Facile syntheses of D-mannose hexa- and nonasaccharides: The di- and trimer of the trisaccharide repeating unit of the cell-wall mannans of Epidermophyton floccosum, Trychophyton mentagrophytes, Microsporum canis and related species of Microsporum

Article abstract of DOI:10.1016/S0040-4039(01)02232-8

A highly efficient strategy for the preparation of D-mannose hexa- and nonasaccharides, the dimer and trimer of the α-D-Manp-(1→6)-[α-D-Manp-(1→2)-]D-Manp trisaccharide repeating unit of the cell-wall mannans from the fungi Epidermophyton floccosum, Trychophyton mentagrophytes, Microsporum canis, M. cookei and M. racemosum, has been developed using 1,2,6-tri-O-acetyl-3,4-di-O-benzoyl-α-D-mannopyranose (6) as the key synthon.

Full text of DOI:10.1016/S0040-4039(01)02232-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 673–675
Facile syntheses of
D-mannose hexa- and nonasaccharides: the
di- and trimer of the trisaccharide repeating unit of the cell-wall
mannans of Epidermophyton floccosum, Trychophyton
mentagrophytes, Microsporum canis and related species of
Microsporum
Jun Ning,a Linsen Hengb and Fanzuo Konga,*
aResearch Center for Eco-Environmental Sciences, Academia Sinica, PO Box 2871, Beijing 100085, PR China
bDaxian Normal College, Department of Chemistry, Sichuan, PR China
Received 25 October 2001; revised 15 November 2001; accepted 22 November 2001
Abstract—A highly efficient strategy for the preparation of
a- -Manp-(1“6)-[a- -Manp-(1“2)-] -Manp trisaccharide repeating unit of the cell-wall mannans from the fungi Epidermophy-
ton floccosum, Trychophyton mentagrophytes, Microsporum canis, M. cookei and M. racemosum, has been developed using
1,2,6-tri-O-acetyl-3,4-di-O-benzoyl-a- -mannopyranose (6) as the key synthon. © 2002 Elsevier Science Ltd. All rights reserved.
D-mannose hexa- and nonasaccharides, the dimer and trimer of the
D
D
D
D
Facile, efficient and selective synthesis of oligosaccha-
rides is a central problem in carbohydrate chemistry.
For the past few years, considerable progress has been
made in the oligosaccharide synthesis field. However,
owing to their structural complexity, attempts to estab-
lish a general process for the construction of oligosac-
charides is still impossible. More new and efficient
strategies for the chemical synthesis of oligosaccharides
having specific structures are needed.
activity, it would be necessary to synthesize different
fragments of these fungi mannans. So far there has
been no general method for the construction of the
fragments of these mannans.2 Here we disclose a highly
efficient strategy for the preparation of this kind of
oligosaccharide using 1,2,6-tri-O-acetyl-3,4-di-O-ben-
zoyl-a-
D
-mannopyranose (6) as a synthon. The synthe-
-non-
ses of allyl-a-
D
-hexamannoside 1 and allyl-a-
D
amannoside 2, the dimer and the trimer of the trisac-
charide repeating unit of these mannans, are presented
as typical examples.
The 2,6-di-O-(a-D-mannopyranosyl)-D-mannopyranose
structure is a common repeating unit of the cell-wall
mannans of many fungi such as Epidermophyton flocco-
sum, Trychophyton mentagrophytes, Microsporum canis,
M. cookei and M. racemosum.1–3 These fungi parasitize
man and animals, and cause superficial cutaneous infec-
tions involving primarily the keratinized tissues of the
epidermis, nails and pilosebaceous follicles.4 Studies
show that one of the causes of the infection resides in
the immunosuppressive effects of the cell-wall mannans
of these organisms.5–7 To elucidate further the molecu-
lar structure responsible for this immunoinhibitory
As shown in Scheme 1, tritylation of 1,2-O-ethylidene-
b-
a one-pot manner gave the 3,4-di-O-benzoyl-6-O-
trityl-1,2-O-ethylidene- -mannopyranose (4) in 70%
yield. Hydrolysis of 4 with 90% CF3COOH afforded
the 3,4-di-O-benzoyl-
D
-mannopyranose8 (3) followed by benzoylation in
D
D
-mannopyranose (5) in 88%
yield. Subsequent acetylation with acetic anhydride
in pyridine furnished 1,2,6-tri-O-acetyl-3,4-di-O-ben-
zoyl-a-
D
-mannopyranose (6) as the key synthon
(Scheme 1).
