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Syntheses of (α2–9) and (α2–8) linked neuraminylneuraminic acid derivatives
Tetrahedron Letters,Vo1.27,No.43,pp Printed in Great Britain
SYNTHESES
OF
(a2-9) AND
5229-5232,1986
(a2-8) LINKED
0040-4039/86 $3.00 + .OO Perqamon Journals Ltd.
NEURAMINYLNEURAMINIC
ACID
DERIVATIVES'
Kaoru Laboratory
Okamoto, ' Tadao of Organic
'+Chemical
Kondo,++*
Chemistry,
Instrument
Center; Nagoya
Chikusa,
and Toshio
Faculty
Goto*
of Agriculture;
Nagoya
and
University
464, Japan
Abstract: A newly prepared glycosyl donor, the acetyl protected 2&bromo-3B-hydroxy-N-acetylneuraminic ester was condensed with the protected 2-deoxy-2,3_dehydroneuraminic ester having a free hydroxy group at 9- or 8-position to form NeuAc(aZ-9)NeuAc and NeuAc(aZ-8)which are involved in the group C NeuAc linkage, respectively, meningococcal polysaccharides and gangliosides. The obtained 38hydroxy disaccharides were phenoxythiocarbonylated, reduced with and deprotected to give the free glycosides in tri-n-butylstannane, high yields.
N-Acetylneuraminic hydrate
chains
ognition.2'3 of NeuAc
acid
(NeuAc) located
of glycoproteins Many
linked
attempts
have
carbohydrate
been done
chains.
that the 28-bromo-38-hydroxy-NeuAc to afford cessful
NeuAc(a2-3)Gal
application
of this
approach
involved This
little
success in the synthesis papar, 4 we have shown
l5
ester
to the syntheses
is the first
in biological
was a useful
glycosides.
in the group
of carbo-
a role
In the previous methyl
ends
plays
with
or NeuAc(a2-3')Lac
NeuAc(a2-8)NeuAc linkages rides 6 and gangliosides.
at the non-reducing
and glycolipids
We
glycosyl
report
here
rec-
donor a suc-
of NeuAc(a2-9)NeuAc
C meningococcal
synthesis
and
polysaccha-
of the NeuAc(a2-8)NeuAc
linkage. The glycosylation (1.1 equiv) ester
with
of the g-unprotected
the 2-bromo-3-hydroxy
1 in toluene-1,2-dichloroethane
(AgOTf) at 0 'C gave
The mixture
derivatives. matography
was
ODS HPLC
address:
Pharmaceutical
Co.,
Institute
gradient
of Bio-Active
Ltd. , Kinashi,
a mixture
of 2-9
by the repeated
(methanol-water,
elution
of silver linked
silica from
Science
47
methyl
triflate
di-NeuAc
gel column
chro-
30:30:0 to 30:30:2)
(IBAS), Nippon
Kato-gun,
ester
NeuAc
46:54) to the protected
Yashiro-cho, 5229
methyl
of peracetylated
(1:l) in the presence yield
separated
(benzene-acetone-methanol,
or by preparative
'Present
in 71% isolated
2,3-dehydro-NeuAc
derivative
Hyogo
NeuAc-
Zoki
673-14,
Japan.
5230
(a2-9)NeuAc glycoside was
glycoside
determined
by analysis
of NeuAc
units
C,6/H-9'-Hm91 values agreed
with
those
unprotected 2-8 linked
ODS
were
from
and
values
33-hydroxy
the corresponding with
of
14 and
them
3-deoxy
7 ' (91% yield,
IY-
15'
(97% yield,
and even
10, in DMF
O.&3ppm),
the previously
if the C-3 was
Deacetylation methanol
at room
13,9
17,'
and
a useful
donor
IH-9'-B-9
authentic
remained
unaltered with
in methanol
11
sample.
reduced
The qlycosides
11'
/=O.O6ppm),
to
were in
for 18 to give
the thio(83%, 4.OH2,
respective-
at room
in which
20
was
The J7 8 coupling
in each
hydroxy
series
and saponification
temp) of 8, 12, and 16 afforded
identical
constant
of (i- and S-qlycosides,
or phenoxythiocarbonyl
temp)
we found
the deprotected
that the 2&bromo-3fi-hydroxy-NeuAc
for the qlycosylation ester
since
of the 8- or 9-unprotected
the 30-hydroxy
2,3-double
in the glycosylation
bond
present
via
and assists
the corresponding
group.
