Synthesis of 2,3:4,6-di-O-isopropylidene-D-allopyranose from D-glucose

Article abstract of DOI:10.1016/j.carres.2005.05.011

2,3:4,6-Di-O-isopropylidene-D-allopyranose can be conveniently prepared from D-glucose via a synthetic sequence, which includes Mitsunobu inversion at O-3, di-O-isopropylidenation of phenyl-1-thio-D-alloside and anomeric deprotection on treatment with NBS/CaCO₃.

Full text of DOI:10.1016/j.carres.2005.05.011

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 1872–1875
Note
Synthesis of 2,3:4,6-di-O-isopropylidene-D-allopyranose
from D-glucose
*
Ana M. Gomez, Marıa D. Company, Attila Agocs, Clara Uriel,
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´
Serafın Valverde and J. Cristobal Lopez
*
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Instituto de Quımica Organica General (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
Received 25 January 2005; received in revised form 12 April 2005; accepted 28 May 2005
Available online 23 June 2005
Abstract—2,3:4,6-Di-O-isopropylidene-D-allopyranose can be conveniently prepared from D-glucose via a synthetic sequence, which
includes Mitsunobu inversion at O-3, di-O-isopropylidenation of phenyl-1-thio-D-alloside and anomeric deprotection on treatment
with NBS/CaCO3.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: 2,3:4,6-Di-O-isopropylidene-D-allopyranose; Phenyl 1-thio-glycosides; NBS; Carbohydrate acetals
As part of a synthetic program intended for the prepara-
tion of carbasugars,1–3 we have recently shown the
usefulness of 2,3:4,6-di-O-isopropylidene acetals 1–3 of
D-mannose,2 D-glucose,3 and D-galactose3 as starting
materials (Scheme 1). In this context, we published some
time ago a method for the efficient preparation of 2 and
3.4 More recently, as a continuation of our research
program, we required gram amounts of D-allose
2,3:4,6-di-O-isopropylidene acetal (4). In this Note, we
disclose a practical method for the preparation of 4 from
D-glucose.
D-Allose (5) is a commercially available monosaccha-
ride, however its high price5 has activated the develop-
ment of several methods for its preparation from
inexpensive D-glucose.6 On the other hand, whereas
the kinetic acetonation of D-mannose, according to
Gelas and Horton,7,8 is the method of choice for the
preparation of 1, similar acetonation of D-allose (5)
led essentially exclusively (81%) to 4,6-O-isopropylid-
ene-D-allopyranose (6) with only a minor amount (9%)
of diacetonide 4.8,9 A survey of the literature did not
show any additional procedure for the preparation of 4.
Our strategy for the preparation of 4 (Scheme 2a)
involved the synthesis of phenyl-1-thio-b-D-allopyrano-
side 8, by Mitsunobu reaction of phenyl-1-thio-b-D-
glucopyranoside 10, followed by deacetylation, 2,3:4,6-
di-O-isopropylidene acetal formation and anomeric
deprotection (8!9!4, Scheme 2a). Phenyl-1-thio-b-D-
glucopyranose (10) was readily prepared, according to
Ferrier and Furneaux,10 by treatment of b-D-glucopyra-
nose pentaacetate11 with boron trifluoride etherate and
thiophenol. Mitsunobu reaction of methyl b-D-gluco-
pyranoside with benzoic acid has been described by
Weinges et al. to yield the corresponding 3,6-di-O-ben-
zoyl-D-allopyranose derivative in 87% yield.6 In the case
of the glucose derivative 10, this procedure gave poor
yields of the corresponding allose dibenzoate. Alterna-
tively, we have found that the use of acetic acid, rather
than benzoic acid, triphenyl phosphine and diethyl azo-
dicarboxylate yielded phenyl-3,6-di-O-acetyl-1-thio-b-D-
allopyranoside 7 in 82–84% yield (Scheme 2a). The
crude acetyl ester was saponified by the method of Zem-
plen12a to yield phenyl-1-thio-b-D-allopyranoside (8),
which upon acetonation yielded thioglycoside 9. Depro-
tection of the anomeric thiophenyl protecting group on
compound 9 was carried out by treatment with NBS in
the presence of CaCO3 to yield the desired compound 4
(J1,2 = 4.5 Hz, CDCl3) in 88% yield. This compound has
*
Corresponding authors. Tel.: +34 91 5622900; fax: +34 91 5644853
(A.M.G.), (J.C.L.); e-mail addresses: clopez@iqog.csic.es; anago@
iqog.csic.es;
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.05.011

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A. M. Gomez et al. / Carbohydrate Research 340 (2005) 1872–1875
1873
Deprotection of the anomeric thiophenyl protecting
group on compound 9 had proved to be troublesome.