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02232-8

674
J. Ning et al. / Tetrahedron Letters 43 (2002) 673–675
Scheme 1. Reagents and conditions: (a) i. trityl chloride (1.2 equiv.), pyridine, 50°C, 32 h, ii. PhCOCl (4.8 equiv.), <40°C, 24 h;
70% (for two steps); (b) F3CCOOH (90%), rt, 4 h, 88%; (c) Ac2O, pyridine, rt, 5 h, 100%.
The synthesis of oligosaccharides from 6 is shown in
Scheme 2. Thus, allyl 2,6-di-O-acetyl-3,4-di-O-benzoyl-
a- -mannopyranoside (7) was prepared using 6 as the
5.33) and three H-1 signals (l 5.32, 5.27, 5.18), confirm-
ing the structure of 11. Selective removal of the
6-O-acetyl group of the trisaccharide 11 gave the glyco-
syl acceptor 12 in 93% yield. Deallylation11 of 11 with
PdCl2 followed by activation with CCl3CN in the pres-
ence of K2CO3 or DBU gave the trisaccharide donor 13
in 71% yield (for two steps). The fully protected hexas-
accharide 14 was smoothly obtained by coupling 12
D
glycosyl donor and allyl alcohol as the acceptor in 87%
yield.9 Selective removal of the acetyl groups of 7 in
methanol containing 0.5% HCl gave the glycosyl accep-
tor 8 in 96% yield.10 Selective 6-O-glycosylation of 8
with 6-O-acetyl-2,3,4-tri-O-benzoyl-a-D-mannopyran-
osyl trichloroacetimidate10 as the glycosyl donor gave
with 13 in 84% yield. The H NMR spectrum of 14
1
the disaccharide 9 in 86% yield. Acetylation of 9 confi-
showed one acetyl signals (l 2.04), allyl signals (l
5.44–5.28) and six H-1 signals (l 5.34, 5.34, 5.31, 5.19,
5.03 and 4.80), characteristic of the structure of the
hexasaccharide 14.12 Selective removal of the 6-O-acetyl
group of the hexasaccharide 14 followed by coupling
with 13 gave the nonasaccharide 16 in 81% yield. The
1H NMR data of 16 contained structurally characteris-
tic information, i.e. one acetyl signals (l 2.35), allyl
signals (l 5.42–5.25) and nine H-1 signals (l 5.40, 5.34,
5.29, 5.29, 5.22, 5.18, 5.17, 4.99 and 4.85). Deprotection
of 14 and 16 in ammonia-saturated methanol gave the
1
rmed 6-O-glycosylation as the H NMR spectrum of
acetylated disaccharide 10 showed a newly emerged
doublet of doublets at l 5.52 ppm for H-2. Coupling 9
with 2,3,4,6-tetra-O-benzoyl-a-D-mannopyranosyl tri-
chloroacetimidate10 afforded the trisaccharide 11 in
85% yield. For accumulation of 11, a one-pot manner
was used. Thus, selective coupling of 8 with 6-O-acetyl-
2,3,4-tri-O-benzoyl-a-
D-mannopyranosyl trichloroace-
timidate, followed by condensation with 2,3,4,6-tetra-
O-benzoyl-a-D-mannopyranosyl trichloroacetimidate
afforded 11 readily. The 1H NMR spectrum of 11
showed one acetyl signal (l 1.99), allyl signals (l 5.47–
title allyl-a-
D
-hexamannoside 1 and allyl-a-D-nonaman-
noside 2. A bioassay of 1 and 2 is in progress.
