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PREPARATION OF RARE SUGARS 8: ADVANCED DERIVATIVES
FROM COMPLEX CARBOHYDRATES 8: CARBOHYDRATE
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PREPARATION OF RARE SUGARS 8: ADVANCED DERIVATIVES FROM
COMPLEX CARBOHYDRATES 8: CARBOHYDRATE POLYMERS

By

Changyou Yuan

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Department of Chemistry

2006

ABSTRACT

PREPARATION OF RARE SUGARS & ADVANCED DERIVATIVES FROM
COMPLEX CARBOHYDRATES & CARBOHYDRATE POLYMERS
By

Changyou Yuan

Carbohydrates have the potential as the ultimate raw materials for highly functionalized,
optically pure chemicals which were extensively used in pharmaceutical, agrichemical
and biotech industry. However, these high potentials of carbohydrates remain nearly
untouched due to the complex structure and ofien redundant hydroxyl groups of
carbohydrates. The aim of this work is to develop strategies to overcome these difficulties

and transform complex carbohydrates to advanced derivatives.

A protocol for the transformation of glycosides to anhydroalditols was established using
Me-D-glucoside as the model compound (Chapter 2). Transformation of the free
hydroxyl groups to ally] ether followed by reductive cleavage of the glycosidic bond
using triethylsilane gave the protected 1,5-anhydroglucitol. Cleavage of the allyl ether
bond was achieved by employing PdClz/CuClz catalytic system. This Protection-
Reduction-Deprotection protocol was successfully used in the transformation of complex
carbohydrates, such as cellulose, starch and levan, to the corresponding anhydroalditols.
The anhydroalditol, 1,5-anhydro-D-glucitol, was transformed to its 6-phosphate, and 2, 3-

deoxy derivatives in Chapter 3.

The carbohydrate derivated (S)-2-hydroxyl-butyrolactone and (S)-2-hydroxyl-
tetrahydrofuran were transformed to their iodo derivatives in Chapter 4. By controlling
the neighboring group effect, the mono and diiodo derivatives were selectively formed.

Chapter 5 presents an efficient route to prepare cyclic nitrone from D-ribose. Optically
pure iminosugar and isoxazolidines were prepared from the nitrone through

stereoselective addition reactions and cycloaddition reactions.

ACKNOWLEDEMENTS

I would like to sincerely thank my advisor Dr. Rawle I. Hollingsworth for his precious
advice, inspiring guidance and essential support throughout the whole period of my
graduate work. I am grateful that he let me explore the carbohydrate chemistry world, full
of challenges and opportunities. I am also grateful to my committee members, Dr. C. K.
Chang, Dr. B. Borhan, and Dr. K. C. Hunt, for their valuable advice and help in my
research. I would also like to thank the members of Dr. Hollingsworth’s group, for their
company and help. Special thank goes to Xuezheng for his help in my thesis writing. I
would also like to thank L. Lee, K. Johnson and Dr. D. Holmes from the NMR facility for

their friendly help.

Finally, I would like to thank my family members, my wife, my parents, my parents-in-

law and my son for their support, understanding and the happy times we spend together.

iv

TABLE OF CONTENTS

LIST OF TABLES ................................................................................ viii
LIST OF FIGURES ............................................................................... vix
Chapter 1. Literature Review: Bulky carbohydrates and their advanced derivatives

1.1. Introduction: Availability and structural features of commodity

carbohydrates .................................................................................... 3
1.1.1. Polysaccharides: cellulose, starch, chitin and inulin ............................ 4
1.1.2. Oligosaccharides: cyclodextrins, maltodextrins ................................ 8
1.1.3. Monosaccharides and disaccharides: sucrose, lactose, maltose, fructose,

xylose ................................................................................ 9

1.2. Progress in use of carbohydrates as general raw materials for organic

synthesis ......................................................................................... 14
1.2.1. General difficulties in the transformation of carbohydrates to organic
synthons ............................................................................. 17

1.2.2. Successes in the preparation of general synthons from carbohydrates. . .18

1.3. Some medicinally important synthesis targets from carbohydrates and

carbohydrate derived synthons ........................................................ 21
1.3.1. From 3 or 4 carbon synthons .................................................... 22
1.3.2. Iminosugar derivatives .......................................................... 24
1.3.3. F uran/pyran derivatives .......................................................... 26
1.4. Conclusion ...................................................................................... 28
1.5. Reference ..................................................................................... 29

Chapter 2. Transformation of Commodity Carbohydrates to High Value Chemical
Intermediates by Reductive Cleavage

2.1. Introduction .................................................................................... 36
2.1.1. Availability and structural features of commodity carbohydrates. ............ 36
2.1.2. Organosilane reduction ............................................................. 38
2.2. Results ........................................................................................... 40
2.2.1. Establishing the protocol for triethylsilane cleavage of the glycosidic
linkage ................................................................................. 40
2.2.2. Practical and economic Palladium chloride catalyzed de-allylation of 1,5-
anhydro-2,3,4,6-tetra-O-allyl-D-glucitol ......................................... 42

2.2.3. Application of the Allylation-Reduction-De-allylation protocol to other

mono, disaccharides and complex carbohydrates ............................... 43
2.3. Discussion ...................................................................................... 49
2.3.1. Establishing the protocol for triethylsilane cleavage of the glycosidic
linkage ................................................................................. 49
2.3.2. Palladium chloride catalyzed de-allylation of l,5-anhydro-2,3,4,6-tetra—O-
allyl-D-glucitol ....................................................................... 56
2.3.3. Application of the Allylation—Reduction-De-allylation protocol to other
mono, disaccharides and complex carbohydrates ................................ 60
2.3.4. Preparation of 1,5-anhydro-D-glucitol, 2,5-anhydro-D-glucitol and 2,5-
anhydro-D-mannitol from sucrose ................................................. 64
2.4. Conclusion ..................................................................................... 68
2.5. Experimental ................................................................................... 70
2.6. Reference ....................................................................................... 82

Chapter 3. Advanced Derivatives of 1, 5-Anhydro-D-Glucitol

3.1. Introduction .................................................................................... 88
3.1.1. Glycolysis and 1,5~anhydro-D-glucitol-6-phosphate ........................... 88

3.1.2. Deoxy anhydroalditols: application in construction of biologically
important molecules and chiral catalysts ......................................... 89

3.2. Preparation of 1,5-anhydro-D-glucitol-6-phosphate ................................... 93
3.3. Preparation of Deoxysugars from 1, 5 -anhydro-D-glucitol .......................... 94
3.3.1. Formation of 2,3-anhydro derivatives of 1,5-anhydro-D-glucitol. . . . . . . . ....94

3.3.2. Preparation of deoxyanhydrohexitols ............................................. 97

3.4. Conclusion ...................................................................................... 98
3.5. Experimental ................................................................................... 99
3.6. References .................................................................................... 107

Chapter 4. Iodo Derivatives of Advanced Carbohydrate Intermediates

4.1. Introduction .................................................................................. 1 1 1

4.2. Preparation of iodo derivatives from (S)-3-hydroxy-butyrolactone .............. 112

vi

4.3. Preparation of iodo derivatives by ring opening of (S)-3-hydroxyl-
tetrahydrofuran with HI ................................................................... 116
4.4. Reactions of 1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol with HI .............. 125

4.5. The application of iodide products in the preparation of advanced

 

derivatives ..................................................................................... 127
4.6. Conclusion 129
4.7. Experimental ................................................................................. 130
4.8. References .................................................................................... 140

Chapter 5. Preparation of Ribose Derived Nitrone and its Application in the

Preparation of Iminosugars

5.1. Introduction ................................................................................... 144
5.1.1. Iminosugars as glycosidases inhibitors ......................................... 144

5.1.2. Application of nitrones in the preparation of iminosugars and aza-C-
glycosides ............................................................................ 145

5.2. An efficient route for the preparation of cyclic nitrone from ribose ............. 149
5.3. Steroeselective Addition of nitromethane to the chiral nitrone .................... 154

5.4. Cyclization reactions of the ribose derived nitrone with non-carbohydrate based
alkenes .......................................................................................... 155

5.5. Cycloaddition reactions of the ribose derived nitrone with carbohydrate based

alkenes .......................................................................................... 160
5.6. Conclusion .................................................................................... 164
5.7. Experimental ................................................................................. 165
5.8. References ..................................................................................... 178

Vii

LIST OF TABLES
Chapter 1.

Table 1.1. Annual world production and prices of some commodity carbohydrates,

carbohydrate derivatives and common solvents ................................................. 13
Chapter 2.
Table 2.1. Reduction of methyl-2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside ............. 41
Table 2.2. Deprotection of 2,3,4,6-tetra-O-allyl-1,5-anhydro-D-glucitol ................... 43
Table 2.3. Transformation of glycosides to anhydroalditols .................................. 68
Chapter 4.

Table 4.1. Ring-opening reactions of (S)-3-hydroxy-butyrolactone with H1 in

AcOH/AczO ......................................................................................... 113
Table 4.2. Ring-opening reactions of (S)-3-hydroxyl-butyrolactone with H1 in
AcOH ................................................................................................ 114
Table 4.3. Reaction of (S)-3-hydroxy-butyrolactone with HI in acetic acid ............... 116

Table 4.4. Light and oxygen effects on the ring opening reaction of (S)-3-hydroxyl-

tetrahydrofuran with HI ........................................................................... 1 19
Table 4.5. Reaction of 1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol ..................... 126
Chapter 5.

Table 5.1. Preparation of nitrone using tosylate as substrate ................................ 150
Table 5.2. Preparation of nitrone using mesylate as substrate ............................... 151

viii

LIST OF FIGURES

Chapter 1.

Figure 1.1. Representative partial structures of complex carbohydrates. .................... 6
Figure 1.2. Representative partial structure of complex carbohydrate inulin. . . . . . . . . . .7
Figure 1.3. Structure of oc-cyclodextrin (a) and maltodextrins (b) ............................. 9
Figure 1.4. Structure of disaccharides (a) sucrose; (b) ot-lactose; (c) B-lactose ............ 10
Figure 1.5. Structure of (a) maltose; (b) fi'uctose; and (c) xylose ............................. 11

Figure 1.6. Sucrose derivatives of amines, uronic acids and crown ether analogues...... 14
Figure 1.7. Isomaltulose derivatives .............................................................. 15

Figure 1.8. Glucose derivatives glucosides, glucals, glycosyl bromides and enolone

bromides .............................................................................................. 16
Figure 1.9. Application of carbohydrates in natural products ................................. 16
Figure 1.10. Structure of some important basic chemicals and D-glucose .................. 18
Figure 1.11. Transformation of starch to (S)—3-hydroxy-butyrolactone ..................... 19
Figure 1.12. Transformation of L-arabinose to (S)-3 -hydroxy-butyrolactone .............. 20

Figure 1.13. Preparation of 2,3-O-isopropylidene-D-glyceraldehyde from D-mannitol..20

Figure 1.14. Oxidation of 1,2-5,6-di-O-isopropylidene-D-mannitol

with Sodium hypochlorite/Ruthenium chloride ................................................. 21
Figure 1.15. 2,3-O-isopropylidene-L-glyceraldehyde from L-ascorbic acid ............... 21
Figure 1.16. Preparation of Linezolid derivatives from (R)-glycidyl butyrate ............. 22
Figure 1.17. Preparation of (L)-carnitine derivatives ............................................ 23

ix

Figure 1.18 Some of the medicinally important compounds derived from chiral 3-carbon

synthons ............................................................................................... 24
Figure 1.19. Important iminosugars ............................................................. 25
Figure 1.20. Medicinally important furan and pyran derivatives ............................ 26
Figure 1.21. Preparation of isonucleoside from 1,4-anhydro-D-xylitol ..................... 27
Chapter 2.

Figure 2.1. Repeating units in complex carbohydrates. (a) cellulose; (b) levan. . . . . . .37
Figure 2.2. Reduction of aldehydes using triethylsilane ....................................... 38
Figure 2.3. Reductive cleavage of polysaccharide by triethylsilane ......................... 39

Figure 2.4. Reaction of methyl 2,3,4,6-tetra-O-acetyl-or-D-glucopyranoside with
Et3SiH ................................................................................................. 41
Figure 2.5. Reduction of methyl 2,3,4,6-tetra-O-allyl-a-D-glucopyranoside with
Et3SiH ................................................................................................ 42
Figure 2.6. Deallylation of l,5-anhydro-2,3,4,6-tetra—O-allyl-D-glucitol with PdClz. ...42

Figure 2.7. Reductive cleavage of methyl 2,3,4,6-tetra-O-alIyl-D-mannopyranoside. . .44

Figure 2.8. Reductive cleavage of methyl 2,3,5-tri-O-allyl-D-ribofuranosides ............ 45
Figure 2.9. Reductive cleavage of Octa-O-allyl-sucrose ...................................... 46
Figure 2.10. Reductive cleavage of tri—O-allyl-cellulose ...................................... 47
Figure 2.11. Reductive cleavage of tri-O-allyl-starch .......................................... 48
Figure 2.12. Reductive cleavage of tri-O-allyl-levan .......................................... 49

Figure 2.13. Mechanism for reaction of methyl 2,3,4,6-tetra-O-acetyl-a-D-

glucopyranoside with Et3SiH ...................................................................... 52

Figure 2.14. Mechanism for reaction of methyl 2,3,4,6-tetra-O-acetyl-oc-D-
glucopyranoside with Et3SiH ...................................................................... 53
Figure 2.15. Mechanism for reaction of methyl 2,3,4,6-tetra-O-allyl-ot-D-
glucopyranoside with Et3SiH ....................................................................... 56
Figure 2.16. Proposed mechanism for catalytic cleavage of allyl ether .................... 59
Figure 2.17. Mechanism for reduction of methyl a-D-glucoside and methyl a-D-

mannoside ............................................................................................ 61

Figure 2.18. Relative acid-catalysed hydrolysis rates of glucoside, galactoside and

guloside ............................................................................................... 61
Figure 2.19. Mechanism for reductive cleavage of Octa-O-allyl-sucrose ................... 65
Chapter 3.

Figure 3.1. Anhydrosugars as substrate analogues in carbohydrate glycolysis ............. 86
Figure 3.2. Sialyl Lewis" analogues as potent E-selectin inhibitors .......................... 91
Figure 3.3. Anhydrohexitol Nucleosides ......................................................... 91
Figure 3.4. Deoxy anhydroalditols based chiral catalysts ..................................... 92
Figure 3.5. Preparation of 1,5-Anhydro-D-glucitol 6-phosphate ............................. 93

Figure 3.6. Preparation of 1,5-Anhydro-D-glucitol 6-phosphate using the direct
phosphorylation method ............................................................................ 94
Figure 3.7. Preparation of 4,6-benzylidene-2,3-epoxide derivatives of 1,5-anhydro-D-
glucitol ................................................................................................ 95
Figure 3.8. Mechanism for the formation of 2,3-anhydro derivatives under Mitsunobu
conditions ............................................................................................ 96

Figure 3.9. Formation of 2,3-anhydro derivatives using NaH/Ist ........................ 97

xi

Figure 3.10. LAH reduction of 2,3-anhydro derivatives to form deoxy

anhydrohexitols ...................................................................................... 98
Chapter 4.
Figure 4.1. Proposed reaction of(S)-3-hydroxy-butyrolactone with HI ................... 112

Figure 4.2. Neighboring acetyl group assisted ring Opening reaction of
(S)-2-hydroxy-butyrolactone with HI ........................................................... 114
Figure 4.3. Formation of optically inactive 4-iodide butanoic acid ......................... 115
Figure 4.4. Reaction of (S)-3-hydroxy-butyrolactone with H1 in acetic acid at various
temperatures ......................................................................................... 1 16
Figure 4.5. Possible iodo products from ring opening reaction of (S)-3-hydroxy-
tetrahydrofuran with HI ........................................................................... 118
Figure 4.6. Ring opening reaction of (S)-3-hydroxy- tetrahydrofuran with H1 in
water ................................................................................................. 118
Figure 4.7. Mechanism for iodine catalyzed ring opening iodination of

(S)-3 -hydroxy- tetrahydrofuran .................................................................. 120
Figure 4.8. Proposed reaction of (S)-3-hydroxy1- tetrahydrofuran and H1 in Acetic

acid ................................................................................................... 121
Figure 4.9. Reaction of (S)-3-hydroxy- tetrahydrofuran and H1 in Acetic acid .......... 121
Figure 4.10. Mechanism for reaction of (S)-3-hydroxy- tetrahydrofuran and H1 in acetic
acid ................................................................................................... 122
Figure 4.11. Reaction of tetrahydrofuran and H1 in Acetic acid ............................ 123
Figure 4.12. Reaction of (S)-3-hydroxy-tetrahydrofiiran and H1 in trifluoroacetic

acid ................................................................................................... 123

xii

Figure 4.13. Reaction of (S)-3 -hydroxy-tetrahydrofi1ran and H1 in acetic acid/acetic
anhydride ............................................................................................ 124
Figure 4.14. Reaction of (S)-3-hydroxy - tetrahydrofuran and HI under various
conditions ........................................................................................... 1 25

Figure 4.15. Proposed reaction of H1 mediated ring opening reaction of 1,5-anhydro-

2,3,4,6-tetra-O-acetyl-D-glucitoI ................................................................. 126
Figure 4.16. Reaction of 1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol .................. 126
Figure 4.17. Preparation of (S)-3-hydroxy-tetrahydrothiophene ........................... 127
Figure 4.18. Preparation of (S)-1-benzyl-3-hydroxy-pyrolidine ........................... 127

Figure 4.19. Preparation of (S)-diethyl-3-acetoxycyclopentane-1 ,1-dicarboxy1ate...... 128

Chapter 5.

Figure 5.1. General structure of carbohydrate based acyclic and cyclic nitrones ........ 146
Figure 5.2. Carbohydrate based acyclic nitrones .............................................. 146
Figure 5.3. Strategies for the preparation of cyclic nitrones ................................. 147
Figure 5.4. Preparation of cyclic nitrone from L-xylose ..................................... 148
Figure 5.5. Preparation of nitrone using tosylate as substrate ............................... 150

Figure 5.6. Possible products from reaction of tosylate 10 with hydroxylamine under

basic conditions ..................................................................................... 152
Figure 5.7. Preparation of nitrone using tosylate as substrate ............................... 153
Figure 5.8. Possible products from addition of nitromethane to nitrone ................... 154
Figure 5.9. Addition of nitromethane to nitrone .............................................. 155
Figure 5.10. Possible products from cyclization of nitrone with allyl alcohol ............ 157
Figure 5.11. Cycloaddition of nitrone with allyl alcohol .................................... 158

xiii

Figure 5.12. Products from cycloaddition of nitrone with vinyl ethyl ether .............. 159

Figure 5.13. Reaction of nitrone with vinyl ethyl ether ...................................... 159
Figure 5.14. Preparation of carbohydrate derived alkenes ................................... 160
Figure 5.15. Cycloaddition of nitrone with carbohydrate derived alkene I ............... 162
Figure 5.16. Cycloaddition of nitrone with carbohydrate derived alkene II ............... 163

xiv

Chapter 1

Literature Review:

Commodity carbohydrates and their advanced derivatives

Abstract

Carbohydrates hold the promise as the general raw materials to substitute. fossil raw
materials. They are renewable and available in large volume. However, the structural
differences between carbohydrates and fossil based raw materials make the development
of carbohydrate based chemistry challenging. At first, the structural features of
carbohydrates available in large quantity are reviewed. These include polysaccharides,
such as cyclodextrins and maltodextrins, monosaccharides and disaccharide, such as
sucrose, lactose, maltose, fructose and xylose. In the last several decades, carbohydrates
have been used extensively in the preparation of naturally occurring and medicinally
important compounds. Recently, progresses have been made in the transformation of
carbohydrates to general chiral 3 and 4 carbon synthons. These more general synthons
have been used directly and more widely in the synthesis of medicinally important

targets.

1.1 Introduction: Availability and structural features of commodity
carbohydrates.
From the beginning of the industrial revolution, more and more fossil resources- coal, oil,
and natural gas, have been used to provide us energy. Fossil resources have also been
used as raw materials to support our more and more luxury lives, from electricity and
gasoline to bulk, intermediate and fine chemicals. One big disadvantage of fossil
resources is that they are not renewable and we are near the peak of the fossil material
production. For petroleum this will be around 2008, for natural gas around 2020 and for
coal in a few decades'. With the depletion of the fossil raw materials, the development of

a chemical industry based on renewable resources becomes inevitable and urgent" 2.

Biomass had been used as the major raw materials before the industrial revolution It is
expected that in the next few decades, or even in the next few years, the use of biomass as
raw materials for chemical industry will become economically viable with the ever
increasing prices of fossil materials, it is estimated that the oil price will reach $182 per

barrel within the decade3.

The widely available biomass is composed of carbohydrates, amino acids and lipids.
Among them, the most important class is carbohydrates in term of volume production,
which account for roughly 75% of the annually renewable biomass of about 200 billion
tons. However, majority of the carbohydrate biomass decays and only a minor fraction

(ca. 4 %) is used by human beings“.

The majority of the annually renewable carbohydrate biomass is polysaccharides, these
include cellulose, starch, chitin, inulin, xylan, etcs. Derived from these polysaccharides
are some oligosaccharides, such as cyclodextrins and maltodextrins. Monosaccharides
and disaccharides, such as sucrose, lactose, fructose, maltose and xylose, are also

available in bulk.

1.1.1 Polysaccharides: cellulose, starch, chitin and inulin.

Cellulose is the most abundant form of living terrestrial biomass, it is found in higher
plants as the principle component of cell walls in the form of microfibrils (2-20 nm
diameter and 100 - 40 000 nm long)6. It is a linear polymer of about 2,000-14,000 [3-(1--
>4)-D-glucopyranose units in 4C. conformation (Fig. 1.1 a). The usage of cellulose
largely takes advantage of its ability to hold water. Uses include anticaking agents,

emulsifiers, stabilizers, dispersing agents, thickeners, and gelling agents.

Chitin, the second most abundant polysaccharide in nature, can be found in the covering
layer of insects, crabs, and shrimps and in the cell walls of many fungi. Each year, at least
10 gigatons of chitin are synthesized and degraded in the biosphere. Chitin mainly
consists of partially deacetylated aminosugar N-acetylglucosamine through [HI-)4)-
linkage, the same as cellulose (Fig 1.1 d)7. The mostly deacetylated form of chitin is
called chitosan. It is used for waste water clearing, for cosmetics and for medical and

veterinary applications.

Another abundant polysaccharide is starch; it is a major carbohydrate reserve in fruits,
seeds, and tubers of plants. 2850 million tones of starch is produced annually by
photosynthesis. Corn is the largest source of starch; the other important sources include
wheat, potato, tapioca and rice. Starch exists in the form of amylose (normally 20-30%)
and amylopectin (normally 70-80%). Both amylose and amylopectin consist of polymers
of ot-D-glucose units in the 4C1 conformation (Fig 1.1 a & b). In amylose, these units are
linked in the form of 0t -(1-->4)- linkage, with the ring oxygen atoms all on the same side
(Fig 1.1 b), whereas in amylopectin about one residue in every twenty units is linked in
the form of a-(l-->6)- linkage to form branch-points (Fig 1.1 c). The ratio of amylose to
amylopectin and the ot-(1-->6)-branch-points in amylopectin depend on the source of the
starch, for example, amylomaizes contain over 50% amylose whereas 'waxy' maize has
almost none (~3%). Starch is an important plant product; it is used as the major food
resources for human beings throughout the history. Even today, starch still provides 80 %
of man’s daily calorie intake in areas such as the Far East and Africas. With the excess
production of starch, the non-food usage of starch increased during the last century. Like
cellulose, the majority usage of starch depends on its ability to hold water, such as

thickener, water binder, emulsion stabilizer and gelling agent.

OH OH
3) 0 HO 0 o "o o
H wow:mlo 0“
o o
0 OH
OH :1 OH

b)
0110
HO
HO H hid n

O
O
I.—T—-l

OH
c) ‘33:
o 0
HO OH
OH OH
0 o
\ 0
35cm OH HO
OH o 0
0 0
HO
OH o
0 on
HO OH
0
o

O
HO
H

or?

d) o=( o=<
"30 ml?" gfifiom «3'16le
A0 OH

Figure 1.1 Representative partial structures of complex carbohydrates. (a) cellulose; (b)

amylose; (c) amylopectin; (d) chitin.

Inulin, or fructose oligosaccharides, is present as plant carbohydrate storageg. High
concentration of inulin can be found in dandelion, wild yam, Jerusalem artichokes, and

chicory. Industrially, chicory has been used for the extraction of inulin.

 

 

 

O
I
O
(95/
O

OH \OH

Figure 1.2 Representative partial structure of complex carbohydrate inulin

Inulin is a polydisperse B-(2-->1) fructan. The fructose units are linked through B-(2-->1)
linkage, a glucose molecule typically resides at the end of each fructose chain and is
linked by an (It—(192) bond. The chain lengths of these fructans range from 2 to 60 units,
with an average DP of ~10"). The unique B—(2-91) bonds in inulin make it cannot be
digested in the upper gastrointestinal tract as a typical carbohydrate and are responsible
for its reduced caloric value and dietary fiber effectsg. The uptake of inulin does not lead

to a rise in serum glucose level or stimulate insulin secretion. Therefore, inulin has been

used to replace fat or sugar to reduce the calories of foods, such as dairy products, baked

foods, etc.

1.1.2 Oligosaccharides: cyclodextrins, maltodextrins
Recently, some oligosaccharides, such as cyclodextrins, maltodextrins, have been

produced on an industrial scale1 1.

Cyclodextrins are a family of three cyclic oligosaccharides composed of a-l,4- linked
glucogan units. The a, B, y, cyclodextrin has 6, 7, 8 glucopyranose units respectively. In
the 1970, cyclodextrins are only available as a rare fine chemical. Now, cyclodextrins are
produced from partial hydrolysis of starch using the enzymes cyclodextrin
gluconotransferases by choosing the type of the microorganism used, or or B cyclodextrin
can be selectively produced”. Many factories are producing cyclodextrins at over 1000
tons/year scale. The usage of cyclodextrins largely depends on their ability to form host-
3

guest complexes with hydrophobic molecules. They have been used for drug release,I

for environmental protection, food industry, cosmetics and personal care items, etc”.

Hiya ..
is i? w
sass/a

Figure 1.3 Structure of ot-cyclodextrin (a) and maltodextrins (b).

OH
3-20

Maltodextrins are also produced from partial hydrolysis of starch using acid or enzyme”‘
'6. Unlike cyclodextrins, maltodextrins are linear a-1,4- linked glucogan units, with the
chain length from 3 to 20 and average chain length 7. Maltodextrins are moderately sweet
polysaccharides and are used as food additive. They are also used as coating agents in

pharmaceutical industries and as water soluble glues among other uses”.

1.1.3 Monosaccharides and disaccharides: sucrose, lactose, maltose, fructose,
xylose

Sucrose, the table sugar, can be obtained from supermarkets in crystalline form in very

high purity (>99%). It is the world’s single most abundant naturally occurring organic

compound. In 2004, 144 million tons of sucrose was produced in the world's. Sucrose is a

major carbohydrate reserve and energy resource in plants. Industrially, sucrose is

extracted from sugar cane (20 % by weight) and sugar beet (15 % by weight). The

structure of sucrose is shown in Figure 1.4 a. It is a non-reducing disaccharide, composed
of one D-glucose and one-D-fructose unit linked through their anomeric carbon atoms by
a, B-l—>2-glycosidic bond. About 95 % of the sucrose produced is used in the food

industry as a sweetener.

3) OH
O CHon
HO 0
HO HO
H
0 ° cazou
OH
b) HO OH HO
0 0
HO 2.0
OH
6)
HO 0" OH
0 0
HO $10 0“
OH OH

Figure 1.4 Structure of disaccharides (a) sucrose; (b) or-lactose; (c) B-lactose

Lactose, also called milk sugar, is a unique carbohydrate only found in mammalian
milk”. Lactose is obtained from whey, the by-product in the production of cheese, quark
and casein. It is a disaccharide composed of one glucose and one galactose unit through
[3-(1-)4) linkage by aldehyde group of D-galactose. Lactose exists in or and B isomeric
forms, with difference in configuration of the hydroxyl moiety at C-1 of the glucose unit.
Lactose is largely used in the food industry; it is also used in the pharmaceutical industry,

infant nutrition and fermentation.

10

Naturally, the disaccharide maltose (Fig. 1.5 a) is present in germinating grain.
Industrially, maltose is produced from the hydrolysis of starch'z‘ 20. The two D-glucose
units in maltose are linked through (l—*4)-(X linkage. The glucose unit at the reducing
end has the B configuration. The major usage of maltose is as a food sweetner in its

reduced form maltitol.

3)
OH
O
HO OH
HO
OH 0
0HO OH
OH
b) C)

OH

O OH O

HO HO

HO
OH OH OH

HO

Figure 1.5 Structure of (a) maltose; (b) fructose; and (c) xylose.

Fructose (Fig. 1.5 b) is a monosaccharide which can be found in many foods such as
honey, tree fruits, berries, and beets, sweet potatoes etc”. It is one of the three most
important blood sugars along with glucose and galactose. Fructose has been consumed by
human beings for thousands of years at the amount of 16-20 grams per day. With the
westernization of the diets, that number has increased significantly to 85-100 grams per
day, mainly coming from the additives to foods and drinks in the form Of high fructose

corn syrup. About 16 billion pounds of high fructose corn syrup was consumed each year

11

in the United States. The increased uptake of fructose has caused problems in human

health, such as Obesity, diabetes, etc.” 23 .
Xylose (Fig. 1.5 c) is the most abundant pentose; it can be easily Obtained from wood,

straw-derived xylan24. Xylose is used in dyeing and tanning and also for diabetic diets.

Besides the polysaccharides, oligosaccharides, disaccharides and monosaccharides
discussed above, some other carbohydrates, such as isomaltoluse, L-sorbose, and
carbohydrate derivatives, such as D-sorbitol, D-xylitol, D-gluconic acid are also available
in large quantities and with the prices comparable to the common fossil based solvents,
such as methanol, toluene. Table 1.1 listed the annual production and price of some

common sugars, sugar derivatives and common solvents.

12

Table 1.1 Annual world production and prices of some

commodity carbohydrates, carbohydrate derivatives and common solvents.

 

World production Price

(metric ton / year) ($/kg)

 

 

 

Carbohydratesa Starch 2,729,000,000 0.34
Sucrose 144,000,000 0.22
glucose 304,073 0.43
Lactose 181,031 0.58
D-Fructose 91,863 0.69
Carbohydrate D-Sorbitol 650,000 1 .80
derivatesb D-Xylitol 30,000 5.00
D-Gluconic acid 60,000 1.40
Solvent?3 Acetone 3,200,000 0.55
Methanol 25,000,000 0.15
Toluene 6,500,000 0.25

 

8 Edited based on data from United States Department Of Agriculture Foreign Agricultural

Service, for the year 2005. http://www.fas.usda.gov
b Values are for the year 2003. Adapted from Table 1 in Lichtenthaler, F. W.

Carbohydrates as Raw Materials for the Chemical Industry. Green Chemistry Series No.

1. Tundo, P. Ed., 3rd Ed., 2004, pp.105-127.

13

1.2 Progress in utilization of carbohydrates as general raw materials for organic
synthesis
In the last several decades, progress have been made in the usage of carbohydrates as
starting materials for organic synthesis and several reviews are available on this subject.
The chemistry for the transformations performed at the terminal positions of sucrose (C-
1’ and/or C-6 and/or C-6’) is reviewed by Jaroszzs. This review focus on the preparation
of sucrose derivatives, such as amines, uronic acids, crown ether analogues, from the
selectively protected sucrose 2,2’,3,3’,4-Penta-0—benzyl sucrose. Some of those

derivatives were shown in Figure 1.6.

R1 OBOM

o /’\
BnO O

O
BnO BOO O
08
n 0 R;
O
o \
9

   
  
  

OBD
1: R, . OH,OTBOPs. R, . OH,NH, Awfl o
2: R, - OH,NH,, R, - CH,OTBOPS AcO ,' ‘
3: R, I R,- CH,NH, 0‘“ I"o\“‘ '. OAc
4: R, . CHZOTBDPS, R, a COOH AcO ’0‘“:
5: R, =- COOH, R, .. CHzOTBDPS
s: R, - R, s coon 7

Figure 1.6 Sucrose derivatives of amines, uronic acids and crown ether analogues
Isomaltulose, a disaccharide produced as the precursor to the sweetener isomalt®, is

available in large quantities and its chemistry has been reviewed by Lichtenthaler's.

