v- - . ‘o
JQ figm

   

  

:2
9007 . LIBRARY
M'FPIQan State
L_ university

 

 

This is to certify that the
thesis entitled

THE DESIGN, SYNTHESIS OF POTENTIAL SIALIDASE
INHIBITORS AS ANTI-INFLUENZA DRUGS AND
SYNTHESIS OF C-2 SYMMETRIC LIGANDS FOR
TRANSITION METAL CATALYZED ASYMMETRIC
REDUCTION REACTIONS

presented by

Chang Liu

has been accepted towards fulfillment
of the requirements for the

MS. degree in Chemistry

I mL I, IV“ \I\(,.__, :r I“.

\ Major Professor’s Signature
w/ t '7 a)

Date

 

 

 

 

MSU is an Affirmative Action/Equal Opportunity Institution

 

 

PLACE IN RETURN Box to remove this checkout from your record.
TO AVOID FINES return on or before date due.
MAY BE RECALLED with earlier due date if requested.

 

DATE DUE

DATE DUE

DATE DUE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2/05 p:/CIRC/DateDue.indd-p.1

 

 

THE DESIGN, SYNTHESIS OF POTENTIAL SIALIDASE INHIBITORS AS
ANTI~INFLUENZA DRUGS AND SYNTHESIS OF C-2 SYMMETRIC LIGANDS
FOR TRANSITION METAL CATALYZED ASYMMETRIC REDUCTION
REACTIONS

By

Chang Liu

A THESIS

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

MASTER OF SCIENCE

Department of Chemistry

2006

ABSTRACT

THE DESIGN, SYNTHESIS OF POTENTIAL SIALIDASE INHIBITORS AS
ANTI-INFLUENZA DRUGS AND SYNTHESIS OF 02 SYMMETRIC LIGANDS
FOR TRANSITION METAL CATALYZED ASYMMETRIC REDUCTION
REACTIONS
By

Chang Liu

The major objective of the work described in this thesis is to develop a strategy for the
design and synthesis of new simple nitrogen containing heterocyclic systems for the
inhibition of influenza sialidase. Azasugars, a common class of sugar derivatives in
which the ring oxygen is replaced by a nitrogen atom, show tremendous potential as
therapeutic agents in wide range of diseases, such as HIV, diabetes, and hepatitis because
of their effective inhibition towards various glycosidases and glycotransferases. We
designed a new azasugar scaffold targeting influenza sialidase which plays an essential
role in the virus replication process and explored a short, efficient synthetic route. The
ease of this synthetic route may provide access to new commercially available
anti-influenza drugs. In the second part of this thesis, the design and synthesis of a new
C-2 symmetric ligand is described. 02 symmetric ligands have shown promising
chirality control on transition metal catalyzed reactions. We developed a potentially
industrially benign 5-step synthetic route with ubiquitous carbohydrate derivative as
starting material. Once the catalyzing capability of this ligand is refined and confirmed,
the costs for some industrial process. such as asymmetric ketone reduction. could be

much reduced.

Copyright by
Chang Liu
2006

ACKNOWLEDGEMENT

I would like to express my sincere gratitude to my academic advisor Dr. Rawle I.
Hollingsworth, for his guidance, encouragement and support throughout my graduate
study in Michigan State University. From him, I learnt not only chemistry, but also how
to understand the world and how to be a decent person. During the 4 years study in MSU,
being under his guidance was my best luck. Twenty years later, I may not even be able to
recognize an organic molecule, but I will never forget the philosophy I learnt from Dr.
Hollingsworth. Also. I am grateful to all my committee members: Dr. James E Jackson,
Dr. Peter J. Wagner and Dr. Joan Broderick for their inspiration and valuable advice on
my research and thesis. I would also thank all the group members in Dr. Hollingsworth’s

lab. They created a friendly and healthy atmosphere for me.

Finally, I would like to thank my parents and my friends for their support and

understanding.

TABLE OF CONTENTS

LIST OF TABLES ........................................................................................................... vii

LIST OF FIGURES ....................................................................................................... viii

Chapter 1: Background
1.1 Background of Influenza Virus and Influenza Neuraminidase

1.1.1 Influenza and Influenza Virus ........................................................................ 2
1.1.2 Influenza and Influenza Virus ........................................................................ 3
1.1.3 How Influenza Virus Invades Human Cells and the Function of
Neuraminidase in This Process ...................................................................... 4
1.2 Current Solutions to Influenza
1.2.1 Traditional Treatment Methods for Influenza ................................................ 7
1.2.2 Neuraminidase Inhibitors as Anti-Influenza Drugs ....................................... 8
1.2.3 Enzyme-Substrate Interaction Study and Mechanism of
Neuraminidase .......................................................................... 8
1.2.4 Mechanism Based Drug Design ................................................................... 12
1.3 References .................................................................................................................. 17

Chapter 2: Azasugar as Neuraminidase Inhibitor and Anti-Influenza Drug
2.1 Azasugar as Glycosidase Inhibitor

2.1.1 Azasugar’s Potent Inhibition Effect ............................................................. 22
2.1.2 Why Azasugar Has Good Inhibition Capability .......................................... 24
2.2 Rational Design of Azasugar Neuraminidase Inhibitor ........................................ 26
2.3 The Synthesis of Azasugars
2.3.1 Background .................................................................................................. 28
2.3.2 Aminomercuration ....................................................................................... 29
2.3.3 Intramolecular N-Alkylation ........................................................................ 30
2.3.4 Reductive Double-Alkylation ...................................................................... 31
2.3.5 Double Reductive Amination ....................................................................... 32
2.3.6 Triple Reductive Amination ......................................................................... 33
2.3.7 Ring Closing Metathesis .............................................................................. 34
2.3.8 Photochemical Approach ............................................................................. 36
2.3.9 Chemo-enzymatic Synthesis ........................................................................ 36
2.4 Summary .................................................................................................................... 37
2.5 References .................................................................................................................. 38

Chapter 3: Design and Synthesis of Polyhydroxylated 2-Carboxypiperidine
Derivatives for Use as Sialidase Inhibitors
3.1 Result and Discussion

3.1.1 Shortcomings of the Currently Available Strategies .................................... 44
3.1.2 Our Proposed Synthetic Strategy ................................................................. 44
3.1.3 Progress and Problems with Our Proposed Strategy ................................... 45
3.1.4 Mechanism for Product 8 ............................................................................. 48
3.1.5 Mechanism for Product 7 ............................................................................. 49
3.1.6 Mechanism for Product 9 ............................................................................. 50
3.2 Alternative Cyanohydrin formation Strategy ........................................................ 51
3.3 Ring Closure Trials
3.3.1 Intramolecular Mitsunobu Reaction ............................................................ 53
3.3.2 Double N-Alkylation Reaction .................................................................... 54
3.4 Summary .................................................................................................................... 55
3.5 Experimental Section ................................................................................................ 56
3.6 References .................................................................................................................. 59

Chapter 4: Design and Synthesis of C-2 Symmetric Ligands for Asymmetric Ketone
Reduction Reactions
4.1 Introduction to C-2 Symmetric Ligands ................................................................. 63
4.2 Typical C-2 Symmetrical Ligands and Their Developments

4.2.1 (4R, 5R)—trans-4, 5-bis [(diphenylphosphino) methyl]-2, 2-dimethyl-1, 3

-dioxolane (DIOP) Family ........................................................................... 64
4.2.2 2, 2’-bis (diphenylphosphino)-l, l’-binaphthyl (BINAP) Family ............... 66
4.3 Summary of C-2 symmetric Ligands ...................................................................... 67
4.4 Asymmetric Ketone Reduction Reaction
4.4.1 Introduction to Asymmetric Ketone Reduction Reaction ............................ 68
4.4.2 Asymmetric Ketones Reduction by Boranes ............................................... 68
4.4.3 Transition Metal Catalyzed Asymmetric Ketone Reduction Reactions
4.4.3.1 Transition Metal Catalyzed Transfer Hydrogenation Reduction ..... 71
4.4.3.2 Ruthenium Catalyzed Asymmetric Hydrogenation Ketone Reduction
.......................................................................................................... 71
4.5 Why Do We Need to Develop More 02 Symmetric Ligands? ............................. 73
4.6 Design and Synthesis of C-2 Symmetric Ligand
4.6.1 Design of C-2 Symmetric Ligand ................................................................ 74
4.6.2 Synthesis of C-2 Symmetric Ligand ............................................................ 75
4.6.3 Result and Discussion .................................................................................. 77
4.6.4 Why Our Strategy is Superior to Others"? ................................................... 79
4.7 Future Directions ...................................................................................................... 80
4.8 Experiment Section ................................................................................................... 82
4.9 References .................................................................................................................. 86

vi

LIST OF TABLES

Chapter 1

ChapterZ
Table 2.1 Inhibition effect of azasugars towards various enzymes .................................. 23
Table 2.2 The overall yields and ratios of the two products formed by the double
reductive amination reaction ............................................................................................. 33
Chapter3

Table 3.1 Trials of different pH conditions and different buffer solutions for the solvent
of cyanohydrin formation reaction .................................................................................... 46

Table 3.2 Trials of different solvent combinations for the cyanohydrin formation reaction

........................................................................................................................................... 47
Table 3.3 Products ratio and total yields for Bucherer type reaction of 2, 3: 4,
6-di-O-isopropylidene-D-mannose ................................................................................... 55
Chapter 4

Table 4.1 Experimental result of Noyori‘s screening of ligands ...................................... 73

Table 4.2 Reaction conditions and yields of the alkylation of C3, C4 positions of our
furan scaffold .................................................................................................................... 78

vii

LIST OF FIGURES

Chapter 1

Figure 1.1 Ribbon diagrams of neuraminidase and its active site ...................................... 3
Figure 1.2 Structure ofinfluenza virus .............................................................................. 4
Figure 1.3 The life cycle of influenza virus ....................................................................... 5
Figure 1.4 Cleavage of sialic acid by neuraminidase ......................................................... 6
Figure 1.5 The structures of Amantadine and Rimantadine ............................................... 7

Figure 1.6 Mechanism of neuraminidase catalyzed hydrolisis of sialic acid linked
glycoprotein ...................................................................................................................... 10

Figure 1.7 von Itszstein’s neuraminidase inhibitors, the comparison with sialic acid

transition state and their inhibition effect ......................................................................... 12
Figure 1.8 Singh’s neuraminidase inhibitors library ...................................................... 13
Figure 1.9 Stevens’s cyclohexene based neuraminidase inhibitors ................................. 14

Figure 1.10 Chand’s cyclopentane system, Wang’s pyrrolidine systems and Babu’s

pyridine system as neuraminidase inhibitors .................................................................... 15
Figure 1.11 The structures of Zanamirvir and Oseltamivir .............................................. 16
Chapter 2

Figure 2.1 Various azasugars which are inhibitors for glycosidases and glycotransferases

........................................................................................................................................... 23
Figure 2.2 Castanospermine mimics the positive charge of the oxocarbenium ion ......... 24
Figure 2.3 5-membered ring azasugars’ conformational mimicking to glycosidase

transition state ................................................................................................................... 25
Figure 2.4 Three most important enzyme-substrate interactions ..................................... 26

Figure 2.5 Design of neuraminidase inhibitor scaffold and its mimicking to glycoside

viii

transition state in the hydrolysis by neuraminidase .......................................................... 27

Figure 2.6 Aminomercuration approach for the synthesis of azasugars .......................... 30
Figure 2.7 Intramolecular N-alkylation approach for the synthesis of azasugars ............ 31
Figure 2.8 Reductive double-alkylation approach for the synthesis of azasugars ........... 32
Figure 2.9 Double reductive amination approach for the synthesis of azasugars ............ 33
Figure 2.10 Triple reductive amination approach for the synthesis of azasugars ............ 34
Figure 2.11 Ring closing metathesis approach for the synthesis of azasugars ................. 35
Figure 2.12 Photochemical approach for the synthesis of azasugars ............................... 36
Figure 2.13 C hemo-enzymatic approach for the synthesis of azasugars ......................... 37
Chapter 3

Figure 3.1 Proposed synthetic strategy for our target scaffold ........................................ 45
Figure 3.2 Cyanohydrin formation reaction under regular Strecker condition ................ 48
Figure 3.3 Possible mechanism of the formation of compound 8 .................................... 49
Figure 3.4 Possible mechanism ofthe formation of compound 7 ................................... 50
Figure 3.5 Possible mechanism of the formation of compound 9 ................................... 51
Figure 3.6 Bucherer-Bergs reaction and its mechanism ................................................. 52

Figure 3.7 Application of Bucherer type reaction to 2, 3, 4,

6-di-O-propylidene-D-mannose ........................................................................................ 53
Figure 3.8 Mitsunobu reaction of compound 28 and 29 ................................................. 54
Figure 3.9 Trials on double N-alkylation to cyclize the ring .......................................... 54
Figure 3.10 Explanation to the unsuccessful ring closing reaction of compound 32 . 55
Chapter 4

ix

Figure 4.1 Most common C-2 symmetrical ligands ........................................................ 63

Figure 4.2 The asymmetric reduction of amino acid by Rhodium catalyst with OZ
symmetric DIOP as ligand ............................................................................................... 64

Figure 4.3 (S. R. R. S)-DIOP coordinated Rhodium catalyzed asymmetric hydrogenation

of alkene ........................................................................................................................... 65
Figure 4.4 BINAP-Pd complex catalyzed Heck reaction ................................................ 67
Figure 4.5 BINAP-Rhodium complex catalyzed propargylic alcohol reaction .............. 67
Figure 4.6 Itsono‘s approach of asymmetric reduction of ketones ................................. 69
Figure 4.7 E. J. Corey’s CBS reduction .......................................................................... 70

Figure 4.8 Noyori’s asymmetric ketone reduction and his screening of ligands for

Ruthenium catalysts ......................................................................................................... 72
Figure 4.9 Furan based C-2 symmetric ligand scaffold .................................................. 74
Figure 4.10 The synthetic route towards our C-2 symmetric ligands ............................. 76
Figure 4.11 Mechanism of the one step reaction from 2-glucosamine salt to tetraol . 77

Figure 4.13 Alternative synthetic routes to avoid O3, O4 alkylation obstacle in
compound 34 .................................................................................................................... 80

Figure 4.14 Synthetic proposals for different kinds of ligands based on intermediate 38

........................................................................................................................................... 81
Figure 4.15 Proposed synthesis of diamine ligand 47 ..................................................... 81
Figure 4.16 The reaction system to test the activities of our ligands .............................. 82

Chapter 1 Background

1.1 Introduction to Influenza Virus and Influenza Neuraminidase

1.1.1 Glycosidase and Neuraminidase

Glycosidase is one kind of enzyme that is responsible for the hydrolysis of poly-and
oligosaccharides into monomers or cleavage of bonds between sugars and a non
carbohydrate aglycon.l This kind of enzyme is involved in several metabolic pathways
and plays a key role in various biological processes including remodeling of cell wall,
DNA repair etc. The successful inhibition of glycosidase is a way to modulate the

cellular interactions and to develop therapeutic agents.

Neuraminidase (NA). also called sialidase, is one type of glycosidase which exists as a
mushroom-shape projection on the surface ofthe influenza virus. It has a head consisting
of four co-planar and roughly 4 spherical subunits, and a hydrophobic region that is
embedded within the interior of the virus's membrane. It is comprised of a single
polypeptide chain that is oriented in the opposite direction to the hemagglutinin antigen.
The composition ofthe polypeptide is a single chain of six conserved polar amino acids,
followed by hydrophilic, variable amino acids (Figure 1.1). There are a large number
of biological functions ascribed to this enzyme such as cell-cell recognition phenomena
and the pathogenicity of some infections by sialidase-bearing microorganisms.2
Neuraminidase can bind to sialic acid selectively and aid the virus to release from cells
efficiently. Neuraminidase cleaves terminal sialic acid residues from carbohydrate
moieties on the surfaces of infected cells. This promotes the release of progeny viruses

. 3 4
from Infected cells. ‘

=1 MAJOR
ANIIGENIC '
VARIABIF
REGIONS

LIPID BILAYER
of ENVE LOPE

 

Figure 1.1 Ribbon diagrams of neuraminidase and its active site (Figure adapted from
University of Cape Town Medical Virology lecture notes
http://web.uct.ac. ’i-,t...’......2,’j... i2-’iuflueuZ.html)

 

1.1.2 Influenza and Influenza Virus

Influenza, also known as the flu, is a contagious disease that is caused by the influenza
virus. It attacks the respiratory tract in humans (nose, throat, and lungs) and may cause
fever, headache, tiredness (can be extreme), dry cough, sore throat, nasal congestion,
body aches. Millions of people in the United States — about 10% to 20% of U.S.
residents — will get influenza each year. According to the data from Department of
Health and Human Services Centers for Disease Control and Prevention, an average of
about 36,000 people per year in the United States die from influenza, and 114,000 per
year have to be admitted to the hospital as a result of influenza. Anyone can get the flu
(even healthy people), and serious problems from influenza can happen at any age. In the

Spanish Flu Pandemic, 50-100 million people were killed within 18 months.

The virion of an influenza virus is generally rounded (about 100 nm in diameter), but
may be long and filamentous. The virus is sheathed in a lipid bilayer (derived from the
plasma membrane of its host). And on the surface of the virus, two integral membrane
proteins stud the lipid bilayer which contains some 3000 molecules of matrix protein and
8 pieces of RNA. The membrane proteins are some 500 molecules of hemagglutinin ("H")

and some 100 molecules of neuraminidase ("N") (Figure 1.2).

Influenza
Virus
Anatomy

  
 

4:: - Neuraminidase
(Sialldase)

Figure 1.2 Structure of Influenza Virus (Figure adapted from
http://micro.magnet.fsu.edu/cells/viruses/influenzavirus.html)

1.1.3 How Influenza Virus Invades Human Cells and the Function of
Neuraminidase in This Process

The life cycle of influenza virus can be divided into 4 steps (Figure 1.3) in which two

proteins on the surface of the influenza virus surface---hemagglutinin (HA) and

neuraminidase (NA) play essential role in the invading process of the virus into the cell.4

1. Invasion step. The virus infection to the epithelial cells of the upper respiratory tract
is initiated by hemagglutinin’s binding to the cell surface receptor---sialic acid.

2. Entry to the cell. The attached virus subsequently undergoes endocytosis into the cell.

3. RNA replication step. After the uncoating process, two RNA strands are made in the
nucleus. One is exported to the cytoplasm and serves as mRNA, whilst the other
(cRNA) is used as a template to synthesize progeny vRNA.

4. Budding step. After virus replication. the progeny virus must be released from the

cell to repeat the cell cycle ofthe infection.