Treatment of 9 with either NBS in THF/saturated so-
dium bicarbonate solution or with AgNO3 in acetone/
water yielded rearranged furanose diacetonide 11 in
35% and 37% yield, respectively (Scheme 2b). In the
course of this study, we have also considered benzyl
allopyranoside 12 (Scheme 1) as a precursor for hemiac-
etal 4 by hydrogenolytic cleavage, and accordingly com-
pound 12 was prepared through a similar synthetic
sequence. However, attempted hydrogenation of 12
under a variety of conditions left, in our hands, its
anomeric benzyl group unchanged.
O
O
O
O
O
O
O
O
O
O
O
O
OH
O
OH
O
OH
O
1
2
3
R4O
R3O
O
R
OR1
R2
R2O
R4
H
R1
R3
R
CMe2
CMe2
CMe2
4
In summary, a synthesis of 2,3:4,6-di-O-isopropylid-
ene D-allopyranose (4) has been developed. This proce-
dure represents the first high yield synthesis of the title
compound and uses inexpensive D-glucose as the start-
ing material.
5
6
7
OH
OH
H
H
H
H
H
H
Ac
H
H
Ac
H
H
H
8
9
CMe2
CMe2
O
1. Experimental
O
O
OH
O
O
O
O
1.1. General methods
O
OBn
OH
HO
HO
SPh
O
OH
Melting points were determined in capillary tubes and
are uncorrected. Optical rotations were determined at
1
the sodium D line. H NMR spectra were recorded at
O
O
10
Scheme 1.
11
12
200, 300 or 500 MHz; chemical shifts (d) are relative
to residual non-deuterated solvent as internal reference.
TLC was conducted in precoated Kieselgel 60 F254.
Detection was first by UV (254 nm), then charring with
a solution of ammonium molybdate(VI) tetrahydrate
(12.5 g) and cerium(IV) sulfate tetrahydrate (5.0 g) in
10% aqueous sulfuric acid (500 mL). Column chroma-
tography was carried out on Kieselgel (230–400 mesh)
and, unless otherwise noted, mixtures of hexane–EtOAc
were used as eluant. All reactions were conducted under
atmosphere of argon. Anhydrous MgSO4 or Na2SO4
was used to dry the organic solutions during work-ups
and the removal of the solvents was done under vacuum
with a rotavapor. Unless otherwise noted, materials
were obtained from commercially available sources
and used without further purification. Solvents were
dried and purified using standard methods. Penta-O-
acetylglucopyranose was prepared according to Wol-
from and Thompson,11 by treatment of D-glucose with
sodium acetate and Ac2O. Phenyl-1-thio-b-D-glucopyr-
anoside, 10, was prepared according to a published
procedure.10
OMe
MeO
Mitsunobu
AcOH
NaOMe
MeOH
NBS
(a)
(b)
10
9
7
8
9
4
pTsOH
CaCO3
NBS/NaHCO3 or AgNO3
11
Scheme 2.
previously been assigned as the b-anomer by Gelas and
Horton,9 which claimed a Ôconsiderable flattening of the
pyranose ring in the region of C-1, C-2 and C-3, with
consequent distortion of the H-1-H-2 dihedral angleÕ
as responsible for the relatively low observed value for
J1,2 (4.8 Hz in CDCl3, 5.8 Hz in dimethyl sulfoxide-d6).
