Acyl chloride/DABCO-promoted acetal migration of 1,2:4,5-di-O-isopropylidene-d-fructopyranose

Article abstract of DOI:10.1016/j.carres.2007.02.005

An unprecedented acetal migration was observed when 1,2:4,5-di-O-isopropylidene-d-fructose was treated with various acyl chlorides and 1,4-diaza-bicyclo[2.2.2]octane (DABCO). 2,3:4,5-Di-O-isopropylidene-d-fructose derivatives were isolated as the only pro

Full text of DOI:10.1016/j.carres.2007.02.005

Carbohydrate Research 342 (2007) 1101–1104
Note
Acyl chloride/DABCO-promoted acetal migration of
1,2:4,5-di-O-isopropylidene-D-fructopyranose
Xiang-Bao Meng, Yun-Feng Li and Zhong-Jun Li*
Department of Chemical Biology, School of Pharmaceutical Sciences, State Key Laboratory of Natural and Biomimetic Drugs,
Peking University Health Science Center, Beijing 100083, PR China
Received 7 January 2007; received in revised form 5 February 2007; accepted 6 February 2007
Available online 13 February 2007
Abstract—An unprecedented acetal migration was observed when 1,2:4,5-di-O-isopropylidene-D-fructose was treated with various
acyl chlorides and 1,4-diaza-bicyclo[2.2.2]octane (DABCO). 2,3:4,5-Di-O-isopropylidene-D-fructose derivatives were isolated as the
only product in high to quantitative yields. The acylium cations generated in situ were speculated as the electrophilic species to ini-
tiate the migration process.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Acetal migration; Acetylation; Acylium cations; Fructose; DABCO
More than 110 years ago Emil Fisher first described
the formation of acetals from D-fructose and acetone.1
Since then, the O-isopropylidene group has been exten-
sively used in organic synthesis, especially in the field of
carbohydrate chemistry. Acetal migration is a well-doc-
umented phenomenon, among which di-O-isopropylid-
ene sugars are found to form thermodynamically
favored isomers under acidic conditions (proton acids
or Lewis acids).2 Herein, we report that a novel acetal
migration occurred when 1,2:4,5-di-O-isopropylidene-
D-fructose was treated with an acyl chloride in the pres-
ence of DABCO.
Two kinds of diacetonide D-fructosides (1 and 2,
Scheme 1) can be formed when D-fructose is treated with
concentrated H2SO4 in dry acetone. The ratios of 1 and
2 depend on the amount of H2SO4 used in the reaction
mixture. If a small amount of H2SO4 is used, compound
1 is the major product,3 whereas a large amount of
H2SO4 leads predominately to compound 2.4 Further-
more, 1 is readily converted into the more stable product
OH
O
O
O
acetone
O
O
D-fructose
or
O
O
O
OH
H2SO4
O
O
1
2
acid
Scheme 1. Formation of 1,2:4,5-di-O-isopropylidene-D-fructose and 2,3:4,5-di-O-isopropylidene-D-fructose.
*
Corresponding author. Tel.: +86 10 82801714; fax: +86 10 62367134; e-mail: zjli@bjmu.edu.cn
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.02.005