Receptor binding Budding
4:} I
£5 a\

 

 

 

 

 

‘ vRNA

 

Transcription Nucleus
Cytoplasm and replication

 

 

 

 

 

 

 

Figure 1.3 The life cycle of influenza virus

Influenza neuraminidase (NA) is involved in the last step of the life cycle of the virus-the
budding step in which it mediates the release of the virus from the cell surface. NA
cleaves the a-ketosidic linkage between terminal NeuSAc (sialic acid) and a neighboring
saccharide, usually galactose (Figure 1.4). The viral enzyme shows some preference for

a 2-3 linkages, but linkage and aglycon specificity is weak.5‘ 6

. Cleavage

COO
OH
HO
H30 0 N 13W“.
HO OH
O
Neuraminidase
coo
OH
HO
0
H30 0 N OH
HO
0 2
Sialic Acid

N-Acetylneuraminic acid (Neu-5Ac)

Figure 1.4 Cleavage of sialic acid by neuraminidase

The role ofthe receptor-destroying enzyme in the viral life cycle iS subtle and may not be
completely understood It has been suggested that by cleaving the sialic acid residue,
Neuraminidase accomplishes the following functions.4

i) Prevents virus aggregation on the cell surface

ii) Releases virus particles from the cells

iii) Destroys cellular receptors recognized by hemagglutinin

iv) Prevents viral inactivation by respiratory mucus

Direct evidence is available to support a role for the enzyme in facilitating release of
progeny virions from the surface of infected cells, where they would otherwise aggregate
as a result of interactions between the hemagglutinin and sialic acid on the surface of the
infected cell and on the progeny virion envelop.7‘ 8‘ 9‘ '0 NA may also promote viral

. . . . . . 1 1-
movement through reSpIratory tract mucus, thus enhancmg Viral InfectIVIty.1

1.2 Current Solutions to Influenza

1.2.1 Traditional Treatment Methods for Influenza

The main strategy for preventing influenza and its more severe complications is
immunoprophylaxis with inactivated (i.e., killed-virus) vaccine. Influenza-specific
antiviral drugs for chemoprophylaxis or therapy are an important adjunct to vaccine, but

they are not a substitute for influenza vaccine.

Actually, the life cycle of the influenza virus provides several targets for drug
development. Those targets include hemagglutinin,“15 M2 protein,'6 neuraminidase,m8
and endonuclease "9 In the United States, four antiviral agents are approved for
preventing or treating influenza: Amantadine hydrochloride and Rimantadine
hydrochloride as well as two recently approved neuraminidase inhibitors, Zanamivir and

. . l3
OseltamIVIr.

Amantadine and Rimantadine (Figure 1.5) act by interfering with the M2 protein ion
channel function that is found only in influenza A. Besides of the insensitivity of
influenza B viruses, clinical use of these agents is also limited because of the rapid

emergence of resistance and apparent side effects.

     

NH; - HCI
\v‘“ ‘MHIINHz-HCI
H a”, , CH3
’H 9H
Amantadine Rimantadine
Symmetrel® Flumadine®
3 4

Figure 1.5 The structures of Amantadine and Rimantadine

1.2.2 Neuraminidase Inhibitors as Anti-Influenza Drugs

Neuraminidase offers attractive site for therapeutic intervention in influenza infection. As
is said that NA catalyzes removal of terminal sialic acids linked to glycoproteins and
glycolipid. It has been postulated that NA activity is necessary in the elution of newly

formed viruses from infected cells by digesting sialic acids in the HA receptor.

For influenza A, nine subtypes of neuraminidase have been identified; whereas only one
subtype is know for influenza B. Despite this diversity, the catalytic site for all influenza
A and B neuraminidases is completely conserved.‘8 This gives people a lot of

opportunity to develop neuraminidase inhibitors as potent influenza drugs.

1.2.3 Enzyme-Substrate Interaction Study and Mechanism of Neuraminidase

The study of the mechanism of Influenza Neuraminidase received large amount of
attention from scientists in the 1990’s. Crystallographic studies of the enzyme showed
that despite up to 50% sequence variation, the enzymes have similar three-dimensional

structures, and the amino acid residues that line the active site are highly conserved in

7

both influenza A and B virus strains.20‘”"22 Their computational study on the binding
between sialic acid and neuraminidase agree with X—ray crystallography very well and
showed that the salt bridge between the carboxylate group of 1 and the charged Arg 371
in the active site contributes the greatest to binding. The ring oxygen appears to
contribute only marginally to ligand binding through a weak charge-dipole interaction
with Arg 292. Each of the hydroxyl groups on C2, C4, C7 and C9 accept protons from
bulk solvent and form hydrogen-bond with the active-site. X-ray crystallographic
structures of Neu5Ac and its analogues complexed with NAs show that the two terminal
hydroxyls of the glycerol side chain form a bidentate interaction with Glu 276.23‘ 34
However it is also noted that the C8 of the glycerol chain makes hydrophobic contacts
with the hydrocarbon chain of Arg 224.]8 This hydrophobic pocket has been confirmed

by scientists by crystallographic study. This hydrophobic pocket and the carboxylic

acid-Arg 371 salt bridge are the most important interaction between NA and sialic acid.

The mechanism of the neuraminidase mediated cleavage of the sialic acid attached at the
end of glycoprotein has been hypothesized to take place in this shallow pocket model

which is shown below (Figure 1.6).25

 

11
Figure 1.6 Mechanism of neuraminidase catalyzed hydrolysis of sialic acid linked
glycoprotein (Figure adapted from von Itzstein, M.; Wu, W. -Y; Kok, G. B. Pegg, M. S.;
Dayson, J. C.; Jin, B. Nature 1993, 363, 418-423)

The catalytic pathway of the sialidase can be regarded as consisting of four major steps.25

The first step is the binding event. The binding of sialoside to sialidase involves
considerable distortion of the pyranose ring. In solution the Neu5Ac pyranose ring adopts
an expected 2C5 chair conformations whereas in the bound state the ring has a pseudo
boat conformation. Though this conformation is the result of complex ionic hydrogen
bond and steric interactions, it is an unfavorable conformation, in which the C2, C3, and
06 atoms are coplanar. The resulting conformational strain induces the cleavage of the

26. 27, 28

glycosidic bond.

The second step of the catalytic reaction involves proton donation from solvent and
formation of the endocyclic sialosyl cation transition-state intermediate. Kinetic isotope
studies on influenza virus sialidase with the synthetic substrate
4-(methylumbelliferyl)-Neu5Ac and the corresponding [3, 3-2H]-substituted substrate, an
SN] type mechanism with proton donation from an activated water molecule and an
endocyclic sialosyl cation transition-state intermediate had been postulated.29 It’s almost
the same process as the most intensely studied and best known enzyme mechanisms of
glycohydrolase, lysozyme.3’0 An oxocarbenium ion 8 is believed to form in this step and
is stabilized by adjacent Glu 277. This oxocarbenium ion flattens the pyranose ring into a

“bed” conformation wherein C2, C3 and OS are on the same plane.

The final two steps of the enzyme mechanism are the formation and release of Neu5Ac.
NMR experiments indicate that Neu5Ac is initially released as the or-anomer, which is

consistent with the proposed SNI mechanism having a high degree of stereofacial

selectivity. It is conceivable that expulsion of product from the active site is favored by
the mutarotation of the a-anomer 10 to the thermodynamically more stable B-anomer 11

for Neu5Ac in solution.3|

1.2.4 Mechanism Based Drug Design

Based on this mechanism, many trials modifying the Sialic acid molecule to make
analogs as sialidase inhibitors were made both chemically and computationally. In 1991,
ltzstein in Monash University, Australia, synthesized the first transition state analogue

inhibitor for influenza neuraminidase Neu5Ac2en (Figure 1.7).27

 

Transition state of sialic acid residue In
neuraminidase catalyzed hydrolysis

 

 

 

 

 

12
NHAc
R = a) OH
HO M NH;
c) NHC(NH2)2*
Neu5Ac-Zen when R = OH
Inhibitor K, (M)
13a 4X10’6
13b 4X10'8
13c 4X10“9

 

Figure 1.7 von Itszstein’s neuraminidase inhibitors, the comparison with sialic acid
transition state and their inhibition effect

12

Comparing these two structures, we can see that Neu5Ac-2en 13a keep the C-1
carboxylic acid and the use a double bond between C2 and C3. The planarization of the
pyranose ring helps mimic the transition state structure. All the other part of the molecule
remains the same. The Neu5Ac-Zen turned out to be a very good inhibitor of
neuraminidase. They also figured out by calculation that when guanidine the group is on
C4. a favorable interaction with active site may be obtained. This was confirmed by the

best inhibition K.- (4X1 0'”).

Afier ltszstein, many potential inhibitors towards neuraminidase have been developed.32
For example, in 1995, Singh in University of Alabama synthesized a series of benzoic
acid derivatives as neuraminidase inhibitors.33 They did the in vitro test of each

compound and found inhibitor 15 was the best with an ICso of 0.01 mM) (Figure 1.8).

R1

COOH
R3 COOH R1 = H. N02
R2 = H, N02
0 R3 = H, N02. NH; O
AcHN R2 R4 . OH, OAc, N02, “H"

NHz. NHCOCHa. NHC(NH)NI‘I2
R, NHC(NH)NH2

14 15

Figure 1.8 Singh’s neuraminidase inhibitors library

On the basis of Singh’s work, in 1998. Stevens and his colleagues synthesized a
cyclohexane system and tested the effect of different substitute groups on the inhibitor.
They focus on the exploration of the alkyl C8-C 10 side chain to fit in the hydrophobic
pocket of neuraminidase active site. A very efficient inhibitor 17 with ICSO as low as

13

0.5nM was found (Figure 1.9).3‘1

at
RC - ,coon
; \ ’ Et 0 \ COOH
I \K‘]
AcHN/x" "i/ \ R2 /\. /\
i AcHN H
R1
R = H, Al I, Aryl etc. N”
R1 = NH;, uanidine
R2 = H, F, M9 HN/I/l’i \ \NH2
16 17

Figure 1.9 Stevens‘s cyclohexene based neuraminidase inhibitors

So far, scientists have put a great deal of effort in searching for good inhibitors towards
neuraminidase. Thousand of compounds have been synthesized and tested.35 Most of
them are transition state analogues. Apart from the scaffold we have discussed, other
inhibitors, such as C hand’s cyclopentane system 18, Wang‘s pyrrolidine systems 19 and
Babu’s pyridine system 20 have shown good inhibition activity toward neuraminidase

(Figure 1.10).36,37.38

l4

H CONR1R2

HOOC
AcHN COO“ N—R'
s?“ HzN
H2N(HN)CHN
R1 = Me, Et, i-Pro, Bu, l-Bu R' = (Et)2CHCO, (Pro)2CHCO,
R2 = H, Pro, Bn, Allyl, etc. (Me)(Et)CHCO, (i-Pro); CHCO,
R3
—N
R2 \ / COOH
R1
R1 = H, NHZ
R2 = NHCOCHa, NHCSCH3
NHSO;CH3

R3 = H, NHz' NHC(NH)NH2
20

Figure 1.10 Chand’s cyclopentane system, Wang’s pyrrolidine systems and Babu’s
pyridine system as neuraminidase inhibitors

Among those compounds, two of the most potent inhibitors, Oseltamivir 21 whose
phosphate is referred as Tamiflu and Zanamivir 22 (known as Relenza), are developed to
commercially available drugs for influenza (Figure 1.11). Zanamivir is approved for
treatment of uncomplicated acute illness caused by influenza virus in persons aged
greater than or equal to 12 years who have been symptomatic for no more than 2 days.
Oseltamivir is approved for treatment of uncomplicated illness caused by influenza
infection in adults aged greater than or equal to 18 years who have been symptomatic for

no more than 2 days.

 

22
Zanamirvir

21

Oseltamivir
Figure 1.11 The structures of Zanamirvir and Oseltamivir

Both of those drugs are transition-state analogs of sialic acid. In the Oseltamivir molecule,

a carbon atom replaces the in-ring oxygen of the sialic acid and the double bond helps to
maintain the coplanar structure mimicking the sialoyl cation intermediate. In the case of
Zanamivir. the 2, 3 positions are dehydrogenated to form an olefin; the function of this

carbon-carbon double bond is the same as Oseltamivir. Both of those two molecules

retain the acetamido group at the C 5 position.

Zanamivir can achieve very good binding through appropriate presentation of its four
pendent substituents and contains hydrogen bonding glycerol side chain. The guanidino
group in Zanamivir is believed to form salt bridges with Glu 119 in the neuraminidase
active site and add a strong charge interaction with Glu 227. This interaction anchors
Zanamivir into the enzyme active site of neuraminidase. On the other hand, the good
inhibition effect of Oseltamivir is believed to be due to that the aliphatic ether branch

chain, which on C6, fits into the hydrophobic pocket ofthe neuraminidase active site.39

1.3 References

10

. Pinto, B. M. Nasi, R. Synthesis of New Analogues of Slacinol Containing a Pendant

Hydroxymethyl Group as Potential Glycosidase Inhibitors Carbohyd. Res. 2006, 341,
2305-2311

Schauer, R. Sialic Acids and Their Roles as Biological Masks. Trends Biochem. Sci.
1985, 10, 357-360

Zhang, J.; Yu, K. O; Zhun, W. L.; Jiang H. Neuraminidase Pharmacophore Model
Derived From Diverse Classes of Inhibitors Bioorg. Med. Chem. Lett. 2006, 16,
3009-3014

Colman, P. M.~Influenza Virus Neuraminidase: Structure, Antibodies, and Inhibitors
Protein Science, 1994, 3, 1687-1696

Corfield A.P.; Higa, H.; Paulson, J. C.; Schauer, R. The Specificity of Viral and
Bacterial Sialidases for Alpha (2-3)— and Alpha (2-6)-linked Sialic Acids in
Glycoproteins Biochem. Biophys. .4610 1983, 744, 121-126

Corfield A.P.; Wember, M.; Schauer, R.; Rott, R. The Specificity of Viral Sialidases:
The Use of Oligosaccharide Substrates to Probe Enzymic Characteristics and
Strain-specific Differences Eur. J. Biochem. 1982, 124, 521-525

Griffin, J. A.; Basak, S.; Compans, R. W. Effects of Hexose Starvation and the Role
of Sialic Acid in Influenza Virus Release Virology 1983, 125, 324-334

Griffin .1. A.; Compans, R. W. J. Exp. Med. 1979, 150, 379—391

Palese, P.; Compans, R. W. J. Gen. Virol. 1976, 33,159-163

. Palese, P.; Tobita, K.; Ueda, M.; Compans, R. W. Characterization of Temperature

Sensitive Influenza Virus Mutants Defective in Neuraminidase Virology 1974, 61,
397-410

. Liu, C.; Eichelberger, M. C.; Compans, R. W.; Air, (1 M. Influenza Type A Virus

Neuraminidase does not Play a Role in Viral Entry, Replication, Assembly, or
Budding J. Virol. 1995, 69, 1099-1106

. Klenk, H. D.; Rott, R. The Molecular Biology of Influenza Virus Pathogenicity. Adv.

Virus Res. 1998, 34, 247

. Winquist, A. G; Fukuda, K.; Bridges, B. C.; Cox, J. N. Neuraminidase Inhibitors for

Treatment of Influenza A and B Infections MMWR December 1999, 48, 1-9

17

16.

20.

21.

23.

24.

25.

. Couch, R. 8.; Six, H.R. In Antiviral Chemotherapy: New Direction for Clinical

Application and Research; Mills J., Corey L., Eds.; Elsevier Science Publishing:
Oxford, 1986 P50-56

. Hayden, F. G.; Belshe, R. B.; Clover, R. B.; Hay, A. J.; Oakes, M. G.; 800, W.

Emergence and Apparent Transmission of Rimantadine-resistant Influenza A Virus in
Families N. Engl. J. Med. 1989, 321,1696

Hay, A. J._; Wostenholme A. J.; Skehel, J. J.; Smith, M. H. The Molecular Basis of
the Specific Anti-influenza Action of Amantadine EMBO J. 1985, 4, 3021

. Colman, P. M. In The influenza viruses: Influenza virus neuraminidase. Enzyme and

Antigen; Krug, R. M. Ed.; Plenum Press: New York, 1989 P175-218

. Colman, P. M. Influenza Virus Neuraminidase: Structure, Antibodies, and Inhibitors

Protein Sci. 1994, 3, I687

. Hastings, J. C.; Selnick, H.; Wolanski, B.; Tomassini, J. E. Anti-influenza Virus

Activities of 4-substituted 2, 4-dioxobutanoic Acid Inhibitors Antimicrob. Agents
Chemother 1996, 40, 1304

Varghese, J. N.; Laver, W. G.; Colman, P. M. Structure of the Influenza Virus
Glycoprotein Antigen Neuraminidase at 2.9 A Resolution Nature 1983, 303,35-40

Colman, P. M.;Varghese. J. N.; Laver, W. G. Structure of the Catalytic and Antigenic
Sites in Influenza Virus Neuraminidase Nature 1983, 303, 41-44

. Varghese, J. N. Mckimm-Breschkin, J.; Caldwell, J. B. Kortt, A. A.:, Colman, P. M.

The Structure of the Complex Between Influenza Virus Neuraminidase and Sialic
Acid, The Viral Receptor Proteins 1992, 14, 327-332

Varghese, J. H.; Colman, P. M. J. Mol. Biol. 1991, 221, 473

Burmeister, W. P.; Ruigrok, R.W.; Cusak. S. The 2.2 A Resolution Crystal Structure
of Influenza B Neuraminidase and Its Complex with Sialic Acid. EMBO J. 1992, I I,
49

von ltzstein, M.; Wu, W. —Y; Kok, G. B. Pegg, M. S.; Dayson, J. C.; Jin, B.; Van
Phan, T.; Smythe, M. L.; White, H. F.; Oliver, S. Bethell, R. C.; Hotham, V. J.;
Cameron, J. M.; Penn, C. R. Rational Design of Potent Sialidase-based Inhibitors of
Influenza Virus Replication Nature 1993, 363, 418-423

.Kerrigan, S. A.; Pritchard, R. G; Smith. P. W.; Staoodley, R. J. Synthesis of

18

28.

30.

31.

32.

33.

34.

35.

36.

