Acceptor-influenced and donor-tuned base-promoted glycosylation

Article abstract of DOI:10.3762/bjoc.8.46

Base-promoted glycosylation is a recently established stereoselective and regioselective approach for the assembly of di- and oligosaccharides by using partially protected acceptors and glycosyl halide donors. Initial studies were performed on partially methylated acceptor and donor moieties as a model system in order to analyze the key principles of oxyanion reactivities. In this work, extended studies on base-promoted glycosylation are presented by using benzyl protective groups in view of preparative applications. Emphases are placed on the influence of the acceptor anomeric configuration and donor reactivities.

Full text of DOI:10.3762/bjoc.8.46

Acceptor-influenced and donor-tuned
base-promoted glycosylation
Stephan Boettcher1, Martin Matwiejuk2 and Joachim Thiem*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 413–420.
1Department of Chemistry, Faculty of Science, University of Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany and 2Glycom
A/S, c/o DTU, Building 201, Anker Engelunds Vej 1, DK-2800 Kgs.
Lyngby, Denmark
doi:10.3762/bjoc.8.46
Received: 06 January 2012
Accepted: 06 March 2012
Published: 20 March 2012
Email:
Joachim Thiem* - thiem@chemie.uni-hamburg.de
This article is part of the Thematic Series "Synthesis in the
glycosciences II".
* Corresponding author
Guest Editor: T. K. Lindhorst
Keywords:
glycosylation; oxyanion; reactivity; regioselectivity
© 2012 Boettcher et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Base-promoted glycosylation is a recently established stereoselective and regioselective approach for the assembly of di- and oligo-
saccharides by using partially protected acceptors and glycosyl halide donors. Initial studies were performed on partially methyl-
ated acceptor and donor moieties as a model system in order to analyze the key principles of oxyanion reactivities. In this work,
extended studies on base-promoted glycosylation are presented by using benzyl protective groups in view of preparative applica-
tions. Emphases are placed on the influence of the acceptor anomeric configuration and donor reactivities.
Introduction
For the assembly of oligosaccharides the complex and chal- partially methylated glucopyranosides as model systems. This
lenging control of regio- and stereochemistry has to be solved. systematic approach allowed determination of the preferred
Various contributions have facilitated enormously the access to positions for glycosylation and the establishment of an
complex oligosaccharide structures so far; however, regioselec- oxyanion reactivity scale. In addition to studies with different
tive and stereoselective glycosylations remain difficult and base promoters and donors, the first successful conversions with
alternative concepts are welcome, and should be considered and benzylated acceptor and donor moieties were reported [1-3].
studied.
This novel glycosylation method could substantially reduce the
Recently regioselective and β-stereospecific glycosylations need to apply protecting-group chemistry. Also, the β-speci-
employing saccharide oxyanions have been presented. Initial ficity and base-promoted activation without any heavy-metal
studies on base-promoted glycosylations were elaborated on salt or Lewis acid are useful for synthetic applications. To
413

Beilstein J. Org. Chem. 2012, 8, 413–420.
develop the synthetic potential and evolve this method into an
applicable alternative pathway towards di-, tri- or oligo-
saccharides, more research needs to be done.
So far, glycosylation reactions have been conducted by
employing methyl α-glycopyranoside acceptors. Therefore, it
was of particular interest to test the base-promoted glycosyl-
ation methodology with methyl β-glycopyranosides. Hence
monobenzylated methyl α- and β-D-glycopyranosides were
synthesized, then fucosylated by employing the base-promoted
glycosylation methodology, and analysed with respect to the
absolute and relative yields.
In addition, donor reactivity in base-promoted glycosylation
reactions was investigated by employing partially benzylated
methyl α- and β-D-glycopyranosides and donor halide mixtures.
Figure 1: Monobenzylated methyl α- and β-D-gluco- and galactopyra-
noside acceptors 1–6.
Results and Discussion
To answer the questions above, monobenzylated methyl α- and
β-D-gluco- and galactopyranosides 1–6 were selected as
acceptor moieties (Figure 1) and synthesized by employing
standard protecting-group chemistry. After base activation of
the acceptor hydroxy groups, glycosylation was performed with
the perbenzylated glycopyranosyl chlorides 7–9 (Figure 2).