Scheme 2. Reagents and conditions: (a) allyl alcohol (2 equiv.), TMSOTf (0.26 equiv.), CH2Cl2, rt, 3 h, 87%; (b) methanol/0.5%
HCl, rt, 12–14 h, 93–96%; (c) 6-O-acetyl-2,3,4-tri-O-benzoyl-a- -mannopyranosyl trichloroacetimidate (1.0 equiv.), CH2Cl2,
TMSOTf (0.08 equiv.), rt, 3 h, 86%; (d) 2,3,4,6-tetra-O-benzoyl-a- -mannopyranosyl trichloroacetimidate (1.4 equiv.), CH2Cl2,
D
D
TMSOTf (0.16 equiv.), rt, 3 h, 85%; (e) Ac2O, pyridine, rt, 5 h, 100%; (f) i. PdCl2, CH3OH–CH2Cl2, 2 h, ii. CCl3CN, DBU,
CH2Cl2, 8 h, 71% (two steps); (g) 13 (1.2 equiv.), CH2Cl2, TMSOTf (0.3 equiv.), rt, 3 h, 84%; (h) CH3OH satd with dry NH3,
rt, 72 h, 95–98%; (m) 13 (1.2 equiv.), CH2Cl2, TMSOTf (0.3 equiv.), rt, 3 h, 81%.

J. Ning et al. / Tetrahedron Letters 43 (2002) 673–675
675
In summary, we have successfully developed a highly
efficient strategy for the preparation of mannose
oligosaccharides found in many fungi cell-wall man-
CH2CHꢀCH2), 98.7, 97.0 (2 C-1), 20.4 (COCH3). Anal.
calcd for C52H48O17: C, 66.10; H, 5.12. Found: C, 66.27;
H, 5.05. For 10: [h]D −35.7° (c 2.0, CHCl3); 1H NMR
(CDCl3, 400 MHz): l 6.05 (m, 1H, CHꢀCH2), 5.52 (dd,
1H, J1,2=1.8 Hz, J3,2=4.6 Hz, H-2), 5.48–5.34 (2H,
CHꢀCH2), 5.14 (d, 1H, J2%,1%=1.2 Hz, H-1%), 5.04 (d, 1H,
nans with the a-
D
-mannopyranosyl-(1“6)-[a-
D-manno-
-mannopyranose trisaccharide
pyranosyl-(1“2)-]
D
repeating unit as a feature. The sole use of acyl groups
in the synthesis substantially simplified the procedure.
J
2,1=1.1 Hz, H-1), 2.21, 1.98 (2s, 6H, 2COCH3). For 11:
1
[h]D −87.1° (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz):
l 5.47–5.33 (m, 2H, CHꢀCH2), 5.32 (d, 1H, J=1.2 Hz,
H-1), 5.27 (d, 1H, J=1.3 Hz, H-1), 5.18 (d, 1H, J=1.5
Hz, H-1), 1.99 (s, 3H, COCH3); 13C NMR (100 MHz,
CDCl3): 170.4 (COCH3), 118.1 (1CH2CHꢀCH2), 99.7,
97.8, 97.4 (3C-1), 20.5 (COCH3). Anal. calcd for
C86H74O26: C, 67.80; H, 4.90. Found: C, 67.61; H, 4.93.