(4R,SS)-5-acetylamino-4-diethylcarbamoyl-5,6—dihydro-4H-pyran-Z-carboxylic Acid
and Its Inhibitory Action Against Influenza Virus Sialidases Tetrahedron Lett. 2001,
42, 8889-8892

. Taylor, N. R.; von ltzstein, M. Molecular Modeling Studies on Ligand Binding to

Sialidase from Influenza Virus and the Mechanism of Catalysis J. Med. Chem. 1994,
3 7, 616-624

Chong, A. K. J.; Pegg, M. 8.; von ltzstein, Characterization of an Ionisable Group
Involved in Binding and Catalysis by Sialidase From Influenza Virus. M. Biochem.
Int. 1991, 24, I65

. Chong, A. K.J.; Pegg, M.S.; Taylor, N. R.; von ltzstein, M. Evidence for a Sialosyl

Cation Transition-state Complex in the Reaction of Sialidase From Influenza Virus.
Eur. J. Biochem. 1992, 207, 335-343

Phillips, C. C. Sci. Am. 1966, 215, 78-90

Thomas, A.; Jourand, D.; Bret, C.; Amara, P.; Field, M. I. Is There a Covalent
Intermediate in the Viral Neuraminidase Reaction? A Hybrid Potential Free-Energy
StudyJ. Am. Chem. Soc. 1999, 121, 9693-9702

Kerrigan, S. A.; Pritchard, R. G; Smith, P. W.; Staoodley, R. J. Synthesis of
(4R,SS)-5-acetylamino-4-diethylcarbamoyl-5,6-dihydro-4H-pyran-2-carboxylic Acid
and Its Inhibitory Action Against Influenza Virus Sialidases Tetrahedron Lett. 2001,
42, 8889-8892

Singh, S. Jedrzejas, M. J.; Air, G. M. Luo, M. Laver, W.G.; Brouilette, W. J.
Structure-based Inhibitors of Influenza Virus Sialidase. A Benzoic Acid Lead with
Novel InteractionJ. Med. Chem. 1995, 38, 3217

Kim. C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L. Chen, X.; Escarpe, P. A.
Mendel, D. B.; Laver, W. G.; Stevens, R. C. Structure-activity Relationship Studies
of Novel Carbocyclic Influenza Neuraminidase Inhibitors J. Med. Chem. 1998, 41,
2451-2460

Verma, R. P.; Hansch, C. A QSAR Study on Influenza Neuraminidase Inhibitors
Bio.& Med. Chem. 2006, 14, 982-996

Chand, P.; Babu, S.Y.; Rowland, S. Dehghani, A.; Kotian, P. L.; Hutchison, T. L.; Ali,
8.; Brouillette, W.; El-Kattan, Y. Lin, T. H. Syntheses and Neuraminidase Inhibitory
Activity of Multisubstituted Cyclopentane Amide Derivatives J. Med. Chem. 2004,
47, 1919

I9

37. Wang, G T.; Chen, Y.; Wang, S.; Gentles, R.; Sowin, T.; Kati, W.; Muchmore, S.;

38.

39.

Giranda, V.; Stewart, K.; Sham, H.; Kempf, D.; Laver, W. G Design, Synthesis, and
Structural Analysis of Influenza Neuraminidase Inhibitors Containing Pyrrolidine
CoresJ. Med. Chem. 2001, 44, 1192

Chand, P.; Kotian, P. L.; Morris, P. E.; Bantia, S.; Walsh, D.A.; Babu, Y. S. Synthesis
and Inhibitory Activity of Benzoic Acid and Pyridine Derivatives on Influenza
Neuraminidase Bio.& Med. Chem. 2005, 13, 2665-2678

Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H. W. Structure-activity Relationship

Studies of Novel Carbocyclic Influenza Neuraminidase Inhibitors J. Med. Chem.
1998, 41, 2451-2460

20

Chapter 2 Azasugar as Neuraminidase Inhibitor and

Anti-Influenza Drug

21

2.1 Azasugar as Glycosidase Inhibitor

2.1.1 Azasugar’s Potent Inhibition Effect

Since the discovery of nojirimycin, a glycosidase inhibitor, polyhydroxylated piperidines
(also called azasugars, the ring O-atom of a carbohydrate is replaced by nitrogen) have
attracted considerable attention and have been the targets of numerous synthetic
strategies during the last decade. The efficient inhibition capabilities of azasugars toward
glycosidases and glycotransferases made them the best candidates for the treatment of a
variety of carbohydrate-mediated diseases, such as influenza, diabetes, viral infections
including HIV, cancer metastasis, hepatitis, and Gaucher’s disease. It is believed that the
potent inhibition capability stems from their structural resemblance to the sugar moiety
of the natural substrate. Up till now. a large number of azasugars have been developed to

defend virus invasion to human body.1

In 1966, nojirimycin was discovered as the first alkaloid that mimics a sugar.2 It is a
potent inhibitor of (x-and B-glucosidases from a variety of scources. The more stable
forms l-deoxynojirimycin (DNJ) and l-deoxymannojirimycin (DMJ), were also isolated

and showd potent inhibitory activities against glycosidases.3"'l’5'("7

DNJ is a potent
inhibitior of all kinds of glycosidases,8 but it is more selective to a-glucosidases and its
inhibitor effect on mammalian or-glucosidases opened the possiblility of a therapeutic
application for DNJ. Apart from DNJ, some natural bicyclic polyhydroxyheterocycles
were also discovered and isolated. The inolizidine castanospermine and swainsonine are

9.10.11.12

typical examples. These compounds (Figure2.1) have less obvious structure

22

relationship to monosaccharide but in each case the configuration of hydroxyl groups on
the ring can be compared to those of sugars. Castanospermine is an excellent
a-glucosidase inhibitor. Swainsonine is believed to be associated with

deoxymannojirimycin (DMJ), and showed inhibition against a-mannosidases (Table

2.1).

«£50 £4: "é;

Nojirimyiin Deoxynojirimycin Me-Deoxynojiorimycin

 

H O OH
OH
H N H -NH
‘1. 940
CH
Castanospermine Deoxymannonojirimycin Swainsonine

Figure 2.1 Various azasugars which are inhibitors for glycosidases and glycotransferases

Inhibiton constants Ki(pM) of some natural inhibitors

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Enzyme and Source Nojirimycin Deoxynojiri Castanosper Swainsoni
-mycin -mine -ne

a-glucosidases

Yeast 6.3 12.6 >1500

Rice 0.01 0.01 0.015

Sucrase(Rabbit intestine) 0.13 0.032

b-glucosidases

Sweet almonds 0.89 47 l .5

Calf Iiver(cytosol) - 210

Calf spleen(lysosomes) 4.5 180

a-mannosidases

Jack beans 0.001

 

 

Table 2.1 Inhibition effect of azasugars towards various enzymes

2.1.2 Why Azasugar Has Good Inhibition Capability
Castanospermine and derivatives of deoxynojirimycin are considered selective inhibitors
for a-glucosidases because they mimic the positive charge character of the ring oxygen

at transition state, which is believed to be an important feature of the a-glucosidase

transition state (Figure 2.2).13“
HO
NH "’
HO + O\
HO
OH . . . .
Oxocarbemum Ion transmon state
Castanospermine in glycosidase active site

Figure 2.2 C astanospermine mimics the positive charge of the oxocarbenium ion

However, it is questionable whether they are real transition state analogues because they
do not have the expected half-chair confirmation. Therefore. inhibitors that mimic both

the positively charged ring oxygen and the half-chair confirmation have been developed.

In 1994, the five-membered azasugars which is expected to be more flexible than
six-membered rings were synthesized by C-H Wong et al.‘5 The five-membered ring has
more flattened chair confirmation and the positive charge can be mimicked by the
positive charged imino group, so compound 1 showed better inhibition against
a-glucosidase (K. = 2.8pM for or-glucosidase) than DNJ and compound 2 showed strong

inhibition to or-galactosidase from coffee bean at Ph=5.5 (K, = 0.05pM). The X-ray

24

crystal structure of compound 1 indicated an envelop conformation of the five member
ring.I6 Figure 2.3 shows the proposed transition state for a-glucosidase and the positive
charged compound 2. Therefore, fived-membered azasugars are better transition state
analogues than six-membered ring azasugars. So, it is also confirmed that for a good

inhibitor, both the charge condition and the conformation are required.

on OH OH

HO NH NH

OH OH

III-I2+

HO
OH

 

 

 

L_

Figure 2.3 5-membered ring azasugar’s conformational mimicking to glycosidase
transition state (Figure adapted from Wong, Y. F.; Takaoka, Y.; Wong, C. H. Angew.
C hem, Int. Ed. Engl. 1994, 33, 1242-1244)

As we already discussed, Zanamirvir’s potent inhibitory activity was due to its 3 most
important interactions with the neuraminidase active site. 1. The salt bridge between
negative charged Cl carboxylic acid and positive charged Arg 372. 2. The electrostatic
interaction between guanidine group on C4 and the carboxylic acids of Asp 152, Glue
229 and Glu 120; 3. C7-C9 polyol fits into the hydrophobic pocket of the active site, as

shown by the cartoon below (Figure 2.4).'7 Furthermore. Zanamirvir’s coplanar structure

25

of C1-C2-C3-OS mimics the NA transition state conformationally.

Glu 278

N/_ Arg 294

 

 

 

Arg 153

 

O

Arg 119
Asp 1526M 22 Glu 12:0
OH [/4-
" ' '1-

 

 

 

 

   

Figure 2.4 3 most important enzyme-substrate interactions (Figure adopted from Kim, C.
U.; Lew, W. Williams, M. A. Wu, H. W. J. Med. Chem. 1998, 41, 2451-2460)

2.2 Rational Design of Azasugar Neuraminidase Inhibitor

Inspired by Zanamirvir and Oseltamivir, in our design of neuraminidase inhibitor for the
treatment of Influenza. we try to find molecules that meet both the conformational and
the interaction requirements. Obviously, azasugar is a good choice. Compound 3 is our

proposed inhibitor scaffold (Figure 2.5).

Three considerations were involved in our design of this piperidine ring as potential

26

inhibitor: 1. Conformationally, both piperidine and sialic acid intermediate are
six-membered ring. A piperidine is appropriate to mimic the conformation of the
transition state. 2. The Pka of an amine is between 10 toll. It means that under the
regular in vitro catalysis condition, almost all the amine is protonated, and the charged
nitrogen (compound 5) will be a good analogue to an oxocarbenium ion (compound 4)
which has a positive charge primarily on the oxygen atom. 3. The third consideration is
the bond length. The bond lengths of C-N bond and C-0 bond are close. This ensures
that our inhibitor does not have a much different special occupation from the sugar
transition state. Those favorable interactions with the neuraminidase active site will be
much retained. Both proved drugs in the market, Zanamivir and Oseltamivir only mimic
the coplanar structure but not the charge. It’s definitely possible that the azasugar sialic
acid analog could have very good inhibition effect against neuraminidase, probably, even

better than Relenza or Tamiflu.

R5)“, N . R2 R, = H, Alkyl, Acyl, Bn, etc.
””COOH R2 = H, OH, Alkoxyl, c=
R3 = H, OH, C= etc.
AcHN - R3 R4 = H, OH, NH2, NHC(NH)NH2, NHAc
R5 = H, Alkyl, Aryl, OH, Alkoxyl, polyol etc.

at
3
g“ o ------- N :2 o ------- N
\ (- +)>— Arg +/ <- +)>— Ar 9
o ------- N -------
R1 = H R2 = R3 = =
4 5

Figure 2.5 Design of neuraminidase inhibitor scaffold and its mimicking to glycoside
transition state in the hydrolysis by neuraminidase

2.3 The Synthesis of Azasugars

2.3.1 Background

Though iminoalditols or azasugars, represented by deoxynojirimycin and
castanospermine and its derivatives have shown potent glycosidase inhibition capability

18, I9

and have been applied to the medical treatment of numerous diseases, such as

21

antimicrobioalsfo‘ cancer,22 and neurological disorders,23 they have not realized their
full clinical potential. This is largely due to the lack of commercially viable syntheses

and difficulty in preparing a comprehensive palette of variant structures. So far, many of

the possible drug candidates are available only in small exploratory amounts.

Although the only difference between an azasugar and a normal sugar pyranose or
furanose is just the replacement of the-ring oxygen by a nitrogen atom, this is a big
challenge for organic chemists. A number of research groups are in this field and various
chemical and enzymatic syntheses of azasugars have been reported in recent years. These
strategies include aminomercuration, double-reductive amination, N-Alkylation,
reductive double-alkylation and triple reductive amination, ring closing metathesis,

photochemical synthesis and chemo-enzymatic synthesis.24'39

Most of the chemo synthesis use readily available and inexpensive chiral-pool starting
materials such as carbohydrates, amino acids. and tartaric acids. The obvious similar
structural features between azasugars and carbohydrates have made the latter ideal

starting materials. Some representative synthetic strategies are described below:

28

2.3.2 Aminomercuration40

Ganem at Cornell University devised an enantioselective synthetic route from readily
available chiral monosaccharides. His strategy hinged on breaking open the pyranose (or
furanose) ring, and reforming the corresponding piperidine (or pyrrolidine) analogue
with retention of the critical stereocenters by the process of intramolecular
aminomercuration. The general approach is shown in Figure 2.6. A one-pot, reductive
ring opening and reductive amination of the pyranose were achieved by heating
tri-O-benzyl-6-bromopyranoside with acid-washed zinc dust in propanol-water
containing benzylamine and NaBH3CN to afford amino alkene. When the key
intermediate 7 reacted with mercuric trifluoroacetate in anhydrous THF, a 3: 2 mixture of
bromomercurials 8 and 9 was isolated. The major cyclization product 9 could be
transformed to l-deoxynojirimycin 10 by reductive oxygenation (NaBH4-DMF-Og) and
hydrogenolytic deprotection. In this synthesis, only one of the bromomercurials 9 can
give the desired product, which results in a low yield of deoxynojirimycin 10. The

mercury toxicity is a big problem for this strategy.

29

 

 

Br
BnO 0 Zn, NaCNBH; _ BnO \ NHBn
BnO BnNHz, 91% BnO
0811 0811
OH
H o NH
HO
OH

"9(OCOCF312.
THF
HgBr
1 NaBH -DMF-O
$1 4 2 Eric NBn , BnO NBn
2)H2, PdIC BnO SW
0311 ems/I 0811
10 g a
3 : 2

Figure 2.6 Aminomercuration approach for the synthesis of azasugars

2.3.3 Intramolecular N-Alkylation4|

In this approach, the nitrogen atom is first introduced by the 8N2 reaction of an azide
group followed by a reduction reaction to transform it to an amine (Figure 2.7). The
amino group, which is a good nucleophile, then kicks out the mesylate leaving group
intramolecularly to form a 5 or 6-membered ring. Kibayashi selected diethyl tartrate 11
as starting material and finally synthesized enantiomerically pure nojirimycin. The

synthetic route is a little bit lengthy.

0" mono

 

 

He
—+_. osi ML. mongol"...

C2H500C cooczn5 2) MOMCI ,

11

OH MOMO
“(2, NH HCI 1) H2’ Pd'c mono"...

O 2) TEA/”OOH
OH reflux

 

16

 

Figure 2.7 Intramolecular N-alkylation approach for the synthesis of azasugars

2.3.4 Reductive Double-Alkylation“

This methodology was first applied by Pearson‘s group for the synthesis of swainsonine
in 1996 (Figure 2.8). They started with D-Arabinose 17, converted it to 2, 3,
4-tri-Obenzyl-D-arabinose 18 followed by Wittig reaction with known phosphonium salt
to give the Z-alkene 19. N3 was installed by the classical Mitsunobu reaction. An
epoxidation reaction provides another electrophilic center apart from the primary
chloride. Upon reduction of azide, primary amine was generated, which were cyclized to
afford quinolizidines 21 and 22. The synthesis yields the bicyclic azasugars, however, the
diastereoselectivity is not high and it still suffers from the drawback that separation of the

diastereoisomers has to be performed.

HIIIO
I
muo
ID
:3
"1110
W
3

8:10 BnO CI
17 18 1 9
il
an
BnO
N30
BnO Cl
20

   

HO

 

Figure 2.8 Reductive double-alkylation approach for the synthesis of azasugars i. BrPh3P
(CH3)4C1, KN (TMS) 2, 71%; ii.a) HN3, PPh3, DEAD, 84%;b) mCPBA, 88%; iii. a) H2,
Pd/C, EtOH; b) K3CO3, EtOH, reflux; c) separate diastereomers; iv. H2 (45 psl), Pd/C,
HCI, MeOH, 99%

2.3.5 Double Reductive Amination” “‘4

Reductive amination is one of the most popular ways to build carbon-nitrogen bond. By
preparing a dicarbonyl compound. nitrogen can easily be introduced into the molecule
and at the same time, forming a ring structure. Reitz used a primary amine and sodium
cyanoborohydride. successfully synthesized l-deoxynojirimycin,
l-deoxymannojirimycin and N-alkylated derivatives (Figure 2.9). They tried different
amines as nucleophiles and got satisfactory results (Table 2.2). The problem with this

methodology is that the stereochemistry of the reduction product is not easily

controllable.

b)
to

CHO

 

H——OH
Ho——H
—"—. H—-—OH
=0
CH20H
27

 

29 28

Figure 2.9 Double reductive amination approach for the synthesis of azasugars i. a)
BuZSnO, MeOH b) BI’z, CH3CI2, 0°C , 48% ii. Dowex-SO, H20, 70% iii. RNHg,
NaBH3CN, MeOH

 

 

 

 

 

 

 

 

RNH; Yield Ratio 29 : 28
PthHNHg 70% 5 : 95
PthHCHgNHg 73% 5 : 95
C4H9NH2 55% 5 : 95
C|2H25NH3 27% 5 2 95

 

 

Table 2.2 The overall yields and ratios of the two products formed by the double
reductive amination reaction

2.3.6 Triple Reductive Amination45

A triple reductive amination reaction involves three carbonyl groups at the same time. It’s
suitable for the synthesis of bicyclic nitrogen-containing compound such as swainsonine
and castanospermine. The allyated monsaccharides are practical precursors for the key
tricarbonyl intermediates required for this strategy. A wide range of analogue structures
will be possible in view of the number of easily accessible monosaccharide precursors of
different configurations and constitution. The triple reductive amination approach is

efficient for the synthesis of compounds with bicyclic indolizidine framework (Figure

33

2.10). But, the preparation of the precursor with aldehyde and ketone functionalities is

not an easy exercise.

OHC HO

  
 
  

BnOum'" mmuoue

 

HOIIIm-o

 

Bn DBn
33

Figure 2.10 Triple reductive amination approach for the synthesis of azasugars i. a)
Swem Oxidation; b) O3. CH2CI2,-78°C then Ph3P; c) THF-9M HCI, 74% for 3 steps; ii.
NH4HCO3, NaCNBH3, MeOH, 78%; iii. 10% Pd-C, MeOH-HCOOH, 80%

 

46. 47

2.3.7 Ring Closing Metathesis
In the last decade, the ring closing metathesis (RCM) reaction has emerged as an
extraordinarily powerful and general method for the construction of nitrogen heterocyclic
compounds and has relevant application in the field of alkaloid synthesis. In the field of
azasugar synthesis, the double bond formed by RC M reaction is well-suited to install
either a cis or trans vicinal diol functionality using a dihydroxylation reaction or an
epoxidation reaction followed by subsequent hydrolysis. The synthesis of DGJ and
analogues starting from D-Garner‘s aldehyde 35 (derived from D-serine) with a
ring-closing metathesis (RCM) as the key step has been reported by Takahata et al., as

shown in the following Scheme (Figure 2.11). The problem with this methodology is that

the catalyst for RCM reaction is too expensive and the cost to maintain the catalysts’

activity is too high for industrial production.

