Synthesis of methyl 4,6-O-benzylidene-2,3-dideoxy-2-C-formyl-α-d- erythro-hex-2-enopyranoside

Article abstract of DOI:10.1016/j.carres.2004.10.018

The synthesis of the title compound was achieved in seven steps and 61% overall yield from methyl α-d-glucopyranoside.

Full text of DOI:10.1016/j.carres.2004.10.018

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 149–153
Note
Synthesis of methyl 4,6-O-benzylidene-2,3-dideoxy-2-C-formyl-a-D-
erythro-hex-2-enopyranoside
*
´ ´
Marıa I. Mangione, Alejandra G. Suarez and Rolando A. Spanevello
´ ´
Instituto de Quımica Organica de Sıntesis, Facultad de Ciencias Bioquımicas y Farmaceuticas, Universidad Nacional de
´
Rosario-CONICET, Suipacha 531, S2002LRK Rosario, Argentina
´
´
Received 7 September 2004; accepted 20 October 2004
Available online 21 November 2004
Abstract—The synthesis of the title compound was achieved in seven steps and 61% overall yield from methyl a-D-glucopyranoside.
Ó 2004 Elsevier Ltd. All rights reserved.
Naturally occurring carbohydrates have served exten-
sively as elements of the chiral pool in the total synthesis
of a wide range of molecules.1,2 However, the scope of
carbohydrates as chiral building blocks relies on the
development of convenient key intermediates that are
capable of meeting appropriate stereochemical and
functional requirements.3 It is well recognized that the
versatility of sugar nuclei as stereochemical templates
is enhanced by the incorporation of an a,b-unsaturated
carbonyl system, which appears to be an unquestionably
useful synthon in organic synthesis.4–7 There are parti-
cularly two reasons for their use: (a) they can be obtained
in high enantiomeric purity, and (b) they can exert regio-
and stereocontrol on different chemical processes.
In view of the increasing importance of a,b-unsatu-
rated carbonyl systems we have already developed an
efficient synthetic route starting from the methyl 2,3-an-
hydro-4,6-O-benzylidene-a-D-mannopyranoside (1) to-
ward 3 and 4 (Scheme 1).
This simple strategy was later applied to the synthesis
of the methyl 4,6-O-benzylidene-2-C-cyano-2-deoxy-a-
D-altropyranoside, which according to the Furst–Plat-
¨
ner rule9 could be derived from the methyl 4,6-O-benzyl-
idene-a-D-allopyranoside 5. The reaction afforded a
very low yield of the desired product, and a detailed
study of this reaction demonstrated the influence of
neighboring-group participation as the factor responsi-
ble for its failure.10
There are a few alternative procedures described in
the literature toward the synthesis of compound 6. Luk-
acsÕ five-step approach involves the nucleophilic oxirane
ring opening of 5 with the 1,3-dithiane anion to produce
a mixture of 1,2- and 2,3-unsaturated systems in variable
yields.11
Fraser-ReidÕs strategy toward methyl 4,6-O-benzylid-
ene-2-C-hydroxymethyl-a-D-erythro-hex-2-enopyrano-
side (7), which can be considered a good precursor for
the aldehyde 6 or vice versa, implied a laborious 10-step
synthetic sequence with 3.8% overall yield12 (Scheme 2).
A third alternative, MalikÕs trimethylsilylcyanide ap-
proach, succeeded in the oxirane ring opening of 5,
but it reported a 47% yield for this only step to afford
the methyl 4,6-O-benzylidene-2-C-cyano-2-deoxy-a-D-
altropyranoside.13
The sequence involved the regioselective oxirane ring
opening of 1 with diethylaluminum cyanide (Et2AlCN),
followed by dehydration of the b-cyanohydrin 2, as a di-
rect approach for obtaining methyl 4,6-O-benzylidene-3-
C-cyano-2,3-dideoxy-a-D-erythro-hex-2-enopyranoside
(3) and subsequently its conversion into the aldehyde 4,
in high overall yield.8
In view of the difficulties mentioned above, we wish to
report a simple and straightforward sequence that af-
forded the aldehyde 6 starting from 8 in high overall
yield (Scheme 3).