Under acidic conditions, dehydration of the fructose portion Of isomaltulose afforded 5-

l4

(a-D-glucosyl)-Oxymethyl—furfural (a-GMF). From oc-GMF, a variety of compounds

have been made (Figure 1.7)

OH
0 01130 I H+ OH
H 0
3° -——-> "0%
OH 0
OH 0

OH H
9 a - GMF
8 Isomaltulose
10: R I CHICHNOZ
11: R =- -CH=CI-ICOOH
OH 12: R 3 -CH3CH2

H 0 13: R . cu
fie
011043 14: R- -COOH
o R 15: R . -CH2NH2

Figure 1.7 Isomaltulose derivatives

The application of D-glucose as a starting material in organic synthesis has also been
reviewed“‘ 5‘ '8‘ 26. The commonly used intermediates in the transformation of glucose to
its derivatives are glucosides, glucals, hydroxyl glucals, glycosyl bromides, 2-
oxoglycosyl bromides, enolone bromides, etc. (Fig. 1.8). The transformations of these

intermediates have been demonstrated”.

15

820

OAc 0” O
A 0 Ac 0 \
Ac AcO
820
16 1 7 1 8
08:
OH OH o
HO A" 320 /
OMe 032
19 20 21

Figure 1.8 Glucose derivatives glucosides, glucals, glycosyl bromides

and enolone bromides

Carbohydrates were also often used in natural product synthesis. In the preparation of
natural products, clinically important compounds, complex oligosaccharides and
carbohydrate-based peptidomimetics, carbohydrate starting materials were extensively

used in Nicolaou’s group”. Some representative structures were shown in Fig. 1.9

  

0
3,11.
/CHO "MO;
Ho'fioflo":
.u R = 0
OR .
‘5‘ 0 MO 3 OOOCH,¢HMe,
me“ O "on “‘0

 

22 Leucomycin A, 23 CarbomycInB

Figure 1.9 Application of carbohydrates in natural products

Leucomycin A3 22 and carbomycin B 23 are two clinically important 16-membered ring

macrolide antibiotics. They were prepared starting from D-glucose.

l6

The carbohydrates used in the above discussed applications are usually very specific, that
is, the carbohydrates used have to be highly modified based on each synthetic targets. For
this reason, the application of carbohydrates in organic synthesis is still limited compared
to their potential. It is expected that if the more general synthons, such as 3, 4, or 5
carbon compounds with one or two stereocenters could be derived from carbohydrates,
the carbohydrate based chemistry will be strong enough to challenge the position of fossil
oil based chemistry. Here, the progress in the preparation of general raw materials for

organic synthesis is reviewed.

1.2.1 General difficulties in the transformation of carbohydrates to organic
synthons
The transition from fossil based production to biomass carbohydrates based production is
hampered by several factors. Fossil raw materials based chemicals are still more
affordable at present and the technology for this transformation is well developed.
Structurally, carbohydrates are very different from the commonly used fossil based
chemicals. The commonly used industrial-scale fossil based raw materials are lipophilic
low molecular weight products and their derivatives with fiinctional groups, such as —OH,
COOH, C=C, C=O added (Figure 1.10). Compared to these compounds, carbohydrates
are hydrophilic, have much higher molecular weight, are overly functionalized with
hydroxyl groups and lack the C=C, C=O functional groups which are advantageous for
chemical transformations. In the last decade, intense efforts have been made for the
development of chemistries and technologies to obtain general raw organic materials

from carbohydrates.

17

M/ H
H H
n-Hexane Ethylene
Butadiene 1 PrOpanol
O O
JLOH /U\
Acetic acid Acetone
HO
mm
H OH
OH
D-glucoee

Figure 1.10 Structure of some important basic chemicals and D-glucose

1.2.2 Successes in the preparation of general synthons from carbohydrates

Recently, 4-linked aldohexoses, such as lactose, maltose starch, maltodextrins, have been
used in the preparation Of 3,4-dihydroxybutyric acid and its lactone28'30. Under basic
conditions, the reducing end of the aldohexoses 24 is isomerized to ketose 25, base
catalyzed B-elimination of the 4-alkoxy substituent gave the a-diketone 27 (Figure 1.11).
Oxidative cleavage Of the diketone formed the dihydroxy butyric acid 28 and glycolic
acid 29, cyclization of the dihydroxy acid gave the lactone 30. The chiral center in the
lactone obtained come from OS of the D-aldohexoses and thus has (S) configuration.

Similarly, the (R)-isomer 36 has been obtained from pentose (Figure 1.12).

18

OH

3‘ O
OH
OH o O
Ho OH
OH 0
HO OH A OH
H OH
OH 0 '
24 HO
\
0.. ,5
OH
‘3 O
O OH
H
H
O
°" 1%., 0"
H0
25 /‘ H O OH
OH OH‘
1‘” O
‘0
0% OH
OH 0
am 0" 0..
OH 0 0” OH
HO \ + \
OH
O HO OH
26 O
27
"202’ OH.
O O
OH
£50 <—— <1 + mr
HO HO o
OH
30 28 29

Figure 1.11 Transformation of starch to (S)-3-hydroxy-butyrolactone

19

OH
0 O OH
X X "mow +°
° r
() 1::::=======:===:. () ‘------I> ()- ______.
K1 OH \
OH OH 0 OH \
O
31 32 33

O
O
HO OH. OH OH
O OH ..____ ‘OOH
‘ . \“‘
HO“ "O
OH o (\0
3° 35 34

Figure 1.12 Transformation of L-arabinose to (R)-3-hydroxy-butyrolactone
One of the oldest yet still widely used methods for the production of chiral 3-carbon
synthons from carbohydrate is through the oxidative cleavage of protected
monosaccharide“. Oxidation of l,2-5,6-di-O-isopropylidene-D-mannitol 38 with
periodate or lead tetra-acetate gave the protected D-glyceraldehyde 39. Although
satisfactory yields were obtained on small scales, the toxicity and high cost of the

reagents prevents the application Of this method on industrial scale.

0
: OH Acetone / H1» We |04 or Pb(OAC)4 O .
HO ; ———————> O ; a 6
OH OH %——6 OH ’ l

37 38 39

 

Figure 1.13 Preparation of 2,3-O-isopropylidene-D-glyceraldehyde from D-mannitol
Recently, a more benign method was developed for the oxidation step. Using sodium

hypochlorite as the oxidation reagent and ruthenium chloride as the catalyst, 1,2-5,6-di-

O-isopropylidene-D-mannitol 38 was oxidized to isopropylidene-D-glyceric acid 39.32

20

 

OH 9% 0
WV NaOCI I RuCI3 Mk
0 O . OH
C) - =T ;
%O .

38 39

Figure 1.14 Oxidation of 1,2-5,6-di-O-isopropylidene-D-mannitol

with Sodium hypochlorite/Ruthenium chloride

To Obtain the L-isomer of glyceraldehydes, L-ascorbic acid, which is widely available,
was used”. Oxidation of the protected L-ascorbic acid 40 with hydrogen peroxide gave
3,4-isopropylidene-D-erythronic acid 41 which was further oxidized by NaOCl to afford

2,3-isopropylidene-L-glyceraldehyde 42.

 

°>< OH I
O 7 o

o 0 H202 / CECO3 o/WOH NaOCI
— 7 1° ° '

OH OH

40 41 42

Figure 1.15 2,3-O-isopropylidene-L-glyceraldehyde from L-ascorbic acid

1.3 Some medicinally important synthesis targets from carbohydrates and
carbohydrate derived synthons.

Carbohydrates and carbohydrate derived 3 or 4 carbon synthons have been used

extensively in natural product synthesis, in the preparation of medicinally important

34-36

targets

1.3.1 From 3 or 4 carbon synthons

21

The development of new antibiotics is always urgent and challenging with the emergence
of multi-drug resistant organism. Linezolid, marketed by Pharrnacia and UpJOhn, is the
newest antibiotic available for the treatment of infections caused by vancomycin-resistant
Enterococcus faecium, hospital acquired pneumonia and methicillin—resistant
Staphylococcus aureus37‘ 38. Chiral 3-carbon synthons are widely used in the preparation

of linezolid and its derivatives3943.

a-Qeg’lkocnfl + izxkfl/V __a_. Rfljikiofl

43

R==-M:::>) -M:::fi-4<j:> uo'-d<:::H-{<::>-4:_fif_\N-:ifgrbn
40.0.... U 0

Figure 1.16 Preparation of Linezolid derivatives from (R)-g1ycidyl butyrate.

NHAc

(a) n-BuLi/hexane; (b) 4-Nitrobenzenesulfonyl chloride/Et3N;
(c) NH3/CH3OH; (d) AczO

Figure 1.16 lists one recent example for the preparation of Linezolid and its derivatives

from of 3-carbon synthon‘“. Deprotonation of the carbamate 43 with n-BuLi followed by

22

addition of (R)—glycidyl butyrate 44 give the (5R)-(hydroxy methyl)-2-oxazolidinone 45,

which is converted to the final Linezolid and its derivatives 47 in two more simple steps.

(L)-Carnitine is a small molecule which was identified more than 100 years ago”. It can
be found in all animals, in bacteria and in some plants. It is present in all cells and body
fluids of human being“. (L)-carnitine is involved in the transfer of fatty acids into
mitochondria. Mitochondria are potentially attractive targets of DNA damaging agents”
5 '. In cancer cells, the amount of mitochondria and the expression of carnitine transporter
increased which makes the mimics of (L)—camitine potential antitumor agent552'53. The
carnitine derivatives can be easily prepared from the 4-carbon synthons as shown in

Figure 1.17“.

o rpopsom 9R
WCOO‘B“ 3._b. NNWCOOtBu
rpopso
48 49
on 0 cu
_Ev_d. c'D/VCOOH R =23 N/—/
Cl Rm
50

Figure 1.17 Preparation of (L)-carnitine derivatives. (3) bis-silylated amine, SiOz, 50 %;
(b) Chloroambucil, Et3N, 52 %; (c) (i) TBAF/THF/imidazole; (ii) p-tosyl chloride,

DMAP, Et3N, 23 %, 2 steps; (d) TFA, 87%.

Ring opening of the chiral epoxide 48 by bis(tert-butyldiphenylsilyloxyethyl)amine

followed by acylation using chloroambucil give the y-amino B-hydroxyester derivative

23

49. The free acid 50 is obtained after deprotection of 49 followed by transforming the

hydroxyl groups to chlorides.

Some other medicinally important compounds derived from 3 and 4 carbon synthons are

listed in Figure 1.18.

° /\/\ k 0"
)~~u 0.. H ° 3 u o
"$er at“ -20 “Y

53

beta-3 Adrenerglc receptor 8 Pro ran 0' 0'
antagonist for obesity, diabetes ( l' P (S)-Atenolol

/ \ (HO)2(O)PCH20 OH
HO NHCH30H3NHCON O

>_/ \_/ Wfluf/
”43° F—t

O
54 55
Xamotarol c f
beta-1 Adrenocoptor partial agonist Ammrgnt

Figure 1.18 Some of the medicinally important compounds derived from chiral 3-

carbon synthons.

1.3.2 Iminosugar derivatives

lmino-sugars, or aza sugars, are a class of sugar mimics with the ring oxygen substituted
with nitrogen atom. They are important inhibitors for glycosidase and glycotransferase
which are involved in many important biological processes, such as intestinal digestion,
glycoprotein post-translation, glycoconjugate catabolism, and etc.55'57. They are potential

drug candidates to treat diabetes, viral disease, lysosomal storage disease, cancer. and

24

etc.58'62 Because of the structural similarity between imino-sugars and carbohydrates.

. . . 3-5
carbohydrates are often used for the preparation of immo-sugars6 6 .

Figure 1.19 lists some of the important imino-sugars. Deoxynojirimycin 56 is a potent a-
glucosidase inhibitor“. Its derivative, N-hydroxylethyl-deoxynojirimycin 57, is a potent
a—glucosidases inhibitor with higher in vivo efficacy and has been approved for the
treatment of type II diabetes (Miglitol)67. N-butyl-Deoxynojirimycin 58 (Zavesca)
recently has been approved for the treatment of a glycosphingolipid lysosomal storage

disease, type I Gaucher disease”.

OH HO
HO "0 N u/\/\
“ .0 " “lid
HO HO HO
HO OH OH
OH
56 57 58

Deoxynojirimycin mgnw Zavesca

Figure 1.19 Important iminosugars

Many methods with different starting materials have been used in the preparation of
imino-sugars. The obvious structural similarities between iminosugars and carbohydrates
make carbohydrates the ideal starting point. Besides carbohydrates, other chiral pool
materials. such as amino acids, tartaric acids have also been used“). Imino-sugars have
also been synthesized from achiral precursors, such as olefins, through Sharpless

O

asymmetric epoxidation and dihydrolylaiton7. This subject has been extensively

reviewed recentlym'n.

25

1.3.3 F uran/pyran derivatives

Functionalized tetrahydrofuran and tetrahydropyran are common components of naturally

. . . . 7
occurring and synthetic bloactlve compounds” 4.

couug

NH, /=( 4;l~\(cormz

</N I j "0 N /N Ho u’

\km

 

 

OH OH OH OH
Antiviral, anticancer agent Tiazofurin Ribavinn
NHCH;

no 0
COOH
N\ \ N
HTerH H < / A
on ”203',on Y I
,90

OH ":0 N \
NH,
52 ea 54
Tyroayl tRNA Synthetaae Inhibitor PZY‘I receptor antagonist ”I‘M?“ '90“

Figure 1.20 Medicinally important furan and pyran derivatives

Figure 1.20 lists some of the medicinally important furan and pyran derivatives.
Compounds 59, 60, 61 are nucleoside analogues, in these analogues, the sugar part of the
nucleosides have been modified to resist hydrolysis and enzyme degradation of the
nucleosides. Isonucleosides, such as (S,S)-iso-ddA 59 and its enantiomer (R,R)~iso-ddA,
have shown activities against viruses and tumor cells75‘76.
Tiazofurin [2-(B-D-ribofuranosyl)thiazole-4-carboxamide, compound 60], the
commercialized drug used for treatment of cancers, is a C-nucleoside which has

7

. . . . . . . . 9
Significant activmes agalnst human lymphoxdn, lung tumors 8, and ovarian cancers7 . It

26

also has activities against chronic myeloid leukemia in blast crisisso. Compound 62 is a
C-pyranosyl peptide which shown Tyrosyl tRN A synthetaswe inhibition properties“. The
six—membered ring anhydrohexitol bisphosphate analogue of adenosine-
3’,5'—bisphosphates (compound 63) is an antagonist of P2Y1 receptors”. Compound 64,
1,5-anhydro-2,3-dideoxy-D-ribohexitolnucleoside, is a moderate but selective antiviral

agent against Herpes simplex type 1 and 282.

Carbohydrates and anhydroalditols are often used in the preparation of these furan and
pyran derivatives”. Figure 1.2] shows a very efficient route for the preparation of

isonucleoside from 1,4—anhydro-D-xylitols4.

 

 

 

 

NH2
N \N
B"° OBn </ I J
= ,0-
OH
65 as

Figure 1.21 Preparation of isonucleoside from 1,4-anhydro-D-xylitol. (a) Tosyl chloride,

Pyr, 98 %; (b) Adenine, 18-c-6, K2CO3, DMF, 58 %; (c). 10 % Pd/C, H2, 93 %.

Tosylation of compound 65 followed by reaction with adenine in the presence of 18-

crown-6 and K2C03 give the protected isonucleoside. Reductive debenzylation provides

isonucleoside 66.

27

1.4 Conclusion

Carbohydrates have been used extensively in the preparation of naturally occurring and
medicinally important compounds. In most of these applications, their usages are largely
case dependent — the carbohydrates have to be modified based on each synthetic target.
Recently, progress have been made in the transformation of carbohydrates to general
chiral 3 and 4 carbon synthons, which have been used directly and more widely in the
synthesis of these medicinally important targets. However, the potential of the annually
renewable biomass carbohydrates is far from being fully explored. Compared to their
large scale availability and structural richness in stereochemistry and functionality, the
usage of carbohydrates as raw materials for both research and industry is still at the very
beginning. A surge in the usage of carbohydrates as green and renewable raw materials is

expected with the depletion of the non-renewable fossil resources.

28

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33

Chapter 2

Transformation of Commodity Carbohydrates to High Value

Chemical Intermediates by Reductive Cleavage

34

Abstract

In this chapter, a practical process for the preparation of anhydroalditols from
commercially available carbohydrates was developed. Using methyl-D-glucopyranoside
as the model compound, a protocol for reductive cleavage of glycosidic linkage was
established. Protecting the hydroxyl groups with allyl groups, the glycosidic bond was
effectively cleaved with Et3SiH/BF3oOEt2. The allyl ether groups were cleaved with the
PdClz-CuClz-Activated-Carbon system. This protocol was successfully applied to
sucrose, cellulose, starch and leven. From these commodity complex carbohydrates, the
valuable anhydroalditols, 1,5-anhydro-D-glucitol, 2,5-anhydro-D-mannitol and 2,5-
anhydro-D-glucitol were obtained in high yields and purity. The transformation was neat
and clean, no column separation was needed for the preparation of 1,5-anhydro-D-
glucitol from cellulose and starch. The catalytic cleavage of the allyl ether with the
PdClz-CuClz-Activated-Carbon system makes these transformations more practical

economically

35

2.1 Introduction

2.1.1 Availability and structural features of commodity carbohydrates

The raw materials used in human history were substantially renewable until the begging
of last century. The discovery of coal tar based materials followed by fossil gas and oil
took the lead as the raw materials in the past 100 years, and the usage of renewable
feedstock dropped to very modest levels. The limits of a chemical industry overly relying
on fossil raw materials are very clear as they are depleting and are irreplaceable. With the
predicted ending of cheap oil period in the near future (2040), the development of

biomass based chemistry is necessary and urgent" 2.

The widely available biomasses are carbohydrates, amino acids and lipids. The most
important class of them in terms of volume produced is carbohydrates, as they represent
roughly 75% of the annually renewable biomass of about 200 billion tons. Of these, only
a minor fraction (ca. 4%) is used by human beings, the rest decays and recycles along
natural pathways3. The bulk of the annually renewable carbohydrate biomass are
polysaccharides, these include cellulose, starch, inulin, xylan, chitin, etc. Their non-food
utilization is confined to textile, paper, and coating industries, either as such or in the

form of simple esters and ethers4.
These complex carbohydrates are composed of repeating units of monosaccharides, and

the repeating units are usually five or six member-carbon-rings with one heteroatom in the

ring and multiple chiral hydroxyl groups attached to the ring (Figure 2.1)5.

36

 

 

 

Figure 2.1 Repeating units in complex carbohydrates. (a) cellulose; (b) levan

The repeating units, if correctly modified, are ideal starting materials for the preparation
of enantiopure building blocks, high-value-added special chemicals intermediates, and
will find wide application in pharmaceutical, agrochemical, and fine chemical industry.
To make the transformation of complex carbohydrates into desired products practical, the
reagents used should be simple, inexpensive, non-toxic or low-toxic, the separation
procedures during work-up should also be simple. However, such kind of chemistry is
not as developed as the one for fossil based raw materials. This originates from the
structural differences between carbohydrates and fossil based raw materials. In
carbohydrates, the multiple hydroxyl groups make them barely soluble in most organic
solvents; the carbon skeleton is over functionalized compared to the target molecules; the
functional groups are only hydroxyl groups, no C=C or C=O functionality available for

further modification6‘ 7.

In this chapter, a new process was developed for the transformation of commodity
carbohydrates, such as sucrose, cellulose, starch and levan, into anhydroalditols. After
protecting the hydroxyl groups of complex carbohydrates with allyl ether, the glycosidic
linkages were cleaved through silane reduction. The free anhydroalditols were obtained

through PdClz catalyzed deprotection of the allyl groups.

37

2.1.2 Organosilane reduction

Gilman found that diphenylsilane can reduce certain diaryl-type ketones to the
corresponding hydrocarbon derivatives at relatively high temperaturesg. In the 1970’s,
Doyle and co-workers published a serial of papers on the silane reductions in acidic
mediag'”. In these papers, they reported more practical methods for the reduction of
aldehydes and ketones. Trialkylsilanes reduce aldehydes and ketones in alcoholic acidic
media to ethers9'l '. Thus, in methanol, using 97 % sulfuric acid as catalyst, benzaldehyde
was reduced to benzyl methyl ether by triethylsilane in 87 % yield. When trifluoroacetic
acid or trichloroacetic acid was used, benzyl methyl ether was obtained in 87 or 85%

respectively.

 

 

 

 

o
. + . u +
0“ Etgsm /°R on2

+ Et3SiOH .___ ©_<
"’0 OR'

Figure 2.2 Reduction of aldehydes using triethylsilane

+
/Ol~l +R'OH OH
OR'

H

Lewis acids, such as AlCl3.ZnC12, SnCl4, and BF 3 can also be used to activate the carbon
center in the reduction of aldehydes and ketones by organosilanes'b'zo. Among the Lewis
acids used, BF 3 gives the best results. In the presence of boron trifluoride etherate,
aldehydes and ketones are rapidly reduced by triethylsilane at room temperature to borate
esters and symmetrical ethersz'. Triethylsilyl fluoride is the oxidation product. The

discovery that acids can catalyze the transfer of hydrides from silicon to carbon makes

38

the ambient temperature organosilane reduction of carbonyl groups possible, which

accelerated the application of silane reduction in organic chemistry.

In the early 80’s, Gray introduced the organosilane reduction method to the structural
determination of polysaccharides23 (Figure 2.3). Reductive cleavage of the perrnethylated
cyclohexaamylose with triethylsilane in the presence of either boron trifluoride etherate
or trimethylsilyl trifluoromethanesulfonate, followed by acetylation of the newly formed
hydroxyl group, gave the methyl-acetyl derivatives of 1,5-anhydro-D-glucitol. The

linkage position can be determined through the analysis of the derivatives 2 obtained.

 

OH 0M0
o o
a,bn:
..o T- 3%
OH 0 ° 0M0
1 2
\ 0M9 . /
+ .
0
R0 \
Md)
0140

3
Figure 2.3 Reductive cleavage of polysaccharide by triethylsilane. (a) methylation; (b)

reductive cleavage; (c) acetylation.

Later on, this method was extensively used to analysis the structure of polysaccharides”

28, for example, the structure of the O-specific polysaccharide from the

lipopolysaccharide fraction of the phytopathogenic bacterium Xanthomonasfi'agariaezs.

39

The reductive cleavage of glycosidic linkage is a powerful method for the analysis of
fully methylated polysaccharides. However, these methods require large amounts of
reducing agent and Lewis acid (often over 50 molar equivalents)23 and are only
applicable to methylated sugars in micro to milligram amounts. Much work has to be
done in applying this type of chemistry on the synthetic scale. Among the questions to be
answered are:

(1) What influence does the nature of the protecting group in the 2 position of the aldo
sugar have on the rate and yield of the reaction?

(2) What influence does the stereochemistry of the 2-position have on the rate and yield.
(3) What influence does ring size have?

(4) What protecting groups are compatible with the reaction conditions?

(5) Is it possible to get a combination of catalyst and reductant that gives synthetically
useful results in a reasonable time?

(7) What carbohydrate polymers or other commodity carbohydrate feedstock can this

chemistry be applied to?

2.2 Results

2.2.1 Establishing the protocol for triethylsilane cleavage of the glycosidic linkage.
The reduction of methyl 2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside was processed with
5 equiv of Et3SiH and 5 equiv of BF3.OEt2 under N2 atmosphere (Table 2.1). No
reduction product was observed when the reaction was run at r.t. with H2804, CF3COOH,
or CF3803H as catalyst. Elevation the temperature did not give any reduction product
either. After workup (MeOH/HCI), the observed products were only the hydrolyzed

starting material.

40

Table 2.1 Reduction of methyl-2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside.I

 

 

Entry Solvent Acid Term. Time Product
1 CH2C12 H2804 r.t. 10hr glucose
2 CHzClz C F3COOH r. t 1 0hr
3 CHZClz CF3SO3H r. t. 10hr
4 CHzClz CF3COOH r.t 3 days
5 CHZCIZ CF3COOH reflux 10hr
6 CICHQCHZCI CF3COOH 60°C 10hr

 

* Reaction conditions: 5 equiv Et3SiH, 5 equiv BF3oOEt2, N3 atmosphere.

When methyl 2,3,4,6-tetra-O-benzyl-a-D-glucopyranoside 4 was treated with
triethylsilane (30 equiv), TMSOTf (30 equiv), and BF3 ° OEtz ( 10 equiv) in
dichloromethane at r.t. for 24 h, the product obtained afier workup is methyl a-D-

glucopyranoside 5.

 

OBn OH
o Et3SiHIBF3_OEt O
BnO : HO
BnO H
can TMSOTf, CH20I2 OH
0M0 O°C-r.t., 24hr 0MB
4 5

Figure 2.4 Reaction of methyl 2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside with Et3SiH

Allyl group was then chosen as protecting group. Treatment of methyl a-D-
glucopyranoside 5 in DMSO with NaOH followed by allyl bromide gave the desired

product methyl 2,3,4,6-tetra-O-allyl-a-D-glucopyranoside 6 in 85 % yield.

Treatment of 6 with triethylsilane (3O equiv), TMSOTf (3O equiv), and BF3 - OEt2( 10

41

equiv) in dichloromethane at r.t for 24 h gave the desired product 1,5-anhydro-2,3,4,6-
tetra-O-allyl-D-glucitol 7 in ~90% yield. Using 2 equiv of triethylsilane, 3 equiv of
trifluoroborane-etherate and catalytic amount of trifluoromethanesulfonic acid, 6 was
reduced to 7 in 91 % yield. NMR shown the product was very pure (>99 %) and no

further purification was needed.

OH 0A" OAII

b AIIO

HO AIIO
HO —"—’ AIIO A110

01" 0M3 OAII 0M9

5 5 7

CA"

Figure 2.5 Reduction of methyl 2,3,4,6-tetra-O-allyl-a-D-glucopyranoside with Et3SiH
(a) Allyl Bromide, DMSO/NaOH, 24 h, 85 %; (b) Et38iH/BF3OEt2, CF3SO3H, CHzClz,

DOC-r.t, 6 h, 91 %.

2.2.2 Practical and economic Palladium chloride catalyzed de-allylation of 1,5-
anhydro-2,3,4,6-tetra-O-allyl-D-glucitol.
By refluxing allyl ether 7 in methanol in the presence of palladium(II) chloride for 12 h,

the deprotected 1,5-anhydro-D-glucitol (8) was obtained in almost quantitative yield.

OAII 0”
o PdCIz, additives 0
AIIO = ”0
AIIO MeOH “0

OAII 0"

7 8

 

Figure 2.6 Deallylation of 1,5-anhydro-2,3,4,6-tetra-O-allyl-D-glucitol with PdClz

Using Cqu as a co-catalyst and activated carbon as an additive, a real catalytic protocol

42

for the cleavage of allyl ether was developed. As shown in table 2.2, when Cqu was
used as a co-catalyst, the product was obtained in 91% with only 1 mol % of PdClz (entry
3). The reaction runs smoothly at 0.1 gram scale. However, when the reaction was carried
out on a 1.0 gram scale, only 15% of the fully de-allyllated product was obtained. When
activated carbon was added to facilitate the distribution of the solid catalyst PdClz, the

reaction can be performed on up to a 5.0 gram scale to yield the desired product in

around 90% yield.

Table 2.2 Deprotection of 2,3,4,6-tetra-O-allyl-D-1,5—anhydro-glucitol

 

 

 

conditions
Entry Allyl-glucitol (gram) C - PdClz (mol %) Yield (%)
uCl2-2HzO Activated
carbon
1 0.] none none 80 93
2 0.1 none none 4 10
3 0.1 1 eq none 1 91
4 1.0 1 eq none 1 15
5 1.0 1 eq 0.5 gram 1 90
6 3.0 leq 3.0 gram 1 91
7 5.0 1 eq 5.0 gram 1 90

 

2.2.3 Application of the Allylation-Reduction-De-allylation protocol to other mono,
disaccharides and complex carbohydrates.

Methyl D-mannopyranoside
Under the same conditions as for the reduction of methyl 2,3,4,6-tetra-O-allyl-a-D-

glucopyranoside, methyl 2,3,4,6-tetra-O-allyl-a-D-mannopyranoside 10 was reduced to

1,5-anhydro-2,3,4,6-tetra-O-allyl-D-mannitol 11 in 90 % yield (Figure 2.15),

43

DA"

on on can
,0
HO ’0 __a___. At _L_.
HO Al

 

0M0 0M0
9 i 10
OAII OAII c OH OH
AIIO HO
Al Ho
1 1 1 2

Figure 2.7 Reductive cleavage of methyl 2,3,4,6-tetra-O-allyl-D-mannopyranoside
(a) Allyl Bromide, DMSO/NaOH, 24 h, 85 %; (b) Et3SiH/BF3OEt2, CF 3SO3H, CHzClz,

0°C, 5 min, 90 %; (c) PdClz/CuClz, activated carbon, MeOH, refulx, 12 h, 90 %.

After refluxing l,5-anhydro-tetra—O-allyl-D-mannitol 11 in methanol for 12 h with 1 mol

% of PdCIz, 1,5-anhydro-D-mannitol 12 was obtained in 91 % yield.

Methyl D-ribofuranoside

Methyl-D-riboside 13 (mixture of a/B anomers, ration 1/9) was first protected with allyl
groups. The reduction of methyl 2,3,5-tri-O-allyl-D-riboside 14 under the same
conditions as for the reduction of methyl-D-glucoside derivative was done within 3

minutes at 0°C and gave the reduced product 15 in 91 % yield.

44

HO A110

0
0
OMG a "9 b
—_—___—.> —____>
0H 011 A110 0A"
13 14
H0
A110 0
0 C
————->
0H 0H
AIIO OAII 15
15

Figure 2.8 Reductive cleavage of methyl 2,3,5-tri-O-allyl-D-ribofuranosides
(a) Allyl Bromide, DMSO/NaOH, 24 h, 87 %; (b) Et3SiH/BF3OEt2, CF3SO3H, CHzClz,

0°C, 3 min, 91 %; (c) PdClz/CuClz, activated carbon, MeOH, refulx, 12 h, 85 %.

Sucrose

Octa-O-allyl-sucrose 18 was prepared through allylation of sucrose 17 with allyl bromide
and sodium hydride in DMF in 68 % yield. The reduction of 18 was done in 8 h, the D-
glucopyranosyl group gave rise to a single anhydroalditol, namely, l,5-anhydro-2,3,4,6-
tetra-O-allyl-D-glucitol 7 (45 %), and the D-fructofuranosyl group gave two
anhydroalditols, identified as 2,5-anhydro-1,3,4,6-tetra-O-allyl-D-mannitol 22 (39 %)

and 2,5-anhydro-1,3,4,6-tetra- O-allyl -D-glucitol 21 (7 %).

45

O H GA"

0 cnzon a 0 (”how
HO o _, A110 0
HO HO AIIO AIIO
OH 0 0A" O cnzoml

cnzon
OH OAII
OAII email"
0 o
b All 0 + AIIO + Alto
A"° Anonzc cnzoau CHIOA"
OAII can
OAII
7 19 20
OH cnon
o o
c 0 HO
_____. HO + “O +
”0 HOHzC cnzon ”2°”
OH on
on
8 21 22

Figure 2.9 Reductive cleavage of Octa-O-allyl-sucrose. (a) Allyl Bromide,
DMSO/NaOH, 24 h, 68 %; (b) Et3SiH/BF3OEt2, CF3S03H, CHzClz, 0°C, 8 h, 91 %;(c)

PdClZ/CuClz, activated carbon, MeOH, refulx, 12 h, 85 %.

Cellulose

For the preparation of tri-O-allyl-polysaccharides, the polysaccharides were first
dissolved in hot DMSO (65°C), followed by addition of powered NaOH and then allyl
bromide. In this way, tri-O-allyl-cellulose 24 was obtained in 85 % yield while tri-O-

allyl-starch 26 and tri-O-allyl-levan 28 were obtained in 80 % and 78 % respectively.

46

OAII

 

on
can
0" 0 a A110 0 O
HO 0 ___.. o
0 HO 0 AIIO
O OH OAII
OH n OAII n
on
b, c 0
¢ 1'10
HO
OH
8

Figure 2.10 Reductive cleavage of tri-O-allyl-cellulose. (a) Allyl Bromide,
DMSO/NaOH, 24 h, 85 %; (b) Et3SiH/BF3OEt2, CF3SO3H, CHzClz, 0°C-r.t, 24 h; (c)

PdClz/CuClz, activated carbon, MeOH, refulx, 66 %, 2 steps.

Under similar conditions as for the reduction of methyl tetra-O-allyl-glucoside, tri-O-
allyl-cellulose 24 was reduced, however, the reaction time was much longer, and it took
24 hours for the reaction to be completely done. After de-allylation, 1,5-anhydro-D-
glucitol was obtained as the single product, and the yield for the two steps (reduction and

de-protection) is 66%.

Starch

The reduction of tri-O-allyl-starch 26 was done in 24 hours, de-allylation of the mixture

gave 1,5-anhydro-D-glucitol as the single product in 69 % yield.

