Synthesis of Thio-Linked Disaccharides
J . Org. Chem., Vol. 65, No. 15, 2000 4613
(dd, 1H, J 1,2 ) 1.8, J 2,3 ) 3.3 Hz, H-2), 4.86, 4.47 (2d, each 1H,
J A,B ) 10.8 Hz, CH2Ph), 4.73 (d, 1 H, H-1), 4.69, 4.52 (2d, each
3.5, J 5′,6b′ ) 1.8 Hz, H-5′), 3.98 (t, 1H, J 3′4′ ) 9.5 Hz, H-4′),
3.92 (dd, 1H, H-3′), 3.74 (dd, 1H, J 6a′,6b′ ) 10.6 Hz, H-6a′), 3.68
(dd, 1H, J 3,4 ) J 4,5 ) 8.9 Hz, H-4), 3.68 (dd, 1H J 5,6a ) 3.1 Hz,
J 6a,6b ) 11.5 Hz, H-6a), 3.64 (dd, 1H, J 5,6b ) 2.0 Hz, H-6b),
3.62 (dd, 1H, J 2,3 ) 8.9 Hz, H-3), 3.58 (dd, 1H, H-6b′), 3.57 (t,
1H, H-2), 3.44 (ddd, 1H, H-5), 2.07 (s, 3H, OAc); 13C NMR
(CDCl3) δ 169.96 (OAc, CdO), 138.65, 138.53, 138.38, 138.23
(2C), 138.11, 137.75 (7 × C-ipso, Ph), 128.40-127.53 (35C, Ph),
86.66 (C-3), 84.22 (C-1), 81.84 (C-2), 81.49 (C-1′), 79.58 (C-5),
78.43 (C-3′), 77.63 (C-4), 75.53, 75.42, 75.13, 74.97 (CH2Ph),
74.38 (C-4′), 73.59, 73.42 (CH2Ph), 73.35 (C-5′), 71.86 (CH2-
Ph), 70.75 (C-2′), 68.87 (C-6′), 68.74 (C-6), 20.92 (OAc); MALDI
MS m/e 1053.8 (M+ + Na). Anal. Calcd for C63H66O11S: C,
73.37; H, 6.45. Found: C, 73.06; H, 6.37.
1H, J A,B ) 11.2 Hz, CH2Ph), 4.68, 4.52 (2d, each 1H, J A,B
)
12.1 Hz, CH2Ph), 3.97 (dd, 1H, J 3,4 ) 9.3 Hz, H-3), 3.87 (dd,
1H, J 4,5 ) 9.3 Hz, H-4), 3.80 (dd, J 5,6a ) 4.2, J 6a,6b ) 10.2 Hz,
H-6a), 3.79-3.68 (m, 2H, H-5 and H-6b), 3.36 (s, 3H, OCH3),
2.17 (s, 3H, OAc); MALDI MS m/e 529.3 (M+ + Na).