(IN NaOH in di-NeuAc 9, 9
Studies
2. A. Rosenberg
and
3. J_ Montreuil,
Adv.
"Biological
New
Carbohydr . Chem.
T. Kondo,
2,3-
1 prevents
reaction.13
can be used
The
for further
5.
C.-L. Schenqrund, Corporation,
the qlycosylation products
peracetyl
of the bromide
1 is
AND FOOTNOTES
on qanqliosides
Publishing
group
derivative
2!3,30-bromohydrin.5
REFERENCES
4. K. Okamoto,
way.
19' (808, 2.7Hz, 0.85ppm),
reaction
Plenum
the and
with
the dehydrohaloqenation
1. Synthetic
The
spectra
respectively.
20 ' (96%, 2.7Hz, 0.9lppm),
substituted
methyl
qlycosylation
(8% yield).
quantitatively.
In conclusion,
dehydro-NeuAc
and
by
qlycoside
and 4-dimethylaminopyridine12
A6
of
tri-n-butylstannane afforded 8' -9 (969, 3 . 4 Hz , 0.67ppm), 16' a~/i~-9'-FI-9l=O.lRppm), 12
and
(t-BuOK
separated
6, 10, 14, and 18 were
for 14, and in DMSO
J7 8=8.9Hz,
obtained
nsiH-9'-11-91 value
was
the &
7.5 and 1.8Hz, respectively,
in the follwinq
of the thionocarbonates
J7 8=8.9Hz,
(95%, 7.8Hz, with
18'
0.41 and 0.9lppm,
(85%, 7.5Hz, 0.42bpm),
Reduction
qlycoside
chlorothionocarbonate
nocarbonates
The mixture
values
a mixture
by the fact that in 'H-NMR
glycosides
for 6 and
with
givlnq
45:55) to the NeuAc(n2-8)NeuAc
of the glycosides
acetonitrile
0.62ppm),
5"
18 showed
were
1 reacted
(1.0 egulv)
con-
and
These
respectively. 10 rule.
in 43% yield.
was determined
qroups
phenyl
ester
the NeuAc(62-8)NeuAc
of
Thus, the J, 8 coupllnq
the bromide
condition,
a-
configuration
0.59ppm,
the empirical
(methanol-water,
constant
ASIH-9'-H-91
0.17 and
methyl
the anomeric
8.4 and 2.7Hz, respectively,
showed
derivatives
HPLC
configuration
J, 8 coupling
treated
of them
and the corresponding
earlier,
II-NMR spectrum.
10
glycosylation
di-NeuAc
(26% yield)
The
1
of
2,3-dehydro-NeuAc
preparative
anomeric
As demonstrated
of 6 and
deduced
In the above
'C, 42% yield)
(mp 137-139
(21% yiled).
stant
149
6'
10'
and T. Goto,
York,
Roles
of
Sialic
Acid,"
1976.
3iochem.,
Tetrahedron
37, 157
(1980).
Lett., preceding
paper
in
5231
AcO
v
AcO+E&--&ooMe
+
RIO*COOMe
:f;eN_;yJJH2C; 0°C
OAc
1
4
R’=H
5
R’=Ac,
- rt
, R*=Ac R*=H
AcO~;~CooMe
OAc
OAc OAc
6
R =OH
(42%)
7
R=OC(=S)OPh(Sl%)
8
R=H(97%)
9
deprotected
COOMe
8 (97%) dAc lo
14
R=OH
(26%)
15 R =OC(=S)OPh(
(21%)
OAc
OAc 85%)
R =OH
AcO*cooMe
16 R =H (95%) 17
deprotected
16 (97Y.)
AcO~~oo~e OAc
18 R=OH(8%) 19
R =oC(=S)OPh(
20
R =H (96%)
80%)
5232
this
issue.
5. K. Okamoto,
T. Kondo,
6. H. J. Jennings
and A. K. Bhattacharjee,
E. C. Gotschlich,
B. A. Fraser, 8915
J. Biol. Chem., 256, 7. The qlycosyl prepared steps:
acceptor
from
(i) trityl 1
"C for
a free hydroxy
chloride
in pyridine
'H-NMR
elemental data
Monatsh. analyses
was
28 in the follwinq (ii) 90% AcOH
two
at
(non-reducing shifts
100, 1295 (1969). Chem _.I were obtained for these compounds.