47

OAII

on
o
0 OH a O
HO AIIO
OH 0 OAII
0
HO
on
n
25

 

26

 

Figure 2.11 Reductive cleavage of tri-O-allyl-starch (a) Allyl Bromide, DMSO/NaOH,
24 h, 80 %; (b) Et3SiH/BF3OEt2, CF 3SO3H, CHzClz, 0°C-r.t, 24 h; (c) PdClz/CuClz,
activated carbon, MeOH, reflux, 69 %, 2 steps.

Levan

Using the same sequence as for reduction of tri-O-allyl-cellulose, reduction of tri-O-allyl-
levan gave 2,5-anhydro-D-mannitol 22 and 2,5-anhydro-D-glucitol 21 as the two
products in the ratio of 5 to l and in 65 % yield afler the reduction and de-protection

steps.

48

HO O 0 OH A110 0

 

HO HO A110
a
OH HO m OH AIIO All
0
HO 0 o AIIO o O
HO HO A110
OH HO OH HO n A110 A110 “'0 A110 n
27 28
cnzou
o o
b,c HO
_______ HO +
Honzc cnzon OHIO”
21 22

Figure 2.12 Reductive cleavage of tri-O-allyl-levan (a) Allyl Bromide, DMSO/NaOH, 24
h, 78 %; (b) Et3SlH/BF3OE12, CF3SO3H, CH2C12, 0°C-r.t, 16 h; (C) PdCIz/CUClz, activated

carbon, MeOH, reflux, 65 %, 2 steps.

2.3 Discussion

2.3.1 Establishing the protocol for triethylsilane cleavage of the glycosidic linkage.
To avoid the decomposition and rearrangement of carbohydrates under acidic conditions,
the free hydroxyl groups must be protected. To find the suitable protecting group for
carbohydrates, especially the complex carbohydrates, such as cellulose, starch, levan,
several factors must be considered. First, what kind of solvent should be used?
Carbohydrates are not soluble in solvents with low dielectric constants, such as toluene,
dichloromethane. The best solvent for carbohydrates is water, but water is not a good
solvent for the protection of complex carbohydrates for several reasons. The first reason
is that the hydroxyl group of water will compete with the hydroxyl groups of
carbohydrates which make some reactions, e.g., acetylation of carbohydrates, impossible

to be run in water. The second reason is that once the majority of the hydroxyl groups are

49

protected, the product tends to precipitate from water due to the hydrophobic properties
of the protecting groups and thus makes it impossible for the protection of all the
hydroxyl groups. The solvents with high dielectric constants, such as DMSO, DMF, can
solve or partially solve the complex carbohydrates, and the protected carbohydrates are
also soluble in them. However, one possible problem still exists: the partially protected
carbohydrate chains tend to fold which makes some of the free hydroxyl groups are
buried in the coil and hard to be functionalized. Using DMSO, DMSO/H20 and DMF,

satisfactory results were obtained for both the monosaccharides and polysaccharides.

Second, what kind of protecting group should be used? The installation and removal of
the protecting group should be friendly and no harsh reaction conditions or toxic reagents
should be used, also, costly reagents should be avoided. The protecting groups must
survive the reduction process: since acid is used so no acid labile functional group should
be used and no functional groups which are easily reduced by triethylsilane should be
used either. The stereo and electronic effects of the installed functional groups on the
reduction process are also crucial: the intermediate formed in the reduction process is
oxocarbenium ion, electron withdrawing group at 2-position will retard or stop the
formation of the oxocarbenium ion while electron giving groups will facilitate the
process. Sterically demanding groups will make the access of the oxocarbenium ion by

triethylsilane difficult, thus retard the reduction process.
Methyl group is the best choice if no deprotection was needed for the reduced products.

Methyl ethers are easy to install, stable to acid and silane, slightly electron giving, and

relatively small in size. Indeed, methyl group was the mostly used protecting group in the

50

analysis of complex carbohydrates by the silane reduction method23'2°. However, the
harsh conditions used in the cleavage of methyl ether bonds make it not a suitable choice
since our purpose is to prepare the unprotected anhydroalditols.

Acetyl groups are easy to install and remove, relatively small in size and it is one of the
least costly protecting groups. One possible problem is that it is an electron withdrawing
group, and participation of 2-acetyl group to the reduction process is also possible
through formation of the dioxonium ion with C-l. However, similar reactions with
saccharides containing propanoate groups at C-2 had been used with Me3SiOSOzCF3 as

the catalyst25 .

Thus acetyl groups were chosen as the protecting groups for evaluation of the reductive
cleavage process. To simplify the reaction process, methyl a-D-glucopyranoside was
chosen as a model compound. However, no reduction product was obtained from methyl
2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside, the only product after workup was the

hydrolyzed starting material, glucose (Table 2.2, Figure 2.13).

A possible reaction pathway was shown in Figure 2.13. Once the carbocation 31 was
formed, the acetyl group from C-2 apparently stabilized it and formed the dioxonium ion
32, thus making the hydride transfer to the anomeric carbon disfavored, so that no

reduction product was formed.

00° 5 equiv Et3SlH

OH
O 5 equiv BF3_OEt
AGO ¢ HR 0
Ac
0
acid HO OH
33

H9
1 MoOHIH-I-

 

 

OAc 0“ OAC
4.
' c) o
O A O AcO
«éfl __. 1% L “3;,
Ac '1 1 O (p O + O
.,\ r r
30 31 32

Figure 2.13 Mechanism for reaction of methyl 2,3,4,6-tetra-O-acetyl-0t-D-

glucopyranoside with Et3SiH

Benzyl group will not participate in the reduction process; one possible problem is that
under the action of hydride, the benzyl ether bond may be cleaved. However, if the
cleavage of the glycosidic bond is faster than that of the benzyl ether bond, the cleavage

of the benzyl ether bond will not be a problem.

0811

 

30 equiv EtasiH OH
O 10 equiv BF3.OEt
”“32 . ; HO 0
mo 30 equnv TMSOTf H
0"“ CH2C'2 Ho one
4 0°C-r.t., 24hr 5
1 BF, I
08" can 1
ca
mfl “£1 "
3"0 - BnO
+ ' F _ __. a 0 0
83; on. H 10‘ 0'“ g“;%\
’ Et3SIH l 3‘2 0\ on.
51381 BF!
C
'F
34 35 36

Figure 2.14 Mechanism for reaction of methyl 2,3,4,6-tetra-O-acetyl-0t-D-

glucopyranoside with Et3SiH

52

No reduction of the glycosidic bond was observed even with excess Et3SiH (3O equiv)
used. Instead, cleavage of the benzyl ether bond was observed. After workup, the product
obtained was methyl a-D-glucoside 5. A mechanism was proposed in Figure 2.8.
Coordination of BF3 with the benzyl ether oxygen formed complex 34; transfer of
hydride from Et3SiH to the benzylic carbon gave the partially deprotected 36. Continued

reductive cleavage of the benzyl ether bonds gave the deprotected 5.

So, an alterative protecting group which will not participate during the reduction process
and is more stable under acidic reductive conditions than benzyl ether is needed. And this
protecting group should be easy to cleave. Allyl group seems to meet all the requirements
for the reductive cleavage reaction: allyl ether is stable under acidic conditions; it will not
participate in the reduction process as ester does, allyl group is relatively small in size,
and the allylic hydrogens are also less reactive compared to benzylic hydrogens. The
installation of allyl ether is relatively easy, and many methods have been reported for the
cleavage of allyl ether. Allyl group was then chosen as the protecting group for the

reductive cleavage reaction.

For the formation of allyl ether, several methods are available. The most obvious and
widely used method is through the reaction of alkali metal alkoxides with allyl halides.
The reaction is best when carried out in polar solvent, such as DMF”. This method is
good for the universal protection of all the hydroxyl groups in a certain compound.
Another extensively used method for the formation of allyl ether is the tin method3°'32.

The hydroxyl groups are first converted to tributylstannyl ethers or, in the case of diols,

to dibutylstannylidene acetals and then alkylation of the alkoxy-tin derivatives give the

53

ally ether. An advantage of this method is that functional groups, such as azido groups,
O-TBDMS groups and acetamido groups can be tolerated” 34. This method is mostly
used when partial of the hydroxyl groups need to be protected selectively35‘37. The third
widely used method is through palladium catalyzed decarboxylative rearrangement of
mixed allyl alkyl carbonates. Alkyl allyl carbonates undergo decarboxylative
rearrangement when heated at 50-70 0C in the presence of palladium catalysts”. The
alcohols were first converted to allyl carbonates, and then palladium catalyzed extrusion
of C02 give the allyl ether. This method has been successfully applied to base sensitive
substrates, such as carbonate or 1,1,3,3-tetraisopropyldisiloxane-l,3-diyl (TIPS)

derivatives of carbohydrates” 39. Alcohols can also be converted to allyl ethers through

S40-42 d43, 44.

their barium salt , or using the trichloracetamidate metho
For the preparation of methyl 2,3,4,6-tetra-O-allyl-a-D-glucopyranoside 6, the most
practical and economic method is through the Williamson synthesis. Using this method,
methyl 2,3,4,6-tetra-O-allyl-a-D-glucopyranoside 6 was obtained in 85 % yield (Figure
2.9). The reduction of 6 gave the desired product 7 in high yield. At first, conditions used
in the reductive cleavage of methyl protected carbohydrates were used23’ 24. With 30
equiv Et3SiH, 3O equiv TMSOTf, and 10 equiv BF3°OEt2, the reaction was done within
24 h at r.t., the desired product 1,5-anhydro-2,3,4,6-tetra-O-allyl-D-glucitol was obtained

in 90% yield.
Although these conditions work well for the reduction, the high equivalents of

triethylsilane and TMSOTf used prevent the practical usage of these conditions for the

preparation of 1,5-anhydro-D-glucitol in gram scale. Fortunately, we found that by using

54

catalytic amount of trifluoromethanesulfonic acid in dichloromethane, even without the
expensive TMSOTf, a very good yield of the desired product can be obtained with much
less triethylsilane and BF3-OEt2 used. Using only 2 equiv of triethylsilane, 3 equiv of
trifluoroborane-etherate and catalytic amount of trifluoromethanesulfonic acid, the
desired product was obtained in 91%, isolated yield. Furthermore, NMR shown the

product was very pure (>99 %) and no further purification was needed.

The proposed mechanism is shown in Figure 2.15. Coordination of boron trifluoride to
the glycosidic oxygen forms the complex 37. At the assistance of the lone pair electrons
from the ring oxygen, the glycosidic linkage is cleaved with the formation of the ring
oxocarbenium ion and boron fluoride methanolate. The boron fluoride methanolate ion
decomposes to form fluoride. and difluoromethoxylborane. At the assistance of fluoride,
hydride transfers from triethylsilane to C-1 of 39 forms the reduced anhydroglucitol 7

and fluorotriethylsilane.

All 4-
A11
0‘" o + BFg-OMO
A110 ---—> A110 A110
All 0‘" 0 A11 9 CA" 8152-0”.
. \
0“ 53/ _+
6 37 38 F
J 58351“
OAII GA"
4.
5:35“: + auo ° .— MIC 97 H
AIIO AIIO U.
CA" GA (31513
' F
7 39

Figure 2.15 Mechanism for reaction of methyl 2,3,4,6-tetra—O-allyl-a-D-

glucopyranoside with Et3SiH

55

2.3.2 Palladium chloride catalyzed de-allylation of 1,5-anhydro-2,3,4,6-tetra-O-allyl-
D-glucitol.
Many methods have been reported for the cleavage of allyl ether bond, most of them

4547

involve prior isomerization of the allyl ether, either base or transition metal

catalysed,°°'50 to labile prop-l-enyl ethers which may then be cleaved under generally
mild conditions.

Several literature methods were evaluated. for the cleavage of the allyl ether. These
included TMSCl/Nal5 ', NaBH4/1252, NBS and light53 and DDQ54. No satisfactory results
were obtained either because the yield was too low (TMSCl/Nal, NaBH4/12, <5 %) or the

recovery of the product was too problematic (N BS/light or DDQ ).

Recently, palladium complexes have been used for the direct cleavage of allyl ether.
PdC12(PhCN)2, used in stoichiometric amount, allows direct cleavage of allyl phenyl
ethers to phenols in 85-95%yield55. Another powerful and selective method for cleavage
of allyl ethers has found extensive use in carbohydrate chemistry5°’°3. In this method, the
substrate is reacted with equimolar (or often excess) amounts of PdClz in aqueous acetic
acid and in the presence of sodium acetate at temperatures ranging from 25°C to 70°C.
The free alcohol is obtained directly. Although the above mentioned palladium mediated
cleavage of allyl ether gave high yield of the deprotected product, stoichiometric amount
of palladium usually is required. Kusama and co—workers devised a catalytic method for
the deprotection of allyl glycosides“. Heating allyl glycosides in acetic acid in the
presence of palladium tetrakis(triphenylphosphine) afforded the deprotected product. The

amount of catalyst required is rather high (ca. 30 mol %).

56

For the deprotection of l,5-anhydro-2,3,4,6-tetra-O-allyl-D-glucitol, which has 4 allyl
groups, 1.2 equivalent of palladium will be needed even 30 mol % of palladium per allyl
group is used. Further more, the reported palladium based catalytic direct deprotection of
allyl ether can only be used to cleave allyl ether as allyl glycosides“ 65. Thus, a more
efficient, more general catalytic protocol must be developed for the deprotection of 1,5-

anhydro-2,3,4,6-tetra-O-allyl-D-glucitol.

We found that by refluxing the allyl ether solution in methanol in the presence of PdClz v
for 12 h, the de-protected 1,5-anhydro-glucitol could be obtained in almost quantitative
yield. In this case, catalytic amount of palladium (II) chloride (0.8 equiv or 0.2 equiv
per allyl group) was used (entry 1, Table 2.2). When 0.04 equiv of PdClz was used,
however, only 10 % of the product was obtained (entry 2, Table 2.2). The large amount
of catalyst needed makes the development of a more efficient catalytic protocol necessary

to make this reductive cleavage method practically viable.

 

CA" CH
PdClz, additives
AIIO ° : o
AIIO ”0
0A1! M90“ ”0
0H
7 8

Figure 2.6 Deallylation of l,S-anhydro-2,3,4,6-tetra—O-allyl-D-glucitol with PdClz

One possible reason for the low efficiency of the palladium(II) chloride was that part of
Pd(ll) was reduced to Pd(0) and thus lost the catalytic property. Cqu has the ability to
oxidize Pd(0) to Pd(lI) and it is expected that by using Cqu as a co-catalyst, the Pd(0)

will be recycled and thus only a very lower loading of PdClz was needed. Indeed, when 1

equiv of CuClz was used, with only 0.01 equiv of PdClz, the product was obtained in very

high yield (91 %) (entry 3, Table 2.2).

The reaction runs smoothly at 0.1 gram scale with the PdClz-CuClz catalytic system,
however, when the reaction was carried out on a 1.0 gram scale, only 15% of the fully
de-allyllated product was obtained (entry 3, Table 2.2). The possible reason was that at
larger scale, as the volume of the solvent increased, the rate of the biphasic reaction
decrease since PdC12 is not soluble in MeOH. A better disperse of the solid catalyst in the
reaction system should be able to solve this problem. We were happy to find that with an
equal amount of activated carbon used along with the substrate, the reaction can be

performed on 5.0 gram scale without decreasing in yield (entry 7, Table 2.2).

Although some palladium based catalysts for the deallylation of allyl ether have been

developed, the mechanism is still not very clear°5'69

. A mechanism, based on anti-
Markovnikov hydroxypalladation followed by B-alkoxy elemination, was proposed for

cleavage of the allyl ether (Figure 2.16)7°.

58

H20

on fl 0"
+ %PdCl 42

'41

I—Pd612 HC'
on
13%
40 ROH
43
pdCl §P0012
2
CUC12 Va
Pdci OH
NO + "<———Pd°" 2 /\5/ R= carbohydrate

Figure 2.16 Proposed mechanism for catalytic cleavage of allyl ether

Coordination of allyl-ether 40 with PdCl2 followed by attacking the terminal carbon of
the olefin by H2O gives the intermediate 42, which loses ROH 43 (the free carbohydrate)
and gives the allyl alcohol complex 44. Dissociation of PdCl2 with 44 gives free PdCl2
and finishes the catalytic cyc1e. The allyl alcohol formed in the process would reduce
palladium(II) to palladium(0) with formation of oxidized by-products such as acrolein".

Pd(0) can be oxidized back to Pd(II) by CuCl2

2.3.3 Application of the Allylation-Reduction-De-allylation protocol to other mono,
disaccharides and complex carbohydrates.

Once the Allylation-Reduction-De-allylation protocol was established, it was tested on
the reduction of other glycosides and complex carbohydrates. It turns out that this

protocol is very general; it can be used on other monosaccharides, such as mannose,

59

ribose, and disaccharide, such as sucrose, and on polysaccharides, such as starch,

cellulose and levan.

Methyl D-Mannopyranoside

The stereochemistry at C-2'of aldohexapyranose has a great effect on the reactivity of C-
1. In this case, methyl ci-D-mannopyranoside was chosen to study the C-2
stereochemistry effect on the reductive-cleavage of the glycosidic linkage. For the
reductive cleavage of the glycosidic linkage in methyl 2,3,4,6-tetra-O-allyl-a-D-
mannopyranoside, the reaction was much faster than that of methyl 2,3,4,6-tetra-O-allyl-
or-D-glucopyranoside, the reaction was done within 5 minutes at 0°C with 90 % yield
(Figure 2.7) The only difference between the glucopyranoside derivatives and
mannopyranoside derivatives is the stereochemistry at C-2: the hydroxyl (allyl ether for
protected glycosides) group is equatorial for glucopyranoside while it is axial for
mannopyranoside. It took 6 hours for the reduction to complete for glucopyranoside
while only 5 minutes for mannopyranoside. What caused the big difference in the

reaction rates between glucopyranoside and mannopyranoside derivatives?

For the reduction of methyl 2,3,4,6-tetra-O-allyl-D-glucopyranoside and methyl 2,3,4,6-
tetra-O-allyl-D-mannopyranoside, the mechanisms are the same (Figure 2.17):
coordination of BF3 with the glycosidic oxygen forms the BF 3 - glycoside complexes 37
and 50, cleavage of the glycosidic bond forms the oxycarbenium ions 38 and 51,
reduction of the oxycarbenium ion give the anhydroalditol derivatives 7 and 11. In this
process, the rate determining step is the formation of the oxycarbenium ions 38 and 51,

the same as in the hydrolysis of alkyl glycopyranosides72’73.

60

OAII 0“" ON. CA"

 

 

 

slow +
A110 0 L A" O _____, AIIO ‘2 fa" All 0
All A" OAII auo Et,sm All
A110 0 - /o< can OAII
\ F33
6 37 38 7
_ AIIO
AIIO AIIO Auo OAII AIIO OAII 0‘0"
BF; . 810W _—_.A"o'
All All
0 _ +
\ i=,a’o \
1o 50 51 11

Figure 2.17 Mechanism for reduction of methyl a-D-glucoside and methyl a-D-

mannoside.

It has been known for many years that stereoisomeric glycosides hydrolyze with

increasing rate depending on the number of axial hydroxyl groups”.

OH HO OH HO 0“
HO O < O < 0
H0 H0
OHocn, . on OCH: OH 0" OCH,
5 ' 48 49

Figure 2.18 Relative acid-catalysed hydrolysis rates of glucoside, galactoside and
guloside.
An explanation for the hydrolysis rate difference between different glycopyranosides was
based on the relief of steric strain. On the basis of available data and some assumptions
on pyranoside reactant-state conformations and the mechanism of hydrolysis, Edward

75-78

gave an explanation to this phenomenon . The rationale as to why guloside 49 reacts

faster than galactoside 48, which again reacts faster than glucoside 5 (Figure 2.18), was

61

based on the easiness for the relief of steric strain. Axial substituents would ease the
rotation around the C2-C3 and C4-C5 bonds and thereby facilitate the transformation

from reactant into intermediate, which possess a more flattened half-chair conformation.

For the reduction of glycopyranoside derivatives, the rate determining step is also the
formation of the oxocarbenium ion (Figure 2.17), the same rational can be used to
explain the rate difference between glucopyranoside and mannopyranoside: the C-2 axial
substitute in mannopyranoside eases the rotation around the C2-C3 and C4-C5 bonds and
thereby facilitate the transformation from reactant into intermediate, which accounts for

the big rate difference.

The stereochemistry at C-1 of methyl 2,3,4,6-tetra-O-allyl-D-mannopyranoside does not
affect the reaction rate much in the reduction process. No difference was observed for the
or and [3 anomers. The de-allylation was also successful with the PdCl2-CuCl2-Activated-

Carbon system. After refluxing 1,5-anhydro-tetra-O-allyl-D-mannitol in methanol for
12 h with 1 mol % of PdCl2, 1 equiv CuCl2 and activated carbon, 1,5-anhydro-D-

mannitol was obtained in 91 % yield.

Methyl D-ribofuranoside

With the successful application of this reductive cleavage protocol on methyl D-
mannopyranoside, the reductive cleavage of pentosides with this protocol should pose no
problem. Ribosides were chosen as substrates to test this method. The reduction of
methyl 2,3,5-tri-O-allyl-D-ribofiiranoside (mixture of a/B anomers. ration 1/9) under the

same conditions as for the reduction of methyl D-glucopyranoside derivative was done

62

within 3 minutes at 0°C and the product was obtained in 91% isolated yield.

In furanose, the ring carbon atoms are distorted from the tetrahedron structure and the
substituents are eclipsed to each other. Thus, the furanose ring is highly strained. This
strain is partially released when the oxocarbenium ion is formed. Compared to furanose,
the pyranose ring is more flexible and the strains in pyranose were released through
pucker of the ring. The structural difference between furanose and pyranose is the reason
for the rate difference in the acid catalyzed hydrolysis of furanose and pyranose. For
example, methyl a-D-mannofuranoside hydrolyzed 150 times faster than methyl a-D-
mannopyranoside”. The same reason can be used to explain the rate difference in the
triethylsilane reduction of methyl D-ribofuranoside and methyl D-glucopyranoside. In the
silane reduction reactions, the 'rate determining step is also the formation of the
oxocarbenium ion, as in the acid catalyzed hydrolysis of glycosides. The faster rate in the
formation of the furan-oxocarbenium ion makes the reduction of methyl D-

ribofuranoside faster than methyl D-glucopyranoside.

2.3.4 Preparation of 1,5-anhydro-D-glucitol, 2,5-anhydro-D-glucitol and 2,5-
anhydro-D-mannitol from sucrose.

Next, the disaccharide, sucrose, was used as the substrate for the reduction. Based on the
results for reduction of monosaccharides, anhydroalditols are the expected products via
the formation and reduction of oxocarbenium ions. The D-glucopyranosyl group was
expected to give rise to a ‘single product, namely, 1,5-anhydro-2,3,4,6-tetra-O-allyl-D-
glucitol The D-fructofuranosyl group can, however, give rise to two anhydroalditols,

namely, 2,5-anhydro-1,3,4,6-tetra-O-allyl-D-mannitol and 2,5-anhydro-l,3,4,6-tetra-O-

63

allyl-D-glucitol. Compounds 2 and 3 are the result of net overall retention and inversion,

respectively, of the stereochemistry at C-2 in the D-fructofuranosyl group.

As expected, three products were obtained: 1, 5-anhydro-2,3,4,6-tetra-O-allyl-D-glucitol
from the D-glucopyranosyl part of sucrose, 2,5-anhydro-l,3,4,6-tetra-O-allyl-D-mannitol
and 2,5-anhydro-l,3,4,6-tetra-O-allyl-D-glucitol from the D-fructofuranosyl moiety of

sucrose (Figure 2.21).

A possible reaction pathway was shown in Figure 2.29. Coordination of trifluoroborane
to the glycosidic oxygen forms the oxoniurn intermediate 52, which breaks down to form
the glucopyranosyl derived oxocarbenium ion 38 and fructosyl derived oxocarbenium ion
53. Similar to the triethylsilane reduction of methyl glucopyranosides, transfer of hydride
from triethylsilane to this oxocarbenium ion gives the allyl protected 1,5-anhydro-D-

glucitol 7.

64

0A11

  

o cnzoau 0“"
“"0 ‘8' BF, A" CH20AII
A1 0
OAII o cnzoau + Allo
OAII _? CHzoAll
3‘3 OAII
18 52
ON! OAII “’03"
+ AIIO
All 0 L’s“ AIIO o + 0
mo A" \ | CH20AII
can 0*" 'a's, OAII
7 38 F 53
, + AIIOHzc
O o H o
5‘39"” anomc /AIIO + | ‘-——H (‘ “'0
CH20AII BF: ? CH20A11
OAII 3F, OAII
55 54
_ KN .
F 3"“ CH20AII
“’1 + O o
AIIOH c /o ___._ “'0 “'0
2 “"0 Alionzc cnzoau t c.4202,"
CH2OAII
can
can cuzoau
56 19 20

Figure 2.19 Mechanism for reductive cleavage of Octa-O-allyl-sucrose

Reduction of the oxocarbenium intermediate 55 gave products 19 and 20. The
symmetrical 2,5-anhydro-D-mannitol derivatives 20 was formed as the major product (39

%) while the 2,5-anhydro-D-glucitol derivative 19, was obtained in 7 %.

Cellulose
The preparation of valuable chemicals from commodity carbohydrates, such as cellulose,
starch, levan, etc., has very high economic potentials and is a great challenge for

synthetic chemistry. The real test for the Allylation-Reduction-De-allylation proctol is

65

whether it can be used for the preparation of anhydroalditols from these commodity
carbohydrates. Using this protocol, 1,5-anhydro-D-glucitol, 2,5-anhydro-D-glucitol and
2,5-anhydro-D-mannitol were prepared from complex carbohydrates, such as cellulose,

starch and levan.

The appropriate solvents for the allylation of polysaccharides should be able to dissolve
or at least partially dissolve the polysaccharides and should also be able to solve the final
products. Two polar, non-protonic solvents, DMSO and DMF, were chosen as the
reaction solvents. When DMSO was used as solvent, the polysaccharides were first
dissolved in hot DMSO (65°C), followed by addition of powered NaOH and then allyl
bromide, the reaction was done in 10 h at 80°C. In this way, tri-O-allyl-cellulose was
obtained in 85 % yield while tri-O-allyl-starch and tri-O-allyl-levan were obtained in 80
% and 78 % respectively (Figure 2.10). With DMF as solvent, NaH was used as the base,
and the reaction was done in 24 h at r.t. A slightly higher yields were obtained with DMF

as solvent (tri-O-allyl-cellulose, 92%, tri-O-allyl-starch, 85 %, tri-O-allyl-levan 85 %).

For the reduction of these tri-O-allyl-polysaccharides, because all the hydroxyl groups
are protected, no ring contraction or rearrangement should occur during the reduction
process, and therefore, the only expected products are 1,5-anhydro-glucitol (from

cellulose, starch), 2,5-anhydro-D-mannitol and 2,5-anhydro-D-glucitol (from levan).

Under similar conditions as for the reduction of methyl tetra-O-allyl-glucoside, tri-O-
allyl-cellulose was reduced, however, the reaction time was much longer, it took 24 hours

for the reaction to be completely done. 13 C NMR analysis of the final product shown that

66

the anomeric carbon signals were totally disappeared. However, it also shown that the
product was a complex mixture of several compounds. It is known that for the
acetylation and alkylation of polysacchrides, it is hard to get the homogeneously
functionalized products. Although no hydroxyl group signal (3100 cm") was detected by
IR, it is still possible that part of the hydroxyl groups are un-allylated and the product
obtained contain 1,5-anhydro-D-glucitol derivatives with different degree of allylation. If
only 1,5-anhydro-D-glucitol derivatives present in the mixture, 1,5-anhydro-D-glucitol
would be obtained as the single product after de-allylation. Indeed, afier de-allylation,
1,5-anhydro-D-glucitol was obtained as the single product, and the yield for the two steps

(reduction and de-protection) is 66% (Figure 2.10).

From tri-O-allyl-starch, 69 % of 1,5-anhydro-D-glucitol was obtained as the single

product after the reduction-deprotection process (Figure 2.11).

Levan is a D-fructan of high molecular weight that is comprised of a (2—6)-linked D-
fructofuranose backbone which is branched at some of the O-l atoms. As for the
reduction of sucrose, the expected products from the fructofuranosyl units are 2,5-
anhydro-D-mannitol and 2.5-anhydro-D-glucitol. The same reaction sequences as for the
reduction of tri-O-allyl-cellulose gave the two expected product 2,5-anhydro-D-mannitol
and 2,5-anhydro-D-glucitol in the ratio of 5 to 1 and in 65 % yield after the reduction and

de-protection steps (Figure 2.12).

Table 2.3 listed the overall yields for the transformation of those commodity

carbohydrates to the corresponding anhydroalditols.

67

Table 2.3 Transformation of glycosides to anhydroalditols.

 

 

 

 

 

 

 

 

 

 

 

Yield
Commodity carbohydrates Anhydroalditols (y)
0
Me-a-D-glucopyranoside l ,5-anhydro-D-glucitol 69.7
Me-a/B-D-mannopyranoside l ,5-anhydro-D-mannitol 70.5
Me-a/B-D-ribofuranosideide l ,4-anhydro-D-ribitol 72.9
1,5-anh dro-D- lucitol
y g 38.3
Sucrose 2,5-anhydro-D-mannitol 33. 1
2,5-anhydro-D-glucitol 6.0
‘ 1,5-anhydro-D-glucitol
Cellulose 56.1
I ,5-anhydro-D-glucitol
Starch 55.2
2.5-anhydro-D-mannitol 42.3
Levan
2,5-anhydro-D-glucitol 8.5

 

 

 

 

 

2.4 Conclusion

The commercially viable transformation of commodity carbohydrates to high value
added small chiral molecules and intermediates are imperative both environmentally and
economically with the depleting of the fossil raw materials. An practical protocol for the
preparation of anhydroalditols from commercially available carbohydrates was developed.
The Allylation-Reduction-De-Allylation process transformed sucrose, cellulose, starch

and levan to 1,5-anhydro-D-glucitol, 2,5-anhydro-D-mannitol and 2,5-anhydro-D-

68

glucitol in high yields and purity. The transformation was neat and clean, no column
separation was needed for the preparation of 1,5-anhydro-D-glucitol from cellulose and
starch. The catalytic cleavage of the allyl ether with the PdCl2-CuCl2-Activated-Carbon

system makes these transformations more practical economically.

69

2.5 Experimental

General procedures: lH, '3 C NMR spectra were recorded at 500, 125, MHz, respectively,
with a Varian instrument at 293 K. The chemical shifts are given in ppm using CDCl3
residue as reference (87.24 ppm) for lH and relative to the central CDCl3 resonance (8:
77.00 ppm) for '3 C NMR unless otherwise specified. 1H and '3C are assigned on the basis
of 2D IH COSY and 1H-13 C chemical-shift correlated experiments. Melting points were
determined on a Fisher-Johns melting point apparatus (uncorrected). Optical rotations
were measured on a Jasco P1010 polarimeter at 20°C. IR spectra (wave numbers in cm")
were recorded on 3 FT IR Nicolet 740 spectrometer in CHC13 solutions or KBr pellets.
All chemicals were purchased from .Aldrich Chemical Co. and used without further

purification.

Methyl-2,3,4,6-tetra-0-ally1-a-D-glucopyranoside (6)

To a stirred solution of methyl-a-D-glucopyranoside (1.94g, lOmmol) in DMSO (50ml),
was added powered NaOH (2.72 g, 68 mmol). After stirring at r.t. for 30 min, allyl
bromide (68 mmol) was drop-wise added during a 30 min periond. Stirring was
continued for 24 h at r.t., the reaction mixture was then poured into ice-water (100ml)
and the stirring was continued for another 30 min. The mixture was extracted with Ethyl
ether(3x50ml), dried over anhydrous Na2SO4. concentrated under reduced pressure, and
the product was purified by column chromatography on silica gel. The product methyl-
2,3,4,6-tetra-allyl-ci-D-glucopyranoside 6 was obtained as a colorless oil (3.0 g, 85 % ).
[(11020 +940 (c 1, CHCl3); 'H NMR(CDC13): 5 3.34 (s, 3H, OCH3), 3.35 (dd, J = 3.4, 9.0

Hz, H-2), 3.40 (m, 1H, H-4), 3.57-3.60 (m, 3 H, H-S, H-6a, H-6b), 3.65 (t, J = 9.5 Hz, 1H,

70

 

H-3), 3.91-4.33 (m, 8H, 4 CH2 O-allyl), 4.70 (d, J = 3.4, 1H, H-l), 5.06-5.24 (m, 8H, 4
CH2 vinyl), 5.78-5.97 (m, 4H, 4 CH vinyl); l3C NMR(CDC13): 8 54.9 (OCH3), 68.3 (C-6),
69.8, 72.3, 72.4, 73.7 (4 CH2 O-allyl), 74.1, 77.2, 79.2, 81.3, 98.2 (C-l), 116.2, 116.5,
117.0, 117.4 (4 CH2 vinyl), 134.4, 134.7, 134.8, 135.2 (4 CH vinyl); IR umax (CHCl3)
(cm") 3080, 2982, 2910, 2844, 1645, 1460, 1422, 1384, 1351, 1200, 1150, 1083, 1052,
980, 920.

