Efficient Carbohydrate Synthesis by Controlled
Inversion Strategies
Hai Dong
Licentiate Thesis
Stockholm 2006
Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm
framlägges till offentlig granskning för avläggande av licentiatexamen i organisk kemi,
torsdagen den 30 nov, kl 10.00 i sal E2, KTH, Osquars backe 14, Stockholm.
Avhandlingen försvaras på engelska.
2
Hai Dong: “Efficient Carbohydrate Synthesis by Controlled Inversion Strategies” Organic
Chemistry, KTH Chemistry, Royal Institute of Technology, S-10044 Stockholm, Sweden.
Abstract
The Lattrell-Dax method of nitrite-mediated substitution of carbohydrate triflates is an
efficient method to generate structures of inverse configuration. In this study it has been
demonstrated that a neighboring equatorial ester group plays a highly important role in this
carbohydrate epimerization reaction, inducing the formation of inversion compounds in
good yields. Based on this effect, efficient synthetic routes to a range of carbohydrate
structures, notably β-D-mannosides and β-D-talosides, were designed. By use of the ester
activation effect for neighboring groups, a double parallel as well as a double serial
inversion strategy was developed.
Keywords: Carbohydrate Chemistry, Carbohydrate Protection, Epimerization, Inversion,
Dynamic, Regioselective Control, Neighboring Group Participation
3
List of publications
I.
Solvent-Dependent, Kinetically Controlled Stereoselective
Synthesis of 3- and 4-Thioglycosides
Zhichao Pei, Hai Dong and Olof Ramström
J. Org. Chem. 2005, 70, 6952-6955
II.
Stereospecific Ester Activation in Nitrite-Mediated Carbohydrate Epimerization
Hai Dong, Zhichao Pei and Olof Ramström
J. Org. Chem. 2006, 71, 3306-3309
III.
Reagent-Dependent Regioselective Control in Multiple
Carbohydrate Esterifications
Hai Dong, Zhichao Pei, Styrbjörn Byström and Olof Ramström
Manuscript
IV.
Efficient Synthesis of β-D-Mannosides and β-D-Talosides by
Double Parallel or Double Serial Inversion
Hai Dong, Zhichao Pei, Marcus Angelin, Styrbjörn Byström and
Olof Ramström
Manuscript
4
Table of Contents
ABSTRACT
LIST OF PUBLICATIONS
ABBREVIATIONS
1 Introduction ..............................................................................................1
1.1 Carbohydrate Synthesis in Biology.....................................................1
1.2 Carbohydrate Epimerization ...............................................................2
1.3 Lattrell-Dax Carbohydrate Epimerization...........................................3
1.4 Neighboring Group Participation ........................................................5
1.5 Design of Synthetic Strategies ............................................................6
2 Regioselective Carbohydrate Protections ..............................................8
2.1 Traditional Protection Strategies.........................................................8
2.1.1 Esterification ................................................................................8
2.1.2 Benzylation...................................................................................8
2.1.3 Combination of Esterification and Benzylation ...........................9
2.2 Organotin Protection Strategies ........................................................12
2.2.1 Organotin Monoprotection.........................................................12
2.2.2 Organotin Multiple Esterification ..............................................12
3 Stereospecific Ester Activation .............................................................15
3.1 Effects in Lattrell-Dax Epimerization ...............................................15
3.1.1 Effects of Protection Patterns.....................................................15
3.1.2 Effects of Neighboring Group Configurations...........................17
3.2 Neighboring Group Participation ......................................................18
3.3 Conclusion.........................................................................................19
4 Synthesis of β-D-Mannosides and β-D-Talosides ................................21
4.1 Introduction .......................................................................................21
4.2 Double Parallel Inversion..................................................................21
4.3 Double Serial Inversion.....................................................................23
4.4 Remote Group Participation..............................................................25
4.5 Conclusion.........................................................................................27
5 General Conclusions ..............................................................................28
ACKNOWLEDGEMENTS
APPENDIX
REFERENCE
5
Abbreviations
Ac
AcCl
Ac2O
aq
Bn
BnBr
Bz
BzCl
Bu2SnO
DMF
equiv.
Gal
Glc
h
Man
NGP
NMR
rt
T
Tal
TBA
TEA
Tf2O
py.
Acetyl group
Acetic chloride
Acetic anhydride
aqueous
Benzyl group
Benzyl bromide
Benzoyl group
Benzoyl chloride
Dibutyltin oxide
Dimethylformamide
equivalent
Galactoside
Glucoside
hour
Mannoside
Neighboring group participation
Nuclear magnetic resonance
room temperature
Temperature
Taloside
Tetrabutylamonium
Triethylamine
trifluoroacetic anhydride
pyridine
6
1 Introduction
1.1 Carbohydrate Synthesis in Biology
Carbohydrates are one of the largest classes of naturally occurring substances, often found
in conjunction with other large bimolecular such as lipids or proteins (Figure 1). This class
of compounds has been attracting an increasing amount of attention up to today, on
account of playing essential roles in diverse biological processes. Specific proteincarbohydrate interactions constitute the underlying aspects of these important processes,
including cell differentiation, cell adhesion, immune response, trafficking and tumor cell
metastasis, occurring through glycoprotein, glycolipid, and polysaccharide entities at cell
surfaces, and lectins, proteins with carbohydrate-binding domains.(1-3) Carbohydrates with
medicinal uses include heparin, which is the most widely used anticoagulant, antibiotics
and vaccines.(4, 5) Uncovering the contributions of carbohydrates to cell biology would
greatly facilitate advancements in science and medicine. However, the functions of
carbohydrates in biology have not been extensively studied due both to the more complex
structures of oligosaccharides and to a lack of general methods for synthesizing and
analyzing these molecules.
HO
OH
O
HN
O
O
HO
OH
OH
glycolipid (galactosyl cerebroside)
HO
OH
HO
O
O
HO
O
OH
O
R
O
AcHN
H3C
O
NH
O
OH
CH3 O
HO OH
glycoprotein (O-glycosidic)
blood group antigen H
Figure 1. Natural carbohydrate containing entities.(6)
One important case is β-mannoside synthesis. The β-mannopyranosidic linkage is a
common structural element in a wide range of natural products.(7-10) This biologically
important and widespread class of structures contains, as relevant component, β-D-Manp
units, for example present as a central component in the ubiquitous N-glycan core structure
of glycoproteins,(7) and makes part of a range of fungal and bacteria (Figure 2).(11, 12) The
chemical synthesis of this 1,2-cis-mannosidic linkage is, however, especially difficult. The
α-mannosidic linkage is strongly favored because of the concomitant occurrence of both
the α-directing anomeric effect and the repulsion between the axial C-2 substituent and the
approaching nucleophile. Moreover, neighboring group participation of a 2-acyl
substituent leads to α-mannosides only.
7
HO
HO
HO
OH
OH
O
HO
HO
OH
O
HO
O
OH
O
OH
NAc
HO
O
O
O
O
O
HO
NAc
OH
N-linked pentasaccharide core structure
HO
HO
OH
OH
O
HO
HO
OH
OH
O
OH OH
OR
O
OR
OH O
HO
Fungal metabolite deacetyl-caloporoside
β-D-Manp
Figure 2. Natural entities containing β-mannopyranosidic linkages.(11, 12)
The other important case is thiosaccharides synthesis. Thiosaccharides, where an exocyclic
oxygen is replaced by a sulfur functionality, constitute an increasingly important group of
compounds in glycochemistry, possessing unique characteristics compared to their
oxygen-containing counterparts (Figure 3). These compounds are often used as efficient
glycoside donors and acceptors in oligosaccharide and neoglycoconjugate synthesis,(13-19)
because the thiolate is a potent nucleophile and a weak base that reacts easily and
selectively with soft electrophiles. Furthermore, the resulting thioglycosides and S-linked
conjugates possess increased resistance to degradation by glycosidases potentiating their
use as efficient building blocks in drug design and therapeutics.(20)
HO
HO
HO
O
SH
OH
1-thio-β-D glucose
HO
OH
HO
OH
OH
S
HO
O
O
HO
HO
O
O
OH
O
S
HO
HO
HO
S
S
HO
HO
HO
O
HO
HO
HO
OH
S
OH
OH
OH
O
O
O
HO
HO
HO
O
partial structure of the cell
wall phosphomannan antigen
modified by a sulfur atom
cyclic thiooligosachharides
Figure 3. Thiosaccharides.(21-23)
1.2 Carbohydrate Epimerization
Initially, we focused on developing convenient routes to 3- and 4-thioglycosides of the
galacto-type, starting from free galactoside or glucoside (Figure 4). In order to obtain the
8
3-thio-galactoside 2 or the 4-thio-galactoside 4, it was thus necessary to choose reasonable
protection strategies and epimerization routes.
HO
OH
HO
O
HO
RO
O
OMe
OH
HS
1
OR
RO
OR
RO
O
O
HO
OMe
OR
OH
OMe
OH
2
OR
O
OMe
AcS
OR
OH
HO
HO
OH
HS
OMe
OR
OH
O
O
OH
OMe
3
HO
OR
AcS
OMe
4
OR
O
HO
RO
OH
O
OMe
OMe
RO
OR
OR
Figure 4. Design of synthesis routes to methyl 3- and 4-thiogalactosides.(24)
Epimerization of carbohydrate structures to the corresponding epi-hydroxy stereoisomers
is an efficient means to generate compounds with inverse configuration that may otherwise
be cumbersome to prepare. Several different synthetic methods have been developed,
including protocols based on the Mitsunobu reaction,(25) sequential oxidation/reduction
routes,(26) as well as enzymatic methods,(27) all of which with their respective advantages
and shortcomings.
1.3 Lattrell-Dax Carbohydrate Epimerization
RO
OR
O
HO
OMe
OR
1. py, Tf2O,
CH2Cl2
2. KNO2,
DMF
OR
RO
O
OMe
OH
OR
Figure 5. Lattrell-Dax epimerization.
A common route to stereocenter inversion in carbohydrate chemistry involves the triflation
of a given hydroxyl group, followed by substitution using a variety of nucleophilic
reagents (Figure 5). This method was used by Dax and co-workers who first reported that
glycoside triflate displacement by nitrite ion, a reaction first found by Lattrell and
Lohaus,(28) produced carbohydrates with inverse hydroxyl configuration under very mild
9
conditions.(29) Due to its efficient and convenient character, we thus preferred to use the
Lattrell-Dax carbohydrate epimerization method. Despite its reported efficiency,(13, 30-32)
the Lattrell-Dax method has unfortunately not been extensively adopted, likely because of
difficulties in predicting the outcome for specific structures.