The synthesis of the monobenzylated glucopyranosyl acceptors
1–4 started with benzylidenation [4] of compound 10 and 11,
respectively (Scheme 1). As the next step, monobenzylation of
12 and 13 by phase-transfer catalysis [5] afforded derivatives
14–17. Subsequent cleavage of the benzylidene protecting
group [4] gave the target compounds 1–4 in yields of up to
95%.
Figure 2: Benzylated glycopyranosyl halide donors 7–9.
compound 5. The synthetic route for the methyl β-glycopyra-
noside acceptor 6 started with benzylidenation [4] of 19, fol-
lowed by monobenzylation via intermediate stannylidene acetal
formation [6] and subsequent cleavage of the benzylidene group
[4].
Preparation of the 3-O-monobenzylated methyl α- and β-D-
galactopyranosyl acceptors 5 and 6 was achieved via stannyli- Formation of the perbenzylated α-fucopyranosyl chloride was
dene acetals [6] (Scheme 2). Compound 18 was subjected to a achieved according to [2]. Starting with peracetylated deriva-
one-step synthesis with Bu2SnO and BnBr, affording target tives 22 and 23, a five-step synthesis was performed in each
Scheme 1: Synthesis of monobenzylated glucopyranosyl acceptors 1–4. Reagents and conditions: (a) Benzaldehyde dimethylacetal, camphorsul-
fonic acid, ACN, 80 °C, 0.5–19 h; (b) NaOH, Bu4NHSO4, DCM, BnBr, 14–17 h, reflux; (c) MeOH, H2O, HCl, 2–22 h, reflux.
414

Beilstein J. Org. Chem. 2012, 8, 413–420.
Scheme 2: Synthesis of 3-O-monobenzylated gluco- und galactopyranosyl acceptors 5 and 6. Reagents and conditions: (a) Benzaldehyde dimethy-
lacetal, camphorsulfonic acid, ACN, 80 °C, 2.5 h; (b) dibutyltin oxide, toluene, BnBr, 24 h, reflux; (c) MeOH, H2O, HCl, 2–22 h, reflux.
case to obtain the galacto- and glucopyranosyl donors 8 and 9 β-(1→6) disaccharides 35 in a ratio of ca. 1:9. By glycosylation
(Scheme 3). Initially, peracetates 22 and 23 were converted into of the 3-O-benzylated methyl α-D-galactopyranoside 5 with 7
the thioglycopyranosides 24 and 25 with BF3∙Et2O/thiophenole only the β-(1→6)-linked disaccharide 37 was found. Thus, in all
[7]. Subsequent deacetylation [8] and benzylation [9] afforded α-methyl glycopyranoside acceptors 1, 3 and 5, successful
compounds 28 and 29, whose thioglycosidic bonds were glycosidic bond formations with high regioselectivity towards
cleaved with NBS in water/acetone [10]. Finally, treatment with position 6 were observed. These findings can be understood by
oxalyl chloride [11] gave the α-glycopyranosyl chlorides 8 and the presence of adjacent hydroxy groups on acceptors 1, 3 and
9 in high yields.
5, such as 4,6-diol and/or 3,4,6-triol structures, respectively.
After deprotonation the negative charge is dispersed by
The results of the base-promoted glycosylation of monobenzyl- hydrogen bonding of unreacted hydroxy groups and located
ated methyl α- and β-D-glycopyranosides with fucopyranosyl predominantly at position 6 due to the higher acidity of OH-6
chloride 7 are summarized in Table 1. Fucosylation of the 2-O- [3]. Additionally, the basicity of the oxyanions stabilized
benzylated α-derivative 1 gave predominantly the β-(1→6)- by hydrogen bonding is decreased in comparison to isolated
linked disaccharide 33. Conversion of the 3-O-benzylated oxyanions, and this favours glycosidic bond formation over
methyl α-D-glucopyranoside 3 resulted in β-(1→2) 34 and elimination.
Scheme 3: Synthesis of 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl chloride (8) and 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride (9).
Reagents and conditions: (a) 1. DCM, PhSH, BF3·Et2O, 0 °C, 1 h; 2. 4–5 d, rt; (b) MeOH, NaOMe, Amberlite IR 120 (H+), rt, 4–15 h; (c) 1. DMF, NaH,
0 °C, 1–2 h; 2. BnBr, 0 °C → rt, 16–40 h; (d) acetone/H2O (10:1), NBS, rt, −45 °C, 10 min to 5 h; (e) DCM, DMF, oxalyl chloride, 1 h, rt.
