Stereoselective synthesis of β-D-mannopyranosides with reactive mannopyranosyl donors possessing a neighboring electron-withdrawing group

Article abstract of DOI:10.1002/1521-3773(20020816)41:16<2972::AID-ANIE2972>3.0.CO;2-4

An electron-withdrawing protecting group at the O-2 atom and a good anomeric leaving group at the mannopyranosyl donor are required for a new, practical approach to the production of β-linked mannopyranoside units (see scheme, MPM=para-methoxybenzyl, TDS=

Full text of DOI:10.1002/1521-3773(20020816)41:16<2972::AID-ANIE2972>3.0.CO;2-4

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Stereoselective Synthesis of
b-d-Mannopyranosides with Reactive
Mannopyranosyl Donors Possessing a
Neighboring Electron-Withdrawing Group**
Adel A.-H. Abdel-Rahman, Simon Jonke,
El Sayed H. El Ashry,* and Richard R. Schmidt*
Dedicated to Professor Wolfgang Pfleiderer
on the occasion of his 75th birthday
The presence of b-linked mannopyranosides in various
natural products,[1] particularly in the N-glycan core structure
of glycoproteins,[1,2] led to the search for efficient method-
ologies for producing this difficult target structure. Above all,
mannopyranosyl donors A (Scheme 1), with nonparticipating
protecting groups and different leaving groups X, were
investigated for their b selectivity. However, in general,
Scheme 1. Preferred a- and b-mannopyranoside synthesis.
tion), is thought to play a decisive role (Scheme 2).[21] Rather,
the anomeric stereocontrol is caused by a conformational
effect enforced by the 4,6-O-benzylidene group on the
pyranosyl ring, which thus favors the generation of a flattened
5]
12]
a products were obtained.[1,3 Several specific methods[6
have led to some success in this endeavour. Finally epimeri-
zation of b-glucopyranosides to b-mannopyra-
nosides through an SN2 reaction[12 16] and intra-
molecular aglycon delivery[17 19] appeared to be
the method of choice.
Mannopyranosyl donors with diol O-protect-
ing groups, which lead to ring annelation, had
already been investigated, but again with
limited success.[20] However, the use of 2,3-di-
O-alkyl-4,6-O-benzylidene-protected manno-
pyranosyl sulfoxides as donors (Scheme 1, B)
gave preferentially b products with various
acceptors at low temperatures.[21] The same
result is more conveniently achieved with
trichloroacetimidate leaving groups, because
these mannopyranosyl donors are highly reac-
tive and accessible to activation with catalytic
amounts of trimethylsilyltrifluoromethanesul-
fonate (TMSOTf).[22] The results obtained on
varying the reaction parameters in this reaction
are not compatible with the reaction mecha-
nism proposed for sulfoxide activation,[22] in
which a-triflate intermediate Bb, formed via
intermediate Ba (with a half-chair conforma-
Scheme 2. Mechanistic proposals for preferred b-mannopyranoside formation. TB ¼ Twist
Boat conformation, H ¼ half-chair conformation.
twist boat conformation Bc as the intermediate.[22] For ster-
[*] Prof. Dr. R. R. Schmidt, Prof. Dr. A. A.-H. Abdel-Rahman, S. Jonke
Department of Chemistry
eoelectronic and steric reasons, Bc will be preferentially
attacked from the b side, which gives a twist boat intermedi-
University of Konstanz
78457 Konstanz (Germany)
4
ate Bd that equilibrates to the C1 conformer. This mecha-
nistic proposal reconciles all results thus far found with
different 4,6-O-benzylidene protected mannopyranosyl do-
nors.
Fax : (þ 49)7531-88-3135
E-mail: Richard.Schmidt@uni-konstanz.de
Prof. Dr. E. S. H. El Ashry
Department of Chemistry
Faculty of Science, ALexandria University
Alexandria (Egypt)
Based on these mechanistic considerations, b-mannopyra-
noside formation should be facilitated by nonparticipating,
strongly electron-withdrawing groups R2 at the 2-O atom
(Scheme 2), because generation of the twist boat intermedi-
ate Bc would gain from a strong dipole effect, as indicated by
the dotted arrows in Bc. Earlier investigations with 2-O-
mesyl- and 2-O-benzylsulfonyl-mannopyranosyl chlorides
and tosylates as donors with some simple acceptors led to
formation of the preferential b product,[23,24] which supports
Fax : (þ 20)3-4271360
E-mail: eelashry@link.net
[**] This work was supported by the Deutsche Forschungsgemeinschaft,
the Fonds der Chemischen Industrie, and the European Community
(Grant No. HPRN-CT-2000-00001/GLYCOTRAIN). A.A.H.A.R.
and E. S. H. El Ashry are grateful to the Alexander von Humboldt
Foundation for a fellowship and for the continued support, respec-
tively.
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Angew. Chem. Int. Ed. 2002, 41, No. 16