For 13: [h]D −49.3° (c 2.0, CHCl3); 1H NMR (CDCl3, 400
MHz): l 8.82 (s, 1H, OC(NH)CCl3), 6.67 (d, 1H, J=1.1
Hz, H-1), 5.38 (d, 1H, J=1.0 Hz, H-1), 5.19 (d, 1H,
J=1.2 Hz, H-1), 1.96 (s, 3H, COCH3); 13C NMR (100
MHz, CDCl3): 170.3 (COCH3), 159.8 (OC(NH)CCl3),
99.5, 97.4, 96.1 (3C-1), 90.5 (OC(NH)CCl3), 20.4
(COCH3). Anal. calcd for C85H70O26NCl3: C, 62.72; H,
4.33. Found: C, 62.90; H, 4.39. For 14: [h]D −55.6° (c 1.0,
CHCl3); 1H NMR (CDCl3, 400 MHz): l 5.44 (dd, 1H,
2J=1.3 Hz, 3Jtrans=17.1 Hz, CHꢀCH2), 5.34 (m, 2H,
2H-1), 5.31 (d, 1H, H-1), 5.28 (dd, 1H, 2J=1.3 Hz,
3Jcis=10.4 Hz, CHꢀCH2), 5.19 (d, 1H, H-1), 5.03 (d, 1H,
H-1), 4.80 (d, 1H, H-1), 2.04 (s, 3H, COCH3); 13C NMR
Acknowledgements
This work was supported by the National Natural
Science Foundation of China (59973026 and 29905004).
References
1. Kawarasaki, I.; Takeda, T.; Shimonaka, H.; Nozawa, Y.
Chem. Pharm. Bull. 1979, 27, 2073–2075.
2. Takeda, T.; Kawarasaki, I.; Ogihara, Y. Carbohydr. Res.
1981, 89, 301–308.
3. Jime´nez-Barbero, J.; Prieto, A.; Go´mez-Miranda, B.;
Bernabe´, M. Carbohydr. Res. 1995, 272, 121–128.
4. Wu-yuan, C. D.; Hashimoto, T. J. Bacteriol. 1977, 129,
1584–1592.
5. Blake, J. S.; Dahl, M. V.; Herron, M. J.; Nelson, R. D.
J. Invest. Dermatol. 1991, 96, 657–661.
(100
MHz,
CDCl3):
170.4
(COCH3),
118.1
6. Grando, S. A.; Hostager, B. S.; Dahl, M. V.; Nelson, R.
(CH2CHꢀCH2), 100.0, 99.8, 98.5, 97.9, 97.9, 97.6 (6C-1),
78.0, 77.3 (2C-2), 20.4 (COCH3). Anal. calcd for
C167H140O50: C, 68.07; H, 4.79. Found: C, 68.19; H, 4.87.
For 1: [h]D +49.2° (c 1.0, H2O); 1H NMR (D2O, 400
MHz): l 5.86 (m, 1H, CHꢀCH2), 5.27–5.17 (m, 2H,
CHꢀCH2), 5.03 (m, 2H, 2H-1), 4.94 (d, 1H, H-1), 4.92 (d,
1H, H-1), 4.83 (d, 1H, H-1), 4.81 (d, 1H, H-1); 13C NMR
(100 MHz, D2O): 119.4 (CH2CHꢀCH2), 103.1, 103.0,
100.3, 100.1, 98.8, 98.3 (6C-1), 79.7, 79.6 (2C-2). HRMS.
calcd for C39H66O31: 1030.93 [M]. found: 1053.4 (M+
Na)+. For 16: [h]D −59.5° (c 1.0, CHCl3); 1H NMR
D. J. Invest. Dermatol. 1992, 98, 876–880.
7. Grando, S. A.; Hostager, B. S.; Dahl, M. V.; Nelson, R.
D. Acta Derm. Venereol. 1992, 72, 273–276.
8. Betaneli, V. I.; Backinowsky, L. V.; Kochetkov, N. K. A.
Carbohydr. Res. 1982, 107, 285–291.
9. Liao, W.; Lu, D. Carbohydr. Res. 1996, 296, 171–182.
10. Heng, L.; Ning, J.; Kong, F. J. Carbohyr. Chem. 2001,
20, 285–296.
