Neighboring-group participation in benzylidene acetal ring-opening of a 2-cyano-2-deoxypyranoside derivative by diethylaluminum cyanide

Article abstract of DOI:10.1016/S0008-6215(03)00377-X

The oxirane ring-opening of an anhydro sugar with diethylaluminum cyanide (Et₂AlCN) is a direct approach for obtaining a cyano derivative. Methyl 2,3-anhydro-4,6-O-benzylidene-α-D-allopyranoside showed anomalous chemical behavior when treated with Et₂AlCN. The reaction afforded the corresponding β-cyanohydrin as the minor component from a mixture of compounds resulting from the benzylidene acetal ring-opening caused by the attack of ethyl or cyano groups.

Full text of DOI:10.1016/S0008-6215(03)00377-X

Carbohydrate Research 338 (2003) 2177Á2183
/
www.elsevier.com/locate/carres
Neighboring-group participation in benzylidene acetal ring-opening
of a 2-cyano-2-deoxypyranoside derivative by diethylaluminum
cyanide
Mar´ıa I. Mangione, Alejandra G. Sua´rez, Rolando A. Spanevello*
Instituto de Qu´ımica Orga´nica de S´ıntesis, Facultad de Ciencias Bioqu´ımicas y Farmace´uticas, Universidad Nacional de Rosario-CONICET, Suipacha
531, S2002LRK Rosario, Argentina
Received 25 April 2003; accepted 20 July 2003
Dedicated to Professor Dr Edmundo A. Ru´veda (Rosario, Argentina) on the occasion of his 70th birthday
Abstract
The oxirane ring-opening of an anhydro sugar with diethylaluminum cyanide (Et2AlCN) is a direct approach for obtaining a
D-allopyranoside showed anomalous chemical behavior when treated
cyano derivative. Methyl 2,3-anhydro-4,6-O-benzylidene-a-
with Et2AlCN. The reaction afforded the corresponding b-cyanohydrin as the minor component from a mixture of compounds
resulting from the benzylidene acetal ring-opening caused by the attack of ethyl or cyano groups.
# 2003 Elsevier Ltd. All rights reserved.
Keywords: Benzylidene acetal; 2-Cyano-2-deoxypyranoside; Diethylaluminum cyanide
1. Introduction
Inch and Lewis12 studied the reactivity problems of
some 2,3-anhydro sugars with several Grignard and
alkyl-(or aryl)-lithium reagents and reported their ten-
dency to afford reduction or elimination by-products.
Gero and co-workers13,14 developed a procedure for
introducing a 1,3-dithianyl residue, but this required
several days of reaction at low temperature, imposing
certain operative difficulties. Kazmi and co-workers15
reported the oxirane ring-opening of the same anhydro
sugars, giving moderate yields, by using cyanotrimethyl-
silane and a catalytic amount of aluminum chloride.
Based on these precedents, we decided to reexamine
Guthrie’s procedure16,17 for the introduction of a cyano
group into a pyranose skeleton, and found that treating
epoxide 1 with diethylaluminum cyanide (Et2AlCN) in
dichloromethane at room temperature afforded the
corresponding b-cyanohydrin 2 in high yield.18 Simulta-
neously, Bobek and co-workers19 reported the epoxide
ring-opening of pentofuranoside derivatives with the
same reagent, observing variable yields and regioselec-
tivities (Scheme 1).
Cyano sugars constitute versatile intermediates in nat-
ural product1Á5 and nucleoside synthesis.6Á8 Some
naturally occurring monosaccharides are branched-
chain sugars, whose side chain generally contains one
or more carbon atoms. Such branched-alkyl, -formyl, or
-amino sugars are part of many compounds that have
important biological activities.9
The oxirane ring-opening of an anhydro sugar is a
straightforward approach for regioselective introduction
of a nucleophile into a pyranoside ring. Usually, this
procedure affords a trans-diaxial substitution pattern.
Methyl 2,3-anhydro-4,6-O-benzylidene-a-
D-mannopyr-
anoside (1) is a useful starting material,10 although it is
reluctant to undergo a nucleophilic epoxide ring-open-
ing under mild conditions.11
* Corresponding author. Tel./fax: ꢀ
/
1-54341-4370477.
E-mail
Spanevello).
address:
rspaneve@fbioyf.unr.edu.ar (R.A.
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0008-6215(03)00377-X

2178
M.I. Mangione et al. / Carbohydrate Research 338 (2003) 2177Á2183
/
Scheme 1.