Binkley reported a simple technique for converting methyl 2,6-dideoxy-β-D-arabinohexopyranosides into the corresponding ribo- and lyxo-isomers through internal triflate
displacement by a neighboring benzoyl group and a direct inversion method through
triflate displacement by nitrite ion when neighboring participation could not take place
(Figure 6).(33) He further reported that the inversion reaction appeared to be related to the
configuration, but no explaination was given.
O
BzO
TfO
H2O
CHCl3
OMe
O
HO
OMe
neighboring group
participation
OMe
Fast
OMe
Slow
OBz
O
BzO
TfO
O
nitrite BzO
toluene
OMe
OH
BzO
BzO
O
OMe
TfO
O
nitrite
toluene
OH
Figure 6. Effect of carbohydrate configuration on inversion reaction.(33)
In a more recent study, von Itzstein and co-workers needed to perform a 3-position
glycoside inversion reaction when they developed a new approach toward the synthesis of
lactose-based S-linked sialylmimetics of α-(2,3)-linked sialosides.(16) Their strategy
however failed when they chose a glycoside where one hydroxyl group in 3-position was
free and the other positions protected with benzyl groups (Figure 7). Interestingly, they
obtained a satisfactory result when the 2-position benzyl group was replaced with a
benzoyl group. It clearly showed that the choice of protecting group was crucial to
inverting the configuration at the 3-position of the galactose ring.
O
Ph
O
nitrite
O
OR
TfO
O
Ph
O
O
OR
DMF
OBz
OH
OBz
O
Ph
O
nitrite
O
TfO
OR
DMF
failed
OBn
Figure 7. Effect of the neighboring groups on the inversion reaction.(16)
10
In light of these studies, a tentative conclusion can be given: the choice and the
configuration of the neighboring protecting group of the triflate are crucial for the
reactivity in the Lattrell-Dax inversion. An equatorial trans-configuration is favored for the
inversion. However, by coincidence the trans-configuration is also favored for the
neighboring group participation. Thus, a question can be put forward: can the neighboring
ester group activate the nitrite inversion process via a neighboring group participation
mechanism?
1.4 Neighboring Group Participation
The neighboring group participation mechanism requires two conditions: a neighboring
ester group and trans-configuration. For example, in the course of 3- and 4-thioglycoside
synthesis, a solvent-dependent kinetically controlled stereoselective mechanism was found
(Figure 8).
AcO
OAc
O
OMe
OAc
SAc 7
a
OAc
AcO
O
O
OMe
OTf
OAc
O
H3C
O
OAc
OMe
OAc
5
6
a
b
AcO
OAc
AcO
AcS
OAc
O
O
OMe
HO
OAc
OMe
OAc
8
9
Figure 8. Solvent-dependent kinetically controlled stereoselective mechanism: a) kinetic
control in toluene; b) neighboring group participation in DMF.
In the polar solvent DMF, the neighboring group participation reaction took place
immediately. However, in the nonpolar solvent toluene the neighboring group participation
is restrained. This indicated that neighboring group participation is favored in polar
solvents. Further analysis showed that the products of the neighboring group participation
always were compounds where the ester group is in axial position and the hydroxyl group
is in equatorial position. For the Lattrell-Dax nitrite-mediated inversion, it was obvious
that the ester group always remained in the same position and the hydroxyl group was
generated on the carbon atom directly connected to the triflate group. Thus, it appeared as
11
if neighboring group participation did not occur. Why is it then important to have a
neighboring ester group for the Lattrell-Dax inversion? Furthermore, how does this ester
group activate the inversion reaction?
1.5 Design of Synthetic Strategies
To investigate the effect of the protecting group pattern to the inversion reaction, a series
of galacto- and gluco-type derivatives, where one hydroxyl group in the 2, 3, or 4-position
was free and the other positions were separately protected with acetyl, benzoyl, and
benzyl/benzylidene groups, respectively, were chosen for further evaluation (Figure 9).
Ph
O
O
BzO
Ph
O
OH
OMe
10
O
O
BnO
O
OH
OMe
11
O
Ph
AcO
OAc
BzO
O
HO
HO
OAc
O
OMe
8
HO
OBz
OBz
O
OMe
12
OBz
O
BzO
O
OBz
OMe
OBz 14
HO
BzO
HO
HO
OBn
OMe
13
OBn
OBn
O
O
OMe
OBz 15
BnO
HO
BnO
OMe
OBn 16
O
OBn
OMe
17
Figure 9. Galacto- and gluco-type derivatives with different protecting group patterns.
These compounds were to be subjected to conventional triflation by triflic anhydride,
followed by treatment with potassium nitrite in DMF. It was expected that in all cases
good inversion yields would be obtained with neighboring ester groups, whereas the
inversion would be inefficient with benzyl groups.
AcO
OBn
HO
HO
OBn
OMe
18
AcO
HO
OMe
OBn
19
O
OBn
HO
AcO
O
AcO
OMe
20
OBn
OH
O
OMe
OBn
21
OMe
22
OBn
OBn
OBn
O
AcO
OBn
OBn
O
O
HO
OBn
OAc
OMe
23
Figure 10. Methyl glycoside derivatives where the 2- and 6-positions are protected with
benzyl ether groups.
To further analyze and explore the effect of the neighboring ester group configuration of
triflate on the reactivity, other systems were designed. To avoid effects from the 2- and 6positions and to isolate the effects arising from ester groups in the 3- and 4-positions, the
12
2- and 6-positions were protected with benzyl ether groups (Figure 10). Thus, a range of
compounds where one of the hydroxyl groups in the 3- or 4-position is protected with an
acetyl group had to be prepared and subsequently tested in the Lattrell-Dax epimerization
reaction. However, all above mentioned compounds must first be synthesized. Therefore
the first challenge was to develop efficient regioselective protection schemes.
13
14
2 Regioselective Carbohydrate Protections
2.1 Traditional Protection Strategies
Regioselectivity is a prominent challenge in carbohydrate chemistry since carbohydrates
contain several hydroxyl groups of similar reactivity. Selective protecting groups and
efficient protecting group strategies are therefore of crucial importance to efficiently obtain
desired carbohydrate structures. With modern protecting groups there is the potential of
fulfilling every possible protection pattern. However, a good protecting group strategy
remains a central challenge in carbohydrate chemistry. The most common protecting
groups for hydroxyl functions are esters, ethers, and acetals. Carbohydrate hydroxyl groups
differ somewhat in reactivity depending on whether they are anomeric, primary or
secondary, and also depending on their configurations. These differences in reactivity can
sometimes be utilized so that a desired protection pattern can be achieved in few steps
without the use of more complex reaction sequences.(34, 35) A carbohydrate protection
strategy was designed for acquiring the desired glycoside derivatives via the use of
esterification, benzylation, etherification, or comprehensive use of all these means.
2.1.1 Esterification
Methyl 2,3,6-tri-O-benzoyl galactoside 14 could be simply synthesized by a one-step
esterification process, starting from galactoside 1 (Scheme 1).
HO
OH
HO
BzCl
O
HO
OH
OMe
1
py, CH2Cl2
-40 oC
60%
OBz
O
BzO
OBz
OMe
14
Scheme 1. Synthesis of compound 14.
As for methyl 2,3,6-tri-O-benzoyl glucoside 15, it was envisaged that a good inversion
yield could be obtained by the Lattrell-Dax method, resulting in efficient synthesis of 15
via the epimerization of galactoside 14. In addition, glucoside 15 can also be synthesized
through a more complex route based on acyl group migration.(36)
2.1.2 Benzylation
The glycoside derivatives 11, 13, 17 could be synthesized by benzylation methods.
Starting from galactoside 1, the 4,6-O-benzylidene 24 was produced first, then directly
reacted with benzyl bromide in the presence of sodium hydride, producing 4,6-Obenzylidene-2-O-benzyl galactoside 13 in 30% total yield (Scheme 2). Higher yield of 13
could be obtained by a more complex synthesis route, where the hydroxyl group in 3-
15
position of 24 was first protected with a p-methyl-benzyl group via regioselective
organotin-mediated benzylation, followed by protection of the hydroxyl group in the 2position with a benzyl group via the general benzylation method, and finally the p-methylbenzyl group in the 3-position was removed by oxidation.
O
Ph
O
HO
O
Ph
O
OH
HO
OH
O
PhCH(OMe)2
OMe
1
DMF, H
O
HO
OH
OMe
24
O
BnBr, NaH
DMF
30%
HO
OBn
OMe
13
Scheme 2. Synthesis of compound 13.
Starting from glucoside 3, the 4,6-O-benzylidene 25 could be produced by the same
method, then 4,6-O-benzylidene-3-O-benzyl glucoside 11 was obtained through the same
as above mentioned tin oxide benzylation method (Scheme 3). The lower yield was caused
by the similar reactivity between the 2- and 3-positions of 25.
OH
HO
HO
O
OH
OMe
3
Ph
PhCH(OMe)2
DMF, H
Ph
Ph
O
O
HO
O
OMe
OH
25
1.Bu2SnO,
MeOH
50%
2.BnBr, TBAI
toluene
O
O
BnO
BnBr, NaH
DMF
90%
O
OH
OMe
11
O
O
BnO
O
OBn
OMe
26
Et3SiH,
80% CF3CO2H
CH2Cl2
OBn
HO
BnO
O
OBn
OMe
17
Scheme 3. Synthesis of compounds 11 and 17.
When the above reaction mixture containing 25 was directly benzylated, the 4,6-Obenzylidene-2,3-di-O-benzyl glucoside 26 was produced in a very high yield. After the
benzylidene ring being opened by reduction, the 2,3,6-tri-O-benzyl glucoside 17 was
finally obtained in 80% yield.
2.1.3 Combination of Esterification and Benzylation
Most of the glycoside derivatives were synthesized using a combination of esterification
and benzylation reactions. Some required only a few steps, whereas others were more
cumbersome. For synthesis of the 4,6-O-benzylidene-3-O-benzoyl glucoside 10, it was
known that compound 25 was easily produced by one step benzylidenelation in light of
Scheme 3. Starting from compound 25, the glucoside 10 was then conveniently obtained
by benzoylation (Scheme 4).
16
Ph
O
O
HO
O
OH
OMe
25
1.Bu2SnO, Ph
MeOH
2.BzCl,
toluene
55%
O
O
BzO
O
OH
OMe
10
Scheme 4. Synthesis of compound 10.