1,5-anhydro-2,3,4,6-tetra-0-allyl-D-glucitol (7)

To a solution of methyl-2,3,4,6-tetra-O-al1y1-a-D-glucopyranoside(2.83 g, 8.0 mmol) in
CH2C12(40 ml) at 0°C, were added Et3SiH(2.68 ml, 16 mmol), BF3OEt2(3.48 ml, 24
mmol), and CF3SO3H(50 DI), and the reaction mixture was stirred at room temperature
for 12 h. The reaction was then quenched with saturated aqueous NaHCO3(50 ml) and
extracted with CH2C12(3 x 50 ml). The combined dichloromethane extracts were washed
with water and brine, dried over anhydrous MgSO4, and concentrated under reduced
pressure. The product 1,5-anhydro-2,3,4,6-tetra-O-allyl-D-glucitol 7 was obtained as
colorless oil (2.36 g, 91 %): [(11920 +587 (c 1, CHC13); 'H NMR (CDC13): 5 3.07 (dd, J=-
10.3Hz, 11.0Hz, 1H, H-l-b), 3.23 (m, 1H, H-5), 3.28-3.31 (m, 2H, H3, H4), 3.35 (m, 1H,
H-2), 3.60 (dd, J=2.0Hz, 10.5Hz, 1H, H-6a), 3.94 (m, 1H, H-la), 3.97-4.08 (m, 5H, CH2
O-allyl), 4.23-4.30 (m, 3H, CH2 O-allyl), 5.08-5.26 (m, 8H, CH2 vinyl), 5.76-5.96 (m, 4H,
CH vinyl); l3C NMR(CDC13): 8 67.8(C-1), 68.7 (C-6), 71.7, 72.1, 73.5, 73.8 ( 4 CH2-
allyl), 77.2 (C-3 or C-4), 77.6 (C-3 or C-4), 79.0 (C-S), 85.5 (C-2), 115.9, 116.2, 116.6,
116.8 (4 CH2 vinyl), 134.3, 134.6, 134.7, 135.1 (4 CH vinyl); umax (CHC13) 3083,

3008, 2924, 2867, 1672, 1462, 1423, 1350, 1243, 1151, 1087, 997, 933 cm’1 .

1,5-anhydro-D-glucitol (8)

(a) With PdCl2 only as the catalyst: To a solution of 1,5-anhydro-2,3,4,6-tetra-O-allyl-
D-glucitol(0.l g, 0.31 mmol) in methanol(7 ml) was added PdCl2(38.5 mg, 0.22 mmol),
and the reaction mixture was stirred at 60°C for 8 h. After remove the solid and the
solvent, the product 1,5-anhydro-D-glucitol 8 was obtained quantitatively (45 mg, 100
%).

(b) With PdCl2-CuC12 catalyst system: To a solution of 1,5-anhydro-2,3,4,6-tetra-O-
allyl-D-glucitol (0.1 g, 0.31 mmol) in methanol (7 ml) was added PdCl2 (385mg, 0.22
mmol), and CuC12 (0.54 mg, 0.0031 mmol), the reaction mixture was stirred at 60°C for 8
h. After remove the solid and the solvent, 1,5-anhydro-D-glucitol 8 was in 91 % yield.

(c) With PdCl2-CuCI2-Activated Carbon catalyst system: To a solution of 1,5-
anhydro-2,3,4,6—tetra-O-allyl-D-glucitol(5.0 g, 15.5 mmol) in methanol(350 ml) was
added PdCl2(27.0 mg, 0.155mmol), and CuC12 (2.1 g, 15.5 mmol), the reaction mixture
was stirred at 60°C for 8 h. After remove the solid and the solvent, ,5-anhydro-D-glucitol

8 was in 90 % yield.

The crude 1,5-anhydro-D-glucitol was crystallized from EtOH: mp 142-143 °C; [a]DZ°
+405 (c 1, H2O); 'H NMR (1)20): 3.83(dd, 1H, J=11.2Hz, 2.6Hz,H-1’),3.73(dd, 1H,
J=13.7Hz, 1.0Hz, H-6), 3.53(ddd, 1H, J= 12.5, 4.2, 1.6, H-6’), 3.43(m, 1H, 1+2), 3.28(m,
1H, 11-3), 3.21(m, 2H, 11-4, 5), 3.12(dd, 1H, 11:12:11.0, H-l-b); 13C NMR: 60.1(C-6),

68.0(C-1), 68.5(C-2), 68.8(C-4), 76.6(C-3), 79.4(C-5).

1,3,4,6-Tetra-O-acety1-2,5-anhydro-D-glucito1.

The 1,5-anhydro-D-g1ucitol product obtained was acetylated using AC2O/Pyr for further
structural identification.

1H NMR (CDC13): 6 2.08, 2.10, 2.11, 2.12 (fours, 12 H, OAc), 4.06 (ddd, l H, H-2),
4.22-4.40 (complex, 4 H, H-1,1',6,6'), 5.00 (dd, J = 1.5, J = 3.5, 4.8, 6.3 Hz, 1 H, H-5),

4.16 (ddd, J= 3.7, 6.4, 11.3 Hz, 3.5 Hz, 1 H, H-4), 5.32 (dd, J= 1.5, 3.7 Hz, 1 H, H-3).

The Allylation, reduction and deprotection of other monosaccharides are the same as the

ones for glucoside, except that the reaction time varied.

Methyl 2,3,4,6-tetra-0-ally1-a-D-mannopyranoside (10)

The same procedure as for the preparation of methyl 2,3,4,6-tetra-O-allyl-a-D-
mannopyranoside gave methyl 2,3,4,6-tetra-O-allyl-or-D-mannopyranoside 10 as a
colorless oil (87 %): lH NMR(500 M Hz, CD3Cl): 5 3.25 (s, OMe), 3.53-3.56 (m, 1H,
H-S), 3.57-3.59 (m, 4H, H-2, H-4, H-6a, H-6b), 3.91-4.08 (m, 8H, 4 CH2 O-allyl), 4.26
(dd, J = 5.7, 11.4 Hz, 1H, H-3), 4.63 (s, 1H, H-l), 5.02-5.23 (m, 8H, 4 CH2 vinyl), 5,78-
5.88 (m, 4H, 4 CH vinyl); 13C NMR ( 125M Hz, CDC13) 8 54.5 (OMe), 69.2 (C-6), 70.9,
71.2, 71.8, 72.2 (4 CH2O-a11yl), 73.7, 74.5, 74.6, 79.3, 98.9 (C-l), 116.3, 116.4, 116.6,

117.2 (4 CH2 vinyl), 134.7, 134.8, 134.9, 135.0 (4 CH vinyl).

1,5-anhydro-2,3,4,6-tetra-0-ally1-D-mannitol (11)
The product was obtained as colorless oil (2.36g, 91 %): 1H NMR (CDC13): 3.29 (dd, J =

12.8, 1.1 Hz, 1H, H-lb), 3.32 (ddd, J = 9.5, 6.3, 2.0 Hz, 1H, H-5), 3.40 (dd, J = 9.3 Hz,

1H, H-3), 3.57(t, J = 9.7 Hz, 1H, H-4), 3.61(dd, J = 10.5, 6.3 Hz, 1H, H-6b); 3.70(dd,

73

J=10.5 Hz, 2.0 Hz, 1H, H-6a); 3.71(m, 1H, H-2); 3.98-4.06(m, 6H, H-la, CH2 O-allyl);
4.14-4.19(m, 2H, CH2 O-allyl), 4.34(m, 1H, CH2 O-allyl), 5.10-5.18(m, 4H, CH2 vinyl),
5.20-5.30(m, 4H, CH2 vinyl), 5.85-5.96(m, 4H, 4 CH vinly); '3 C NMR(CDC13): 67.1(C-
l), 69.8(C-6), 70.6, 70.7, 72.5 (3 carbon, 3 CH2 O-allyl), 72.7 (C-2), 74.1 (CH2 O-allyl),
75.2(C-4), 79.6 (C-5), 82.3 (C-3), 116.6, 116.9, 117.2, 117.5 (4 CH2 vinyl), 134.8,
134.9, 135.0, 135.1 (4 CH2 vinyl); umax (CHC13) cm'I 3080, 3010, 2928, 2865, 1674,

1459, 1424, 1355, 1244, 1157, 1087, 995, 930 cm'l .

1,5-Anhydro-D-mannitol (12)

To a solution of 1,5-anhydro-2,3,4,6-tetra-O-allyl-D-mannitol (1.0 g, 3.1 mmol) in
methanol(70 ml) was added PdCl2(6.0 mg, 0.031 mmol), and CuCl2 (0.42 g, 3.1 mmol),
the reaction mixture was stirred at 60°C for 8 h. After remove the solid and the solvent,
1,5-anhydro-D-mannitol 9 was in 92 % yield (0.47 g): mp 154-155 °C; [a]DZ°- 50.5 (c 1,
H2O); lH NMR (D20): 8 3.86 (br s, 1H), 3.80 (dd, J = 12.5, 1.5 Hz, 1H), 3.77 (dd, J =
12.5, 2.5, Hz, 1H), 3.57 (dd, J = 12.5, 6.4 Hz, 1H), 3.55-3.48 (m, 2 H), 3.46 (d, J = 9.5 Hz,
1H), 3.18 (ddd, J = 9.5, 6.5, 2.5 Hz, 1H); l3C NMR (D20): 8 82.21, 75.20, 71.48,

70.69, 68.93, 62.85.

1,S-anhydro-Z,3,4,6-tetra-O-acetyl-D-mannitol.

lH NMR (CDC13): 2.01, 2.05, 2.11, 2.17 (4 s, 12 H, OAc), 3.59 (ddd, H-la), 4.07 (dd, J
= 2.1, 13.2 Hz, 1 H, H-le), 4.14 (dd, J= 2.4, J: 2.4, 5.4, 9.9 Hz, 1 H, H-S), 3.67 (dd, J=
1.3, 13.2 Hz, 1 H, 12.3 Hz, 1 H, H-6), 4.24 (dd, J = 5.4, 12.3 Hz, 1 H, H-6), 5.06 (dd, J =

3.5, 10.0 Hz, 1 H, H-3), 5.28 (t, J = 10.0 Hz, 1 H, H-4), 5.32 (complex, 1 H, H-2).

74

For methyl D-ribofuranosides, a 01/8 mixture was used as the starting material for
reduction. The tri-O-allyl products were partially separated, and methyl 2,3,5-tri-O-ally1-
B-D-ribofuranoside was obtained while the a anomer was obtained as its mixture with the

B anomer.

Me-2,3,5-tri-0-alIyl-a-D-ribofuranoside.
13C NMR (CDC13): 8 55.0 (OMe), 70.0 (C-S), 71.2, 71.3, 71.5 ( 3 CH2 0-allyl), 75.2(C-),
77.9 (C-), 81.6 (C-), 102.0 (C-l), 116.7, 117.1, 117.3 (3 CH2 vinyl), 134.3, 134.4, 134.7

(3 CH vinyl).

Me-2,3,5-tri-0-allyl-B-D-ribofuranoside

lH-NMR 8 3.26 (s, 3H, OMe), 3.42 (dd, J = 5.9, 10.8 Hz, 1H, H-Sa), 3.50 (dd, J = 4.0,
10.7 Hz, 1H, H-Sb), 3.72 (d, J = 4.7’Hz, 1H, H-2), 3.86 (dd, J = 4.5, 7.5 Hz, 1H, H-3),
3.95-4.00 (m, 4H, 2 CH2 0-ally1),4.03-4.06(m, 2 H, CH2 O-allyl), 4.12 (ddd, J = 4.3, 6.0,
10.7 Hz, 1H, H-4), 4.79 (s, 1H, H-l). 5.05-5.24(m, 6H, 3 CH2 vinyl), 5.74-5.89(m, 3H, (3
CH vinyl); l3C NMR(CDC13): 8 54.7 (OMe), 71.2 (3 carbon, 3 CH2 O-allyl), 71.9 (C-5),
78.1, 79.5, 80.1, 106.1 (C-l), 116.5, 117.1, 117.2 (3 CH2 vinyl), 134.1, 134.2, 134.5(3

CH vinyl).

l,4-anhydro-2,3,5-tri-0-allyl-D-ribitol (15)
Reduction of pure methyl-2,3,5-tri-O-allyl-B-D-ribofuranoside and a mixture of

01/13 anomers gave the same product 1,4-anhydro-2,3,5-tri-O-a11yl-D-ribitol 15 as a

75

colorless oil in 90 % yield: lH-NMR 8 3.44 (dd, J = 4.4, 10.8 Hz, 1H, H-Sa), 3.54 (dd, J
= 3.5, 10.7 Hz, 1H, H-Sb), 3.81 (t, J = 5.6 Hz, 2H, H-), 3.92-4.03 (m, 8H, 3 CH2 0-
allyl), 4.08 (m, 1H, H-S), 5.08-5.26(m, 6H, 3 CH2 vinyl), 5.78-5.91(m, 3H, 3 CH vinyl);
l3C NMR(CDC13): 8 69.9, 70.4, 70.8, 71.1, 72.2, 76.4, 78.1, 80.1, 116.7, 117.1, 117.2 (3

CH2 vinyl), 134.3, 134.4, 134.4(3 CH vinyl).

1,4-anhydro-D-ribitol (16)
De-allylation of l,4-anhydro-2,3,5-tri-O-ally1-D-ribitol gave 1,4-anhydro-D-ribitol 16 in
89 % yield: mp 101-102 °c ; [011920 +63.0; 'H-NMR (1320) a 3.45 (m, 2 H, 115, H-S’),

3,63 (m 3 H), 3.89 (m, 2 H), 4.09 (m, l H); l3C NMR (D20) 8 61.5, 71.2, 71.7, 72.4, 81.7.

1,4-anhydro-2,3,5-Tri-0-acetyl-D-ribitol.

lH NMR (CDC13): 8 2.08, 2.09, 2.10( 3 s, 9 H, OAc), 3.87 (dd, J = 3.9, 10.3 Hz, 1 H,
H-la), 4.12 (dd, J = 5.0, 11.3 Hz, 1 H, H-S), 4.16 (complex, 1 H, H-4), 4.23 (dd, J = 5.2,
10.3 Hz, 1 H, H-lb), 4.33 (complex, 1 H, H-S'), 5.13 (complex, 1 H, H-3), 5.37 (dt, J =
3.9, 5.3 Hz, 1 H, H-2); l3C NMR(CDC13): 8 19.9, 20.0, 20.0 (3 Me from Ac), 61.0, 61.2

(C-1 and C-5), 67.4(C-2), 68.5, 68.6 (C-3 and C-4), 169.0, 169.2, 169.6(3 Ac)

Octa-O-allyl-sucrose (18)

In a 250 m1 round bottom flash was added NaH (60 % in mineral oil, 6.7 g, 140 mmol),
after washing with hexanes (3 x 20 ml), DMSO (150 ml) was added, followed by
addition of a solution of sucrose (3.0 g, 8.77 mmol)1 in DMSO (30 ml). Water bath was

used to control the temperature of the reaction mixture below 45°C. After stirring for 1 h,

allyl bromide (9.2 ml, 105 mmol) was drop wised added over 30 min period, with water
bath to control the temperature below 50°C. After stirring at 45°C for 12 h, the
reaction mixture was poured into cold water, and extracted with diethyl ether (4 x 70 ml).
The combined organic layer was washed with water (3 x 100 ml), brine (3 x 100ml) and
then dried over anhydrous sodium sulfate. After filtration and removal of the solvent
under reduced pressure, a colorless oil (5.9 g) was obtained. NMR shown the product was
the desired octa-O-allylsucrose with > 96 % purity (85 % yield). Small amount the raw
product was further purified by flash column (Hexanes/Ethyl Acetate: 1/9) for
characterization purpose. [00020 + 58.0° (c 1.00, EtOAc); lH-NMR 8 3.25 (dd, J = 3.9, 9.7
Hz, 1H, H-2), 3.34 (dd, J = 6.4, 9.1 Hz, 1H, H-4), 3.41 (s, 1H, H-lb’ ), 3.52-3.62 (m, 6 H,
H-3, H-6a, H-6b, H-l’a, H-6’a, H-6’b), 3.87 (m, 1H, H-5’), 3.91-3.96(m, 5 H, H-5, 2 CH2
O-allyl), 3.98 (m, 2 H, CH2 O-allyl), 4.00(m, 3 H, H-4’, CH2 O-allyl), 4.04-4.06(m, 4
H, 2 CH2 O-allyl), 4.11-4.18(m, 4 H, 2 CH2 0-ally1), 4.22-4.30(m, 1H, H-3’), 5.14-5.30
and 4.98-5.13 (m, 16H, CH2 vinyl), 5.49(d, J = 3.8 Hz, 1H, H-l), 5.74-5.94 (m, 8H,
CH2 vinyl); 13C NMR(CDCI3): 8 68.4 (C-6), 70.2 (C-5), 70.6 (C-l’), 71.2 (CH2-3’ 0-
allyl), 71.5 (CH2-4’ 0-allyl), 71.5 (CH2-2 O-allyl), 71.9 (C-6’), 71.9 (CH2-6’ O-allyl),
72.2 (CH2-6 O-allyl), 72.2 (CH2-1’ O-allyl), 73.5 (CH2-4 O-allyl), 73.9 (CH2-3 O-allyl),
76.9 (C-4), 79.2 (C-2), 79.4 (C-5’), 81.1 (C-3), 82.2 (C-4’), 83.3 (C-3’), 89.9 (C-l), 104.3
(C-2‘), 116.0, 116.2, 116.2, 116.5, 116.5, 116.6, 116.7, 116.8, (8 CH2 vinyl), 134.4, 134.5,

134.6 (3 carbon), 134.8, 135.0, 135.4, (s CH vinyl).

Reduction of Octa-O-allyl-sucorse
To a solution of Octa-O-al'lyl-sucrose 18 (3.31 g, 5.0 mmol) in CH2C12 (40 ml) at 0°C,

were added Et3SiH (3.35 ml, 20 mmol), BF30Et2 (4.35 ml, 30 mmol), and CF3SO3H (60

77

01), and the reaction mixture was stirred at room temperature for 12 h. The reaction was
then quenched with saturated aqueous NaHC03 (50 ml) and extracted with CH2Cl2 (3 x
50 ml). The combined dichloromethane extracts were washed with water and brine, dried
over anhydrous MgS04, and concentrated under reduced pressure. Flash column

chromatography gave three products 7, 19 and 20.

l,5-anhydro-2,3,4,6-tetra-0-allyl-D-glucitol (7): 45 % yield, gave the same spectra data

as the product from reduction of methyl 2,3,4,6-tetra-O-allyl-a-D—glucopyranoside.

2,5-anhydro-l,3,4,6-tetra-0-allyl D-mannitol 20: 39% yield, [91620 + 26.4° ( c 1.00,
CHC13); lH-NMR 8 3.48 (dd, J = 4.3, 5.8 Hz, 4H, H-la, H-lb, H-6a, H-6b), 3.88 (dd, J =
1.4, 2.5 Hz, 2H, H-3, H-4), 3.95-3.99 (m, 8H, 4 CH2 O-allyl), 4.03-4.06 (m, 2H, H-2,
H-S), 5.08-5.12 (m, 4H, CH2 vinly), 5.18-5.24 (m, 4H, CH2 vinly), 5.78-5.86 (m, 4H, CH
vinly); l3C NMR(CDC13): 8 70.0 (2 carbon, C-1, C-6), 70.5 (2 carbon, CH2 O-allyl), 72.1
(2 carbon, CH2 O-allyl), 81.4 (2 carbon, C-2, C-5), 84.6 (2 carbon, C-3, C-4), 116.7 (2
carbon, 2 CH2 vinyl), 116.8 (2 carbon, 2 CH2 vinyl), 134.2 (2 carbon, 2 CH vinyl),
134.5 (2 carbon, 2 CH2 vinyl); Anal. Calcd for C18H2805: C, 66.64; H, 8.70. Found: C,

66.56; H, 8.62.

2,5-anhydro-D-mannito1 (22): [61020 +522 °( c 1.00, H20); M.p. 100-102 °C; 'H

NMR (D20): 8 3.68 (dd, J1 = J2 = 5.6 Hz, 2H. H-lb, H-6b), 3.78 (dd, J = 3.1, 12.4 Hz,

78

2H, H-la, H-6a), 3.90(m, 2H, 11-2, 11-5), 4.05(m, 2H, H-3, H-4); l3c NMR(CDC13):

8 61.3 (2 carbon, C-1, C-6), 76.6 (2 carbon, C-3, C-4), 82.4 (2 carbon, C-2, C-5).

1,3,4,6-Tetra-0-acetyl-2,5-anhydro-D-mannitol: [a][22° + 26.5 °( c 1.00, CHC13); 1H
NMR (CDCl3): 8 2.11 (s, 12 H, 4 OAc), 4.25 (s, 6 H, H-la,1H-1b, H-2, H-5, H-6a, H-
6b), 5.16 (ss, 2 H, H-3, H-4); ”C NMR(CDC13): 8 21.2 (4 carbon, CH3 OAc), 63.4 (2
carbon, C-1, C-6), 78.5 (2 carbon, c3. 04), 81.4 (2 carbon, c.2, 05), 170.3 and 171.0

(2 carbon, C=O Ac).

2,5-anhydro-l,3,4,6-tetra-0-allyl D-glucitol (19) 7 % yield,

lH-NMR 8 3.46 (m, 4 H, H-la, H-lb, H-6a, H-6b), 3.90 (m, 2H, H-3, H-4), 3.93-3.99 (m,
8H, 4 CH2 O-allyl), 4.00-4.05 (m, 2H, H-2, H-S), 5.07-5.12 (m, 4H, CH2 vinly), 5.19-
5.25 (m, 4H, CH2 vinly), 5.79—5.86 (m, 4H, CH vinly); l3C-NMR 8 70.2( C-l or C-6),
70.4 (C-l or C-6), 70.5, 70.9, 72.0, 72.9 (4 CH2 0 allyl), 75.3, 79.0, 83.1, 83.7, 116.1,

1 16.6, 116.7, 117.0 (4 CH2 vinyl), 134.4, 134.7, 134.9, 135.3 (4 CH vinyl).

2,5-Anhydro-D-glucitol (21)

lH NMR (D20): 8 3.68 (dd, J = 12.1, 6.0 Hz, 1H, H-l), 3.73 (dd, J = 7.0, 11.8 Hz, 1H, H-
6), 3.77 (dd, J = 3.8, 12.1 Hz, 1H, H-l’), 3.82 (dd, J = 4.3, 11.8 Hz, 1H, H6’), 3.84 (ddd,
J = 3.7, 4.3, 6.0 Hz, 1H, H-2), 4.01 (dd. J —- 2.4, 4.3 Hz, 1H, H-3), 4.12 (dt, J = 4.4, 7.0
Hz, 1H, H-5), 4.17 (dd, J = 2.5, 4.3 Hz, 1H, H-4); l3C-NMR(D20): 8 60.7, 62.3 (C-l, C-

6), 77.5, 78.6, 81.5, 85.2 (C-2, C-3, C-4, C-5).

79

General method for the preparation of tri-O-allyl-polysaccharides:

Unprotected polysaccharide(1.0 gram) was dissolved in DMSO (50ml) at 60 °C, NaH (60
% in mineral oil, 5.84g, 122 mol, 5 mol/mol hydroxlyl group) was added to this after
washing with hexanes (3 x 20 ml). Afier stirring at r.t for 1 h under nitrogen atmosphere,
allyl bromide (10.7 ml, 122 mmol) was drop wised added over 30 min period, with water
bath to control the temperature below 50°C. After stirring at r.t. for 12 h, the reaction
mixture was poured into cold water, and extracted with chloroform (4 x 50 ml). The
combined organic layer was washed with water (3 x 100 ml), brine (3 x 100ml) and then
dried over anhydrous sodium sulfate. After filtration and removal of the solvent under
reduced pressure, the tri-O-allyl-polysaccharides were obtained as a syrup.

General method for the reduction of tri-O-allyl-polysaccharides:

The methods for the reduction of tri-O-allyl-polysaccharides are the same as for

monosaccharides, except longer times (24 h) were needed for the reduction to complete.

Tri-O-allyl-cellulose (24) .

85 % yield for allylation: 1H NMR (CDCl;): 8 3.14 (br, 1H), 3.54 (br, 1H), 3.84-4.00
(br, 2H), 4.12 (br,lH ), 4.16-4.30 (br, 1H), 4.49-4.64 (br, 8H, 4 CH2 O-allyl ), 4.93-5.27
(br, 9H, H-1, 4 CH2 vinyl), 5.66-5.93 (br, 4H, 4 CH vinyl); '3 C NMR(CDCl3): 8 69.2 (br,
C-6), 73.3 (br, C-S), 75.2-76.0 (br, CH2 O-allyl), 76.1 (br. C-3), 82.3 (br, 02), 84.2 (br,
C-4), 102.9 (br, C-l), 116.3-117.0 (br, CH2 vinyl), 134.9-135.5 (br, CH vinyl);

Reduction-deprotection steps gave 1,5-anhydro-D-glucitol in 66 % for 2 steps.

Tri-O-allyl-starch (26)

80

85 % yield for allylation: : IH NMR (CDC13): 8 3.32 (br, 1H), 3.55 (br, 1H), 3.65 (br,
1H), 3.85-4.28 (br, 12 H, H-1, 4 CH2 O-allyl ), 5.00-5.23 (br, 8H, 4 CH2 vinyl), 5.60—
5.85 (br, 4H, 4 CH vinyl); l3C NMR(CDC13): 8 68.2(br, C-6), 70.0(br, C-5), 72.0-72.4
(br, 4 CH2 0-allyl), 73.1 (br, C-3), 79.5 (br, C-4), 81.4 (br, C-2), 116.2-117.0 (br, CH2
vinyl), 134.7-135.8 (br, CH vinyl);

Reduction-deprotection steps gave 1,5-anhydro-D-glucitol in 65 % for 2 steps.

Tri-O-allyl-levan (28)

78 % yield for allylation: 'H NMR (CDC13): 8 3.42-3.58 (m, 2H, H-6a, H-6b), 3.79-
3.94(m, 2H, H-3, H-4), 4.02-4.44(m, 11H, H-la, H-lb, H-5, 4 CH2 O-allyl), 5.18-5.55(m,
8H, CH2 vinyl ), 5.84-6.12(m,' 4H, CH vinyl); 13C NMR(CDC13): 8 62.2(br, C-6),
71.0(br), 71.1(br), 72.2(br), 72.3(br, 4 CH2 O-allyl), 72.3(br, C-5), 78.0(br, C-l), 82.1(br,
C-4), 83.9(br, C-3), 103.8(br, C-2), 116.4(2 CH2 vinyl ), 116.7(2 carbon CH2 vinyl),
134.5, 134.7, 134.8, 135.0(4 CH vinyl).

Reduction-deprotection gave 2,5-anhydro-D-mannitol (54.2 %), 2,5-anhydro-D-glucitol

(10.8 %).

81

2.6 Reference

[11

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[3]

[41
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85

Chapter 3

Advanced Derivatives of 1, 5-Anhydro-D-Glucitol

86

Abstract

Anhydroalditols and their derivatives are considered metabolically inert for lacking the
C1 hydroxyl group. The glucose 6-phophate analogue 1,5-Anhydro-D-glucitol 6-
phosphate is widely used as a hexokinase inhibitor in the study of enzyme mechanisms
and as a probe to study carbohydrate metabolic pathways. Recently, deoxy
anhydroalditols have been used in the construction of biologically important molecules,
such as anhydrohexitol nucleosides, which showed activities against herpes simplex
virus, Sialyl Lewisx analogues as potent E-selectin inhibitors. They have also been used
in the preparation of catalysts for enantioselective cyanation of ketones. With the easily
available anhydroalditols through the reductive cleavage of complex carbohydrates, these
anhydroalditols and deoxy anhydroalditols can be easily prepared. From 1,5—anhydro-D-
glucitol, l,5-Anhydro-D-glucitol—6-phosphate was prepared from 1,5-anhydro-D-glucitol
in two steps in over 60 % yield. The important deoxy-anhydrohexitols, which are
components of E-selectin inhibitors, scaffolds of anhydrohexitol nucleosides and chiral

catalysts, were also prepared from 1,5-anhydro-D-glucitol efficiently.

87

3.1 Introduction

3.1.1 Glycolysis and l,S-anhydro-D-glucitol-6-phosphate

Glycolysis is a catabolic pathway in the cytoplasm that is found in almost all organisms-
irrespective of whether they live aerobically or anaerobically]. During glycolysis, glucose
is oxidized to either lactate or pyruvate. Figure 3.1 lists the substrates and enzymes for
the first several steps of glycolysis and the corresponding anhydrosugars as the substrate
analogues. The first step of glycolysis is the ATP-dependent phosphorylation of glucose
to form glucose 6-phosphate catalyzed by the isoenzymes known as hexokinases. The
phosphorylation of glucose accomplishes two goals: First, nonionic glucose was
converted into glucose 6-phosphate (G6P), an anion that is trapped in the cell, since cells
lack transport systems for phosphorylated sugars. Second, the otherwise biologically inert

glucose becomes activated into a labile form capable of being further metabolized.

The second reaction of glycolysis is an isomerization, in which G6P is converted to
fructose 6-phosphate (F6P). The enzyme catalyzing this reaction is glucose 6-phosphate
isomerase. The reaction is freely reversible at normal cellular concentrations of the two
hexose phosphates and thus catalyzes this interconversion during glycolytic carbon flow

and during gluconeogenesis.

88

P\

 

0" hexokinase O'P gulcose-S—phophate O 0 OH
H O glucoklnase isomerase HO
—-—D
910 11% 0 fi’ OH
OH OH O 0”
0H 0H
1 2 3
’P
0H 0
0
o = .-
"iifiK/(a "1334 " ”3”:
0H 0H
_ 1 .5-anhydro-D-glucitol
1 ,5-anhydro-D—glucitol 6—phosphate
4 5

Figure 3.1 Anhydrosugars as substrate analogues in carbohydrate glycolysis.

Substrate analogues are useful tools in the study of enzyme catalyzed reaction
mechanisms. Such analogues could help in the identification of the active substrate
conformation or configuration or in the stabilization of reaction intermediates. Thus
changes of the substrates during the enzyme catalyzed reactions could be identified at
molecular level. Some sugar metabolizing enzymes have been studied using this methodz'
4.

1,5-Anhydro-D-glucitol 4 and 1,5-anhydro-D-glucitol 6-phosphate 5 are the analogue of
D-glucose l and D-glucose-6-phosphate 2. Because 4 and 5 lack a hydroxyl group at the
C1 position of the pyranose ring, they are considered to be metabolically inert. 1,5-
Anhydro-D-glucitol 6-phosphate 5 is widely used as a hexokinase inhibitor in the study

of enzyme mechanisms and as a probe to study carbohydrate metabolic pathwayss'w.

3.1.2 Deoxy anhydroalditols: application in construction of biologically important

molecules and chiral catalysts

89

Deoxysugars are carbohydrates in which one or more of the normally occurring oxygen
atoms are deleted (i.e., replaced by hydrogen atoms) or replaced by any other heteroatom
or heteroatomic group, such as sulfur (thiosugars), halogen, nitrogen (aminosugars) or

NO,( (nitro- and nitrososugars)I '.

Many of those naturally occurring deoxysugars have been shown to serve as ligands for
cell-cell interactions or as targets for toxins, antibodies, and microorganisms'z'w. The
replacement of one or more hydroxyl groups in these sugars by various functionalities
generally induces fundamental changes in the chemical properties of the resulting
monosaccharides and, therefore, has a direct bearing on the wide range of their biological
activities”. Deoxysugars are also frequently found in the secondary metabolites of
microorganisms and plants, such as cardioglycosides, antibiotics, and anticancer agents”.
These sugar residues play crucial roles in conferring optimal biological activity for many
natural products. Their removal often results in the loss of all biological activity of the
parent compounds”.

Recently, another class of deoxysugars, the deoxy 1-deoxy sugars, or deoxy
anhydrosugars, has been used in the construction of molecules which have important

biological functionsZO'23 .

90

C02Na Sialy Lewis"

0 0“” relative 1050 (E-Sel) = 1.0
W00 0 1 .. 2 _ _
OH 6 R - Me R — H 1c50 — 0.020

0“ no 7 1::1 = H R2 = H 1050 = 0.305
R1 0H 8 R1 = Me R2 = Bz IC5O = 0.010
9 R1 = H R2 = 82 1050 = 0.090

COOH

k on
0W0
go 10 R=H IC50>5
0H %J Ho 11 R =32 1c50=0290
0 OH
OH OH

Figure 3.2 Sialyl Lewis" analogues as potent E-selectin inhibitors.