H O
___'_. —-——-> Boc\u l37%
Boc—N Boc—N

coé tit
00 / °,,\ g B“,
be moot
1.. 4° 1.. ‘1
1m 1...
Hafiz/fl H0», ,,,,, (1%

Figure 2.11 Ring closing metathesis approach for the synthesis of azasugars i. VinylZnBr,
Et2O,-78°C to room temp., 2h, chromatography then recystallization form n-hexane/
EtOAc (5: l), 72%, 92% de; ii. HCI gas, CHCI3, room temp., 12h 69%; iii. Allyl iodide,
NaH, THF, 0°C, 12b, 76% iv. [Ru], CH2CI2, room temp., 2h, 95%; v. Oxone, CF3COCH3,
NaHCO3, aqueous Na2EDTA, CH3CN, 0°C, 20min 90%; vi. K2OsO4'2H2O, NMO,
acetone, H2O, 0°C to room temp., 12h, 85%; vii. a) 0.3M KOH, 1,4-dioxane, H2O, reflux,
26h; b) 6N HCI, MeOH, reflux, 1h, then Amberlite IRA-410(OH-form), 87%(2 steps);
viii.6N HCI, MeOH, reflux, 1h, then Dowex 50Wx8(HT form), 90%

2.3.8 Photochemical Approach"l8

35

Photochemical reactions were applied to the synthesis of azasugar too (Figure 2.12). A
cyclic amine can be synthesized from D-Tartaric Acid 44.49The piperidine ring was
closed by photoinduced electron transfer (PET) reaction. A variety of l-N-iminosugars
are accessible through this approach. But the stereochemistry on the carbon adjacent to

the nitrogen atom can not be controlled.

COOH

Howl:
—————>
———>
HO

COOH
44

 

Figure 2.12 Photochemical approach for the synthesis of azasugars i.
PhCH2NHCH2TMS, K2C03, CH3CN, reflux, 96h, 65%; ii.hv, DCN, 2-PrOH, 90min,
60%; iii. a) 9-BBN, THF, 0°C to room temp., 20h, then NaOH, H202, 0°C to room temp.,
4h, 45%; b) HCI, MeOH, rt, 1h, then NH.,OH, 100%; c) Pd(OH)2 on C, H2, 75 psi, EtOH,
10h, 95%

2.3.9 Chemo-enzymatic Synthesis°°‘53

This methodology was developed by Wong and his group. It is generally a two step
process involving an enzymatic aldol condensation and a catalytic intramolecular
reductive amination. The detailed synthetic route is shown below (Figure 2.13). Two
azasugars 52 and 53 were obtained as products. However. this method of synthesis is not

a general method because the limitation of scale-up of enzymatic reactions.

OEt

O
°3P°\/“\/OH + EtO/IY\N3 1) H+

OH 2) FDP aldolase
49 50

 

OH OH 1) Phosphatase
+ -
H O "(HO 53:52 = 1:1.2 -1:4.1
OH overall yield 48% - 64%
53 52

Figure 2.13 Chemo-enzymatic approach for the synthesis of azasugars

2.4 Summary

Although people have developed a lot of synthetic methods towards carbohydrates, the
synthesis of azasugar remains troublesome. First, it’s really hard to find a route leading to
a general precursor for most of the azasugars. Second, as with all carbohydrates,
azasugars are multi-hydroxyl compounds. In most of modification processes, protecting
these hydroxyl groups is a problem due to limited orthogonal protecting groups. And last,
most of the synthetic routes start with a carbohydrate with five to seven carbons. Then,
how to make the C-glycoside structure with more than eight carbons is a challenge
because of difficulties to form carbon-carbon bond. So, more strategies towards the

synthesis of azasugars should be developed in the future.

37

2.5 References

10.

. Stutz, A. E.; Iminosugars as Glii’cosiduse Inhibitiors. Nojirimycin and Beyond

WILEY-VCH; New York; 1999

Inouye, S.; Tsuruoka. T.; Niida, T. The Structure of Nojirimycin, A Piperidinose
Sugar Antibiotic J. Antibiot. 1966, 19, 288-292

Inouye, S. T. T.; Ito, T.; Niida, T. Structure and Synthesis of Nojirimycin Tetrahedron
1968, 24, 2125

Dzure, Y.; Maruo, S.; Miyazaki, K.; Kawamata, M. Moranoline(l-deoxynojirimycin)
Fermentation and Its Improvement Agricultural and Biological Chemistry 1985, 49,
1119-1125

Fellows, L. E.; Bell, E. A.; Lynn, D. G; Pilkiewicz, F.; Miura, 1.; Nakanishi, K.
Isolation and Structure of an Unusual Cyclic Amino Alditol form a Legume Chem.
Comm. 1979, 977-978

Kite, G C.; Fellows, L. E.; Fleet, G W. J.; Liu, P. S.; Scofield, A. M.; Smith, N. G
a-Homonojirimycin 2.6-Dideoxy-2.6-Imono-D-Glycero-L-Gulo-Heptitol from
Omphalea-Doamdra L-Isolation and Glucosidase Inhibition Tetrahedron Lett. 1988,
29, 6483-6486

Molyneux, R. J.; Pan, Y. T.; Tropea, J. E.; Elbein, A. D.; Lawyer, C. H.; Hughes, D. J.;
Fleet, G. W. 2-Hydroxymethyl-3,4-Dihydroxy-6-Methylpyrrolidin (6-Deoxy-Dmdp),
an Alkaloid Beta-Mannosidase Inhibitor from Seeds of Angylocalyx-Pynaertii J. Nat.
Prod. 1993, 56. 1356-1364

Legler, G. Glycoside Hydrolases: Mechanistic Information from Studies with
Reversible and Irreversible Inhibitors Adv. C arbohvdr. Chem. Biochem. 1990, 48,
319-385

Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.; Pryce, R. 1.; Arnold,
E.; Clardy, J. Castanospermine, a l,6,7,8-Tetrahydroxyoctahydroindolizine Alkaloid,
from Seeds of Castanospennum-Australe Phytochemistry 1981, 20, 811-814

Nash, R. J.; Fellows, L. E.; Dring, J. V.; Trirton. C. H.; Carter, D.; Hegarty, M. P.;
Bell, E. A. Castanospermine in Alexa Species Phi'tochemistrv 1988, 27, 1403-1404

.Colegate, S, M.;Dorling, P. R.; Huxtable, C. R. Spectroscopic Investigation of

Swainsonine-Alpha-Mannosidase Inhibitor Isolated from Swainsona-Canescens
Australian Journal of Chemistry 1979, 32, 225 7-2264

38

12.

13.

I4.

18.

I9.

20.

21.

22.

23.

Molyneux, R. J.; James, L. F. Loco Intoxication-Indolizidine Alkaloids of Spotted
Locoweed (Astragalus-Lentiginosus) Science 1982, 216, 190-191

Harris, E, M. S.; Aleshin, A. E.; Firsov, L. M. Honzatko, R. B. Refined Structure for
the Complex of l-Deoxynojirimycin with Glucoamylase from
Aspergillus-Awamori Var X100 to 2, 4-Angstrom Resolution Biochemistry 1993, 32,
1618-1626

Dorling, P. R.; Huxtable, C. R.; Colegate, S. M. Inhibition of Lysosomal
Alpha-Mannosidase by Swainsonin, an Indolizidine Alkaloid Isolated from
Swainsona-Canescens Biochem. J. 1980, 191, 649-651

. Wong, Y. F.; Takaoka, Y.; Wong, C. H. Remarkable Stereoselectivity in the Inhibition

of Alpha-Galactosidase from Coffee Bean by a New Polyhydroxypyrrolidine
Inhibitor Angew. Chem, Int. Ed. Engl. 1994, 33, 1242-1244

. Liu, K. K. C.; Kajimoto, T.; Chen, L. R.; Zhong, Z. Y.; Ichikawa, Y.; Wong C. H. Use

of Dihydroxyacetone Phosphate Dependent Aldolases in the Synthesis of
Deoxyazasugars J .Org. Chem. 1991, 56, 6280-6289

.Kim, C. U.; Lew, W. Williams, M. A. Wu, H. W. Structure-Activity Relationship

Studies of Novel Carbocyclic Influenza Neuraminidase Inhibitors J. Med. Chem.
1998, 41, 2451-2460

Scheen, A. J. Drug Treatment of Non-Insulin-Dependent Diabetes Miellitus in the
19905 —Achievements and Future Developments Drug 1997, 54, 355-368

Witczak, A. J. In Carbohydrates as New and ()Id Targets for Future Drug Design in
Carbohydrates in Drug Design Witczak, Z. J., Ed; Marcel Dekker Inc.: New York,
1997,p1

Karpas, A.; Fleet. G W.; Dwek, R.A.; Petursson, S.; Namgoong, S. K.;Ramsden, N.
G; Jacob, G S.; Rademacher, T. W. Aminosugar Derivatives as Potential Anti-Human
Immunodeficiency Virus Agents Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9229-9233

Taylor, D. L.; Sunkara, P.S.; Liu, P. S.; Kang, M. S.; Bowlin, T. L. Tyme, A.
S.6-6-Butanoylcastanospermine(Md| 28, 574) Inhibits Glycoprotein Processing and
the Growth of HIV Aids 1991, 5, 693-698

Goss, P. E.; Baker, M. A.; Carvber, J. P.; Dennis. J. W. Inhibitors of carbohydrate
processing: A new class of anticancer agents Clinical Cancer Research 1995, I,

935-944

Molyneux, R .J.; McKenzie, R. A.; Osullivan, B. M.; Elbein, A. D. Identification of

39

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

the Glycosidase Inhibitors Swainsonine and Calystegine B-2 in Weir Vine(Ipomoea
Sp Q6 Aff Calobra) and Correlation with Toxicity J. Nat. Prod. 1995, 58, 878-886

Pearson, W. H.; Hembre, E. 1.; Synthesis of tetrahydroxyquinolizidines:
Ring-expaned analogures of the mannosidase inhibitor swainsonine J. Org. Chem.
1996, 61, 5537-5545

Iida, H. Yamazaki, N.; Kibayashi, C. Total Synthesis of (+)-Nojirimycin and
(+)-1-Deoxynojirimycin J. Org. Chem. 1987, 52, 3337-3342

Zhao, H.; Hans, 8.; Cheng, X. H.; Mootoo, D. R. Allylated Monosaccharides as
Precursors in Triple Reductive Amination Strategies: Synthesis of Castanospermine
and Swainsonine J. Org. Chem. 2001, 66, 1761-1767

Dhavale, D. D.; Saha, N. N.; Desai, V. N. A Stereoselective Synthesis of
1,6-dideoxynojirimycin by Double-Reductive Amination of Dicarbonyl SugarJ. Org.
Chem. 1997, 62, 7482-7484

Baxterm E. W.; Reitz, A. B. Expeditious Synthesis of Azasugars by the Double
Reductive Amination of Dicarbonyl Sugars J. Org. Chem. 1994, 59, 3175-3185

Ganem, B. Inhibitors of carbohydrate-processing enzymes: Desing and Synthesis of
Sugar-Shaped Heterocycles Acc. Chem. Res. 1996, 29, 340-347

Liu, K. K. C; Kajimoto, T.; Chen, L. R.; Zhong, Z. Y.; Ichikawa, Y.; Wong C. H. Use
of Dihydroxyacetone Phosphate Dependent Aldolases in the Synthesis of
Deoxyazasugars J. Org. Chem. 1991, 56, 6280-6289

Wong, C. H.; Ichikawa, Y.; Krach, T.; Gautheronlenarvor, C.; Dumas, D. P.; Look, G.
C. Probing the Acceptor Specificity of beta-1,4-Ga1actosyltransferase for the

Development of Enzymatic-Synthesis of Novel Oligosaccharides J. Am. Chem. Soc.
1991, 113, 8137-8145

Kajimoto, T.; Chen, L .R.; Liu, K. K. C.; Wong, C. H. Palladium-Mediated
Stereocontrolled Reductive Amination of Azido Sugars J. Am. Chem. Soc. 1991, 113,
6678-6680

Kajimoto, T. Liu, K. K. C.; Pederspm. R. L.; Zhong, Z. Y.; Ichikawa, Y.; Porco. J. A.;
Wong, C. H. Enzyme-Catalyzed Aldol Condensation for Asymmetric Synthesis of
Azasugars -—Synthesis, Evaluation, and Modeling of Glycosidase Inhibitors J. Am.
Chem. Soc. 1991, 113, 6187-6196

Defoin, A. S. H.; Streith, J. Synthesis of 1, 6-dideoxynojirimycin, 1,
6-dideoxy-D-allo-nojirimycin, and 1, 6-dideoxy-D-gulo-nojirimycin via Asymmetric

4O

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

Hetero-Diels-Alder Reactions Helv. Chim. Acta. 1996, 79, 560-567

Takahashi, S. K. H. Synthesis of L-Fucopyranose and Its Homologs with Ring
Heteroatoms Other than Oxygen. Stereocontrolled Conversion of a Common
D-arabinofuranoside Intermediate Chem. Lett. 1992, 21-24

Legler, G; Stutz, A. E.; Immich, H. Synthesis of 1,
5-Dideoxy-l ,5-Imono-D-Arabinitol (5-nor-L-Fuco-1-Deoxynojirimycin) and Its
Application for the Affinity Purification and Characterization of Alpha-L-Fucosidase
Carbohydr. Res. 1995, 272, 17-30

Igarashi, Y. 1., M.; Ichikawa, Y. Synthesis ofa New Inhibitor of Fucosidase Bioorg.
Med. Chem. Lett. 1996, 6, 553-558

Brandstetter, T. W.; Davis, 8.; Hyett, D.; Smith, C.; Hackett, L. Winchester, B. G;
Fleet, G W. J. Tetrazoles of Manno-Pyranoses and Rhamno-Pyranoses-Inhibition of

Glycosidases by Tetrazoles and Other Mannose Mimics Tetrahedron Lett. 1995, 36,
7511-7514

Ermert, P.; Vase, A. A. Synthesis of a Glucose-Derived Tetrazole as a New
Beta-Glucosidase Inihibitor — a New Synthesis of l-Deoxynojirimycin 11er C him.
Acta 1991, 74, 2043-2053

Ganem, B. Inhibitors of carbohydrate-processing enzymes: Design and synthesis of
sugar-shaped heterocycles Acc. Chem. Res. 1996, 29, 340-347

Iida, H.; Yamazaki, N; Kibayashi C. Total synthesis of (+)-nojirimycin and
(+)-l-deoxynojirimycin J. Org. Chem. 1987, 52, 3337-3342

Pearson, W. H.; Hembre, E. J. Synthesis of Tetrahydroxyquinolizidines:
Ring-expanded Analogues of the Mannosidase Inhibitor Swainsonine J. Org. Chem.
1996, 61, 5537-5545

Baxter, E. W.; Reitz, A. B. Expeditious Sythesis of Azasugars by the Double
Reductive Amination of Dicarbonyl Sugars J. Org. Chem. 1994, 59, 3175-3185

Dhavale, D. D.; Saha, N. N.; Desai, V. N. A Stereoselective Synthesis of l,
6-dideoxynojirimycin by Double-Reductive Amination of Dicarbonyl Sugar J. Org.
Chem. 1997, 62, 7482-7484

Zhao, H. Hans, S.; Cheng. X. H.; Mootoo, D. R. Allylated Monosaccharides as

Precursors in Triple Reductive Amination Strategies: Synthesis of Castanospermine
and Swainsonine J. Org. Chem. 2001, 66, 1761-1767

41

46.

47.

48.

49.

51.

52.

53.

Banba, Y.; Abe, C.; Kato, A.; Adchi, 1.; Takahata, H. Asymmetric Synthesis of
Fagomine and Its Congeners Tetrahedron: Asymmetry 2001, 12, 817-819

Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H. Concise and Highly Stereocontrolled
Synthesis of l-Deoxygalactonojirimycin and Its Congeners Using
Dioxanylpiperidene, a Promising Chiral Builiding Block Org. Lett. 2003, 5,
2527-2529

Pandey, G; Kapur, M.; Khan, M. 1.; Gaikwad, S. M. A New Access to Polyhydroxy
Piperidines of the Azasuagr Class: Synthesis and Glycosidase Inhibition Studies Org.
Biomol. Chem. 2003, 1, 3321-3326

Pandey, G; Kapur, M. A General Strategy towards the Synthesis of l-N-imonosugar
Type Glycosidase Inhibitors: Demonstration by the Synthesis of D-as well as
L-Glucose Type lminosugars (Isofagomines) Tetrahedron Lett. 2000, 41, 8821-8824

. Kajimoto, T.’ Liu, K. K. C.; Pederson, R. L.; Zhong, Z. Y.; Ichikawa, Y.; Porco, J. A.;

Wong, C. H. Enzyme-catalyzed Aldol Condensation for Asymmetric-Synthesis of
Azasugars-Synthesis, Evaluation, and Modeling of Glycosidase Inhibitors J. Am.
Chem. Soc. 1991, 113, 6187-6196

Kajimoto, T.; Chen, L. R.; Liu, K. K. C.; Wong, C. H. Palladium-Mediated
Stereocontrolled Reductive Amination of Azido Sugars Prepared from Enzymatic
Aldol Condensation-a General Approach to the Synthesis of Deoxy Aza Sugars J. Am.
Chem. Soc. 1991, 113, 6678-6680

Wong, C. H.;Ichikawam Y.; Krach, T.; Gautheronlenarvor, C.; Dumas, D. P.; Look, G
C. Probing the Acceptor Specificity of Beta-1, 4-Galactosyltransferase for the
Development of Enzymatic-Synthesis of Novel Oligosaccharides J. Am. Chem. Soc.
1991,113, 8137-8145

Liu, K. K. C.; Kajimoto, T.; Chen, L. R.; Zhong, Z. Y.; Ichikawa, Y.; Wong, C. H. Use
of Dihydroxyacetone Phosphate Dependent Aldolases in the Synthesis of
Deoxyazasuagrs J. Org. Chem. 1991, 56, 6280-6289

Chapter 3 Design and Synthesis of Our Azasugar Target

3.1 Result and Discussion:

3.1.1 Shortcomings of the Currently Available Strategies

Though great effort has been put into the synthesis of azasugar and various approaches

have been proposed, they suffer different drawbacks which either prohibit the industrial

usage or not be able to give the desired scaffold. The reasons are listed below:

a) The synthesis is too lengthy. A more then 10 steps strategy is very unlikely for large
scale production.

b) The synthesis is too costly. For example, the transition metal catalyzed RCM. The
expensive catalyst itself significantly reduces the practicality.

c) The reagents are expensive, toxic or corrosive. Organic compounds like HCN etc.
should be avoided.

d) The reaction conditions are severe. The desired route should not require extreme
conditions such as very high temp, very low temp, or high pressure etc.

e) None of these approaches afford a carboxylic group on the B-position of the

piperidine nitrogen.