2-O-Acet yl-3,4,6-t r i-O-b en zyl-1-t h io-r-D-m a n n op yr a -
n ose (8). A solution of 3,4,6-tri-O-benzyl-â-D-mannopyranose
1,2-(methyl orthoacetate) 4b12 (2.58 g, 5.09 mmol) in CH2Cl2
(40 mL) was stirred in an ice bath while HBr/HOAc (3.0 mL,
35 wt %) was added dropwise. After 15 min, the solution was
washed with ice-water and cold saturated NaHCO3 solution,
dried over MgSO4, and concentrated to leave the unstable
mannosyl bromide 6 as a pale yellow oil (2.88 g). The oil was
dissolved in dry acetone (10 mL), and the solution was added
to freshly activated 4 Å molecular sieves (2 g) and thiourea
(388 mg, 5.10 mmol). The mixture was maintained at reflux
temperature under a dry N2 atmosphere for 2.5 h, cooled, and
filtered through Celite. Solvent removal and trituration of the
syrupy residue with hexanes gave 7 as a colorless amorphous
powder (3.10 g). Attempted crystallization of this salt from a
variety of mixed-solvent systems was unsuccessful. The crude
product was dissolved in CH2Cl2 (40 mL), a solution of Na2S2O5
(2.0 g) in water (20 mL) was added, and the mixture was
heated at 40 °C for 45 min. After cooling, the CH2Cl2 layer
was separated and washed with water and saturated aqueous
sodium chloride solution. Drying over anhyd Na2SO4, filtration,
and evaporation of the solvent gave the thiol 8 as a syrup (2.32
g, 89%): [R]D +60.3 (c 2.2, CHCl3); 1H NMR (CDCl3) δ 7.4-7.1
(m, 15H, Ph), 5.59 (dd, 1 H, J 1,2 ) 1.7 Hz, J 1,SH ) 7.2 Hz, H-1),
5.42 (dd, 1H, J 2,3 ) 3.1 Hz, H-2), 4.84, 4.48 (2d, each 1H, J A,B
) 10.7 Hz, CH2Ph), 4.69, 4.54 (2d, each 1H, J A,B ) 11.2 Hz,
CH2Ph), 4.66, 4.50 (2d, each 1H, J A,B ) 12.1 Hz, CH2Ph), 4.13
(ddd, 1H, J 4,5 ) 9.3, J 5,6a ) 4.3, J 5,6b ) 1.9 Hz, H-5), 3.96 (dd,
2,3,4,6-Tetr a-O-ben zyl-â-D-glu copyr an osyl 2-O-Meth an e-
su lfon yl-3,4,6-tr i-O-ben zyl-1-th io-r-D-m a n n op yr a n osid e
(11). A solution of the acetate 9 (1.96 g, 1.90 mmol) in CH2Cl2
(30 mL) was added to a NaOMe/MeOH solution (100 mL, 0.04
M), and the mixture was kept at room temperature for 4 h.
The reaction mixture was neutralized by stirring with Rexyn
101 H+ ion-exchange resin, filtered, and concentrated to give
a syrup. Pure 10 was obtained by column chromatography
(hexanes/EtOAc, 2:1) as a colorless glass (1.63 g, 89%): [R]D
1
+78 (c 1.4, CHCl3); H NMR (CDCl3) δ 7.4-7.1 (m, 35H, Ph),
5.69 (d, 1H, J 1′,2′ ) 1.6 Hz, H-1′), 4.89, 4.75 (2d, each 1H, J A,B
) 10.5 Hz, CH2Ph), 4.88, 4.85 (2d, each 1H, J A,B ) 11.1 Hz,
CH2Ph), 4.82, 4.49 (2d, each 1H, J A,B ) 11.0 Hz, CH2Ph), 4.80,
4.57 (2d, each 1H, J A,B ) 10.9 Hz, CH2Ph), 4.70, 4.66 (2d, each
1H, J A,B ) 11.5 Hz, CH2Ph), 4.54, 4.37 (2d, each 1H, J A,B
)
12.1 Hz, CH2Ph), 4.53, 4.49 (2d, each 1H, J A,B ) 9.9 Hz, CH2-
Ph), 4.47 (d, 1H, J 1,2 ) 9.5 Hz, H-1), 4.14 (dd, 1H, J 2′,3′ ) 3.1
Hz, H-2′), 4.14 (ddd, 1H, J 4′,5′ ) 9.6 Hz, J 5′,6a′ 3.6, J 5′,6b′ 2.0 Hz,
H-5′), 3.97 (dd, 1H, J 3′4′ 9.1 Hz, H-4′), 3.84 (dd, 1H, H-3′), 3.68
(dd, 1H, J 6a′,6b′ ) 10.8 Hz, H-6a′), 3.67-3.59 (m, 4H, H-3, H-4,
H-6a, H-6b), 3.58-3.53 (m, 1H, H-2), 3.54 (dd, 1H, H-6b′), 3.44
(m, 1H, H-5); 13C NMR (CDCl3) δ 138.54, 138.39, 138.09 (4C),
137.67 (7 × C-ipso, Ph), 128.55-127.59 (35C, Ph), 86.63
(C-3), 84.22 (C-1), 82.97 (C-1′), 81.73 (C-2), 80.06 (C-3′), 79.28
(C-5), 77.52 (C-4), 75.60, 75.34, 75.05, 74.99 (4 × CH2Ph), 74.20
(C-4′), 73.37 (2C, 2 × CH2Ph), 72.85 (C-5′), 72.04 (CH2Ph),
70.35 (C-2′), 68.62 (C-6), 68.47 (C-6′); MALDI MS m/e 1011.6
(M+ + Na).