Sialyl Lewis" is a tetrasaccharide which is a weak E-selectin inhibitor (KD = 1060 uM), it
is a lead structure in the identification of simplified but more-potent selectin
antagonistszo'zz. Thoma and co-workers prepared the simplified Sialyl Lewis" analogues
6-11, which contain a 1,5-anhydro-2-deoxy-D-glucitol building block (Figure 3.2)20'22.
The much simplified trisaccharides showed enhanced inhibitory properties against E-
selectin. The most potent compound is 8, which is lOO-fold more potent than Sialyl

Lewis" in the binding assay and has an ICso value of 1-2 UM in a cell-based in vitro flow

assay.
0
R

""JE/ 12 R=l 15 R= J.,-é )\

0%" 13 R=Cl S
o 1‘ R=CF3 17 R: -§-cscn

15 R: g—CH2CH2
HO _ - _. : _
Ho 16 R- E C—0 CH3

Figure 3.3 Anhydrohexitol Nucleosides

91

Recently, a series of anhydrohexitol nucleosides (compounds 12-18, Figure 3.3) are
prepared and tested against herpes simplex virus (HSV)23. The trifluoromethyl, vinyl, and
propynyl analogues 14,. 15 and 18 showed potent activity against HSV. The selectivity

index for 15 is large than 16000 against HSV-l and larger than 1000 against HSV-2.

The deoxy anhydroalditols have also been used as scaffold for the construction of catalyst

for enantioselective cyanosilylation of ketones. High yields and ee’s were obtained for

24,25

we,

. ...{y
<5

aryl ketones (Figure 3. 4)

 

19
O 19
0
)L + TMSCN THF. -20 c.0611= 1113ch
Ph CH: 92 0/0 YIBId Ph CH;
94 % ee

Figure 3.4 Deoxy anhydroalditols based chiral catalysts

Although these anhydroalditols derivatives have been used extensively, no general route
is available for their preparation. With the easily available anhydroalditols through our
reduction method as discussed in chapter 2, these anhydroalditols derivatives can be

easily prepared.

92

3.2 Preparation of 1,5-anhydro-D-glucitol-6-phosphate

With 1,5-anhydro-D-glucitol in hand, 1,5-Anhydro-D-glucitol 6-phosphate was easily

prepared in several steps (Figure 3.5).

on 01101091112
011 C
b
110 o a Pin/\Bo o H O _, Ho 0
H PIVO Pl ”V
0Plv
0H OPIV OPIV
4 20 21 22
ll
0, (0.. ii 1

0H
"$3 “—8—" HH‘%L ”fir
P H0
OPIV

Figure 3.5 Preparation of 1,5-Anhydro-D-glucitol 6-phosphate

(a) l). PhCH(OMe)2, p-TsOH, DMF; 2). PivCOCl, Pyr, 83 %, 2 steps; (b). EtOH-H2O-
CF3C00H, 85%; (c). (Ph0)2P0Cl/Pyr, 62%; ((1). H2, Pt02, MeOH, 100%; (e). NaOMe,
MeOH, 83%; (f). NH3, 100%.
The 4,6-hydroxy groups were first protected with benzylidene by treatment of 1,5-
anhydro-D-glucitol 4 with benzaldehyde dimethyl acetal in DMF. The 2 and 3 hydroxy
groups were then protected with pivolyl groups to afford the fully protected 1,5-anhydro-
D-glucitol derivative 20. Treatment of 20 with EtOH-H20-CF3C00H (60:8:1) gave
compound 21 with 4, 6 hydroxyl groups freed. Phosphorylation of 21 using
(PhO)2P(0)C1 in pyridine was selective among the primary and secondary hydroxyl

groups and gave the protected phosphate ester 22. The final product 19 was obtained

93

from 22 by first removing the Ph group using H2/Pt02 and then removing the pivolayl
group using NaOMe/MeOH. Because 19 is a strong acid, it was converted to its ammonia

salt 24 by treatment with ammonia.

o
1' 0..
0H 01:0(01311)2 0’ \OH
1'10 0 a 1'10 0 0 H0 0
1'10 H0 1'10
0H OH OH
4 25 19

Figure 3.6 Preparation of 1,5-Anhydro-D-glucitol 6-phosphate using the direct

phosphorylation method. (a) (PhO)2P0Cl/Pyr; (b) H2, Pt02, MeOH.

Because (PhO)2P(0) is a sterically demanding reagent, it is expected that under
controlled conditions, the selective mono-functionalization of 4 is possible. Thus, the
direct transformation of 4 to 25 was attempted (Figure 3.6). Treatment of 4 with 1
equivalent of (PhO)2P(0)Cl in pyridine gave the protected 6-phosphate 25 in 60 %
isolated yield. Deprotection of 25 using H2/Pt02 gave 19 directly in quantitative yield.
Compared to the method in figure 3.5, this method is more straightforward, and 1,5-
anhydro-D-glucitol-6-phosphate 19 was prepared in two steps in 60 % overall yield from

1,5-anhydro-D-glucitol 4.

3.3 Preparation of Deoxysugars from 1, 5 —anhydro-D-g1ucitol

3.3.1 Formation of 2,3-anhydro derivatives of 1,5-anhydro-D-glucitol

94

The 2,3-anhydro derivatives 27 and 28 can be easily prepared from 26 since the 2, 3
hydroxyl groups are anti to each other. Transforming one of the hydroxyl groups to a
good leaving group followed by an intramolecular attack from the other free hydroxyl

group will form the 2,3-anhydro derivatiesz°'29.'

0H
PIC/m 3 Ph 09% b 27
H0 0 HO OH Fri/29%
4 25 Minor

0
28

Figure 3.7 Preparation of 4,6-benzylidene-2,3-epoxide derivatives of 1,5-anhydro-D-
glucitol (a) PhCH(OMe)2, stOH, DMF, r.t. 12 h, 82 %; (b.) Ph3P, DIAD, THF,

60°C, 12 h, 72 %, 27/28 2.1/1

Reaction of 4 with benzaldehyde dimethyl acetal in DMF with catalytic amount of p-
Ts0H gave 4,6-0-benzylidene protected derivative 26 in 82 % yield. Treatment of 26
under Mitsunobu conditions (Ph3P, DIAD) at room temperature for 24 hour gave no
product. Raising the reaction temperature to 60°C, the reaction was done in 12 hour.
Compound 27 with manno configuration was formed as the major product in 48.8 % and

compound 28 with allo configuration was formed as the minor product in 23.2 % (Figure

3.7).

The mechanism for formation of 127 and 28 is shown in figure 3.8. Formation of the
triphenylphosphonium intermediate 29 followed by intramolecular attach by 3-0H gave
27, while formation of the triphenylphosphonium intermediate 30 at 3-0H followed by

intramolecular attach by 2-0H gave 28. In intermediate 30, there is a very severe steric

95

interaction between the triphenylphosphonium ion and the 4,6-0-benzylidene ring, while

in 29, this steric interaction is greatly reduced.

 

n’?0
——> °g°4 " ' P" 59% Meter
H o O
27

 

+1396,
Ph’voo o Ph3P,D|AD 29
Ho 0
911’ Y‘
0” Ph’VS’A/o _. 0 °
26 o w Minor
9 OH O
Ph3Pi’ K/ 28

30

Figure 3.8 Mechanism for the formation of 2,3-anhydro derivatives under Mitsunobu

conditions.

(p-Tolylsulfonyl)imidazole (Ist) has also been used in the construction of 1,2 anhydro
sugars from 1,2 diols in carbohydrates. With Ist, the separation of the products from
the reaction mixture is easier compared to Ph3P/D1AD3°'33. For substrate 26, another
advantage using Ist is that formation of epoxides 27 and 28 can be controlled by the
reaction conditions. If Ist was added immediately after adding NaH (2.2 equivalent), a
mixture of 27 and 28 was obtained in 67 % yield (27/28 3/1). While if 26 was treated
with NaH (2.2 equivalent) for 2 hour and then adding Ist, only 27 was obtained and the

yield is very high (86 %).

The different results came from the formation of either monoalkoxide or dialkoxide
derivative of 26. After adding NaH, the C-2 or C-3 monoalkoxide (31 or 32) was formed
at first. If adding Ist at this time, a mixture of 02 or C-3 tosylate was formed and thus
the final products were obtained as mixture of 27 and 28. However, if adding Ist after

the dialkoxide 33 was formed, the formation of C-2 or C-3 tosylate was controlled by the

96

steric effect, and the more sterically favored C-2 tosylate was formed. Once the C-2
tosylate was formed, it immediately transformed to product 27 since the C-3 alkoxide is

already formed.

PH’E§%§_. lst "(29%
27

 

 

 

lib/29m NaH _’ Flt/YrfiA—fi lst ”(39%
O

0
H
OH 28

——’ "Tea ”freq

27

28

 

Figure 3.9 F orrnation of 2.3-anhydro derivatives using NaH/Ist.

3.3.2 Preparation of deoxyanhydrohexitols

From the 4,6-0-benzylidene-2,3-anhydro derivatives, the 2 or 3 deoxy derivatives 34 and
35 were prepared. Reduction of 27 with LAH gave compound 4,6-0-benzylidene-3-
deoxy-1,5-anhydro-D-mannitol 34 exclusively in 96 % yield with the delivery of the

hydride to the axial position.

 

 

OH
Pn/Yfifi LAH, E120 2 "(3% H2. Pd/C ”%E
7 HO

r, 1 n r.t 12 h

 

o o 100 %

27 '6 /° 34 36

o LAH, E! 0 H2. Pd/C H
Ph 0% 2 : Ph 00 o —-—> "o O
r.t 12 h
o r.t1 h

95 % 10° % 0H

28 35 37

97

Figure 3.10 LAH reduction of 2,3-anhydro derivatives to form deoxy anhydrohexitols

Similarly, 1,5-anhydro-4,6-O-benzylidene-2-deoxy-D-allitol 35 was prepared in 95 %
yield from 28 (Figure 3. 10). Deprotection of the protecting group in 34 and 35 gave the

free deoxy anhydrohexitols 36 and 37 in quantitative yield.

3.4 Conclusion
Important anhydroalditol derivatives were prepared efficiently from the anhydroalditols.

1,5-Anhydro-D-glucitol —6-phosphate, the inert analogue of D-glucose-6-phosphate, was
prepared from 1,5-anhydro-D-glucitol in two steps in over 60 % yield. The important
deoxy-anhydrohexitols, which are components of E-selectin inhibitors, scaffolds of
anhydrohexitol nucleosides and chiral catalysts, were also prepared from 1,5-anhydro-D-

glucitol efficiently.

98

3.5 Experimental
General Procedures

lH, '3 C NMR spectra were recorded at 500, 125, 121 MHz, respectively, with a Varian
instrument at 293 K. The chemical shifts are given in ppm using CDC13 residue as
reference (57.24p) for 1H and relative to the central CDCl3 resonance (5: 77.00p) for 13C
NMR unless otherwise specified. 31P NMR chemical shifts are given in ppm with H3PO4
as an external reference. 1H and '3C are assigned on the basis of 2D lH COSY and 1H-
'3 C chemical-shift correlated experiments. Melting points were determined on a melting
point apparatus (uncorrected). Optical rotations were measured on a Jasco P1010
polarimeter at 20°C. IR spectra (wave numbers in cm") were recorded on a FT IR Nicolet
740 spectrometer in CHC13 solutions or KBr pellets. All chemicals were purchased from

Aldrich Chemical Co. and used without further purification.

1,5-Anhydro-2,3-dipivolyl-4,6-O-benzylidene-D-glucitol (20)

To a solution of 1,5-anhydro-glucitol 4 (0.984g, 6.0mmol) in anhydrous DMF, were
added benzaldehyde dimethyl acetal( 1.65ml, 12.0mmol), sulfuric acid(98%, 45ul). The
mixture was stirred overnight under N2 atmosphere. After adding anhydrous pyridine
(1.0ml) and stirring for 10 minutes, methanol was removed under reduced pressure. The
mixture was cooled to 0°C, then anhydrous pyridine (9.7ml, 120mmol), and pivaloyl
chloride (2.22ml, 60mmol) were added. After stirring at room temperature for 24hr, water
and chloroform were added, the organic layer was separated, and the aqueous layer was
dried over anhydrous Na2804. After remove the solvent, the residue was crystallized

from Hexane-Ethyl acetate to give 20 (2.1g, 83%): [(11020 +192 (c l, CHC13); lH NMR

99

(500 MHz, CDC13): 6 l.14(s, 9H, tBu); 1.16(s, 9H, tBu), 3.36(dd, 1H, J1=J2=10.7 Hz, H-
l-b), 3.47(dd, 1H, J=9.7 Hz, 4.9 Hz, H-6-b); 3.65(dd, 1H, J1=J2=9.7 Hz, H-4), 3.69(dd,
1H, J1=J2=10.4 Hz, H-6-a), 4.09(dd, 1H, J=8.4 Hz, 5.9 Hz, H-l-a), 4.33(dd, 1H, J=7.7
Hz, 5.0 Hz, H-5), 5.03(ddd, 1H, J1=J2=8.2Hz, J3=5.6Hz, H-2), 5.35(dd, 1H, J=9.7Hz,
9.7Hz, H-3), 5.50(s, 1H, PhCHO), 7.40(m, 5H, H-arom); 13C NMR: 27.1, 38.8, 67.5(C-
1), 68.6(C-5), 69.3(C-2), 71.3(C-4), 71.9(C-3), 79.1(C-6), 101.0, 125.8, 1289.1, 128.8,
136.9, 177.2,177.4; omax (KBr) 3072, 2973, 2935, 2873, 1731, 1602, 1585, 1481, 1454,
1284, 1168, 1101, 709. Anal. Calcd for C23H3207: C, 65.70; H, 7.67. Found: C, 65.50;

H, 7.49

1,S-Anhydro-2,3-dipivolyl-D-glucitol (21)
A solution of 20 (1.68g, 4.0mmol) in EtOH-H20-CF3COOH (60:8:1, 50ml) was stirred at
room temperature for 24hr. The mixture was concentrated. Column chromatography of

the residue on silica gel using EtOAC-Hexane 1:1 as eluant afforded the desired product
1,5-anhydro-2,3-dipivolyl-glucitol 21 (1.11 g, 85%): mp 84-85°C; MD” +493 (0 1,
CHC13); 1H NMR (500 MHz, CDC13): 6 1.13(s, 9H); 1.17(s, 9H), 3.26(dd, J=10.5 Hz,
1H, H-l-a), 3.33(ddd, J1=12=9.6 Hz, J3=4.5 Hz, 1H, H-5), 3.65(dd, J 1=J2=9.0 Hz, 1H,
H-1-4), 3.78(dd, J=4.5 Hz, 12.0 Hz, .1 H, H-6-b), 3.90(dd, J=3.0 Hz, 12.0 Hz, 1H, H-6-a),
4.05(dd, J=5.4 Hz, 10.8 Hz, 1H, H-l-b), 4.94(ddd, J 1=JZ=11.4 Hz, J3=5.7, 1H, H-2),
5.04(dd, J1=J2=9.6Hz, 1H, H-3); 13C: 27.1, 38.8, 39.0, 62.2, 66.8, 68.8, 69.9, 76.6, 80.4;
omax (KBr) 3380, 2976, 2973, 2873, 1739, 1286, 1174, 1153; Anal. Calcd for

C16H2807: C, 57.82; H, 8.49. Found: C, 67.30; H, 8.10.

100

1,5-Anhydro-2,3-dipivolyl-6-diphenylphosphate-D-glucitol (22)

To a solution of 21 (0.664g, 2.0mmol) in CHzClz, pyridine (0.9ml) and
diphenylchlorophosphate (0.62ml, 3.0mmol) were added at 0°C. After stirring at room
temperature for 1.5hr, water and CHzClz were added. The organic layer was separated,
and the aqueous layer was extracted with CHzClz. The combined organic layer was
washed with 1M HCl, saturated NaHCO3, and water, then dried over anhydrous NaZSO4.
After remove the solvent under reduced pressure and purify by column chromatography
on silica gel using CH2C12-CH3OH(13:1) as an eluant afforded the product 22 ( 0.701g,
62%): mp 75-76 °C; [011.320 +123 (c 1. CHC13); ‘H NMR (500 MHz,CDCl3):51.11(s,
9H, tBu); l.14(s, 9H. tBu), 3.18(dd, J1=12=10.2 Hz, 1H, H-l-b), 3.37(m, 2H, H-4,5),
3.97(dd, J 1=10.8 Hz, JZ=J3=5.4 Hz, 1H, H-l-a), 4.42(dd, J 1=J2=11.7 Hz, 1H, H-6-b),
4.50(ddd, J 1 =12 =9.8 Hz, J3, 5 =3.5 Hz, H-6-a), 4.76(ddd, J l=10.2 Hz, J2=J3=5.7 Hz,
1H, H-2), 5.06(dd, J=9.3Hz, 1H, H-3), 7.25(m, 10H, H-arom); l3C NMR (CDC13):
526.9, 38.5, 38.6, 66.4(C-1), 67.4(C-6), 67.9(C-5), 68.5(C-2), 75.0(C-3), 78.9(C-4),
120.1, 125.6, 129.0, 150.1, 177.1, 178.1; 3'P NMR (CDCl3): 6 -9.77; umax (KBr) 3399,
2971, 2873, 1735, 1590, 1487, 1280, 1184, 1166, 1056, 962, 773, 690; Anal. Calcd for

C28H37010P: C, 59.57; H, 6.61. Found: C, 59.27; H, 6.10.

l,S-Anhydro-2,3-dipivolyl-6-phosphate-D-glucitol (23)

To a solution of 22 (0.564g, 1.0mmol) in methanol, Pt02 (0.113g, 0.50mmol) was added.
After stirring vigorously at room temperature under H2 atmosphere for 6 hr, the solid was
removed by filtration. The product 23 was obtained after removing the solvent under

reduced pressure as syrup (0.412g, 100%): 1H NMR (500 MHz, CDC13): 5 1.03(s, 9H,

101

tBu); 1.08(s, 9H, tBu), 3.30(dd, 11:12:10.2 Hz, 1H, H-lb), 3.45(m, 1H, H-5), 3.67(dd,
J1=JZ=9.8 Hz, 1H, H-4), 4.03(dd, J1=JZ=11.0 Hz, 6.1 Hz, 1H, H-6b), 4.20(m, 2H, H-la,
H-6a), 4.88(ddd, 11:-9.0 Hz, 12=J3=6.1 Hz, 1H, H-2), 5.16(dd,J1=12=9.8Hz, 1H, H-3);
l3C NMR: 8 26.8, 38.5, 38.6, 65.3, 66.3, 68.0, 68.8, 75.1, 79.0, 177.4, 178.2; 3'P NMR

(CD3CN): 5 1.97

1,S-Anhydro-D-glucitol-6-phosphate (5)

To a solution of 23 (0.247 g, 0.60 mmol) in methanol, 95% powered NaOMe (65.0 mg,
1.2 mmol) was added. After stirring at 40°C for 10 hr, the solution was passed through a
cation ion-exchange resin to remove the salt. Removal of the solvent gave the free acid 5
as a syrup (0.123 g, 83 %). [(1)020 +295 (c 1, D20); lH NMR(D20): 8 2.85(dd, 11:12:95
Hz, 1H, H-l-b); 3.02(m, 2H, H-l-a, H-S), 3.04(m, 1H, H-4; 3.16(m, 1H, H-3), 3.53(dd,
J 1=5.7 Hz, 12=11.0 Hz, 1H, H-2), 3.69(ddd, J1=9.0 Hz, JZ=J3=4.5 Hz, 1H, H-6-b),
3.80(ddd, J1=9.0Hz, J2=7.1Hz, J3=3.9 Hz, 1H, H-6-a); l3C NMR(D20): 8 65.2, 68.8,
69.9, 69.1, 77.2, 78.5; 3'P NMR (D20): 0.96; 0mm (KBr) 3382, 2925, 2898, 1203, 1097,

1051;

l,S-Anhydro-D-glucitol-6-phosphate monoammonium salt (24)

In the preparation of 5, the elute from cation ion-exchange was condensation to about 2
ml, ammonia (0.5 M in 1,4-dioxane, 10ml) was then added to the solution. After stirring
at room temperature for 1hr, the product was precipitated as white solid. Filtration gave
24 in quantitative yield: mp. 105-107°C; 'H NMR(D20): 8 3.10(t, J=10.9Hz, H-l-b),

3.20(m, 1H, H-2), 3.27(d, J=9.0Hz, H-3 or H-4), 3.33(d, J=9.3Hz, H-3 or H-4), 3.42(m,

102

1H, H-5), 3.76-3.81(m, 3H, H-6-a, H-6-b, H-l-a); l3c NMR(D20): 8 63.8 (C-6), 67.9(C-
1), 68.1(C-3 or C-4), 68.3(C-3 or G4), 76.3(C-2), 77.9(c-5); 3'? NMR(DZO):4.30;1)mam

(KBr) 3411, 3222, 2919, 2867, 1631, 1459, 1097, 1054.

1,5-anhydro-D-Glucitol-6-diphenolphosphate (25)

To a solution of 4 (0.328g, 2.0 mmol) in dry pyridine (5m1) at 0°C
diphenylchlorophosphate (0.43 ml, 2.1 mmol) was drop-wise added. After stirring at 0°C
for 1.5 h and then 0.5 h at room temperature, MeOH (2.0ml) was added to quench the
reaction. Removal of the solvent followed by flash chromatography (10:1 CHC13: MeOH)
afford 25 as a crystal (0.46g, 60%): mp 113-114°C; [61020 +221 (c 1, CH3OH); ‘H
NMR(DMSO): 8 2.99(t, J=9.6Hz, H-l-b), 3.06(t, J=8.8Hz, H-l-a), 3.12(t, J=8.8Hz, H-4),
3.22-3.30(m, 2H, H3 and H5), 3.71(dd, J 1=10.8Hz, 12:4.9Hz, 1H, H-2), 4.24(m, 1H, H-
6-b), 4.47(m, 1H, H-6-a), 4.96(d, J=3.6Hz, 1H, OH), 5.02(sb, 1H, OH), 5.20(d, J=4.9Hz,
1H, OH), 7.24(m, 5H, H-arom), 7.42(m, 4H, H-arom); l3C NMR(DMSO): 5 64.7(C-6),
65.2(3 C. C-1, C-2, C-3), 73.6(C-4), 74.4(C-5), 115.7(C-arom), 121.3(C-arom), 125.8(C-
arom), 145.7(C-arom); 3'? NMR (DMSO): -10.65; umax (KBr) 3382, 3282, 3066, 2971,
2904, 2877, 2852, 1590, 1488, 1454, 1390, 1253, 1224, 1190, 1101, 1083, 1043, 943,
771, 688, 520 cm'I ; Anal. Calcd for C18H2108P: C, 54.55; H, 5.34. Found: C, 54.21; H,

5.12.

Formation of epoxides 27, 28 from 4,6—O-benzylidene-1,5-anhydro-D-glucitol:

NaH-Ist method:

103

In a 100ml flask, Sodium hydride (50% in mineral oil, 0.525 g, 10.5 mmol) was washed
free of oil with hexane, anhydrous DMF (20 ml) was added followed by addition of 4,6-
O-benzyliden-l,5-anhydro-D-glucitol (26) (1.01g, 4.0 mmol). After stirring at r.t. under
N2 for 0.5 h, Ist (1.16 g, 5.24 mmol, in 5 ml DMF) was added. The reaction mixture
was let to stir for another 4 h at r.t., and then EtOAc (30 m1) and brine (30 ml) was added.
After separation, the aqueous phase was extracted with EtOAc (2x30ml), the combined
organic phase washed with water (30ml), brine(3‘0m1), and dried over anhydrous MgSO4.
Evaporation of the solvent under reduced pressure gave a syrup. Flash column

(Hexane/EtOAc 5/1) gave 27 (0.337 g, 46.5 %) and 28 (0.160 g, 22.1 %).

1,5:2,3-Dianhydro-4,6-O-benzylidene-D-mannitol (27)

[61920 -1932 (c 1, CHC13); ‘H NMR (500 MHz, CDC13) 8 3.40(m, 1H, H-2); 3.54 (d, J =-
4.4 Hz, 1H, H-3), 3.63 (td, J = 10.3, 1.5 Hz, 1H, H-6’), 3.72 (ddd, J = 9.8, 4.9, 1.5 Hz,
1H, H-S), 4.00 (d, J = 9.8 Hz, H'-4), 4.06 (m, 2H, H-l, H-l’), 4.21 (dd, J = 10.3, 4.8Hz,
1H, H-6), 5.57 (s, 1H, PhCI-I),-7.36 (m, 3H, Ph-H), 7.50 (m, 2H, Ph-H); 13c NMR (125 M
Hz, CDC13) 8 51.0 (02); 53.1 (03), 64.4 (C-l or OS), 64.5 (01 or 05), 68.8 (C-6),
78.1 (04), 102.5 (PhCH), 126.2, 128.2, 129.1, 137.1; Anal. Calcd for C13H1404: C,

66.66; H, 6.02. Found: C, 66.54; H, 6.10.

1,5:2,3-Dianhydro-4,6-O-benzylidene-D-Allitol (28)
[(1][)20 -4.22 (c 1, CHC13); 1H NMR (500 MHz, CDC13) 8 3.14 (td, J = 9.8, 4.7Hz, 1H, H-
5), 3.19(dd, J = 4.0, 1.2 Hz, 1H, H-2), 3.48(d, J = 4.0Hz, 1H, H-3), 3.66 (d, J = 10.0Hz,

1H, H-4), 3.68 (t, J = 10.3Hz, 1H, H-6), 3.91 (dd, J = 13.7, 1.3 Hz, lH,H-1’), 4.21 (d, J =

104

13.7 Hz, 1H, H-l), 4.27 (dd, J= 10.5, 4.6Hz, 1H, H-6), 5.56 (s, 1H, PhCH), 7.38 (m, 3H,
Ph-H),7.50(m,2H,Ph-H);13C NMR (125M Hz, CDC13) 8 49.8 (C-2), 53.3 (03), 65.2
(C-l), 69.2 (OS), 69.3 (C-6), 75.3 (04), 102.1 (PhCH), 126.0, 128.2,129.1, 137.0; Anal.

Calcd for C13H1404: C, 66.66; H, 6.02. Found: C, 66.40; H, 5.92.

1,5-Anhydro-3-deoxy-4,6-O-benzylidene-D-arabino-hexitol (34)

To a stirred solution of 27 (0.117 g, 0.5 mmol) in 320 (5 ml) was added LAH (37 mg,
1.0 mmol). After stirring under nitrogen atmosphere for 4 h, ethanol (1 ml) was added.
Stirring was continued for another 30 min. Filtration followed by removal of the solvent
gave the crude product as a syrup. Column chromatography (CH2C12:MeOH 30:1) gave
the pure 34 (113 mg, 96 %): [61920 -30 (c 1, CHCl3); m.p 101-103°C; ‘H NMR (500
MHz, CDC13) 5 7.34-7.51 (m, 5 H, Ar-H), 5.56 (s, 1H, PhCH), 4.31-4.27 (m, 1H), 3.98-
3.95 (m, 1 H), 3.89-3.83 (m, 1H), 3.70 (t, J = 10.2 Hz, 1H), 3.57-3.52 (m, 1H), 3.42 (t, J
= 10.2 Hz, 1H), 3.40-3.31 (m, 1H), 2.65 (br s, 1H, OH), 2.03-1.98 (m, 1H), 1.84-1.75 (m,
1H); 137.3, 129.2, 128.3, 126.2, 101.9, 83.9, 71.1, 69.5, 68.8, 66.3, 33.2; Anal. Calcd for

C13H1604: C, 66.09, H, 6.83. Found C: 66.01; H, 6.89.

1,5-Anhydro-2-deoxy-4,6-O-benzylidene—D-ribo-hexitol (35)

Using the same procedure as for the preparation of 34 from 27, 35 was obtained from 28
in 95 %. [61920 - 23.7 (c 1, CHC13); 'H NMR (500 MHz, CDC13) 8 1.86 (ddd, J = 3.1,
11.8, 13.0 Hz, 1H, H-2), 2.12 (br s, 1H, OH), 2.33 (m, 1H, H-2’), 3.42 (ddd, J = 5.0, 9.2,
10.1 Hz, 1H, H-6), 3.71 (dd, J = 1.5, 2.4 Hz, 1H), 3.81 (t, J = 10.3 Hz, 1H), 3.96 (ddd, J =

1.7, 2.1, 12.4 Hz, 1H), 4.04 (ddd, J = 4.6, 9.2, 11.9 Hz, 1H), 4.14 Our 5, 1H), 4.33 (dd, J =

105

4.9, 10.4 Hz, 1H, H-4), 5.63 (s, 1H), 7.38-7.54 (m, 5H, Ar-H); l3C NMR (125M Hz,
CDC13) 835.6, 67.0, 69.0, 72.5, 74.2, 74.3, 101.9, 126.1, 128.3, 129.0, 137.4; Anal.

Calcd for C13H1604: C, 66.09, H, 6.83. Found C: 66.05; H, 6.78.

1,S-Anhydro-Z-deoxy-D-ribo-hexitol (37)

A solution of 35 (100 mg, 0.42 mmol) in methanol (3 ml) with Pd/C (10 %, 40 mg) was
stirred under hydrogen atmosphere over night. After filtration through celite, the solvent
was removed under vacuum. Water (1 ml) was added to the flask and the solution was
washed with toluene (2 x 1 m1). Removal of the solvent gave 37 in quantitative yield (62
mg, 100 %); 1H NMR (500 MHz, D20) 5 3.97—3.95 (m, 1H), 3.79 (dd, J = 2.4, 12.2 Hz,
1H), 3.72 (td, J = 2.1, 12.2 Hz, 1H), 3.68 (dddd, J = 0.5, 4.8, 6.8, 9.6 Hz, 1H), 3.56 (dd, J
= 6.8, 12.2 Hz, 1H), 3.48 (dd, J = 0.5, 12.5 Hz, 1H), 3.17 (ddd, J = 2.2, 6.9, 9.6 Hz, 1H),
2.09 (m, 1H), 1.59 (ddd, J = 3.2, 11.4, 14.6 Hz, 1H); 13C NMR (125M Hz, CDC13)5 82.2,
71.0, 66.3, 62.5, 61.5, 37.5; Anal. Calcd for C6H1204: C, 48.64, H, 8.16. Found C:

48.52; H, 8.09.

106

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Bennett, M. S.; Champness, J. N.; Summers, W. C.; Sanderson, M. R.;
Herdewijn, P. J. Med. Chem. 1998, 41, 4343.

[24] Hamashima, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42, 691.

[25] Masumoto, S.; Yabu, K.; Kanaia, M..: Shibasakia, M. Tetrahedron Lett. 2002,
43, 2919.

[26] Ermolenko, M. S.; Shekharam, T.; Lukacs, G.; Potier, P. Tetrahedron Lett.
1995, 36, 2461-2464.

[27] Paquette, L. A.; Arbit, R. M.; Funel, J.-A.; Bolshakov, 8. Synthesis, 2002, 14,
2105-2109.

[28] Baer, H. H.; Mekarska, M.; Bouchard, F. Carbohydr. Res. 1985, 136, 335-45.
[29] Sunay, U.; Fraser-Reid, B. Tetrahedron Lett. 1986, 27, 5335-533 8.

[30] Sato, K.; Miyama, D.; Akai, S. Tetrahedron Lett. 2004, 45, 1523—1525.

[31] Keck, G. E.; Kachensky, D. F. J. Org. Chem. 1986, 51, 2487-2493.

[32] Magnusson, G.; Ahlfors, S.; Dahmn, J.; Jansson, K.; Nilsson, U.; Noori, G.;
Stenval, K.; Tjornebot, A. J. Org. Chem. 1990, 55, 3932-3946.

[33] Pasetto, P.; Franck, R. W. J. Org. Chem. 2003, 68, 8042-8060.

108

Chapter 4

Iodo Derivatives of Advanced Carbohydrate Intermediates

109

Abstract

Using hydriodic acid as an economic and general reagent, the general 4-carbon synthons
derived from carbohydrates, (S)-3-hydroxy-butyrolactone and (S)-3-hydroxy-
tetrahydrofuran, were successfully transformed to the acyclic iodo derivatives. From (S)-
3-hydroxy-tetrahydrofuran, all the mono and diiodo derivatives were prepared selectively
by taking advantage of the electron withdrawing property of the 3-hydroxy group and
controlling the neighboring group effect of the 3-acetyl group. The application of these
iodo derivatives was demonstrated in the preparation (S)-3-hydroxyl cylopentane, (S)-3-

hydroxyl tetrahydrothiphene and (S)-3-hydroxyl-pyrolidien derivatives.