The syntheses of methyl 2,4,6-tri-O-acetyl galactoside 8 and methyl 2,4,6-tri-O-benzoyl
galactoside 12 were somewhat more complex. The hydroxyl group in the 3-position of
galactoside 1 was first protected with a benzyl group by regioselective tin oxide
benzylation, and then the obtained 26 was acylated in the presence of pyridine in methanol.
Finally after removing the benzyl group in the 3-position by a catalytic hydrogenation
process, the methyl galactosides 8 or 12 were acquired in high yield (Scheme 5).
HO
OH
O
HO
BzO
HO
OH
Bu2SnO
MeOH
OMe BnBr, TBAI
1
90 oC
80%
OBz
HO
Pd, H2
OMe
OBz 12
100%
AcO
O
BnO
OH
OMe
26
OAc
O
Ac2O, py
MeOH
90%
BnO
90% BzCl, py
MeOH
BzO
O
OH
100%
OBz
AcO
OAc
Pd,
H2
OAc
O
O
BnO
OMe
27
OMe
28
OBz
HO
OAc
OMe
8
Scheme 5. Syntheses of compound 8 and 12.
It proved most difficult to synthesize the glycoside derivatives where one of the hydroxyl
groups in the 3- or 4-position was protected with an acetyl group whereas the 2- and 6position were blocked with benzyl groups. The methyl 4-O-acetyl-2,6-di-O-benzyl
galactoside 18 could however be relative easily obtained in 70% total yield via a one-pot
reaction (Scheme 6).(37)
HO
OH
EtO O
O
HO
OH
CH3(OEt)3
OMe
1
THF, H
EtO O
OH
O
O
OH
OH
O
BnBr, NaH
OMe
THF
29
O
OH
OMe
30
H
AcO
OBn
O
70%
HO
Scheme 6. Synthesis of compound 18.
17
OBn
OMe
18
Starting from the obtained compound 18, and removing the acetyl group, then the 2,6-diO-benzyl galactoside 31 could be easily changed into 2,3,6-tri-O-benzyl galactoside 16 or
3-O-acetyl-2,6-di-O-benzyl galactoside 19 by organotin methods (Scheme 7).
AcO
OBn
HO
OBn
HO
O
MeOH
MeONa
90%
OMe
OBn 18
1.Bu2SnO
MeOH
O
OMe
OBn 31
HO
85%
HO
1.Bu2SnO
MeOH
2.BnBr, TBAI
toluene
OBn
2.Ac2O
toluene
85%
HO
OBn
O
AcO
OBn
OMe
19
O
BnO
OBn
OMe
16
Scheme 7. Syntheses of compound 16 and 19.
The 3-O-acetyl-2,6-di-O-benzyl glucoside 21 could be acquired via the epimerization of 19
(Figure 11). The 4-O-acetyl-2,6-di-O-benzyl glucoside 20 could be produced via acetyl
group migration of 21. Furthermore, the 4-O-acetyl-2,6-di-O-benzyl guloside 22 could be
acquired via the epimerization of 20 and the 3-O-acetyl-2,6-di-O-benzyl guloside 23 could
be produced via neighboring group participation of 20.
HO
OBn
OBn
O
AcO
inversion
OMe
OBn 19
O
HO
AcO
OBn
OBn
OBn
HO
AcO
O
TEA
OMe
OBn 21
O
AcO
HO
OBn
O
OBn
OMe
20
O
inversion AcO
OH
O
OBn
OBn
OMe
22
OBn
OBn
AcO
HO
OMe
20
OBn
OBn
AcO
HO
OMe
21
NGP
OMe
20
O
AcO
OH
OBn
OMe
23
Figure 11. Synthesis approach to 20, 21, 22, 23.
18
2.2 Organotin Protection Strategies
2.2.1 Organotin Monoprotection
For obtaining mono-substituted compounds in one or a few steps, the use of organotin
reagents such as tributyltin oxide or dibutyltin oxide,(38) provide useful means to efficient
regioselective acylations,(39-42) alkylations,(39, 43-45) silyations,(46) sulfonylations,(39, 47, 48) and
glycosylations.(49-51) Stannylene acetals are easily prepared, and generally lead to
intermediate structures with predictable reactivities. In these reactions, stoichiometric
amounts of organotin reagent are normally used. Several acylation and benzylation
examples have been given in the above syntheses.
2.2.2 Organotin Multiple Esterification
However, of particular importance in this respect is the possibility of acquiring multiple
protections in single step processes, and so far no efficient, general methods have been
developed. Interestingly, a protocol was recently described where products with one or
two free hydroxyl groups were produced by use of excess organotin reagent.(52) This
potentially general approach is very convenient and efficient for multiple protection
schemes. Combining this organotin method with the Lattrell-Dax (nitrite-mediated)
carbohydrate epimerization method,(53) very convenient and highly efficient methods to
modify carbohydrate structures that traditionally require many steps,(36, 54) can be
developed. For example, the syntheses of 2,4,6-tri-O-acetyl (or benzoyl) galactoside 8 (or
12) and 2,3,6-tri-O-benzoyl galactoside (or glucoside) 14 (or 15), which can be used to
synthesize 3- and 4-thioglycosides, normally require many steps in light of the above
(Scheme 5), or the literature(36). For this reason, is it possible that they are produced in
high yield via the convenient organotin multiple esterification?
In order to advance the organotin-mediated multiple carbohydrate protection method, a
study of regioselective single-step acylations of unprotected pyranosides was initiated. The
unprotected glycoside was first treated with excess amount (2-3 equivalents) of
dibutyltinoxide, producing a stannylene intermediate that was not isolated. This
intermediate was subsequently treated with the acylation reagent to yield the protected
products in a one-pot process (Figure 12).
O
HO
HO
OH
O
OR'
OH
unprotected
glycoside
Excess
Bu2SnO
O
Bu
O
Sn
Bu
O
O
O
R
OR'
Sn O
Bu Bu
stannylene
intermediate
R
O
X
O
HO
R
O
OR'
OH
O
acylated
product
Figure 12. Example of organotin-mediated multiple carbohydrate esterification.
19
During this study it was however found that the multiple esterification processes were
highly dependent on the acyl reagent used. Different protection patterns could be acquired
from the same starting material by control of temperature, acyl reagents, reagent mole ratio,
and solvent polarity (Scheme 8, 9, 10).
HO
OH
Bu2SnO
MeOH
O
HO
HO
OH
OMe
1
OH
O
HO
HO
OH
OMe
1
OH
O
HO
OH
OMe
1
BzCl, rt,
toluene
2eq.
HO
O
BzO
Bu2SnO
MeOH
BzO
BzCl, 90 oC
toluene
2eq.
HO
Bu2SnO
MeOH
BzO
BzCl, 90 oC
toluene
3eq.
OBz
OMe
32 90%
OH
OBz
O
OH
OMe
33 85%
OBz
O
BzO
OH
OMe
34 90%
Scheme 8. Multiple benzoylation controlled by temperature and reagent mole ratio.
In the course of these studies (Scheme 8), it was found that the benzoyl group can migrate
to 3- and 4-position from 2- and 3-position at high temperature. Thus temperature could be
used for dynamic migration control.
HO
OH
Bu2SnO
MeOH
O
HO
HO
OH
OMe
1
OH
Bu2SnO
MeOH
O
HO
OH
OMe
1
OH
HO
HO
OMe
1
OH
HO
HO
Ac2O, rt
DMF
Bu2SnO
MeOH
O
OH
AcCl, rt
toluene
Bu2SnO
MeOH
O
OH
Ac2O, rt
toluene
OMe
1
BzCl, rt
CH3Cl
HO
OAc
O
AcO
AcO
OAc
OMe
35 70%
OAc
O
AcO
OH
OMe
36 57%
OAc
HO
AcO
O
OH
OMe
37 70%
OBz
HO
HO
O
OBz
OMe
38 51%
Scheme 9. Multiple esterifications controlled by acyl reagents and solvents.
In light of the tentative organotin benzoyl group migration mechanism suggested, (48, 55-57)
the resulting tin alkoxide intermediate is able to attack the acyl carbonyl group. It is
however reasonable to assume that acyl regents in general are able to migrate under the
same conditions. And yet, different from benzoyl chloride and acetyl chloride, it was found
that the migration could only be observed with acetyl chloride at room temperature,
whereas acetyl anhydride proved inefficient in this reaction (Scheme 9).
20
On the other hand, since no migration resulted with whether acetic anhydride or benzoyl
chloride at room temperature, it is apparent that the results controlled by acyl reagents,
where the 3,6-position protected product 37 was obtained with acetic anhydride whereas
the 2,6-position protected product 38 was obtained with benzoyl chloride at room
temperature, were not brought about by the organotin acyl group migration mentioned
above (Scheme 9).
HO
OH
Bu2SnO
MeOH
O
HO
HO
OH
OMe
1
OH
Bu2SnO
MeOH
O
HO
OH
OMe
1
OH
HO
HO
OMe
1
OH
HO
HO
Ac2O, rt
CH3CN
Bu2SnO
MeOH
O
OH
Ac2O, rt
DMF
Bu2SnO
MeOH
O
OH
Ac2O, rt
CH3CN
OMe
1
BzCl, rt
toluene
HO
OAc
O
AcO
HO
OAc
OMe
35 85%
OAc
O
AcO
OH
OMe
39 90%
OAc
HO
AcO
O
OAc
OMe
40 85%
OBz
HO
BzO
O
OBz
OMe
15 58%
Scheme 10. Multiple esterifications controlled by solvent polarity.
Good selectivity was always obtained when the esterification reactions were done in a
more polar solvent (Scheme 10). The reason is likely due to decreased reactivity of the
esterification reagent from solvent-induced destabilization of the stannylene
intermediates.(58) If the experiments were performed in polar solvents, higher yields of 15
and 38 would be acquired.
21
22
3 Stereospecific Ester Activation
3.1 Effects in Lattrell-Dax Epimerization
All the glycoside derivatives, which were designed to explore the effect of the neighboring
group on the Lattrell-Dax epimerization, were synthesized via the use of esterification,
benzylation or organotin methods. It was hypothesized that, whenever the triflate group is
in 2-, 3-, or 4-position of these pyranosides, good inversion yields would be obtained with
neighboring ester groups, whereas poor inversion yields or complex mixtures would be
obtained with neighboring benzyl groups. Furthermore, good inversion yields would be
obtained with only neighboring equatorial ester groups, and it would be inefficient with
neighboring axial ester groups. Our first approach was to investigate the effect of the
protecting group pattern to the inversion reaction.