415

Beilstein J. Org. Chem. 2012, 8, 413–420.
Table 1: Glycosylation results for acceptors 1–6 with NaH as base and 2,3,4-tri-O-methyl-α-L-fucopyranosyl chloride (Fuc-Cl, 7) as donor.a
Acceptor
Products
Yield [%]b
Relative yield [%]c
β-(1→2) β-(1→3) β-(1→4) β-(1→6)
25
■d
–
–
40
60
1
2
no reaction
–
■
–
–
48e
13
■
–
87
3
4
30
33
–
–
–
–
■
■
■
–
–
–
>98
>98
–
36
5
6
37
no reaction
aGeneral reaction conditions: NaH (1.1–1.3 equiv), DMF, rt, 1 h, then donor 7 (1.0 equiv), rt, 4 h to 7 d; btotal yield of possible disaccharide regioiso-
mers; cafter separation by column chromatography; d■: benzylated position, no linkage possible; e [1].
Surprisingly glycosylation of the corresponding β-glucopyrano- the partially deprotonated methyl β-glycospyranosides in the
sides 2, 4, and 6 only showed conversion for the 3-O-benzyl- solvent used.
ated glucopyranosyl derivative 4. Acceptors 2 and 6 did not
react at all with the fucopyranosyl chloride 7. Obviously, the The results of base-promoted glycosylations with donor
anomeric configuration in the acceptor structure has a notice- mixtures are shown in Table 2. Reaction of the 3-O-benzylated
able effect on the glycosylation, resulting in lower oxyanion re- α-D-glucopyranoside 3 with an equimolar mixture of the fuco-
activity for methyl β-glycopyranosides. The considerable effect and galactopyranosyl donors 7 and 8 gave both β-(1→6)-linked
of the anomeric configuration on the reactivity of remote disaccharides 35 and 38 in 20% yield, with a ratio of 85% in
hydroxy groups may be rationalized by stereoelectronic effects favour of the fucosylated product. The corresponding β-config-
[12]. Moreover, the lower reactivities of the methyl β-glycopy- ured acceptor 4 yielded only the β-(1→6)-linked galactosylated
ranosides may also be dependent on the decreased solubility of disaccharide 39 in poor yield (5%). With the same acceptors,
416

Beilstein J. Org. Chem. 2012, 8, 413–420.
Table 2: Reactivity studies of acceptors 3 and 4 with donors 7–9.a
Acceptor
Donor (equimolar mixture)
Products
Yield [%]b Ratio [%]
Gal/Fuc
15:85c
20
3
5
Gal only
4
39
35
15
14
Fuc only
Fuc only
3
4
36
aGeneral reaction conditions: NaH (1.1–1.3 equiv), DMF, rt, 1h, then donor 7 and 8 or 7 and 9 (1.0 equiv), rt, 4 h to 7 d; btotal yield of possible disac-
charide regioisomers; cratio determined by 1H NMR.
equimolar mixtures of the perbenzylated fuco- and glucopyra- Furthermore, a comparison between the reactivities of several
nosyldonors 7 and 9 gave just the β-(1→6)-fucosylated prod- donor mixtures was established. For this purpose the perbenzyl-
ucts 35 and 36 in corresponding yields of 15% and 14%. ated donors 7–9 were synthesized and reacted in equimolar
Furthermore, a mixture of galacto- and glucopyranosyl donors 8 mixtures with acceptors 3 and 4. The fucopyranosyl donor 7
and 9 was employed, but this did not show any reaction at all. showed the highest reactivity, followed by the galactopyra-
In all cases, disaccharide yields from donor mixtures were nosyl donor 8. The glucopyranosyl donor 9 showed no reaction
significantly lower; as rational of which, some unknown kind of at all. It turned out that the disaccharide yields from the
interaction between the donors may be assumed.
mixtures were significantly lower, indicating unknown interac-
tions between donors.