110

4.1 Introduction

Organic halides, especially organic iodides, are important intermediates in organic
synthesis; they are often involved in the formation of C-C bond via radical1 or ionic
reactionsz. They are also important indispensable intermediates in substitution reactions,
rearrangement reaction and elimination reactions3’4’5. Iodides are the most reactive among
halides; therefore, many methods have been developed for the preparation of organic

iodides“8

. The most used method is converting the corresponding alcohol to the iodides,
and a number of methods for this transformation have been reported. The classical
method is through a two-step procedure — the alcohol is first converted to the tosylate and
then a SNZ substitution with iodide ion gives the organic iodideg. Recently, many new

methods have been reported, such as BF3-EtzO/KI'0, P.;/12”, Clst-DMF/KIIZ, Mg12'3,

Me3SiCl/Na1”, Ph3P/12'5, Ph3P/DDQ/R4N+I' ‘6.

The reported methods suffer from one or the other problems. Using BF3-EtzO/KI, Only
allylic or benzylic alcohols can be used as substrates"). Other methods involve the usage
of expensive reagents (PdClz/Et3SiH)”, give low yields (lg/petroleum ether)”, need long
reaction time (Clst-DMF/KI)8, and require tedious workup procedures

(Ph3P/DDQ/R4N+I')‘6.

Using hydriodic acid as an economic and general reagent, we successfully transformed
the general 4-carbon synthons derived from carbohydrates, (S)-3-hydroxy-butyrolactone

and (8)-3-hydroxy-tetrahydrofuran'9’20, to the acyclic iodo derivatives. The application of

111

these iodide derivatives was demonstrated in the preparation of the S and N containing

heterocycles.

4.2 Preparation of iodo derivatives from (S)-3-hydroxy-butyrolactone
The ring-opening reaction of (S)-3-hydroxy-butyrolactone l with HI seemed to be very
straight forward: under acidic conditions, iodide attacks C-4 position to give the acyclic

4-iodo product 3 (Figure 4.1).

Figure 4.1 Proposed reaction of (8)-3-hydroxy-butyrolactone with HI

Reaction of (S)-3-hydroxy-butyrolactone l with HI was very slow when the reaction was
run in water. No reaction product was observed after treating compound 1 with 5

equivalent of H1 in water for 24 h.

To accelerate the reaction, the free hydroxyl group was acetylated. It is known that acyl
groups can participate in reactions involving carbocations through formation of 1,3-
dioxonium ions and thus stabilize the carbocation formedmz. For acetylated compound
1, with the assistance of the acetyl group, under acidic conditions, the ring opening

reaction of 1 would be much faster.

112

To avoid the hydrolysis of the acetate, the reaction was run in AcOI-I/AczO. The results

are shown in Table 4.1 (Figure 4.2)

Table 4.1 Ring-opening reactions of
(S)-3-hydroxy-butyrolactone with H1. in AcOH/AczO
Iodo Product

 

 

Entry AczO (%) Tlme (h) 4 (%)
l 50 20 0
2 50 44 < 1
3 50 68 1.9
4 5 20 21.5
5 5 44 35.0
6 5 68 40.0

 

* 5 equiv HI **AczO concentration in AcOH

No product was observed after treating (S)-3-hydroxy1-butyrolactone 1 with 5 equiv H1 in
acetic acid containing 50 % AczO. Even after 68 h, only 1.9 % of the desired product 4
was observed. The yield of 4 increased with the decreased concentration of AczO. With
only 5 % AczO in acetic acid solution, 21.5 % of 4 was formed after 20 h, after 68 h, 40

% of 4 was formed.

The increased yield of product 4 with the decreased concentration of acetic anhydride is
related to the dissociation of H1 in the solution. H1 is a weaker acid in acetic anhydride
than in acetic acid. With the increasing concentration of acetic anhydride, less free iodide

and proton is available and thus the rate for the ring-opening reaction of 5 decreased. It is

113

expected then that with no AczO in the reaction system, the iodide product should be

formed much faster.

Table 4.2 listed the results for ring-opening reactions of (S)-2-hydroxyl-butyrolactone 1
with H1 in AcOH without AczO.

Table 4.2 Ring-opening reactions of
(8)-3-hydroxy1-butyrolactone with H1 in AcOH

 

Temp Time Iodo product

 

my (’0 (h) 4(%>
1 25 0.5 16.5
2 25 6 58.1
3 25 22 61.5
4 25 48 10

 

The reaction rate was highly accelerated without AczO. After only 0.5 h, 16.5 % of the

desired iodide product 4 was formed, 61.5 % of 4 was formed after 22 h.

(ofo HI In AcOH '/\/\[]/°H
a 5M: 0

 

Figure 4.2 Neighboring acetyl group assisted ring opening reaction of

(S)-2-hydroxy-butyrolactone with H1

114

However, the yield of the iodide product cannot be further improved by simply
prolonging the reaction time. Product 4 was obtained in only 10 % yield after stirring the
reaction solution at room temperature for 48 h (Figure 4.3). Two new products were
formed. The but-3-enoic acid 9 was formed in 5 % and 3-iodo butanoic acid 8 was

formed in 85 % yield. Compound 8 is optically inactive.

5A0 O I O

4 8

l ..

1"
A on \ OH
9

4

Figure 4.3 Formation of optically inactive 4-iodide butanoic acid

It is known that iodide can reduce organic iodo compounds”. In this case, once the 4-
iodo product 4 was formed, the free iodide in the reaction system attacks the primary
iodide. Elimination of the 3-acetate group gave the olefin 9 (Figure 4.3). Addition of H1
to 9 formed the secondary iodo compound 3-iodo butanoic acid 8. The optical activity
was lost in the elimination step. Without excess iodide ion in the system, the byproducts
would be greatly diminished. Thus, when the reaction was run with only 1 equivalent of

H1 for every equivalent of lactone, no elimination product 8 or 9 was observed.

115

Acé
0 o
8 HI in AcOH 4 5
———>
oli
OH \ 0H
1 W + W
1 o 0
a 9

Figure 4.4 Reaction of (S)-3-hydroxy-butyrolactone with H1 in acetic acid at various

temperatures

Table 4.3 Reaction of (S)-3—hydroxy-butyrolactone with H1 in acetic acid‘

 

 

 

Temp Time Products (%)
Entry

(°C) (h) 1 4 5 8 + 9
1 4 12 6 20 74 0
2 4 36 4.2 59.5 34.1 2.2
3 30 4 0 2.4 97.6 0
4 30 6 0 70.6 29.4
5 30 12 0 81.0 16.4 2.6
6 30 22 0 90.5 4.7 4.8
7 40 6 0 70.6 22.0 7.4
8 4O 22 0 73.5 15.1 11.4
9 60 6 O 89.5 0 10.5
10 60 22 0 47.6 0 52.4

 

* 1 equivalent of H1 used.

At lower temperature (4°C), the desired iodo product 4 was formed in about 60 % after
36 h (Table 4.3, entry 2), along with 34 % of the cyclic lactones (1 + 5), and small

amount (2.2 %) of the elimination products (Table 4.3, entry 2). At higher temperature

116

(30, 40, and 60 °C), product 4 was formed in more than 70 % yield after 6 h (Table 4.3,
entry 4, 7, 9). However, substantial amount of elimination products were formed when
the reaction was run at 40 °C and 60°C, especially with longer reaction time (Table 4.3,
entry 8, 10). The best results were obtained when the reaction was run at 30°C for 22 h.
The desired iodo product 4 was obtained in 90.5 % yield with a fraction of elimination
products (4.8 %) and acelyted starting lactone (4.5 %) left (Table 4.3, entry 6). The

optical purity of compound 4 was greater than 98 % determined by optical rotation.

4.3 Preparation of iodo derivatives by ring opening of (S)-3-hydroxyl-
tetrahydrofuran with H]

After successful preparation of (8)-3-acetoxy-4-iodobutanoic acid 4 through the ring
opening reaction of (S)-3-hydroxy-butyrolactone with HI, (S)-3-hydroxyl-
tetrahydrofuran was used as the substrate for the ring opening reaction with HI. Unlike
the lactone l, which can only cleave the C4-O bond in the ring opening reactions and
thus can only get the 4-iodo product, the cyclic ether 10 has 2 possible sites for iodination
and thus 3 iodo products can be obtained: the monoiodo products 11, 12 and the diiodo

product 13.

117

10
HI
i
eon :011 :9"
.fLen Hrs—FL. ._/_\_.
11 12 13

Figure 4.5 Possible iodo products from ring opening reaction of (S)-3-hydroxy-

tetrahydrofuran with HI

Water as solvent

When water was used as solvent, the mono iodide product 11 was obtained. However, the
yields varied if the reaction was run in an open flask. Two factors can affect the yield in
this reaction: light and oxygen. Light can catalyze the formation of iodine from HI;
oxygen can oxidize HI to iodine.24 Table 4.4 listed the light and oxygen effects on the

ring opening reaction of (S)-3-hydroxyl- tetrahydrofuran 10 with HI.

 

3°” 1.2 oqulv HI :0“
0 H20, 60°C '
5 l—'/__\—OH
0 Conditions
10 1 1

Figure 4.6 Ring opening reaction of (S)-3-hydroxy- tetrahydrofuran with H1 in water

118

Table 4.4 Light and oxygen effects on the ring opening reaction of

(S)-3-hydroxy1- tetrahydrofuran with HI

 

 

 

. Yield (%)
Entry condit1ons
1.5 h 3 h 6 h
1 - 35.5 43.5 25
2 hv 44.1 40.2 15.6
3 02 93.5 68.0 18.6
4 hv + 02 95.2 78.1 13.0

 

These results indicate that light and oxygen can accelerate the reaction. Without light or
oxygen, the highest yield obtained was 43 %, with light slightly higher yield was
obtained, while with oxygen, 93 % of the iodide compound was obtained in 1.5 h. The
effects of light and oxygen were additive: with both light and oxygen, 95 % of the iodo
product was obtained. It is noted that during the first 1.5 h of the reaction process, the
color of the reaction solution (which came from H13) increased in the order of
Without light/oxygen < light < oxygen < light and oxygen

the same order as for the formation of the iodide compound. It has been reported that
iodine can catalyze the ring opening polymerization of THFZS, a similar iodine catalyzed

ring opening iodination of (S)-3-hydroxy- tetrahydrofuran was proposed in Figure 4.7.

119

9H 9H

'1' fl
'—_’ I OH

/ :.
OOH—L. @0 14 11

\ OH 9”
a ,
l 5 1" _/—\__
5+ ——-> HO 1
9 L I.

l'—'—l

14 12
Figure 4.7 Mechanism for iodine catalyzed ring opening iodination of

(S)-3-hydroxy- tetrahydrofuran

Reaction of H1 with oxygen forms iodine, light can catalyze this process. Coordination of
iodine with the ring oxygen forms the iodine complex. Iodide can attack the complex in
two possible pathways: from path A iodide attacks C-5 to form the 4-iodo 1,2 diol
product 11, from path B iodide attacks C-2 to form the 4-iodo 1,3-diol product 12. The
exclusive formation of 1,2 diol product 11 is understandable as the electron withdrawing
2-hydroxyl group makes C2 of 14 less reactive toward the nucleophile iodide compared

to C5 of 14, and thus the cleavage of C5-O bond is much easier than that of C2-O bond.

Acetic acid as solvent

If the HI mediated ring opening iodination of (S)-3-hydroxy- tetrahydrofuran was run in
acetic acid, it is expected that the acetyl group at C-3 position would participate in the
ring opening process to form the five membered 1,3-dioxolanium followed by iodide

attacking C-l to form the 4-iodo 1,3-diol derivative 16 as shown in Figure 4.8.

120

10 17 18 16

Figure 4.8 Proposed reaction of (S)-3-hydroxyl- tetrahydrofuran and HI in Acetic acid

When 2 equiv of H1 was used, the diiodo product 20 was obtained in 90 % with 10 % of
acetylated starting material 19 lefi, while no expected mono iodide product was formed.
Reducing the amount of H1 to 1 equiv, still, only diiodo product 20 was obtained, even

though 55 % of 19 remained in the reaction system.

59“ 59A° QAc 19 : 20
CH3COOHIHI : I
Z 2 = Z 9 "’ ,/\/\/ Zequiv HI 10: 90

0 r.t.. 1 h 0
tequiv H1 55 I 45

 

1o 19 20

Figure 4.9 Reaction of (S)-3-hydroxy- tetrahydrofuran and H1 in Acetic acid

The formation of only diiodo product indicated that the monoiodo intermediate was very

reactive. Once it was formed, it quickly transformed to the diiodo product. A mechanism

based on this observation is shown in Figure 4.10.

121

39H :‘Ojl/ \‘0
Z S ' l 1 04-
HI 3

20 22 21
Figure 4.10 Mechanism for reaction of (S)-3-hydroxy- tetrahydrofuran and H1 in Acetic
acid
Once the monoiodo compound 21 was formed, the 4-hydroxyl group attacks the acetyl
carbonyl carbon to form the six-membered orthoester intermediate 22, iodide attacked C-
4 to cleave the orthoester and give the diiodo product 20. In this process, the rate
determining step is the formation of the 1,3-dioxolanium 18 from 17. To form 18, a
highly strained fused bicyclic ring transition state must be formed. Once 18 was formed,

it was quickly transformed to 20 through 21 and 22.

If no participation group exists, the opening of the THF ring is expected to be slower and
the monoiodo product should be formed predominately. Indeed, treating THF with 2
equiv H1 in acetic acid at room temperature for 3 hour gave 64 % monoiodo product 4-
iodo butyl acetate 24 with 36 % THF remaining, no diiodo product was observed (Figure

4.11).

122

2 equiv HI, CH3000H /\/\/OAC
= I
Z 5 r.t 3 h
0 64 %

23 24

Figure 4.11 Reaction of tetrahydrofuran and H1 in Acetic acid

Trifluoroacetic acid (TFA) as solvent

If the reaction of (8)-3-hydroxy-tetrahydrofuran 10 with HI was run in a non-
participation solvent, such as TF A, the monoiodo product should be formed exclusively
without the formation of the diiodo product. Also, without participation in the opening of
the THF ring, the 1,2-diol derivative should be obtained because the position of the

electron withdrawing hydroxyl group.

911

 

00(0)“,
2 equiv HI, cracoorl Momma,
Z 5 t I
O 60°C, 2 h
8.4 %
10 25

Figure 4.12 Reaction of (S)-3-hydroxy-tetrahydrofuran and H1 in trifluoroacetic acid

Reaction of (S)-3-hydroxy-tetrahydrofi1ran 10 with 2 equiv H1 at room temperature for 5
hour gave 3.2 % of the expected 4-iodo-1,2-diol derivative 25 without formation of the
1,3 diol or diiodide product (Figure 4.12). However, the reactions in TFA were very

slow. After 64 h at room temperature, only 12 % of the product 25 was obtained. Raising

123

the reaction temperature to 60 °C did not give satisfactory results either. Product 25 was

obtained in 4.7 % and 6.8 % after 2 and 5 hour respectively.

Acetic Acid/Acetic Anhydride as solvent
If extra acetic anhydride existed in the reaction system with acetic acid as solvent, then
once the ring was opened, the free hydroxyl group will be acetylated and thus the

monoiodo 1,2 diol product should be obtained.

 

 

pH 2equiv HI OAc OAc
. AcOH/Aczo CL A020 WI
Z S g = AcO
l
0 60°C 3 h OH
77.8 %
10 26 16

Figure 4.13 Reaction of (S)-3-hydroxy-tetrahydrofuran and H1 in acetic acid/acetic

anhydride

Reaction of (S)-3-hydroxy-tetrahydrofuran 10 with 2 equiv HI and 5 equiv AczO in
AcOH at 60°C for 3 h gave 77.8 % of the expected 4-iodo-1,3 diol derivative 16 without
formation of the 1,2 diol or diiodo product (Figure 4.13). As discussed in Chapter 4.2, the
existence of AczO in the reaction system lowered the reaction rate (without AczO, 90 %

of the diiodo product was obtained at room temperature for 1 hour, Figure 4.9).

The results for the reaction of (S)-3-hydroxy-tetrahydrofuran with HI under different

conditions are shown in Figure 4.14. The regio selectivity is realized by taking advantage

124

of the electron withdrawing property of the 3-hydroxy group and controlling the

neighboring group effect of the 3-acetyl group.
9H
./\/\/0H
11

H20

911

; AcOH/ACZO 3
Aeo/VV' ‘ l 2

 

9A1:

 

O
16 10

TFA

QCIOICFs

I momma:

25

20

Figure 4.14 Reaction of (S)-3-hydroxy - tetrahydrofuran and HI under various conditions

4.4 Reactions of 1,S-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol with HI

Under similar conditions as for the reaction of (S)-3-hydroxy-tetrahydrofi1ran with H1 in

acetic acid, the reaction of the tetrahydropyran derivative 1,5-anhydro-2,3,4,6-tetra-O-

acetyl-D-glucitol 27 should give the open chained 6-iodo product 30 as proposed in

Figure 4.15. Protonation of the ring oxygen followed by 6-acetyl group assisted cleavage

of the ring C5-O bond should give the open chained dioxonium ion 29, which should be

opened by iodide at O6 to give the iodo product 30.

H1 OAC
AcO O ......... .. AcO OAc

 

 

A OH O c
37 on c 30
= t
t :
r )2 5 7
0 ° 036‘
'9' ------- ->
AcO AcO OH
AcO AcO
0A6 0A6
L. .4
28 29

Figure 4.15 Proposed reaction of H1 mediated ring opening reaction of 1,5-anhydro-
2,3,4,6-tetra-O-acetyl-D-glucitol

The results for reaction of 1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol with HI are

listed in table 4.5 (Figure 4.16).
ON: I

o 10equiv HI 0
AcO AcO AcO
AcO A00“ AcO AcO

O
4.
OM: OM: OM:

 

27 31 32

Figure 4.16 Reaction of 1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol

Table 4.5 Reaction of 1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol

 

 

Entry Temp (°C) Time (h) Product(s)
1 25 18 27 (95 %)
2 55 18 27 (95%)
27 (30 %)
3 95 18 31 (30 %)
32 (10 %)

4 1 10 . 7 Decomposed

 

At lower temperature (25 °C, 55 °C) after 18 h (Table 4.5, entry 1, 2), no product is

obtained while 95 % of the starting 27 is recovered. Raising the temperature to 95 °C for

126

18 h, the cyclic 6-iodo product 31 was obtained in 30 % yield along with 10 % olefin
product 32. 27 is recovered in ~30% and no open chained iodo product was observed. At
higher temperature (110 °C), no significant amount of any product or starting material can

be isolated.

It is known that the cleavage of tetrahydropyran (THP) is much slower than that of THF,
as the six-membered cyclic THP is more stable than the five-membered cyclic THF. As
for l,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol, the 4 electron withdrawing groups
make the THP ring more electron deficient and harder to be cleaved. Under the

conditions used, no ring-cleavage product can be formed.

4.5 The application of iodide products in the preparation of advanced derivatives
The chiral iodide products prepared can easily be converted to other heteroatom
containing compounds, such as S, N heterocyclic compounds and carbocyclic

compounds.

Refluxing 1,4-diiodo-2-butanol-acetate 20 with sodium sulfide in ethanol for 5 h gave

(8)-3-hydroxy-tetrahydrothiophene 33 in quantitative yield. The optical purity of 33 is

 

higher than 99 %.2°
OH
QAC N328.9H20 3‘
l/\/\/ ' 7‘ l )
EtOH. reflux, 5h 8
100 %
20 33

Figure 4.17 Preparation of (S)-3-hydroxy-tetrahydrothiophene

127

Reaction of the diiodo compound with benzyl amine in toluene at the existence of
potassium carbonate for 5 h under reflux followed by hydrolysis of the acetyl gave the
desired (8)-l-benzyl-3-hydroxy-pyrolidine 34 in 60 % over 2 steps. The optical purity of

31 is larger than 99 %.27

 

9H
9A0 ( 1
T | a. b N
l/\/\/ V
20 34

Figure 4.18 Preparation of (S)-1-benzy1-3-hydroxy-pyrolidine
Reaction conditions: a). BnBHz, KzCOy, Toluene, reflux, 5 h;

b) K2CO3, H20 2 steps, 60 %.

Compound 20 is also a good intermediate for the construction of carbocyclic compounds.
Reaction of 20 with diethyl malonate in the presence of t-butoxyl potassium gave the

chiral cyclopentane derivative 35 in 65 % yield.

 

9A1:
gm: 0 O tBuOK / omso
/\/\/ I M =
' + 51° 05‘ Etozc c0251
20 35

Figure 4.19 Preparation of (S)-diethy1-3-acetoxycyclopentane-l ,l-dicarboxylate

4.6 Conclusion

Using HI as an economic and general iodide source, the important 4-carbon iodide
synthons, (S)-3-hydroxy-4-iodo-butanoic acid, (S)-4-iodo-1,3-butanediol, (S)-4-iodo-
1,2-butanediol, (S)-1,4-diiodo-2-butanol and their acetylated derivatives are prepared.
The usefulness of the iodide synthons were demonstrated through the preparation of the
heterocyclic compounds (S)-3-hydroxy-tetrahydrothiophene and (S)-l-benzyl-3-hydroxy-
pyrolidine and also the carbocyclic compound (S)-diethyl-3-acetoxycyclopentane-1,1-

dicarboxylate.

129

4.7 Experimental

General procedures: '11, '3 C NMR spectra were recorded at 500, 125, MHz, respectively,
with a Varian instrument at 293 K. The chemical shifts are given in ppm using CDC13
residue as reference (5 7.24 p) for 1H and relative to the central CDC13 resonance (5=
77.00p) for I3C NMR unless otherwise specified. Optical rotations were measured on a
Jasco P1010 polarimeter at 20°C. IR spectra (wave numbers in cm") were recorded on a
FT IR Nicolet 740 spectrometer in CHC13 solutions or KBr pellets. All chemicals were

purchased from Aldrich Chemical Co. and used without further purification.

The H1 in acetic acid, acetic acid/acetic anhydride, trifluoroacetic acid solution was
prepared as needed. For the preparation of H1 in acetic acid solution, 47 % H1 in H20
(6.16 g) was cooled to 0°C with ice-bath, AczO (17.16 ml) was added drop-wised with
the control of the solution temperature no higher than 40°C. Stirring was continued for
another 30 min at r.t. after the addition was done, the solution prepared contain 11 % HI.
For the preparation of H1 in acetic acid/acetic anhydride, trifluoroacetic acid, the same

protocol is followed with the addition of the amount of anhydrides needed.

For HI mediated reactions, the progress of the reaction was monitored with 1H and '3C
No-Deuterium NMR. The signal monitored for the ring opening reaction of (S)-3-
hydroxy-butyrolactone is H-3 and C-4. For (8)-3- hydroxy-tetrahydrofuran, the signal

monitored are H-3 and C-1 or 04 (whichever is iodinated).

(S)-3-acetoxy-butyrolactone (5)

To a stirred solution of AC2O (4.7 ml) in dry pyridine (15 ml) at r.t was added (8)-3-
hydroxy-butyrolactone (1.02 g, 10mmol). After stirring at r.t overnight, most of the
solvent was removed under high vacuum, diethyl ether (50 ml) was added and washed
successively with cold water, saturated aqueous NaHC03, and brine (30 ml each) and
dried over anhydrous Na2SO4. Removal of the solvent gave compound 5 as a colorless oil
(1.32 g, 94 %). [(11200 -455 (e 1, CHC13); 'H NMR(CDC13): 8 2.03 (s, 3H, CH3 Ac),
2.48-2.54(m, 1H, H-2a), 2.82(dd, J = 6.7, 18.4 Hz, 1H, H-2b), 4.27—4.30(m, 1H, H-4a),
4.45 (dd, J = 5.0, 11.1 Hz, 1H, H-4b), 5.36 (m, 1H, H-3); l3C NMR(CDC13): 5 20.5,

34.2 (02), 69.6 ((3-3), 72.7 (04), 170.0, 174.5.

Reaction of (S)-3-hydroxy-butyrolactone 1 with HI:
H20 as solvent:
(8)-3-hydroxy-butyrolactone (0.102 g, 1 mmol) was added to a solution of H1 in H20

(47%, 1.36 g), after stirring at r.t for 24 h, no reaction product was observed from NMR.

AcOH, AcOH/Ac20 as solvent:
(S)-3-hydroxy-butyrolactone (0.102 g, 1 mmol) was added to a solution of H1 in AcOH
with excess AC2O (50 %, 5 % or 0 %), the samples were stirred at the desired

temperature, and were tested using NMR for the formation of products at the time listed

in table 4.1, 4.2.

131

For workup: after removing most of AcOH under vacuum, EtOAc (20 ml) was added
followed by addition of saturated aqueous NaHCO3, after separation, the aqueous layer
was extracted with EtOAc(2 x 20 ml), the combined organic layer was washed with brine
(20 ml) and dried over anhydrous Na2SO4. Removal of the solvent gave a colorless oil.
Column chromatography (if needed) gave 3-acetoxy-4-iodo-butyric acid .3: 1H NMR
(CDCI3): 5 2.04(s, 3H, CH3 Ac), 2.76(dd, J = 6.7, 7.0 Hz, 2H, H-2), 3.34 (dd, J = 4.5,
11.0 Hz, 1H, H-4a), 3.39 (dd, J = 5.2, 11.0 Hz, 1H, H-4b), 4.99(m, 1H, H-3); 13 C

NMR(CDC13): 5 6.8 (C-4), 20.8, 38.6 (C-2), 68.3 (C-3), 170.1, 175.6.

Ethyl 3-(S)-hydroxy-4-iodo-butyrate

For the preparation of Ethyl 3-(S)-acetoxy1-4-iodo-butyrate, ethanol (30ml) was added to
the condensed reaction solution (~2 ml) of (S)-3-hydroxy-butyrolactone (0.102 g) with
H1 in acetic acid along with 2 drops of concentrated sulfuric acid. After stirring at r.t. for
12 h, the reaction solution was concentrated, EtOAc (20 ml) and saturated aqueous
NaHCO3 (20 ml) was added, after separation, the aqueous layer was extracted with
EtOAc(20 ml), the combined aqueous layer was washed with brine (20 m1), dried over
anhydrous Na2SO.; and condensed. Column chromatography gave Ethyl (S)-3-hydroxy-
4-iodo-butyrate as a colorless oil (0.21 g, 81 %), [01]2°D -9.7 (c 1, CHC13); 1H NMR
(CDC13): 5 1.16 (t, J = 7.2 Hz, 3 H, CH3 0 ethyl), 2.47 (dd, J = 4.2, 16.6 Hz, 1 H), 2.58
(dd, J = 4.1, 16.5 Hz, 1H), 3.20-3.36 (m, 2H, ), 3.86-4.00 (m, 1H, H-3), 4.05 (q, J = 7.0
Hz, 2 H, 0CH2); l3C NMR(CDC13): 5 12.0 (C-4), 13.8 (CH; O-ethyl), 40.7 (C-2), 60.8

(CH2 O-ethyl), 67.3 (C-3), 171.4 (C=O).

132

(S)-3-Tetrahydrofuryl-acetate (l9)

[a]20[) -16.75 (c 1, CHC13); 'H NMR (coc13): 81.89 (m, 1H, H-4), 1.95 (s, 3H,
COCHy), 2.06 (m, 1H, H-4’), 3.69-3.83 (m, 4H, H-2, H-5), 5.17 (m, 1H, H-3); l3C
NMR(CDC13): 8 20.8 (COCHy), 32.4 (04), 66.7 (05), 72.8 (02), 74.5 (C-3), 170.5

(C0CH3).

4-Iodo-(S)-2-hydroxy-butan-l-o| (11)29

General method for the reaction of (S)-3-hydroxy-tetrahydrofuran with H1 in water: (S)-
3-hydroxy-tetrahydrofuran (0.088 g, 1 mmol) was added to a solution of H1 in water (47
%, 0.33 g, 1.2 mol) at 60°C, under the conditions listed as in table 4.4 (for the
conditions with no light, no oxygen, the reactions were run in a deep-dark colored flask
under argon atmosphere; for the conditions with light only, the reactions were run in a
ordinary flash under argon atmosphere; for the conditions with both light and oxygen, the
reactions were run with ordinary flask and air was bubbled to the reaction solution
through the process).

For workup:

Sodium thiosulfate (~ 0.05 g) was added to the stirred solution until the Iodine color
disappear, then brine (10 ml) was added, the mixture was extracted with THF (4 x 15 ml),
the organic layers were combined, dried and condensed to give a colorless oil, column
chromatography gave the pure product 11. [01200 'H NMR (CDCI3): 5 1.81-1.88 (m, 1H,
H-3), 1.93-2.00(m, 1H, H-3’), 3.23-3.32 (m, 2H, H-l, H-l’), 3.46 (dd, J = 6.6, 11.6 Hz,
1H, H-4), 3.56 (dd, J = 3.8, 11.6 Hz, 1H, H-4’), 3.76 (m, 1H, H-2); l3c NMR(CDClg):

5 1.28 (C-4), 34.0 (C-3), 63.0 (C-l), 69.7 (C-2).

133

(S)—4-(2-iodoethyl)-2,2-dimethyl- 1,3-Dioxolane

A solution of 4-Iodo-(S)-2-hydroxy-butan-1-ol (0.216 g, Immol) in acetone with catalytic
amount of concentrated sulfuric acid was stirred at r.t for 5 h and then solid sodium
bicarbonate (0.5 g) was added and stirring was continued for 1 h. After filtration,
concentration, the residue was dissolved in diethyl ether and washed successively with
saturated aqueous sodium bicarbonate, water and brine. Evaporation of the solvent gave
the product as a colorless oil (0.235 g, 92 %).[oz]2°p (c l, CHC13); 1H NMR (CDC13):
5 1.35 (s, 3H, CH3), 1.40 (s, 3H, CH3), 2.01-2.14 (m, 2H, H-), 3.15-3.30 (m, 2H, H-),
3.55 (dd, J = 6.2, 7.9 Hz, 1H, H—), 4.07 (dd, J = 6.2, 7.9 Hz, 1H, H-), 4.14-4.19 (m, 1H,

H-); 13C NMR (CDC13): 5 1.51 (C-4), 25.5, 27.0, 37.8, 68.7, 75.7

1, 4—diiodo-(S)-2-bntanol-acetate (20)29

To a stirred solution of H1 in water (47 %, 3.1 g, 11.4 mmol) under ice-water bath was
added drop-wised acetic anhydride (8.6 ml). After stirring another 10min, the ice-water
bath was removed and (S)-hydroxytetrahydrofuran (0.50 g, 5.7 mmol) was added. After
stirring at r.t. for 1 h, the reaction solution was cooled to r.t. and then concentrated to
about 3 ml under vacuum at r.t. Diethyl ether and saturated aqueous NaHCO3 (30 ml
each) were added to the reaction solution. After separation, the aqueous layer was
extracted with EtOAc, the combined organic layer was washed with 5 % aqueous sodium
thiosulfate, brine and dried over anhydrous Na2SO4. Removal of the solvent gave 20 a
colorless oil ( 1.88 g, 90 %).[a]2°D -35.9 (c 1, CHC13); 1H NMR (CDC13): 5 4.56(m, 1H,

H-2), 3.23(dd, 1H, J=10.7 Hz, 5.3 Hz, li-l.a), 3.13(dd, 1H, J= 10.7 Hz, 4.8 Hz, H-lb),

134

2.94-3.04(m, 2H, H-4), 2.03-2.10(m, 2H, H-3), 1.92(s, 3H, CH3CO); 13C NMR (CDC13):
8 -020 (C-4), 7.53 (C-l), 20.77 (CH3CO), 37.41(C-3), 71.42(c-2), 169.1 (CH3CO);

Anal. Calcd for C6H101202: C, 19.59; H, 2.74. Found: C, 19.69; H, 2.62.

Triflnoroacetic acid as solvent for the reaction of (S)-3-hydroxy-tetrahydrofuran
with HI:

To a stirred solution of H1 in water (47 %, 1.55 g, 5.7 mmol) under ice-water bath was
added drop-wised trifluoroacetic anhydride (6.3 ml). After stirring another 10 min, the
ice-water bath was removed and (S)-hydroxytetrahydrofuran (0.50 g, 5.7 mmol) was
added. After stirring at 60°C for 2 h, NMR shown 8.4 % of 4-Iodo-l,2-butanediol — di-
trifluoroacetate was formed. The reaction solution was cooled to r.t. and then
concentrated to about 3 ml under vacuum at r.t, brine (10 ml) was added, followed by
addition of solid sodium thiosulfate until the Iodine color disappear, the mixture was then
extracted with THF (4 x 15 ml), the combined organic layer was dried, condensed. 82 %
(0.41 g) of the starting (S)-2-hydroxy-tetrahydrofuran was recovered through column
chromatography, 4-Iodo-(S)-2-hydroxy-butan-1-ol 11 was obtained as the hydrolyzed
product (67.5 mg, 5 %), which gave the same spectra as the product from reaction in

water.