3.1.2 Our Proposed Synthetic Strategy

We designed a short synthetic pathway toward our target scaffold 6 (Figure 3.1). It starts
with cheap monosaccharide D-(+)-Mannose 1. We can protect 2, 3-0 and 4, 6-0 with
two acetal groups leaving anomeric position intact. Then, we plan to apply a Strecker
type reaction"9 to add cyanide group to anomeric position and open the ring to afford a

diol 3. Because generation of HCN does not obey our industry-friendly principle, we do

44

not want to do the reaction in acidic condition. In addition, the propylidene protecting
groups do not tolerate acid as well. The two hydroxyl group can be converted to good
leaving groups by mesyl chloride to form intermediate 4. An amine (benzylamine for
example) is proposed to close the ring to form the piperidine by 8N2 reaction. Then,
hydrolysis by acid would transform the cyanide to the carboxylic acid form, and also
remove the acetal protecting groups as acetone to afford the proposed scaffold 6. All the
hydroxyl groups are subject to further modification. The Benzyl group can be easily
removed by hydrogenation to expose the nitrogen as a secondary amine which can be

acylated to become an amide or alkylated to become a tertiary amine. It’s a good mother

scaffold for an azasugar library.

 

Figure 3.1 Proposed synthetic strategy for our target scaffold i. 2-Methoxypropene,
p-Toluenesulforic acid, anhydrous DMF; ii. KCN, H20, room temp. iii. Mesyl chloride,
pyridine, room temp. iv. BnNH2, DMF v. HCI aqueous solution, acetic acid

3.1.3 Progress and Problems with Our Proposed Strategy

45

In the second step to synthesize compound 3, by treating the protected mannose with
NaCN in neutral condition, we did not obtain the desired product. The results are shown

below (Table 3. 1):

 

 

 

 

 

 

 

 

 

Conditions ;
Conditions Results

1. NaCN (2 equiv.) , H2O, room temp, 24 h No reaction
2. NaCN (2 equiv.), H2O, 50°C, 24 b No reaction
3. NaCN (2 equiv.), HCI conc., room temp. 20min Deprotection product
4. NaCN (2 equiv.), HCI 2%, room temp. 20min Deprotection product
5. NaCN (2 equiv.), NaHSO3 (2 equiv), room temp. 24h, No reaction

H20
6. NaCN (2 equiv.), NaHCO3 (2 equiv), room temp. 24h, No reaction

H2O

 

 

 

 

Table 3.1 Trials of different pH conditions and different buffer solutions for the solvent
of cyanohydrin formation reaction

Condition 1 and 2 failed to work presumably because: 1. The poor solubility of the 2, 3:4,
6-di-O-isopr0pylidene-D-mannose 2 in water. 2. Low reactivity of NaCN in neutral or
basic conditions. Acidic conditions 3 and 4 remove the isopropylidene quickly as we
expected. We also tried to add sodium bisulfite or sodium bicarbonate as buffer reagents

to keep the pH value of the solution around 7. Unfortunately, these kinds of buffers did

46

not help at all.

To solve the problem of solubility, we tried different solvent combinations. The results

are shown below (Table 3. 2):

 

 

 

 

Solvent Result
1. MeOH/ H2O 1:1 45% starting material reacted after 24h
2. EtOH/ H2O 1:1 50% starting material reacted afier 24h
3. EtOH/ H20 1:1 50°C 60% starting material reacted after 24h

 

4. EtOH/ H2O 1:1 50°C, NaCN 3 equiv. 65% starting material reacted after 24h

 

 

 

 

 

 

5. THF/ H2O 1:1 10% starting material reacted after 24b
6. EtOH/ H2O 1:2 30% starting material reacted after 24b
7. EtOH/H2O 2:1 25% starting material reacted after 24h

 

Table 3.2 Trials of different solvent combinations for the cyanohydrin formation reaction
unless noted, all the reactions above were done in room temperature, NaCN (2 equiv.),
5ml solvent for 0.3g 2, 3: 4, 6-di-O-propylidene-D-mannose 2

Best reaction rate was achieved in 1:1 mixture of ethanol and water. Higher temperature
and more NaCN will speed up this reaction. but we did not detect much yield
improvement after more than 3 equivalents NaCN is used. Based on these results, we
chose condition 4 (EtOH; H20 1: l/ NaCN 2.5-3 equiv. / 50 °C) for all the further
research. Though under this condition, the conversion rate for starting protected mannose
was only 80%. In the products, we separated compound 7 with 20% yield (Figure 3.2).
The cyanide was successfully installed and at the same time. and was hydrolyzed to form

a carboxylic acid in the solution because of the basic condition (pH =10 during the

reaction). The other part of the products was complicated. It was an inorganic

47

salt-organic compound mixture. On the TLC, the spots of organic compounds were
covered completely by salt and very hard to observe. We did not use resin to remove the
salt because t the acid generated from the resin would destroy acetal protecting groups in
the products. Acylation was applied for this mixture in order to reduce the polarity of the
organic compounds and make them separable from salts. Compound 8 and 9 were
obtained at the end. We assumed that before acylation, they were in their sodium salt
forms mixed with inorganic salts. The yields for both of these products were not
satisfactory and the e possible mechanisms for the formation of 7 to 9 are discussed

afterwards. .

NaCN (2.7 equivi
H 1:1 EtOHI H20,
50°C, 48h

Mixture of
inorganic salt
and organic
compounds

 

   

A620,
2 7 Pyridine,
20% 11:, 3h

   

10% 20%

Figure 3.2 Cyanohydrin formation reaction under regular Strecker condition

3.1.4 Possible Mechanism for Product 8
In all the three products obtained, compound 8 is the expected product and the

mechanism is the most straightforward one (Figure 3.3). First, cyanide attacks the

48

electrophilic anomeric carbon to form a cyanohydrin 11. Under basic condition, the
cyanide is hydrolyzed to afford a carboxylic acid salt 12. This salt is mixed with other
inorganic salt and was taken for the acylation reaction. Both the carboxylic group and the
a — hydroxyl group are acetylated. Finally, the 5-0 attacks carboxylic group, kicks out

acetate, and closes the seven member ring to give product 8.

N
11
Hydrolysis J
OH
“r OH
000'
12

Mixed with inorganic salt

 

Figure 3.3 Possible mechanism of the formation of compound 8

3.1.5 Possible Mechanism for Product 7
One of the possible mechanisms for compound 7 is almost the same as compound 8.

After the formation of cyanohydrin 11 (Figure 3.4), cyanide group is hydrolyzed to form

49

a carboxylate 12. The solution is not basic enough to maintain all the 12 in its ion form.

So, after workup, part of the 12 obtains a proton to form acid 7.

>g, .. >{ ..
1m»- OH illuu OH

CN 11 yd rolysis C00'

0
11 12

 

 

Figure 3.4 Possible mechanism of the formation of compound 7

3.1.6 Possible Mechanism for Product 9

It’s possible that after intermediate 11 (Figure 3.5), the C-2 hydrogen leaves as a proton
as the strong charge holding capability of cyanide and hydroxyl group are able to
stabilize the partial negative charge. This process is similar to the first two steps of the

benzoin condensation reaction.”'M

The lone pair of electron left by the leaving proton
pushes the C-3 oxygen away to form enol 17. Enol is not a stable structure, it
automatically tautomerizes to its ketone form 18. Compound 18 is hydrolyzed and

remains in its salt form before the acylation reaction. After the carboxylic group of 18 is

acetylated. the C-6 hydroxyl group would easily cyclize the ring to afford lactone 9.

50

 

OH'
OH
N

'O

  

EN
r: >

OH‘
11 ”<6“ 17 13

l

(‘0\
Ac H 3
’3
19 ”/0?ng

Ho

 

Ohm-

 

Figure 3.5 Possible mechanism of the formation of compound 9

3.2 Alternative Cyanohyd rin Formation Strategy

After several messy trials of Strecker reaction, we switched to Bucherer-Bergs
reaction.'5'°° Bucherer reaction is to treat a ketone with potassium cyanide and sodium
carbonate to form a heterocycle 22 (Figure 3.6). The mechanism of this reaction is also
shown in the following scheme. In the first step, the cyanide attacks the carbonyl group
to afford a cyanohydrin 23. Then the ammonia release by ammonium carbonate in the
solution kicks out the hydroxyl group to form structure 24. 24 has an amino group on the
(It—carbon to a cyanide, which is a carboxylic precursor. This kind of structure is exactly
what we need. However, Bucherer reaction does not stop here. The amino group on 24
will attack CO2 (or carbonate) to form amide 25. 25 experiences a series of

transformation to reach the final product lactam 22.

39
2::

R1 KCV Y0
> o (Vlld) co R2
R2 ‘ 4 2 3 NH
21 0 22
@1031)
H— H N”2
R1 NH R1 f. =
R R
2 CN' 2 R2 \
21 23 24

R1 ”(H
. N

R1:)\KO
R2
NH
firm; :2
° 22

Figure 3.6 Bucherer-Bergs reaction and its mechanism

K21

Inspired by Bucherer reaction, we tried to use ammonium chloride instead of ammonium
carbonate, attempting to stop the reaction at compound 24 stage. It was successful
(Figure 3.7). We got two series of product: 28, 29 which are cyanoamine and 30, 31
which are cyanohydrin. The ratio of these products depends on the reaction temperature.
Higher temperature favors 28& 29; Lower temperature favors 30& 31 (Table 3.3).
However, in either condition, we can not convert all the starting material afier 48h. At
lOOOC, we got almost pure 28 and 29 in a ratio of l :2. At room temperature, only 30 and

31 are obtained with a relative ratio of2:l.

52

OH NH;
+ 0"" cu +

 

x1140,

Eton/H20
OH ,OH
“IMO. " CN

      

30

Figure 3.7 Application of Bucherer type reaction to 2, 3: 4,
6-di-O-propylidene-D-mannose

 

 

 

 

Temperature 28 + 29 : 30 + 31 28 : 29 30 : 31 Total Yield
100°C 80 :20 l : 2 — 75%
55°C 60: 40 l :l l : l 65%
20°C 90 :10 - 2: 1 60%

 

 

 

 

 

 

 

Table 3.3 Products ratio and total yields for Bucherer type reaction of 2, 3: 4,
6-di-O-isopropylidene-D-mannose

3.3 Ring Closure Trials

3.1.1 Intramolecular Mitsunobu Reaction

We took compound 28 and 29 for a classic Mitsunobu reaction in the hope that the C2
amino group would displace the hydroxyl group on C6 to form the piperidine scaffold.

But, we got no reaction even afler heating (Figure 3.8).

PPh3. DEAD
TH r. 50 °(:.
48h

No reaction

   

29

(J1
b)

Figure 3.8 Mitsunobu reaction of compound 28 and 29

3.3.2 Double N-Alkylation Reaction

We took compound 30 and 31 (Figure 3.9), convened the C2, C6 hydroxyl groups to
mesylates first (compound 32 and 33). Then we tried to use benzylamine as nucleophile
to do a double substitution reaction to built up the 6 member ring. It was really hard to do
this alkylation on two secondary carbons. We got only monosubstituted products alter

bringing the reaction temperature to l50°C, extending the reaction time to 72 hours.

 

   

.‘rlsCl. Py BnNH M000 SUMtlflied
-—--—-> —-—-2—>
Xylene. prom“:
150 “C
33
Figure 3.9 Trials on double N-alkylation to cyclize the ring
There are two possible reasons for this unsuccessful 3N2 reaction:
1. Kinetic factors. Generally, 8N2 reaction on a secondary carbon is much more

difficult than on a primary carbon. Two 8N2 on two secondary carbons would be

even harder. The mesylate on C5 is surrounded by C6 and C4, which are on a

54

six-membered ring. These groups hinder the incoming benzyl amine to approach
C5.

2. Thermodynamic factors. On the C4-C5-C6-isopropylidene ring, both C5 mesylate
and the C3 on C4 are on equatorial positions before the substitution reaction. It’s a
quite stable structure. The amine has to come in from the axial position on C5 to
kick the mesylate out. This would result in an axial C4-N bond. One of the two
large groups on the ring, C3 or NHR, has to be on axial position even the ring flips.

So, this substitution is thermodynamically disfavored.

CH3

CH3
H H
.1,c 0' ous___....c ZQKHMMWM
0 0
CK CNHR ”3 c3
NHzR

Figure 3.10 Explanation to the unsuccessful ring closing reaction of compound 32

A possible solution to this substitution reaction is to make a better leaving group than

mesylate, for example, trifiate.

3.4 Summary

In summary, we have successfully made the cyanohydrins and cyanoamines on the
anomeric position of protected mannose 2 by Bucherer reaction. But we failed to close
the ring by double 8N2 reaction due to both kinetic and thermodynamic factors. We
believe that by switching to a better leaving group, the piperidine ring could be closed

and the Influenza inhibitor library could be built.

55

3.5 Experimental Section

2, 3: 4, 6-di-O-isopropylidene-D—Mannose 2

1.01g (5.6mmol) D-(+)-Mannose l was dissolved in 25ml anhydrous DMF. The solution
was cooled in ice bath for 10min, then 0.95g (l2.8mmol, 2 equiv.) 2-methoxypropene
and 0.05g (3.2mmol) p-toluenesulfuric acid two hydrates were added. After 2 hours, the
solution was warmed to room temperature, then another portion of 2—methoxypropene
(0.95g, 12.8mmol, 2equiv.) was added. The solution was kept in room temperature while
stirring overnight before being dumped into a beaker containing 20g ice and 0.1 g sodium
bicarbonate. The water-DMF solution was extracted with ethyl acetate for three times
(30ml *3). The ethyl acetate extracts were combined, dried with sodium sulfate and the
solvent was removed. The white solid obtained was recrystallized fiom ethyl acetate and
hexane. The product is the white needle crystal (1.10g, 76%); mp153-154°C, [a] 020-1
(3min)-+-l6 (5min) ——>-24° (final, 48h; c 1.2, water);m/e 205 (4.5, Mi-Me), 187 (1.2,
205-H20, in. 170.6), 161(0.7, M+-Me2COH), 145 (1.2, 205-AcOH), 131(3.3), 115 (1.5),
103(1.2), 102(1), 101(6.5), 85(2.4), 73(7), 59(30), 58(26) and 43(100)

3, 4: 5, 7-di-O-isopropylidene-D-Manno-heptulopyransonic acid 7

lsoprpylidene protect Mannose 2 (0.5g, 1.92mmol) was dissolved in 5ml ethanol and 5ml
water solution. 231mg NaCN (4.71mmol) was added, and then the solution was kept at
55 degree for 48 hours. The mixture turned reddish. The solvent was removed and
column chromatography was applied to separate the products (Eluent: 1:1 Ethyl Acetate:
Hexanes). 0.1g starting material 2 was recovered and 0.12g 7 (0.384mmol, 20%) was
obtained. Methanol was used to wash the column. After removing the methanol, white
solid mixture was obtained. Data for isomer 1: 1H NMR (300MHz, CDC13) 8 6.86 (1 H, s),
6.58 (1H, s), 5.60-5.80 (1H, br.), 4.78 (1H, q, J = 4Hz, 3H2), 4.59 (1H, d, J = 7H2),
4.30-4.35 (1H, m), 4.08 (1H, q, J = 5H2), 3.90-4.00 (2H, m), 1.38 (3H, s), 1.35 (3H,s),
1.27 (3H, s), 1.22 (3H, s); 13C NMR (300MHz, CDC13) 8 171.0, 113.0, 109.2, 102.3, 86.0,
80.1, 79.6, 72.8, 66.6, 26.8, 25.6, 24.9, 23.9 ppm; Data for lsomer 2: IH NMR (300MHz,
CDC13) 6 6.71 (1H, s), 6.62 (1H, s), 5.60-5.80 (1H, br.), 4.82 (1H, q, J = 4Hz, 3H2), 4.71

(1H, d, J = 7H2), 4.20-4.25 (1H, m), 3.90-4.00 (2H, m), 1.47 (3H, s), 1.33 (3H, s), 1.31

(3H, s), 1.25 (3H, s); 13C NMR (300MHz, CDC13) 6 172.0, 113.7, 109.2, 99.9, 80.1, 78.8,
77.7, 72.9, 66.8, 26.8, 25.7, 25.0, 24.3 ppm

2-O-acetyl-3, 4: 5, 7-di-O—isopropylidene-D-Manno-1, 6-heptanolactone 8

The white solid mixture from the preparation of 7 was mixed with 10 ml anhydrous
pyridine to form syrup. The syrup was cooled to 0 degree, and then excessive amount of
acetic anhydride was dropped in. The solution was kept stirring and warmed up to room
temperature in 3 hours. The syrup afler removal of the solvent was distributed into water
and ethyl acetate. The ethyl acetate extract was dried with sodium sulfate. Column
chromatography (Eluent: 1:2 ethyl acetate to 1:1 ethyl acetate) was used to separate
product 8 (0.127g 20%). 1H NMR (300MHz, CDC13) 6 5.48 (1H, d, J = 5H2), 4.81 (2H,
dd, J = 8H2), 4.41 (1 H,m J = 3H2), 4.13 (3H, m, J=4Hz),2.28 (3H, s), 2.18 (1H, d, J =
3H2), 1.49 (3H, s), 1.46 (3H, s), 1.41 (3H, s), 1.39 (3H, 5); ‘3C NMR (300MHz, CDC13)

56

5 170.2, 165.1, 112.3, 110.0, 73.5, 72.8, 72.4, 69.5. 66.5, 27.0, 25.8, 25, 24.4, 20.5 ppm

3-O-acetyl-4, 6-O-isopropylidene-2-deoxy-D-gluconic-1, 5-lactone 9

The procedure is the same as the preparation of compound 8. Lactone 9 was obtained in
yellow oil (94 mg, 20%). lH NMR (300MHz, CDC13) 5 5.52 (1 H, td, J = 9H2), 4.38 (2H,
m, J: 6H2), 4.10 (1 H, t, J = 6H2), 4.00 (1 H, q, J = 4H2), 2.87 (1 H, q, J = 4H2), 2.58 (1H,
q, J = 2H2), 2.07 (3H, s), 1.37 (3H, s), 1.30 (3H, s); 13C NMR(300MH2, CDC13)
5 173.5, 169.4, 119.4, 82.0, 71.9, 69.3, 67.3, 36.5, 26.8. 25.2, 20.0 ppm