1H, J 3,4 ) 9.3 Hz, H-3), 3.91 (dd, 1H, H-4), 3.81 (dd, J 6a,6b
)
10.9 Hz, H-6a), 3.67 (dd, H-6b), 2.17 (d, 1H, SH), 2.16 (s, 3H,
OAc); 13C NMR (CDCl3) δ 170.32 (OAc, CdO), 138.15, 138.03,
137.50 (3 × C-ipso, Ph), 128.47-127.65 (15C, Ph), 77.38, 77.23
(C-1, C-3), 75.26 (CH2Ph), 74.36 (C-4), 73.44 (C-5), 72.44 (CH2-
Ph), 71.92 (CH2Ph), 71.36 (C-2), 68.59 (C-6), 21.10 (OAc);
MALDI MS m/e 531.3 (M+ + Na). Anal. Calcd for C29H32O6S:
C, 68.48; H, 6.34. Found: C, 68.52; H, 6.56.
The alcohol 10 (1.60 g, 1.62 mmol) was dissolved in CH2Cl2
(15 mL), pyridine (2.5 mL) and methanesulfonyl chloride (1.0
mL, 13 mmol) were added, and the reaction mixture was kept
at room temperature for 3 h. The mixture was diluted with
CH2Cl2 and stirred with saturated aqueous NaHCO3 solution
for 0.5 h to hydrolyze excess methanesulfonyl chloride. The
organic phase was separated, washed with saturated aqueous
NaHCO3, and dried over MgSO4. Solvent removal left a yellow
oil that was purified by column chromatography (hexanes/
EtOAc, 5:2) to yield 11 as a colorless waxy solid (1.54 g, 89%):
2,3,4,6-Tetr a -O-ben zyl-â-D-glu cop yr a n osyl 2-O-Acetyl-
3,4,6-tr i-O-ben zyl-1-th io-r-D-m an n opyr an oside (9). 2,3,4,6-
Tetra-O-benzyl-D-glucopyranose (1.35 g, 2.50 mmol) was dis-
solved in CH2Cl2 (25 mL) containing a catalytic amount of
DMF (0.20 mL). A solution of oxalyl chloride (0.85 mL, 9.7
mmol) in CH2Cl2 (5 mL) was added dropwise over 10 min. The
mixture was stirred at room temperature for 2 h and concen-
trated in vacuo to give the glycosyl chloride 1 quantitatively.
To the chloride 1 was added a solution of the thiol 8 (1.13 g,
2.22 mmol) in acetone (20 mL). Solid n-Bu4NBr (0.15 g, 0.46
mmol) and K2CO3 (1.0 g, 7.2 mmol) were added, and the
heterogeneous mixture was refluxed under N2 for 18 h. The
mixture was cooled, the acetone was removed in vacuo, and
the residue was partitioned between CH2Cl2 and water. The
organic phase was washed with water, dried over anhyd
MgSO4, and concentrated to give a dark, red-brown oil. The
oil was acetylated by treatment with acetic anhydride (3 mL),
pyridine (7 mL), and a catalytic amount of 4-(dimethylamino)-
pyridine for 4 h at 45 °C. The mixture was concentrated on