(S)-4-Iodo-l,3-butanediol—diacetate (16)::9
To a stirred solution of H1 in water (47 %, 1.55 g, 5.7 mmol) under ice-water bath was
added drop-wised acetic anhydride (9.1 ml). After stirring another 10min, the ice-water

bath was removed and (8)-hydroxytetrahydrofuran (0.50 g, 5.7 mmol) was added. After

135

stirring at 60°C for 3 h, the reaction solution was cooled to r.t. and then concentrated to
about 3 ml under vacuum at r.t. Diethyl ether and saturated aqueous NaHCO3 (30 ml
each) were added to the reaction solution. After separation, the aqueous layer was
extracted with diethyl ether, the combined organic layer was washed with cold 5 %
aqueous sodium thiosulfate, brine and dried over anhydrous Na2SO4. Removal of the
solvent gave 16 as a colorless oil (1.32 g, 77.8 %): 1H NMR (CDC13): 5 4.42-4.51 (m,
1H, H-3), 4.11 (t, J = 6.2 Hz, 1H), 3.22-3.43 (m, 2H), 2.13-2.2.25 (m, 2H), 2.09, 2.03 (2

s, 3H each, 2 OAc); ”C NMR (CDC13): 5 171.7, 171.0, 69.4, 60.3,34.8, 21.1, 21.0, 7.8.

Reactions of 2,3,4,6-tetra-O-Acetyl-1.5-Anhydro-D-glucitol (27) with HI

A solution of H1 in AcOH (11 % w/w, 23.3 g, 20 mmol) containing compound 27 (0.664
g, 2.0 mmol) was stirred at 95°C for 18 h. Afler removing the solvent under vacuum,
EtOAc and saturated aqueous NaHCO3 (30 ml each) were added to the reaction solution.
After separation, the aqueous layer was extracted with EtOAc (2 x 30 ml), the combined
organic layer was washed with, brine and dried over anhydrous Na2S04. Removal of the
solvent followed by column chromatography gave compound 27 (30 %), 31 (30 %) and
32 (10 %).

1,5-anhydro-6-deoxy-6-iodo-D-glucitol (31)

'H NMR (CDCI3): 5 5.18 (t, J = 9.4 Hz, 1H), 4.98 (ddd, J = 5.8, 9.6, 10.6 Hz, 1H, H-),
4.86 (t, J = 9.3 Hz, 1H), 4,16 (dd, J = 5.7, 10.3 Hz, 1H), 3.36-3.26 (m, 3H, H-6, H-6’, H-
1), 3.10 (dd, J = 7.6, 11.7 Hz, 1H, H-l’), 2.04, 2.01, 2.00 (s, 3 H each, 3 OAc); l3c
NMR(CDC13): 5 170.18, 169.60, 169.35 (3 OAc), 77.27. 73.16, 72.22, 68.94, 66.56,

20.62, 20.59, 20.59 (3 OAc), 3.55 (06).

136

2,6-anhydro-l-deoxy-3,4,5-tri-O-acetate-L-xylo-Hex-l-enitol (32)

[(1]ZOD + 9.00 (c 1 CHC13); 'H NMR (CDC13): 8 2.12, 2.10, 2.09 (3 s, 9 H, 3 x OAc), 3.45
(dd, J = 8.3, 11.5 Hz, 1H, H-6), 4.07 (dd, J = 4.9, 11.5 Hz, 1H, H-6’), 4.35 (t, J = 1.5 Hz,
1H, H-l), 4.60 (t, J = 1.5 Hz, 1H, H-l’), 4.93 (m, 1H, H-S), 4.99 (t, J = 7.8 Hz, 1H, H-4),
5.47 (d, J = 7.8 Hz, 1H, H-3); l3C NMR(CDC13): 8 20.3, 20.3, 20.6 (3 Carbon, 3 CH3),
66.7 (C-6), 68.5 (2 Carbon) 72.0 (03, 4, 5), 95.4 (C-2), 153.5 (C-l), 168.9, 169.4, 169.4

(3 x OAc).

(S)-3-Hydroxy-tetrahydrothiophene (33)” 31

To a stirred solution of 1, 4—diiodo-2-butanol- acetate (0.368 g, 1.0 mmol) in ethanol (6.0
ml) was added Sodium sulfide nonahydrate (0.360 g, 1.5 mmol). After stirring under
reflux for 5 h, EtOAc (20 ml) was added. After filtration and condensation, 33 was
obtained as colorless oil (1.04g, 100%) [a]2°D -14.1 (c 1 CHC13); 1H NMR (CDC13):
5 1.75-1.84 (m, 1H, H-4a), 2.07-2.14 (m, 1H, H-4b), 2.13 (s, 1H, C(3) 0H), 2.76-2.98
(m, 4H, 2 H-2, 2 111-5), 4.56(m, 1H, H-3); l3C NMR(CDC13): 5 28.1 (C-5), 37.9 (C-4),

39.7 (02), 74.4 (GB).

l-Benzyl-3-(S)-hydroxypyrrolidine(34)°2’°°

To a mixture of benzylamine (0.54 g, 5.0 mmol) and potassium carbonate (1.4 g, 10.0
mmol) in acetonitrile (30 mL) was added 1,4-diiodo-(S)-2-butanol-acetate (1.84 g, 5.0
mmol). After refluxing for 12 h, the solvent was removed under vacuum, water (2.0 g)

and ethanol (10 ml) were added. The solution was then stirred under reflux forl h. After

137

removing the solvent, water and ethyl acetate (30 mL each) were added to the residue.
After separation and extracting the aqueous layer with ethyl acetate (2 x 30 mL), the
organic layers were combined. dried over Mg804 and concentrated under vacuum.
Purification using column chromatography on silica gel gave 34 as a colorless oil (0.53 g,
60%); [a]20[) -3.6 (c 1 CHC13); 'H NMR(CDC13): 8 1.62-1.77 (m, 1H), 207235 (in, 2
H), 2.50 (br, 1H), 2.52 (dd, J = 5.1, 10.0 Hz, 1H), 2.65 (dd, J = 2.2, 10.0 Hz, 1H), 2.82
(ddd, J = 4.1, 8.3, 8.3 Hz, 1H), 3.60 (s, 2H), 4.31 (m, 1H), 7.29 (m, 5H); I3C
NMR(CDC13): 5 35.0 (C-4), 52.6 (C-S), 60.3 (C-2), 63.1 (PhCH2), 70.7 (C-3), 127.0,

128.1, 128.8, 138.6.

3-Acetoxy-cyclopentane-1,l-dicarbohylic acid diethyl ester (35)

To a mixture of dimethyl malonate (0.66 g, 5.0 mmol) and KOBut in DMSO (15 ml) was
added a solution of 1,4-diiodo-(S)-2-butanol-acetate (1.84 g, 5.0 mmol) in DMSO(5 ml).
After stirring at r.t. for 48 h, brine and ethyl acetate (30 ml each) were added to the
residue. After separation and extracting the aqueous layer with ethyl acetate (2 x 30 mL),
the organic layers were combined, dried over MgSOa and concentrated under vacuum.

Purification using column chromatography on silica gel gave 3-Acetoxy-cyclopentane-
1,1-dicarbohy1ic acid diethyl ester 35 as a colorless oil (0.88 g, 65 %); [01]2°D -2.26 (c 1
CHC13); IH NMR (CDC13): 5 1.07-1.15 (m, 6 H, 2 0CH2CH3), 1.66-1.72 (m, 1H, H-5),
1.84 (s, 3H, OAc), 1.92 (dd, J = 1.1, 22.1 Hz, 1H, H-4), 2.03 (dddd, J = 4.8, 8.3, 13.4 Hz,
1H, H-4’), 2.23 (m, 1H, H-2), 2.30 (dt, J = 8.3, 13.4 Hz, 1H, H-5’), 2.44 (dd, J = 6.1, 14.9
Hz, 1H, H- 2’), 4.01-4.07 (1n, 4H, 2 OCH2CH3), 5.00-5.04 (m, 1H, H-3); I3C

NMR(CDC13): 513.67, 13.71 ( 2 OCH2CHy), 20.78 (OAc-CH3), 31.58 (C-4 or C-S),

138

31.63 (C-4 or C-5), 39.88 (C-2), 58.77 (C-l), 61.14, 61.28 (2 OCH2CH3), 75.33 (C-3),

170.13, 171.16, 171.59 (3 CH3CO).

139

4.8 References

[l] Giese B. Radicals in Organic Synthesis: Formation of Carbon—Carbon
Bonds, Pergamon Press, Oxford, 1986.

[2] Wakefield, B. J. Organolithium Methods; Academic: London, 1988.
[3] Yang, L.M.; Huang, L.F.; Luh, T.Y.. Org. Lett. 2004, 6, 1461.

[4] Bohlmann, R. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, 1.,
Ed.; Pergamon Press: Oxford, 1991, Vol 6, pp 203.

[5] Jeropoulos, S.; Smith, E. H. J. Chem. Soc, Chem. Comm. 1986, 21,1621.
[6] Rydon, H. N.; Tonge, B. L. J. Chem. Soc. 1956, 3043.
[7] Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem. 1972, 37, 2289.

[8] Garegg, P. J.; Johansson, R.; Orthega, C.; Samuelson, B. J. Chem. Soc., Perkin
Trans. 1 1982, 681.

[9] Harrison, G. C.; Diehl, H. Organic Synthesis, Wiley: New York, 1953; Collect.
Vol. 111. pp 370.

[10] Bandgar, B. P.; Sadavarte, V. S.; Uppalla, L. S. Tetrahedron Lett.200l, 42. 951.
[11] Jung, M.E.; Ornstein, P. L. Tetrahedron Lett. 1977, 31, 2659.
[12] Fernandez, 1.; Garcia, B.; Munoz, 8.; Pedro, J. R.; Salud, R. Synlett 1993, 489.

[13] Martinez, A. G.; Alvarez, R. M.; Vilar, E. T.; Fraile, A. G.; Barnica, J. 0.;
Hanack, M.; Subramanian, L. R. Tetrahedron Lett. 1987, 28, 6441.

[14] Olah, G. A.; Gupta, B. G.; Malhotre, R.; Narang, S. C. J. Org. Chem. 1980, 45,
1638.

[15] Wiley, G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. J. Am. Chem. Soc.
1964, 86, 964.

[16] Iranpoor, N.; Firouzabadi, H.; Aghapour, G.; Vaez zadeh, A. R. Tetrahedron 2002,
58, 8689.

[17] Ferreri, C.; Costantino, C.; Chatgilialoglu, C.; Boukherroub, R.; Manuel, G. J.
Organometallic. Chem. 1998, 554, 135.

[18] Joseph, R.; Pallan, P.; Sudalai, A.; Ravindranathan, T. Tetrahedron Lett. 1995, 36,
609.

140

[19] Hollingsworth, R 1.; J. Org. Chem. 1999, 64, 7633.

[20] Hollingsworth, R. 1.; Wang, G. J. Chem. Rev. 2000, 100, 4267.
[21] Bowden, K. Adv. Phys. Org. Chem. 1993, 28, 171.

[22] Bowden, K. Chem. Soc. Rev. 1995, 24, 431.

[23] Gervay, J .; Gregar, T. Q. Tetrahedron Lett. 1997, 38, 5921.

[24] Wiberg, N.; Holleman, A. F .; Wiberg, E. Inorganic Chemistry, Academic Press,
2001,pp432.

[25] Cataldo, F. Eur. Polym. J. 1996,32, 1297.

[26] Brown, H. C.; Prasad, J. V. N.; Vara, R. B. W. J. Am. Chem. Soc. 1986, 108,
2049.

[27] Bhat, K. L.; Flanagan, D. M.; Joullie, M. M. Synth Comm.1985, 15, 587.

[28] Hoye T. R.; Eklov B. M.; Ryba T. D.; Voloshin M.; Yao L. J. Org. Lett. 2004, 6,
953.

[29] Mimer, P.; Saluzzo, C.; Amouroux, R. Synth. Comm. 1995, 25, 613-627.

[30] Zhang, X.; Taketomi, T.; Yoshizumi, T.; Kumobayashi, H.; Akutagawa, S.;
Mashima, K.; Takaya, H. J. Am. Chem. Soc. 1993, 115, 3318-3319.

[31] Brown, H. C.; Prasad, J. V. N. V.; Zee, S. H. J. Org. Chem. 1985, 50, 1582.
[32] Bhat, K. L.; Flanagan, D. M.; Joullie, M. M. Synth Comm. 1985, 15, 587-598.

[33] Mehta, A.; Gupta, J. B.; Sarma, P. K. S. Preparation of 1-substituted-3-
pyrrolidine derivatives as muscarinic receptor antagonists. PCT Int. Appl. WO
2004056767 (2004).

141

Chapter 5

Preparation of Ribose Derived Nitrone and its

Application in the Preparation of Iminosugars

142

Abstract

Starting from D-ribose, a six-membered cyclic nitrone was prepared in 3 steps. The
nucleophilic reaction and 1,3-dipolar cycloaddition reaction of the nitrone prepared were
explored. Employing nitromethane as the nucleophile, a 2-aminomethyl-3,4,5-
piperidinetriol derivative was prepared without using the toxic TMSCN reagent.
Isoxazolidines were prepared by the 1,3-dipolar cycloaddition of the nitrone with allyl
alcohol and vinyl ethyl ether. Spiro-isoxazolidines were also prepared by employing
carbohydrate derived alkenes. The cycloaddition reactions of nitrone and carbohydrate
derived alkenes are highly regio and diastereoselective, only one product was obtained

from each alkene.

143

5.1 Introduction

5.1.1 Iminosuars as glycosidases inhibitors

Glycosidases catalyze the hydrolysis of glycosidic bonds in carbohydrates, glycoproteins
and glycolipids" 2. Glycosidases are involved in the biosynthesis of the oligosaccharide
chains and quality control mechanisms in the endoplasmic reticulum of the N-linked
glycoproteins. Inhibition of these glycosidases can have prbfound effects on quality

control, maturation, transport, and secretion of glycoproteins and can alter cell-cell or

cell-virus recognition processesz' 3 .

In 1966 nojirimycin was discovered as the first glucose analog with the nitrogen atom in
place of the ring oxygen (iminosugars)4. Nojirimycin was first described as an antibiotic
produced by Streptomyces roseochromogenes R-468 and S. lavendulae SF-425 and was
shown to be a potent inhibitor of 01- and B-glucosidases from various sourcess. Since
then, over 100 iminosugars have been isolated from plants and microorganisms and many

of those natural occurring glycosidase inhibitors and their derivatives or analogues have

been synthesized”.

In recent years, the biological activities of these iminosugars have been extended to the

10. ll 13

inhibition of glycosyltransferases , of nucleosidase'z‘ and

14

glycogenphosphorylases , and of sugar nucleotide mutase's‘ '°. These remarkable

properties of iminosugar give tremendous opportunities in the development of iminosugar

17,18 19,20

based medicines for a wide range of diseases, such as diabetes , viral infections ,

and tumor metastasis” 22.

144

The strong therapeutic potential of iminosugars has generated a huge interest in their
synthesis and structural modification and has stimulated many groups to develop short

and stereoselective routes for their synthesis. Many recent syntheses use readily available

2 26-28

and inexpensive chiral-pool starting materials such as carbohydrate323' 5, amino acids ,

and tartaric acids29‘ 3°. Sharpless asymmetric epoxidation and dihydroxylation reactions

have found successful applications in the chiral synthesis of azasugars3 "33.

5.1.2 Application of nitrones in the preparation of iminosugars and aza-C-
glycosides.

For the preparation of the iminosugars and aza-C-glycosides from carbohydrates23'25,
usually, the nitrogen functionalities were installed at very late stage of the synthesis and
thus make the preparation of libraries of nitrogen containing carbohydrate mimics very
tedious. If the nitrogen functionality can be introduced at the early stage, or carbohydrate
derivated synthons containing nitrogen functionality can be prepared, the preparation of
the iminosugar libraries will be much easier. Recently, carbohydrate derivated nitrones
have been used as the nitrogen containing chiral starting materials for the preparation of

iminosugars34'38.

The carbohydrate derivated nitrones can be classified into two categories based on the

position of the nitrone functionality: the acyclic nitrones and the cyclic nitrones (Figure

5.1).

145

'1'
2—0

'1’
PO / §\

11
GP

Figure 5.1 General structure of carbohydrate based acyclic and cyclic nitrones.

The acyclic nitrones can be prepared very efficiently by condensation of the carbonyl
groups, usually aldehydes. with hydroxyl amines”. Figure 5.2 list some of the acyclic

nitrones.

 

Figure 5.2 Carbohydrate based acyclic nitrones.

For the preparation of cyclic nitrones, usually, the protected carbohydrates are first
condensed with protected hydroxylamines to form the protected oximes. Transforming
one of the hydroxyl groups to a good leaving group followed by deprotection of the

oxime give the cyclic nitrones (Figure 5.3 I).

146

op
”WM... OP

Deprotection

Cyclization

O'
I

Ni

ii)

POWO

n-‘l

fl LG formation

OP

PO 114
LG
Condensation
fl Cyclization

2—0

+
\

OP

Figure 5.3 Strategies for the preparation of cyclic nitrones.

Recently, Goti et al reported the preparation of the cyclic nitrone 8 from L-xylose (Figure

5.4)“.

147

BnO OBn

“0 9°” a, b, c 3110 pan (1 g
b "“ “ —*
HO O "II/OH HO O .,,’/oan 5n...— u,,/OBn
THPO "0
4 5 6
8110 QBn f g Bnobf:
e 3 .
—-———. -——-—>
\ OBn
éN....——-f—>'I”/OB'1 H N
THPO "8° 1')
7 8

Figure 5.4 Preparation of cyclic nitrone from L-xylose (a) MeOH/H2SO4, anhydr.
Na2SO4, rt, 21 h; (b) BnCl/KOH, Na2SO4, reflux, 8 h; (c) 6N HCl, CH3COOH, 60—70°C
(50% over three steps); (d) NH2OTHP, no solvent, rt, 6 d, 100%; (e) MsCl, TEA, CH2C12,
rt, 24 h, 50%; (DDOWEX 50W X8, MeOH, rt, 24 h, 96%; (g) 0.1 M NaOH, dioxane,

0°C, 2 h, 55%.

From these acyclic and cyclic nitrones, a variety of iminosugar derivatives have been
prepared through the addition reaction and 1,3-dipolar cycloaddition reactions. For recent
developments in the nucleophilic addition reactions of chiral nitrones, Merino’s review is
a good resource“. in another review, the application of 1,3-dipolar cycloaddition

reactions of nitrones in the construction of carbohydrate mimics were discussed”.

Although progresses have been made in the preparation of carbohydrate derived nitrones,
these processes are not very efficient, especially for the preparation of cyclic nitrones.
Usually, the expensive THPONH243 or TBDPSONH244 is needed or the oxime

intermediates formed have to be protected” .

148

In this chapter, a different method was used for the preparation of cyclic nitrone. In this
approach, the good leaving group is installed at first. The following one-pot
condensation-cyclization reaction gives the cyclic nitrone directly. No protected

hydroxylamines or extra steps to protect-deprotect the oxime is needed (Figure 5.3 II).

In the addition reactions of nitrones, for the introduction of the aminomethyl group,
TMSCN as a nucleophile gave good results4°’ 47. However, the high toxicity of TMSCN
prohibits its practical application. For the cycloaddition reactions of nitrones, usually, the
alkenes used were not derivated from carbohydrates. In the rare cases where the alkenes
were derivated from carbohydrates, the olefin functionalities are usually not connected to

the carbohydrate ring“.

Here, our efforts for the development of a more efficient and economic method for the
preparation of carbohydrate derived nitrone and its application in the addition and

cycloaddition reactions involving carbohydrate derived alkenes are discussed.

5.2 An efficient route for the preparation of cyclic nitrone from ribose.

Reaction of D-ribose with acetone using concentrated H2804 as the catalyst gives 2,3-
O-isopropylidene-D-ribofuranose in quantitative yield. Reaction of 2,3-O-isopropylidene-
D-ribofuranose with tosyl chloride in pyridine at 0°C affords 5-O-tosy1-2,3-O-

isopropylidene-D-ribofuranose 10 in 78 %. 10 is unstable at room temperature and is

149

used directly in the next step without further purification. (At -17 °C, tosylate 10 can be

stored for several weeks without obvious change).

1'(DH Ct (P- (3
8 2 + O
HOH2C O OH C N\
C) (”1 ——3LE—a» “""“_" +
W “0‘ ' "o

O O ; O O
on 01-1 x o-fi X
9 1o 11 12
Figure 5.5 Preparation of nitrone using tosylate as substrate. (a) acetone, conc. H2804,

quantitative; (b) tosyl chloride. pyridine, 78 %; (c) H2NOH.HC1, base, various yields.

For the condensation-cyclization step, various bases and solvents are used. The results are
listed in Table 5.1.

Table 5.1 Preparation of nitrone using tosylate as substrate.

 

 

Entry Base Solvent Time (h) Yield (%)
l NaHCO; MeOH 24 6

2 NaHCO; MeOH/H2O 12 1 1

3 NaHCO; i-PrOH 30 5

4 NaHCO; i-PrOH/ H20 12 ~7

5 NaHCO; EtOH 24 ~ 5

6 NaHCO3 EtOH/H2O 12 ~ 6

7 Pyridine MeOH 24 -

8 Et3N MeOH 24 12

9 Et3N EtOH 24 15

 

* Reactions are run at room temperature, TLC are used to monitor the reactions.

150

The base used is crucial to this reaction. If pyridine is used, no nitrone 11 can be formed.
Changing the base to NaHCO3, nitrone 11 is formed in various solvent. The best result is
obtained in MeOH/ H2O with 11 % of nitrone 11 formed (Table 5.1, entry 2). A better
result was obtained by using Et3N as the base and ethanol as solvent (15 %, Table 5.1,
entry 9). For all the reaction conditions listed in table 5.1, except entry 7, along with the
nitrone, a small amount of the 2,3-O-isopropyliden-l,4-anhydro-D-ribopyranose was
formed (4-10 % yield). The other components obtained were complex mixture of
compounds. The possible products from the reaction of tosylate 10 with hydroxylamine
under basic conditions are shown in Figure 5.6. No further efforts are made to separate

and characterize these compounds except 11 and 12.

151

9-
TOO /\ N"
kl \
°" -u*°” —. O
HO‘ L ’o
o 0 °“{\
X 11
no
OQNmH

T30 T80 OH
NHOH '
N H2N0H ""0" U
——* —+ ‘ ‘ . 0’

 

\ o’"‘ 0’ \
%‘OH I K) ' 'OX 4» T.o\\\‘ do

0 o 8.9 6t
x

Figure 5.6 Possible products from reaction of tosylate 10 with hydroxylamine under

basic conditions

152

Fortunately, much better results are obtained by switching tosylate 10 to mesylate 14

(Figure 5.7, Table 5.2).

Figure 5.7 Preparation of nitrone using tosylate as substrate.

' (a) Mesyl chloride, pyridine, 75 %; (b) H2NOH.HC1.

Table 5.2 Preparation of nitrone using mesylate as substrate.

 

 

Entry Base Solvent Time (h) Yield (%)
l NaHCO; MeOH 24 14
2 NaHCO3 MeOH/H2O 12 18
3 NaHC03 EtOH 24 l 5
4 NaHCO; EtOH/H20 12 22
5 Et3N MeOH 24 25
6 Et3N EtOH 24 62

 

* Reactions are run at room temperature. TLC is used to monitor the reaction.

The best result is obtained with Et3N as the base and EtOH as solvent (62 %, entry 6,

Table 5.2). Although the yield is still not very high, considering the short steps and the

cheap reagents used, this is still a practical route for the preparation of nitrone from D-

ribose.

153

5.3 Steroeselective addition of nitromethane to the chiral nitrone.
To search for a substitute of TMSCN as the reagent for the introduction of an

aminomethyl group to the nitrone, nitromethane is chosen since it is much less toxic

compared to TMSCN and also it has been used extensively for Michael Reactions,”52

Henry Reaciton553’ 54.

I '1

N —K .

N02 6~$
15 15
OH
N «NO: I
1' N (R) /N02

1”

Figure 5.8 Possible products from addition of nitromethane to nitrone

Two possible transition states were shown in figure 5.8 for the nucleophilic addition of
nitromethane to nitrone. Addition of nitromethane from the Re face (TS 15) of the nitrone
will give the 8 product 16 while addition of nitromethane from the Si face (TS 17) of the
nitrone will give the R product 18. In TS 15, the incoming nitromethane is anti to the
isopropylidene group, while in TS 17, it is syn to the isopropylidene group. The strong
steric interaction between the nitromethane group and the isopropylidene in TS 17 will
prohibit the Si face approach and thus it is expected that only the Re face attack will

happen and only the S product 16 can be obtained.

154

fl NH2

0
I
I
O

\“ ‘O’o \\ a \\‘
HO HO H0

11 16 19
Figure 5.9 Addition of nitromethane to nitrone. (a) MeN02, MeONa, MeOH, r.t, 12 h, 82
%; (b) H2, Pd/C (10 %), MeOH, 100 %.
The reaction of nitrone 11 with nitromethane is very efficient. Using MeONa as the base,
with 2 equivalent of MeN02, the reaction is completed in 12 h with a high yield (82 %).
NMR showed only one product is formed. The stereochemistry of the nitro compound
was confirmed by the NOE. No NOE is observed between H3a and H4, which suggests
that they are anti to each other as in structure 16. Treatment of the nitro compound 16
with H2 using Pd/C as catalyst give the reduced product 19 in quantitative yield (Figure

5.9).

5.4 Cyclization reactions of the ribose derived nitrone with non-carbohydrate based
alkenes

For the 1,3-dipolar cycloadditions of nitrones to akenes, usually, the 5-substituted
isoxazolidines are obtained from mono-substituted and 1,1-disubstituted alkenes with
electron-donating and moderate electron-withdrawing groupsss’ 5°. For olefins with strong
electron-withdrawing groups, the 4-substituted isoxazolidines are forrned57’58. If 1,2-
disubstituted alkenes are used, mixtures of regioisomers are often formed. Usually, the
isomer with the less electron rich substituent at 4-position is formed as the major

product59'°' .

155

To control the stereochemistry outcome of the 1,3-dipolarcycloaddtion, many methods
have been developed, for example, Lewis acids activation of the dipolarophiles, using
chiral auxiliaries, employing enantioselective catalysts (metal or organo-catalysts), etc°2’
°3. For chiral nitrones, the steric hindrance plays an important role in control the
approaching of the alkenes toward the nitrones, which makes it possible to achieve high
regio and stereo control for cycloaddition reactions of chiral nitrones without the

assistance of Lewis acids, chiral auxiliaries or catalysts“.

A model for the cycloaddition of the chiral nitrone 11 with allyl alcohol is shown in
figure 5.10. As in the nucleophilic addition reactions of the chiral nitrone (Figure 5.8),
allyl alcohol can only approach nitrone 11 from the Re face to form the anti product. In
figure 5.10, only the transition states with Re attack of the alkenes to the nitrone are

shown.

156

1' HO‘ ‘ ‘

L_:’,’/—OH HO‘ v

110‘“
I

 

24

 

, 140‘"
ll

270

Figure 5.10 Possible products from cyclization of nitrone with allyl alcohol

26

There are 4 possible products from the 1,3-dipolar cycloaddition of nitrone toward allyl
alcohol: the exo-4 (4 substituted isoxazolidines 21), endo-4 (23), exo-S (5 substituted
isoxazolidines 25) and endo-S (27). Since no strong electron withdrawing group present
in allyl alcohol, the cycloaddition reaction should show high region-selectivity with only
the 5 substituted isoxazolidines 25, 27 formed. As for 25 and 27, the exo-S product 25 is

expected to be formed as the major product for steric reason. It is reported that for the

157

cycloaddition of 6-member-ring nitrone, 3-(tert-butyldiphenylsi1yl)oxy-l-piperidine-l-
oxide with allyl alcohol, a 90:10 exo/endo-selectivity, 74:26 diastereofacial selectivity
was observed“. For the cycloaddition of 5-member—ring nitrone, 3-(tert-
butyldimethylsilyl)oxy-l-pyrroline-l-oxide with allyl alcohol, a 85:15 exo/endo-
selectivity, 82:18 diastereofacial selectivity was observed in the favorite formation of the

exo product65 .

Refluxing nitrone 11 with allyl alcohol in toluene for 4 h give the cycloaddition products
in 92 % yield (Figure 5.11). The reaction is highly regio-selective as no endo-4 or exo-4
product 21 or 23 is observed. For the two exo-5 and endo-5 products 25 and 27, 25 is
formed as the major product (89:11). The stereochemistry was confirmed by NOESYID.

No NOE between H-2 and H-3a is observed for the major product 25 while a 13 % NOE

is observed between H-2 and H-3a in the minor product 27.

+ _
0 KO”
110“" . "/0 toluene, reflux

3 4n92% ,
O$ HO\\‘

11 25 89:11

2—0

 

   

Figure 5.11 Cycloaddition of nitrone with allyl alcohol

Next, the cycloaddition of nitrone 11 with vinyl ethyl ether is studied. Similarly, no syn
product should be formed as the vinyl ethyl ether can only attack the nitrone from the Si

face. Vinyl ether type alkenes always give the 5-substituted isoxazolidines in

158

cycloaddition reaction with nitrones°°88. So the expected products are only the exo-5 and

the endo-5 products 29 and 31 (Figure 5.12).

..——--0'
1+
““Q
OX0
I
i
1 CD
1 X
1 O
l or
l
I
l
l

 

_ 110“"
/—0
28
OH 0
. + f , endo 5
(?_N\ O7< ------------------ ->
x0 : ’1 \\" '2
\ I _ I H0 '. I
30 WK

31

Figure 5.12 Products from cycloaddition of nitrone with vinyl ethyl ether
Heating a mixture of nitrone 11 and vinyl ethyl ether in chloroform at 62°C in a sealed
flask for 4 h give the cycloaddition products in 94 % yield (Figure 5.13). As expected, no
endo-4 or exo-4 product is observed. For the two exo-5 and endo-5 products, exo-5 is
formed as the major product (68:32). The stereochemistry is confirmed by NOESYID.
No NOE between H-2 and H-3a is observed for the major product while 11 % NOE was

observed between H-2 and H-3a in the minor product.

 

   

O
I ——
it: \o /
Ho“" , "/0 chloroform, 62°C H0“ H0
6‘0 4h, 94%
11 2° 68 :32

Figure 5.13 Reaction of nitrone with vinyl ethyl ether

159

5.5 Cycloaddition reactions of the ribose derived nitrone with carbohydrate based
alkenes

After the successful cycloaddition reactions of the nitrone with non-carbohydrate based
alkenes, the carbohydrate based alkenes are used in the 1,3-dipolar cycloaddition
reactions. Alkenes 34 and 37, derived from methyl-D-glucopyranoside and 1,5-anhydro-

D-glucitol, are used.

OH
c
HO O a! b A60 0 ACAO O O
HO ————’ A60 c
OH R

32R'OMO 33R'OMO 32:35“
35RBH 38R=H

Figure 5.14 Preparation of carbohydrate derived alkenes. (a) Ph3P/I2, imidazole, toluene,
70°C, 3 h; (b). AC2O/pyridine, r.t, 12 h, 2 steps, 68 % for 33, 65 % for 36. (c) DBU,

DMF, 751151, 3 h, 75 % for 34, 76 % for 37.

Conversion of the primary hydroxyl groups to iodides followed by elimination of H1
under strong basic conditions give the carbohydrate derived alkenes 34 and 37 in modest

yields (~52 %, Figure 5.14).

As discussed above, alkenes only approach the nitrone 11 from the Si face. For the vinyl
ether type alkenes, the 5—substituted isoxazolidines are formed with modest to high
exo/endo selectivity. Similar results are expected for the 1,3-dipolar cycloaddition of the
carbohydrate derived vinyl ether type alkenes 34 and 37. However, higher exo/endo

selectivity is expected since the chiral alkenes 34 and 37 are used.

160

Refluxing nitrone 11 and alkene 34 in toluene for 12 h give only one product in a very
high yield (96 %, Figure 5.15). No NOE was observed between H3’ and H301, which
suggests the structure of the product is the spiro-isoxazolidine 39. The high
diastereoselectivity is not surprising when the two possible transition states 38 and 40 are
considered. In the two transition states, the one with fewer groups which are endo to the
nitrone ring and at the same time syn to the isopropylidene group will be favored. In
transition state 38, the 3- and 4-acetyl groups are endo to the nitrone ring while only 3-
acetyl group is syn to the isopropylidene group. In transition state 40, only the 1-
methoxyl group is endo to nitrone the nitrone ring and at the same time syn to the
isopropylidene group. Although both the 3-acetyl group in 38 and l-methoxyl group in
40 are at [5 position to the alkene, the shorter C-O bond makes the l-methoxyl group in
40 more sterically hindered than the 3-acetyl group in 38. From the sterically favored

transition state 38, the product 39 is formed exclusively.