*
Corresponding author. Tel./fax: +54 341 4370477; e-mail:
rspaneve@fbioyf.unr.edu.ar
0008-6215/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.10.018

150
M. I. Mangione et al. / Carbohydrate Research 340 (2005) 149–153
O
O
R
OCH
O
OCH
3
OCH
OH
3
3
O
O
O
O
O
H C
O
H C
5 6
H C
5
6
5
6
O
CN
3 R = CN
4 R = CHO
1
2
Scheme 1.
O
O
OCH
O
OCH
3
OCH
3
3
O
O
O
O
O
H C
O
H C
5 6
H C
CH OH
2
CHO
5
6
5
6
O
5
6
7
Scheme 2.
HO
HO
HO
HO
O
OCH
O
OCH
3
O
CH3NO2,
NaOCH3
OCH
OH
3
3
HO
NaIO4
OHC
CHO
H2O, pH 5-6
CH3OH
OH
NO
OH
2
8
9
10a,b,c,d
MsCl, Et3N
CH2Cl2
KCN, H2O
Amberlite
C6H5CH(OCH3)
CSA, CHCl3
O
OCH
3
O
OCH
OH
3
O
O
CH3CN
95%
81% (3 steps)
O
H C
O
H C
5
6
5
6
NO
NO
2
2
11a,b
12
DiBAL-H
CH2Cl2
O
OCH
CN
O
OCH
O
OCH
3
3
3
O
O
O
O
+
81%
O
H C
O
H C
H C
CHO
CN
5
6
5
6
5
6
NO
2
6
14
13
Et3N, acetone/H2O
91% (2 steps)
Scheme 3.
The synthesis involved the oxidative cleavage of the
methyl a-D-glucopyranoside 8 with sodium periodate to
yield the dialdehyde 9, according to the procedure devel-
oped by Baer.14 The crude material was treated with
nitromethane and sodium methoxide to yield a mixture
of four condensation products from which the gluco-
and manno-isomers 10a,b were the major ones. The
crude mixture was treated with a,a-dimethoxytoluene
to form the benzylidene acetal following a modification
of a standard procedure.15 Flash chromatographic puri-
fication of the crude reaction product afforded the com-
bined manno- and gluco-nitro glycosides in 87% overall
yield from 8. The mixture of stereoisomers 11a,b were
then treated with MsCl and Et3N in CH2Cl2 to afford
the methyl 4,6-O-benzylidene-2,3-dideoxy-3-C-nitro-a-
D-erythro-hex-2-enopyranoside (12) as a crystalline prod-
uct in 95% yield. Introduction of the cyano group at C-2
was achieved according to the procedure described by
Sakakibara and Sudoh16 through a Michael-type addi-
tion of hydrogen cyanide to the a,b-unsaturated nitro
system. The procedure afforded a mixture of the 1,4-ad-
duct 13 plus product 14 derived from a direct elimination
of the nitro group. Treating the crude mixture with Et3N
produced the complete conversion of 13 into 14. This
process afforded 14 in 91% overall yield from 12. Finally,
DIBAL-H reduction of nitrile derivative 14 produced the
desired a,b-unsaturated aldehyde 6 in 81% yield.
This synthetic procedure allowed the preparation of 6
from glucopyranoside 8 in seven steps and 61% overall
yield. It is worth mentioning that only two chromato-
graphic purifications were necessary during the whole
synthetic process.

M. I. Mangione et al. / Carbohydrate Research 340 (2005) 149–153
151
1. Experimental
and added dropwise with magnetic stirring. The reaction
mixture was kept in the ice bath for 25min, and then it
was allowed to reach rt and stirred for an additional
45min. The solution was deionized by slowly pouring
the reaction mixture onto a suspension of Amberlite
IR 120 (H+) (23g) in MeOH (31mL) at 4°C with
vigorous stirring. This mixture was allowed to stand
at 4°C overnight, passed through an Amberlite
column (23g), and washed with cold MeOH. Con-
centration of the methanolic solution produced an
orange syrup (5.1g) of the crude 3-deoxy-3-nitro-a-D-
hexopyranosides.
1.1. General
Melting points were taken on a Leitz Wetzlar Micro-
scope Heating Stage, Model 350 apparatus, and are
uncorrected. Optical rotations were recorded with a
Jasco DIP 1000 polarimeter. Nuclear magnetic resonance
spectra were recorded on a Bruker AC-200 spectrometer
with Me4Si as the internal standard and chloroform-d as
solvent. Reactions were monitored by TLC on 0.25mm
E. Merck Silica Gel plates (60F254), using UV light and
anisaldehyde–H2SO4–AcOH as detecting agents. Flash
column chromatography, using E. Merck Silica Gel
60H, was performed by gradient elution created by mix-
tures of hexanes and increasing amounts of AcOEt.
