (3.8 g, 20.0 mmol) was added to the solution while stirring at room temperature. The suspension was left to stir for a day and allowed to stand overnight at 0 °C. TLC (1:3 hexane : ethyl acetate) analyses were carried out at intervals. Upon consumption of the starting material, the reaction mixture was

poured into ice water, the precipitate formed was vacuum filtered and off-white crystals

(tosylate) were formed. The product was re-crystallized from hot methanol giving white crystals of the tosylate 11 (2.52 g, 97%).

1 H NMR (400 MHz, CDCl3, ppm): 7.84 (2H, d, J = 8.37 Hz), 7.34 (2H, d, J = 7.98 Hz),

5.93 (1H, d, J = 3.68 Hz), 4.83 (1H, d, J = 3.68 Hz), 4.79 (1H, d, J = 2.35 Hz), 4.05-3.98

(4H, m), 2.46 (3H, s), 1.48 (3H, s), 1.31 (3H, s), 1.39 (3H, s), 1.15 (3H, s).

13 C NMR (100 MHz, CDCl3, ppm): 145.02, 132.96, 129.65, 128.38, 112.50, 109.07,

105.12, 83.34, 82.11, 79.93, 71.85, 67.10, 26.62, 26.55, 26.21, 24.91, 21.56.

Melting Point: 119-123 °C.

1,2:5,6‑Di‑O‑isopropylidene‑3‑O‑trifluoromethanesulfonyl‑α‑D‑glucofuranose (12).

1,2,5,6-Di-O-isopropylidene-α-D-glucofuranose (0.26 g, 1.0 mmol) was dissolved in dichloromethane (3 mL). Dry pyridine (0.5 mL 6.0 mmol) was then added followed by the dropwise addition of trifluoromethanesulfonic anhydride (0.28 mL, 2.0 mmol). The reaction was maintained at -10 °C for 1.5 h after which TLC (3:1 hexane : ethyl acetate) indicated a complete consumption of the starting material (DAG). The reaction mixture was washed three times using distilled water (10 mL) and dried over anhydrous magnesium sulfate, gravity filtered into a pre-weighed round bottom flask, and evaporated under

reduced pressure until the mass was constant. This gave rise to a thick orange paste of triflate 12 (0.17 g, 65%).

1 H NMR (400 MHz, CDCl3, ppm): 5.90 (1H, d, J = 3.44 Hz), 5.20 (1H, d, J = 3.53 Hz),

4.68 (1H, d, J = 3.46 Hz), 4.14 - 4.05 (1H, m), 3.92 - 3.87 (2H, m), 1.44 (3H, s), 1.35 (3H, s), 1.26 (3H, s), 1.25 (3H, s).

13 C NMR (100 MHz, CDCl3, ppm): 111.80, 109.61, 105.31, 85.15, 81.25, 75.27, 73.49,

67.70, 26.84, 26.72, 26.18, 25.13.

Attempted Synthesis of

1,2:5,6‑Di‑O‑isopropylidene‑3‑azido‑3‑deoxy‑α‑D‑allofuranose (7).

In a 100 mL round bottom flask equipped with a magnetic stir bar, purged with nitrogen, and sealed with a septum,

1,2:5,6‑di‑O‑isopropylidene‑3‑O‑trifluoromethanesulfonyl‑α‑D‑glucofuranose (0.4 g, 1.0 mmol) was dissolved in dry DMF (2.0 mL) at room temperature. Sodium azide (0.19 g, 3.0 mmol) was added to the solution and stirred at 50 °C overnight. The reaction was monitored by TLC (hexane : ethyl acetate 3:1). The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate (20 mL) and washed with water (4 x 15 mL). The

aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried using anhydrous magnesium sulfate, gravity filtered and evaporated in vacuo to yield a slightly yellow oil (0.21 g, 69%).

1 H NMR (400 MHz, CDCl3, ppm): 6.06 (2H, d, J = 5.14 Hz), 4.18-4.11 (2H, m), 4.04-3.93

(3H, m), 2.95 (1H, s), 2.87 (1H, s), 1.57 (3H, s), 1.46 (3H, s), 1.43 (3H, s), 1.38 (3H, s).

