Regioselective Benzoylation of 4,6-O-Benzylidene Acetals of Glycopyranosides in the Presence of Transition Metals

Article abstract of DOI:10.1080/07328303.2014.996291

Benzoylation of 4,6-O-benzylidene acetals of glycopyranosides by benzoic anhydride in acetonitrile in the presence of Cu(CF₃COO)₂ as a promoter gave 2-benzoates for α-D-glucopyranosides and α-D-mannopyranosides and 3-benzoates for β-D-galactopyranosides in good yields with high regioselectivity. Benzoylation of 4,6-O-benzylidene acetals of glycopyranosides of D-galactose and D-mannose by benzoyl chloride in the presence of MoO₂(acac)₂ as a catalyst in all studied cases led to regioselective 3-substitution.

Full text of DOI:10.1080/07328303.2014.996291

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Regioselective Benzoylation of 4,6-O-
Benzylidene Acetals of Glycopyranosides
in the Presence of Transition Metals
Evgeny V. Evtushenkoa
a G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East
Branch, Russian Academy of Sciences, Vladivostock 690022, Russian
Federation
Published online: 03 Feb 2015.
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To cite this article: Evgeny V. Evtushenko (2015) Regioselective Benzoylation of 4,6-O-Benzylidene
Acetals of Glycopyranosides in the Presence of Transition Metals, Journal of Carbohydrate Chemistry,
34:1, 41-54, DOI: 10.1080/07328303.2014.996291
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Journal of Carbohydrate Chemistry, 34:41–54, 2015
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2014.996291
Regioselective Benzoylation
of 4,6-O-Benzylidene Acetals
of Glycopyranosides in the
Presence of Transition Metals
Evgeny V. Evtushenko
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian
Academy of Sciences, Vladivostock 690022, Russian Federation
GRAPHICAL ABSTRACT
Benzoylation of 4,6-O-benzylidene acetals of glycopyranosides by benzoic anhy-
dride in acetonitrile in the presence of Cu(CF3COO)2 as
a promoter gave
2-benzoates for α-D-glucopyranosides and α-D-mannopyranosides and 3-benzoates for
β-D-galactopyranosides in good yields with high regioselectivity. Benzoylation of 4,
6-O-benzylidene acetals of glycopyranosides of D-galactose and D-mannose by benzoyl
chloride in the presence of MoO2(acac)2 as a catalyst in all studied cases led to regiose-
lective 3-О-substitution.
Keywords 4,6-O-benzylidene acetals; Copper (II) trifluoroacetate; Molybdenum (VI)
dioxide bis(acetylacetonate); Regioselective benzoylation
Received April 3, 2014; accepted December 4, 2014.
Address correspondence to Evgeny V. Evtushenko, G.B. Elyakov Pacific Institute of
Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, Vladivostok
690022, Russian Federation. E-mail: evt@piboc.dvo.ru
41