Reactions were performed under an argon atmosphere
with dry, freshly distilled solvents under anhydrous con-
ditions, unless otherwise noted. Yields refer to chroma-
tographically and spectroscopically (1H NMR)
homogeneous materials, unless otherwise stated.
1.2.3. Preparation of methyl 4,6-O-benzylidene-3-deoxy-
3-C-nitro-a-D-hexopyranosides (11a,b). The mixture of
methyl 3-deoxy-3-nitro-a-D-hexopyranosides (5.1g,
15.4mmol) obtained from the previous procedure was
dissolved in CHCl3 (78mL), and camphorsulfonic acid
(160mg, 0.64mmol) and benzaldehyde dimethyl acetal
(4.6mL, 30.6mmol) were added successively. The result-
ing mixture was stirred and refluxed in a flask fitted with
a Dean–Stark trap for solvents heavier than water and
˚
1.2. Preparation of methyl 4,6-O-benzylidene-3-deoxy-3-
C-nitro-a-D-hexopyranosides (11a,b)
loaded with 4A molecular sieves (8.2g, activated at
350°C for 3h) overnight. K2CO3 (639mg, 4.6mmol)
was added, and the reaction mixture was refluxed for
an additional 30min. The hot reaction mixture was fil-
tered through a filter funnel with a porosity E sintered
glass fritted disc with suction, and the filtrate was con-
centrated under reduced pressure. The resulting crude
product was purified by flash chromatography to fur-
nish the mixture of isomers 11a and 11b (4.2g, 87%,
three steps) and used without further purification in
the next synthetic transformation. Separation of an ali-
quot of the mixture was performed in order to charac-
1.2.1. Preparation of 2-O-[(S)-formyl(methoxy)methyl]-
(R)-glyceraldehyde (9). A magnetically stirred aqueous
solution (78mL) of NaIO4 (6.6g, 30.9mmol) was cooled
at +5°C, and methyl a-D-glucopyranoside (3.0g,
15.4mmol) was added portionwise during 5min. The
solution was allowed to stand in the dark at room tem-
perature (rt), and the formic acid formed was gradually
neutralized by the addition of 1.0M NaHCO3 solution
(approximately 8mL). The reaction mixture was always
maintained between pH5 and 6. Completion of the oxi-
dation usually took 2–3h, and was indicated by a nega-
tive starch–potassium iodide test of an aliquot sample to
which excess of NaHCO3 had been added. The NaIO3
was partially precipitated from the solution by the addi-
tion of EtOH. The solid was filtered under vacuum and
washed with EtOH. The combined filtrate and washings
were concentrated under reduced pressure. The addition
of more EtOH produced the precipitation of more solid
material that was removed by filtration. This procedure
was repeated until no more EtOH-insoluble material
was formed. Finally the solution was evaporated to ob-
tain a syrup, which still contained a small amount of salt
crystals, but these do not need to be removed.
terize both isomers. Methyl 4,6-O-benzylidene-3-
25
D
deoxy-3-C-nitro-a-D-mannopyranoside (11a): ½aꢀ 32.9
(c 2.54, CHCl3), reported17 [a]D 27.7 (c 0.8, CHCl3);
1H NMR (CDCl3): d 2.75 (br s, 1H, OH), 3.44 (s, 3H,
OCH3), 3.85–3.95 (m, 2H, H-5 and H-6ax), 4.34 (m,
1H, H-6eq), 4.47 (m, 1H, H-2), 4.58 (m, 1H, H-4),
4.77 (d, 1H, J 1.7Hz, H-1), 4.91 (dd, 1H, J3,4 10.7, J2,3
3.2Hz, H-3), 5.67 (s, 1H, H-7), 7.27–7.50 (m, 5H, aro-
matics); 13C NMR (CDCl3): d 55.0 (OCH3), 62.8 (C-
5), 68.5 (C-6), 69.7 (C-2), 73.6 (C-4), 83.6 (C-3), 100.7
(C-1), 101.7 (C-7), 125.9 (2C, Cortho), 128.1 (2C, Cme-
ta), 129.1 (Cpara), 136.4 (Cipso). Methyl 4,6-O-benzylid-
ene-3-deoxy-3-C-nitro-a-D-glucopyranoside (11b): mp
27
D
167.0–168.0°C (CHCl3–petroleum ether); ½aꢀ 91.5 (c
27
0.98, abs EtOH); reported18 mp 167°C, ½aꢀ 87.2
D
1.2.2. Condensation of 2-O-[(S)-formyl(methoxy)methyl]-
(R)-glyceraldehyde with nitromethane (10a–d). The
crude dialdehyde obtained from 3.0g of methyl a-D-
glucopyranoside was dissolved in MeOH (19mL).