13 C NMR (100 MHz, CDCl3, ppm): 111.80, 109.61, 105.31, 85.15, 81.25, 75.27, 73.49,

67.70, 26.84, 26.72, 26.18, 25.13.

3-Deoxy-1,2:5,6-di-o-isopropylidene-α-D-erythrohex-3-enofuranose (13) from the

Tosylate (11).

1,2:5,6-di-O-isopropylidene-3-o-toluenesulfonyl-α-D-glucofuranose (1.0 g, 2.41 mmol) was dissolved in dry THF (40 mL) and added to a 100-mL round bottom flask equipped with a magnetic stir bar, purged with nitrogen, sealed with a septum, at room temperature which was then cooled in an ice bath to ~0 °C. Over a 10-min period potassium tert-butoxide (KOtBu) (0.81 g, 7.22 mmol) was added in four portions to the stirred solution and the reaction was monitored by TLC (hexane : ethyl acetate 3:1) until the tosylate was consumed (~2 h). The entire reaction mixture was then partitioned between hexane (40 mL) and water (40 mL) in a separatory funnel. The layers were separated, and the aqueous 38

layer was extracted with two additional 25-mL portions of hexane. The combined organic layers were washed with 5% sulfuric acid (50 mL) and water (50 mL) and then dried using anhydrous magnesium sulfate, gravity filtered and evaporated in vacuo to yield alkene 16

(0.43 g, 43%) as a pale-yellow syrup that crystallized upon standing.

1 H NMR (400 MHz, CDCl3, ppm): 6.08 (1H, d, J = 5.25 Hz), 5.29 (1H, m), 4.58 (1H, dd,

J = 12.72 Hz, 6.56 Hz), 4.15 (1H, m), 3.97 (1H, dd, J = 8.36 Hz, 5.82 Hz), 1.47 (6H, s),

1.45 (3H, s), 1.39 (3H, s).

13 C NMR (100 MHz, CDCl3, ppm): 160.02, 112.29, 110.31, 106.57, 98.96, 83.37, 71.27,

66.93, 28.23, 27.91, 26.22, 25.51.

Synthesis of o-Nitrobenzenesulfonate ester (17).

1-Tridecanol (0.20 g, 1.0 mmol) was dissolved in in dichloromethane (3.0 mL) and cooled to 0 °C. Pyridine (0.16 mL, 2.0 mmol) was then added followed by the addition of o-nitrobenzenesulfonyl chloride (0.33 g, 1.5 mmol) in small portions with constant stirring.

The reaction was monitored by TLC (3:1 hexane : ethyl acetate). After 24 h, the alcohol had completely reacted, and a new compound had formed. During extraction, dichloromethane (25 mL) was added to the reaction mixture and extracted three times using

5% sulfuric acid (10 mL). The organic layer was washed three times using distilled water

(10 mL), dried over anhydrous magnesium sulfate, gravity filtered into a pre-weighed

round bottom flask, and evaporated under reduced pressure until the mass was constant.

The product was recrystallized from hot ethanol to give 17 (0.0154 g, 8%) as fiber-like crystals.

1 H NMR (400 MHz, CDCl3, ppm): 6.08 (2H, d, J = 5.25 Hz), 5.29 (1H, m), 4.58 (1H, dd,

J = 12.72 Hz, 6.56 Hz), 4.15 (1H, m), 3.97 (1H, dd, J = 8.36 Hz, 5.82 Hz), 1.47 (6H, s),

1.45 (3H, s), 1.39 (3H, s).

13 C NMR (100 MHz, CDCl3, ppm): 160.02, 112.29, 110.31, 106.57, 98.96, 83.37, 71.27,

66.93, 28.23, 27.91, 26.22, 25.51.

Preparation of the azide anion

Diphenyl phosphoryl azide (0.22 mL, 1.0 mmol) was measured into a 25 mL round- bottom flask and acetonitrile (5.0 mL) was then added followed by the addition of 1,8- diazabicyclo[5.4.0]undec-7-ene (0.22 mL, 1.5 mmol). The reaction was monitored by IR and TLC. After 30 minutes, the DPPA peak at 2125.13 cm-1 had significantly reduced.

