Highly optimized β-mannosylation via p-methoxybenzyl assisted intramolecular aglycon delivery

Article abstract of DOI:10.1055/s-1998-1894

Highly efficient and stereoselective β-mannosylation was achieved by using mannosyl thioglycosides 5 and 19. Intramolecular aglycon delivery (IAD) from mixed acetal 12, 15 and 20, obtainable by oxidative coupling of aglycon onto mannosyl thio-glycosides which carry p-methoxybenzyl (PMB) group at C-2 position, was performed by the action of MeOSO₂CF₃ to afford β-mannosides 13/16/21. It is to be noted that efficiency of IAD was substantially improved by changing the protecting group at the 4- and 6- positions from previously utilized benzylidene to cyclohexylidene (5) or TIPDS (19) group. As a result, it is now possible to perform the β-manno glycosylation in a highly optimized manner to afford di- and trisaccharides with a backbone structure corresponding to asparagine-linked oligosaccharides in 75-85% yield as single stereoisomers.

Full text of DOI:10.1055/s-1998-1894

1102
LETTERS
SYNLETT
Highly Optimized β-Mannosylation via p-Methoxybenzyl Assisted Intramolecular Aglycon
Delivery
a
a
a
a,b
Yukishige Ito *, Yuki Ohnishi , Tomoya Ogawa and Yoshiaki Nakahara
a
The Institute of Physical and Chemical Research (RIKEN) and CREST, Japan Science and Technology Corporation (JST), 2-1 Hirosawa,
Wako-shi, Saitama 351-0198, Japan
Fax +81-48-462-4680; yukito@postman.riken.go.jp
b
Department of Industrial Chemistry, Tokai University, 1117 Kitakame, Hiratsuka-shi, Kanagawa 259-1292, Japan
Received 7 July 1998
Abstract: Highly efficient and stereoselective β-mannosylation was
achieved by using mannosyl thioglycosides 5 and 19. Intramolecular
aglycon delivery (IAD) from mixed acetal 12, 15 and 20, obtainable by
oxidative coupling of aglycon onto mannosyl thio-glycosides which
carry p-methoxybenzyl (PMB) group at C-2 position, was performed by
At the earlier stage of our investigation by using 4,6-benzylidene
4a b
4c
protected ( / ) as well as tribenzylated ( ) donors, it was quickly
recognized that having a cyclic 4,6-O-protection is important in IAD
6
using thioglycosides . This observation lead us to the working
hypothesis that the rigidity of hexopyranoside chair conformation may
4a b
be responsible for successful IAD starting from / . Therefore, 4,6-O-
the action of MeOSO CF to afford β-mannosides 13/16/21. It is to be
2
3
4
5
cyclohexylidene protected was designed, in which C form should be
noted that efficiency of IAD was substantially improved by changing
the protecting group at the 4- and 6- positions from previously utilized
benzylidene to cyclohexylidene (5) or TIPDS (19) group. As a result, it
is now possible to perform the β-manno glycosylation in a highly
optimized manner to afford di- and trisaccharides with a backbone
structure corresponding to asparagine-linked oligosaccharides in 75-
85% yield as single stereoisomers.
1
4a
5
frozen more rigidly compared to . Preparation of was performed as
7
Scheme 2
6
depicted in
. Thus, starting from methyl-thiomannoside
cyclohexylidene group was installed to give . Subsequent formation of
2,3-O-p-methoxybenzylidene acetal was effected under Yonemitsu's
conditions to afford (77% yield), that was subjected to the reductive
,
7
8
8
ring opening process effected by DIBAL which gave 2-O-PMB
9
10
protected in 60% yield as well as a minor amount of in ca. 5:1 ratio.
9,10
5
Further protection of the 3-position afforded
.
1
In 1994, we reported a novel strategy for the stereoselective synthesis
2
of β-manno glycoside , as a new entry into the so called intramolecular
3
aglycon delivery (IAD) approach. In our version of IAD, p-
methoxybenzyl (PMB) group at 2-position of mannosyl donor 1
4
functions as a scaffold for the DDQ mediated formation of the tethered
intermediate 2. Subsequent activation of the anomeric position triggers
IAD to afford β-manno glycoside 3 (Scheme 1). This strategy was
subsequently applied to the completely stereocontrolled synthesis of the
core structure of asparagine (Asn) linked glycoprotein
5
oligosaccharides . Selectively protected thioglycosides 4a/b were used
as mannosyl donors to afford di-, tri- and tetrasaccharide products in 49-
60% yield. We report here the highly optimized version of PMB assisted
IAD protocol which gives >80% yield of β-mannosides corresponding
to the common structural units of Asn-linked oligo-saccharides [i.e.
βMan1-4βGlcNAc(±1-4GlcNAc)].
Scheme 2
β-Mannosylation by using 5 was examined under our standard
conditions and proved to be highly efficient. (Scheme 3) Thus,
11
treatment of glucosamine derived acceptor 11 with 5 (1.3 equiv.) and
DDQ (1.5 equiv.) in CH Cl (25 ml/mmol of 11) in the presence of
2
2
molecular sieves 4A (room temp. 2 h) afforded mixed acetal 12 in an
1
essentially quantitative yield (based on H-NMR analysis). Subsequent
12
IAD was effected by methyl trifluoromethanesulfonate (MeOTf) and
2,6-di-tert-butyl-4-methylpyridine (DBMP) in 1,2-dichloroethane (ca.
10 mM concentration of 12; 45°C, 24 h) to afford an 83% yield of
10
disaccharide 13 which corresponds to βMan1-4GlcNAc. In a similar
11
10
10
manner, the reaction with disaccharide 14 gave 16 via 15 in 85%
yield.
17
4,6-O-Isopropylidene protected donor , which was prepared from
5
(1. CSA/MeOH; 2. Me C(OMe) , CSA/MeCN), gave a less satisfactory
2
2
10
Scheme 1
18
). Comparison of yields obtained by
result (61% yield of