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our postulate. However, to demonstrate the
potential of this direct approach to b-mannopyr-
anoside synthesis 1) an excellent leaving group at
the glycosyl donor, 2) success with an important
acceptor, and 3) successful removal of the strong
electron-withdrawing 2-O-protecting group are
required. These preconditions are met by the
method outlined herein.
For our study 3-O-allyl-2-O-benzylsulfonyl-
4,6-O-benzylidene-protected
mannopyranosyl
trichloroacetimidate (1) was selected as the
donor because this is a properly protected build-
ing block for the glycopeptide N-glycan syn-
thesis[16] (Scheme 3). Compound 1 was synthe-
sized from readily available methoxyphenyl
(MP) mannopyranoside (2).[22] Treatment with
benzylsulfonyl chloride in pyridine followed by
removal of the MP group with ceric(iii) ammo-
nium nitrate (CAN) in a mixture of acetonitrile/
water at 08C, and then reaction with trichloro-
acetonitile in the presence of DBU as the base
afforded 1 in a high overall yield. Coupling of
donor 1 (1.5 equiv) with 4-O-unprotected glucos-
amine derivative 3[25] as the acceptor (1 equiv), in
dichloromethane at À508C and in the presence
of TMSOTf as the catalyst, under inverse con-
ditions afforded, as hypothesized, mainly the
b(1-4)-linked disaccharide 4b (80% based on 3,
b:a ¼ 8:1); the mixture of anomers could be
readily separated by flash column chromatogra-
phy. The benzylsulfonyl group was removed by
treating 4b with a solution of sodium amide in
DMF at room temperature,[23f] which afforded 2-
O-unprotected 5b in 91% yield.
Scheme 3. Synthesis of 4 from 1; a) BnSO2Cl, pyr (91%); b) CAN, MeCN/H2O (4:1), O8C
(82%); c) CCl3CN, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (94%); d) TMSOTf, CH2Cl2,
À508C (80% b:a ¼ 8:1); e) NaNH2, DMF, RT (91%). All ¼ allyl; MPM ¼ para-
methoxybenzyl.
Because of the principal importance, 2-O-
benzylsulfonyl-3,4,6-tri-O-benzyl-protected
mannopyranosyl
trichloroacetimidate
(6)
(Scheme 4) was also investigated in b-manno-
pyranoside synthesis. The strong dipole effect
enforced by the benzylsulfonyl group should
favor formation of the twist boat intermediate of
type Bc (Scheme 2) even in the absence of the
4,6-O-benzylidene ring, and thus lead to b pro-
duct formation. The required donor 6 was pre-
pared from 3,4,6-tri-O-benzyl-d-mannose (7)[26]
by regioselective anomeric-O-silylation[11] with
thexyldimethylsilyl (TDS) chloride in the pres-
Scheme 4. Synthesis of Manb(1-4)GlcNAc disaccharide from 6 and 8 (R ¼ Bn); a) TDS-Cl,
imidazole, DMF (95%); b) BnSO2Cl, pyr (92%); c) TBAF, THF (90%); d) CCl3CN, DBU,
CH2Cl2 (97%); e) TMSOTf, CH2Cl2 (82%; b:a ¼ 9:1); f) TMSOTf, CH2Cl2 (78%, b:a ¼
7.4:1); g) NaNH2, DMF, RT (93%).
ence of imidazole; the ensuing reaction with benzylsulfonyl
chloride in pyridine, removal of the TDS group with
tetrabutylammonium fluoride (TBAF) in THF, and then
treatment with trichloroacetonitrile in the presence of DBU
afforded the donor 6 in high overall yield. Coupling 6 with
acceptor 3 under the above-described conditions led to even
better results than 1, and mainly afforded b-linked disacchar-
ide 9b (82%, 9b:9a 9:1). Similar results were obtained with
the corresponding mannopyranosyl donor 8;[27] presumably,
because of the lower reactivity, the b:a-ratio was somewhat
decreased (78%, 9b:9a 7:1). The 2-O-benzylsulfonyl group
(!10b) was again removed in high yield.[28]
The a and b configuration of the disaccharides 4a,b, 5a,b,
1
9a,b, and 10a,b, could be assigned with the J1C,1H coupling
constants of the anomeric protons. As expected,[29] these
values are 174.1 175.7 Hz for the a anomers and 162.3 163-
6 Hz for the b anomers.
In conclusion, a convenient and highly efficient method for
the synthesis of b-mannopyranosides is introduced. The
mannopyranosyl donors possess a strongly electron-with-
drawing 2-O-benzylsulfonyl group and a trichloroacetimidate
or pyridylthio group, respectively, as the leaving group at the
anomeric center. The deprotection of the 2-O-benzylsulfonyl
group was readily performed; thus, in addition, an often
Angew. Chem. Int. Ed. 2002, 41, No. 16
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2973

