Reducing oligosaccharides via glycal assembly: On the remarkable stability of anomeric hydroxyl groups to global deprotection with sodium in liquid ammonia

Article abstract of DOI:10.1016/S0040-4039(02)01551-4

Several partially benzylated 1-hydroxy sugars were rapidly deprotected by sodium/liquid ammonia. The terminal hemiketal linkage of the substrates remained intact under these conditions and does not generate ring-opened alditols. Peracetylated glucose and glucosamine derivatives were obtained in 64-79% isolated yields.

Full text of DOI:10.1016/S0040-4039(02)01551-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7027–7030
Reducing oligosaccharides via glycal assembly: on the
remarkable stability of anomeric hydroxyl groups to global
deprotection with sodium in liquid ammonia
a
a
a
a,b,
Ulrich Iserloh, Vadim Dudkin, Zhi-Guang Wang and Samuel J. Danishefsky
*
a
Laboratory for Bioorganic Chemistry, The Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York,
NY 10021, USA
b
Department of Chemistry, Columbia University, Havemeyer Hall, New York, NY 10027, USA
Received 11 July 2002; accepted 26 July 2002
Abstract—Several partially benzylated 1-hydroxy sugars were rapidly deprotected by sodium/liquid ammonia. The terminal
hemiketal linkage of the substrates remained intact under these conditions and does not generate ring-opened alditols.
Peracetylated glucose and glucosamine derivatives were obtained in 64–79% isolated yields. © 2002 Published by Elsevier Science
Ltd.
Glycopeptides are classified on the basis of the attach-
ment mode of an oligosaccharide to the amino acid side-
chain of the peptide domain. In N-linked glycopeptides
From the perspective of our laboratory it would be
particularly convenient if we could merge the advan-
tages of the glycal route to complex oligosaccharides
with the Kochetkov–Lansbury methodology for
advancing from oligosaccharides to N-linked
3
(
4), the asparagine g-carboxamide is glycosylated with a
conserved (high mannose) pentasaccharide core struc-
1
ture. Within the cellular context, this linkage is gener-
constructs.
ated via glycosylation of the asparagine amide
side-chain. By contrast, the most promising laboratory
approach for synthesizing these compounds involves
peptide-bond formation between a glycosylamine (2)
Preparations of generic precursors of the type 1 can be
achieved via a number of pathways. One such route,
4
involving the glycal assembly technology, is shown in
and the g-carboxylate of a uniquely disposed aspartate
Scheme 2: glucal 5 was converted into the prototypical
2
5
(
3, Scheme 1). The glycosylamine (2) is, in turn, most
2-N-acetylglucose (1) via thioglycosides 6 and 7. In the
readily generated via standard Kochetkov–Lansbury
amination (NH HCO /H O, 25°C) from the globally
deprotection of resident benzyl groups, either Pd-medi-
ated hydrogenolysis or dissolving metal conditions have
been extensively employed. However, out of concern
for the integrity of the terminal hemiketal linkage
during Birch-type reductive conditions, such deprotec-
tion of the systems of the type 8 had not been
attempted.
3
4
3
2
deprotected parent saccharide 1, presenting a free
anomeric hydroxy group. Given our interest in synthe-
sizing N-linked glycopeptide constructs of complex gly-
cans, we had a need to reach systems such as 2 in the
context of structurally challenging oligosaccharides.
Scheme 1.
*
Corresponding author.
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01551-4

