A simple one-pot method for the synthesis of partially protected mono- and disaccharide building blocks using an orthoesterification-benzylation-orthoester rearrangement approach

Article abstract of DOI:10.1016/S0008-6215(03)00349-5

A simple one-pot method is reported for making partially protected glycosyl acceptors from O-methyl or S-alkyl/aryl glycosides of D-glucose, D-galactose, D-arabinose, L-rhamnose, L-fucose and lactose via orthoester formation, benzylation and selective hydrolysis.

Full text of DOI:10.1016/S0008-6215(03)00349-5

Carbohydrate Research 338 (2003) 2149ꢀ2152
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www.elsevier.com/locate/carres
Note
A simple one-pot method for the synthesis of partially protected
mono- and disaccharide building blocks using an orthoesterificationꢀ
benzylationꢀorthoester rearrangement approach
/
/
Balaram Mukhopadhyay, Robert A. Field*
Centre for Carbohydrate Chemistry, School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK
Received 15 May 2003; accepted 25 June 2003
Abstract
A simple one-pot method is reported for making partially protected glycosyl acceptors from O-methyl or S-alkyl/aryl glycosides
-glucose, -galactose, -arabinose, -rhamnose, -fucose and lactose via orthoester formation, benzylation and selective
hydrolysis.
# 2003 Elsevier Ltd. All rights reserved.
of
D
D
D
L
L
Keywords: Orthoester; Benzylation; Rearrangement; One-pot reaction
A basic challenge in oligosaccharide synthesis is the
preparation of partially protected building blocks where
the protecting groups can be manipulated such that each
can be selectively removed during the course of the
synthetic route. In connection with the synthesis of
various biologically active oligosaccharides, we had a
need for a practical approach to partially protected
building blocks. In the present note we describe a simple
one-pot method for the synthesis of some useful glycosyl
solution to effect orthoester rearrangement, giving the
expected products.4 The same approach could also be
applied for the thioglycosides, but it worked equally well
only when N,N-dimethylformamide has been used as
solvent, as noted previously5 (Table 1, entries 5ꢀ
7).
/
In conclusion, we have shown that a number of useful
glycosyl building blocks can be derived from O-methyl
or S-alkyl/aryl glycosides by executing several reaction
steps in a single pot and purifying only at the final stage
by flash chromatography. The strategy significantly
reduces the time for making these building blocks, and
overall yields are higher compared to those obtained by
stepwise reactions. Scale-up reactions have been per-
formed with compounds 1, 3 and 10, which showed that
this procedure can be applied on a 10-g (50 mmol) scale
(Table 1).
acceptors and donors based on an orthoesterificationꢀ
/
benzylationꢀorthoester rearrangement approach.
/
The well-known formation of cyclic orthoesters
involving cis-hydroxyl groups and selective rearrange-
ment thereof, has been successfully used as the key
reaction in this strategy. A selection of methyl glycopyr-
anosides (Table 1) were treated with triethylorthoacetate
and catalytic p-toluenesulfonic acid in dry acetonitrile1
to form the corresponding orthoesters, which were then
benzylated2 in the same pot to protect the remaining free
hydroxyl groups (Scheme 1).$ The reaction mixture was
diluted with dichloromethane and shaken with 1M HCl
1. Experimental
1.1. General procedure
1.1.1. Methyl glycosides. To a suspension of the methyl
glycoside (1 mmol) in dry MeCN (10 mL), triethy-
lorthoacetate (1.5 mmol) was added, followed by addi-
tion of a catalytic amount of p-TsOH. The mixture was
* Corresponding author. Fax: ꢁ44-1603-592003.
/
E-mail address: r.a.field@uea.ac.uk (R.A. Field).
$
For the two-pot synthesis of the corresponding 2,4-di-O-
benzoyl derivative, see Ref. 3.
allowed to stir for 45ꢀ60 min. After complete conver-
/
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0008-6215(03)00349-5

2150
B. Mukhopadhyay, R.A. Field / Carbohydrate Research 338 (2003) 2149ꢀ2152
/
Table 1
Results obtained from the one-pot reactions with various sugars