Conclusion
These studies gave evidence that the configuration of the In cases with low yields or even no glycosylation products at
anomeric centre of acceptors has a decisive influence on the all, elimination became the dominant reaction and led to the
base-promoted glycosylation approach, but which so far cannot corresponding glycals. Hence, and based on the workup, the
be explained. Several α-monobenzyl acceptors (1, 3 and 5) and recovery of glycosyl halides was neither practicable nor
their β counterparts (2, 4 and 6) were synthesized and coupled achieved.
with the perbenzylated fucopyranosyl donor 7. Whereas all
α-glycosidic acceptors gave disaccharides in moderate to Experimental
acceptable yields, only the β-glycosidic acceptor 4 reacted, to General: All reagents were purchased from commercial
give the dissacharide in much lower yield.
sources and used as received. Sodium hydride (NaH) was used
417

Beilstein J. Org. Chem. 2012, 8, 413–420.
as a 60% suspension in paraffin. TLC was performed on Merck Methyl 2-O-benzyl-4-O-(2,3,4-tri-O-benzyl-β-L-fucopyra-
silica gel 60 F254 plates. Compounds were detected by UV and/ nosyl)-α-D-glucopyranoside (32) and Methyl 2-O-benzyl-6-
or by treatment with EtOH/H2SO4 (9:1) and subsequent O-(2,3,4-tri-O-benzyl-β-L-fucopyranosyl)-α-D-glucopy-
heating. Column chromatography was performed with Merck/ ranoside (33): Prepared according to the general procedure.
Fluka silica gel 60 (230–400 mesh). Solvents for column chro- Compound 1 (70 mg, 0.25 mmol), NaH (31 mg, 0.77 mmol), 7
matography were distilled prior to use. 1H and 13C NMR (335 mg, 0.739 mmol), DMF (20 mL). Yield: 43 mg
spectra were recorded with Bruker AMX-400 or Bruker (0.061 mmol, 25%), yellow sirup, relative yield 32:33 = 40:60
AV-400 spectrometers (400 MHz for 1H, 100 MHz for 13C) and (1H NMR).
calibrated by using the solvent residual peak. In CDCl3 TMS
was used for calibration. Melting points were measured with an 32: 1H NMR (400 MHz, CDCl3) δ 7.31–7.19 (m, 20H, Har),
Apotec melting point apparatus. Optical rotations were obtained 4.89 (d, 1H, C(4’)-CH2-Ph-A), 4.80 (d, JC(2’)OCH2Ph-A,B = 10.9
by using a Krüss Optronic P8000 polarimeter (589 nm, 25 °C). Hz, 1H, C(2’)-CH2-Ph-A), 4.77 (d, 1H, C(2’)-CH2-Ph-B),
HRMS (ESI) were recorded with a Thermo Finnigan MAT 4.70–4.53 (m, 5H, JC(4’)OCH2Ph-A,B = 11.6 Hz, C(2)-CH2-Ph-A/
95XL mass spectrometer. MS (MALDI–TOF) were recorded B, C(3’)-CH2-Ph-A/B, C(4’)-CH2-Ph-B), 4.59 (d, J1’,2’ = 7.8
with a Bruker Biflex II (positive reflection mode, matrix: 2,5- Hz, 1H, H-1’), 4.50 (d, J1,2 = 3.8 Hz, 1H, H-1), 4.02–3.96 (m,
dihydroxybenzoic acid). Relative yields of disaccharide 1H, H-3), 3.96–3.90 (m, 1H, H-6A), 3.74 (dd~vt, 1H, H-2’),
mixtures were determined by integration of the signals in the 3.62–3.56 (m, 1H, H-6B), 3.53–3.50 (m, 2H, H-4, H-5),
1H NMR spectra of the anomeric or other well-separated 3.48–3.46 (m, 1H, H-4’), 3.46–3.40 (m, J5’,6’ = 6.7 Hz, 2H,
protons. The abbreviation “dd~vt” stands for a double doublet H-3’, H-5’), 3.28 (dd, J2,3 = 9.6 Hz, 1H, H-2), 3.27 (s, 3H,
that turns into a virtual triplet because of similar coupling -OCH3), 1.10 (d, 3H, H-6’) ppm; 13C NMR (100 MHz, CDCl3)
constants. Physical and NMR data for 34 and 35 were published δ 128.4, 128.4, 128.3, 128.2, 128.2, 128.1, 127.9, 127.8, 127.7,
previously [1].