E.V. Evtushenko
42
INTRODUCTION
Currently, the rapid development of glycobiology requires the creation of con-
venient and efficient methods for the synthesis of complex carbohydrates
and oligosaccharides. Since carbohydrates are multifunctional molecules, it
is necessary to use temporary protections in their synthesis, which requires
multiple steps and considerable time. Regioselective introduction of pro-
tecting groups in carbohydrates is an alternative approach to obtain inter-
mediates in oligosaccharide synthesis.[1,2] The ready availability of 4,6-O-
benzylidene acetals of sugars also simplifies the task of functionalization of
sugar molecules, such as monoacylation, to conveniently obtain intermedi-
ates that often are acceptors in the synthesis of oligosaccharides containing
1→2 and 1→3 linkages. For monoacylation of 4,6-O-benzylidene acetals of car-
bohydrates, metal chelates,[3–8] organotin intermediates,[9–20] organoboron[21]
and organosilicon[22] compounds, amines,[23–27] organocatalysts,[28–29] TMS
ethers,[30–32] and enzymes[33] have been used. However, despite some progress
in this area, the regioselective protection of hydroxyl groups in sugars can still
benefit from improvements in methodology.
RESULTS AND DISCUSSION
Earlier we found that regioselective acylation of glycopyranosides could be ob-
tained by use of the salts of transition metals. In this case, molybdenum (V, VI)
compounds[34,35] oriented substitution on 3-ОН in 2,3- and 3,4-cis-vicinal diols,
but regioselectivity of acylation in the presence of copper (II) salts depended
both on the configurations of the hydroxyl groups and on the configuration
of the aglycone probably due to formation of intermediate complex glycosides
with copper (II) ions.[36] In general, the causes that determine the differences
in reactivity of the hydroxyl groups of carbohydrates in the acylation reactions
are varied and may be because of steric and stereoelectronic effects,[37] as well
as intramolecular hydrogen bonds.[38–42] In addition, regioselectivity may also
be obtained by rearrangement of initially formed products to the most stable
products.[43] The complexation of carbohydrates can change the ratio of these
factors and, as a consequence, the reactivity of the hydroxyl groups.
In the present work we wanted to study the influence of Cu(CF3COO)2
and MoO2(acac)2 on regioselective benzoylation of 4,6-O-benzylidene acetals of
glycopyranosides. The results of benzoylation of 4,6-O-benzylidene acetals of
glycopyranosides in the presence of Cu(CF3COO)2 are presented in Table 1.
As seen from Table 1, the use of Cu(CF3COO)2 as the promoter in the
benzoylation of methyl 4,6-O-benzylidene-α-D-glucopyranoside 1 is prefer-
able from the viewpoint of regioselectivity (entry 1). From Table 1, it can
also be seen that benzoylation of 4,6-O-benzylidene acetals of methyl α-D-
galactopyranosides 3 and 4 (entries 10 and 12, respectively) in the presence

43

44

45

E.V. Evtushenko
46
Scheme 1: Proposed mechanism of regioselective benzoylation of methyl α-D-
galactopyranoside in the presence of Cu(CF3COO)2.
of copper (II) trifluoroacetate formed significant amounts of both 2-O- and 3-O-
benzoates. It is possible to assume that it was the result of benzoylation of the
complexes of copper (II) atoms with the participation of adjacent atoms О-1, О-
2, О-3, and О-4 of α-D-galactopyranoside (Sch 1). It is interesting that the ben-
zoylation of methyl 6-O-trityl-α-D-galactopyranoside[36] under the same condi-
tions gave mainly the 2-O-benzoate, perhaps as a result of interference from
the bulky trityl group at C-6 to form an intermediate complex of ion Сu(II)
with 3-ОН and 4-ОН.
At the same time, the benzoylation of methyl and benzyl 4,6-O-
benzylidene-β-D-galactopyranosides 5, 6, and 7 (entries 14, 16, and 18, respec-
tively), which could possibly form only one complex of copper (II) with О-3 and
О-4 (Fig 1a), gave practically only 3-O-benzoate with 73% to 79% yields and
high regioselectivity. Similar results were observed in the benzoylation of 4,
6-O-benzylidene-β-D-galactopyranoside by N-benzoylimidazole[27] and by ben-
zoyl chloride with the use of copper (II) chelates[6] and silver (I) oxide.[44] The
benzoylation of methyl 4,6-O-benzylidene- and 4,6-O-p-methoxybenzylidene-
α-D-glucopyranosides 1 and 2 (entries 1 and 8, respectively) resulted in se-
lective formation of 2-benzoates that was possibly determined by the for-
mation of an intermediate complex of copper (II) atoms with О-2 and О-1
(Fig 1b). The benzoylation of methyl 4,6-O-benzylidene-α-D-glucopyranoside
1 by benzoyl chloride in the presence of organotin compounds,[11] by
1-(benzoyloxy)benzotriazole,[45] or under the conditions of phase-transfer catal-
ysis[46] earlier also demonstrated the highest reactivity of 2-ОН, although the
Figure 1: The proposed coordination of methyl 4,6-O-benzylidene-β-D-galactopyranoside
(a) and methyl 4,6-O-benzylidene-α-D-glucopyranoside (b) with Cu+(CF3COO).