These conditions were very efficient for obtaining the
3-cyano-3-deoxy derivative, and we envisaged the same
approach for synthesizing the 2-cyano-2-deoxy deriva-
spectra showed that they had undergone similar ring-
opening, but the 13C NMR spectrum indicated that
another cyano group was attached at the benzylic
position (Scheme 2).
tive from methyl 2,3-anhydro-4,6-O-benzylidene-a-
D-
1
The H and 13C NMR signals of 5a,b and 6a,b were
allopyranoside (3), according to the FurstÁPlattner
/
¨
rule.20
assigned based on homo and heteronuclear 2D NMR
1
techniques. The H NMR spectrum of 5a,b showed a
CH3 triplet at 0.90 ppm, a complex multiplet for CH2 at
1.80 ppm, and the benzylic proton signal was shifted
upfield at 4.26 ppm and appears as a multiplet. The
pyranose backbone was confirmed by the anomeric
proton singlet at 4.97 ppm, and two methoxy groups,
one for each epimer, as sharp singlets at 3.41 and 3.43
ppm. The 13C NMR spectrum indicated an extra methyl
group at 10.1 ppm and two methylene groups, one for
each epimer, at 30.7 and 30.8 ppm, respectively. The
signals for the benzylic carbons were shifted upfield in
both epimers and appeared at 84.6 and 85.0 ppm. A very
characteristic peak at 116.3 ppm was assigned to the
cyano group introduced by oxirane ring-opening, and
the signal for C-2 appeared at 36.6 ppm showing the
shielding effect of the cyano group, and confirming the
regioselectivity of the attack on the epoxide. The IR
spectrum also showed an absorption peak at 2260 cmꢁ1
corresponding to the cyano group.
2. Results and discussion
Methyl 4,6-O-benzylidene-a-D-glucopyranoside was
converted into methyl 2,3-anhydro-4,6-O-benzylidene-
D
-allopyranoside (3) by the literature procedure.21
a-
However, when 3 was treated with Et2AlCN, the
reaction was very slow and the b-cyanohydrin 4 was
isolated as only a minor component from a mixture of
two more polar products by thin layer chromatography
(TLC) analysis.
Similar reactivity problems with this substrate had
been reported by Guthrie and co-workers,17 but the by-
products were not identified and the reaction was not
further studied. It was suggested that this behavior was
related to the more complicated nature of the reaction
with the anhydro-alloside because of further reaction of
the expected 2-cyano-2-deoxy-altro product. An expla-
nation then offered was the fact that the carbonÃ
/oxygen
Determination of the regioselectivity of the 1,3-
bonds in the ring and the methoxy group are b to the
cyano group and therefore labile to base. This explana-
tion is in agreement with Inch and Lewis’ results12 and a
precedent in other reports.1,15,22,23
dioxane ring-opening was achieved by a CÃ
/
H correla-
tion via long-range coupling (COLOC)24 that clearly
showed a cross peak between the benzylic proton and C-
6. This evidence allows us to postulate the formation of
the primary benzyl ether.
Our synthetic interest in substrate 4 led us to
reinvestigate this reaction to find a suitable way of
optimizing it. The spectroscopic data of compound 4
were consistent with the expected chemical structure.
Analysis of the proton NMR spectrum of the mixture
6a,b also showed duplicated singlet peaks at: 3.4/3.5,
4.99, 5.02 and 5.49 ppm corresponding to the methoxy
groups, anomeric, and benzylic protons, respectively,
for each isomer. The 13C NMR showed two different
sets of peaks at 115.7/115.8 and 117.0/117.1 ppm
assigned to the cyano groups attached at C-2 and C-7.
The signals for both carbons are also shifted upfield by
the shielding effect of the cyano group, C-2 resonated at
36.7 ppm for both epimers and C-7 at 71.3 and 71.4 ppm
for each of them. The IR spectrum showed a distinctive
absorption band at 2230 cmꢁ1 for the cyano group. The
1
The H NMR spectra of products 5 and 6 revealed
that both had two very close sets of signals of equal
intensity, with similar chemical shifts and coupling
constants. This observation indicated that each sample
was a mixture of epimers, which were not separable by
standard flash chromatographic procedures.