127.7, 127.6 (Car), 104.7 (C-1’), 98.4 (C-1), 82.4 (C-3’), 79.1
(C-2’), 78.9 (C-4), 78.5 (C-2), 76.2 (C-4’), 75.5 (C(2’)-O-CH2-
General Procedure: Base-promoted glycosylations: The Ph), 74.8 (C(4’)-O-CH2-Ph), 73.6 (C-3), 73.2 (C(3’)-O-CH2-
acceptor molecule (1.0 mmol) was dissolved in dry dimethyl- Ph), 73.1 (C(2)-O-CH2-Ph), 70.9 (C-5’), 69.6 (C-5), 61.8 (C-6),
formamide (2–4 mL), and sodium hydride (1.1–1.3 mmol for 55.2 (-OCH3), 16.7 (C-6’) ppm.
each hydroxy group; as a 60% suspension in paraffin) was
added. After being stirred for one hour under argon at room 33: 1H NMR (400 MHz, CDCl3) δ 7.33–7.19 (m, 20H, Har),
temperature, the donor (1.0 mmol for each hydroxy group; 4.89 (d, 1H, C(4’)-CH2-Ph-A), 4.85 (d, 1H, C(2’)-CH2-Ph-A),
donor-mixtures 0.5 mmol of each donor) dissolved in dry 4.75–4.53 (m, JC(2’)OCH2Ph-A,B = 10.9 Hz, JC(4’)OCH2Ph-A,B =
dimethylformamide (2–4 mL) was successively added to the 11.6 Hz, 6H, C(2’)-CH2-Ph-B, C(2)-CH2-Ph-A/B, C(3’)-CH2-
reaction. After stirring for 4–100 h, methanol (2 mL) was Ph-A/B, C(4’)-CH2-Ph-B), 4.55 (d, J1,2 = 3.8 Hz, 1H, H-1),
added. The crude product was purified by flash column chroma- 4.28 (d, J1’,2’ = 7.8 Hz, 1H, H-1’), 4.07–3.99 (m, 1H, H-6A/B),
tography (petroleum ether/ethyl acetate, 2:1 v/v).
3.88–3.85 (m, 1H, H-3), 3.76–3.70 (m, 1H, H-2’, H-5),
3.62–3.59 (m, 1H, H-4), 3.47–3.45 (m, 1H, H-4’), 3.44–3.39
Methyl 3-O-benzyl-β-D-glucopyranoside (4): Prepared by (m, J5’,6 = 6.3 Hz, 2H, H-3’, H-5’), 3.27–3.24 (m, 1H, H-2),
hydrolysis of 17 [5] with hydrochloric acid [2]. Compound 17 3.23 (s, 1H, -OCH3), 1.10 (d, 1H, H-6’) ppm; 13C NMR (100
(3.49 g, 9.37 mmol), MeOH (80 mL), H2O (8.0 mL), 2 N HCl MHz, CDCl3) δ 138.8, 138.4, 137.8, 128.5, 128.5, 128.4, 128.2,
(1.0 mL), 21.5 h, reflux. Yield: 80% (2.13 g, 7.49 mmol), 128.0, 127.9, 127.7, 127.6, 127.6, 127.5 (Car), 104.2 (C-1’),
colourless solid, mp 105 °C.
−7.7 (c 1.0, H2O); 1H NMR 97.9 (C-1), 82.3 (C-3’), 79.4 (C-2’), 79.1 (C-2), 79.1 (C-5), 76.3
(400 MHz, MeOD) δ 7.47–7.43 (m, 2H, Har), 7.36–7.24 (m, (C-4’), 75.0, 74.7, 73.2, 73.0 (-O-CH2-Ph), 72.6 (C-3), 70.6
3H, Har), 4.92 (d, JC(3)OCH2Ph-A,B = 11.1 Hz, 1H, C(3)-O-CH2- (C-5’), 70.1 (C-4), 68.8 (C-6), 55.2 (-OCH3), 16.7 (C-6’) ppm;
Ph-A), 4.88 (d, 1H, C(3)-O-CH2-Ph-B), 4.21 (d, J1,2 = 7.3 Hz, MALDI–TOF–MS (DHB, positive mode; m/z): [M + Na]+
1H, H-1), 3.90 (dd, J6A,6B = 11.8 Hz, 1H, H-6A), 3.69 (dd, 1H, calcd for C41H48O10Na, 723.3; found, 723.5.