Benzoylation of 4,6-O-Benzylidene Acetals
47
Figure 2: The proposed coordination of methyl 4,6-O-benzylidene-α-D-mannopyranoside
with Cu+(CF3COO).
benzoylation of 1 by benzoyl chloride in the presence of silver (I) oxide basically
resulted in the substitution of 3-ОН.[44]
Treatment of 2-O and 3-O-benzoates of methyl 4,6-O-benzylidene-α-
D-glucopyranoside 8 and 9 with benzoyl anhydride in the presence of
Cu(CF3COO)2 (entries 20 and 21) showed little migration of the benzoyl
group, indicating that the products’ distribution is determined by the ki-
netic control. The benzoylation of methyl 4,6-O-benzylidene- and methyl 4,6-
O-p-methoxybenzylidene-α-D-mannopyranosides 10 and 11 (entries 22 and
24, respectively) also gave 2-O-benzoates in good yields with high selectiv-
ity. In the latter case, it was possible to assume the formation of two inter-
mediate complexes of copper (II) atoms with О-2, О-3, and O-5 (Fig 2a, 2b).
It is known[47,48] that the benzoylation of methyl 4,6-O-benzylidene-2,3-O-
dibutylstannylene-α-D-mannopyranoside by benzoyl chloride in dioxane gave
2-O and 3-O-benzoates in roughly equal amounts, but replacing the solvent
with benzene gave mainly 2-O-benzoate.[12] At the same time, benzoylation
of this acetal in the presence of N-methylimidazole[12] as well as the benzoyla-
tion of methyl 4,6-O-benzylidene-α-D-mannopyranoside in pyridine[49] resulted
mainly in a 3-O-benzoate.
Next, we explored the benzoylation of 4,6-O-benzylidene acetals of glycopy-
ranosides in the presence of MoO2(acac)2. The results are presented in Table 2.
As can be seen from this table, using acetonitrile as solvent (entry
1 vs. 2 and 3) was preferable in the reaction. Table 2 also shows that
4,6-O-benzylidene derivatives of α- and β-D-galactopyranoside and α-D-
mannopyranoside demonstrated preferable reactivity for 3-ОН in comparison
with 2-ОН in the benzoylation by benzoyl chloride even without a catalyst,
but the reactions gave only moderate yields of 3-benzoate in the reaction mix-
ture (entries 4, 6, 8, 10, and 12). The use of MoO2(acac)2 as the catalyst in
these cases greatly increased the yields of 3-O-benzoates in the reaction mix-
ture along with increased regioselectivity. Similar results were obtained ear-
lier[35] on the benzoylation of pyranosides by benzoyl chloride in the presence
MoO2(acac)2. This was probably determined by the increase of the nucleophilic-
ity of 3-OH after complexation with Mo(VI). Table 2 also shows that the ben-
zoylation of methyl 4,6-O-benzylidene-α-D-glucopyranoside 1 both with and