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X.-B. Meng et al. / Carbohydrate Research 342 (2007) 1101–1104
O
O
O
R
O
O
O
O
RCOCl
base
R
O
1
O
O
O
O
O
O
4
3
a. R = CH2=CH- b. R = ClCH2- c. R = trans-PhCH=CH- d. R = Ph-
Scheme 2. Various acyl chloride/base combinations that promoted acetal migration.
2 after the treatment with H2SO4 in acetone.5 To the
best of our knowledge, no reagents other than strong
acid can accomplish this type of migration.
onto the central pyranose ring. However, the coupling
constant between H-3 and H-4 is ꢀ2.4 Hz; and ꢀ5 Hz,
respectively. Another criterion is the relative chemical
shifts of H-1 and H-6,6a: HO-1 was acylated in com-
pounds 3, and its H-1 signal was found at lower field
than that of H-6,6a. HO-3 was acylated in compounds
4, and the signal of H-1 was closer to that of H-6,6a.
A proposed mechanism for this unique transforma-
tion is shown in Scheme 3. An acylium cation, the elec-
trophilic species, that is generated in the presence of acyl
chloride and DABCO in CH3CN, reacts with the most
reactive oxygen, O-1, to give the migration product via
a ring-opening and ring-closing procedure (path A) or
in a concerted manner (path B). The free hydroxyl
group, which is reluctant to react with the highly reac-
tive oxocarbonium ion, may be sterically hindered from
the bulky 1,2-acetal.
Compound 4a, where the sugar is used as a chiral aux-
iliary, has been used as a dienophile in an asymmetric
Diels–Alder reaction.6 In our synthesis of 4a, after we
changed the base from pyridine to DABCO in CH3CN,
to our astonishment, compound 3a was found as the
only product in quantitative yield, and the ‘normal’
acetylated product was not observed at all (Scheme 2).
When either acryloyl chloride or DABCO was used
independently (Table 1, entries 1 and 2), the starting
material 1 remained intact. These results excluded the
possibility of the migration caused by DABCO or by a
trace of HCl. Furthermore, no migration product was
formed when compound 3a was treated with acryloyl
chloride and DABCO, indicating that the migration
took place before the acylation.
Various acyl chloride and base combinations were
subsequently tried (Scheme 2 and Table 1) to investigate
the efficacy and scope of this reaction. When cinnamoyl
chloride, chloroacetyl chloride, and benzoyl chloride
were used under similar conditions, acetal migration
products 3b, 3c, and 3d were isolated as the only prod-
ucts in excellent yields, respectively, though the last
one was produced in a sluggish manner (Table 1, entries
5, 7 and 9). In contrast, when pyridine was used instead
of DABCO, no migration product was observed.
Compounds 3a–d and 4a,b,d can be unambiguously
characterized by 1H NMR spectroscopy. Both com-
pounds 3 and 4 adopt a skew boat conformation be-
cause of the two five-membered rings that are cis-fused
1. Experimental
1.1. General methods
1H and 13C NMR spectra were recorded on a Jeol-300
instrument using TMS as internal standard. Mass spec-
tra were measured on an IBI-MDS Sciexciex Q-Star
mass spectrometer. Optical rotations were measured at
25 ꢁC using an Optical Activity AA-10R automatic
polarimeter. TLC was performed on self-made glass
plates coated with Silica Gel GF254 (Hai Yang Chemi-
cal Factory, Qingdao, Shandong, PR China). Column
chromatography was performed on Silica Gel H60
Table 1. Various acyl chloride/base combinations that promoted acetal migration
Entry
RCOCl
Base
Product 3/4
Yield (%)
1
2
3
4
5
6
7
8
9
CH2@CHCOCl
No
No
—
—
0
0
DABCO
DABCO
Pyridine
DABCO
Pyridine
DABCO
DABCO
Pyridine
CH2@CHCOCl
CH2@CHCOCl
ClCH2COCl
ClCH2COCl
trans-PhCH@CHCOCl
PhCOCl
3a/4a, 100/0
3a/4a, 0/100
3b/4b, 100/0
3b/4b, 0/100
3c/4c, 100/0
3d/4d, 100/0
3d/4d, 0/100
Quantitative
Quantitative
Quantitative
Quantitative
91
81
83
PhCOCl