H-6B), 3.48–3.42 (m, 1H, H-3), 3.41–3.38 (m, 1H, H-4),
3.37–3.34 (m, 1H, H-2), 3.32–3.28 (m, J5,6A = 2.3 Hz, J5,6B = Methyl 3-O-benzyl-6-O-(2,3,4-tri-O-benzyl-β-L-fucopyra-
5.8 Hz, 1H, H-5) ppm; 13C NMR (100 MHz, MeOD) δ 140.4, nosyl)-β-D-glucopyranoside (36): (a) Prepared according to
129.2, 129.0, 128.5 (Car), 105.5 (C-1), 86.3 (C-4), 77.9 (C-5), the general procedure: Compound 4 (71 mg, 0.25 mmol), NaH
76.0 (C(3)-O-CH2-Ph), 75.3 (C-2), 71.5 (C-3), 62.7 (C-6), 57.3 (31 mg, 0.71 mmol), 7 (350 mg, 0.774 mmol), DMF (16 mL).
(-O-CH3) ppm; HRMS–ESI (m/z): [M + Na]+ calcd for Yield: 53 mg (0.074 mmol, 30%). (b) Prepared according to the
C14H20O6Na, 307.1158; found, 307.1150.
general procedure by using a donor mixture: Compound 4
418

Beilstein J. Org. Chem. 2012, 8, 413–420.
(65 mg, 0.23 mmol), NaH (30 mg, 0.75 mmol), 7 (150 mg, Prepared according to the general procedure by using a donor
0.330 mmol)/9 (182 mg, 0.325 mmol), DMF (18 mL). Yield: mixture: Compound 3 (70 mg, 0.25 mmol), NaH (30 mg, 0.75
22 mg (0.031 mmol, 14%), yellow sirup.
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.42–7.27 (m, 20H, (20 mL). Yield: 34 mg (0.042 mmol, 20%). Relative yield 35:38
Har), 4.99 (d, JC(4’)OCH2Ph-A,B = 11.6 Hz, 1H, C(4’)-O-CH2-Ph- = 85:15. Slightly yellow sirup. +53.4 (c 0.70, CHCl3);
−106 (c 0.31, mmol), 7 (170 mg, 0.375 mmol)/8 (208 mg, 0.372 mmol), DMF
A), 4.93 (d, JC(2’)OCH2Ph-A,B = 10.7 Hz, 1H, C(2’)-O-CH2-Ph- 1H NMR (400 MHz, CDCl3) δ 7.34–7.19 (m, 25H, Har),
A), 4.91 (d, JC(3)OCH2Ph-A,B = 11.3 Hz, 1H, C(3)-O-CH2-Ph- 4.89–4.84 (m, 3H, -O-CH2-Ph), 4.73–4.61 (m, 5H, H-1,
A), 4.86 (d, 1H, C(3)-O-CH2-Ph-B), 4.79 (d, JC(3’)OCH2Ph-A,B = -O-CH2-Ph), 4.52 (d, 1H, -O-CH2-Ph), 4.41–4.31 (m, J1’,2’ =
11.7 Hz, 1H, C(3’)-O-CH2-Ph-A), 4.76 (d, 1H, C(2’)-O-CH2- 7.5 Hz, 3H, H-1’, -O-CH2-Ph), 4.09–4.01 (m, 1H, H-6A),
Ph-B), 4.72 (d, 1H, C(3’)-O-CH2-Ph-B), 4.69 (d, 1H, C(4’)-O- 3.83–3.80 (m, 1H, H-4), 3.77 (dd~vt, 1H, H-2’), 3.73–3.66 (m,
CH2-Ph-B), 4.36 (d, J1’,2’ = 7.5 Hz, 1H, H-1’), 4.19 (d, J1,2 = 2H, H-5’, H-6B), 3.56–3.42 (m, 7H, H-2, H-3, H-3’, H-4’, H-5,
7.5 Hz, 1H, H-1), 4.15 (dd, J6A,6B = 11.0 Hz, 1H, H-6A), H-6’A/B), 3.29 (s, 1H, -OCH3) ppm; 13C NMR (100 MHz,
3.86–3.79 (m, 3H, H-2’, H-4, H-6B), 3.57–3.38 (m, J5,6A = 4.1 CDCl3) δ 138.7, 138.7, 128.5, 128.4, 128.4, 128.3, 128.2,
Hz, J5’,6A = 6.6 Hz, 6H, H-2, H-3, H-3’, H-4’, H-5, H-5’), 3.51 128.1, 128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 127.5 (Car),
(s, 1H, -OCH3), 1.17 (d, 3H, H-6’) ppm; 13C NMR (100 MHz, 104.2 (C-1’), 99.3 (C-1), 82.7 (C-3), 82.3 (C-3’), 79.3 (C-2’),
CDCl3) δ 138.7, 138.6, 138.5, 138.5, 138.4, 128.7, 128.5, 75.2, 74.9, 74.5, 73.6, 73.0 (-O-CH2-Ph), 73.5 (C-4), 73.5
128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.9, 127.8, (C-4’), 72.6 (C-2), 70.8 (C-5), 70.2 (C-5’), 69.2 (C-6), 68.7
127.6 (Car), 104.0 (C-1’), 103.7 (C-1), 83.5 (C-3) 82.4 (C-3’), (C-6’), 55.3 (-OCH3) ppm; HRMS–ESI (m/z): [M + Na]+ calcd
79.0 (C-2’), 76.2 (C-4’), 75.2, 74.7, 74.6, 73.2 (-O-CH2-Ph), for C48H54O11Na, 829.3564; found, 829.3545.