1-amino-1-cyano-1-deoxy-2, 3: 4, 6-di-O-isopropylidene-D-Mannitol 28&29

To a solution of protected mannose 2 (1.0 g, 3.85mmol) in 60ml 1:1 Ethanol and water,
KCN (0.75g 11.5mmol) and NH4CI (1.235g, 23.1mmol) were added. The solution was
stirred at 100°C for 24h. The solvent is removed and the solid is dissolved in 20 ml water.
Ether was used to extract the water solution (20ml *3). All the ether layers were
combined and dried. Column chromatography (1:2 Ethyl acetate to hexanes 1:2 ethyl
acetate to hexanes) was used to separate the starting material and compound 28 and 29
(0.83g, 75% overall) were obtained as a 2:1 mixture. Data for 28: 1H NMR (300MHz,
CDC13) 5 4.56 (1 H, d, J = 7H2), 4.26 (1 H, t, J = 8H2), 4.10 (m, 1H), 3.82-3.91 (3H, m),
360-370 (1 H, m), 1.90-2.20 (2H. br.), 1.52 (3H, s), 1.48 (3H, s), 1.36 (3H, s), 1.38 (3H,
5); '3C NMR(300MH2, CDC13) 5 119.8, 109.7, 99.0, 78.8, 74.6, 72.0, 64.5, 63.0, 44.0,
28.8, 26.7, 25.7, 19.0 ppm; Data for 29: lH NMR (300MHz, CDC13) 5 4.47 (1H, q, J =
6H2, 2H2), 4.19 (1H, t, J = 8H2), 3.95-4.10 (2H, m), 3.80-3.90 (2H, m), 3.60-3.70 (1H,
m), 1.90-2.20 (2H, br.), 1.53 (3H, s), 1.51 (3H, s), 1.48 (3H, s), 1.46 (3H, 5); '3C
NMR(300MH2, CDC13) 5 121.9, 109.8, 98.9, 77.2, 75.0, 71.3, 64.7, 63.6, 44.9, 28.2,
26.8, 25.4, 19.5 ppm

l-cyano-2, 3: 4, 6-di-O-isopropylidene-D-Mannitol 30&31

To a solution of protected mannose 2 (1.0 g 3.85mmol) in 60ml 1:1 Ethanol and water,
KCN (0.75g, 11.5mmol) and NH4C1 (1 .235g, 23.1 mmol) were added. The solution was
stirred in room temperature for 24h. The solvent is removed and the solid is dissolved in
20 ml water. Ether was used to extract the water solution (20ml *3). All the ether layers
were combined and dried. Column chromatography (1:2 Ethyl acetate to hexanes 1:2
ethyl acetate to hexanes) was used to separate the starting material and compound 30 and
31 (0.66g, 60% overall) were obtained as a 1:2 mixture. Data for 30: 1H NMR (300MHz,
CDC13) 5 455-460 (2H, m), 4.24 (1H, t, J = 6H2), 402-408 (1 H, m), 3.83-3.90 (2H, m),
3.64 (1H, t, J = 5H2), 1.99 (1H, s), 1.53 (3H, s), 1.46 (3H, s), 1.39 (3H, s), 1.32 (3H, 5);
'3C NMR(300MH2, CDCI3) 5 118.7, 109.4, 99.8, 76.9, 74.2, 69.8, 64.3, 62.7, 61.8, 28.3,
26.3, 25.2, 19.0 ppm: Data for 31: IH NMR (300MHz, CDC13) 5 4.55-4.60 (2H, m), 4.29
(1H, t, J = 6H2), 4.02-4.08 (1 H, m), 3.83-3.90 (2H, m). 3.64 (1H. t, J = 5H2), 1.99 (1H, s),
1.50 (3H, s), 1.36 (3H, s), 1.34 (3H, s), 1.32 (3H, 5); '3C NMR (300MHz, CDCI3) 5 118.0,
109.8. 99.4, 77.4, 74.0, 71.3, 64.5, 62.8, 61.4, 28.0, 26.2, 25.3, 19.1 ppm

1-cyano-2, 3: 4, 6-di-O-isopropylidene-1, 5-di-O-mesyl-D-Mannitol 32& 33
Cyanohydrin mixture of 30& 31 (100mg, 0.35 mmol) was dissolved in 2m1 anhydrous

57

pyridine, cooled in ice bath while stirring. 0.06m1 (0.77mmol) mesyl chloride was
dropped into the solution in 5 min. The solution was kept stirring while it warmed up to
room temperature in 3 hours. The reaction was quenched by 5ml anhydrous ether and
100 mg sodium bicarbonate. Another 2 portions (10ml) of ether was used to extract the
water solution. All the ether extracts were combined, dried with sodium sulfate. After the
ether was removed, mixture of 32 and 33 as a white solid was obtained (134mg, 90%).
Data for isomer 1: lH NMR (300MHz, CDC13) 5 5.21 (1H, d, 2H2), 4.70 (1H, q, 3H2),
4.42-4.50 (2H, m), 4.0 (2H, m), 3.78 (1H, m), 3.12 (3H, s), 2.96 (3H, s), 1.49 (3H, s),
1.40 (3H, s), 1.31 (3H, s), 1.25 (3H, s); 13C NMR(300MH2, CDC13) 5 114.4, 110.5, 100.1,
75.6, 73.5, 71.3, 67.8, 67.2, 61.9, 39.2, 37.5, 26.6, 25.9, 24.7, 19.8 ppm; Data for isomer
2: 1H NMR (300MHz, CDC13) 5 5.48 (1H, d, J = 7H2), 4.70 (1H, q, 3H2), 4.42-4.50
(2H, m), 4.0 (2H, m), 3.78 (1H. m), 3.05 (3H, s), 2.98 (3H,s), 1.44 (3H, s), 1.39 (3H, s),
1.29 (3H, s), 1.24 (3H, s); 13C NMR (300MHz, CDC13) 5 114.2, 110.5, 99.6, 75.0, 73.1,
70.2, 68.6, 65.6, 61.7. 38.7, 37.6, 27.4, 26.2, 25.0, 18.9 ppm

58

3.6 References

1.

11.

12.

Strecker, A. Ann. 1850. 75, 27. Strecker, A. Ann. 1854, 91, 349

. Kendall, E. C.; McKenzie, B. F. Organic Syntheses, C011. 1941, Vol. I, p.21; 1929,

Vol. 9, p.4

. Clarke, H. T.; Bean. H. J. Organic .Si’ntlze.ses. C011. 1943, Vol. 2, p.29; 1931, Vol. 11,

p.4

Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. Catalytic
Enantioselective Strecker Reaction of Ketoimines J. Am. Chem. Soc. 2003, 125,
5634-5635

Davis, F. A.; Reddy R. E.; Portonovo P. S. Asymmetric Strecker Synthesis Using
Enantiopure Sulfinimines: A Convenient Synthesis of a-Amino Acids Tetrahedron
Lett. 1994, 35, 9351-9354

Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. Catalytic Asymmetric
Strecker Synthesis. Preparation of Enantiomerically Pure oc-Amino Acid Derivatives
from Aldimines and Tributyltin Cyanide or Achiral Aldehydes, Amines, and
Hydrogen Cyanide Using a Chiral Zirconium Catalyst J. Am. Chem. Soc. 2000, 122,
762-766

Huang, 1.; Corey, E. J. A New Chiral Catalyst for the Enantioselective Strecker
Synthesis of Amino Acids Org. Lett. 2004, 6, 5027-5029

Inouye, S.; Tsuruoka, T.; Niida, The Structure of Nojirimycin, A Piperidinose Sugar
Antibiotic T. J. Antibiot. 1966, 19, 288-292

Inouye, S. T. T.; Ito, T.; Niida, T. Structure and Synthesis of Nojirimycin Tetrahedron
1968, 24, 2125

.Ashby, E. C., et al., Concerning the Formation of Hydrogen in Nuclear Waste.

Quantitative Generation of Hydrogen via a Cannizzaro lnterrnediate, Jour. Am. Chem.
Soc. 1993,115, 1171-1173

Roger, A.; Marvel, C. S. Benzoin Organic Syntheses, 1941, 1, 94
Lapworth, A. Reactions Involving the Addition of Hydrogen Cyanide to Carbon

Compounds. Part 11. Cyanohydrins Regarded as Complex Acids Jour. Chem. Soc,
Transactions, 1904, 85, 1206-1214

. Niemeier, 0.; Balensiefer, T. Asymmetric Intramolecular Crossed-Benzoin Reactions

59

18.

19.

20.

21.

22.

23.

24.

25.

by N-Heterocyclic Carbene Catalysis DieterEnders Angew. Chem. Int. Eng]. 2006,
45,1463-1467

.Takikawa, H.’ Hachisu, H.’ Bode. J. W.; Suzuki, K.Cata1ytic Enantioselective

Crossed Aldehyde-Ketone Benzoin Cyclization Angew. Chem. Int. Eng]. 2006,45,
3492-3494

. Bergs, H. Ger. Pat. 566, 094, 1929
. Bucherer, H. T.; Fischbeck, H. T. J.Prakt. Chem. 1934, 140, 69

. Bucherer, H. T.; Steiner, W. Syntheses of hydantoins. 1. Reactions of a-hydroxy and

oc-amino NitrilesJ. Prakt. Chem. 1934, 140, 291
Ware E. The Chemistry of the Hydantoins Chem. Rev. 1950, 46, 403

Chubb, F. L.; Edward, J. T.; Wong, S. C. Simplex Optimization of Yields in the
Bucherer-Bergs ReactionJ. Org. Chem. 1980, 45, 2315

Rousset, A.; Lasperas, M.; llades, J. Commeyras, A. Systemes de Strecker et
Apparentes—XI : Formation et Stabilité de l'a-Carboxyaminonitrile.lnterme'diaire
Essentiel dans la Synthése des Hydantoi’nes Selon Bucherer-Bergs Tetrahedron 1980,
36, 2649

Bowness, W. (1; Howe, R. Rao, B. S. Application of the Bucherer Hydantoin
Synthesis to Diacetyl Mono-oxime. The Mechanism of the Bucherer Reaction, and
the Constitution of the Hypothetical 'Dimethylbishydantoin’of Bucherer and Lieb J.
Chem. Soc. Perkin Trans. I 1983, 2649

Taillades, J. Rousset, A.; Lasperas, M.; Commeyras, A. Bull. Soc. Chim. Fr. 1986,
650

Herdeis, C.; Gebhard, R. Synthesis of (5-hydroxy-2-pyridyl)glycine. Oxazole
formation in the Bucherer-Bergs reaction. Studies on amino acids. VI Heterocycles
1986, 24. 1019

Haroutounian, S. A.; Georgiadis, M. P.: Polissiou, M. G J. Heterocvcl. Chem. 1989,
26, 1283

Tanaka, K.—i.; lwabuchi, H.; Sawanishi, H. Synthesis of Homochiral
4-amino-4-carboxy-2-phosphonomethylpyrrolidines via a Diastereoselective
Bucherer-Bergs Reaction of 4-oxopyrrolidine Derivative: Novel Conformationally
Restricted AP 5 Analogues Tetrahedron: Asymmetry 1995, 6, 2271-2279

60

 

26.Micova, J.; Steiner, B.; Koos, M.; Langer, V.; Gyepesova, D. Synthesis of
4-Carbamoyl-2-oxazolidinones C-4-Linked with a Saccharide Moiety via
Bucherer-Bergs Reaction of Hexofuranos-S-uloses Synlett 2002, 1715-1718

61

Chapter 4 Design and Synthesis of C-2 Symmetric Ligands for

Asymmetric Ketone Reduction Reactions

4.1 Introduction to C-2 Symmetric Ligands

More than ever, synthetic chemists are faced with the requirement of preparing materials

in enantioselective fashion. While there are several options for entering this optically

active world, the one with the greatest benefit is the use of asymmetric catalysts. The key
feature responsible for the success of these catalysts is the chiral ligands that surround the

catalytic core. They create a chiral environment in which the reaction proceeds. The
enantioselectivity of these catalysts ultimately can be traced back to the ligands,
especially C-2 symmetric ligands.

C-2 symmetric ligands are chiral and exhibit an axis of symmetry which make them

bidentate ligands in many the cases. Some of the most common C-2 symmetric ligands
are shown below (Figure 4.1).

    

R' R'
P o
R l
/ X N N .
P
R R
R““\N-
BlNOL (x = OH)
BINAP (x = Pth) ”up” BOX
1 2 3
R R
><° °” >6pr”
PPh
0 R7<OH 0 "’In/ 2
R
TADDOL (S, S) - DIOP
4 5
Figure 4.1 Most common C-2 symmetrical ligands

63

Because C-2 symmetric ligands allow high levels of enantiocontrol in many different
metal-catalyzed reactions, they stand out from thousands of chiral ligands prepared so far

and were called “privileged ligands".

4.2 Typical C-2 Symmetrical Ligands and Their Developments

4.2.1 (4R, 5R)-trans-4, 5-bis [(diphenylphosphino) methyll-Z, 2-dimethyl—1,
3-dioxolane (DIOP) Family

The C-2 symmetric ligand DlOP was first introduced by Dang and Kagan in 1971. They
found its good catalytic activity in the asymmetric hydrogenation in the synthesis of

hydratropic acid and amino-acids (Figure 4.2)." 2

 

c6115 >——<NHCOCH3 Camlyst 0,115 He,’ fNI-icocm

H COOH H COOH
5 7
N- Acetyl- (R)-
phenylalanine
Catalyst : RhC'lH - DloplicsHslz 95% Yield 72% ee
8

Figure 4.2 The asymmetric reduction of amino acid by Rhodium catalyst with G2
symmetric DIOP as ligand

The reason for choosing a C-2 symmetric ligand with two equivalent phosphine atoms
was to reduce the number of possible isomeric metal complexes. as well as the number of
different substrate-catalyst arrangements and reaction pathways, when compared with a
nonsymmetrical ligand. This consequence of C-2 symmetry can have a beneficial effect

on enantioselectivity because the competing less-selective pathways are possibly

64

eliminated. Because fewer reaction intermediates to take into account, C-2 symmetry is
of particular advantage in mechanistic studies because it facilitates analysis of the

ligand-substrate interactions that may be responsible for enantioselection.

Based on Kagan’s work, scientists tried to make modifications on DIOP to discover more
efficient C-2 symmetric ligands. Zhang3 and Rajanbabu"‘5 have independently reported
that the (S. R. R, S)-DIOP which has two alkyl substituents at or positions of the
diphenylphosphine groups on the DIOP, provides excellent enantioselectivity in

Rh-catalyzed hydrogenation for arylenamides (Figure 4.3).

 

Rh (2 mol%) + L (2.2 mol%)_ NHAc
2 6113011, rt, 6011

13
ea: 91 11.44%
Pth

(S,R,R,S)- DIOP
PPM

14

 

Figure 4.3 (S. R, R. S)-DIOP coordinated Rhodium catalyzed asymmetric hydrogenation
of alkene

The capability of enantiocontrol offered by (S. R. R. S)-DIOP is much better than the (S,
S)-DIOP prepared by Kagan. It is believed that the two methyl groups of (S. R, R,
S)-DIOP are oriented at pseudoequatorial postions in the "effective” conformer of the
DIOP metal complex, therefore stabilizing the “effective” conformer to promote high

enantioselectivity.

65

 

Apart from those two DIOP derivatives. other DIOP analog have been developed. They
showed satisfactory catalytic activities. For example, (2R,
2’R)-bis(diphenylphosphino)-(1R, 1’R)-dicyclopentane (BICP) has been found efficient
for hydrogenation of a-dehydroamino acids, B-dehydroamino acids, arylenamides, and
MOM-protected B-hydroxy enamidesf"9 Also, Lee’s 1. 4 diphosphane ligands (4S,
SS)-4,5-bis(dipenylphosphinomethyl)imidazolidin-2-one (BDPMI) which has a
imidazolidin-Z-one backbone have been successfully applied in Rh-catalyzed

hydrogenation of arylenamides with up to 99% ee’s .10-]:

4.2.2 2, 2’-bis (diphenylphosphino)-1, 1’-binaphthyl (BINAP) Family

Another important family of C-2 symmetrical ligands is the BINAP family. BINAP was
first synthesized by Noyori in 5 steps from BINOL. Noyori brought BINAP into the
spotlight by applying it to his asymmetric ketone reduction. BINAP become one of the
most popular ligands for transition metals including Ru ([1), Rh (1), Pd and Ir. Many of
these species have been found to promote asymmetric transformations including
hydrogenation. isomerisation, hydrosilylation, hydroboration, allylic alkylation and the
Heck reaction (Figure 4.4).'3 Now, BINAP is being assessed for several industrial and

pharmaceutical applications.

66

 

+ i \E [Pd(OAc)2-2(R)-BINAP; \
ArOTf Base, Benzene ""01,“

O
15 16

Ar = Ph (>96% ee) p- AcCsH4 (>96% ee)
p- CIC5H4 (>96°/o ee) 2- Naphthyl (>96°/o ee)
m- 01051-14 (>96% ee)

Figure 4.4 BINAP-Pd complex catalyzed Heck reaction

After screening lots of different ligands, Tanaka and Takeaki reported in 2005 that
BINAP is the only ligand to enable Rh to efficiently catalyze the following propargylic

alcohols to or, B-enal transformation (Figure 4.5).14

 

OH H O
5% [Rh(R)-BINAP)]BF4 \
Et é
% CHzclzt rt, 4011 P“ '5‘
Ph H
17 18
Conversion 100%

trans:cis=100:0

Figure 4.5 BlNA P-Rhodium complex catalyzed propargylic alcohol reaction

1, l’-bi-2-naphthol (BINOL), another C-2 symmetric ligand in BINAP family, also

showed very promising catalytic activities. It has been used for asymmetric

17,18

expoxidation,15 asymmetric Diel-Alder reaction, '6 asymmetric Michael addition, and

l. 3-dipolar cycloaddition reactions“): 30

4.3 Summary of C-2 symmetric Ligands
In summary, C-2 symmetric ligands have been widely used in transition metal catalyzed

asymmetric reactions. Their highly ordered structures create steric hindrance so that the

67

substrate can only approach the core metal from a specific direction with a specific
conformation. We believe that as more C-2 symmetric ligands are developed, people will

have more power to control the chirality in a compound.

4.4 Asymmetric Ketone Reduction Reaction
4.4.1 Introduction
The reduction of ketones to enantiomerically enriched alcohols is a pivotal

21-23

transformation in synthetic organic chemistry. In recent years, the demand for
optically active secondary alcohols in the area of pharmaceuticals and advanced
materials increased dramatically.24 In response to that, a series of asymmetric reductions
of prochiral ketones has been developed.25 Two major methodologies have been
developed so far. One is introduced by E. J. Corey; he used asymmetric boranes to do the

reduction; another is transition metal catalyzed reduction which has also been studied by

Noyori intensively after 1995.

4.4.2 Asymmetric Ketones Reduction by Boranes

The introduction of aluminum and boron hydrides for the reduction of carbonyl groups
half a century ago had an enormous impact on the field of synthetic chemistry, and
helped to usher in a golden age for the rationally planned multistep construction of
complex organic molecules.”28 In 1981 . ltsuno and his collaborators achieved promising
result with mixtures of chiral l, 2-amino alcohols and borane. ltsuno reported that by

mixing (S)-valinol and BH3 - THF in a ratio of 1:2 in THF at 20°C, the enantioselective

68

reduction of a number of achiral ketones to chiral secondary alcohols could achieve
nearly 100% yield with enantiomeric excesses in the range of 10-73% ee (Figure 4.6).
This discovery led to the world of borane-mediated enantioselective reduction of a wide
variety of prochiral ketones (CBS reduction).29'32 On screening numerous amino alcohols,
it was discovered that the tertiary amino alcohol 21 derived from (S)-Va1ine, in most of

the cases was the best ligand for BH3 ° THF at-78 0C to 0 0C.