However, based on the observed large coupling constant
H-1–H-2 (J1,2 = 8.8 Hz, CDCl3) in the b-allose diaceto-
nide 9, we believed that the anomeric stereochemistry
in 4 needed to be established unequivocally. In this con-
text, heating of 4 in C6D6 (40 ꢁC) did not result in any
observable mutarotation, which might have permitted
assignment of the anomeric configuration. However,
the observation of a NOE effect (400 MHz, CDCl3)
between H-1 and H-5 in 4, allowed us to unambiguously
assign a b-anomeric configuration for this compound.
1.2. Phenyl 3,6-di-O-acetyl-1-thio-b-D-allopyranoside (7)
To a suspension of phenyl 1-thio-D-glucoside 10 (10 g,
40 mmol) in dry THF (200 mL), acetic acid (6.4 mL,
120 mmol) and triphenylphosphine (29 g, 120 mmol)
were added and the resulting solution heated at 60 ꢁC.

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A. M. Gomez et al. / Carbohydrate Research 340 (2005) 1872–1875
1874
To this mixture, diisopropyl azodicarboxylic acid
(22 mL, 120 mmol) was added dropwise for 20 min
and the solution refluxed for 3 h, after which the solu-
tion was cooled to room temperature and diethyl ether
(500 mL) added. The resulting mixture was then washed
with satd aq NaHCO3 and brine, and the organic layer
concentrated. Flash chromatography (hexane/ethyl ace-
tate 3:7) yielded compound 7 as a syrup (10.5 g, 82%).
[a]D À28.5 (c 1.7, CHCl3); m/z 379.1 (M+Na+), 1H
NMR (300 MHz, CDCl3): d 2.12 (s, 3H, OAc), 2.17 (s,
3H, OAc), 3.6 (m, 2H, H-2, H-4), 3.85 (ddd, 1H, H-5,
J2,3 = 4.9 Hz), 4.72 (d, 1H, H-1, J1,2 8.8 Hz,), 7.40 (m,
5H, Ph). 13C NMR (75 MHz, CDCl3): d 19.4, 26.5,
28.7, 29.5 (4 · CH3), 62.8 (C-6), 67.6, 69.6, 74.1, 76.4
(C-2, C-3, C-4, C-5), 87.1 (anomeric carbon), 100.5,
112.3, (2C quaternary), 128.2, 129.4 (·2), 132.5 (·2),
133.5 (6C, Ph). Anal. Calcd for C18H24O5S: C, 61.34;
H, 6.86. Found: C, 61.22; H, 6.83.
1.4. 2,3:4,6-di-O-isopropylidene-a-D-allopyranose (4)
To a vigorously stirred suspension of phenyl thioglyco-
side 9 (180 mg, 0.52 mmol) and calcium carbonate
(500 mg, 2.5 mmol) in acetone/water (9:1, 10 mL) was
added N-bromosuccinimide (190 mg, 1 mmol). After
the disappearance of the starting material (24 h), the
suspension was filtered and treated with satd aq NaH-
CO3 and washed with ethyl acetate. The organic phase
was separated, dried, filtered and evaporated. The prod-
uct was filtered through a small silica gel column to give
118 mg (89%) of b–4 as white crystals. Mp = 140–
142 ꢁC, Ref. 9 141–143 ꢁC, [a]D À19.5 (c 0.8), Ref. 9
0
J5,6 = 2.4 Hz, J5,6 = 4.9 Hz, J4,5 = 10.0 Hz) 4.32 (dd,
0
0
1H, H-6, J5,6 = 4.9 Hz, J6,6 = 12.2 Hz) 4.42 (dd, 1H,
0
H-60, J5,6 = 2.4 Hz, J6,6 = 12.2 Hz) 4.9 (d, 1H, H-1,
J1,2 9.6 Hz), 5.6 (t, 1H, H-3, J2,3 = J3,4 = 4.5 Hz), 7.5
(m, 5H, Ph). 13C NMR (75 MHz, CDCl3): d 20.8 (Ac),
21.0 (Ac), 63.7 (C-6), 66.4, 68.0, 72.5, 74.7 (C-2, C-3,
C-4, C-5), 85.0 (anomeric carbon), 128.1, 128.8 (·2),
131.6, 132.7 (·2), (6C, Ph), 171.3, 171.5 (C@O). Anal.