Consequently, the azide peak at 2020.28 cm-1 was becoming more intense. The reaction was left to run overnight. After 18 h, the DPPA peak had disappeared and the azide peak at 2017 cm-1 was evident.

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Appendix A

NMR and IR Spectra

)

(

nitrobenzenesulfonyl azide azide nitrobenzenesulfonyl

trum of trum

H NMR spec NMR H

ure 14 ure Fig

)

(

nitrobenzenesulfonyl azide azide nitrobenzenesulfonyl

trum of trum

NMR spec NMR

ure 1 ure Fig

)

(

nitrobenzenesulfonyl azide azide nitrobenzenesulfonyl

trum of trum

H NMR spec NMR H

ure 1 ure Fig

)

(

nitrobenzenesulfonyl azide azide nitrobenzenesulfonyl

trum of trum

NMR spec NMR

ure 1 ure Fig

Sulfonate Ester Sulfonate Intermediate Ester

trum of trum

NMR spec NMR

ure 1 ure Fig

Sulfonate Ester Sulfonate Intermediate Ester

trum of trum

NMR spec NMR

ure 1 ure Fig

(7)

allofuranose

‑

oxy‑

‑

Attempted Synthesis of of Synthesis Attempted

ido‑

‑3‑

trum of trum

NMR spec NMR

isopropylidene

‑

i‑

‑

ure ure 1,2:5,6 Fig

(7)

allofuranose

‑

oxy‑

‑

Attempted Synthesis of of Synthesis Attempted

ido‑

‑3‑

trum of trum

NMR spec NMR

isopropylidene

‑

i‑

‑

ure ure 1,2:5,6 Fig 51

hloride and hloride

itrobenzenesulfonyl itrobenzenesulfonyl

from from

ide reaction product product reaction ide

trum of trum

pyridine.

NMR spec NMR

ure ure

imethylamino d Fig

hloride

itrobenzenesulfonyl itrobenzenesulfonyl

from from

ide ide reaction product

trum trum of

pyridine.

NMR NMR spec

imethylamino

ure ure and and Fig 53

itrobenzenesulfonyl itrobenzenesulfonyl

from

ntermediate

ster ster

ulfonate ulfonate

trum trum of

NMR NMR spec

ure ure

hloride c Fig

itrobenzenesulfonyl itrobenzenesulfonyl

from from

ntermediate

ster ster

ulfonate ulfonate

trum of trum

NMR spec NMR

ure ure

hloride c Fig 55

(

glucofuranose glucofuranose

‑

‑α

toluenesulfonyl

‑

‑3‑

trum trum

isopropylidene

NMR spec NMR

‑

‑di‑

ure ure

1,2:5,6

of Fig 56

(

glucofuranose glucofuranose

‑

‑α

toluenesulfonyl

‑

‑3‑

trum

NMR spec NMR

isopropylidene

‑

‑di‑

ure ure

1,2:5,6

of Fig

(

glucofuranose

‑

nyl‑

trifluoromethanesulfo

‑

‑3‑

trum trum

isopropylidene

‑

NMR spec NMR

i‑

‑

ure ure

1,2:5,6

of Fig 58

(

glucofuranose

‑

nyl‑

trifluoromethanesulfo

‑

‑3‑

trum

isopropylidene

‑

NMR spec NMR

i‑

‑

ure ure

1,2:5,6

of Fig 59

)

(

enofuranose

erythrohex

trum trum

isopropylidene

NMR spec NMR

1,2:5,6

eoxy

ure ure

of Fig 60

)

(

enofuranose

erythrohex

trum

isopropylidene

NMR spec NMR

1,2:5,6

eoxy

ure ure

of 61 Fig

nitrobenzenesulfonate ester ester nitrobenzenesulfonate

trum

NMR spec NMR

3 ure ure

Fig 62

nitrobenzenesulfonate ester ester nitrobenzenesulfonate

trum

NMR spec NMR

3 ure ure

Fig 63

) Scheme 7 Scheme ionic azide ( azide ionic

trum spec

: 4 3 ure

Fig

. ionic azide ionic an

of showing the formation formation the showing

trum spec

: 5 3 ure

Fig