Our strategy involves a one-pot regioselective synthesis
of 2,4-di-O-acyl-3-O-tert-butyldimethylsilyl-6-O-trityl gly-
coside, exemplified by the preparation of corresponding R-D-
mannopyranoside 2. In this protocol, allyl R-D-mannopyra-
noside 1 was subjected to the following three sequential
reactions in one-pot: (1) treatment of 1 with 1.25 equiv of
trityl chloride and catalytic amount of 4-(dimethylamino)-
pyridine (DMAP) in pyridine at 80 °C; (2) regioselective
silylation on C-3 with 1.1 equiv of tert-butyldimethylchlo-
rosilane (TBDMSCl) and 2 equiv of imidazole at room
temperature; and (3) benzoylation on C-2 and C-4 with 2.5
equiv of BzCl at 50 °C.5 One column separation gave allyl
2,4-di-O-benzoyl-3-O-tert-butyldimethylsilyl-6-O-trityl-R-
D-mannopyranoside (2) in an isolated yield of 79%. The
higher reactivity of the 3-OH in mannopyranoside is not
unexpected since the 2-OH is in the sterically hindered axial
position, and the 4-OH is generally known to be the least
reactive. We were gratified to find that the new method was
also effective for other sugar derivatives.6 For example, â-D-
glucopyranoside 5, 7 and â-D-galactopyranoside 11 were
transformed into the corresponding 3,6-disubstituted com-
pound 6, 8, and 12, respectively, in good to excellent yields.
On the other hand, when the aforementioned one-pot reaction
was applied to the R-D-glucopyranoside 9, 2-selective
silylation was given leading to methyl 3,4-di-O-acetyl-2-O-
tert-butyldimethylsilyl-6-O-trityl-R-D-glucopyranoside 10 in
high yield (86% after column purification), while the same
reaction for methyl R-D-galactopyranoside 13 generated a
regio-isomeric mixture of 14 and 15 (91% yield in total). It
is worth to note that changing 6-O-trityl to 6-O-tert-
butyldiphenylsilyl, as in 3, afforded 3,6-disubstituted man-
nopyranoside 4 in good yield (71%).7
Table 1. Regioselective Tritylation and Silylation on
Monosaccharide
(5) Typical reaction procedure is as following: To a solution of 1 (7 g,
31.8 mmol) in pyridine (65 mL) was added 1.25 equiv of TrCl and 30 mg
of DMAP. The mixture was stirred at 80 °C for 16 h, then cooled to 0 °C,
added 2 equiv of imidazole. Finally, 1.1 equiv of TBDMSCl in DMF (5
mL) was added portion in portion during 2 h. The mixture was stirred at
room temperature overnight, then a premixed BzCl (2.5 equiv) and pyridine
(5 mL) was added. Let the reaction mixture stirred at 50 °C overnight,
then poured into ice-cold water, extracted with EtOAc. The organic phase
was concentrated to dryness with the help of toluene. The residue was
subjected to column chromatography on silica gel with petroleum ether/
EtOAc as the eluent (12/1) to give 2 (19.7 g, 79%). Similarly, using Ac2O
(3 equiv) instead of BzCl in the aforementioned acylation step furnished
the corresponding acetylated derivatives smoothly.
(6) We cannot give an unbeatable explanation for this regioselectivity.
We found that the orientation of anomeric oxygen or sulfur atom is critical
to the reaction outcomes. Generally, R-D-manno-, â-D-gluco- and â-D-
galactopyranosides gave 3,6-disubstituted products. Interestingly, R-D-
glucopyranosides generated 2,6-disubstitutes while R-D-galactopyranosides
gave 2,6- and 3,6-disubstituted mixtures.
These 3,6- or 2,6-differentially protected carbohydrates are
very useful intermediates for oligosaccharide synthesis.
