Synthesis of 2,3,4,6-tetra-O-benzyl-D-glucal on the gram scale. A convenient method for its facile synthesis and subsequent stereoselective cyclopropanation

Full text of DOI:10.1016/j.carres.2003.12.016

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 897–899
Note
Synthesis of 2,3,4,6-tetra-O-benzyl-D-glucal on the gram scale.
A convenient method for its facile synthesis and subsequent
stereoselective cyclopropanation
Corin M. Storkey, Anna L. Win and John O. Hoberg*
School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
Received 4 November 2003; accepted 21 December 2003
Keywords:
D-Glucal; Elimination; Cyclopropanation
BnO
BnO
BnO
BnO
Due to their utility in a variety of processes, glycals
have received considerable attention in the carbohydrate
field.1 Examples include DanishefskyÕs epoxidation/gly-
cosidation methodology,2 Ferrier-type rearrangements,3
cyclopropanations,4 C-glycosylations,5 and metal-cata-
lyzed transformations.6 Reports on the use of 2,3,4,6-
1. Ms2O
O
O
OH
BnO
BnO
2. Pd(PPh3)4
85%
ð1Þ
BnO
OBn
2
1
Glycal 1 has been shown to be useful in epoxidation10
and lithiation11 chemistry and would presumably be an
excellent substrate for our12 and othersÕ recently devel-
oped cyclopropanation chemistry.4 We have therefore
developed a more facile synthesis of 1 based on well-
established procedures13 using Fraser-ReidÕs n-pentenyl
glycoside chemistry. Thus, pentenyl glycoside 3 is pre-
pared according to literature procedure in two steps and
overall 68% yield (Eq. 2).14 Glycoside 3 is subsequently
treated with bromine,15 followed by DBU. As reported,
tetra-O-benzyl-D-glucal (1), however, have been limited,
perhaps due to its low yielding and problematical syn-
thesis. The most recently reported synthesis involves the
mesylation then Pd(PPh3)4-catalyzed elimination of 2
(Eq. 1).7 We have found this strategy to be difficult as
the use of pristine methanesulfonic anhydride is
required, purification of 1 by radial chromatography is
required, and the synthesis of 28 is low yielding (29%).
Other reports of the formation of 1 as byproducts in
reactions of diazirines have also appeared, but these do
not appear to be synthetically useful.9
the bromination of 3 gives exclusively a-D-gluco-
pyranosyl bromide, thus allowing for the subsequent
OH
BnO
BnO
BnO
1.
1. Br2
O
O
BnO
Glucose
BnO
OPent
BnO
ð2Þ
2. BnBr, NaH
2. DBU
73-80%
BnO
68%
OBn
1
3
* Corresponding author at present address: Department of Chemistry, University of Wyoming, Laramie, WY 82071, USA. Tel.: +307-766-2795; fax:
+307-766-2807; e-mail: hoberg@uwyo.edu
Our attempted purification via flash chromatography resulted in an impure product.
0008-6215/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2003.12.016