NeuAc
unit
in chloroform-d)
[nl,
are shown below.
(6) and J7 8 coupl.inq constants,
Hz in 'H-NMR
[qy H-3eq (dd)
H-3ax H-4 H-7 H-8 H-5 H-6 (dd) (dd) (ddd) (dd) (dd)(ddd)
4.37
3.83d
5.67
7.5
4.02
4.44
3.81d
5.48
7.5
5.31
3.95
4.48
3.83d
5.14
7.8
3.54
3.78
3.62
3.83
4.66
5.35
5.32
3.95
4.86
3.82d
6.03
1.8
4.38
4.72
5.38
5.33
4.00
4.85
3.Jgd
6.20
2.7
4.08
4.62
5.37
5.31
4.01
4.92
3.78d
6.06
2.7
3.9393.93
14
+27.4’
4.00
4.19
4.38
15
i35.4”
5.8gb5.47
4.40
16 17e
+22.3”
2.19
4.88”
4.00
1.78
3.66c
18
+20.3’
3.85
4.99
19
+22.9O
20
+31 .2”
+35.7
0f2.Jl
2.49
5.37 5.11 5.36 5.48 5.40 3.87 5.05 5.19 5.17
3.24 3.40 3.61c4.05 4.08 4.25 4.17 4.23 4.12 4.30 3.62 3.85 4.08 4.67 4.09 4.71 4.13 4.80
3.56
3.84
3.64
3.83
5.24
5.28
3.96
4.38
5.32
5.34
3.81
5.31
3.8493.67 4.21
5.84b5.26 1.84
5.24
5.09’
J7,8
3.82d 3.80d 3.81d
1 3e
2.65
H-9' Me,e;ter(Ip H-9 (dd) (dd) s
5.5 5.6 8.4 8.9 8.9 8.9 2.7 6.52 4.0 6.26 3.4
5.58 5.46 5.27 5.30 5.33 3.54 5.37 5.42 5.41
12
and T.-Y. Lui,
at 9-position
ester
3', 84%);
4.27 4.48 4.49 4.39 4.16 4.62 4.19 4.88 3.97 4.13 3.8893.81 4.16 4.29 4.38 4.44 4.05 4.30
10
105 (1979);
at 60 'C for 2 h, then Ac20-pyridine
+38.3" 6.05b 5.50 +58.7" 5.98b 5.52 +29.9O 3.77 5.22 +35.3O 5.68b5.73 +11.8' 2.53 1.89 4.94' +12.7 Of2.70 1.80 3.77c +23.9O 3.81 5.24 +35.4" 5.82b5.54 +35.1" 2.44 1.84 5.28c + 6.6 0f2.45 1.76 4.10c
11
group
methyl
h (4,7,8-tri-g-acetyl-9-0_Tr
Chemical
3 4 6 7 8 9e
Res., 55,
J. B. Robbins,
(1981).
5 having
and H. Tuppy,
9. Satisfactory
Cornpound
Carbobdr.
in contribution.
1 h (g-01 4', 71%).
8. P. Meindl
and
Sot. Jpn.,
0. Nishimura,
2-deoxy-2,3-dehydro-NeuAc
at 60 OC for 60
Chem ;
and T. Goto, A Bull
3.75 3.81 3.81d 3.80d 3.80d
5.66 5.91 5.73 5.72 5.37
9.5
9.0
b Multiplicity: a Measured in chloroform. d. c Multiplicity: ddd. d Assignments may be interchanged with reducing unit. e Measured in D20 f Measured in water. (A-BuOH=1.23 ppm). g Multiplicity: dd. 10.
K. Okamoto, H. Paulsen
T. Kondo,
and T. Goto,
and H. Tietz,
11.
K. Okamoto,
12.
M. J. Robins
13.
When
T. Kondo,
and T. Goto,
and J. S. Wilson,
the 3-G-acetylated
qlycosides (Received
Bull /LA Carbohydr. &.,
J 2:
compound
was obtained. in Japan
10 July
1986)
Chem 125,
sot
;ipn., in contribution 47 (1984).