October 1998
SYNLETT
1103
acetal. In this case the 3-position of 19 is protected by trimethylsilyl and
the C-3 oxygen traps intramolecularly the immediate product 22 to
neutralize the positive charge effectively. Since similar transformation
with 4,6-O-benzylidene counterpart 23 gave lower yield (55%) of the
product 24, having a larger ring system bridging the 4- and 6-positions
seems to be beneficial for the ring closure step.
Scheme 3
11
4a
5
17
glycosylation of using (60%), (83%) and (61%) suggests that
rigidity of the pyranose ring system is actually a significant factor
controlling the efficiency of our system.
During the course of IAD, rigid chair conformation of mannose residue
would encourage the S 2 type reaction, thereby suppressing side
N
13
Eq 1
( . ).
reactions arising from oxocarbenium ion-like species
Scheme 4
Due to their protection patterns, the potential utility of β-mannoside
products (13, 16, 21) in synthetic studies of Asn-linked oligosaccharides
is obvious. In summary, fine-tuning of p-methoxybenzyl assisted β-
mannosylation was successfully made by using
a
4,6-O-
cyclohexylidene (5) and -TIPDS (19) carrying mannosyl donor.
Typical β-mannosylation procedure: Preparation of 21:
To a stirred
mixture of compounds 19 (504 mg, 0.78 mmol) and 11 (580 mg, 0.98
mmol) in CH Cl (15 ml) containing molecular sieves 4A was added
On the other hand, 4,6-O-disiloxanylidene carrying 19 also gave us a
highly satisfactory result (Scheme 4). Glycosyl donor 19 was assumed
to represent the relaxed hexopyranose ring system compared to 4a, 5
and 17. Compound 19 was prepared from 6 in 5 steps (1. NaOMe,
2
2
DDQ (219 mg, 0.96 mmol) under positive flush of argon at 0°C. The
mixture was stirred at room temperature for 2 h and quenched with an
aqueous solution (10 ml) of ascorbic acid (0.7%)-citric acid (1.3%)-
NaOH (0.9%). The resulting lemon-yellow mixture was diluted with
ether and filtered through Celite. The filtrate was washed with aq.
NaHCO and brine, successively, dried over Na SO and evaporated in
MeOH, 93%; 2. TIPDSCl , imidazole/DMF, 84%; 3. p-
2
MeOC H CH(OMe) , PPTS/DMF, 85%; 4. DIBAL/toluene, 86%; 5.
6
4
2
TMSCl, imidazole/DMF, 94%) and was subjected to the β-
3
2
4
10
vacuo. The residue was purified by chromatography on florisil (2-5%
EtOAc in toluene) to afford 929 mg (96%) of mixed acetal 20, which
was transferred, as a solution in CH Cl (90 ml), into the reaction flask
mannosylation conditions to react with 11. Mixed acetal 20 was
isolated in 96% yield after purification by florisil and treated with
10
MeOTf-DBMP to give 21 in 78% yield, which can be compared quite
2
2
containing DBMP (796 mg, 3.88 mmol) and molecular sieves 4A (3.5
g). Under ice-water cooling, MeOTf (1M in 1,2-dichloroethane, 3.0 ml,
3.0 mmol) was added and the whole was stirred at room temperature for
favorably with the results obtained by 4a/17. The higher efficiency
observed here may be ascribed to the concomitant formation of cyclic