Nitromethane (0.85mL, 15.7mmol) was added, and
the solution was cooled at 0°C in an ice bath. NaOMe
(3% w/v soln in MeOH, 11.2mL, 14.6mmol) was chilled
(c 1, EtOH); 1H NMR (CDCl3): d 2.46 (d, 1H, J
11.50Hz, OH), 3.49 (s, 3H, OCH3), 3.75–3.90 (m, 2H,
H-5 and H-6ax), 4.00–4.12 (m, 1H, H-4), 4.21 (ddd,
1H, J2,1 3.80, J2,3 10.10, J2,OH 11.60Hz, H-2), 4.35 (m,
1H, H-6eq), 4.81 (dd, 1H, J3,2 = J3,4 10.11Hz, H-3),
4.86 (d, 1H, J1,2 3.60Hz, H-1), 5.53 (s, 1H, H-7), 7.27–
7.50 (m, 5H, aromatics); 13C NMR (CDCl3): d 55.8

152
M. I. Mangione et al. / Carbohydrate Research 340 (2005) 149–153
(OCH3), 61.9 (C-5), 68.5 (C-6), 70.3 (C-2), 77.0 (C-4),
88.3 (C-3), 98.8 (C-1), 101.3 (C-7), 125.9 (2C, Cortho),
128.1 (2C, Cmeta), 129.1 (Cpara), 136.0 (Cipso).
matics); 13C NMR (CDCl3): d 56.6 (OCH3), 62.8 (C-
5), 68.8 (C-6), 73.9 (C-4), 94.9 (C-1), 102.4 (C-7), 114.1
(C„N), 115.2 (C-2), 126.1 (2C, Cortho), 128.2 (2C,
Cmeta), 129.3 (Cpara), 136.5 (Cipso), 145.0 (C-3).
1.3. Preparation of methyl 4,6-O-benzylidene-2,3-dide-
oxy-3-C-nitro-a-D-erythro-hex-2-enopyranoside (12)
1.5. Preparation of methyl 4,6-O-benzylidene-2,3-dide-
oxy-2-C-formyl-a-D-erythro-hex-2-enopyranoside (6)
A mixture of manno- and gluco-nitro glycosides 11a,b
(629mg, 2.0mmol) was dissolved in dry CH2Cl2
(10.0mL) and cooled at 20°C under an argon atmos-
phere. MsCl (190.0lL, 2.4mmol) and Et3N (1.4mL,
10.1mmol) were successively added to the stirred soln
at ꢁ20°C, and stirring was continued for 15min at this
temperature. The mixture was then diluted with AcOEt,
washed with 5% aq NaHCO3 and water, and dried
(Na2SO4). Concentration furnished compound 12
Methyl 4,6-O-benzylidene-2-C-cyano-2,3-dideoxy-a-D-
erythro-hex-2-enopyranoside (14) (579mg, 2.1mmol)
was azeotropically dried with dry benzene under vac-
uum, dissolved in anhyd CH2Cl2 (43mL) and cooled
at ꢁ80°C under an argon atmosphere. Diisobutylalum-
inum hydride (1M soln in hexane, 4.8mL, 4.8mmol)
was slowly added to the magnetically stirred solution.