1
It was evident from the H NMR spectrum of the
epimeric mixture of 5a and 5b that the epoxide had
undergone the expected nucleophilic opening, but the
benzylidene acetal ring had also been cleaved with
concomitant alkylation of the benzylic carbon by an
CÃ
/
H correlation via long-range coupling, performed to
1
ethyl group. In the case of 6a and 6b, the H NMR
determine the course of the benzylidene ring-opening,

M.I. Mangione et al. / Carbohydrate Research 338 (2003) 2177Á
/2183
2179
Scheme 2.
was not conclusive and it was necessary to prepare the
corresponding acetates 7a,b.
In the H NMR spectrum of 7a,b, the H-4 protons
have a chemical shift of 5.35 ppm whereas the same
While it is premature to propose a mechanism taking
into account our observations, particularly because of
the presence of multiple coordinating sites in the
substrate, the results suggest that chelation of the
aluminum center of the alkoxide with O-4 plays an
important role in promoting nucleophilic attack on the
benzylic carbon and determining the regiochemistry of
the ring cleavage. The affinity of the Lewis acid for this
site in the aluminum alkoxide derivative 8 is probably
attributable to the favorable spatial disposition of O-4
(Fig. 1).
1
protons in 6a,b appear at 3.73Á4.24 ppm, this deshield-
/
ing effect is indicative of the position occupied by the
free hydroxyl group.
It could be assumed that the lack of stereoselectivity
in the benzylidene ring-opening may be due to the attack
of the nucleophile through an open-chain oxonium ion
or through a hydrogen-bonded carbene model, like the
one proposed by Frejd and co-workers25 with no facial
selectivity. We did not consider an isomerization process
induced by base during the reaction work up for the
cyano derivatives 6a,b, because this process could not
explain the same result for the ethyl derivatives 5a,b.
We did not detect any by-product resulting from b-
elimination, nor the benzylidene acetal ring-cleavage
without the corresponding epoxide ring-opening. This
observation led us to consider that the presence of the
aluminum b-alkoxy-nitrile was necessary to cause the
benzylidene ring-opening.
To test this hypothesis, we chose to block the free
hydroxyl group present in compound 4 as the corre-
sponding benzyl ether 9 and acetate 10. Both com-
pounds were treated with Et2AlCN under the same
conditions previously mentioned, but no reaction was
observed (Scheme 3).
In order to determine whether this chemical behavior
could be extended to other, related methyl 4,6-O-
benzylidene-glycopyranosides, compounds 11Á15 were
/
In order to secure evidence of the intervention of
chelated species, we treated in parallel experiments the
pure methyl 4,6-O-benzylidene-2-cyano-2-deoxy-a-
tropyranoside (4) and methyl 4,6-O-benzylidene-3-cya-
no-3-deoxy-a- -mannopyranoside (2) with Et2AlCN.
D-al-
D
With the first one we again obtained the 1:1 epimeric
mixture of compounds 5a,b and 6a,b, whereas with the
latter, the starting material was recovered completely
after work up.
Fig. 1. Possible chelated intermediate.

2180
M.I. Mangione et al. / Carbohydrate Research 338 (2003) 2177Á
/2183
Scheme 3.
treated with Et2AlCN under standard conditions. These
experiments could provide information regarding the
effect of the stereochemistry at C-3, the relative position
of the hydroxyl group, and the substituents at C-2 (Fig.
2).
observed chemical phenomenon; however, it demon-
strates that formation of the O-3 aluminum alkoxide is a
requirement, but not the unique one, for the benzylidene
acetal cleavage.
The NMR spectra of the aluminum alkoxides pre-
pared from the reaction of alcohols 2, 4 and 12 with
trimethylaluminum add further evidence in favor of the
formation of the aluminum alkoxide chelate with O-4
and its probable effects on the aromatic portion of the
molecule, as it is evident by the chemical-shift differ-
ences (Dd) in Table 1.
Substrates 11Á14 did not react with Et2AlCN even
/
after longer reaction times than those used with
compound 4, whereas bromohydrin 15 underwent
intramolecular nucleophilic substitution, affording the
corresponding epoxide 3 in 20% yield and recovering
77% of the starting material. Nagata and co-workers26
assumed the intermediacy of the corresponding epoxide
in the direct conversion of b-bromohydrins into b-
cyanohydrins when treating the former with hydrogen
The 13C NMR spectrum of the aluminum alkoxide
derived from the b-cyanohydrin 4 shows that the
benzylic carbon (C-7) suffers higher deshielding than
the equivalent carbon in the other two substrates, and a
similar effect is observed with C-4. The difference in the
shielding effect observed in C-ipso is also remarkable.