161

3’
.3
.3 0‘"

toluene, reflux
12 h, 96 %

O
I

>
o
10

AcO

U
-----o -
l I
Egg
:-
O
0
cl
0
-----o-
|
2+
{2‘2
o>€

Aco‘“.

0%

I
8.
8
D
O
01:.
O
>
0

OAc

OM
AcO e

110“"

   

39

41
96 % not observed

Figure 5.15 Cycloaddition of nitrone with carbohydrate derived alkene I

From the above analysis, if the 1-methoxyl group was removed, as shown in figure 5.16,

transition state 44 should be favored and the product 45 should be formed as the major
product.

162

‘1’
N
Ac 0 \
AcO + ,. .
Ho“ . ’I

OAc ;
o“/\
37 1 1

toluene. reflux
10 h. 89 %

AGO " I
be
AcO‘w 0

110“"

 

not observed

Figure 5.16 Cycloaddition of nitrone with carbohydrate derived alkene 11

Only one product was obtained by the cycloaddition reaction of nitrone 11 and alkene 37
(89 %, Figure 5.16). A high NOE between H3’ and H301 was observed (NOE: H301, H30

30 %, H301, H3’ 15 %), which means the structure is the spiro-isoxazolidine 45 from

transition state 44.

163

5.6 Conclusion

Start from D-ribose, a six-membered cyclic nitrone was prepared in 3 steps. The
nucleophilic reaction and 1,3-dipolar cycloaddition reaction of the nitrone prepared were
explored. Employing nitromethane as the nucleophile, a 2-aminomethyl-3,4,5-
piperidinetriol derivative was prepared without using the toxic TMSCN reagent.
Isoxazolidines and Spiro-isoxazolidines were prepared by the 1,3-dipolar cycloaddition of
the nitrone with achiral and chiral alkenes. For the chiral carbohydrate derived alkenes,
the cycloaddition reaction is highly diastereoselective, only one product was obtained

from each alkene.

164

5.7 Experimental

General procedures: lH, l3C NMR spectra were recorded at 500, 125, MHz, respectively,
with a Varian instrument at 293 K. The chemical shifts are given in ppm using CDC13
residue as reference (5 7.24 ppm) for lH and relative to the central CDC13 resonance (5=
77.00 ppm) for '3 C NMR unless otherwise specified. lH and 13 C are assigned on the basis
of 2D lH COSY and IH-BC chemical-shift correlated experiments. For the 1,3
cyclization products, all the NMR were done at 100°C with DMSO-d6 as solvent.
Melting points were determined on a Fisher-Johns melting point apparatus (uncorrected).
Optical rotations were measured on a Jasco P1010 polarimeter at 20°C. IR spectra (wave
numbers in cm") were recorded on a PT IR Nicolet 740 spectrometer in CHC13 solutions
or KBr pellets. All chemicals were purchased from Aldrich Chemical Co. and used

without further purification.

2,3-O-isopropylidene-D-ribofuranose (13)

In a 250 ml flask containing 100 m1 acetone, D-Ribose (10.0 gram, 66.6 mmol) was
added followed by the addition of cone. H2804 (1.0 ml). After stirring at r.t. for 4 h,
NaHCO3 (4.0 gram) was added. Stirring was continued until the pH of the solution is 7.
Filtration followed by removal of the solvent gave the product 13 as a syrup (12.6 g, 100
%). The product was used without further purification. lH NMR(CDC13): 5.43(s, 1H, H-
1); 4.59(d, J=5.9 Hz, 1H, H-2); 4.85(d, J = 5.9 Hz, 1H, H-3), (br, 1H, H-4), 3.81-3.66
(m, 2H, H-5, H-5’); 1.58(s, 3H, CH3); 1.41 (s, 3H, lH NMR (CDC13): 5.43(s, 1H, H-l);
4.59(d, J=5.9 Hz, 1H, H-2); 4.85(d, J = 5.9 Hz, 1H, H-3), (br, 1H, H-4), 3.81-3.66 (m,

2H, H-5, H-S’); 1.58(s, 3H, CH3); 1.41 (s, 3H, CH3); CH3); l3C NMR(CDC13): 112.06 (

165

C(CH3)2 ); 103.07(C-1); 87.82 (C-4); 86.89 (C-2); 81.68 (C-3); 63.65 (C-5); 24.74, 26.28

( 2 C(CH3)2 );

2,3-0-isopropylidene-S-O-Tosyl-I)-ribofuranose (10)

To a stirred solution of 2,3-O-isopropylidene-D-ribofuranose 13 (6.3 g, 33.3 mmol) in
pyridine (100 ml) at 0°C was added Tosyl chloride (6.35 g, 33.3 mmol) in 3 portions at
30 minutes apart. The reaction solution was warmed to r.t gradually and stirred for
another 12 h. Ethanol (5 ml) was added to quench the reaction. After removal of the
pyridine, the remaining syrup was partitioned between CHC13 and saturated aqueous
NaHCO3 (60 ml each). The aqueous phase was extracted with CHCl3 (30 ml) once and
the combined organic phases were washed with water, brine, dried over MgSO4 and
condensed to gave 10 as a syrup (8.9 g, 78 %). The product 10 is not stable at r.t and it is
used directly for the next step without further purification. A small amount of the product
was purified through column chromatography for characterization purpose. mp. 94-95
(lit 92.5-94 )69 'H NMR (CDC13): 8 7.73 (d, J = 18.2 Hz, 2H), 7.30 (d, J = 18.2 Hz, 2H),
5.36 (d, J = 2.6 Hz, 1H, H-l), 4.58 (dd, J = 0.9, 5.8 Hz, 1H, H-3), 4.51 (d, J = 5.9 Hz, 1H,
H-2), 4.25 (m, 1H, H-4), 4.02-4.06 (m, 2H, H-5, H-S’), 3.69 (br s, 1H, OH), 2.39 (s,
ArCH3), 1.39, 1.23 (s, 2 C(CH3); l3C NMR(CDC13): 5145.07, 132.37, 129.95, 127.84,

112.52, 102.82, 85.44, 83.55, 81.41, 69.87, 26.17, 24.65, 21.50.

2,3-O-Isopropylidene-S-O-methanesulfonyl-B-D-ribofuranose (14)
To a stirred solution of 2,3-0-isopropylidene-D-ribose 13 (5.0 g, 26.3 mmol) in pyridine
(50 m1) at 10251 was drop-wise added methanesulfonyl chloride (3.10 g, 26.3 mmol). The

reaction mixture was gradually warmed to r.t and stirring was continued for another 4 h.

166

Ethanol (5 ml) was added to quench the reaction. After removal of the pyridine under
vacuum, CH2Cl2 (30 ml) and water (30 ml) were added. After extraction the aqueous
phase with CH2C12 (30 ml), the organic phases were combined, washed with cold 3 M
HCl (20 ml), saturated aqueous NaHCO3, and dried over MgSO4. Removal of the solvent
gave 14 as a white solid (5.4 g, 76.6 %). Part of the product was recrystalized from
CH2Cl2/Et20 for characterization purpose. M.p. 112-113°C (lit 112-114)70 'H NMR
(CD3CN): 5 5.35 (s, 1H, H-I), 4.68 (d, J = 5.9 Hz, 1H, H-3), 4.55 (d, J = 5.9 Hz, 1H, H-
2), 4.18-4.27 (m, 3H, H-4, 11-6, H-6’), 3.09 (s, MeSO2), 1.49, 1.34 (s, 2 C(CH3); l3C

NMR(CD3CN): 5 112.18, 102.74, 85.93, 83.46, 81.58, 71.13, 37.01, 26.10, 24.44.

(3aS, 7R, 7aR)-3a, 6, 7, 7a-tetrahydro-2, 2-dimethyl-5-oxide-1, 3-Dioxolo [4, 5-c]
pyridin-7-ol (1 1)

Method 1: From 2,3-O-isopropylidene-5-O-Tosyl-D-ribofuranose

To 5 ml water was added NaHCO3 (1.26 g, 15 mmol) and H2NOH.HCI (1.04 g, 15
mmol), the mixture was stirred until no bubble come out. This solution was then
transferred to a flask containing a solution of 2,3-O-isopropylidene-5-O-Tosyl-D-
ribofuranose (1.03 g, 3 mmol) in methanol (15 ml). After stirring at r.t. for 24 h, the
solution was then condensed under vacuum with the bath temperature at no higher than
25°C to a syrup. Column chromatography of this syrup gave the desired nitrone 11 in 24

% yield.

Method 2: From 2,3-O-Isopropy1idene-S-O-methanesulfonyl-B-D-ribofuranose

167

 

To 5 ml water was added NaHC03 (1.26 g, 15 mmol) and H2N0H.HCI (1.04 g, 15
mmol), the mixture was stirred until no bubble come out. This solution was then
transferred to a flask containing a solution of 2,3-O-isopropylidene—5-0-
methanesulfonyl-D-ribofitranose (0.805 g, 3 mmol) in methanol (15 ml). After stirring at
r.t. for 24 h, the solution was then condensed under vacuum with the bath temperature at
no higher than 25°C to a syrup. Column chromatography of this syrup gave the desired

nitrone 11 in 30 % yield.

Method 3: From 2,3-O-Isopropylidene-5-O-methanesulfonyl-B-D-ribofuranose with
Et3N as base

To 10 ml ethanol was added Et3N (1.52 g, 15 mmol) and H2NOH.HC1 ( 1.04 g, 15 mmol),
the mixture was stirred until the entire solid dissolved. This solution was then transferred
to a flask containing a solution of 2,3-0-isopropylidene-S-O-methanesulfonyl-B—D-
ribofuranose ( 1.03 g, 3 mmol) in ethanol (15 ml). After stirring at r.t. for 24 h, the
solution was then condensed under vacuum with the bath temperature at no higher than
25°C to a syrup. Column chromatography (Hexane/EtOAc/EtOH 1:1:0 to 0:1 :1) of this

syrup gave the desired nitrone in 11 62 % yield.

[61200 -148.75 (c 1 CHC13); 'H NMR (CDC13): 1.41 (s, 3H, ), 1.44 (s, 3H), 2.15 (s, 1H,
0H), 3.88 (dd, J = 4.8, 14.3 Hz, 1H, H-6a), 3.96 (ddt, J = 1.5, 11.3, 14.3 Hz, 1H, H-6b),
4.14 (ddd, J = 3.1, 4.8, 9.2 Hz, 1H, H-7), 4.50 (dd, J = 3.0, 6.4 Hz, 1H, H-7a), 4.85 (dd, J
= 3.5, 6.4 Hz, 1H, H-3a), 7.05 (dd, J = 1.8, 3.5 Hz, 1H, H-4); I3C NMR (CDC13): 134.3
(C-4), 110.9, 72.2, 70.6, 64.1, 58.1 (06), 26.8, 25.4. Calculated for C8H13N04 C,

51.33, H, 7.00, N, 7.48; Found C 51.30, H, 6.94, N, 7.50.

168

1,5-anhydro-2,3-O-(l-methylethylidene} B-D-Ribofuranose (12)70

[61200 -72 (c 1 CHC13); 'H NMR(CDC13): 8 5.43 (s, 1H, H-l), 4.69 (d, J = 3.7 Hz, 1H,
H-4), 4.27 (d, J = 5.5 Hz, 1H, H-2), 3.42 (dd, J = 3.8, 7.2 Hz, 1H, H-5a), 3.30 (d, J = 7.2
Hz, 1H, H-Sb), 1.46, 1.29 (2 s, 3 H each, C(Me)2 ); 13C NMR (CDC13): 112.0, 99.7 (C-l),

81.1 (C-2), 79.3 (C-3), 77.4 (C-4), 63.0 (C-5), 25.8, 25.1 (CMe2).

(3aS, 4S, 7R, 7aR)-2,2-Dimethyl-4-nitromethyl-tetrahydro-[1,3]dioxolo[4,5-
c]pyridine-5,7-diol (16)

To a stirred solution of nitrone 11 (46.7 mg, 0.25 mmol) in methanol (2.0 ml) was added
nitromethane (61 mg, 1.0 mmol) and MeONa (13.0 mg, 0.25 mmol). After stirring at r.t
for 8 h, the reaction mixture was cooled to 0°C and 3 N HCl was added to adjust the
solution pH to 7. After condensation, ethyl acetate and water (10 ml each) were added to
the flash. The aqueous layer was separated and extracted with ethyl acetate twice (2 x 10
ml). The combined organic extracts were washed with water, brine, dried over MgSO4.
Condensation followed by column chromatography (chloroform : methanol 25 : 1) gave
16 as a white solid (50.8 mg, 82 %). [6120.) -352 (c 1 CHC13); 1H NMR (DMSO): 8 7.87
(br s, 1H, N-OH), 4.63 (dd, J =. 7.7, 13.0 Hz, 1H, CH2N02), 4.56 (dd, J = 3.6, 13.0 Hz,
1H, CH2NO2), 4.32 (t, J = 4.2 Hz, 1H, H-7a), 4.09 (ddd, J = 3.9, 5.0, 11.3 Hz, 1H, H-7),
4.01 (dd, J = 4.5, 9.1 Hz, 1H, H-3a), 3.23; (ddd, J = 3.5, 7.7, 11.2 Hz, 1H, H-4), 3.08 (dd,
J = 5.1, 11.3 Hz, 1H, H-6), 2.73 (t, J = 11.3 Hz, 1H, H-6’), 1.50, 1.34 (2 s, 3 H each,
CMe2); l3C NMR(DMSO): 5108.59, 75.47, 74.73, 72.77, 64.10, 61.95, 57.70, 27.37,

25.68; NOESYID: no NOE observed between H-4 and H-3a;

169

(3aS, 4S, 7R, 7aR)-4-Aminomethyl-2,2-dimethyl-hexahydro-[l,3]dioxolo[4,5-
c]pyridine-7-ol (19)

To a solution of 16 (0.128 g, 0.5 mmol) in methanol (5 ml) was added Pd/C (10 %, 40
mg), the solution was stirred under H2 atmosphere (1 atm) for 8 h. Filtration of the
solution through celite followed by removal of the solvent gave the hydrogenated product
19 in quantitative yield ( 0.101 g, 100 %).

[01200 (c 1 CHCl3); lH NMR (DMSO): 5 4.61 (dd, J = 4.6, 11.3 Hz, 1H), 4.34 (t, J = 4.2
Hz, 1H), 4.27 (t, J = 4.2 Hz, 1H), 4.07 (ddd, J = 4.2, 4.9, 11.3 Hz, 1H), 4.00 (dd, J = 4.6,
9.4 Hz, 1H), 3.81-3.84 (m, 1H), 3.67-3.74 (m, 1H), 3.06-3.12 (m 1H), 3.03 (dd, J = 5.5,
9.8 Hz, 1H), 2.90-2.98 (m, 1H), 2.77 (dd, J = 6.5, 11.5 Hz, 1H), 1.47, 1.33 (2 s, 3 H each,

2 CMe2); '3 C NMR(DMSO): 5 74.83, 74.40, 62.37, 57.75, 57.77, 53.50, 27.49, 25.80.

Cycloaddition of nitrone (11) with allyl alcohol:

To a solution of nitrone (93.5 mg, 0.5 mmol) in toluene (5.0 ml) was added allyl alcohol
(145 mg, 2.5 mmol). The reaction mixture was stirred under reflux for 6 h. Removal of
the solvent gave a syrup (112 mg, 92 %, 89 : 11 by NMR), which is a diastereomeric
mixture of the cyclization products and can not be separated by column chromatography.
Crystallization from chloroform gave the 2S anomer 25 as white crystals (75 mg, 61 %). '
Upon standing at —17°C for 48 h, the 2R anomer 27 was obtained as a crystal from the

mother liquid (14 mg, 11 %).

(ZS, 3aS, 48, SR, 6R) 2-methanol-4,5-0-isopropylidene-6-hydroxyl-hexahydro-2H-

Isoxazolo [2,3a] pyridine (25)

170

 

1H NMR (DMSO): 5 4.28-4.42 (br, 2 H, 2 OH), 4.23 (t, J = 4.3 Hz, 1H, H-5), 3.98-4.03
(m, 3 H, H-2, H-4, H-6), 3.40-3.42 (m, 2 H, CH2OH), 3.16 (dd, J = 4.9, 10.1 Hz, 1H, H-
7), 2.65-2.72 (m, 2 H, H-3a, H-7), 2.08-2.14 (m, 1H, H-3), 1.98 (ddd, J = 8.4, 11.2, 18.0
Hz, 1H, H-3’). 1.45, 1.32 (2 s, 3 H each, 2 CMe2); 13C NMR (DMSO): 5 108.02, 76.63,
75.81, 74.59, 63.88, 63.70, 62.61, 53.95, 34.91, 27.13, 25.36; Calculated for

C11H19N05 C, 53.87, H, 7.81, N, 5.71; Found C 53.60, H, 7.65, N, 5.86.

(2R, 3aS, 4S, 5R, 6R) 2-methanol-4,5-0-isopropylidene-6-hydroxyl-hexahydro-2H-
Isoxazolo [2,3a] pyridine (27)

1H NMR (DMSO): 5 4.49 (d, J = 2.1 Hz, 1H, C-6 0H), 4.27 (t, J = 5.5 Hz, 1H, CH2OH),
4.23 (t, J = 4.2 Hz, 1H, H-S), 3.98-4.02 (m, 3 H, H-2, H-4, H-6), 3.37-3.43 (m, 2 H,
CH2OH), 3.16 (dd, J = 5.7, 10.2 Hz, 1H, H-7), 2.65-2.71 (m, 2H, H-3a, H-7’), 2.12 (ddd,
J = 4.9, 7.0, 16.8 Hz, 1H, H-3), 1.98 (ddd, J = 8.5, 8.5, 16.8 Hz, 1H, H-3’), 1.46, 1.32 (2
s, 3 H each, 2 CMe2); 13C NMR (DMSO): 5 76.59, 75.78, 74.59, 63.87, 63.62, 62.57,
53.95, 34.88, 27.13, 25.36; NOESYID: no NOE observed between H-2 and H-3a;

Calculated for C11H19N05 C, 53.87, H, 7.81, N, 5.71; Found C 53.89, H, 7.88, N, 5.79.

Cycloaddition of Nitrone 11 with Vinyl ethyl ether

To a solution of nitrone 11 (93.5 mg, 0.5 mmol) in chloroform (5.0 ml) was added ethyl
vinyl ether (180 mg, 2.5 mmol). After sealing the flask, the reaction mixture was stirred
at 62°C 4 h. Removal of the solvent gave a syrup, which is a diastereomeric mixture of

the cyclization products (121.8 mg, 94 %). The diastereomeric mixture was separated by

171

 

 

column chromatography gave the pure 2R anomer 29 (58.3 mg, 45 %) and the 2S anomer

31 (40.1 mg, 31 %)

(2S, 3aS, 48, SR, 6R) 2-ethoxy-4,5-0-isopropylidene—6-hydroxyl-hexahydro-ZH-
Isoxazolo [2,3a] pyridine (29)

[(11200 + 57.53 (c 1 CHC13); lH NMR (DMSO): 5 5.10 (t, J = 4.3 Hz, 1H, H-2), 4.26 (t, J
= 4.8 Hz, 1H, H-5), 4.05 (t, J = 6.1 Hz, 1H, H-4), 3.99 (dt, J = 3.9, 9.9 Hz, 1H, H-6),
3.56-3.66 (m, 1H, OCH2CH3), 3.38-3.49 (m, 1H, OCH2CH3), 3.06-3.17 (m, 2 H, H-3a,
H-7), 2.94 (dd, J = 9.9, 11.1 Hz, 1H, H—7’), 2.16-2.20 (m, 2 H, H-3, H-3’), 1.44, 1.31 (s, 3
H each, , 2 C(CH3)2), 1.12 (t, J = 7.0 Hz, 3H, OCH2CH3); 13C NMR (DMSO): 5 107.91
(C(CH3)2), 99.86(C-2), 75.56, 74.15, 62.07 , 61.68, 60.33, 52.33, 40.29 (C-3), 26.72,
25.00 (2 C(CH3)2), 14.31; NOESYID: no NOE observed between H-2 and H-3a; Calcd.
for C21H31NO4 489.1846, found 489.1846; Calculated for C12H21N05 C, 55.58, H,

8.16, N, 5.40; Found C 55.70, H, 8.12, N, 5.10.

(2R, 3aS, 48, SR, 6R) 2-ethoxy-4,5-O-isopropylidene-6-hydroxyl-hexahydro-ZH-
Isoxazolo [2,3a] pyridine (31)

[a]200 -105.56 (c 1 CHC13); 'H NMR (DMSO): 8 5.11 (t, J = 3.1 Hz, 1 H, H-2), 4.24 (t, J
= 3.9 Hz, 1H, H-S), 4.04 (t, J = 5.4 Hz, 1H, H-4), 3.99 (m, 1H, H-6), 3.57-3.72 (m, 1H,
0CH2CH3), 3.40-3.53 (m, 1H, OCH2CH3), 3.25 (dd, J = 5.1, 9.4 Hz, 1H, H-7), 2.53-2.65
(m, 2 H, H3a, H-7’), 2.17-2.21 (m, 1H, H-3), 1.79-1.86 (m, 1H, H-3’), 1.45, 1.32 (2 s, 3
H each, 2 CMe2), 1.13 (t, J = 6.9 Hz, 3H, OCH2CH3); 108.09, 100.70, 75.24, 74.71,

65.15, 64.33, 62.22, 54.99, 40.38, 27.24, 25.38, 14.27; NOESYID: 11 % NOE observed

172

between H-2 and H-3a; Calculated for C12H21N05 C, 55.58, H, 8.16, N, 5.40; Found C

55.68, H, 8.19, N, 5.49.

l,5-anhydro-2,3,4-tri-O-acetyl-6-deoxy-6-iodo-D-glucitol (36)

To a solution of toluene (25 ml) containing triphenylphosphine (3.05 g, 12.0 mmol),
iodine (2.98 g, 12.0 mmol) and imidazole (2.45 g, 36.0 mmol) were added 1,5-anhydro-
D-glucitol (1.64 g, 10 mmol). The reaction mixture was stirred at 701151 for 3 h and then
cooled to r.t. After adding water (30 ml), the mixture was stirred vigorously for 30 min.
After separation, the toluene phase was extracted with water (3 x 20 ml). The combined
water extracts were condensed and dried under high vacuum. Pyridine (40 ml) was added
to dissolve the residue, followed by the addition of acetic anhydride (20 ml). The mixture
was stirred at r.t. for 12 h. After concentration of the reaction mixture, EtOAc (50 ml)
and aqueous saturated NaHCO3 (50 ml) were added to the flask. The aqueous phase was
separated and extracted with EtOAc (30 ml) once. The combined organic phase was
washed with water, brine, and dried over MgSO4. Column chromatography gave the iodo
product 36 (2.60 g, 65 %). 1H NMR (CDC13): 5 5.18 (t, J = 9.4 Hz, 1H), 4.98 (ddd, J =
5.8, 9.6, 10.6 Hz, 1H, H-), 4.86 (t, J = 9.3 Hz, 1H), 4,16 (dd, J = 5.7, 10.3 Hz, 1H), 3.36-
3.26 (m, 3H, H-6, H-6’, H-l), 3.10 (dd, J = 7.6, 11.7 Hz, 1H, H-l’), 2.04, 2.01, 2.00 (s, 3
H each, 3 OAc); l3C NMR(CDC13): 5 170.18, 169.60, 169.35 (3 OAc), 77.27, 73.16,

72.22, 68.94, 66.56, 20.62, 20.59, 20.59 (3 OAc), 3.55 (C-6).

MethyI-6-deoxy-6-iodo-2,3,4-tri-O-acetyl-a-D-glucopyranoside (33)
Methyl-6-deoxy-6-iodo-2,3,4-tri-O-acetyl-a-D-glucopyranoside was prepared from

methyl-a-D-glucopyranoside using the same sequences as for the preparation of 1,5-

173

anhydro-2,3,4-tri-O-acetyl-6-deoxy-6-iodo-D-g1ucitol (68 %). [a]20[) + 113.5 (c 1
CHC13); 'H NMR (CDC13): 8 5.45 (dd, J = 9.4, 10.0 Hz, 1H, H-3), 4.94 (d, J = 3.7 Hz,
1H, H-l), 4.87 (dd, J = 3.7, 10.1 Hz, 1H, H-2), 4.86 (t, J = 10.1 Hz, 1H, H-4), 3.77 (ddd, J
= 2.4, 9.5, 8.3 Hz, 1H, H-5), 3.46 (s, 3H, OMe), 3.28 (dd, J = 2.4, 10.9 Hz, 1H, H-6), 3.12
(dd, J = 8.3, 10.9 Hz, 1H, H-6’), 2.05, 2.03, 1.98 (s, 3 H each, 3 OAc); ”C NMR(CDC13):
8 170.1, 170.0, 169.6 (3 OAc), 96.69 (C-1 ), 72.45, 70.89, 69.65, 68.62, 55.74, 20.69,

20.67, 20.64 (3 OAc), 3.59 (C-6).

2,6-anhydro-l-deoxy-3,4,5-tri-O-acetate-L-xylo-Hex—l-enitol (37)

To a solution of 1,5-anhydro-2,3,4-tri-0-acetyl-6-deoxy-6-iodo-D-glucitol (2.0 g, 5.0
mmol) in anhydrous DMF (20 ml) was added DBU (4.8 ml, 30 mmol) and the mixture
was stirred at 75°C for 3, h. After cooling to r.t, water and ethyl acetate (30 ml each) were
added to the reaction mixture. The aqueous layer was separated and extracted with ethyl
acetate twice (2 x 20 ml). The combined organic extracts were washed with saturated
aqueous NaHCOg, water, brine, dried over MgS04. Condensation followed by column
chromatography (ethyl acetate: hexane l : 5) gave 37 as a white solid (1.03 g, 76 %).
[011200 + 9.00 (c 1 CHC13); 1H NMR (CDC13): 5 5.47 (d, J = 7.8 Hz, 1H, H-3), 4.99 (t, J =
7.8 Hz, 1H, H-4), 4.93 (m, 1H, H-5), 4.60 (t, J = 1.5 Hz, 1H, H-l’), 4.35 (t, J = 1.5 Hz,
1H, H-l), 4.07 (dd, J = 4.9, 11.5 Hz, 1H, H-6’), 3.45 (dd, J = 8.3, 11.5 Hz, 1H, H-6),
2.12, 2.10, 2.09 (3 s, 9 H, 3 x OAc), l3C NMR(CDC13): 5 168.9, 169.4, 169.4 (3 x OAc),
153.5 (C-l), 95.4 (C-2), 72.0 68.5 (2 Carbon) (C-3, 4, 5), 66.7 (C-6), 20.3, 20.3, 20.6 (3

Carbon, 3 CH3).

Methyl 2,3,4 tri-O-acetyl 6-deoxy-or—D-xylohex-5-enopyranoside (34)

174

Methyl 2,3,4 tri-O-acetyl 6-deoxy-01—D-xylohex-5-en0pyranoside was prepared from
Methyl-6-deoxy-6-iodo-2,3,4-tri-O-acetyl-01-D-glucopyranoside using the same
sequences as for the preparation of 2,6-anhydro-1-deoxy-3,4,5-tri-O-acetate-L-xylo-Hex-
l-enitol (75 %). [a]200 (c 1 CHC13); 'H NMR (CDC13): 8 5.42-5.48 (m, 2H, H-6, 11-1),
4.95-4.98 (m, 2H, H-6’, H-3), 4.76 (t, J = 1.8 Hz, 1H, H-4), 4.58 (t, J = 1.8 Hz, 1H, H-2),
3.42 (s, 3 H, OMe), 2.09, 2.05, 2.00 (3 s, 3 OAc); l3C WR(CDC13): 5 170.1, 169.8,
169.5 (3 OAc), 97.74, 97.46, 70.63, 69.68, 69.37, 55.53 (OMe), 20.67, 20.66, 20.64 (3
OAc).

(3aR, 3’S, 4R, 4’R, S’R, 6’S, 9aS, 9bS)-4-hydroxy-6'-methoxy-2,2-
dimethyldecahydrospirol1,3-dioxolo[4,5-c]isoxazolo[2,3-a]pyridine-8,2'-pyran]-
3',4',5'-triyl triacetate (39)

A solution of toluene (10.0ml) containing nitrone (93.5 mg, 0.5 mmol) and methyl 6-
deoxy-a—D-xylo-hex-S-enopyranoside (151 mg, 0.5 mmol) was stirred under reflux for 12
h. Removal of the solvent followed by column chromatography gave the cyclization

product 39 (235 mg, 96 %).

[6:120D +3741 (c 1 CHC13); 'H NMR (DMSO): 8 8.12 (s, 1H,
0H), 5.17 (t, J = 8.1 Hz, 1H, H-4), 4.99 (d, J = 3.5 Hz, 1H, H-2),
4.98(d, J = 8.0 Hz, 1H, H-5, ), 4.94 (dd, J = 3.5, 8.2 Hz, 1H, H-3),
4.30(dd, J = 4.4, 5.4 Hz, 1H, H12), 4.26 (t, J = 5.9 Hz, 1H, H-1 1),

3.92 (dt, J -'= 4.4, 10.0 Hz, 1H, H-l3), 3.43 (s, 3H, OMe), 3.31 (m,

 

1H, H-9), 3.12 (dd, J = 4.2, 11.5 Hz, 1H, H-l4), 2.90 (t, J = 10.8 Hz, 1H, H-14), 2.60 (dd,
J = 6.2, 12.8 Hz, 1H, H-lO), 2.23 (dd, J= 10.7. 12.8 Hz, 1H, H-IO’), 2.05, 2.01, 2.00 (s, 3

OAc), 1.46, 1.32 (s, 2 Me); l3C NMR (DMSO): 5168.56, 168.17, 167.82 (3 OAc),

175

108.04, 104.49 (C-6), 95.98 (C-2), 78.30, 74.71, 73.88, 69.22, 68.65, 67.82, 62.60, 61.28,
55.49, 53.51, 40.21(C-10), 26.57, 24.78, 19.44, 19.38, 19.38; NOESYID: NOE H10 -
H10’ 25 %, H10 — HS’ < 1 %; HRFABMS; Calcd. for C21H31N04 489.1846, found
489.1846; Calculated for C21H31N012 C, 51.53, H, 6.38, N, 2.86; Found C 51.50, H,
6.44, N, 3.10.

(3aR, 3’S, 4R, 4’R, 5’R, 9aS, 9bS)-4-hydroxy-2,2-dimethyldecahydrospiro[l,3-
dioxolo[4,5-c]isoxazolo[2,3-a]pyridine-8,2'-pyran]-3',4',5'-triyl triacetate (39)

To a stirred solution of nitrone (93.5 mg, 0.5 mmol) in toluene (5.0 ml) was added 2,6-
anhydro-l-deoxy-3,4,5-tri-O-acetate-L-xylo-Hex-l-enitol (163 mg, 0.6 mmol). The
reaction mixture was stirred under reflux for 10 h. Removal of the solvent followed by
column chromatography gave the cyclization product as a single diastereomer 45 (204

mg, 89 %).

6' s
0r>-OA0 [61209 -12220 (c 1 CHC13); 'H NMR (CDC13): 8 5.13 (t, J =
31

"" "’OAc

  

9.8Hz, 1H, H-4), 5.02 (dd, J = 1.0, 10.2 Hz, 1H, H-S), 4.87-
4.95(m, 1H, H-3), 4.22 (t, J = 4.3 Hz, 1H, H-12), 4.05 (dd, J =
4.9, 8.3 Hz, 1H, H—1 1), 4.02 (t, J = 4.9 Hz, 1H, H-3, 2H), 3.81
(dd, J = 6.1, 11.0 Hz, 1H, H-2), 3.65 (t, J = 10.9 Hz, 1H, H-2’),
3.34 (dd, J = 5.2, 9.0 Hz, 1H, H-l4), 2.96 (br s, 1H), 2.69 (t, J = 9.5 Hz, 1H, 11-14:), 2.54-
2.62 (m, 1H, H-9), 2.40 (dd, J —-= 6.6, 13.0 Hz, 1H, H-10), 2.08 (dd, J = 10.3, 13.0 Hz, 1H,
H-10’), 2.03, 1.97, 1.95 (3 OAc), 1.30, 1.42 (s, 3 H each, 2 CH3); l3C NMR(DMSO):
8 168.75, 168.61, 168.55 (3 OAc), 108.28, 103.57, 78.50, 74.78, 74.75, 70.34, 68.23,

65.99, 64.31, 56.63, 55.22; 42.11, 27.25. 25.38, 19.53, 19.47, 19.44; NOESYID: NOE

176

H3 — H3’ 30 %, H3 — H5” 15 %. Calculated for C20H29N011 C, 52.28, H, 6.36, N, 3.05;

Found C 52.20, H, 6.42, N, 3.26.

177

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