898
C. M. Storkey et al. / Carbohydrate Research 339 (2004) 897–899
antiperiplanar elimination reaction. The overall process
is highly reproducible, and we have synthesized glycal 1
on the gram scale. We prefer using Fraser-ReidÕs
methodology for the formation of the glucopyranosyl
bromide, as apposed to other methods,16 since it is a
highly robust, short, and facile procedure and allows for
a multigram synthesis. It should be noted that the
addition of bromine to 3, followed by immediate treat-
ment with DBU, is critical, as prolonged exposure to
bromine leads to lower yields.
with CH2Cl2, and the aqueous layer was concentrated
under vacuum to give a brown crystalline substance.
Flash chromatography using a gradient mixture of 20:1–
10:1 CH2Cl2–MeOH gave 5.70 g (85% yield) of pent-4-
enyl
D
-glucopyranoside as an oil. Rf 0.15 (9:1 CH2Cl2–
MeOH). A 2.00-g (8.10 mmol) sample of this oil was
dissolved in DMF (20 mL), then added dropwise to a
suspension of NaH (1.35 g, 56.5 mmol) in DMF (20 mL)
at 0 ꢁC. After hydrogen evolution subsided, benzyl
bromide (6.07 g, 35.5 mmol) was slowly added and then
stirred overnight, while warming to room temperature.
The reaction was quenched with MeOH, diluted with
Et2O (250 mL), and washed with water (100 mL), satd
Straightforward access to 1 has enabled us to initiate a
new area of chemistry of this glycal (Eq. 3). Using
Furukawa cyclopropanation conditions,17 the allylic
oxygen-directed cyclopropanation18 gave cyclopropane
4 in 87% yield and as a single diastereomer. The ste-
reochemistry of the cyclopropane derivative 4 was
determined by NOE experiments in which positive
effects were observed between H-1, H-3, and H-5. This
stereochemistry is in agreement with the cyclopropana-
aqNaHCO
(100 mL), and brine (100 mL), and the
3
Et2O extract was then dried with Na2SO4. After filtra-
tion and concentration, the crude residue was purified
by flash chromatography (10:1 hexanes–EtOAc) to give
4.00 g (82% yield) of 3 as a mixture of a and b anomers
that existed as a white crystalline solid (b anomer) in a
colorless oil (a anomer): Rf 0.58 (5:1 hexanes–EtOAc).
Comparison of the NMR spectrum to that reported was
identical in all respects.21
tion of tri-O-benzyl-D
-glucal.12c;19
BnO
BnO
BnO
7
CH2I2
5
O
O
BnO
BnO
BnO
1
Et2Zn
87%
ð3Þ
3
1.1.2. 1,5-Anhydro-2,3,4,6-tetra-O-benzyl-D-arabino-hex-
OBn
OBn
1
4
1-enitol (1). Bromine (1.83 mL of a 1.98 M soln in
CH2Cl2, 3.33 mmol) was added dropwise to a solution of
3 (2.0 g, 3.30 mmol) in CH2Cl2 (20 mL) at 0 ꢁC until the
solution maintained an orange color. The solvent was
immediately removed in vacuo at 20 ꢁC, leaving an
orange oil characterized by a one-proton doublet at 6.45
In summary, we have developed new methodology
suitable for the convenient and large-scale synthesis of
2,3,4,6-tetra-O-benzyl-D-glucal. The cyclopropanation
of this glycal has been achieved in excellent yield and
selectivity, and the chemistry of this new derivative will
be reported in due course.
1
(J 3.7 Hz) in the H NMR spectrum. The resulting oil
was redissolved in CH2Cl2 (20 mL), cooled to )20 ꢁC,
and 1,5-diazabicyclo[5,4,0]-undec-5-ene (DBU) (1.01 g,
6.60 mmol) was added dropwise over 10 min. The solu-
tion was stirred for 30 min in the dark, with warming to
room temperature. The mixture was diluted with
CH2Cl2 (50 mL), washed successively with 5% HCl,
1. Experimental
1.1. General
All reactions were carried out under argon using oven-
dried glassware unless otherwise stated. Purification of
products via flash chromatography was conducted using
E. Merck Silica Gel 60 using distilled MeOH, CH2Cl2,
hexanes, or EtOAc. 1H and 13C NMR spectra were
recorded on a Varian INOVA spectrometer at 300 and
75 MHz, respectively, in CDCl3. 4-Penten-1-ol was syn-
thesized using the published procedure.20 The synthesis
of 3 is reported as a modification of literature proce-
dures15;21 and was obtained as a mixture of anomers.
water, and satd aqNaHCO , and the extract was dried
3
with MgSO4, filtered, and concentrated. The crude res-
idue was purified by flash chromatography (10:1 hex-
ane–EtOAc) to give 1 as a colorless oil that solidified on
standing (1.25 g, 73% yield). Recrystallization from
MeOH can be performed but is generally not required:
Rf 0.54 (5:1 hexanes–EtOAc). IR: 1098, 1070, 1027 cmꢁ1
;
1H NMR: d 3.70–3.82 (m, 2H, H-6), 3.92 (dd, J 5 Hz, J
2 Hz, 1H, H-4), 4.11–4.16 (m, 1H, H-5), 4.29 (d, J 5 Hz,
1H, H-3), 4.55–4.80 (m, 8H, CH2Ph), 6.34 (s, 1H, H-1),
7.26–7.37 (m, 20H, Ar); 13C NMR: d 139.1, 138.6, 138.3,
138.1, 137.4, 128.7–127.8 (aromatic), 76.4, 75.9, 75.8,
74.4, 73.7, 73.1, 72.5, 71.2, 68.5. Anal. Calcd for
C34H34O5: C, 78.14; H, 6.56. Found: C, 78.56; H, 6.76.
1.1.1. Pent-4-enyl 2,3,4,6-tetra-O-benzyl-D-glucopyrano-
side (3). A mixture of -glucose (5.00 g, 27.8 mmol),
D
4-penten-1-ol (40 mL), and camphorsulfonic acid
(100 mg, 0.43 mmol) was refluxed for 48 h with vigorous
stirring. The solution was quenched with Et3N
(ꢀ0.25 mL), and the bulk of the pentenol alcohol was
distilled for reuse under vacuum using a liquid nitrogen
condenser. The residue was poured into water, washed
1.1.3. 1,5-Anhydro-2,3,4,6-tetra-O-benzyl-2-deoxy-1,2-C-
(methylene)-
D
-glycero-D-hexitol (4). To a solution of 1
(380 mg, 0.727 mmol) in CH2Cl2 (4.0 mL) at 0 ꢁC was
added Et2Zn (4.4 mL, 1 M in hexane, 4.36 mmol), fol-

C. M. Storkey et al. / Carbohydrate Research 339 (2004) 897–899
899
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stirred at 0 ꢁC for 1 h, then 9 h at room temperature. The
solution was poured into satd aqNH Cl (50 mL) and
4
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extracted with Et2O (2 · 20 mL). The ether layers were
washed with brine (50 mL), dried with MgSO4, filtered,
and concentrated. Flash chromatography with 10:1
hexanes–EtOAc gave 4 (340 mg, 87%) as a colorless oil.
1
IR: 1163, 1078 cmꢁ1; H NMR (300 MHz, CDCl3): d
1.20 (m, 1H, H-7b), 1.31–1.38 (m, 1H, H-7a), 3.93 (dd, J
3.9 Hz, 1H, H-1), 4.46 (d, J 10.9 Hz, 1H, H-3), 3.25 (m,
1H, H-4), 3.56 (m, 1H, H-5), 3.73 (d, J 8.5 Hz, 2H, H-6),
4.49–5.01 (m, 8H, CH2Ph), 7.17–7.41 (m, 24H, CH2Ph);
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66.3 (C-2), 69.5 (C-6), 77.5 (C-5), 79.5 (C-4), 80.4 (C-3);
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We thank the New Zealand Cancer Society and Genesis
Oncology Trust for funding.
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