3.1.1 Effects of Protection Patterns
Initially, glycoside derivatives carrying a triflate group in the 3-position, were subjected to
the test. In order to compare the effects of different ester groups, two types of esterprotected galactopyranosides (8, 12) were synthesized.
OAc
AcO
O
OMe
OAc
8
HO
OBz
BzO
O
HO
Ph
O
OBz
OMe
12
OAc
AcO
O
OH
OAc
OMe
41 73%
OBz
1. py, Tf2O, BzO
O
CH2Cl2, 2h
OMe
2. KNO2, 6h
OBz 42 77%
DMF, 50 oC
OH
O
O
HO
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 3h
DMF, 50 oC
OBn
OMe
13
1. py, Tf2O,
CH2Cl2, 2h
Mixture
2. KNO2, 3h
DMF, 50 oC
Scheme 11. Epimerization of glycosides where one hydroxyl group in 3-position is free.
As can be seen (Scheme 11), good yields were in these cases obtained only on the
condition that esters were chosen as protecting groups, benzoyl groups being slightly less
activating than the acetyl counterparts. When the ester protecting groups were replaced by
benzyl/benzylidene groups, a mixture of different products was instead obtained.
Similar results were obtained from the epimerization of glycopyranosides where the
hydroxyl group in the 4-position was unprotected, and all other positions were protected
with either benzoyl or benzyl groups (Scheme 12). Only when an ester group was present
at the carbon adjacent to the carbon atom carrying the leaving triflate group did the
23
reaction proceed smoothly, the axially oriented triflate being less reactive than the
equatorial leaving group.
HO
OBz
O
BzO
OBz
OMe
14
OBz
HO
BzO
HO
O
OMe
OBz 15
OBn
O
BnO
OBn
OMe
16
OBn
HO
BnO
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 5h
DMF, 50 oC
OBz
OMe
OBn 17
OMe
15 75%
OBz
O
BzO
1. py, Tf2O,
CH2Cl2, 2h
OBz
OMe
14 70%
Mixture
2. KNO2,0.5h
DMF, 50 oC
1. py, Tf2O,
CH2Cl2, 2h
O
OBz
HO
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 2h
DMF, 50 oC
O
HO
BzO
Mixture
2. KNO2, 0.5h
DMF, 50 oC
Scheme 12. Epimerization of glycosides where one hydroxyl group in 4-position is free.
In contrast to this effect, no efficient reaction occurred when benzyl groups were employed
where compound mixtures were instead rapidly obtained. These results suggest that a
neighboring ester group is able to induce or activate the inversion reaction, whereas an
ether derivative is unable to produce this effect. The results also show that the inversion
reaction proceeded smoothly regardless of the triflate configuration.
Ph
Ph
O
O
BzO
O
O
BnO
O
OH
OMe
10
O
OH
OMe
11
1. py, Tf2O, Ph
CH2Cl2, 2h
2. KNO2, 6h
DMF, 50 oC
1. py, Tf2O,
CH2Cl2, 2h
2. KNO2, 3h
DMF, 50 oC
O
O
BzO
OH
O
OMe
43 74%
Mixture
Scheme 13. Epimerization of glycosides where one hydroxyl group in 2-position is free
Further tests were performed for glucopyranosides where the hydroxyl groups in the 2position was free (Scheme 13). Instead of observing the inversion behavior in the 3- and 4positions of the hexopyranosides, the 2- and 3-positions were probed (2,3-trans). The
results also indicated that the ester-protecting group would prove efficient in inducing the
inversion, whereas the corresponding ether protecting group would fail to produce this
effect. The ester-protected glucopyranoside compound 10 afforded the inversion
mannopyranoside product 43 in good yields, whereas the ether-protected compound 11
24
proved inefficient. In this case, slightly longer reaction times were, however, necessary due
to the lower reactivity of the 2-OTf derivative.
3.1.2 Effects of Neighboring Group Configurations
It was demonstrated that a neighboring ester group was essential for the reactivity of the
nitrite-mediated triflate inversion from the above experiments. To further analyze these
findings and explore the effects of the neighboring ester group configurations of triflate on
the reactivity, glycoside derivatives 18 to 23, where to avoid the effects from the 2- and 6positions and to isolate the effects arising from ester groups in the 3- and 4-positions, the
2- and 6-positions were protected with benzyl ether groups, were subsequently tested in the
nitrite-mediated inversion reactions. The experimental results presented in Table 1 clearly
indicate that the configuration of the neighboring ester group was decisive for the
reactivity of the epimerization reaction. Good inversion yields depended mainly on the
relative configurations between the two groups, and only with the ester group in the
equatorial position, whatever the configuration of the triflate, did the reaction proceed
smoothly, whereas a neighboring axial ester group proved inefficient.
Table 1. Epimerization reaction studied.
Reactant
entry
OBn
O
AcO
1
OBn
O
HO
6
OMe
OBn 19
AcO
2
5
3
OBn
O
AcO
HO
OMe
OBn 20
AcO
HO
4
OBn
OMe
21
OMe
22
4
OMe
23
3
OBn
OBn
OH
1.5
HO
OBn
75
OMe
22
69
OMe
19
72
OMe
20
73
OBn
O
AcO
AcO
HO
OMe
21
OBn
O
AcO
0.5
OBn
O
OAc
_
OBn
O
HO
AcO
OBn
O
OBn
Yield
OBn
O
OMe
OBn 44
OH
HO
OBn
OH
4
3
OBn
O
HO
AcO
product
AcO
OMe
OBn 18
HO
Time(h)
OBn
O
OBn
OBn
O
OAc
OBn
OMe
45
_
Rapid internal triflate displacements by neighboring acetyl or benzoyl groups have been
mentioned above when the ester group and the leaving group have trans-diaxial
relationships. This leads to products where the configuration is retained, thus excluding
25
these combinations from the present investigation. This internal displacement is indicative
of the fast formation of an intermediate acyloxonium carbocation, stabilized by polar
solvent. In our cases, compounds 20 and 21 hold 3,4-trans configurations in diequatorial
relationships, where the internal triflate displacement by the neighboring ester group is
considerably less efficient. Contrary to this situation, compounds 19 and 22 hold 3,4-cis
configurations, where the ester groups are in the equatorial positions, a structural situation
largely excluding the conventional neighboring group participation.(59, 60)
3.2 Neighboring Group Participation
The results obtained seem to point to the importance of a neighboring group
(acyloxonium) effect, where compounds 20 and 21 (3,4-trans) expressed a higher
reactivity as a result of activation from the neighboring ester group in inducing the
inversion reaction compared to compounds 19 and 22 (3,4-cis). This is reflected in the
longer reaction times for the 3,4-cis compounds, as displayed in Table 1. However,
acyloxonium formation is still unlikely to be the sole explanation of the results,
contradictory to the results for two reasons: first, starting compounds 14, 19, and 22 all
have a cis relationship between the ester and the leaving group, which largely disqualifies
acyloxonium formation;(59, 60) and second, formation of a carbocation intermediate would
result in a nucleophilic displacement from the triflate face of the compound leading to
retention (double inversion) of configuration rather than single inversion (Figure 13).
AcO
HO
OBn
O
OBn
O
AcO
OMe Tf2O/pyridine
TfO
OBn
CH2Cl2
OBn
OMe
KNO2
DMF
20
OBn
O
OAc
OBn
H2O
OMe
OBn
O
O
OBn
O
AcO
OMe
OBn
OMe
OBn
O
OH
23
OBn
OMe
22
O N O
HO
AcO
OBn
O
O N O
DMF
HO
AcO
TfO
OBn
O
OMe Tf2O/pyridine
OBn
CH2Cl2
TfO
AcO
OBn
O
OBn
OMe
KNO2
DMF
TfO
AcO
OBn
O
OBn
OMe
21
DMF
AcO
O
OBn
O
HO
OBn
H2O
OMe
HO
OBn
O
O
OBn
18
OMe
AcO
OBn
O
OBn
OMe
19
Figure 13. Comparison of nitrite-mediated inversion with neighboring group participation
26
However, that acyloxonium formation is important in the trans-configuration cases was
further supported by studies with added water. Thus, compounds 20 and 21, both with 3,4trans-diequatorial relationships, mainly yielded compounds 19 and 22 from reaction with
potassium nitrite in dry DMF (Table 2). If on the other hand wet DMF was used,
compounds 18 and 23 were instead obtained as the main products. This suggests
acyloxonium formation to the five-membered-ring intermediate, which rapidly collapses in
the presence of water to produce the axial ester and the equatorial hydroxyl group. These
results are indicative of (partial) acyloxonium formation in the trans-configuration cases,
but that the nitrite ion is unable to open the five-membered ring from either the triflate face
or from attacking the carbonyl cation, as has been suggested for water.(33) More
importantly, the ester group is, therefore, likely to induce or stabilize the attacking nitrite
ion regardless of the trans- or cis-configurational relationships.
Table 2. Water effects in studied nitrite-mediated inversion reactions.
Nucleophile
Reactant
AcO
HO
AcO
HO
HO
AcO
HO
AcO
OBn
O
OBn
OMe
OMe
HO
H2O
OMe
KNO2
AcO
21
AcO
OBn
O
H2O
OBn
OMe
69
22
OBn
O
OAc
HO
Yield/%
OBn
O
OH
20
OBn
O
OBn
AcO
KNO2
20
OBn
O
OBn
product
OBn
OMe
OBn
O
OBn
70
23
OMe
72
19
OBn
O
70
OMe
HO
OBn 18
21
i: Tf2O, py, CH2Cl2, -20 oC-10 oC, 2h, ii: KNO2, 50oC, DMF, 0.5-1.5h, or H2O, rt, DMF, 6h
OBn
OMe
The effects observed for the ether-protected carbohydrates are likely a result of their lower
degree of positive charge destabilization than the corresponding ester groups, leading to
side reactions such as ring contraction and elimination.(61, 62)
3.3 Conclusion
In conclusion, it has been demonstrated that esters play highly important roles in the
Lattrell-Dax reaction, facilitating nitrite-mediated carbohydrate epimerizations. Despite the
higher reactivity of carbohydrate triflates protected with ether functionalities, these
compounds proved inefficient in these reactions, where mixtures of compounds were
rapidly obtained. Neighboring ester groups, on the other hand, could induce the formation
of inversion compounds in good yields. The reactions further demonstrated
stereospecificity, inasmuch as axially oriented neighboring ester groups were unproductive
27
and only equatorial ester groups induced the nucleophilic displacement reaction. These
findings expand the utility of this highly useful reaction in carbohydrate synthesis as well
as for other compound classes.
28
4 Synthesis of β-D-Mannosides and β-D-Talosides
4.1 Introduction
It has been demonstrated that a neighboring equatorial ester group plays a highly important
role in the Lattrell-Dax (nitrite-mediated) carbohydrate epimerization reaction, inducing
the formation of inversion compounds in good yields. These studies suggested that new,
efficient synthetic methods to complex glycosides would be feasible under the guidance of
this principle, where the activating ester groups should be able to control the inversion of
two neighboring positions simultaneously. Thus, we next attempted to meet the synthetic
challenges of β-D-mannoside synthesis.
In consequence to these synthetic challenges, several different synthetic methods have
been developed for β-mannoside synthesis. These include Koenigs-Knorr coupling
methods using insoluble silver salt promoters blocking the α-face of mannosyl halides,(6365)
sequential oxidation/reduction routes,(66-68) use of 2-oxo and 2-oximinoglycosyl
halides,(69, 70) use of intermolecular, (71-74) or intramolecular,(75-77) SN2 reactions and
intramolecular aglycon delivery method, (78-85) inversion of configuration of α-mannosyl
triflate donors,(86-88) epimerization of β-glucopyranosides to β-mannopyranosides through
SN2 reactions,(31, 49, 50, 89, 90) as well as enzymatic methods,(91-93) all of which with their
respective advantages and short-comings. The 1,2-cis-glycosidic linkage is present also in
β-D-talopyranosides. However interesting, recently evaluated for their intriguing Hbonding motifs, these structures have been less investigated in part due to their
cumbersome synthesis.(94-96)
Based on multiple regioselective acylation via the respective stannylene intermediates,
followed by the ester-activated inversion, novel and efficient methods to synthesizing β-Dmannopyranoside and β-D-talopyranoside derivatives can be designed.
4.2 Double Parallel Inversion
The glycoside derivatives 32, 34, 36, 37 and 39, which were synthesized by the one-pot
organotin multiple esterification strategy, were chosen as starting materials (Figure 14).
HO
OBz
BzO
BzO
OH
OBz
AcO
O
O
OMe BzO
32
OH
O
OMe AcO
34
OAc
OAc
OH
HO
OMe AcO
36
HO
O
OH
OAc
O
OMe AcO
37
OH
OMe
39
Figure 14. Glycosides obtained by organotin multiple esterification
The taloside derivatives can be acquired starting from 34 and 36 via the inversion of the 2position, or starting from 37 via the double parallel inversion of 2- and 4-positions, if the
equatorial ester group in the 3-position is able to activate the epimerization of the
neighboring 2- and 4-positions at the same time (Figure 15). On the other hand, the
29
mannoside derivatives can be acquired starting from 32 and 39 via the same double
parallel inversion strategy.
HO
O
OH
O
HO
OMe
O
R
OPG
i) Tf2O, Py, CH2Cl2
ii) KNO2, DMF
OPG
O
OMe
O
R
OH
O
Figure 15. Double parallel inversion.
In order to evaluate whether an equatorial ester group in the 3-position would be able to
activate the epimerization of the neighbouring 2- and 4-positions at the same time, a series
of inversion reactions was probed (Scheme 14). Galacto- and gluco-type derivatives 32, 37
and 39 where the 3- and 6-positions were protected with acetyl groups and the other two
positions left unprotected were subjected to conventional triflation by triflic anhydride
followed by treatment with tetrabutylammonium nitrite in acetonitrile or toluene at 50 oC.
In acetonitrile, when methyl 3,6-di-O-acetyl glucopyranoside 37 was used as reactant,
methyl 3,6-di-O-acetyl talopyranoside 47 was obtained in 85% yield. In contrast, the
double inversion of methyl 3,6-di-O-acetyl galactopyranoside 39 was not successful and a
very complex mixture was produced. It was hypothesized that this effect is likely due to
acetyl group migration and neighboring group participation from the 3-O-acetyl group. If
this explanation would be valid, the products produced would constitute an inversed-type
mixture, that is to say, only the free methyl β-D-talopyranoside would be obtained if the
inversed mixture was not isolated but directly deprotected under basic conditions. The
experimental results showed that only one compound was obtained following deprotection
of the complex mixture, indicating that this hypothesis was indeed valid.
HO
1. py, Tf2O,
CH2Cl2, 2h
OBz
O
BzO
OH
OMe
32
OAc
HO
AcO
HO
1. py, Tf2O,
CH2Cl2, 2h
O
OH
OMe
37
OAc
HO
OH
OMe
39
OAc
OH
2. TBANO2,
toluene, rt
5h
HO
AcO
1. py, Tf2O,
CH2Cl2, 2h
O
AcO
HO
OMe
39
OMe
46 70%
OAc
OH
O
OMe
47 85%
2. TBANO2,
AcO
CH3CN, 50 oC
5h
1. py, Tf2O,
CH2Cl2, 2h
O
AcO
HO
2. TBANO2,
BzO
CH3CN, 50 oC
5h
OBz
OH
O
2. TBAOAc,
CH3CN, rt
5h
AcO
AcO
OAc
OH
O
OMe
48 76%
OAc
OAc
O
OMe
49 90%
Scheme 14. Double parallel inversion reagent and conditions.
30
It is however well known that benzoyl groups are less reactive than acetyl counterparts to
migration, as well as for neighboring group participation. In addition, neighboring group
participation is disfavored in non-polar solvent.(24, 53) Thus, in order to avoid these side
reactions, both these approaches were tested. On the one hand, reactions with methyl
glucoside 37 and methyl galactoside 39 were performed in the non-polar solvent toluene;
on the other hand, the inversion of methyl 3,6-di-O-benzoyl galactopyranoside 32 was
attempted in acetonitrile. For comparison, the triflate of methyl galactoside 39 reacting
with tetrabutylammonium acetate in acetonitrile was also tested. When methyl glucoside
37 was inversed at 50 oC in toluene, the reaction time had to be prolonged to twelve hours
to obtain product 47 in 85% yield. This result indicates, as expected, that the reactivity was
decreased in non-polar solvent. In addition, both these approaches proved successful for
the double inversion of the methyl galactosides, efficiently reducing the neighboring group
participation.
4.3 Double Serial Inversion
During this epimerization process, it was found that the reactivity in the 4-position was
however much higher than in the 2-position. At room temperature, the epimerization
reaction in the 4-position occurred instantaneously, completed within ten to twenty
minutes, whereas in the 2-position the epimerization reaction proceeded very slowly under
these conditions. This result incited us to make use of the reactivity difference between the
different positions to develop a new method, stepwise inversion of the hydroxyl groups
amounting to a double serial inversion protocol, by which carbohydrate structures where
one position is a hydroxyl group and the other positions were protected with ester groups
could be obtained.
HO
OPG
O
O
R
i) Tf2O, Py, CH2Cl2
ii)TBAOAc, CH3CN
OH
O
OPG
O
O
O
AcO
O
R
OMe
OTf
O
HO
R
O
AcO
O
R
OMe
OH
OMe
O
HO
OMe
O
OPG
i) Tf2O, Py, CH2Cl2
ii) TBAOAc, CH3CN
OPG
R
OH
O
O
i) Tf2O, Py, CH2Cl2
ii)TBANO2, CH3CN
OMe
OPG
i) Tf2O, Py, CH2Cl2
ii) TBANO2, CH3CN
OPG
OTf
O
OAc
O
HO
O
R
OMe
O
Figure 16. Double serial inversion
Using the same initial step for the double serial inversion strategy, from methyl glucoside
37, the 2,4-triflate intermediates 50 could be produced via a triflation process (Scheme
15). The 4-triflates of these intermediates were subsequently inversed to the corresponding
4-O-acetyl intermediates 51 by substitution with tetrabutylammonium acetate, followed by
inversion of the 2-position by tetrabutylammonium nitrite, to yield a mixture of methyl
31
3,4,6-tri-O-acetyl taloside 53 and methyl 2,3,6-tri-O-acetyl taloside 54. Conversely, When
the 2,4-triflates of intermediates 50 were first inversed to the corresponding 4-hydroxyl
groups intermediates 52 via the use of tetrabutylammonium nitrite, directly followed by
inversion of the 2-position by tetrabutylammonium acetate, in this case, however, product
54 could not be formed, likely due to the steric effect of the nucleophilic reagent.
AcO
TBANO2,
CH3CN, 24h
OAc
AcO
O
AcO
OAc
HO
AcO
Tf2O, py,
CH2Cl2, 2h
O
OMe
OH
37
TfO
AcO
OAc
90%
O
OTf
50
OMe
90%
HO
OMe
OTf
51
TBAOAc,
toluene
OH
O
OMe
45%
AcO
90%
53
+
TBANO2,
CH3CN
OAc
HO
O
AcO
OAc
OMe
X
OAc
OAc
O
OMe
45%
AcO
OTf
52
54
Scheme 15. Double serial inversion from 37.
Starting from methyl glucoside 39, the 2,4-triflate intermediate 55 could be produced as
well (Scheme 16). The 4-triflate of this intermediate was subsequently inversed to the
corresponding 4-O-acetyl intermediates 56 by substitution with tetrabutylammonium
acetate, followed by inversion of the 2-position by tetrabutylammonium nitrite, to yield
methyl 3,4,6-tri-O-acetyl mannoside 58. When the intermediates 55 were first inversed to
the corresponding 4-hydroxyl groups intermediates 57 via the use of tetrabutylammonium
nitrite, directly followed by inversion of the 2-position by tetrabutylammonium acetate,
methyl 2,3,6-tri-O-acetyl mannoside 59 was efficiently produced.
OAc
AcO
AcO
HO
OAc
Tf2O, py,
CH2Cl2, 2h TfO
AcO
OMe
OH
39
OAc
O
O
AcO
O
OAc
TBANO2,
toluene, 6h
OMe
OTf
56
90% TBAOAc,
toluene
90%
AcO
AcO
OH
O
OMe
58
OMe
OTf
55
TBANO2,
90% CH3CN
OAc
HO
AcO
O
OMe
OTf
OAc
TBAOAc,
CH3CN, 6h
75%
HO
AcO
57
OAc
O
OMe
59
Scheme 16. Double serial inversion from 39.
In addition, due to the fact that methyl glucoside 3 was produced in a lower yield (70%)
than methyl galactoside 1 (90%), following the double serial inversion strategy, an
32
alternative, more high-yielding, synthetic route to methyl taloside could be devised starting
from methyl galactoside 1 instead of methyl glucoside 3. Thus, compound 39 acquired
from methyl galactoside 1 by organotin method, could be inversed to the intermediate 50
via intermediate 55 (Scheme 17). As a result, the use of methyl glucoside 2 could be
avoided and the overall yield increased.
OAc
HO
O
OMe
AcO
TfO
Tf2O, py,
CH2Cl2
OH
39
1. TBANO2,
CH3CN, 1h
TfO
OMe
AcO
OTf
2. Tf2O, py,
55
CH2Cl2
OAc
OAc
O
AcO
O
OMe
OTf
50
Scheme 17. Alternative double serial inversion strategy to intermediate 50
4.4 Remote Group Participation
When the inversion of intermediate 56 was performed in acetonitrile, a mixture of methyl
mannosides 58 (60%) and 60 (40%) was obtained due to the neighboring group
participation. Thus, to avoid neighboring participation, a high yield of methyl mannoside
58 could only be obtained in non-polar solvent. It is however more difficult to explain how
the mixture of methyl talosides 53 and 54 was generated. Changing the acetyl groups for
benzoyl groups proved inefficient, and the inversion of the 2-position of methyl 3,4,6-triO-benzoyl galactoside 34 in acetonitrile resulted in a mixture of methyl talosides 61 and
62.
OAc
AcO
AcO
AcO
O
a
OMe
OTf
56
OAc
AcO
O
AcO
BzO
b
OMe
OH
36
c,d
OH
c
HO
OMe +
OAc
OAc
O
OBz
OH
O
BzO
OAc
OAc
O
OMe
61
34
54
BzO
60
40
b
53(%)
50
54 (%)
50
c
d
45
52
55
48
60
AcO
HO
OMe +
58 (%) 60(%)
OMe
53
b
OMe
AcO
OMe + HO
58
OAc
OH
O
AcO
BzO
OBz
O
BzO
AcO
AcO
OAc
OH
O
OBz
OBz
O
61 (%) 62(%)
OMe
62
b
80
20
c
40
60
NMR-yields.
(a) i: TBANO2, CH3CN, 50 oC, 6h.
(b) i: Tf2O, py, CH2Cl2, ii: TBANO2, CH3CN, 50 oC, 30h.
(c) i: Tf2O, py, CH2Cl2, ii: TBANO2, DMF, 50 oC, 20h.
(d) i: Tf2O, py, CH2Cl2, ii: TBAOAc, CH3CN, 50 oC, 30h.
Scheme 18. Epimerization by neighboring and remote group participation.
In order to further analyze this reaction, methyl 3,4,6-tri-O-benzoyl galactoside 34 and
methyl 3,4,6-tri-O-acetyl galactoside 36 was tested in the more polar solvent DMF. The
33
experimental results indicate that the formation of methyl talosides 53 and 61, where the
hydroxyl group in the 2-position is unprotected, were more favored in non-polar solvent
(50%, 80%) and less favored in polar solvent (45%, 40%), whereas the formation of
methyl talosides 54 and 62, where the hydroxyl group in 4-position is free, were more
favored in polar solvent (55%, 60%) and less favored in non-polar solvent (50%, 20%). As
a comparison, starting from intermediate 50, it was expected that the fully protected
methyl taloside would be produced via the use of five equivalents of tetrabutylammonium
acetate. However, the same mixture of methyl talosides 53 (52%) and 54 (48%) was
produced.
All of these results support a 4-position participation mechanism, where a six-membered
ring is generated first, and then opened by trace water to produce either a free 4-hydroxyl
group or a free 2-hydroxyl group in a reaction that is favored by polar solvents (Figure
17). The direct nitrite competition reaction resulted in that the 2-hydroxyl group products
(53, 61) were favored in less polar solvents. In combination with the steric effects of the
nucleophilic reagent, this also explains why a mixture of methyl talosides 53 and 54 were
primarily obtained when tetrabutylammonium acetate was employed as a nucleophilic
reagent.
AcO
AcO
O
OAc
O
O
OMe
AcO
AcO
O
O
OTf
O
H2 O
OMe
AcO
OH
O
OMe
AcO
OTf
51
HO
OAc
AcO
OAc
O
OMe
AcO
+
OAc
OH
O
OMe
AcO
54
53
Figure 17. Remote group participation.
To further support this mechanism, the triflate of methyl taloside 36 was directly tested in
wet acetonitrile at 50 oC for 20 hours. As a result, a complex mixture was obtained, not
only including methyl talosides 53 and 54. However, these experimental results also
showed that the nucleophilic reagent tetrabutylammonium nitrite/acetate play an important
role for the remote group participation. The test for neighboring group participation of
intermediate 56 also supported this result. When the intermediate 56 was directly subjected
to reaction in wet acetonitrile at 50 oC for 20 hours, a very low conversion was recorded;
whereas with two equivalents of tetrabutylammonium nitrite, talosides 58 and 60 were
obtained in 60% and 40% yield during the same reaction time. The experimental results
indicate that not only the neighboring ester group can activate the nitrite-mediate
epimerization but also suggest that the nitrite ion can activate the neighbouring or remote
group participation.
34
4.5 Conclusion
In conclusion, novel and convenient double parallel- and double serial inversion methods
have been developed, by which methyl β-D-mannosides and methyl β-D-talosides have
been efficiently synthesized in very high yields at very mild conditions in few steps. By
use of the reactivity difference of the hydroxyl groups or the neighboring/remote group
participation between the 2- and 3-position / 2- and 4-positions, a range of methyl β-Dmannoside and methyl β-D-taloside derivatives could be easily synthesized. It was found
that not only the neighboring ester group can active the nitrite-mediate epimerization but
also that the nitrite ion can activate the neighboring or remote group participation. The
results also indicate that an ester group can, either in parallel or serially, induce its two
neighboring groups in the epimerization reaction.
35
36
5 General Conclusions
The effects of neighboring group on Lattrell-Dax epimerization have been explored. Based
on this effect, efficient synthetic routes to β-D-mannosides and β-D-talosides, from the
corresponding β-D-galactosides and β-D-glucosides, have been designed. During this
research, reagent-dependent regioselective organotin multiple carbohydrate esterifications
were also developed.
•
•
•
•
It has been demonstrated that organotin-mediated multiple carbohydrate
esterifications can be controlled by the acylating reagent and the solvent polarity.
When acetyl chloride is used, the reactions are under thermodynamic control,
whereas when acetic anhydride is employed, kinetic control takes place. Very
good selectivity can furthermore be obtained in more polar solvents. These results
can be used in the efficient preparation of prototype carbohydrate structures.
It has been demonstrated that a neighboring ester group was essential for the
reactivity of the Lattrell-Dax nitrite-mediated triflate inversion. Furthermore, a
good inversion yield also depended on the relative configuration of the
neighboring ester group to the triflate. Only with the ester group in the equatorial
position, whatever the configuration of the triflate, did the reaction proceed
smoothly, whereas a neighboring axial ester group proved largely inefficient.
Based on the efficient multiple carbohydrate esterifications and Lattrell-Dax
carbohydrate epimerization, novel and convenient double parallel- and double
serial inversion methods have been developed, by which methyl β-D-mannosides
and methyl β-D-talosides have been efficiently synthesized in very high yields at
very mild conditions in few steps. The results also indicate that an ester group
can, either in parallel or serially, induce its two neighboring groups in the
epimerization reaction.
It was found that neighboring group- or remote group participation could easily
take place if a five-membered or six-membered ring is generated between the
neighboring or remote ester group and the carbon atom carrying the triflate group
in more polar solvent. Further, not only the neighboring ester group can active the
nitrite-mediate epimerization but the nitrite ion can also activate the neighboring
or remote group participation.
37
38
Acknowledgements
I owe my sincere gratitude to:
My supervisor Doc Olof Ramström for accepting me as a PhD-student, for your inspiring
guidance and for your patience whenever I want to discuss with you.
My co-workers in the Ramström group: A special thanks to Zhichao Pei and Rikard
Larsson for helping me during my first time at the department. Marcus Angelin, Pornrapee
Vongvilai, Remi Caraballo, Gunnar Duner, Oscar Norberg, Alexandra Martinsson for
being good friends, for pleasant times in the lab and for spreading a nice atmosphere
throughout the group, and all past and present group-members.
Everyone at the chemistry deparment for a friendly and pleasant working atmosphere.
The Swedish Research Council (VR), the Swedish Foundation for International
Cooperation in Research and Higher Education, the Carl Trygger Foundation, the AulinErdtman foundation, Knut och Alice Wallenbergs Stiftelse, and Ragnar och Astrid
Signeuls for financial support.
39
Appendix
The following is a description of my contributions to papers I-IV.
Paper I: I performed labwork and wrote parts of the article.
Paper II: I performed labwork and wrote the article.
Paper III: I performed labwork and wrote the article.
Paper IV: I performed labwork and wrote the article.
40
Reference
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Bertozzi, C. R.; Kiessling, L. L., Chemical glycobiology. Science 2001, 291, 23572364.
Lis, H.; Sharon, N., Lectins: Carbohydrate-specific proteins that mediate cellular
recognition. Chem. Rev. 1998, 98, 637-674.
Smith, E. A.; Thomas, W. D.; Kiessling, L. L.; Corn, R. M., Surface plasmon
resonance imaging studies of protein-carbohydrate interactions. J. Am. Chem. Soc.
2003, 125, 6140-6148.
Vicens, Q.; Westhof, E., Molecular recognition of aminoglycoside antibiotics by
ribosomal RNA and resistance enzymes: An analysis of x-ray crystal structures.
Biopolymers 2003, 70, 42-57.
Schofield, L.; Hewitt, M. C.; Evans, K.; Siomos, M. A.; Seeberger, P. H., Synthetic
GPI as a candidate anti-toxic vaccine in a model of malaria. Nature 2002, 418, 785789.
Lindhorst, T. K., Essentials of Carbohydrate Chemistry and Biochemistry. WileyVCH: Weinheim, 2000.
Dwek, R. A., Glycobiology: Toward understanding the function of sugars. Chem. Rev.
1996, 96, 683-720.
Kornfeld, R.; Kornfeld, S., Assembly of Asparagine-Linked Oligosaccharides. Annu.
Rev. Biochem. 1985, 54, 631-664.
Crich, D.; Banerjee, A.; Yao, Q. J., Direct chemical synthesis of the beta-D-mannans:
The beta-(1 -> 2) end beta-(1 -> 4) series. J. Am. Chem. Soc. 2004, 126, 14930-14934.
Bundle, D. R.; Rich, J. R.; Jacques, S.; Yu, H. N.; Nitz, M.; Ling, C. C.,
Thiooligosaccharide conjugate vaccines evoke antibodies specific for native antigens.
Angew. Chem. Int. Ed. 2005, 44, 7725-7729.
Tatsuta, K.; Yasuda, S., Total synthesis of deacetyl-caloporoside, a novel inhibitor of
the GABA(A) receptor ion channel. Tetrahedron Lett. 1996, 37, 2453-2456.
Wu, X. Y.; Bundle, D. R., Synthesis of glycoconjugate vaccines for Candida albicans
using novel linker methodology. J. Org. Chem. 2005, 70, 7381-7388.
Rich, J. R.; Bundle, D. R., S-linked ganglioside analogues for use in conjugate
vaccines. Org. Lett. 2004, 6, 897-900.
Rye, C. S.; Withers, S. G., The synthesis of a novel thio-linked disaccharide of
chondroitin as a potential inhibitor of polysaccharide lyases. Carbohydr. Res. 2004,
339, 699-703.
Zhu, X. M.; Stolz, F.; Schmidt, R. R., Synthesis of thioglycoside-based UDP-sugar
analogues. J. Org. Chem. 2004, 69, 7367-7370.
Liakatos, A.; Kiefel, M. J.; von Itzstein, M., Synthesis of lactose-based S-linked
sialylmimetics of alpha(2,3)-sialosides. Org. Lett. 2003, 5, 4365-4368.
Knapp, S.; Myers, D. S., Synthesis of alpha-GalNAc thioconjugates from an alphaGalNAc mercaptan. J. Org. Chem. 2002, 67, 2995-2999.
Marcaurelle, L. A.; Bertozzi, C. R., Chemoselective elaboration of O-linked
glycopeptide mimetics by alkylation of 3-ThioGalNAc. J. Am. Chem. Soc. 2001, 123,
1587-1595.
41
19. Crich, D.; Li, H. M., Direct stereoselective synthesis of beta-thiomannoside. J. Org.
Chem. 2000, 65, 801-805.
20. Driguez, H., Thiooligosaccharides as tools for structural biology. ChemBioChem 2001,
2, 311-318.
21. Witczak, Z. J.; Chhabra, R.; Chen, H.; Xie, X. Q., Thiosugars.2. A novel approach to
thiodisaccharides - The synthesis of 3-deoxy-4-thiocellobiose from levoglucosenone.
Carbohydr. Res. 1997, 301, 167-175.
22. Fan, L. F.; Hindsgaul, O., Synthesis of novel cyclic oligosaccharides: beta-1,6-thiolinked cycloglucopyranosides. Org. Lett. 2002, 4, 4503-4506.
23. Bundle, D. R.; Rich, J. R.; Jacques, S.; Yu, H. N.; Nitz, M.; Ling, C. C.,
Thiooligosaccharide conjugate vaccines evoke antibodies specific for native antigens.
Angew. Chem. Int. Edit. 2005, 44, 7725-7729.
24. Pei, Z. C.; Dong, H.; Ramstrom, O., Solvent-dependent, kinetically controlled
stereoselective synthesis of 3-and 4-thioglycosides. J. Org. Chem. 2005, 70, 69526955.
25. Weinges, K.; Haremsa, S.; Maurer, W., The Mitsunobu Reaction on Methyl
Glycosides as Alcohol Component. Carbohydr. Res. 1987, 164, 453-458.
26. Chang, C. W. T.; Hui, Y.; Elchert, B., Studies of the stereoselective reduction of
ketosugar (hexosulose). Tetrahedron Lett. 2001, 42, 7019-7023.
27. Samuel, J.; Tanner, M. E., Mechanistic aspects of enzymatic carbohydrate
epimerization. Nat. Prod. Rep. 2002, 19, 261-277.
28. Lattrell, R. L., G., Justus Liebigs Ann. Chem. 1974, 901-920.
29. Albert, R.; Dax, K.; Link, R. W.; Stutz, A. E., Carbohydrate Triflates - Reaction with
Nitrite, Leading Directly to Epi-Hydroxy Compounds. Carbohydr. Res. 1983, 118,
C5-C6.
30. Trost, B. M.; Yang, H. B.; Probst, G. D., A formal synthesis of (-)-mycalamide A. J.
Am. Chem. Soc. 2004, 126, 48-49.
31. Abdel-Rahman, A. A. H.; Jonke, S.; El Ashry, E. S. H.; Schmidt, R. R.,
Stereoselective synthesis of beta-D-mannopyranosides with reactive mannopyranosyl
donors possessing a neighboring electron-withdrawing group. Angew. Chem. Int. Ed.
2002, 41, 2972-2974.
32. Hoffmann, H. M. R.; Dunkel, R.; Mentzel, M.; Reuter, H.; Stark, C. B. W., The total
synthesis of C-glycosides with completely resolved seven-carbon backbone polyol
stereochemistry: Stereochemical correlations and access to L-configured and other
rare carbohydrates. Chem. Eur. J. 2001, 7, 4771-4789.
33. Binkley, R. W., Inversion of Configuration in 2,6-Dideoxy Sugars - Triflate
Displacement by Benzoate and Nitrite Anions. J. Org. Chem. 1991, 56, 3892-3896.
34. Kattnig, E.; Albert, M., Counterion-directed regioselective acetylation of octyl beta-Dglucopyranoside. Org. Lett. 2004, 6, 945-948.
35. Kurahashi, T.; Mizutani, T.; Yoshida, J., Effect of intramolecular hydrogen-bonding
network on the relative reactivities of carbohydrate OH groups. J. Chem. Soc. Perkin
Trans. 1 1999, 465-473.
36. Graziani, A.; Passacantilli, P.; Piancatelli, G.; Tani, S., A mild and efficient approach
for the regioselective silyl-mediated protection-deprotection of C-4 hydroxyl group on
carbohydrates. Tetrahedron Lett. 2001, 42, 3857-3860.
42
37. Mukhopadhyay, B.; Field, R. A., A simple one-pot method for the synthesis of
partially protected mono- and disaccharide building blocks using an
orthoesterification-benzylation-orthoester rearrangement approach. Carbohydr. Res.
2003, 338, 2149-2152.
38. David, S.; Hanessian, S., Regioselective Manipulation of Hydroxyl-Groups Via
Organotin Derivatives. Tetrahedron 1985, 41, 643-663.
39. Takeo, K.; Shibata, K., Regioselective Alkylation, Benzoylation, and Para-Toluene
Sulfonylation of Methyl 4,6-O-Benzylidene-Beta-D-Glucopyranoside. Carbohydr.
Res. 1984, 133, 147-151.
40. Iwasaki, F.; Maki, T.; Onomura, O.; Nakashima, W.; Matsumura, Y., Chemo- and
stereoselective monobenzoylation of 1,2-diols catalyzed by organotin compounds. J.
Org. Chem. 2000, 65, 996-1002.
41. Reginato, G.; Ricci, A.; Roelens, S.; Scapecchi, S., Group 14 Organometallic
Reagents.9. Organotin-Mediated Monoacylation of Diols with Reversed
Chemoselectivity - a Convenient Synthetic Method. J. Org. Chem. 1990, 55, 51325139.
42. Peri, F.; Cipolla, L.; Nicotra, F., Tin-mediated regioselective acylation of unprotected
sugars on solid phase. Tetrahedron Lett. 2000, 41, 8587-8590.
43. Srivastava, V. K.; Schuerch, C., Synthesis of Beta-Deuterium Mannopyranosides and
Regioselective Ortho-Alkylation of Dibutylstannylene Complexes. Tetrahedron Lett.
1979, 3269-3272.
44. Jenkins, D. J.; Potter, B. V. L., On the Selectivity of Stannylene-Mediated Alkylation
and Esterification of Methyl 4,6-O-Benzylidene Alpha-D-Glucopyranoside.
Carbohydr. Res. 1994, 265, 145-149.
45. Ballell, L.; Joosten, J. A. F.; el Maate, F. A.; Liskamp, R. M. J.; Pieters, R. J.,
Microwave-assisted, tin-mediated, regioselective 3-O-alkylation of galactosides.
Tetrahedron Lett. 2004, 45, 6685-6687.
46. Glen, A.; Leigh, D. A.; Martin, R. P.; Smart, J. P.; Truscello, A. M., The
Regioselective Tert-Butyldimethylsilylation of the 6'-Hydroxyl Group of Lactose
Derivatives Via Their Dibutylstannylene Acetals. Carbohydr. Res. 1993, 248, 365-369.
47. Martinelli, M. J.; Vaidyanathan, R.; Van Khau, V., Selective monosulfonylation of
internal 1,2-diols catalyzed by di-n-butyltin oxide. Tetrahedron Lett. 2000, 41, 37733776.
48. Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.;
Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Van Khau, V.; Kosmrlj, B., Catalytic
regioselective sulfonylation of alpha-chelatable alcohols: Scope and mechanistic
insight. J. Am. Chem. Soc. 2002, 124, 3578-3585.
49. Hodosi, G.; Kovac, P., A fundamentally new, simple, stereospecific synthesis of
oligosaccharides containing the beta-mannopyranosyl and beta-rhamnopyranosyl
linkage. J. Am. Chem. Soc. 1997, 119, 2335-2336.
50. Hodosi, G.; Kovac, P., Manipulation of free carbohydrates via stannylene acetals.
Preparation of beta-per-O-acyl derivatives of D-mannose, L-rhamnose, 6-O-trityl-Dtalose, and D-lyxose. Carbohydr. Res. 1997, 303, 239-243.
51. Hodosi, G.; Kovac, P., Glycosylation via locked anomeric configuration:
stereospecific synthesis of oligosaccharides containing the beta-D-mannopyranosyl
and beta-L-rhamnopyranosyl linkage. Carbohydr. Res. 1998, 308, 63-75.
43
52. Zhang, Z. Y.; Wong, C. H., Regioselective benzoylation of sugars mediated by
excessive Bu2SnO: observation of temperature promoted migration. Tetrahedron
2002, 58, 6513-6519.
53. Dong, H.; Pei, Z. C.; Ramström, O., Stereospecific ester activation in nitrite-mediated
carbohydrate epimerization. J. Org. Chem. 2006, 71, 3306-3309.
54. Yu, H.; Ensley, H. E., An efficient method for the preparation of glycosides with a
free C-2 hydroxyl group from thioglycosides. Tetrahedron Lett. 2003, 44, 9363-9366.
55. Bredenkamp, M. W.; Spies, H. S. C., Tin-mediated equilibration of the benzoate esters
of methyl 4,6-O-benzylidene-alpha-D-glucopyranoside. Tetrahedron Lett. 2000, 41,
543-546.
56. Roelens, S., Organotin-mediated monoacylation of diols with reversed
chemoselectivity. Mechanism and selectivity. J. Org. Chem. 1996, 61, 5257-5263.
57. Bredenkamp, M. W.; Spies, H. S. C.; van der Merwe, M. J., Structure elucidation of
the dibutylchlorostannyl intermediate during dibutyltin oxide-mediated acylation of
sugars. Tetrahedron Lett. 2000, 41, 547-550.
58. David, S.; Thieffry, A.; Forchioni, A., Sn-119 Nuclear Magnetic-Resonance and
Mass-Spectrometric Studies of the Stannylenes of Chiral and Achiral Diols - an
Interpretation of Their Regiospecific Activation. Tetrahedron Lett. 1981, 22, 26472650.
59. Anslyn, E. V.; Dougherty, D. A., Modern Physical Organic Chemistry. University
Science Books: Sausalito, CA, 2006; pp 659-660; p 659-660.
60. Winstein, S.; Grunwald, E.; Ingraham, L. L., J. Am. Chem. Soc. 1948, 70, 821-828.
61. Kassou, M.; Castillon, S., Ring Contraction Vs Fragmentation in the Intramolecular
Reactions of 3-O-(Trifluoromethanesulfonyl) Pyranosides - Efficient Synthesis of
Branched-Chain Furanosides. J. Org. Chem. 1995, 60, 4353-4358.
62. ElNemr, A.; Tsuchiya, T., alpha-Hydrogen elimination in some 3- and 4-triflates of
alpha-D-glycopyranosides. Carbohydr. Res. 1997, 301, 77-87.
63. Grice, P.; Ley, S. V.; Pietruszka, J.; Osborn, H. M. I.; Priepke, H. W. M.; Warriner, S.
L., A new strategy for oligosaccharide assembly exploiting cyclohexane-1,2-diacetal
methodology: An efficient synthesis of a high mannose type nonasaccharide. Chem.
Eur. J. 1997, 3, 431-440.
64. Matsuo, I.; Nakahara, Y.; Ito, Y.; Nukada, T.; Nakahara, Y.; Ogawa, T., Synthesis of a
Glycopeptide Carrying a N-Linked Core Pentasaccharide. Bioorg. Med. Chem. 1995,
3, 1455-1463.
65. Jain, R. K.; Matta, K. L., Chemical synthesis of a hexasaccharide comprising the
Lewis(x) determinant linked beta-(1->6) to a linear trimannosyl core and the precursor
pentasaccharide lacking fucose. Carbohydr. Res. 1996, 282, 101-111.
66. Kerekgyarto, J.; Vanderven, J. G. M.; Kamerling, J. P.; Liptak, A.; Vliegenthart, J. F.
G., Synthesis of a Selectively Protected Trisaccharide Building Block That Is Part of
Xylose-Containing Carbohydrate Chains from N-Glycoproteins. Carbohydr. Res.
1993, 238, 135-145.
67. Liu, K. K. C.; Danishefsky, S. J., Route from Glycals to Mannose Beta-Glycosides. J.
Org. Chem. 1994, 59, 1892-1894.
68. Danishefsky, S. J.; Hu, S.; Cirillo, P. F.; Eckhardt, M.; Seeberger, P. H., A highly
convergent total synthetic route to glycopeptides carrying a high-mannose core
44
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
pentasaccharide domain N-linked to a natural peptide motif. Chem. Eur. J. 1997, 3,
1617-1628.
Lichtenthaler, F. W.; Schneideradams, T., 3,4,6-Tri-O-Benzyl-Alpha-D-ArabinoHexopyranos-2-Ulosyl Bromide - a Versatile Glycosyl Donor for the Efficient
Generation of Beta-D-Mannopyranosidic Linkages. J. Org. Chem. 1994, 59, 67286734.
Cipolla, L.; Lay, L.; Nicotra, F., New and easy access to C-glycosides of glucosamine
and mannosamine. J. Org. Chem. 1997, 62, 6678-6681.
Sato, K.; Yoshitomo, A., A Novel Method for Constructions of Beta-D-Mannosidic,
2-Acetamido-2-Deoxy-Beta-D-Mannosidic, and 2-Deoxy-Beta-D-ArabinaHexopyranosidic Units from the Bis(Triflate) Derivative of Beta-D-Galactoside. Chem.
Lett. 1995, 39-40.
Matsuo, I.; Isomura, M.; Walton, R.; Ajisaka, K., A new strategy for the synthesis of
the core trisaccharide of asparagine-linked sugar chains. Tetrahedron Lett. 1996, 37,
8795-8798.
Furstner, A.; Konetzki, I., A practical synthesis of beta-D-mannopyranosides.
Tetrahedron Lett. 1998, 39, 5721-5724.
Weiler, S.; Schmidt, R. R., A versatile strategy for the synthesis of complex type Nglycans: Synthesis of diantennary and bisected diantennary oligosaccharides.
Tetrahedron Lett. 1998, 39, 2299-2302.
Unverzagt, C., Synthesis of a Biantennary Heptasaccharide by Regioselective
Glycosylations. Angew. Chem. Int. Ed. 1994, 33, 1102-1104.
Seifert, J.; Unverzagt, C., Synthesis of a core-fucosylated, biantennary octasaccharide
as a precursor for glycopeptides of complex N-glycans. Tetrahedron Lett. 1996, 37,
6527-6530.
Unverzagt, C., Chemoenzymatic synthesis of a sialylated undecasaccharide-asparagine
conjugate. Angew. Chem. Int. Ed. 1996, 35, 2350-2353.
Stork, G.; LaClair, J. J., Stereoselective synthesis of beta-mannopyranosides via the
temporary silicon connection method. J. Am. Chem. Soc. 1996, 118, 247-248.
Dan, A.; Ito, Y.; Ogawa, T., Stereocontrolled Synthesis of the Pentasaccharide Core
Structure of Asparagine-Linked Glycoprotein Oligosaccharide Based on a Highly
Convergent Strategy. Tetrahedron Lett. 1995, 36, 7487-7490.
Dan, A.; Ito, Y.; Ogawa, T., A Convergent and Stereocontrolled Synthetic Route to
the Core Pentasaccharide Structure of Asparagine-Linked Glycoproteins. J. Org.
Chem. 1995, 60, 4680-4681.
Dan, A.; Lergenmuller, M.; Amano, M.; Nakahara, Y.; Ogawa, T.; Ito, Y., pMethoxybenzylidene-tethered beta-mannosylation for stereoselective synthesis of
asparagine-linked glycan chains. Chem. Eur. J. 1998, 4, 2182-2190.
Ito, Y.; Ogawa, T., Intramolecular aglycon delivery on polymer support: Gatekeeper
monitored glycosylation. J. Am. Chem. Soc. 1997, 119, 5562-5566.
Lergenmuller, M.; Nukada, T.; Kuramochi, K.; Dan, A.; Ogawa, T.; Ito, Y., On the
stereochemistry of tethered intermediates in p-methoxybenzyl-assisted betamannosylation. Eur. J. Org. Chem. 1999, 1367-1376.
Barresi, F.; Hindsgaul, O., Synthesis of Beta-Mannopyranosides by Intramolecular
Aglycon Delivery. J. Am. Chem. Soc. 1991, 113, 9376-9377.
45
85. Ziegler, T.; Lemanski, G., Prearranged glycosides. Part 7. Synthesis of betamannosides via prearranged glycosides. Angew. Chem. Int. Ed. 1998, 37, 3129-3132.
86. Crich, D.; Sun, S. X., Formation of beta-mannopyranosides of primary alcohols using
the sulfoxide method. J. Org. Chem. 1996, 61, 4506-4507.
87. Crich, D.; Sun, S. X., Are glycosyl triflates intermediates in the sulfoxide
glycosylation method? A chemical and H-1, C-13, and F-19 NMR spectroscopic
investigation. J. Am. Chem. Soc. 1997, 119, 11217-11223.
88. Crich, D.; Sun, S. X., Direct formation of beta-mannopyranosides and other hindered
glycosides from thioglycosides. J. Am. Chem. Soc. 1998, 120, 435-436.
89. Nicolaou, K. C.; vanDelft, F. L.; Conley, S. R.; Mitchell, H. J.; Jin, Z.; Rodriguez, R.
M., New synthetic technology for the stereocontrolled construction of 1,1'disaccharides and 1,1':1'',2-trisaccharides. Synthesis of the FG ring system of
everninomicin 13,384-1. J. Am. Chem. Soc. 1997, 119, 9057-9058.
90. Abdel-Rahman, A. A. H.; Jonke, S.; El Ashry, E. S. H.; Schmidt, R. R.,
Stereoselective synthesis of beta-D-mannopyranosides with reactive mannopyranosyl
donors possessing a neighboring electron-withdrawing group. Angew. Chem. Int. Ed.
2004, 43, 4389-4389.
91. Wong, C. H.; Halcomb, R. L.; Ichikawa, Y.; Kajimoto, T., Enzymes in OrganicSynthesis - Application to the Problems of Carbohydrate-Recognition.1. Angew. Chem.
Int. Ed. 1995, 34, 412-432.
92. Singh, S.; Scigelova, M.; Crout, D. H. G., Glycosidase-catalysed synthesis of
oligosaccharides: A two-step synthesis of the core trisaccharide of N-linked
glycoproteins using the beta-N-acetylhexosaminidase and the beta-mannosidase from
Aspergillus oryzae. Chem. Commun. 1996, 993-994.
93. Watt, G. M.; Revers, L.; Webberley, M. C.; Wilson, I. B. H.; Flitsch, S. L., Efficient
enzymatic synthesis of the core trisaccharide of N-glycans with a recombinant betamannosyltransferase. Angew. Chem. Int. Ed. 1997, 36, 2354-2356.
94. Vicente, V.; Martin, J.; Jimenez-Barbero, J.; Chiara, J. L.; Vicent, C., Hydrogenbonding cooperativity: Using an intramolecular hydrogen bond to design a
carbohydrate derivative with a cooperative hydrogen-bond donor centre. Chem. Eur. J.
2004, 10, 4240-4251.
95. Ivanova, I. A.; Nikolaev, A. V., Synthesis of beta-D-talopyranosides and beta-Dmannopyranosides via intramolecular nucleophilic substitution. J. Chem. Soc. Perkin
Trans. 1 1998, 3093-3099.
96. Knapp, S.; Kukkola, P. J.; Sharma, S.; Dhar, T. G. M.; Naughton, A. B. J., Amino
Alcohol and Amino Sugar Synthesis by Benzoylcarbamate Cyclization. J. Org. Chem.
1990, 55, 5700-5710.
46