11. Boss, R.; Scheffold, R. Angew. Chem. 1976, 88, 578–579.
12. All new compounds gave satisfactory elemental analysis
results. Selected physical data for some key compounds
are as follows, for 6: mp 142–144°C; [h]D −28.2° (c 1.0,
CHCl3); 1H NMR (CDCl3, 400 MHz): l 6.21 (d, 1H,
2
3
(CDCl3, 400 MHz): l 5.42 (dd, 1H, J=1.2 Hz, Jtrans
=
15.7 Hz, CHꢀCH2), 5.40 (d, 1H, H-1), 5.34 (d, 1H, H-1),
2
3
5.29 (m, 2H, 2H-1), 5.25 (dd, 1H, J=1.2 Hz, Jcis=10.4
Hz, CHꢀCH2), 5.22 (d, 1H, H-1), 5.18 (d, 1H, H-1), 5.17
(d, 1H, H-1), 4.99 (d, 1H, H-1), 4.85 (d, 1H, H-1), 2.35 (s,
3H, COCH3); 13C NMR (100 MHz, CDCl3): 118.0
(CH2CHꢀCH2), 100.1, 100.1, 99.9, 98.8, 98.6, 98.0, 97.9,
97.9, 97.6 (9C-1), 78.2, 78.0, 77.2 (3C-2). Anal. calcd for
C248H206O74: C, 68.16; H, 4.75. Found: C, 68.01; H, 4.81.
For 2: [h]D +37.2° (c 1.0, H2O); 1H NMR (400 MHz,
J
2,1=1.9 Hz, H-1), 5.84 (dd, 1H, J3,4=J5,4=9.9 Hz, H-4),
5.75 (dd, 1H, J2,3=4.7 Hz, J4,3=10.1 Hz, H-3), 5.48 (dd,
1H, J1,2=1.9 Hz, J3,2=4.7 Hz, H-2), 4.36–4.20 (m, 3H,
H-5, H-6a, H-6b), 2.24, 2.18, 2.05 (3s, 9H, 3COCH3).
Anal. calcd for C26H26O11: C, 60.70; H, 5.09. Found: C,
60.45; H, 5.06. For 8: [h]D −18.6° (c 2.0, CHCl3); 1H
NMR (CDCl3, 400 MHz): l 8.00–7.32 (m, 10H, 2PhH),
5.97 (m, 1H, CHꢀCH2), 5.82–5.75 (m, 2H, H-3, 4),
5.39–5.27 (m, 2H, CHꢀCH2), 5.05 (d, 1H, J2,1=1.6 Hz,
H-1). For 9: [h]D −50.0° (c 1.0, CHCl3); 1H NMR
(CDCl3, 400 MHz): l 6.04 (m, 1H, CHꢀCH2), 5.49–5.33
(m, 2H, CHꢀCH2), 5.16 (d, 1H, J2%,1%=1.3 Hz, H-1%), 5.08
(d, 1H, J2,1=1.0 Hz, H-1), 2.01 (s, 3H, COCH3); 13C
NMR (100 MHz, CDCl3): 170.4 (1C, COCH3), 165.5,
165.4, 165.3, 165.1, 165.0 (5C, 5COPh), 117.9 (1C,
D2O):
l
5.84 (m, 1H, CHꢀCH2), 5.24–5.14 (2H,
CHꢀCH2), 4.98–4.97 (m, 3H, 3H-1), 4.93–4.89 (m, 3H,
H-1), 4.79–4.77 (m, 3H, H-1); 13C NMR (100 MHz,
D2O): 114.7 (CH2CHꢀCH2), 98.5, 98.4, 98.4, 95.8, 95.7,
95.7, 94.4, 94.4, 93.9 (9C-1), 75.0, 74.9, 74.9 (3C-2).
HRMS. calcd for C57H96O46: 1517.34 [M]. Found: 1540.1
(M+Na)+.