1104
LETTERS
SYNLETT
1982
,
0.5 h and at 60°C for 14 h. The reaction was quenched with Et N (3 ml),
diluted with ether and filtered through Celite. The filtrate was washed
8.
9.
Y. Oikawa, T. Yoshioka, O. Yonemitsu, Tetrahedron Lett.
23, 889-892.
3
successively with aq. NaHCO , water and brine, dried over Na SO and
3
2
4
5
Preparation of can be conveniently performed in 35 % overall
evaporated in vacuo. The residue was chromatographed over silica gel
(5-10% EtOAc in toluene) to afford 659 mg (78%; 75% over 2 steps) of
compound 21.
7
8
9
yield from , without isolation of intermediates and .
10. Selected NMR data (CDCl ) are given for key compounds. 5: δ
3
H
(270 MHz) 4.81 (1H, d, J = 1.3 Hz, H-1), 3.78 (3H, s, OMe), 3.22
(1H, br.s, H-2). 1.89 (3H, s, SMe), 1.12 (9H, s, t-Bu). 12: δ (270
MHz) 5.59 (1H, d, J < 1 Hz, H-1 ), 5.59 (1H, d, J = 8.3 Hz, H-1 ),
5.42 (1H, s, acetal CH), 5.16 and 4.89 (each 1H, d, J = 13.2 Hz,
H
Acknowledgments:
A part of this work was financially supported by a
2
1
Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, and Culture and also by the Special Coordination Funds of the
Science and Technology Agency of the Japanese Government. We thank
Ms. A. Takahashi for her technical assistance.
benzylic CH ), 3.78 (3H, s, OMe), 3.68 (3H, s, OMe), 1.90 (3H, s,
2
1
SMe). 13: δ (400 MHz) 5.55 (1H, d, J = 8.3 Hz, H-1 ), 4.36 (1H,
H
2
s, H-1 ), 3.68 (3H, s, OMe), 1.11 (9H, s, t-Bu); δ (67.5 MHz)
C
1
2
1
100.2 ( J
= 159 Hz, C-1 ), 99.8 (ketal C), 97.7 ( J
= 165
C-H
C-H
1
3
References and Notes
Hz, C-1 ). 15: δ (270 MHz) 5.66 (1H, s, H-1 ), 5.472 (1H, s,
acetal CH), 5. 465 (1H, d, J = 8.2 Hz, H-1 ), 5.28 (1H, d, J = 8 Hz,
H-1 ), 5.16 (1H, d, J = 13.2 Hz, benzylic CH), 3.72 (3H, s, OMe),
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(1H, d, J = 8.3 Hz, H-1 ), 5.23 (1H, d, J = 8.3 Hz, H-1 ), 4.43 (1H,
H
2.
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1
2
3
s, H-1 ), 3.63 (3H, s, OMe), 1.11 (9H, s, t -Bu); δ (67.5 MHz)
C
1
3
100.1 ( J
= 161 Hz, C-1 ), 99.8 (cyclohexylidene), 97.5, 96.7
C-H
1
1,2
( J
= 165, 167 Hz, C-1 ). 18: δ (270 MHz) 5.56 (1H, d, J =
H
C-H
1
2
2
8.2 Hz, H-1 ), 4.42 (1H, s, H-1 ), 3.93 (1H, t, J = 9 Hz, H-4 ),
3.69 (3H, s, OMe), 2.80 (1H, m, H-5 ), 2.72 (1H, br, OH), 1.09
(9H, s, t-Bu);
(isopropylidene), 98.2 (C-1 ). 19: δ (270 MHz) 5.25 (1H, dd, J =
2
2
δ
(67.5 MHz) 100.8 (C-1 ), 100.0
C
1
H
1.1 Hz, H-1), 4.60 (2H, s, CH Ar), 4.38 (1H, t, J = 9.2 Hz, H-4),
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F. Barresi, O. Hindsgaul, J. Am. Chem. Soc.
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H
1
s, acetal CH), 5.55 (1H, d, J = 8.2 Hz, H-1 ), 5.11 (1H, d, J = 12.5
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(3H, s, SMe). 21: δ (270 MHz) 5.94 (1H, acetal CH), 5.61 (1H,
H
1
d, J = 8.6 Hz, H-1 ), 5.05 (1H, d, J = 12.9 Hz, benzylic CH), 4.90
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d, J = 12.9 Hz, benzylic CH), 3.72 (3H, s, OMe), 3.70 (3H, s,
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2
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