 

 

0
CH3 8H3 THF (2.5 equiv.)_
Ligand (1.25 equiv.)
19 20 100%. 94% ee
Ligand =
H2” OH
21

Figure 4.6 Itsono’s approach of asymmetric reduction of ketones

Based on ltsuno’s work, E. J. Corey33'36 and his collaboraters did a more detailed study
on this asymmetric reduction reaction. In 1986-1987, Bakshi and Shibata from Corey’s
group discovered that the effective reagent for this reaction was the oxazoborolidine
which is created when amino alcohol meets two equivalents of BH3 in THF. This was

confirmed by further IR and NMR studies (Figure 4.7).

69

8H3 -THF(3 equiv.)
THF,A,1.7 barfi

 

   

CH3

8H3 .11.": B- “-4 (0.1 ”1%)
(1 equiv.) THF, 23°C

 

100%, 97% 99

Figure 4.7 C orey-Bakshi-Shibata reduction (CBS reduction)

Though Corey-Bakshi-Shibata reduction (CBS reduction) achieved some success on
specific types of asymmetric ketone reduction. this methodology has some drawbacks
that prevent it from being used in industrial production. Most of the CBS reduction
reagents are difficult to handle and require a tedious workup, involving hydrolysis and
separations, plus the disposal of the large amounts of inorganic hydroxides produced.
Now, this methodology is losing popularity to transition metal catalyzed asymmetric

ketone reductions.

4.4.3 Transition Metal Catalyzed Asymmetric Ketone Reduction Reactions

The transition metal catalyzed asymmetric reactions have been used in organic synthesis
for a long time. Chemists also tried to explore the possibility of reducing prochiral
ketones to secondary alcohol by applying transition metal catalysts. Different metal
complexes have been used, such as Pd, Ru, and some other Lanthanide metals. Among

them, Ru has the best catalytic activi 9740 Based on the mechanisms, this kind of

70

reduction can be divided into two categories: 1. transfer hydrogenation reduction; 2.

catalytic hydrogenation.

4.4.3.1 Transition Metal Catalyzed Transfer Hydrogenation Reduction
In the 19905, two new Ruthenium systems based on transfer hydrogenation for
asymmetric reduction of prochiral ketones were developed by professors Noyori and

lkariya. 41‘ 42

The ketone was reduced to alcohol while the isopropanol, working as
solvent, was oxidized to actone. These systems enable catalytic asymmetric reduction to
provide a route for the generation of enantiomerically pure secondary alcohols in a

highly efficient, simple and economic way.43 However, Noyori found that the direct

hydrogenation reduction would be much more efficient and faster.

4.4.3.2 Ruthenium Catalyzed Asymmetric Ketone Hydrogenation

In 1995, Noyori and his co-workers44 expanded the scope of Phosphine-Ru(ll) catalyst.
They found that by adding 1 equivalent of ethylenediamine and a >2.8M solution of
KOH in isopropanol to the already known Rqu [P (C6H5)3]3 system, the turnover
frequency (TOF. defined as moles of the product per mole of the catalyst per hour) of the
reduction was increased to 6700 from less than 5. Noyori examined the catalytic
activities of different phosphine ligands and found BINAP 26 and diamine 27 to be good
catalytic couples (Figure 4.8). This methodology has a great industrial potential because
it does not involve a great deal of workup. In addition, excess H3 can be used in the

reaction. At the end. both H3 and the catalyst are recycled. It is much superior to CBS

71

reduction because of total atom economy, low cost, and effortless separation on
degassing. Also, it beats transfer hydrogenation by its fast reaction rate and high yield.

Noyori was awarded the Nobel Prize in 2001 due to this work.

A variety of aromatic ketones can be hydrogenated enantioselectively by the BINAP-Ru
(lI)-diamine-inorganic base catalyst system, where the C-2 symmetric BINAP and C-2 or
pseudo C-2 symmetric diamine 28-30 act as the most effective chiral controllers (Table

4.1).

OH

O
Ru,li ands,H
R I I 9 2: \ R
Propanol ‘
/

 

   

(S) - 26: Ar = can, (8. S)- 28 (S) - 29: R= CH3
(BINAP) (S) - 30: chnaizcncnz
(S) . 27: Ar = p-CH3C3H4
(TolBINAP)
o o
O . 6*
RT
/
31a: R: CH3 328: R = CH3
3"” R" “'C4H9 32b: R =(CH3)3C
316: R: (CH3)2CH 326: R = CH3O

Figure 4.8 Noyori‘s asymmetric ketone reduction and his screening of ligands for
Ruthenium catalysts

72

 

Catalyst combination Conditions Alcohol product

 

 

 

Ketones H3, Time, Yield
Phosphine Diamine ee % Config
atm h %
31a (S)-26 (S)-30 4 3 >99 87 R
31b (S)-26 (S)-29 4 3 >99 90 R
0-32a (S)-27 (S,S)-28 4 5 >99 94 R
p-32b (S)-27 (S,S)-28 4 1 .5 >99 96 R

 

Table 4.1 Experimental result of Noyori’s screening of ligands

We can see from the result (Table 4.1) that the combination of 27 and 28, both of them
are C-2 symmetric ligands, showed the best catalytic activity. It opens a door to the
research on the development of new, more C-2 symmetric ligands for the Ru catalyzed

ketone reduction reaction.

4.5 Why Do We Need to Develop More 02 Symmetric Ligands?

Though C-2 symmetric ligands have been widely applied to organic synthesis, they still

suffer from the following drawbacks:

1. C-2 symmetric ligands are quite expensive. Asymmetric synthesis depends on high
purity ligands. However, the synthesis of C -2 symmetric ligands itself is
asymmetric synthesis involving lengthy and costly chirality control, separation and
purification steps. The high price is a big barrier for its industrial application.

2. No general synthetic strategies for C-2 symmetric ligands are available. In most of
the cases, each synthetic route is applicable to only one type of ligands.

3. C-2 symmetric ligands are still limited. There are thousands of possible C-2

73

symmetric structures in nature of which only a small number have been synthesized
and tested. By exploring more compounds, it’s very likely to find more efficient
ligands for asymmetric catalysis.

4. Most of the C-2 symmetric ligands are bidentate. In fact, by introducing another
binding atom, we can create a tridentate C-2 symmetric ligand. It is believed that
tridentate ligands have tighter interactions with the boundmetal, thus be able to

exert stronger enantiocontrol during reactions.

4.6 Design and Synthesis of C-2 Symmetric Ligand
4.6.1 Design of C-2 Symmetric Ligand
To solve the problems above, we designed a 02 symmetric furan ligand scaffold which

is very easy to synthesize and modify.

/ C-2 axis
R. g \R'
R = alkyl phophine R' = alkyl phosphlno
_ : alkyl amine aryl hydrxyl
\\\\\“‘ 1 alkyl alcohol amino alkyl amino
| f? etc. alkoxy etc.
R R

Figure 4.9 Furan based C-2 symmetric ligand scaffold

The advantages of this scaffold are:

1 . It’s a perfect C-2 symmetric system with a furan ring: the oxygen on the furan may
provide another coordination center.

74

2. There are two possible sets of coordination sites---l , 6 or 3, 4 positions. We can
develop at least two types of ligands based on that.

3. The flexibility of the furan ring is adjustable. When R’s on C3 and C4 positions
are big, the bulky repulsion between them will twist the furan more and lock the
C-2 symmetry. On the other hand, if they are smaller, the furan ring would gain
more flexibility

4. By using different substituents on the furan, we can vary the polarity of the
ligands. For example, when Rs are alkyl groups, the ligand tends to be
hydrophobic; if R’s are carboxylic acids. the ligand may be soluble in aqueous
solution. By adding hydroxyl groups on the side chain, we can manipulate the
solubility of the ligand elaborately and even obtain phase transfer characteristics
of the ligands.

5. As shown later, we use the ubiquitous cheap carbohydrate as starting material to
synthesize this molecule. The synthetic route is less than 6 steps and does not
involve extreme high temp, low temp, high pressure, toxic or environment-hostile
reagents. All those offer this kind of ligands big advantages on their industrial

scale application.

4.6.2 Synthesis of C-2 Symmetric Ligands

Carbohydrate is cheap and pure natural product that offers multiple chiralities. We

decided to take advantage of it (Figure 4.10).

75

 

37a: R=Me
38b: R=Et 37b: R-Et

 

th

39a: R=Me
39b: R=Et

Figure 4.10 The synthetic route towards our C-2 symmetric ligands a) i. Acetic acid, Na
N02; ii. NaBH4; b) TrCl, pyridine, room temperature; c) NaH, RI, THF; d) Pd/C, H2,
CHgClg; e) CBr4, Ph3P, pyridine; f) PthK, THF

We started from 2-glucosamine hydrochloric acid 33, transform it to C-2 symmetric
tetraol 34 within one step. The detailed mechanism is shown below (Figure 4.11). The
nitrous acid oxidizes the C2 amino group to form N3, leaving C2 an electrophilic site.
The 05 then attacks C2 to close the furan ring and form an intermediate aldehyde 40.

Sodium borohydride reduces the carbonyl group to afford 34.

76

NaeH4
-—-———>

   

33

Figure 4.11 Mechanism of the one step reaction from 2-glucosamine salt to tetraol

Next, we modified the substituents on the hydroxyl groups. The bulky triphenyl methyl
protecting group was used to selectively protect two primary alcohols. Two secondary
hydroxyls of C3 and C4 were alkylated by methyl or ethyl groups. The trityl groups were
removed by hydrogen gas/Pd. Then, dibromide is prepared through a classic Mitsunobu
reaction. The last step is the replacement of bromides with diphenyl phosphine to afford

the diphosphine ligand 39a or 39b.

4.6.3 Result and Discussion
The whole synthesis route has six steps. It turned out that the third step, which is
protection of C3 and C4 hydroxyl groups with alkyls is the yield limiting step (Figure

4.12).

RI, NaH

1 I, ’///

   

OTr OTr OTr OTr
35 3682 R = Me
361): R = Et

Figure 4.12 C3, C4 hydroxyl group protection of compound 35

77

 

 

 

 

 

Reagents Conditions Yields of 36
Mel NaH (4 equiv.), room temp., 24h, DMF 87%
EtI NaH (4 equiv.), 50°C., 24h, DMF 45%
n-Bul NaH (4 equiv.), 75 °C, 24h, DMSO Trace amount
n-Hexl NaH (4 equiv.), 85 °C, 48h, DM SO No reaction

 

 

 

 

 

Table 4.2 Reaction conditions and yields of the alkylation of C3, C4 postions of our
furan scaffold

When R is methyl group, the yield was pretty good (85%). However, if the size of the
alkyl groups goes bigger. the yields drop dramatically. We got no hexyl substituted
product even when the reaction temperature was increased to above 85°C and the
reaction time was extended to 2 days. We think the reason is the bulkiness of the trityl
groups on C1 and C6. They stretch into the space and prevent oxygen anion from
attacking the alkyl iodides. It‘s a dilemma situation because if we used smaller protecting
group than trityl to protect the CI and C6 hydroxyl groups, the selectivity for primary

hydroxyl groups would decrease.

Another handicap is the deprotection of trityl groups. After we got fully protected tetraol
36a/ 36b (Figure 4.12), the two most common ways to deprotect the trityl groups were
tried: 1. Acidic deprotection. Compound 36a was thrown into a 1:1 ether and formic acid
mixture and stirred in room temperature for 10 minutes. We found that the acid not only
removes the trityl group. but opens the furan ring as well. The yield of the desired
product 37a remained below 30% even after we shortened the reaction time. So, we
switched to solution 2: Catalytic Hydrogenation. We used 5% Pd/ C and 2 atm of H3 gas,

stirred in room temperature. The catalyst lost its activity after 3 hour. To get 1 gram of

78

36a converted, a huge amount of catalyst (0.3 g) was consumed. After further trials, we

found that a couple of drops of acetic acid would keep the catalyst active. After mixing 2

drops of acetic acid in 20ml solution, we obtained 93% yield on the conversion from 36a

to 373. Also, the reaction time was significantly decreased from 2 days to 8 hours.

4.6.4 Why Our Strategy is Superior to Others’

Compared to other synthetic approaches towards C-2 symmetric ligands, our approach

shows obvious advantages on cost and potential for industrial production:

1.

Our approach is short. In 6 steps, we converted a carbohydrate to a C2 symmetric
diphosphine ligand.

Cost advantage. None of the reagents used in our synthesis are very expensive.
Especially, the starting material D-glucosamine hydrochloride is very cheap.

Ease of operation. In the 6 step synthesis. column chromatography is not required
until the fifth step. Furthermore, in some steps, even quantitative control of
reagents is not indispensable. In step from 34 to 35 and from 35a/35b to 36/36b,
excessive amount of triphenyl methyl chloride and methyl iodide/ ethyl iodide were
used respectively. The unreacted trityl chloride was recovered by recrystallation
and the unreacted methyl iodide/ ethyl iodide was removed by rotavapor. All those
operations can be done in large scale.

General applicability. As we have already discussed, apart from the I, 6 position,
we can also develop 3, 4 position to be the coordination sites. In addition, by

varying substitution groups. we can synthesize a library of ligands of different

79

polarities.

4.7 Future Directions

1. Find out the solution for the low yield in the protection step of O4 and OS in
compound 34. To solve this problem, we should avoid bulky protecting groups on
01 and O6 when we alkylate O3 and O4 (Figure 4.13). Two primary hydroxyl
groups in 34 may be converted to bromide first to form 41. Alkylation of 41 could
produce intramolecular substitution side product 43 and intermolecular substitution
product 42. Due to the high strach of the four-membered ring and the reaction rate
superiority of alkyl iodides over bromides, we believe that these two side products
will be minor. By applying this approach. we are even able to make our synthetic

pathway one step shorter.

Hg, OH

   
  

   

Mistunobu
Reaction
/

   

Pth Pen,

39'

R = Me, 8n, Et. t-Bu,
Bu, Acyl, Oct etc.

Figure 4.13 Alternative synthetic route to avoid O3. O4 alkylation obstacle in compound
34

80

2. By using different nucleophiles at the last step of the synthetic pathway, we can
obtain not only diphosphine ligands. but also diamine ligands like scaffold 44
(Figure 4.14). Carbon nucleophiles may extend the “arm” of the ligand to make the
ligand looser and more flexible. For example, we can treat the dibromide 38 with
nitromethane and sodium methoxide to extend one carbon on C1, C6 positions.

After a reduction reaction, a diamine ligand 47 could be obtained (Figure 4.15).

Roe 0R

    
  
 

 
  

"II/I/ WWI

 

1’th PPh2 NR'z NR'Z (CHzln ((3112)::

39 44 NR';/ PR', 45 NR3! PR';
R = R' = H, Aryl, Alkyl, Acyl etc.

Figure 4.14 Synthetic proposal for different kinds of ligands based on intermediate 38

CH3N02,
CH3ONa, CH30H

II I [III

H2, Pd/C

 

 

   

Bf OZN N02 HZN "Hz

38 46 47

Figure 4.15 Proposed synthesis of diamine ligand 47

3. A ligand is made to catalyze. So, we want to apply the ligand to reactions and

examine the catalytic activity (Figure 4.16):

81

0

/H\ [RhClz(COD)2], BINAP, ?
R1 R2 Ligand, H2, i-PrOH, i-PrOK '
Figure 4.16 The reaction system to test the activities of our ligands

 

The catalyst can be prepared by simply mixing 0.5mol% Ru (II) complex, 1.5 mol% of
BINAP and 3 mol% of the ligands we prepared in isopropanol. A little bit of base (5 mol
%) and dihydrogen are also needed.45 This system is suitable for testing our ligands’s

activity in asymmetric ketone reductions.

The application of our C-2 symmetric ligand library is not limited to ketone reduction
reaction. We can try our ligands on other transition metal catalyzed asymmetric reactions,

such as asymmetric Michael addition reaction, Asymmetric Heck reaction etc.

4.8 Experimental Section

2, 5-anhydro-D-mannitol 34

A solution of D-glucosamine hydrochloride (10g, 46.4 mmol) in 150ml water was cooled
to 0°C in ice bath. After 30 minutes, sodium nitrate (13.6g, 197.1 mmol) was added to
the solution and 8.3 ml acetic acid was slowly added dropwise within 3 hours. The
mixture was warmed up to room temperature while stirring, and then air was bubbled
into the solution to get rid of the yellow color. Cationic Resin DOW-50 was used to
remove the inorganic salt. The solution was concentrated to 30ml, cooled in ice bath
again; sodium borohydride (3g, 81mmol) was added slowly. After 4 hours, 2N
hydrochloric acid was used to remove the unreacted sodium borohydride. The salt was
removed by the DOW-50 again. A yellowish sticky liquid (6.13g, 82%) was obtained
after the solvent was rotavapored. [0L]D= +50 (c=l .0); H20); 1H NMR (D20) 5 3.70 (2H,
dd, Jib‘g = 15, 6b: 5.6 HZ, H-Ib and H-6b), 3.79 (2H, dd, 113,2 = J51”: 3.] HZ, 113,11) =Jm 6b
= 12.4 Hz, H-la and H-6a), 3.90 (m, 2H, H-2 and H-5), 4.07 (2H, m, J23 = 7.3 Hz, H-3
and 11-4). 13(2 NMR (D30) 5 61.5 (2C, C-1 and C-6), 76.6 (2c, C-3 and 04), 82.6 (2c,
C-2 and C-5); MS (IS, MeOH +5-10% H30) m/z =165 [M+H] 1, 187.0 [M+ Na] +; calcd.
187.0582; found 187.0576 (HR-ESl-TOF-MS)

82

2, 5-anhydro- 1 , 6-di-O-trityl-D-mannitol 35

To a solution of 2, 5-anhydro-D-mannitol 34 (0.207g, 1.26mmol) in 2ml anhydrous
pyridine, triphenyl methyl chloride (0.773g, 2.77mmol) was added. The mixture was
stirred in room temperature for overnight. Another portion of trityl chloride was added
(0.387g, 1.38mmol). After 5 hours, pyridine solvent was removed and excessive trityl
chloride was recrystallized from the solution (solvent: Ethyl acetate and Hexanes). A
white solid of 35 (0.69g, 85%) was obtained after the solvent is removed. mp= 92-93 °C;
[61250 875" (CHC13, c 0.93); ‘H NMR(CDC13 300MHz) 5 3.23 (s, 2H), 3.40 (2H, dd, J
= 3.8, 9.8Hz), 3.48 (2H, dd, J = 5.4, 9.8Hz), 4.25 (2H, d, J = 2.8Hz), 4.41 (2H, m), 7.0
(30H, m); 13C NMR (CDCI3) 5 62.8, 78.6, 78.8, 87.2, 127.0-143.2 ppm; Anal. Calcd for
C44H4005: C, 81.46; H, 6.21. Found: C, 81.19, H, 6.19.