Chem Lett., in press. ;_ Am Chem. SE., 103, 932
of 1 was
used
(1981).
in this glycosylation,
no
SYNTHESES
OF
(a2-9) AND
5229-5232,1986
(a2-8) LINKED
0040-4039/86 $3.00 + .OO Perqamon Journals Ltd.
NEURAMINYLNEURAMINIC
ACID
DERIVATIVES'
Kaoru Laboratory
Okamoto, ' Tadao of Organic
'+Chemical
Kondo,++*
Chemistry,
Instrument
Center; Nagoya
Chikusa,
and Toshio
Faculty
Goto*
of Agriculture;
Nagoya
and
University
464, Japan
Abstract: A newly prepared glycosyl donor, the acetyl protected 2&bromo-3B-hydroxy-N-acetylneuraminic ester was condensed with the protected 2-deoxy-2,3_dehydroneuraminic ester having a free hydroxy group at 9- or 8-position to form NeuAc(aZ-9)NeuAc and NeuAc(aZ-8)which are involved in the group C NeuAc linkage, respectively, meningococcal polysaccharides and gangliosides. The obtained 38hydroxy disaccharides were phenoxythiocarbonylated, reduced with and deprotected to give the free glycosides in tri-n-butylstannane, high yields.
N-Acetylneuraminic hydrate
chains
ognition.2'3 of NeuAc
acid
(NeuAc) located
of glycoproteins Many
linked
attempts
have
carbohydrate
been done
chains.
that the 28-bromo-38-hydroxy-NeuAc to afford cessful
NeuAc(a2-3)Gal
application
of this
approach
involved This
little
success in the synthesis papar, 4 we have shown
l5
ester
to the syntheses
is the first
in biological
was a useful
glycosides.
in the group
of carbo-
a role
In the previous methyl
ends
plays
with
or NeuAc(a2-3')Lac
NeuAc(a2-8)NeuAc linkages rides 6 and gangliosides.
at the non-reducing
and glycolipids
We
glycosyl
report
here
rec-
donor a suc-
of NeuAc(a2-9)NeuAc
C meningococcal
synthesis
and
polysaccha-
of the NeuAc(a2-8)NeuAc
linkage. The glycosylation (1.1 equiv) ester
with
of the g-unprotected
the 2-bromo-3-hydroxy
1 in toluene-1,2-dichloroethane
(AgOTf) at 0 'C gave
The mixture
derivatives. matography
was
ODS HPLC
address:
Pharmaceutical
Co.,
Institute
gradient
of Bio-Active
Ltd. , Kinashi,
a mixture
of 2-9
by the repeated
(methanol-water,
elution
of silver linked
silica from
Science
47
methyl
triflate
di-NeuAc
gel column
chro-
30:30:0 to 30:30:2)
(IBAS), Nippon
Kato-gun,
ester
NeuAc
46:54) to the protected
Yashiro-cho, 5229
methyl
of peracetylated
(1:l) in the presence yield
separated
(benzene-acetone-methanol,
or by preparative
'Present
in 71% isolated
2,3-dehydro-NeuAc
derivative
Hyogo
NeuAc-
Zoki
673-14,
Japan.
5230
(a2-9)NeuAc glycoside was
glycoside
determined
by analysis
of NeuAc
units
C,6/H-9'-Hm91 values agreed
with
those
unprotected 2-8 linked
ODS
were
from
and
values
33-hydroxy
the corresponding with
of
14 and
them
3-deoxy
7 ' (91% yield,
IY-
15'
(97% yield,
and even
10, in DMF
O.&3ppm),
the previously
if the C-3 was
Deacetylation methanol
at room
13,9
17,'
and
a useful
donor
IH-9'-B-9
authentic
remained
unaltered with
in methanol
11
sample.
reduced
The qlycosides
11'
/=O.O6ppm),
to
were in
for 18 to give
the thio(83%, 4.OH2,
respective-
at room
in which
20
was
The J7 8 coupling
in each
hydroxy
series
and saponification
temp) of 8, 12, and 16 afforded
identical
constant
of (i- and S-qlycosides,
or phenoxythiocarbonyl
temp)
we found
the deprotected
that the 2&bromo-3fi-hydroxy-NeuAc
for the qlycosylation ester
since
of the 8- or 9-unprotected
the 30-hydroxy
2,3-double
in the glycosylation
bond
present
via
and assists
the corresponding
group.