The reaction mixture was stirred for an additional
90min at ꢁ80°C and then quenched with 1:1 HOAc–
water soln (3.4mL). Stirring was continued for 30min
while the temperature rose to 0°C. The mixture was ex-
tracted with CH2Cl2, washed with H2O, 5% NaHCO3
soln and brine, dried (Na2SO4), and concentrated to fur-
nish compound 6 (506mg, 86%) as a white solid. Recrys-
(563.0mg, 95%) as white needles: mp 182.0–183.0°C
29
(CHCl3–petroleum ether); ½aꢀ ꢁ93.4 (c 0.93, AcOEt),
D
23
D
reported19 mp 183°C, ½aꢀ ꢁ93 (c 0.9, AcOEt); 1H
NMR (CDCl3): d 3.47 (s, 3H, OCH3), 3.89 (dd, 1H,
Jgem = J5,6 10.1Hz, H-6ax), 4.02–4.13 (m, 1H, H-5),
4.34 (dd, 1H, J5,6 4.1, Jgem 9.9Hz, H-6eq), 4.65 (ddd,
1H, J4,5 8.6, J2,4 = J1,4 1.5Hz, H-4), 5.11 (dd, 1H, J1,2
2.99, J1,4 0.75Hz, H-1), 5.66 (s, 1H, H-7), 6.77 (dd,
1H, J2,4 2.1, J1,2 3.0Hz, H-2), 7.30–7.50 (m, 5H, aromat-
ics); 13C NMR (CDCl3): d 56.5 (OCH3), 64.2 (C-5), 68.4
(C-6), 72.6 (C-4), 95.2 (C-1), 101.9 (C-7), 126.0 (2C,
Cortho), 128.1 (2C, Cmeta), 128.6 (C-2), 129.0 (Cpara),
136.4 (C-8), 149.4 (Cipso).
tallization afforded crystals as white needles: mp 195.0–
20
196.0°C (CH2Cl2–petroleum ether); ½aꢀ 131.6 (c 0.80,
D
CHCl3); reported11 mp 190–192°C; [a]D 100.4 (c 0.25,
CHCl3); 1H NMR (CDCl3): d 3.54 (s, 3H, OCH3),
3.85 (dd, 1H, Jgem = J5,6 10.2Hz, H-6ax), 4.00–4.15 (m,
1H, H-5), 4.35–4.45 (m, 2H, H-6eq and H-4), 5.21 (s,
1H, H-1), 5.63 (s, 1H, H-7), 6.97 (s, 1H, H-3), 7.30–
7.55 (m, 5H, aromatics), 9.47 (s, 1H, CHO); 13C NMR
(CDCl3): d 56.5 (OCH3), 63.3 (C-5), 69.3 (C-6), 75.4
(C-4), 94.6 (C-1), 102.6 (C-7), 126.1 (2C, Cortho),
128.3 (2C, Cmeta), 129.3 (Cpara), 136.8 (Cipso), 139.5
(C-2), 146.5 (C-3), 189.8 (CHO).
1.4. Preparation of methyl 4,6-O-benzylidene-2-C-cyano-
2,3-dideoxy-a-D-erythro-hex-2-enopyranoside (14)
KCN (920mg, 14.1mmol) was dissolved in water
(2.5mL) and poured into a column of cation-exchange
resin (Amberlite IR-120, H+, 2.6g). The column was
washed successively with water (2.5mL) and acetonitrile
(14.0mL). The eluate was added directly to a soln of the
nitro-olefin (12) (683.6mg, 2.3mmol) in acetonitrile
(14mL) at 4°C and stirred for 30min. The mixture
was diluted with AcOEt and washed with 5% aq NaH-
CO3, water, and brine. The organic layer was dried
(Na2SO4) and concentrated to furnish a mixture of
products 13 and 14 as a yellow syrup. The crude product
was dissolved in 3:2 acetone–water (15.3mL), and Et3N
(0.35mL, 2.5mmol) was added with stirring at rt for
12min. The soln was diluted with AcOEt, washed with
water and brine, and dried (Na2SO4). Concentration
and purification by flash chromatography furnished 14
Acknowledgements
This research was supported by the International Foun-
dation for Science, Stockholm, Sweden, the Organiza-
tion for the Prohibition of Chemical Weapons, The
Hague, The Netherlands and Agencia Nacional de Pro-
´
´
´
mocion Cientıfica y Tecnologica, Argentina through the
grants to A.G.S. and R.A.S. M.I.M. thanks CONICET
for the award of a fellowship.
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(590mg, 93%, two steps) as white needles: mp 194.5–
24
D
196.0°C (CHCl3–petroleum ether); ½aꢀ 164.3 (c 1.01,
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