B. Mukhopadhyay, R.A. Field / Carbohydrate Research 338 (2003) 2149ꢀ
/2152
2151
Scheme 1. (i) Triethyl orthoacetate, p-TsOH, CH3CN; (ii) BnBr, NaH; (iii) 1 N HCl.
sion thin layer chromatography (TLC) [2:1 n-hexaneꢀ
/
EtOAc], Et3N was added to neutralize the solution.
NaH (1.5 mmol, 60% dispersion in mineral oil) was
added, followed by BnBr [1.2 mmol (2.2 mmol for
glucose derivative)], and the mixture was allowed to stir
(dd, 1 H, J1,2 1.6 Hz, J2,3 2.8 Hz, H-2), 5.41 (d, 1 H, J1,2
,
H-1), 4.93, 4.77 (2d, 2 H, J 11.2 Hz, CH2Ph), 4.30 (m, 1
H, H-5), 4.12 (dd, 1 H, J2,3, J3,4 9.6 Hz, H-3), 3.50 (t, 1
H, J3,4, H-4), 3.19 (bs, 1 H, OH), 2.34 (s, 3 H, Sꢀ
/
PhCH3), 2.17 (s, 3 H, COCH3), 1.42 (d, 3 H, J5,6 6.4
Hz, H-6). 13C NMR (100 MHz, CDCl3): d 170.6
(COCH3), 137.9, 137.5, 132.0, 129.8 129.6, 128.2,
127.6 (aromatic carbons), 85.9 (C-1), 81.4, 74.9, 74.2,
for 1 h at room temperature. When TLC (3:1 n-hexaneꢀ
/
EtOAc) showed complete conversion, MeOH (1 mL)
was carefully added to destroy excess NaH, and the
mixture was diluted with CH2Cl2 (20 mL). The organic
70.3, 68.4, 20.8 (COCH3), 20.8 (Sꢀ
(Cꢀ
420.1839; found: m/z 420.1843.
/
C6H4ꢀ
/
CH3), 17.6
NH4):
layer was shaken with M HCl (3ꢂ
washing with satd NaHCO3 solution (3ꢂ
water (3ꢂ15 mL). Finally the organic layer was
/15 mL), followed by
/
CH3). HRMS: Calcd for C22H30NO5S (Mꢁ
/
/15 mL) and
/
separated, dried (Na2SO4) and evaporated to syrup.
The crude product was purified by flash chromatogra-
1.4. Methyl 4-O-acetyl-2-O-benzyl-1-thio-b-
fucopyranoside (13)
L-
phy using 2:1 n-hexaneꢀ
/
EtOAc as eluent. The yields are
given in Table 1.
/
[a]2D3
ꢃ
/
11.38 (c 1.9, CHCl3). 1H NMR (400 MHz,
7.23 (m, 5 H, aromatic protons), 5.02
CDCl3): d 7.39ꢀ
/
1.1.2. S-Alkyl/aryl glycosides. The same experimental
procedure described for O-glycosides (above) was
followed, except that N,N-dimethylformamide has
been used as solvent instead of MeCN.5
Compounds 2,6 6,7 8a8,9 and 8b10 are known; specific
rotation and NMR data were in accord with the
literature. Specific rotation, NMR and HRMS data of
new compounds 4, 11, 13 and 15 are given below.
(d, 1 H, J3,4 3.2 Hz, H-4), 4.87, 4.67 (2d, 2 H, J 10.4 Hz,
CH2Ph), 4.27 (d, 1H, J1,2 9.6 Hz, H-1) 3.70 (dd, 1 H, J2,3
9.2 Hz, J3,4, H-3), 3.51 (q, 1 H, J5,6 6.4 Hz, H-5), 3.44 (t,
1 H, J1,2 9.2 Hz, J2,3, H-2), 3.01 (bs, 1 H, OH), 2.20 (s, 3
H, Sꢀ
/
CH3), 2.10 (s, 3 H, COCH3), 1.11 (d, 3 H, J5,6 6.4
Hz, H-6). 13C NMR (100 MHz, CDCl3): d 171.2
(COCH3), 137.8, 128.2, 128.0, 127.7 (aromatic carbons),