(IN NaOH in di-NeuAc 9, 9
Studies
2. A. Rosenberg
and
3. J_ Montreuil,
Adv.
"Biological
New
Carbohydr . Chem.
T. Kondo,
2,3-
1 prevents
reaction.13
can be used
The
for further
5.
C.-L. Schenqrund, Corporation,
the qlycosylation products
peracetyl
of the bromide
1 is
AND FOOTNOTES
on qanqliosides
Publishing
group
derivative
2!3,30-bromohydrin.5
REFERENCES
4. K. Okamoto,
way.
19' (808, 2.7Hz, 0.85ppm),
reaction
Plenum
the and
with
the dehydrohaloqenation
1. Synthetic
The
spectra
respectively.
20 ' (96%, 2.7Hz, 0.9lppm),
substituted
methyl
qlycosylation
(8% yield).
quantitatively.
In conclusion,
dehydro-NeuAc
and
by
qlycoside
and 4-dimethylaminopyridine12
A6
of
tri-n-butylstannane afforded 8' -9 (969, 3 . 4 Hz , 0.67ppm), 16' a~/i~-9'-FI-9l=O.lRppm), 12
and
(t-BuOK
separated
6, 10, 14, and 18 were
for 14, and in DMSO
J7 8=8.9Hz,
obtained
nsiH-9'-11-91 value
was
the &
7.5 and 1.8Hz, respectively,
in the follwinq
of the thionocarbonates
J7 8=8.9Hz,
(95%, 7.8Hz, with
18'
0.41 and 0.9lppm,
(85%, 7.5Hz, 0.42bpm),
Reduction
qlycoside
chlorothionocarbonate
nocarbonates
The mixture
values
a mixture
by the fact that in 'H-NMR
glycosides
for 6 and
with
givlnq
45:55) to the NeuAc(n2-8)NeuAc
of the glycosides
acetonitrile
0.62ppm),
5"
18 showed
were
1 reacted
(1.0 egulv)
con-
and
These
respectively. 10 rule.
in 43% yield.
was determined
qroups
phenyl
ester
the NeuAc(62-8)NeuAc
of
Thus, the J, 8 coupllnq
the bromide
condition,
a-
configuration
0.59ppm,
the empirical
(methanol-water,
constant
ASIH-9'-H-91
0.17 and
methyl
the anomeric
8.4 and 2.7Hz, respectively,
showed
derivatives
HPLC
configuration
J, 8 coupling
treated
of them
and the corresponding
earlier,
II-NMR spectrum.
10
glycosylation
di-NeuAc
(26% yield)
The
1
of
2,3-dehydro-NeuAc
preparative
anomeric
As demonstrated
of 6 and
deduced
In the above
'C, 42% yield)
(mp 137-139
(21% yiled).
stant
149
6'
10'
and T. Goto,
York,
Roles
of
Sialic
Acid,"
1976.
3iochem.,
Tetrahedron
37, 157
(1980).
Lett., preceding
paper
in
5231
AcO
v
AcO+E&--&ooMe
+
RIO*COOMe
:f;eN_;yJJH2C; 0°C
OAc
1
4
R’=H
5
R’=Ac,
- rt
, R*=Ac R*=H
AcO~;~CooMe
OAc
OAc OAc
6
R =OH
(42%)
7
R=OC(=S)OPh(Sl%)
8
R=H(97%)
9
deprotected
COOMe
8 (97%) dAc lo
14
R=OH
(26%)
15 R =OC(=S)OPh(
(21%)
OAc
OAc 85%)
R =OH
AcO*cooMe
16 R =H (95%) 17
deprotected
16 (97Y.)
AcO~~oo~e OAc
18 R=OH(8%) 19
R =oC(=S)OPh(
20
R =H (96%)
80%)
5232
this
issue.
5. K. Okamoto,
T. Kondo,
6. H. J. Jennings
and A. K. Bhattacharjee,
E. C. Gotschlich,
B. A. Fraser, 8915
J. Biol. Chem., 256, 7. The qlycosyl prepared steps:
acceptor
from
(i) trityl 1
"C for
a free hydroxy
chloride
in pyridine
'H-NMR
elemental data
Monatsh. analyses
was
28 in the follwinq (ii) 90% AcOH
two
at
(non-reducing shifts
100, 1295 (1969). Chem _.I were obtained for these compounds.