74.6 (C-5), 73.9 (C-2), 70.8 (C-4), 70.6 (C-5’), 69.1 (C-6), 56.9
(-OCH3), 16.7 (-CH3) ppm; HRMS–ESI (m/z): [M + Na]+ calcd Methyl 3-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-β-D-galac-
for C41H48O10Na, 723.3145; found, 723.3136.
topyranosyl)-β-D-glucopyranoside (39): Prepared according
to the general procedure by using a donor mixture: Compound 4
Methyl 3-O-benzyl-6-O-(2,3,4-tri-O-benzyl-β-L-fucopyra- (65 mg, 0.23 mmol), NaH (29 mg, 0.73 mmol), 7 (151 mg,
nosyl)-β-D-galactopyranoside (37): Prepared according to the 0.334 mmol)/8 (175 mg, 0.313 mmol), DMF (16 mL). Yield:
general procedure. Compound 5 (72 mg, 0.25 mmol), NaH 8.6 mg (0.011 mmol, 5%). Yellow sirup.
−9.6 (c 0.40,
(26 mg, 0.65 mmol), 7 (343 mg, 0.731 mmol), DMF (10 mL). CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.31–7.19 (m, 25H,
Yield: 58 mg (0.083 mmol, 33%), colourless solid, mp 98 °C. Har), 4.88–4.82 (m, 3H, -O-CH2-Ph), 4.74–4.69 (m, 2H,
+72 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ -O-CH2-Ph), 4.66–4.62 (m, 2H, -O-CH2-Ph), 4.52 (d, 1H,
7.42–7.25 (m, 20H, Har), 4.99 (d, 1H, -O-CH2-Ph), 4.90 (d, 1H, -O-CH2-Ph), 4.42–4.30 (m, 2H, -O-CH2-Ph), 4.37 (d, J1,2 = 3.5
-O-CH2-Ph), 4.82–4.75 (m, J1,2 = 4.0 Hz, 3H, H-1, -O-CH2- Hz, 1H, H-1), 4.08–4.03 (m, J6A,6B = 10.8 Hz, 1H, H-6A), 4.06
Ph), 4.73 (d, 1H, -O-CH2-Ph), 4.71 (d, 1H, -O-CH2-Ph), 4.56 (s, (d, J1’,2’ = 7.6 Hz, 1H, H-1’), 3.82–3.80 (m, 1H, H-4),
2H, -O-CH2-Ph), 4.40 (d, J1’,2’ = 7.8 Hz, 1H, H-1’), 4.16–4.13 3.78–3.74 (m, 1H, H-2), 3.74 (dd, 1H, H-6B), 3.56–3.42 (m,
(m, 1H, H-4), 4.01 (dd, J6A,6B = 8.8 Hz, 1H, H-6A), 3.98 (dd, J5,6B = 6.0 Hz, 6H, H-3, H-4’, H-5, H-5’, H-6’A/B), 3.39 (dd,
J2,3 = 9.8 Hz, 1H, H-2), 3.93–3.89 (m, J5,6A = 4.3 Hz, J5,6B = J2’,3’ = 9.8 Hz, 1H, H-2’), 3.36 (s, 1H, -OCH3), 3.31 (dd~vt,
8.6 Hz, 1H, H-5), 3.86 (dd, 1H, H-6B), 3.82 (dd, J2’,3’ = 9.5 Hz, 1H, H-3’) ppm; 13C NMR (100 MHz, CDCl3) δ 138.6, 128.6,
1H, H-2’), 3.62–3.55 (m, 2H, H-3, H-4’), 3.53 (dd, J3’,4’ = 3.0 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 128.2, 128.1, 128.0,
Hz, 1H, H-3’), 3.51–3.44 (m, J5’,6’ = 6.5 Hz, 1H, H-5’), 3.39 (s, 127.9, 127.8, 127.8, 127.6, 127.5 (Car), 104.0 (C-1), 103.6
3H, OCH3), 1.19 (d, 3H, H-6’) ppm; 13C NMR (100 MHz, (C-1’), 83.7 (C-3’), 82.2 (C-3), 79.1 (C-2), 75.2, 74.7, 74.5,