E.V. Evtushenko
48
Table 2: Regioselective benzoylation of 4,6-O-benzylidene acetals of glycopyra-
nosides by benzoyl chloride in acetonitrile in the presence of MoO2(acac)2
Benzoate yields
(%)а
Substrate
Glycoside
Recovered
Entry
1
Catalyst
Glycoside (%) НО-2 НО-3 Di-
MoO2(acac)2
16
10
71 (64)
3
b
2
3
4
5
MoO2(acac)2c
MoO2(acac)2
no
15
14
29
11
13
14
7
69
67
3
5
16
48
MoO2(acac)2
7
82 (76)
6
7
no
40
10
6
7
46
83 (75)
8
MoO2(acac)2
8
9
no
35
8
7
5
48
85 (77)
10
2
MoO2(acac)2
10
11
no
23
5
22
4
43
88 (82)
12
3
MoO2(acac)2
12
13
no
27
42
19
50
43
6
11
2
MoO2(acac)2
14
no
45
48
5
2
аDetermined by 1H NMR, and isolated yields are in brackets.
bDioxane was used as solvent.
cEtAc was used as solvent.
without a catalyst (entries 13 and 14, respectively) gave the same result with
preferable formation of 2-O-benzoate. It indicates the absence of an intermedi-
ate complex of this acetal with molybdenum (VI).
In conclusion, we have found that using transition metal salts,
Cu(CF3COO)2 and MoO2(acac)2 in particular, allowed the manipulation of re-
activities of hydroxyl groups in 4,6-O-benzylidene acetals of glycopyranosides

Benzoylation of 4,6-O-Benzylidene Acetals
49
in their benzoylation with benzyoyl anhydride or chloride. This has provided
an efficient method for monobenzoylation of these compounds in one step in
good to excellent yields and high regioselectivity.
EXPERIMENTAL
General Methods
Melting points were determined on a Boethius micro hot-stage apparatus
and were uncorrected. Optical rotations were measured with a Perkin–Elmer
1
model 141. Spectra H and 13C NMR were registered on a Bruker DPX-300
(1H at 300 MHz and 13C at 75 MHz). Chemical shifts (δ) are reported in ppm
related to Me4Si. Positive mode HR LSI mass spectra were obtained on an
Agilent Technology 6510 Q TOF LC/MS mass spectrometer (USA). The sam-
ples were dissolved in methanol (c 0.01 mg/mL). TLC was performed on silica
gel L (5–40 μm; Chemapol) with hexane–acetone 7:3 as eluent. For detection,
10% sulfuric acid in ethanol at 130ºC was used. Column chromatography was
performed on silica gel (100–160 μm; Chemapol).
General Procedure for the Monobenzoylation of
4,6-O-benzylidene Acetals of Glycopyranosides by Benzoic
Anhydride using Cu(CF3COO)2 as Promoter
A solution of acetal (0.25 mmol), benzoic anhydride (0.32 mmol),
Cu(CF3COO)2 (0.32 mmol), and 2,4,6-collidine (0.32 mmol) in acetonitrile
(2 mL) was stirred at rt for 6 h. The reaction was monitored by TLC. Chloro-
form (20 mL) was added to the reaction mixture. The organic layer was washed
with 2 N HCl, aq. NaHCO3, and water and was then concentrated to a small
volume under reduced pressure at rt. The products were finally purified by
flash chromatography on a column of silica gel using gradient acetone in hex-
ane as eluents.
Methyl 2-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranoside (1a)
It (73 mg) was obtained in a 76% yield from 1. Rf 0.50. m.p. 169–170◦C
(recrystalized from EtOAc-hexane). [α]D +108.9 (с 0.6, CHCl3). Lit. data:[50]
20
m.p. 169–170◦C; [α]D +111.
20
Methyl 2-O-benzoyl-p-methoxy-4,6-O-benzylidene-α-D-glucopyranoside (2a)
It (75 mg) was obtained in a 72% yield from 2. Rf 0.44. m.p. 153.5–154.5◦C
(recrystalized from EtOAc-hexane). [α]D +88.5 (с 0.4, CHCl3). 1H NMR
20
(300 MHz, CDCl3): δ 8.13–8.07 (m, 2H, PhH), 7.62–7.55 (m, 1H, PhH),
7.50–7.40 (m, 4 H, PhH), 6.93–6.88 (m, 2H, PhH), 5.53 (s, 1H, PhCH),
5.09–5.01 (m, 2 H, H-1, H-2), 4.38–4.28 (m, 2H, H-3, H-6a), 3.95–3.85 (m, 1H,