NeuAc
unit
in chloroform-d)
[nl,
are shown below.
(6) and J7 8 coupl.inq constants,
Hz in 'H-NMR
[qy H-3eq (dd)
H-3ax H-4 H-7 H-8 H-5 H-6 (dd) (dd) (ddd) (dd) (dd)(ddd)
4.37
3.83d
5.67
7.5
4.02
4.44
3.81d
5.48
7.5
5.31
3.95
4.48
3.83d
5.14
7.8
3.54
3.78
3.62
3.83
4.66
5.35
5.32
3.95
4.86
3.82d
6.03
1.8
4.38
4.72
5.38
5.33
4.00
4.85
3.Jgd
6.20
2.7
4.08
4.62
5.37
5.31
4.01
4.92
3.78d
6.06
2.7
3.9393.93
14
+27.4’
4.00
4.19
4.38
15
i35.4”
5.8gb5.47
4.40
16 17e
+22.3”
2.19
4.88”
4.00
1.78
3.66c
18
+20.3’
3.85
4.99
19
+22.9O
20
+31 .2”
+35.7
0f2.Jl
2.49
5.37 5.11 5.36 5.48 5.40 3.87 5.05 5.19 5.17
3.24 3.40 3.61c4.05 4.08 4.25 4.17 4.23 4.12 4.30 3.62 3.85 4.08 4.67 4.09 4.71 4.13 4.80
3.56
3.84
3.64
3.83
5.24
5.28
3.96
4.38
5.32
5.34
3.81
5.31
3.8493.67 4.21
5.84b5.26 1.84
5.24
5.09’
J7,8
3.82d 3.80d 3.81d
1 3e
2.65
H-9' Me,e;ter(Ip H-9 (dd) (dd) s
5.5 5.6 8.4 8.9 8.9 8.9 2.7 6.52 4.0 6.26 3.4
5.58 5.46 5.27 5.30 5.33 3.54 5.37 5.42 5.41
12
and T.-Y. Lui,
at 9-position
ester
3', 84%);
4.27 4.48 4.49 4.39 4.16 4.62 4.19 4.88 3.97 4.13 3.8893.81 4.16 4.29 4.38 4.44 4.05 4.30
10
105 (1979);
at 60 'C for 2 h, then Ac20-pyridine
+38.3" 6.05b 5.50 +58.7" 5.98b 5.52 +29.9O 3.77 5.22 +35.3O 5.68b5.73 +11.8' 2.53 1.89 4.94' +12.7 Of2.70 1.80 3.77c +23.9O 3.81 5.24 +35.4" 5.82b5.54 +35.1" 2.44 1.84 5.28c + 6.6 0f2.45 1.76 4.10c
11
group
methyl
h (4,7,8-tri-g-acetyl-9-0_Tr
Chemical
3 4 6 7 8 9e
Res., 55,
J. B. Robbins,
(1981).
5 having
and H. Tuppy,
9. Satisfactory
Cornpound
Carbobdr.
in contribution.
1 h (g-01 4', 71%).
8. P. Meindl
and
Sot. Jpn.,
0. Nishimura,
2-deoxy-2,3-dehydro-NeuAc
at 60 OC for 60
Chem ;
and T. Goto, A Bull
3.75 3.81 3.81d 3.80d 3.80d
5.66 5.91 5.73 5.72 5.37
9.5
9.0
b Multiplicity: a Measured in chloroform. d. c Multiplicity: ddd. d Assignments may be interchanged with reducing unit. e Measured in D20 f Measured in water. (A-BuOH=1.23 ppm). g Multiplicity: dd. 10.
K. Okamoto, H. Paulsen
T. Kondo,
and T. Goto,
and H. Tietz,
11.
K. Okamoto,
12.
M. J. Robins
13.
When
T. Kondo,
and T. Goto,
and J. S. Wilson,
the 3-G-acetylated
qlycosides (Received
Bull /LA Carbohydr. &.,
J 2:
compound
was obtained. in Japan
10 July
1986)
Chem 125,
sot
;ipn., in contribution 47 (1984).
Chem Lett., in press. ;_ Am Chem. SE., 103, 932
of 1 was
used
(1981).
in this glycosylation,
no