CDCl3) δ 128.6, 128.5, 128.4, 128.3, 127.9, 127.8, 127.6, 73.5, 72.9 (-O-CH2-Ph), 73.5 (C-4), 74.6 (C-5), 74.2 (C-2’),
127.6, 127.6 (Car), 103.9 (C-1’), 99.5 (C-1), 82.5 (C-3’), 79.4 73.4 (C-4), 71.4 (C-5’), 69.3 (C-6), 68.7 (C-6’), 57.1 (-OCH3)
(C-2’), 78.4 (C-3), 76.2 (C-4’), 75.1, 74.6, 73.2, 71.7 (-O-CH2- ppm; MALDI–TOF–MS (DHB, positive mode; m/z): [M + Na]+
Ph), 70.5 (C-5’), 68.6 (C-2), 68.1 (C-5), 67.3 (C-6), 66.0 (C-4), calcd for C48H54O11Na, 829.36; found, 830.1.
55.4 (OCH3), 16.8 (C-6’) ppm; HRMS–ESI (m/z): [M + Na]+
References
1. Matwiejuk, M.; Thiem, J. Chem. Commun. 2011, 47, 8379–8381.
calcd for C41H48O10Na, 723.3135; found, 723.3140.
doi:10.1039/c1cc11690h
Methyl 3-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-β-D-galac-
2. Matwiejuk, M.; Thiem, J. Eur. J. Org. Chem. 2011, 5860–5878.
topyranosyl)-α-D-glucopyranoside (38): (a) Prepared
doi:10.1002/ejoc.201100861
according to the general procedure: Compound 3 (70 mg,
3. Matwiejuk, M.; Thiem, J. Eur. J. Org. Chem. 2012.
0.25 mmol), NaH (32 mg, 0.80 mmol), 8 (415 mg, 0.742
doi:10.1002/ejoc.201101708
mmol), DMF (20 mL). Yield: 20 mg (0.025 mmol, 10%). (b)
419

Beilstein J. Org. Chem. 2012, 8, 413–420.
4. Demchenko, A. V.; Pornsuriyasak, P.; de Meo, C. J. Chem. Educ.
2006, 83, 782–784. doi:10.1021/ed083p782
5. Garegg, J.; Iversen, T.; Oscarson, S. Carbohydr. Res. 1976, 50,
C12–C14. doi:10.1016/S0008-6215(00)83867-7
6. David, S.; Hanessian, S. Tetrahedron 1985, 41, 643–663.
doi:10.1016/S0040-4020(01)96443-9
7. Charbonnier, F.; Penadés, S. Eur. J. Org. Chem. 2004, 3650–3656.
doi:10.1002/ejoc.200400141
8. Zemplén, G.; Pacsu, E. Ber. Dtsch. Chem. Ges. 1929, 62, 1613–1614.
doi:10.1002/cber.19290620640
9. Girard, C.; Miramon, M.-L.; de Solminihac, T.; Herscovici, J.
Carbohydr. Res. 2002, 337, 1769–1774.
doi:10.1016/S0008-6215(02)00206-9
10.Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc. 1983,
105, 2430–2434. doi:10.1021/ja00346a053
11.Iversen, T.; Bundle, D. R. Carbohydr. Res. 1982, 103, 29–40.
doi:10.1016/S0008-6215(82)80005-0
12.Pedersen, C. M.; Olsen, J.; Brka, A. B.; Bols, M. Chem.–Eur. J. 2011,
17, 7080–7086. doi:10.1002/chem.201100020
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.8.46
420