E.V. Evtushenko
50
H-5), 3.80 (s, 3H, OCH3), 3.78 (t, 1H, J = 10.1 Hz, H-6b), 3.62 (t, 1H, J =
9.3 Hz, H-4), 3.39 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3): δ 166.2, 160.2,
133.3, 129.9, 129.4, 128.3, 127.6, 113.6, 101.9, 97.7, 81.4, 74.0, 68.8, 68.7, 62.0,
55.4, 55.2. HRMS (ESI) calcd for C22H24O8Na m/z (M+Na)+: 439.1363. Found:
439.1353.
Methyl 3-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside (5a)
It (70 mg) was obtained in a 73% yield from 5. Rf 0.31. m.p. 165–166◦C
(recrystalized from EtOAc-hexane). [α]D +91.3 (с 0.4, CHCl3). Lit. data:[51]
20
m.p .165◦C; [α]D +94.4.
20
Benzyl 3-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside (6a)
It (91 mg) was obtained in a 79% yield from 6. Rf 0.40. m.p. 177–179◦C
(recrystalized from EtOAc-hexane). [α]D +61.7 (с 0.6, CHCl3). Lit. data:[27]
20
m.p. 178–179◦C; [α]D +64.4.
20
Benzyl 3-O-benzoyl-p-methoxy-4,6-O-benzylidene-β-D-galactopyranoside (7a)
It (95 mg) was obtained in a 77% yield from 7. Rf 0.34. m.p. 62–63◦C
(recrystalized from EtOAc-hexane). [α]D +46.8 (с 0.4, CHCl3). 1H NMR
20
(300 MHz, CDCl3): δ 8.11–8.04 (m, 2H, PhH), 7.60–7.51 (m, 1H, PhH),
7.45–7.28 (m, 9 H, PhH), 6.88–6.83 (m, 2H, PhH) 5.47 (s, 1H, PhCH), 5.12
(dd, 1H, J = 3.6 Hz, J = 10.1 Hz, H-3), 5.03 (d, 1H, J = 11.8 Hz, CH2), 4.66 (d,
1H, J = 11.8 Hz, CH2), 4.52 (d, 1H, J = 7.7 Hz, H-1), 4.47 (m, 1H, H-4), 4.38
(dd, 1H, J = 12.5 Hz, H-6a), 4.24 (dd, 1H, J = 7.8 Hz, J = 10.0 Hz, H-2), 4.09
(dd, J = 1.2 Hz, J = 12.5 Hz, H-6b), 3.78 (s, 3H, OCH3), 3.55 (m, 1H, H-5). 13
C
NMR (75 MHz, CDCl3): δ 166.4, 159.9, 137.0, 133.1, 129.9, 128.4, 128.3, 128.1,
128.0, 127.4, 113.4, 101.9, 100.7, 74.0, 73.6, 70.9, 68.9, 68.7, 66.5, 55.2. HRMS
(ESI) calcd for C28H28O8Na m/z (M+Na)+: 515.1676. Found: 515.1673.
Methyl 2-O-benzoyl-4,6-O-benzylidene-α-D-mannopyranoside (10a)
It (68 mg) was obtained in a 70% yield from 10. Rf 0.50. [α]D20 –42.7 (с 0.5,
CHCl3). Lit. data: [α]D20 –44[39] or [α]D21 –39.[12]
Methyl 2-O-benzoyl-p-methoxy-4,6-O-benzylidene-α-D-mannopyranoside (11a)
20
It (75 mg) was obtained in a 72% yield from 11. Rf 0.44. [α]D –45.2
(с 0.4, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.13–8.06 (m, 2H, PhH), 7.63–7.57
(m, 1H, PhH), 7.50–7.42 (m, 4H, PhH), 6.92–6.88 (m, 2H, PhH) 5.61 (s, 1H,
PhCH), 5.45 (dd, 1H, J = 1.4 Hz, J = 3.6 Hz, H-2), 4.83 (d, 1H, J = 1.2 Hz, H-
1), 4.35–4.28 (m, 2H, H-3, H-6a), 4.05–3.98 (m, 1H, H-5), 3.93–3.85 (m, 2H, H-
4, H-6b), 3.80 (s, 3H, OCH3), 3.43 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3): δ
166.0, 160.2, 133.4, 130.0, 129.9, 129.6, 129.5, 128.4, 128.3, 127.6, 113.7, 102.2,