COMMUNICATIONS
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Received: March 6, 2002 [Z18837]
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[24] These results have had little attention; in some reviews on b-
mannopyranoside formation they are not even mentioned.
[25] 3: TLC (petroleum ether:ethyl acetate, 2:1) Rf ¼ 0.54; [a]D ¼ À6.58
(c ¼ 1.0, chloroform); 1H NMR (600 MHz, CDCl3): d ¼ 0.02 (s, 3H;
CH3), 0.09 (s, 3H; CH3), 0.80, 0.82, 0.84, 0.86 (4s, 12H; 4 CH3), 1.20
1.34 (m, 1H; CH), 1.98 (s, 3 H COCH3), 3.21 (m, 1H; 2-H), 3.45 (m,
1H; 4-H), 3.56 (m, 1H; 5-H), 3.73 3.81 (m, 4H; 6-H, OCH3), 4.10
[5] F. Barresi, O. Hindsgaul in Modern Methods in Carbohydrate Syn-
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895 911.
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¼
4.21 (m, 3H; 6’-H, CH2CH CH2), 4.35 4.40 (m, 3H; 3-H,
¼
CH2CH CH2), 5.28 (d, J ¼ 7.8 Hz, 1H; 1-H), 5.48 (s, 1H; CH2Ar),
¼
5.56 5.63 (m, 2H; NH, CH2CH CH2), 7.03 (d, J ¼ 7.5 Hz, 2H; Ar-H),
7.34 ppm (d, J ¼ 7.4 Hz, 2H; Ar-H); FAB-MS: (positive mode, NBOH/
NaI-matrix); m/z: 524 [MHþ], 546 [MNaþ].
[26] N. E. Franks, R. Montgomery, Carbohydr. Res. 1968, 3, 286 298; T. G.
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[27] 8: TLC (petroleum ether:ethyl acetate, 3:1) Rf ¼ 0.53; [a]D ¼ þ 1118
(c ¼ 0.2, chloroform); 1H NMR (600 MHz, CDCl3): d ¼ 3.70 (d, J ¼
11.0 Hz, 1H; 6-H), 3.85 (dd, J ¼ 4.0, 11.2 Hz, 1H; 6-H), 3.99 (dd, J3,2
¼
3.2 Hz, J3,4 ¼ 9.3 Hz, 1H; 3-H), 4.15 (t, J ¼ 9.6 Hz, 1H; 4-H), 4.16 (m,
1H; 5-H), 4.45 (d, J ¼ 11.9 Hz, 1H; CH2), 4.53 (d, J ¼ 10.7 Hz, 1H;
CH2), 4,55 (d, J ¼ 11.2 Hz, 1H; CH2), 4.59 (s, 2H; SO2CH2), 4.66 (d,
J ¼ 11.9 Hz, 1H; CH2) 4.75 (d, J ¼ 11.2 Hz, 1H; CH2), 4.80 (d, J ¼
10.9 Hz, 1H; CH2), 5.66 (m, 1H; 2-H), 6.45 (d, J ¼ 1.8 Hz, 1H; 1-H),
7.19 (d, J ¼ 7.0 Hz, 1H; Ar-H), 7.23 (d, J ¼ 7.1 Hz, 1H; Ar-H), 7.25 7.33
(m, 20H; 4 Ph), 7.50 (d, J ¼ 7.1 Hz, 1H; Ar-H), 8.50 ppm (d, J ¼ 6.0 Hz,
1H; Ar-H); MALDI-MS: m/z: 720 [MNaþ].
[28] 10b: TLC (petroleum ether:ethyl acetate, 5:1) Rf ¼ 0.34; [a]D ¼ þ
53.18 (c ¼ 0.1, chloroform); 1H NMR (600 MHz, CDCl3): d ¼ 0.12 (s,
3H; CH3), 0.23 (s, 3H; CH3), 0.85 0.89 (m, 12H; 4CH3), 1.64 1.71 (m,
1H; CH), 1.98 (s, 3H; COCH3), 3.31 (m, 1H; 2a-H), 3.50 (m, 1H;
4a-H), 3.56 (m, 1H; 5a-H), 3.66–3.71 (m, 10H; 2b-H, 3b-H, 4b-H,
2 6a-H, 2 6b-H, OCH3), 4.01 4.19 (m, 4H; 3a-H, 5b-H, CH2CH ¼ CH2),
4.48 (m, 2H; CH2), 4.52 4.68 (m, 9H; 1b-H, 3CH2, CH2CH ¼ CH2),
5.44 5.58 (m, 3H; 1a-H, NH, CH2CH ¼ CH2), 7.09 (d, J ¼ 7.5 Hz, 2H;
Ar-H), 7.16 (d, J ¼ 7.5 Hz, 2H; Ar-H), 7.22 7.33 ppm (m, 15H; 3Ph);
MALDI-MS: m/z: 979 [MÀNaþ].
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2974
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