H-6), 4.14 (ddd, 1 H, H-5), 4.20-4.53 (m, 12 H), 4.58 (dd, 1 H, H-6), 4.67
(dd, 1 H, H-3), 4.73 (dd, 1 H, H-3), 4.78 (d, 1 H, H-1), 5.17-5.19 (m, 2
H, H-1 and one proton of CH2dCH-CH2-), 5.21 (d, 1 H, H-1), 5.29-
5.32 (m, 3 H, H-1, H-2, and one proton of CH2dCH-CH2-), 5.37 (d, 1
H, H-1), 5.44 (dd, 1 H, H-2), 5.57 (dd, 1 H, H-2), 5.65 (dd, 1 H, H-3),
5.69-5.74 (m, 2 H, H-2, H-3), 5.82 (dd, 1 H, H-2), 5.85-6.01 (m, 4 H,
H-3, 2 H-4, CH2dCH-CH2), 6.04 (t, 1 H, H-4), 6.07 (t, 1 H, H-4), 6.08 (t,
1 H, H-4), 7.18-8.35 (m, 80 H, Ph). (27) δ 0.88 (t, 3 H, CH3), 1.25-1.35
(bs, 10 H, 5 CH2), 1.45-1.55 (m, 2 H, CH2), 2.00, 2.02, 2.02, 2.03, 2.04,
2.06, 2.09, 2.09, 2.09 (7 s, 27 H, 9 CH3CO), 3.40 (dt, 1 H, one proton of
OCH2), 3.55-3.68 (m, 5 H, H-5B, H-5C, H-3A, H-6aA, H-6bA), 3.80-3.90
(m, 3 H, H-3C, H-5A, one proton of OCH2), 4.03 (dd, 1 H, J ) 2.2, J )
12.4 Hz, H-6aB/H-6aC), 4.10 (dd, 1 H, J ) 2.1, J ) 12.3 Hz, H-6aC/H-
6aB), 4.25-4.32 (m, 3 H, J ) 8.1 Hz, H-1A, H-6bB, H-6bC), 4.50 (d, J )
8.1 Hz, H-1C), 4.55 (s, 2 H, PhCH2), 4.57 (d, 1 H, J ) 8.1 Hz, H-1B), 4.69
(t, 1 H, J ) 9.7 Hz, H-4A), 4.88-5.00 (m, 3 H, H-2A,B,C), 5.06 (t, J ) 9.7
Hz, H-4C), 5.09 (t, 1 H, J ) 9.7 Hz, H-4B), 5.18 (t, 1 H, J ) 9.5, H-3B),
7.21-7, 33 (m, 5 H, Ph). (30) δ 0.88 (t, 3 H), 1.24-1.27 (m, 10 H), 1.40-
1.50 (m, 2 H), 1.94 (s, 3 H), 1.95 (s, 3 H), 1.96 (bs, 6 H), 1.98 (s, 3 H),
1.99 (s, 6 H), 2.01 (s, 9 H), 2.02 (s, 3 H), 2.03 (s, 3 H), 2.08 (s, 3 H), 2.09
(2 s, 6 H), 2.13 (s, 3 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 2.24 (s, 3 H), 3.40 (dt,
1 H, one proton of OCH2), 3.50-3.55 (m, 1 H), 3.56-3.72 (m, 6 H), 3.72-
3.77 (m, 1 H), 3.78-3.91 (m, 5 H), 3.96 (dd, 1 H), 4.05 (dd, 1 H), 4.09-
4.40 (m, 3 H), 4.43-4.58 (m, 6 H), 4.62-4.75 (m, 3 H), 4.86-4.94 (m, 2
H), 4.95-5.05 (m, 4 H), 5.10-5.22 (m, 6 H). Selected 13C NMR (CDCl3,
100 MHz) δ 95.48, 99.95, 100.24, 100.38, 100.75, 100.89 (6 C-1), 168.55,
168.73, 168.81, 169.20 (2 C), 169.24, 169.28, 169.39, 169.44 (2 C), 170.13
(2 C), 170.20, 170.24, 170.49, 170.60, 170.63, 171.10, 171.17 (19 CH3CO).
(7) Selected 1H NMR (400 MHz, CDCl3, 25 °C, TMS): (19) δ 3.84
(dd, 1 H, J < 1, J ) 9.2 Hz, H-6a), 4.15 (dd, 1 H, J ) 6.3, J ) 11.0 Hz,
H-6b), 4.30-4.37 (m, 2 H), 4.48-4.58 (m, 5 H), 4.73 (dd, 1 H, J ) 3.4,
J ) 9.8 Hz, H-3), 5.10 (d, 1 H, J ) 1.2 Hz, H-1), 5.38-5.41 (m, 2 H, H-1,
H-2), 5.69-5.73 (m, 2 H, H-2, H-3), 5.90-5.95 (m, 2 H), 6.01 (t, 1 H, J
) 10.8 Hz, H-4), 6.07 (t, 1 H, J ) 10.0 Hz, H-4), 6.12 (t, 1 H, J ) 10.0
Hz, H-4), 6.59 (d, 1 H, J ) 1.5 Hz, H-1), 7.00-8.13 (m, 50 H, Ph), 9.00
(s, 1 H, NH). (21) δ 2.89 (bs, H, OH), 3.75-3.80 (m, 2 H, 2 H-6), 4.00
(ddd, 1 H, H-5), 4.07 (ddd, 1 H, H-5′), 4.18-4.25 (m, 1 H, CH2dCH-
CH2), 4.35 (dd, 1 H, J5′,6′a ) 3.6, J6′a, 6′b ) 12.3 Hz, H-6′a), 4.44-4.50 (m,
1 H, CH2dCH-CH2), 4.61 (dd, 1 H, J5′,6′b ) 2.4 Hz, H-6′b), 4.70 (dd, 1
H, J2,3 ) 3.5, J3,4 ) 9.8 Hz), 5.15 (d, 1 H, J1,2 ) 1.4 Hz, H-1), 5.23-5.36
(m, 3 H, H-2 and CH2dCH-CH2), 5.41 (d, 1 H, J1′,2′ ) 1.7 Hz, H-1′),
5.65-5.69 (m, 2 H, H-2′, H-3′), 5.72 (t, 1 H, J3,4 ) 10 Hz, H-4), 5.89 (m,
1 H, CH2dCH-CH2), 6.02 (t, 1 H, J3′,4′ 10.0 Hz, H-4′), 7.19-8.25 (m, 30
H, Ph). (22) δ 3.44 (bd, 1 H, H-6), 3.82 (dd, 1 H, H-6), 4.01 (dd, 1 H,
3798
Org. Lett., Vol. 2, No. 24, 2000