These observations support the formation of an alumi-
num chelated species 8.
cyanideÁtriethylaluminum. In our case, the rate of
/
oxirane ring-closure must be higher than the corre-
sponding ring-opening, allowing isolation of the epoxide
without its further transformation into the cyanohydrin
derivative. This result clearly demonstrated the reactiv-
ity of the aluminum alkoxide and the stability of
compound 3. On the other hand, full analysis of the
results do not provide a conclusive explanation for the
Several literature reports are in agreement with our
investigations. De las Heras and co-workers22 used
trimethylsilyl cyanide, in combination with a Lewis
Fig. 2. Other substrates tested.

M.I. Mangione et al. / Carbohydrate Research 338 (2003) 2177Á
/2183
2181
Table 1
Selected 13C NMR data a
3. Conclusions
We were able to isolate and identify the reaction by-
products from the reaction of 3 with Et2AlCN and
prove that they did not originate from a b-elimination
process. Instead they were the products of benzylidene
acetal cleavage with concomitant nucleophilic attack by
an ethyl or cyano group.
Interpretation of the results obtained from the
benzylidene acetal cleavage with different substrates is
not straightforward, however, some speculations are
possible: the process may be induced by the neighboring
aluminum alkoxide that coordinates with O-4, yielding a
chelate structure 8. This coordination could enhance the
Carbon
Dd: 2
Dd: 4
Dd: 13
1
ꢁ
/
1.6
1.8
0.3
1.2
0.4
0.6
0.3
0.4
0.6
1.6
ꢁ
/
0.5
0.6
0.6
0.2
0.2
0.1
0.6
1.0
0.1
0.3
ꢁ
/
0.3
0.3
0.3
0.2
0.1
0.2
0.3
0.4
0.3
2
ꢁ
/
ꢁ
/
3
ꢁ
/
4
ꢁ
/
5
ꢁ
/
6
ꢁ
/
7
Ipso
OCH3
CN
ꢁ
/
ꢁ
/
ꢁ
/
ꢀ
/
ꢁ
/
ꢁ
/
Dd: dRÃOAl(Et)
We could not use the alkoxide formed with Et2AlCN
ꢁ
/
dRÃOH ppm.
liability of the C-7Ã
/
O-4 bond, thus making the C-7
2
a
susceptible to nucleophilic attack, but it still remains
unclear as to the role of the cyano group at C-2
compared with other substituents at the same position.
because this reagent caused the transformation of 4 into 5a,b
and 6a,b during the time the measurements were made, making
the spectra difficult to analyze because of the complex mixture
of compounds present in solution.
4. Experimental
acid, to obtain mandelonitrile ethers, by opening of the
1,3-dioxane benzylidene ring of 3 with low regioselec-
tivity at room temperature, yielding a mixture of the 6-
O- and 4-O-(cyanophenylmethyl) regioisomers of the
anhydro derivative. The regioselectivity was greatly
enhanced when methyl 4,6-O-benzylidene-2,3-di-O-to-
4.1. General methods
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. Infrared spectra were
recorded on a Beckman Acculab 8 spectrometer. Nu-
clear magnetic resonance spectra were recorded on a
Bruker AC-200 spectrometer with Me4Si as the internal
standard and chloroform-d as solvent.
syl-a-
rial, affording methyl 6-O-(cyanophenylmethyl)-2,3-di-
O-tosyl-a- -glucopyranoside in 80% yield as the only
D-glucopyranoside was used as the starting mate-
D
product. This is a clear precedent, because the product
obtained, and the regioselectivity observed with a
substrate that has an adequate coordination site vicinal
to the benzylidene acetal ring, is comparable to our
work. These assumptions are also in accord with the
results reported by Frejd and co-workers.27 They
studied the substituent effects on the alkylative cleavage
of glycosides with organoaluminun reagents, and noted
the importance of aluminum alkoxide formation in
some of their examples in allowing the reaction to
proceed. In another report, they also mentioned the
difficulties encountered when the primary alcoholate,
product of the oxirane ring-openings of 2,3-anhydro-
pentopyranosides with trimethylaluminum, underwent
subsequent reaction with trimethylaluminum to give
unknown compounds23 thus constituting another coin-
cidence with our example. Finally, Davis and co-work-
ers28 have shown that addition of 2-propanol to
Et2AlCN resulted in the irreversible formation of
ethylaluminum cyanide alkoxide, which is capable of
coordinating and activating the imine double bond and
Reactions were monitored by TLC on 0.25 mm E.