2, 5-anhydro-3, 4-di-0-methyl-l , 6-di-O-trityl-D-mannitol 36a

To a solution of 2, 5-anhydro-l, 6-di-O-trityl-D-mannitol 35 (0.3g, 0.46mmol) in 5m1
anhydrous THF, sodium hydride (0.028g, 1.16mmol) was added under 0°C. The solution
was stirred in ice bath with drying tube contain calcium chloride on the flask. Then,
methyl iodide was dropped into the mixture (0.210g, 1.38mmol). After 3 hours, all the
solvent was removed. 10 ml water was used to dissolve the remaining sodium hydride.
The water layer was extracted by ether (3* 20ml). The product was got as a reddish solid
(0.264g, 87%) after all the ether is evaporated. mp 163-164 °C, [01b +4.3° (c 1.2,
CHC13); lH NMR (CDC13 300MHz) 5 3.15-3.40 (10H, m, 2* OMe, H-1 1, 1’, 6, 6’), 3.80
(2H, m, H-3 and H-4), 4.13 (2H, m, H-2 and H-S), 7.15-7.60 (30H, m, Ar); l3C NMR
(CDCI3) 5 143.9, 128.6, 127.3, 126.8, 86.9, 81.4, 64.0, 57.3 ppm; m/z 676 (0.5, M+), 599
(3, M-Ph), 433 (5, M-Tr), 403 (l 1, M-CH20TI'), 243 (100, Tr"), 165 (38, thCi); Anal.
Calc. for C46H4405: C, 81.60; H, 6.51; Found C, 81.60; H, 6.49

2, 5-anhydro-3, 4-di-0-ethyl-1, 6-di-O-trity1-D-mannitol 36b

To a solution of 2, 5-anhydro-1, 6—di-O-trityl-D-mannitol 35 (0.3g, 0.46mmol) in 5m1
anhydrous THF, sodium hydride (0.028g, 1.16mmol) was added under 0°C. The solution
was stirred in ice bath with drying tube contain calcium chloride on the flask. Then, ethyl
iodide was dropped into the mixture (0.229g, 1.38mmol). After 3 hours, all the solvent
was removed. 10 ml water was used to dissolve the remaining sodium hydride. The water
layer was extracted by ether (3* 20ml). The product was got as a reddish solid (0.051 g,
45%) after all the ether is evaporated. 1H NMR (CDCI3 300MHz) 5 7.3-7.7 (30H, m, Ar),
4.32 (2H, d, J = 4H2), 4.08 (2H,d, J = 3H2), 3.60 (4H, m), 3.44 (4H, d, J = 7H2), 1.22
(6H, t, 5H2); l3C NMR (CDCI3) 5 143.9, 128.6, 127.5, 126.7, 86.5, 85.4, 81.9, 65.0, 64.1,
29.7 ppm

2, 5-anhydro-3, 4-di-0-methyl-D-mannitol 37a

2, 5-anhydro—3, 4-di-O-methyl-l, 6-di-0-trityl-D-mannitol 36a (lg, 1.55mmol) was
dissolved in 5 ml dichloromethane. 5% Pd/ C catalyst (0.05g 5%) and 3 drops of acetic
acid were added. Hydrogen gas was applied while stirring in room temperature overnight.
The Pd /C catalyst was filtered out. The filtrate was rotavapored and the solid left was

83

run through a flash column (Eluent 5:1 hexanes: ethyl acetate). The product is a white
solid (0.277g, 93%). lH NMR (CDC13 300MHz) 5 4.15-4.01 (2H, m), 3.80-3.63 (6H, m),
3.40 (6H,-OCH3, s), 2.95-2.73 (2H, br, s,-OH); 13C NMR (CDC13) 5 85.80 (CH),
83.21(CH), 62.70 (-CH20H), 57.59 (-OCH3) PPm

2, 5-anhydro-3, 4-di-0-ethyl-D-mannitol 37b

2, 5-anhydro-3, 4-di-O-ethyl-l, 6-di-O-trityI-D-mannitol 36b (1 g, 1.42mmol) was
dissolved in 5 ml dichloromethane. 5% Pd/ C catalyst (0.05g, 5%) and 3 drops of acetic
acid were added. Hydrogen gas was applied while stirring in room temperature overnight.
The Pd /C catalyst was filtered out. The filtrate was rotavapored and the solid left was
run through a flash column (Eluent 5:1 hexanes: ethyl acetate). The product is a white
solid (0.280g, 90%). IH NMR (CDC13 300MHz) 4.30 (2H, d, J = 4H2), 4.08 (2H, d, J =
3H2), 3.60-3.62 (4H, m), 3.41 (4H, d, J = 7H2), 1.22 (6H, t, 5H2); 13C NMR (CDCI3) 5

85.5, 82.9, 64.2, 60.8, 29.6 ppm

2, 5-anhydro-l, 6-dibromo-l, 6-dideoxy-3, 4-di-0-methyl-D-mannitol 38a

The solution of 2, 5-anhydro-3, 4-di-O-methyl-D-mannitol 37a (600mg, 3.13mmol) in
10ml anhydrous pyridine was cooled to 0°C in ice bath. Triphenyl phosphine (2.46g,
9.38 mmol) and carbon tetrabromide (1.55g, 4.70mmol) was put into the solution. After
kept in ice bath for 30 min, the reaction flask was warmed up to 75 °C and stired for
another 2 hours. The reaction was cooled down and column chromatography (Eluent 4:1
hexanes: ethyl acetate) was applied to separate the product out (0.90g, 90%). lH NMR
(CDC13 300MHz) 5 4.24 (2H, t, J = 4H2), 3.82 (2H, d, 2H2), 3.37-3.39 (2H, m), 3.36 (6H,
s); ”C NMR (cock) 5 87.5, 83.0, 57.3, 32.2 ppm

2, 5-anhydro-l, 6-dibromo-l , 6-dideoxy-3, 4-di-O-ethyl-D-mannitol 38b

The solution of 2, 5-anhydro-3, 4-di-0-ethyl-D-mannitol 37a (689mg, 3.13mmol) in
10ml anhydrous pyridine was cooled to 0°C in ice bath. Triphenyl phosphine (2.46g,
9.38 mmol) and carbon tetrabromide (1.55g. 4.70mmol) was put into the solution. After
kept in ice bath for 30 min, the reaction flask was warmed up to 75 °C and stired for
another 2 hours. The reaction was cooled down and column chromatography (Eluent 4:1
hexanes: ethyl acetate) was applied to separate the product out (0.98g, 90%). 1H NMR
(CDCI3 300MHz) 5 4.31 (2H, t, J = 4H2), 4.0 (2H, s), 3.42-3.66 (8H, m), 1.24 (6H, J =
10 Hz); 13C NMR (CDCI3) 5 84.5, 83.8, 65.0, 22.1, 15.4 ppm

2, 5-anhydro-l, 6-di (diphenyl phosphenyl)-l, 6-dideoxy-3, 4-di-0-methyl-D-mannitol
39a

Dibromide 38a (410mg, 1.29mmol) was put into 3ml 0.5 M diphenyl phosphomium
patasium THF solution. The mixture was stirred in room temperature overnight. The
solvent is removed and the product (0.50g, 73%) was separated out by column
chromatography (Eluent 10:1 hexanes: ethyl acetate). 1H NMR (CDCI3 300MHz)
5 7.3-7.5 (20H, m, Ar), 4.34 (2H, q, J = 4H2), 3.7l(2H, d, J = 2H2), 3.28 (6H, s),
2.35-2.55 (4H, m); l3C NMR (CDCI3) 5 138.2 (q), 132.8 ((1). 128.6, 128.4 (d), 89.6 (d),
80.5 (d), 57.2. 33.8(d) ppm

84

 

2, 5-anhydro-l, 6-di (diphenyl phosphenyl)-l, 6-dideoxy-3, 4-di-O-ethyl-D-mannitol 39b
Dibromide 38b (449mg, 1.29mmol) was put into 3ml 0.5 M diphenyl phosphomium
patasium THF solution. The mixture was stirred in room temperature overnight. The
solvent is removed and the product (0.230g, 32%) was separated out by column
chromatography (Eluent 10:1 hexanes: ethyl acetate). 1H NMR (CDC13 300MHz)
5 7.3-7.5 (20H, m, Ar), 4.10 (2H, q, J = 4H2), 3.43 (4H, m), 2.42 (4H, m), 1.18(6H, t, J =
5H2); l3C NMR (CDC13) 5 138.2 (q), 132.8 (q), 128.6 ((1), 128.3 (d), 88.2 (d), 80.8 (d),
67.1, 32.9 (d), 15.3 ppm

85

4.9 References

11.

. Kagan, H. B.; Dang, T. P. The Asymmetric Synthesis of Hydratropic Acid and

Amino-acids by Homogeneous Catalytic Hydrogenation J. Chem. Soc, Chem.
Commun. 1971, 481.

Kagan, H. B.; Dang, T. P. Asymmetric Catalytic Reduction with Transition Metal
Complexes. 1. Catalytic System of Rhodium(l) with
(-)-2,3-0-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butane, A New
Chiral Diphosphine J. Am. Chem. Soc. 1972, 94, 6429

Li, W.; Zhang, X. Synthesis of
3,4-O-Isopropylidene-(3S,4S)-dihydroxy-(2R,5R)-bis(diphenylphosphino)hexane
and Its Application in Rh-Catalyzed Highly Enantioselective Hydrogenation of
Enamides J .Org. Chem. 2000, 65, 5871

Yan, Y.-Y.; Rajanbabu, T. V. Ligand Substituent Effects on Asymmetric Induction.
Effect of Structural Variations of the DIOP Ligand on the Rh-Catalyzed Asymmetric
Hydrogenation of Enamides Org. Lett. 2000, 2, 4137-4140

Yan, Y.-Y.; Rajanbabu, T. V. Ligand Tuning in Asymmetric Catalysis: Mono-and
Bis-Phospholanes for a Prototypical Pd-Catalyzed Asymmetric Allylation Reaction
Org. Lett. 2000, 2, 199-202

Zhu, 0.; Cao, R; J iang, Q.; Zhang X. Highly Enantioselective Rh-Catalyzed
Hydrogenations with a New Chiral 1,4-Bisphosphine Containing a Cyclic Backbone
J. Am. Chem. Soc. 1997, 119, 1799-1800

Zhu, 0.; Zhang, X. Asymmetric Rh-Catalyzed Hydrogenation of Enamides with a
Chiral 1,4-Bisphosphine Bearing Diphenylphosphino Grousz. Org. Chem 1998, 63,
9590-9593

Zhu, G.; Casalnuovo, A. L.; Zhang, X. Practical Syntheses of B-Amino Alcohols via
Asymmetric Catalytic Hydrogenation J. Org. Chem. 1998, 63, 8100-8101

Zhu, (1; Zhang, X. Additives Effects in Ir-BICP Catalyzed Asymmetric
Hydrogenation of Imines Tetrahedron: Asymmetry 1998, 9, 2415-2418

. Lee, S.-g.; Zhang, X. J.; Song, C.E.; Lee, J. K.; Choi, J. H. Novel 1,4-Diphosphanes

with Imidazolidin-Z-one Backbones as Chiral Ligands: Highly Enantioselective
Rh-Catalyzed Hydrogenation of Enamides Angew. C hem. Int. Ed. Engl. 2002, 41,
847-849

Lee, S.-g.; Zhang, Y. J. Rh(I)-Cataly2ed Enantioselective Hydrogenation of (E)-and

86

12.

l6.

l7.

18.

20.

21.

22.

23.

(Z)-B-(Acylamino)acrylates Using 1,4-Bisphosphine Ligands under Mild Conditions
Org. Lett. 2002, 4, 2429-2431

Lee, S.-g.; Zhang, Y. J. Rhodium-catalyzed Asymmetric Hydrogenations of Electron
Deficient Olefins Using 1,4-diphosphine Ligands Bearing an Imidazolidin-Z-one
Backbone Tetrahedron: Asymmetry 2002, 13, 1309-1042

. Hayashi, T.; Kubo, N. Ozawa, F. Catalytic Asymmetric Arylation of Olefins Pure &

App]. Chem. 1992, 64, 421-427

.Tanaka, K.; Takeaki, S. Cationic Rhodium(I)/BINAP Complex-Catalyzed

lsomerization of Secondary Propargylic Alcohols to or, B-Enones Org. Lett .2005, 7,
3561-3563

. Bougauchi, M.; Watanabe, S.; aria, T.; Sasai, H.; Shibasaki, M. Catalytic Asymmetric

Epoxidation of a, B-Unsaturated Ketones Promoted by Lanthanoid Complexes J. Am.
Chem. Soc. 1997, 119, 2329-2330

Kelly, T. R.;Whiting, A.; Chandrakumar, N. S. Rationally designed, chiral Lewis acid

for the asymmetric induction of some Diels-Alder reactions J. Am. Chem. Soc. 1986,
108, 3510-3512

Kitajima. H.; Katsuki, T. Chiral Lewis Acid Promoted Asymmetric Michael Addition
Reaction of 2-(Trimethylsilyloxy)furans Syn/ett 1997, 5, 568-570

Kitajima, H.; Ito, K.; Katsuki, T. A new methodology for the stereoselective synthesis
of 4-substituted butenolides: Asymmetric Michael Addition Reaction of
2-(trimethylsilyloxy) furans to Oxazolidinone Enoates Tetrahedron 1997, 53,
17015-17028.

.Kobayashi,S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.; Kobayashi, J. Catalytic

Enantioselective Inverse-Electron Demand 1,3-Dipolar Cycloaddition Reactions of
Nitrones with AlkenesJ. Am. Chem. Soc. 1999, 121, 3845-3853

Chen, Y.; Yekta, S.; Yudin, K. A. Modified BINOL Ligands in Asymmetric Catalysis
Chem. Rev. 2002, 103, 3155-3211

Noyori, R. Asymmetric Catalysis in Organic Synthesis, John Wiley&Sons ltd.; New
York, 1994

Catalytic Asymmetric Synthesisi: Ojima, 1., Ed.; VCH Press: Berlin, 1993

Singh, V. K. Practical and Useful Methods for the Enantioselective Reduction of
Unsymmetrical Ketones Synthesis 1992, 605

87

 

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

Chirality in Industry: The Commercial Manufacture and Applications of Optically
Active Compounds; Collins, A. N., Sheldrake, G N., Crosby, J., Eds,; John
Wiley&Sons: Chichester, 1992

Hashiguchi, S.; Fujii A.; Takehar J.; lkariya T.; Noyori R. Asymmetric Transfer
Hydrogenation of Aromatic Ketones Catalyzed by Chiral Ruthenium(ll) Complexes J.
Am. Chem. Soc. 1995, 117, 7562-7563

N.G. Gaylord, Reduction with complex Metal Hydrides, lnterscience, New York,
1956
Reduction Techniques and Applications in Organic Synthesis Marcel Dekker, New

York, 1968
A. Hajos, Complex Hydrides in Organic Synthesis, Elsevier, New York, 1979

ltsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. Highly Enantioselective Borane
Reduction of Ketones Catalyzed by Chiral Oxazaborolidines. Mechanism and
Synthetic lmplicationsJ. Chem. Soc. C hem C ommrtn. 1983, 469-470

ltsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. Asymmetric Reduction of Aliphatic
Ketones with the Reagent Prepared From
(S)-(-)-2-amino-3-methyl-l,l-diphenylbutan-l-ol and Borane J. Org. Chem. 1984, 49,
555-557

ltsuno. S. Nakano, M.; Miyazaki, K.; Masudam H.; Ito, K.; Hirao, A,; Nakahama, S.
Asymmetric Synthesis Using Chirally Modified Borohydrides. Part 3.
Enantioselective Reduction of Ketones and Oxime Ethers with Reagents Prepared
From Borane and Chiral Amino Alcohols J. Chem. Soc, Perkin Trans 1 1985,
2039-2044

ltsuno, S.; Nakano, M.; Ito, K.; Hirao, A.; Owa, M.; Kanda, N.; Nakahama, S.
Asymmetric Synthesis Using Chirally Modified Borohydrides. Part 4.
Enantioselective Reduction of Ketones and Oxime Ethers with the Reagent Prepared
From Borane and Polymer-supported
(S)-(-)-2-amino-3-(p-hydroxyphenyl)-l,1-diphenylpropan-l-ol J. Chem, Soc, Perkin
Trans 1 1985, 2615-2619

Corey, E. J.; Bakshi, R. K.; Shibata, S. A Stable and Easily Prepared Catalyst for the
Enantioselective Reduction of Ketones: Applications to Multistep Syntheses J. Am.

Chem. Soc. 1987, 109, 7925—7926

Corey, E. J.; Bakshi, R. K.; Shibata. S. Highly Enantioselective Borane Reduction of

88

35.

36.

37.

Ketones Catalyzed by Chiral Oxazaborolidines: Mechanism and Synthetic
ImplicationsJ. Am. Chem. Soc. 1987, 109, 5551-5553

Corey, E. J.; Shibata, S.; Bakshi, R. K. An Efficient and Catalytically
Enantioselective Route to (S)-(-)-Phenyloxirane J. Org. Chem. 1988, 53, 2861-2863

Corey, E. J.; Helal, C. J. The Catalytic Enantioselective Construction of Molecules
with Quaternary Carbon Stereocenters Angew. Chem. Int. Ed. Engl., 1998, 37,
388-401

Palmer, M. J.; Wills, M. Asymmetric transfer hydrogenation of C=0 and C=N bonds
Tetrahedron: Asymmetry 1999, 10, 2045

38. Noyori, R.; Hashiguchi, S. Asymmetric Transfer Hydrogenation Catalyzed by Chiral

39.

40.

41.

Ruthenium Complexes Acc. Chem. Res. 1997, 30, 97

Gladiali, S.; Alberico, E. Asymmetric transfer hydrogenation: chiral ligand and
applications Chem. Soc. Rev. 2006, 35, 226

lkariya, T.; Murata, K.; Noyori, R. Bifunctional transition metal-based molecular
catalysts for asymmetric syntheses Org. Biomo]. Chem. 2006, 4, 393

Docet, H.; Ohkuma, T.; Murata, K.; England, T.; lkariya, T.; Noyori, R. trans-[RuClg
(phosphane) 3(1, 2-diamine)] and Chiral trans-[RuClg (diphosphane) (I, 2-diamine)]:
Shelf-Stable Precatalysts for the Rapid, Productive, and Stereoselective
Hydrogenation of Ketones A gew. Chem. Int. Ed. 1998, 37, 1703-1707

42.Noyori, R.; Ohkuma, T. Asymmetric Catalysis by Architectural and Functional

43.

44

45.

Molecular Engineering: Practical Chemo-and Stereoselective Hydrogenation of
Ketones Angew. Chem. Int. Ed, 2001, 40, 40-73

Zanotti-Gerosa, A.; Hems, W.; Groarke, M.; Hancock F. Ruthenium-catalyzed
asymmetric reduction of ketones Platinum Metals Rev. 2005, 49, 158-165

.Ohkuma, T.; Ooka, H.; Hashiguchi, S.;, lkariya, T.; Noyori, R. Practical

Enantioselective Hydrogenation of Aromatic Ketones J. Am. Chem. Soc. 1995, 117,
2675-2676

Aveline S. Y.; Wills, M. Asymmetric Transfer Hydrogenation Using Amino Acid
Derivatives; Further Studies and A Mechanistic Proposal Tetrahedron 2005, 61,
7994-8004

89

l11111111111111lily: