-
Efficient Carbohydrate Synthesis by Controlled Inversion
Strategies
Hai Dong
Licentiate Thesis Stockholm 2006
Akademisk avhandling som med tillstnd av Kungliga Tekniska
Hgskolan i Stockholm framlgges till offentlig granskning fr
avlggande av licentiatexamen i organisk kemi, torsdagen den 30 nov,
kl 10.00 i sal E2, KTH, Osquars backe 14, Stockholm. Avhandlingen
frsvaras p engelska.
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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 -D-mannosides and -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
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List of publications
I. Solvent-Dependent, Kinetically Controlled Stereoselective
Synthesis of 3- and 4-Thioglycosides Zhichao Pei, Hai Dong and Olof
Ramstrm J. Org. Chem. 2005, 70, 6952-6955
II. Stereospecific Ester Activation in Nitrite-Mediated
Carbo-
hydrate Epimerization Hai Dong, Zhichao Pei and Olof Ramstrm J.
Org. Chem. 2006, 71, 3306-3309
III. Reagent-Dependent Regioselective Control in Multiple
Carbohydrate Esterifications Hai Dong, Zhichao Pei, Styrbjrn
Bystrm and Olof Ramstrm Manuscript
IV. Efficient Synthesis of -D-Mannosides and -D-Talosides by
Double Parallel or Double Serial Inversion Hai Dong, Zhichao
Pei, Marcus Angelin, Styrbjrn Bystrm and Olof Ramstrm
Manuscript
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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 -D-Mannosides and -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
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Abbreviations Ac Acetyl groupAcCl Acetic chloride Ac2O Acetic
anhydride aq aqueous Bn Benzyl group BnBr Benzyl bromide Bz Benzoyl
group BzCl Benzoyl chloride Bu2SnO Dibutyltin oxide DMF
Dimethylformamide equiv. equivalent Gal Galactoside Glc Glucoside h
hour Man Mannoside NGP Neighboring group participation NMR Nuclear
magnetic resonance rt room temperature T Temperature Tal Taloside
TBA Tetrabutylamonium TEA Triethylamine Tf2O trifluoroacetic
anhydride py. pyridine
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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 protein-carbohydrate 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.
OO
OHHO
HOOH
OH
HN
O
glycolipid (galactosyl cerebroside)
OO
OHHO
HO
O
O
OHHO
H3C OH
R
blood group antigen H
O
O
OHHO
OAcHN
CH3
NH
O
glycoprotein (O-glycosidic) Figure 1. Natural carbohydrate
containing entities.(6)
One important case is -mannoside synthesis. The
-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,
-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 -mannosidic linkage is strongly favored
because of the concomitant occurrence of both the -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 -mannosides
only.
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OO
O
HOO
OH
OO
OH
HONAc
OOH
HONAc
OHO
HOHO
OH
O
OH
HOHO
OH
N-linked pentasaccharide core structure
OO
OH
HOHO
OH
OR
HOOOH
OH OH
Fungal metabolite deacetyl-caloporoside
OOR
OH
HOHO
OH
-D-Manp Figure 2. Natural entities containing -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)
OS
HOHO
HO
OH
OHO
HOHO
OHO
HOHO
O
OHO
HOHO
O
partial structure of the cell wall phosphomannan antigenmodified
by a sulfur atom
OSH
HOHO
HOOH
1-thio--D glucose
O
S
HOHO
OH
O OHOH
HO
O
S
S
OHOH
OH
OS
HOOH
HO
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
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3-thio-galactoside 2 or the 4-thio-galactoside 4, it was thus
necessary to choose reasonable protection strategies and
epimerization routes.
OOMe
OHHO
HOOH 1
OOMe
ORRO
HOOR
OOMe
ORRO
OHOR
OOMe
ORRO
AcSOR
OOMe
OHHO
HSOH 2
OOMe
OH
OH
HOHO 3
OOMe
OHHS
HOOH 4
OOMe
OR
OR
HORO
OOMe
ORAcS
ROOR
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
OOMe
ORRO
HOOR
OOMe
ORRO
OHOR
1. py, Tf2O, CH2Cl22. KNO2, DMF
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
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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--D-arabino-hexopyranosides 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
OMeBzO
TfO
OOMe
HO
OBz
OOMe
BzOTfO
OOMe
BzO
OH
OOMe
BzO
TfO
OOMe
BzO
OH
H2O
nitritetoluene
toluenenitrite
neighboring groupparticipation
Fast
Slow
CHCl3
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 -(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.
OOR
O
TfOOBz
OPh
OOR
O
OHOBz
OPh
OOR
O
TfOOBn
OPh
failed
nitriteDMF
nitriteDMF
Figure 7. Effect of the neighboring groups on the inversion
reaction.(16)
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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).
OOMe
OAcAcO
OAcOTf
OOMe
OAcO
OAcO
OOMe
OAcAcO
AcSOAc
OOMe
OAcAcO
HOOAc
OOMe
OAcAcO
OAcSAc
5
7
9
6
8
a
a
b
H3C
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
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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).
OOMe
O
HOOBn
OPh
OOMe
OAcAcO
HOOAc
OOMe
OBzBzO
HOOBz
OOMe
OBzHO
BzOOBz
OOMe
OBnHO
BnOOBn
OOMe
OOBzO
OH
PhO
OMe
OOBnO
OH
Ph
OOMe
OBn
HOBnO
OBn
8
10 11
12 13
14 16 17
OOMe
OBz
HOBzO
OBz 15 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.
OOMe
OBnAcO
HOOBn 18
OOMe
OBn
AcOHO
OBn 20
OOMe
OBn
HOAcO
OBn
OOMe
OBn
AcO
OHOBn 22
21
OOMe
OBnHO
AcOOBn 19
OOMe
OBn
HO
OAcOBn 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 6-positions
and to isolate the effects arising from ester groups in the 3- and
4-positions, the
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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.
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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).
OOMe
OHHO
HOOH 1
OOMe
OBzHO
BzOOBz 14
BzClpy, CH2Cl2 -40 oC
60% 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-O-benzylidene-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-
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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 2-position with a benzyl
group via the general benzylation method, and finally the
p-methyl-benzyl group in the 3-position was removed by
oxidation.
OOMe
OHHO
HOOH 1
OOMe
O
HOOH
OPh
24
OOMe
O
HOOBn
OPh
13
PhCH(OMe)2DMF, H
BnBr, NaHDMF30%
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.
PhCH(OMe)2DMF, H
BnBr, NaHDMF
OOMe
OH
HOHO
OH 3
OOMe
OOHO
OH
Ph
25
OOMe
OOBnO
OBn
Ph
26
OOMe
OBn
HOBnO
OBn 17
Et3SiH,CF3CO2HCH2Cl2
1.Bu2SnO, MeOH2.BnBr, TBAI
OOMe
OOBnO
OH
Ph
11
toluene
90%
80%50%
Scheme 3. Synthesis of compounds 11 and 17.
When the above reaction mixture containing 25 was directly
benzylated, the 4,6-O-benzylidene-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).
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1.Bu2SnO, MeOH2.BzCl,
OOMe
OOHO
OH
Ph
25
OOMe
OOBzO
OH
Ph
10toluene55%
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).
OOMe
OHHO
HOOH 1
OOMe
OHHO
BnOOH 26
OOMe
OAcAcO
HOOAc 8
Bu2SnOMeOH
BnBr, TBAI 90 oC
Ac2O, py MeOH
OOMe
OAcAcO
BnOOAc 27
Pd,H2
BzCl, pyMeOH
OOMe
OBzBzO
BnOOBz 28
OOMe
OBzBzO
HOOBz 12
Pd, H2
80%90%
90% 100%
100% 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 6-position 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)
OOMe
OHHO
HOOH 1
CH3(OEt)3THF, H
BnBr, NaHTHF
OOMe
OHO
OOH 29
EtO
H
OOMe
OBnAcO
HOOBn 18
70%
OOMe
OHO
OOH 30
EtO
Scheme 6. Synthesis of compound 18.
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18
Starting from the obtained compound 18, and removing the acetyl
group, then the 2,6-di-O-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).
OOMe
OBnAcO
HOOBn 18
OOMe
OBnHO
HOOBn 31
OOMe
OBnHO
AcOOBn 19
MeOHMeONa
1.Bu2SnO MeOH2.Ac2O toluene
1.Bu2SnO MeOH2.BnBr, TBAI toluene
OOMe
OBnHO
BnOOBn 16
90%85%
85%
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.
OOMe
OBnHO
AcOOBn 19
OOMe
OBn
HOAcO
OBn 21
inversion
OOMe
OBn
HOAcO
OBn 21
OOMe
OBn
AcOHO
OBn 20
TEA
OOMe
OBn
AcOHO
OBn 20
OOMe
OBn
AcO
OHOBn 22
inversion
OOMe
OBn
AcOHO
OBn 20
OOMe
OBn
AcO
OHOBn 23
NGP
Figure 11. Synthesis approach to 20, 21, 22, 23.
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19
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).
OOR'
OO
O
OSnBuBu
SnBuBu
ExcessBu2SnO R X
O
OOR'
HOHO
OH
OHO
OR'OHO
OH
O
R
O
R
O
stannyleneintermediate
acylatedproduct
unprotectedglycoside
Figure 12. Example of organotin-mediated multiple carbohydrate
esterification.
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20
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).
OOMe
OHHO
HOOH 1
OOMe
OBzHO
BzOOH 32
Bu2SnOMeOHBzCl, rt, toluene 2eq.
OOMe
OHHO
HOOH 1
OOMe
OBzBzO
HOOH 33
Bu2SnOMeOHBzCl, 90 oCtoluene 2eq.
OOMe
OHHO
HOOH 1
OOMe
OBzBzO
BzOOH 34
Bu2SnOMeOHBzCl, 90 oCtoluene 3eq.
90%
85%
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.
OOMe
OHHO
HOOH 1
OOMe
OAcHO
AcOOAc 35
Bu2SnOMeOHAc2O, rttoluene
OOMe
OHHO
HOOH 1
OOMe
OAcAcO
AcOOH 36
Bu2SnOMeOHAcCl, rttoluene
OOMe
OH
HOHO
OH 1
OOMe
OAc
HOAcO
OH 37
Bu2SnOMeOHAc2O, rtDMF
70%
57%
70%
OOMe
OH
HOHO
OH 1
OOMe
OBz
HOHO
OBz 38
Bu2SnOMeOHBzCl, rtCH3Cl 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).
-
21
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).
OOMe
OHHO
HOOH 1
OOMe
OAcHO
AcOOAc 35
Bu2SnOMeOHAc2O, rtCH3CN
OOMe
OHHO
HOOH 1
OOMe
OAcHO
AcOOH 39
Bu2SnOMeOHAc2O, rtDMF
OOMe
OH
HOHO
OH 1
OOMe
OAc
HOAcO
OAc 40
Bu2SnOMeOHAc2O, rtCH3CN
85%
90%
85%
OOMe
OH
HOHO
OH 1
OOMe
OBz
HOBzO
OBz 15
Bu2SnOMeOHBzCl, rttoluene 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.
-
22
-
23
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 ester- protected
galactopyranosides (8, 12) were synthesized.
OOMe
OAcAcO
HOOAc
OOMe
OAcAcO
OAcOH
OOMe
OO
OBnHO
Ph
OOMe
OBzBzO
HOOBz
OOMe
OBzBzO
OBzOH
Mixture
8
12
13
41
42
1. py, Tf2O,CH2Cl2, 2h2. KNO2, 3hDMF, 50 oC
1. py, Tf2O,CH2Cl2, 2h2. KNO2, 6hDMF, 50 oC
1. py, Tf2O,CH2Cl2, 2h
2. KNO2, 3hDMF, 50 oC
73%
77%
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
-
24
reaction proceed smoothly, the axially oriented triflate being
less reactive than the equatorial leaving group.
OOMe
OBzHO
BzOOBz
Mixture
OOMe
OBz
HOBzO
OBz
OOMe
OBz
HOBzO
OBz
OOMe
OBzHO
BzOOBz
OOMe
OBnHO
BnOOBn
OOMe
OBn
HOBnO
OBn
Mixture
14
15
16
17
15
14
1. py, Tf2O,CH2Cl2, 2h
2. KNO2, 5hDMF, 50 oC
1. py, Tf2O,CH2Cl2, 2h
2. KNO2, 2hDMF, 50 oC
1. py, Tf2O,CH2Cl2, 2h
2. KNO2,0.5hDMF, 50 oC
1. py, Tf2O,CH2Cl2, 2h
2. KNO2, 0.5hDMF, 50 oC
75%
70%
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.
OOMe
OOBzO
OH
Mixture
PhO
OMe
OOBzO
OHPh
OOMe
OOBnO
OH
Ph
10
11
43
1. py, Tf2O,CH2Cl2, 2h
2. KNO2, 6hDMF, 50 oC
1. py, Tf2O,CH2Cl2, 2h
2. KNO2, 3hDMF, 50 oC
74%
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 2-position was free (Scheme 13). Instead of
observing the inversion behavior in the 3- and 4-positions 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
-
25
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 6-positions 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 Time(h) product Yield
OOMe
OBnAcO
HO OBn
OOMe
OBnAcO
OH OBn
OOMe
OBn
AcO
OH OBn
OOMe
OBn
AcO
OH OBn
OOMe
OBn
AcOHO OBn
OOMe
OBn
AcOHO OBn
OOMe
OBn
HOAcO OBn
OOMe
OBnHO
AcO OBn
OOMe
OBnHO
AcO OBn
OOMe
OBn
HOAcO OBn
18 44
20 22
22 20
23
19
19 21
entry
1
2
6
4
3
OOMe
OBn
HO
OAcOBn
OOMe
OBnHO
OAcOBn 45
215
3
0.5
4
3
1.5
4
69
73
72
75
_
_
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
-
26
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).
Tf2O/pyridine KNO2
NO O20
2223
DMF
OOMe
OBn
AcO
OH OBn
OOMe
OBn
HO
OAcOBn
OOMe
OBn
AcOHO OBn
OOMe
OBn
AcOTfO OBn
OOMe
OBn
AcOTfO OBn
OOMe
OBn
O
O OBn
CH2Cl2
DMF
H2O
Tf2O/pyridine KNO2
NO O
21
19
DMF
OOMe
OBnHO
AcO OBn
OOMe
OBn
HOAcO OBn
OOMe
OBn
TfOAcO OBn
OOMe
OBn
TfOAcO OBn
OOMe
OBnO
OOBn
CH2Cl2
DMF
H2O
18
OOMe
OBnAcO
HO OBn
Figure 13. Comparison of nitrite-mediated inversion with
neighboring group participation
-
27
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
3,4-trans-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.
Reactant Nucleophile product Yield/%
OOMe
OBn
AcO
OHOBn
OOMe
OBn
AcOHO OBn
OOMe
OBn
HOAcO OBn
OOMe
OBnHO
AcO OBn
OOMe
OBn
HO
OAcOBn
69
72
OOMe
OBnAcO
HO OBn70
70O OMe
OBn
AcOHO OBn
OOMe
OBn
HOAcO OBn
i: Tf2O, py, CH2Cl2, -20 oC-10 oC, 2h, ii: KNO2, 50oC, DMF,
0.5-1.5h, or H2O, rt, DMF, 6h
KNO2
H2O
KNO2
H2O
20
20
21
21
19
18
22
23
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
-
28
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.
-
29
4 Synthesis of -D-Mannosides and -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 -D-mannoside
synthesis. In consequence to these synthetic challenges, several
different synthetic methods have been developed for -mannoside
synthesis. These include Koenigs-Knorr coupling methods using
insoluble silver salt promoters blocking the -face of mannosyl
halides,(63-65) 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 -mannosyl triflate donors,(86-88) epimerization of
-glucopyranosides to -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 -D-talopyranosides.
However interesting, recently evaluated for their intriguing
H-bonding 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 -D-mannopyranoside and
-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).
OOMe
OAcAcO
AcOOH 36
OOMe
OAc
HOAcO
OH 37
OOMe
OAcHO
AcOOH 39
OOMe
OBzHO
BzOOH 32
OOMe
OBzBzO
BzOOH 34
Figure 14. Glycosides obtained by organotin multiple
esterification
The taloside derivatives can be acquired starting from 34 and 36
via the inversion of the 2-position, 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
-
30
mannoside derivatives can be acquired starting from 32 and 39
via the same double parallel inversion strategy.
OOMe
OPGHO
OOHR
O
OOMe
OPG
HOO
OH
R
O
i) Tf2O, Py, CH2Cl2ii) KNO2, DMF
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 -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.
OOMe
OAcHO
AcOOH
OOMe
OAc
AcOAcO
OAc
39 49
OOMe
OAc
HOAcO
OH
OOMe
OAcHO
AcO
OH
37 47
OOMe
OAcHO
AcOOH
OOMe
OAc
HOAcO
OH
39 48
OOMe
OBzHO
BzOOH
OOMe
OBz
HOBzO
OH
32 46
1. py, Tf2O,CH2Cl2, 2h
2. TBANO2,CH3CN, 50 oC 5h
70%
1. py, Tf2O,CH2Cl2, 2h
2. TBANO2,CH3CN, 50 oC 5h
1. py, Tf2O,CH2Cl2, 2h
2. TBANO2,toluene, rt 5h
1. py, Tf2O,CH2Cl2, 2h
2. TBAOAc,CH3CN, rt 5h
85%
76%
90%
Scheme 14. Double parallel inversion reagent and conditions.
-
31
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.
OOMe
OPGHO
OOHR
O
i) Tf2O, Py, CH2Cl2ii)TBANO2, CH3CN O
OMe
OPG
HOO
OTfR
O
i) Tf2O, Py, CH2Cl2ii) TBAOAc, CH3CN
OOMe
OPG
HOO
OAc
R
O
OOMe
OPGHO
OOHR
O
i) Tf2O, Py, CH2Cl2ii)TBAOAc, CH3CN O
OMe
OPG
AcOO
OTfR
O
i) Tf2O, Py, CH2Cl2ii) TBANO2, CH3CN
OOMe
OPG
AcOO
OH
R
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
-
32
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.
45%
45%
OOMe
OAcHO
AcOOTf
52
OOMe
OAcAcO
AcOOTf
51
OOMe
OAcAcO
AcO
OH
53
OOMe
OAcHO
AcO
OAc
54
90%
90%
OOMe
OAc
HOAcO
OH37
OOMe
OAc
TfOAcO
OTf50
90%
X
+
Tf2O, py,CH2Cl2, 2h
TBANO2, CH3CN
TBAOAc, toluene
TBANO2, CH3CN, 24h
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.
OOMe
OAc
HOAcO
OTf57
OOMe
OAc
AcOAcO
OTf56
OOMe
OAc
AcOAcO
OH
OOMe
OAc
HOAcO
OAc
59
90%
90%
OOMe
OAcHO
AcOOH
39
OOMe
OAcTfO
AcOOTf
55
90%
75%
58Tf2O, py,CH2Cl2, 2h
TBANO2, CH3CN
TBAOAc, toluene
TBANO2, toluene, 6h
TBAOAc, CH3CN, 6h
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
-
33
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.
OOMe
OAcHO
AcOOH
39
OOMe
OAcTfO
AcOOTf
55
OOMe
OAc
TfOAcO
OTf50
Tf2O, py,CH2Cl2
1. TBANO2,CH3CN, 1h
2. Tf2O, py,CH2Cl2
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-tri-O-benzoyl galactoside 34 in acetonitrile resulted in a
mixture of methyl talosides 61 and 62.
OOMe
OAcAcO
AcOOH
OOMe
OAcAcO
AcO
OHb
36 53
OOMe
OBzBzO
BzOOH
c,d
34
+O
OMe
OAcHO
AcO
OAc
54
OOMe
OBzBzO
BzO
OH
61+
OOMe
OBzHO
BzO
OBz
62
bc
OOMe
OAc
AcOAcO
OTf 56
OOMe
OAc
AcOAcO
OH
58
OOMe
OAc
AcOHO
OAc
60+
a 58 (%)
60 40
53(%) 54 (%)bcd
60(%)
50 5045 5552 48
61 (%) 62(%)bc
80 20
40 60
(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.
NMR-yields.
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
-
34
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.
OOMe
OAc
AcOOTf
OOMe
O
AcOOTf
O
AcO
OOMe
O
AcO
O
AcO
H2O
OH
OOMe
AcO
AcO
OHOAc
OOMe
HO
AcO
OAc
OAc
AcO
51
5354
+
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.
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35
4.5 Conclusion In conclusion, novel and convenient double
parallel- and double serial inversion methods have been developed,
by which methyl -D-mannosides and methyl -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 -D-mannoside
and methyl -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.
-
36
-
37
5 General Conclusions The effects of neighboring group on
Lattrell-Dax epimerization have been explored. Based on this
effect, efficient synthetic routes to -D-mannosides and
-D-talosides, from the corresponding -D-galactosides and
-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 -D-mannosides and methyl -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.
-
38
-
39
Acknowledgements I owe my sincere gratitude to: My supervisor
Doc Olof Ramstrm 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 Ramstrm 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
Aulin-Erdtman foundation, Knut och Alice Wallenbergs Stiftelse, and
Ragnar och Astrid Signeuls for financial support.
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40
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.
-
41
Reference 1. Bertozzi, C. R.; Kiessling, L. L., Chemical
glycobiology. Science 2001, 291, 2357-
2364. 2. Lis, H.; Sharon, N., Lectins: Carbohydrate-specific
proteins that mediate cellular
recognition. Chem. Rev. 1998, 98, 637-674. 3. 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.
4. 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.
5. 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, 785-789.
6. Lindhorst, T. K., Essentials of Carbohydrate Chemistry and
Biochemistry. Wiley-VCH: Weinheim, 2000.
7. Dwek, R. A., Glycobiology: Toward understanding the function
of sugars. Chem. Rev. 1996, 96, 683-720.
8. Kornfeld, R.; Kornfeld, S., Assembly of Asparagine-Linked
Oligosaccharides. Annu. Rev. Biochem. 1985, 54, 631-664.
9. 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.
10. 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.
11. 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.
12. Wu, X. Y.; Bundle, D. R., Synthesis of glycoconjugate
vaccines for Candida albicans using novel linker methodology. J.
Org. Chem. 2005, 70, 7381-7388.
13. Rich, J. R.; Bundle, D. R., S-linked ganglioside analogues
for use in conjugate vaccines. Org. Lett. 2004, 6, 897-900.
14. 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.
15. Zhu, X. M.; Stolz, F.; Schmidt, R. R., Synthesis of
thioglycoside-based UDP-sugar analogues. J. Org. Chem. 2004, 69,
7367-7370.
16. 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.
17. Knapp, S.; Myers, D. S., Synthesis of alpha-GalNAc
thioconjugates from an alpha-GalNAc mercaptan. J. Org. Chem. 2002,
67, 2995-2999.
18. 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.
-
42
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-thio-linked 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, 6952-6955.
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-D-glucopyranoside. 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.
-
43
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, 5132-5139.
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, 3773-3776.
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-D-talose, 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.
-
44
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.; Ramstrm, 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,
2647-2650.
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
-
45
pentasaccharide domain N-linked to a natural peptide motif.
Chem. Eur. J. 1997, 3, 1617-1628.
69. Lichtenthaler, F. W.; Schneideradams, T.,
3,4,6-Tri-O-Benzyl-Alpha-D-Arabino-Hexopyranos-2-Ulosyl Bromide - a
Versatile Glycosyl Donor for the Efficient Generation of
Beta-D-Mannopyranosidic Linkages. J. Org. Chem. 1994, 59,
6728-6734.
70. Cipolla, L.; Lay, L.; Nicotra, F., New and easy access to
C-glycosides of glucosamine and mannosamine. J. Org. Chem. 1997,
62, 6678-6681.
71. 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-Arabina-Hexopyranosidic Units from the Bis(Triflate)
Derivative of Beta-D-Galactoside. Chem. Lett. 1995, 39-40.
72. 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.
73. Furstner, A.; Konetzki, I., A practical synthesis of
beta-D-mannopyranosides. Tetrahedron Lett. 1998, 39, 5721-5724.
74. Weiler, S.; Schmidt, R. R., A versatile strategy for the
synthesis of complex type N-glycans: Synthesis of diantennary and
bisected diantennary oligosaccharides. Tetrahedron Lett. 1998, 39,
2299-2302.
75. Unverzagt, C., Synthesis of a Biantennary Heptasaccharide by
Regioselective Glycosylations. Angew. Chem. Int. Ed. 1994, 33,
1102-1104.
76. 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.
77. Unverzagt, C., Chemoenzymatic synthesis of a sialylated
undecasaccharide-asparagine conjugate. Angew. Chem. Int. Ed. 1996,
35, 2350-2353.
78. Stork, G.; LaClair, J. J., Stereoselective synthesis of
beta-mannopyranosides via the temporary silicon connection method.
J. Am. Chem. Soc. 1996, 118, 247-248.
79. 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.
80. 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.
81. Dan, A.; Lergenmuller, M.; Amano, M.; Nakahara, Y.; Ogawa,
T.; Ito, Y., p-Methoxybenzylidene-tethered beta-mannosylation for
stereoselective synthesis of asparagine-linked glycan chains. Chem.
Eur. J. 1998, 4, 2182-2190.
82. Ito, Y.; Ogawa, T., Intramolecular aglycon delivery on
polymer support: Gatekeeper monitored glycosylation. J. Am. Chem.
Soc. 1997, 119, 5562-5566.
83. Lergenmuller, M.; Nukada, T.; Kuramochi, K.; Dan, A.; Ogawa,
T.; Ito, Y., On the stereochemistry of tethered intermediates in
p-methoxybenzyl-assisted beta-mannosylation. Eur. J. Org. Chem.
1999, 1367-1376.
84. Barresi, F.; Hindsgaul, O., Synthesis of
Beta-Mannopyranosides by Intramolecular Aglycon Delivery. J. Am.
Chem. Soc. 1991, 113, 9376-9377.
-
46
85. Ziegler, T.; Lemanski, G., Prearranged glycosides. Part 7.
Synthesis of beta-mannosides 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 Organic-Synthesis - 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
beta-mannosyltransferase. Angew. Chem. Int. Ed. 1997, 36,
2354-2356.
94. Vicente, V.; Martin, J.; Jimenez-Barbero, J.; Chiara, J. L.;
Vicent, C., Hydrogen-bonding 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-D-mannopyranosides 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.