Merck silica gel plates (60F254), using UV light and
anisaldehydeÁ
/
H2SO4ÁAcOH as detecting agent. Flash
/
column chromatography, using Merck silica gel 60H,
was performed by gradient elution with mixtures of
hexanes and increasing amounts of EtOAc.
Reaction were performed under argon with dry,
freshly distilled solvents under anhydrous conditions,
unless otherwise noted. Yields refer to chromatographi-
cally and spectroscopically (1H NMR) homogeneous
materials, unless otherwise stated.
4.1.1. Methyl 4,6-O-benzylidene-2-C-cyano-2-deoxy-a-
D
-altropyranoside (4), methyl 2-C-cyano-2-deoxy-6-O-
ethylphenylmethyl-a- -altropyranoside (5a/b)- and
methyl 2-C-cyano-6-O-cyanophenylmethyl-2-deoxy-a-
altropyranoside (6a/b). Methyl 2,3-anhydro-4,6-O-ben-
zylidene-a- -allopyranoside (3, 198.8 mg, 0.75 mmol)
D
D-
D
was azeotropically dried with anhydrous benzene under
vacuum and dissolved in dry CH2Cl2 (3 mL) under
argon. Diethylaluminum cyanide (1 M soln in toluene,
1.5 mL, 1.5 mmol) was added at room temperature (rt)
to the magnetically stirred soln. Stirring was continued
during 6 days at rt. The mixture was then diluted with
ultimately delivering cyanide to the CÄ
/
N double bond.
This result is applicable to alkoxide 8, which could be
the intermediate responsible for delivering the ethyl
group intermolecularly.

2182
M.I. Mangione et al. / Carbohydrate Research 338 (2003) 2177Á2183
/
CH2Cl2 and poured onto iceÁ/Na2CO3 soln. The organic
mL) under argon. Silver oxide (freshly prepared, 52.2
layer was separated and the aqueous phase further
extracted with CH2Cl2. The combined organic layers
were washed with 10% aq NH4Cl and brine and dried
(MgSO4). Concentration and purification by flash
chromatography furnished 4 (43.9 mg, 20%) as a white
crystalline solid and four other, more-polar products:
5a/b (46.4 mg, 19%) and 6a/b (108.1 mg, 45%);
mg, 0.22 mmol) and benzyl bromide (freshly distilled, 20
mL, 0.17 mmol) were added consecutively at rt to the
magnetically stirred soln. Stirring was continued during
2 h at rt. The mixture was diluted with CH2Cl2 and
filtered through a silica gel column and the organic layer
was concentrated under vacuum. Purification by flash
chromatography furnished 9 (24.2 mg, 100%) as a
colorless oil. Compound 9: [a]3D2 13.7 (c 0.99, CHCl3);
IR (NaCl) nmax: 2920, 2720, 2250 (CN), 1460, 1380,
compound 4: mp 198.5Á
/
200.0 8C (petroleum etherÁ
/
CHCl3); [a]D 19.8 (c 0.71, CHCl3); IR (KBr) nmax:
ꢀ
/
3490, 2940, 2920, 2280 (CN), 1460, 1375, 1240, 1220,
1
1240, 1110, 1055, 920, 760, 705 cmꢁ1
(CDCl3): d 3.26 (d, 1 H, J2,3 2.43 Hz, H-2), 3.41 (s, 3
H, OCH3), 3.80 (t, 1 H, Jgem J5,6 10.23 Hz, H-6ax),
4.00 (dd, 1 H, J3,4 2.77 , J4,5 8.70 Hz, H-4), 4.18 (t, 1 H,
J2,3 J3,4 2.53 Hz, H-3), 4.27Á4.52 (m, 2 H, H-5 and H-
;
1H NMR
1140, 1060, 1030, 990, 900, 820, 760 cmꢁ1; H NMR