7
028
U. Iserloh et al. / Tetrahedron Letters 43 (2002) 7027–7030
1
. I(coll)2ClO4
NH2SO2Ph
. LiSEt, DMF
–40° C
3. Na/NH3
4. MeOH,
5. Hg(OAc)2,
BnO
HO
RO
2
O
O
2
H O
RO
SEt
SEt
NHAc
BnO
BnO
2
Ac O
HO
O
NHSO2Ph
HO
RO
6
8
7
O
BnO
RO
OH
NHAc
1
. I(coll)2ClO4
NH SO Ph
HO
BnO
5
O
2
2
RO
OH
1
BnO
Dissolving-metal reduction
on 1-hydroxy saccharides ?
2. H2O, NEt3
NHSO2Ph
Scheme 2.
6
Rather, we resorted to iodosulfonamidation of glucal
, followed by LiSEt-induced rearrangement at −40°C
(Table 1). Following iodosulfonamidation with IDCP/
5
NH SO Ph, the resulting intermediates were directly
2
2
giving rise to a protected thioglycoside intermediate (6).
This type of system was subjected to dissolving metal
reduction. After N-acetylation, deprotected thiogly-
coside 7 is hydrolysed in the presence of Hg(II) salts to
introduce the required anomeric hydroxyl group.
subjected to hydrolysis (H O/Et N) to provide sulfon-
2 3
6
amides 10a and 10c in good yield. The corresponding
1,2-dihydroxy saccharides 10b and 10e were prepared
by DMDO-mediated glycal-epoxidation, followed by
exposure of the oxiranes to an aqueous ZnCl solution.
2
With ample quantities of compounds 10 in hand, we
began investigating the effect of reaction time in Birch-
type deprotections (ammonia/sodium at −78°C). Reac-
In this letter, we report the important finding that, in
fact, deprotection of partially benzylated mono- and
disaccharides containing free anomeric hydroxyl-groups
under dissolving metal conditions is entirely possible.
Happily, the terminal hemiketal linkage remains intact
and ring-opened alditol products are not produced.
This capability obviates the need for more complex
protocols for accomplishing the overall transformation
of synthetic glycals to Kochetkov–Lansbury precursors.
tions were quenched with solid NH Cl, concentrated in
4
vacuo and peracetylated, prior to analysis by LCMS for
any traces of ring-opened alditols. Interestingly, the
anomeric linkage of amides 10a, 10c, and 10d proved
very robust and survived the Birch-type conditions for at
least 60 min. In contrast, 1,2-dihydroxy saccharides 10b
and 10e were less stable and generated about 15% of
alditols over the course of 60 min. In these cases, a
10–20 min reaction time was sufficient to achieve com-
plete deprotection without observable hemiketal reduc-
tive opening. For the purposes of obtaining accurate
yields the fully deprotected products were subjected to
direct peracetylation followed by silica gel chromatog-
raphy. The yields for peracetylated materials 11a–11d
were in the range of 64–79%. All products exhibited
satisfactory LRMS data and spectral properties as pre-
We note at the outset that these studies were occa-
7
sioned by a recent isolated case in 2001. During the
synthesis of pentadecasaccharide 9, 37 benzyl groups
and two sulfonamido groups were removed in a single
massive deprotection step (1. Na/NH , 2. Ac O, 46%;
3
2
Scheme 3). While the product was obtained in 46%
yield, we deemed this result promising. Based on this
precedent, we proceeded to evaluate the scope of the
method in the context of simpler model structures,
featuring either a 1,2-dihydroxy or a 1-hydroxy-2-
amino-based functionality in their reducing domains.
8
viously described in the literature.
In summary, free anomeric hydroxy-groups in carbohy-
drate–hemiketal linkages are stable to sodium–ammo-
nia debenzylation conditions. Since it can well be
assumed that any free aldehydes at the sugar terminus
would be rapidly reduced, the success of these reactions
The preparation of test substrates 10a–10e was carried
out along established routes, starting from commer-
cially available tribenzylglucal or hexabenzyllactal
RO OR
RO
RO
OR
O
RO
RO
O
O
O
O
O
NHAc
O
RO
O
O
RO
NHAc
OR
2
3
O
R=Bn, R =SO2Ph, R =PMB
Na, NH3
–78° C
OR
2
3
R=R = R =H
OR
RO
RO OR
RO
OR
OR
RO
O
O
RO
O
OR
O
RO
RO
O
O
O
RO
O
O
O
RO
NHAc
RO
NHAc
RO
RO
RO
O
OR
pentadecasaccharide 9
O
OR
OR
OAc
RO
O
O
RO
RO
3
O
R O
O
O
O
O
OH
RO
2
R HN
2
glycopeptide
R HN
Scheme 3.

U. Iserloh et al. / Tetrahedron Letters 43 (2002) 7027–7030
7029
Table 1.
Deprotection substrate
Peracetylated product
AcO
Timea Yieldb
D-glucal derivatives
BnO
BnO
O
O
AcO
OH
NHSO2Ph
0a
OAc
NHAc
60 min 64%
20 min 75%
BnO
AcO
1
11a
BnO
BnO
AcO
O
O
OH
AcO
OAc
BnO
AcO
OH
OAc
10b
11b
D-lactal derivatives
BnO OBn
AcO OAc
O
BnO
AcO
O
BnO
O
O
AcO
O
O
OH
NHSO2Ph
0c
60 min 76%
60 min 72%
OAc
BnO
AcO
OBn
OAc
NHAc
1
11c
BnO OBn
AcO OAc
O
BnO
AcO
O
BnO
O
O
AcO
O
O
OH
OAc
NHAc
BnO
AcO
OBn
OAc
NHAc
1
0d
11c
AcO OAc
O
BnO OBn
AcO
BnO
O
O
AcO
O
O
BnO
O
OH
OAc
AcO
BnO
OAc
20 min 79%
OBn
OAc
OH
1
0e
11d
a
Reaction time for dissolving metal reduction. Reactions were performed by the addition of
saccharide 1, dissolved in THF, to a stirred solution of Na (6 equiv per benzyl-group) in NH3 at
b
–
78° C. After quenching and workup, the crude solid was peracetylated for analysis. Isolated
yield by column chromatography.
underscores the dominance of the closed hemiacetal
form (or its corresponding alkoxide) under these condi-
tions. This route to glycal-derived 1-hydroxy sugars
presents several major advantages in terms of simplicity
over the thioglycoside route described above: the mois-
ture sensitive LiSEt-mediated rearrangement of iodosul-
fonamide 12 (Scheme 4) into thioglycoside (6) can now
be circumvented and replaced with a much simpler
protocol utilizing aqueous triethylamine (12“8). Toxic
Hg(II)-salts are no longer required in the route shown
here. Moreover, both anomers of 12 are efficiently
utilized in this protocol to give 8, whereas progression
to a generic type 6 system is only possible with the
trans-diaxial iodosulfonamide. The streamlined synthe-
sis allows for increased efficiency, which is paramount
for producing required quantities of glycosyl amines (2)
en route to N-linked glycopeptides and, eventually,
N-linked glycoproteins. Applications of these findings
will be disclosed shortly.
Acknowledgements
This work was supported by grants from the National
Institutes of Health (CA-28824). A postdoctoral fellow-
ship is gratefully acknowledged by U.I. (NIH F32
CA88478-02).
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12
2
8
Scheme 4.

7
030
U. Iserloh et al. / Tetrahedron Letters 43 (2002) 7027–7030
3
. (a) Likhosherstov, L. M.; Novikova, O. S.; Derevitskaja,
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3
2
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1
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3
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1
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9
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−
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4
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vigorously stirred until the blue color disappeared. The