X.-B. Meng et al. / Carbohydrate Research 342 (2007) 1101–1104
1103
O
N
N
R
R
Cl
OH
OH
OH
O
O
R
O
R
O
O
Path A
O
O
O
O
O
O
O
O
O
O
O
O
O
CH3CN
O
R
1
N
Path B
N
N
N
H
O
H
O
O
O
3
O
O
O
O
O
O
O
O
R
O
R
O
Scheme 3. Proposed mechanism for acetal migration.
(Hai Yang Chemical Factory, Qingdao, Shandong, PR
China). Melting points were measured on an X4 melting
point apparatus, and the thermometer was uncorrected.
Solvents were purified by standard procedures. Yields
are given in Table 1.
1.4. 1-O-Cinnamoyl-2,3:4,5-di-O-isopropylidene-b-D-
fructopyranose (3c)
1
[a]D À26.2 (c 1.22, CHCl3). H NMR d 7.75 (d, 1H, J
16.2 Hz), 7.50–7.53 (m, 2H, Ph), 7.38–7.40 (m, 3H,
Ph), 6.47 (d, 1H, J 16.2 Hz), 4.63 (d, 1H, J 2.4, 7.8 Hz,
H-4), 4.57 (dd, 1H, J 11.7 Hz, H-1a), 4.40 (d, 1H, J
2.4 Hz, H-3), 4.26 (d, 1H, J 8.4 Hz, H-5), 4.20 (d, 1H,
J 11.7 Hz, H-1b), 3.94 (dd, 1H, J 12.9, 1.8 Hz, 6a),
3.80 (d, 1H, J 12.9 Hz, H-6b), 1.56, 1.50, 1.44, 1.35
(4s, 4 · 3H, 4CH3). 13C NMR d 166.2, 145.5, 134.2,
130.4, 128.9, 128.1, 117.5, 109.1, 108.7, 70.8, 70.6,
70.1, 65.3, 61.3, 40.7, 26.5, 25.9, 25.3, 24.0. ESI TOF
MS m/z 390.2, found 391.1 [M+H]+, 408.1
[M+NH4]+. Anal. Calcd for C21H26O7: C, 64.60; H,
6.71. Found: C, 64.44; H, 6.82.
1.2. General procedure for the acetal migration
To a solution of compound 1 (260 mg, 1.0 mmol) and
DABCO (183 mg, 1.5 mmol) in anhyd CH3CN (3 mL),
was added acyl chloride (1.5 mmol, for PhCOCl,
2.5 mmol was used) dropwise. The resulting mixture
was stirred at room temperature (monitored by TLC,
2–24 h). After quenching with MeOH, the mixture was
evaporated and purified on a silica-gel column. The data
for compounds 4a, 3a, 4b, and 4d, were consistent with
those of Refs. 6–9, respectively.
1.5. 1-O-Benzoyl-2,3:4,5-di-O-isopropylidene-b-D-fructo-
pyranose (3d)
1.3. 1-O-Chloroacetyl-2,3:4,5-di-O-isopropylidene-b-D-
fructopyranose (3b)
Mp 80–82 ꢁC (82 ꢁC, Ref. 10). 1H NMR d 8.06–8.09 (m,
2H, Ph), 7.54–7.60 (m, 1H, Ph), 7.41–7.47 (m, 4H, Ph),
4.69 (d, 1H, J 12.0 Hz, H-1a), 4.65 (dd, 1H, J 2.4,
7.8 Hz, H-4), 4.48 (d, 1H, J 2.4 Hz, H-3), 4.33 (d, 1H,
J 12.0 Hz, H-1b), 4.27 (d, 1H, J 7.8 Hz, H-5), 3.96 (d,
1H, J 12.9 Hz, H-6a), 3.81 (d, 1H, 12.9 Hz, H-6b),
1.55, 1.47, 1.38, 1.35 (4s, 4 · 3H, 4CH3).
1
[a]D À22.4 (c 1.07, CHCl3). H NMR d 4.62 (dd, 1H, J
7.8 Hz, 2.7 H-4), 4.65 (d, 1H, J 11.7 Hz, H-1a), 4.32
(d, 1H, J 2.4 Hz, H-3), 4.25 (d, 1H, J 7.2 Hz, H-5),
4.14 (d, 1H, J 11.7 Hz, H-1b), 4.13 (s, 2H, –CH2Cl),
3.91 (dd, 1H, J 12.9, 1.8 Hz, H-6a), 3.78 (d, 1H,
12.9 Hz, H-6b), 1.55, 1.49, 1.42, 1.35 (4s, 4 · 3H,
4CH3). 13C NMR d 109.1, 108.9, 70.6, 70.5, 69.9, 66.6,
61.3, 40.7, 26.4, 25.8, 25.1, 24.0. ESI TOF MS m/z found
337.1 [M+H]+, 354.1 [M+NH4]+. Anal. Calcd for
C14H21ClO7 (336.1): C, 49.93; H, 6.29. Found: C,
49.86; H, 6.40.
Acknowledgement
We thank the National Science Foundation of PR
China (NSFC, No. 20372003) for financial support.

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