Calcd for C16 H20O7S: C, 53.92; H, 5.66. Found: C,
54.04; H, 5.63.
1
À24.6 (c 0.1, CHCl3) m/z 260.1 (M+Na+), H NMR: d
1.3. Phenyl 2,3:4,6-di-O-isopropylidene-1-thio-b-D-allo-
pyranoside (9)
1.37, 1.45, 1.49, 1.55 (4s, 4 · 3H, 4 · CH3), 3.69 (m,
1H, H-6), 3.80 (m, 1H, H-5), 3.92 (dd, 1H, H-60,
0
J5,6 = 5.1 Hz, J6,6 = 10.0 Hz), 4.07 (m, 3H, H-2, H-4,
Diacetate 7 (5 g, 14 mmol) was dissolved in MeOH
(100 mL) and NaOMe (0.1 equiv) was added. After the
disappearance of the starting material (3–4 h), the solu-
tion was neutralized with Amberlite (weakly acidic), fil-
tered and concentrated. The crude product was
dissolved in water and was subjected to continuous
liquid–liquid extraction with hot ethyl acetate (24 h).
Evaporation of the organic phase gave 2.8 g (75%) of
OH) 4.45 (dd, 1H, J2,3 = 5.8 Hz, J3,4 = 3.5 Hz, H-3),
4.95 (t, 1H, H-1, J1,2 = J1,OH 4.5 Hz). 13C NMR: d
18.8, 25.3, 27.2, 29.0, 62.8 (C-6), 63.3, 68.6, 72.6, 77.7
(C-2, C-3, C-4, C-5), 95.0 (anomeric carbon), 100.0,
111.3. Anal. Calcd for C12H20O6: C, 55.37; H, 7.74.
Found: C, 55.33; H, 7.76.
Acknowledgements
1
tetraol 8 as a yellowish syrup. m/z 295.0 (M+Na+), H
NMR (300 MHz, DMSO-d6): d 3.2–3.7 (m, 4H, H-2,
H-4, H-5, H-6), 4.5 (t, 1H, H-3, J2,3 = J3,4 = 4.5 Hz),
4.9 (d, 1H, H-1, J1,2 9.6 Hz), 7.5 (m, 5H, Ph). 13C
NMR (75 MHz, DMSO-d6): d 61.6 (C-6), 67.5, 69.9,
71.8, 77.2 (C-2, C-3, C-4, C-5), 84.7 (anomeric carbon),
126.5, 129.2 (·2), 129.9 (·2), 135.8 (6C, Ph).
We thank our colleague Prof. Pal Herczegh (Debrecen)
for helpful suggestions. This research was supported with
´
funds from the Direccion General de Ensen˜anza Superior
(grant: PPQ2003-00396). A.A. thanks The Ministerio de
´
Ciencia y Tecnologıa for financial support. M.D.C.
thanks The Comunidad Autonoma de Madrid for a schol-
´
Phenyl 1-thio-D-alloside, 8, (2 g, 7.35 mmol) was dis-
solved in dry DMF (40 mL), then Sikkon-blue (4 g),
dimethoxypropane (4.7 mL, 45 mmol) and p-toluene-
sulfonic acid (160 mg, 0.7 mmol) were added and the
resulting solution was stirred overnight. A mixture of
ether and toluene (8:2, 200 mL) was then added, and
the organic phase was washed with satd NaHCO3 solu-
tion (2 · 50 mL) and with water several times. Column
chromatography of the crude product (hexane/EtOAc
8:2) furnished 1.9 g (73%) of diacetonide 9, which was
recrystallized from hot hexane to obtain white crystals.
Mp = 122–124 ꢁC, [a]D À68.4 (c 1.05), m/z 375.1
(M+Na+), 1H NMR: d 1.43, 1.49, 1.53, 1.58 (4s,
4 · 3H, 4 · CH3), 3.79 (m, 2H, H-6, H-60), 3.95 (m,
2H, H-4, H-5), 4.07 (dd, 1H, H-2, J1,2 = 8.8 Hz,
J2,3 = 4.9 Hz), 4.49 (dd, 1H, H-3, J3,4 = 3.6 Hz,
arship. C.U. thanks The CSIC for financial support.
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