84.9 (C-1), 78.1, 75.2, 73.2, 72.9, 72.7, 20.6 (COCH3),
16.3 (Sꢀ
C16H26NO5S (Mꢁ
344.1528.
/
CH3), 12.8 (Cꢀ
/
CH3). HRMS: Calcd for
1.2. Methyl 4-O-acetyl-2-O-benzyl-b-L-
arabinopyranoside (4)
/
NH4): 344.1526; found: m/z
/
[a]2D3
ꢁ
/
125.18 (c 2.1, CHCl3). 1H NMR (400 MHz,
7.26 (m, 5 H, aromatic protons), 5.14
CDCl3): d 7.38ꢀ
/
1.5. Methyl 4-O-acetyl-2,6-di-O-benzyl-b-
galactopyranosyl-(104)-2,3,6-tri-O-benzyl-1-thio-b-
glucopyranoside (15)
D-
(m, 1 H, H-4), 4.73, 4.64 (2d, 2 H, CH2Ph), 4.67 (d, 1 H,
J1,2 3.9 Hz, H-1), 4.11 (m, 1 H, H-3), 3.75 (dd, 1 H, J5a,5b
12.9 Hz, H-5a), 3.71 (dd, 1 H, J1,2, J2,3 9.9 Hz, H-2), 3.62
/
D-
(dd, 1 H, J5a,5b, H-5b), 3.33 (s, 3 H, Oꢀ
/
CH3), 2.60 (bs, 1
/
[a]2D3
CDCl3): d 7.47ꢀ
5.37 (dd, 1 H, J4?,5? 3 Hz, H-4?), 5.15ꢀ
5 CH2Ph), 4.51 (d, 1 H, J1?,2? 6.2 Hz, H-1?), 4.41 (d, 1 H,
J1,2 6.6 Hz, H-1), 4.11 (dd, 1 H, J2?,3? 6.4 Hz, H-3?),
ꢁ
/
21.38 (c 1.2, CHCl3). 1H NMR (400 MHz,
7.22 (m, 25 H, aromatic protons),
4.27 (10d, 10 H,
H, OH), 2.11 (s, 3 H, COCH3). 13C NMR (100 MHz,
CDCl3): d 171.0 (COCH3), 138.1, 128.5, 128.0 (aro-
matic carbons), 98.2 (C-1), 76.6, 72.9, 71.3, 67.0, 60.2,
55.4 (OCH3), 20.9 (COCH3). HRMS: Calcd for
/
/
C15H24NO6 (MꢁNH4): 314.1598; found: m/z 314.1597.
/
3.87ꢀ
H-4, H-5), 3.59ꢀ
2 H, H-6a, H-6b). 13C NMR (100 MHz, CDCl3): d 170.9
(COCH3), 139.1, 138.3, 138.2, 137.9, 137.8, 128.3ꢀ
/
3.81 (m, 3 H, H-5?, H-6?a; H-6b?); 3.70ꢀ
/3.61 (m, 2 H,
/
3.43 (m, 3 H, H-2, H-2?, H-3), 3.40 (m,
1.3. p-Tolyl 2-O-acetyl-4-O-benzyl-1-thio-a-L-
rhamnopyranoside (11)
/
127.2, 102.3 (C-1?), 84.4 (C-1), 85.1, 80.2, 79.9, 76.0,
75.9, 75.3, 75.2, 73.2, 72.9, 72.5, 71.8, 69.5, 67.2,
/
[a]2D3
ꢃ
/
148.18 (c 1.0, CHCl3). 1H NMR (400 MHz,
7.12 (m, 9 H, aromatic protons), 5.42
CDCl3): d 7.45ꢀ
/
20.5(COCH3), 12.3 (Sꢀ
/
CH3). HRMS: Calcd for

2152
B. Mukhopadhyay, R.A. Field / Carbohydrate Research 338 (2003) 2149ꢀ2152
/
7. Paulsen, H.; Hasenkamp, T.; Paal, M. Carbohydr. Res.
1985, 144, 45ꢀ56.
8. Paulsen, H.; Buensch, H. Chem. Ber. 1981, 114, 3126ꢀ
C50H60NO11S (MꢁNH4): 882.3882; found: m/z
882.3887.
/
/
/
3145.
9. Boren, H. B.; Ekborg, G.; Eklind, K.; Garegg, P. J.;
Pilotti, A.; Swahn, C. G. Acta Chem. Scand. 1973, 27,
Acknowledgements
2639ꢀ
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2644.
This work was supported by the EPSRC. We gratefully
acknowledge the EPSRC Mass Spectrometry Service
Centre, Swansea for invaluable support.
10. Wolflehner, W. Carbohydr. Res. 1978, 65, 132ꢀ
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