Benzoylation of 4,6-O-Benzylidene Acetals
51
99.6, 79.3, 72.5, 68.8, 67.4, 63.3, 55.3, 55.2. HRMS (ESI) calcd for C22H24O8Na
m/z (M+Na)+: 439.1363. Found: 439.1354.
General Procedure for the Monobenzoylation of
4,6-O-benzylidene Acetals of Glycopyranosides by Benzoyl
Chloride with MoO2(acac)2 as a Catalysis
A solution of acetal (0.25 mmol), 2,4,6-collidine (0.5 mmol), and
MoO2(acac)2 (0.005 mmol) in acetonitrile (2 mL) was allowed to stir at rt for
6 h. BzCl (0.37 mmol) was added to the solution in three portions. The reac-
tion was monitored by TLC. Chloroform (20 mL) was added to the solution.
The organic layer was washed with 2 N HCl, aq. NaHCO3, and water and then
concentrated to a small volume under reduced pressure at rt. The product was
purified by flash chromatography on a column of silica gel using gradient ace-
tone in hexane as eluents.
Methyl 3-O-benzoyl-4,6-O-benzylidene-α-D-galactopyranoside (3a)
It (62 mg) was obtained in a 64% yield from 3. Rf 0.36. m.p. 136.5–138.5◦C
(recrystallized from EtOAc-hexane). [α]D +227.0 (с 0.4, CHCl3). Lit. data:[51]
20
m.p. 139◦C; [α]D +235.7.
20
Methyl 3-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside (5a)
It (73 mg) was obtained in a 76% yield from 5. Its properties were the same
as mentioned above.
Benzyl 3-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside (6a)
It (87 mg) was obtained in a 75% yield from 6. Its properties were the same
as mentioned above.
Methyl 3-O-benzoyl-4,6-O-benzylidene-α-D-mannopyranoside (10b)
It (74 mg) was obtained in a 77% yield from 10. Rf 0.41. m.p. 128–130◦C
(recrystallized from EtOAc-hexane). [α]D –23.5 (с 0.4, CHCl3). Lit. data:[49]
20
m.p. 131–132◦C; [α]D20 –24.
Methyl 3-O-benzoyl-p-methoxy-4,6-O-benzylidene-α-D-mannopyranoside (11b)
20
It (85 mg) was obtained in a 82% yield from 11. Rf 0.38. [α]D –33.1
(с 0.3, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.09–8.02 (m, 2H, PhH), 7.59–7.31
(m, 5H, PhH), 6.85–6.80 (m, 2H, PhH), 5.56 (s, 1H, PhCH), 5.53 (dd, 1H, J =
3.3 Hz, J = 10.2 Hz, H-3), 4.79 (d, 1H, J = 1.4 Hz, H-1), 4.33–4.18 (m, 3H,
H-2, H-4, H-6a), 4.03–3.84 (m, 2H, H-5, H-6b), 3.76 (s, 3H, OCH3), 3.43 (s, 3H,
OCH3). 13C NMR (75 MHz, CDCl3): δ 165.4, 159.9, 133.2, 129.7, 129.6, 128.3,

E.V. Evtushenko
52
127.3, 113.5, 101.7, 101.4, 76.0, 71.4, 69.7, 68.7, 63.7, 55.2, 55.0. HRMS (ESI)
calcd for C22H24O8Na m/z (M+Na)+: 439.1363. Found: 439.1350.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s
website.
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