high vacuum and coevaporated with toluene. Purification by
silica gel chromatography (hexanes/EtOAc, 3:1) yielded 9 as
a pale-yellow syrup (1.02 g, 45%). Analysis by 1H NMR
indicated a purity of >90% with minor amounts of anomeric
1
[R]D +43 (c 1.2, CHCl3); H NMR (CDCl3) δ 7.4-7.1 (m, 35H,
Ph), 5.82 (d, 1H, J 1′,2′ ) 1.9 Hz, H-1′), 5.20 (dd, 1H, J 2′,3′ ) 2.3
Hz, H-2′), 4.90, 4.85 (2d, each 1H, J A,B ) 11.1 Hz, CH2Ph),
4.89, 4.74 (2d, each 1H, J A,B ) 10.3 Hz, CH2Ph), 4.82, 4.48
(2d, each 1H, J A,B ) 10.7 Hz, CH2Ph), 4.81, 4.57 (2d, each 1H,
J A,B ) 10.8 Hz, CH2Ph), 4.80, 4.62 (2d, each 1H, J A,B ) 11.1
Hz, CH2Ph), 4.56, 4.50 (2d, each 1H, J A,B ) 12.1 Hz, CH2Ph),
4.55, 4.39 (2d, each 1H, J A,B ) 12.0 Hz, CH2Ph), 4.47 (d, 1H,
J 1,2 ) 9.2 Hz, H-1), 4.10-4.04 (m, 1H, H-5′), 3.96-3.88 (m,
2H, H-3′, H-4′), 3.72 (dd, 1H, J 5′,6a′ ) 4.0, J 6a′,6b′ ) 11.0 Hz,
H-6a′), 3.70-3.63 (m, 3H, H-4, H-6a, H-6b), 3.68 (dd, 1H, H-4),
3.64 (dd, 1H, J 2,3 ) J 3,4 ) 8.6 Hz, H-3), 3.58 (dd, 1H, H-2),
3.57 (dd, 1H, J 5′,6b′ ) 1.9 Hz, H-6b′), 3.47 (ddd, 1H, J 4,5 ) 9.4,
J 5,6a ) 3.4, J 5,6b ) 2.3 Hz, H-5), 2.92 (s, 3H, OSO2-CH3); 13C
NMR (CDCl3) δ 139.0-137.0 (7 × C-ipso, Ph), 128.46-127.53
(35C, Ph), 86.60 (C-3), 83.77 (C-1), 81.46 (C-2), 80.88 (C-1′),
79.54 (C-5), 78.80 (C-2′), 77.85 (C-3′), 77.18 (C-4), 75.52, 75.35,
75.10, 74.94 (4 × CH2Ph), 74.16 (C-4′), 74.06 (C-5′), 73.55,
73.45, 72.64 (3 × CH2Ph), 68.94 (C-6), 68.56 (C-6′), 32.87 (OMs,
CH3); MALDI MS m/e 1089.3 (M+ + Na). Anal. Calcd for
1
isomers: [R]D +47 (c 1.5, CHCl3); H NMR (CDCl3) δ 7.4-7.1
(m, 35H, Ph), 5.67 (d, 1H, J 1′,2′ ) 1.5 Hz, H-1′), 5.53 (dd, 1H,
J 2′,3′ ) 2.9 Hz, H-2′), 4.89, 4.85 (2d, each 1H, J A,B ) 10.7 Hz,
CH2Ph), 4.89, 4.75 (2d, each 1H, J A,B ) 10.3 Hz, CH2Ph), 4.85,
4.46 (2d, each 1H, J A,B ) 10.3 Hz, CH2Ph), 4.80, 4.57 (2d, each
1H, J A,B ) 10.8 Hz, CH2Ph), 4.70, 4.52 (2d, each 1H, J A,B
)
11.1 Hz, CH2Ph), 4.58, 4.36 (2d, each 1H, J A,B ) 12.0 Hz,
CH2Ph), 4.56, 4.49 (2d, each1 H, J A,B ) 12.0 Hz, CH2Ph), 4.46
C
62H66O12S2: C, 69.79; H, 6.23. Found: C, 69.77; H, 6.22.
Meth yl 3,4,6-Tr i-O-ben zyl-2-S-(2,3,4,6-tetr a -O-ben zyl-
â-D-glu cop yr a n osyl)-2-t h io-r/â-D-glu cop yr a n osid e (12r
(d, 1H, J 1,2 ) 9.2 Hz, H-1), 4.14 (ddd, 1H, J 4′,5′ ) 9.5, J 5′,6a′
)