(CDCl3): d 3.00 (broad, 1 H, OH), 3.29 (d, 1 H, J2,3 2.59
ꢂ
/
Hz, H-2), 3.46, (s, 3 H, OCH3), 3.91 (t, 1 H, Jgem
9.65 Hz, H-6ax), 4.34 (dd, 1 H, J3,4 2.89, J4,5 9.24 Hz, H-
4), 4.20Á4.45 (m, 3 H, H-3, H-5 and H-6eq), 4.97 (s, 1 H,
ꢂJ5,6
/
ꢂ
/
/
/
6eq), 4.70 (d, 1 H, Jgem 12.40 Hz, CH2 benzylic), 4.83 (d,
H-1), 5.68 (s, 1 H, H-7), 7.30Á7.50 (m, 5 H, aromatics);
/
1 H, Jgem 12.40 Hz, CH2 benzylic), 4.90 (s, 1 H, H-1),
13C NMR (CDCl3): d 37.4 (C-2), 56.1 (OCH3), 58.1 (C-
5), 66.4 (C-3), 68.6 (C-6), 76.3 (C-4), 97.6 (C-1), 102.2
5.60 (s, 1 H, H-7), 7.24Á
7.58 (m, 10 H, aromatics); 13C
NMR (CDCl3): d 36.5 (C-2), 55.6 (OCH3), 58.3 (C-5),
66.6 (C-6), 72.1 (C-3), 73.0 (CH2 benzylic), 77.0 (C-4),
/
(C-7), 116.4 (CÅ
/
N), 126.1 (2 C, Cortho), 128.3 (2 C,
C
meta), 129.3 (Cpara), 136.6 (Cipso). Anal. Calcd for
97.3 (C-1), 102.2 (C-7), 117.2 (CÅ
/
N), 126.1 (2 C,
aromatic), 127.5 (2 C, Caromatic),127.7 (Cpara), 128.2 (2
C15H17NO5: C, 61.85; H, 5.88, N, 4.81. Found: C, 61.69;
H, 5.86; N, 4.78. Compounds 5a/b: IR (NaCl) nmax: 3480
(OH), 3030, 2940, 2260 (CN), 1460, 1390, 1230, 1115,
1080, 1010, 770, 710 cmꢁ1; 1H NMR (CDCl3): d 0.90 (t,
C
C, Caromatic), 128.3 (2 C, Caromatic), 129.1 (Cpara), 137.2
(Cipso), 137.4 (Cipso).
3 H, J16,17 7.40 Hz, CH2CH3), 1.60Á
CH2CH3), 3.05 (s, 1 H, OH), 3.24 (dd, 1 H, J1,2
1.90 Hz, H-2), 3.41/3.43 (s, 3 H, OCH3), 3.46Á3.73 (m, 2
H, H-6ax and H-6eq), 3.73Á4.00 (m, 2 H, H-3 and H-4),
4.05Á4.33 (m, 2 H, H-5 and H-7) 4.97 (s, 1 H, H-1),
7.24Á
7.44 (m, 5 H, aromatics); 13C NMR (CDCl3): d
/
1.97 (m, 2 H,
4.1.3. Methyl-3-O-acetyl-4,6-O-benzylidene-2-C-cyano-
D
-altropyranoside (10). Methyl 4,6-O-benzyl-
ꢂ/J2,3
2-deoxy-a-
/
idene-2-cyano-2-deoxy-a-
D-altropyranoside (4, 18.1 mg,
/
0.06 mmol) was dissolved in dry CHCl3 (0.8 mL) and
cooled at 0 8C under argon atmosphere. Dry pyridine
(35 mL, 0.43 mmol), 4-(dimethylamino)pyridine (2.5 mg,
0.02 mmol) and Ac2O (25 mL, 0.26 mmol) were
successively added to the stirred soln at 0 8C. The
cooling bath was then removed and stirring was
continued during 4 h at rt. The mixture was diluted
with EtOAc, washed with 10% aq CuSO4, water and
brine, dried (MgSO4) and concentrated. The crude
product was purified by flash chromatography to
furnish pure 10 (17.7 mg, 86%) as a colorless oil.
Compound 10: [a]2D0 64.6 (c 0.59, CHCl3); IR (NaCl)
/
/
10.1 (CH2CH3), 30.7/30.8 (CH2CH3), 36.6 (C-2), 55.8
(OCH3), 66.0 (C-4), 67.7 (C-5), 67.8 (C-3), 68.6/68.8 (C-
6), 84.5/85.0 (C-7), 97.0/97.1 (C-1), 116.3 (CÅ
(2 C, Cortho), 127.6 (Cpara), 128.9 (2 C, Cmeta), 141.5
(Cipso); HRMS (CI): Calcd for C17H23NO5: (Mꢀ
Naꢀ)
344.147393. Found: (Mꢀ
Naꢀ) 344.146854. Com-
/
N), 126.6
/
/
pounds 6a/b: IR (NaCl) nmax: 3470 (OH), 3020, 2930,
2230 (CN), 1705, 1480, 1440, 1260, 1175, 980, 735, 655
cmꢁ1; 1H NMR (CDCl3): d 2.67 (broad, 1 H, OH), 3.29
(m, 1 H, H-2), 3.41/3.45 (s, 3 H, OCH3), 3.73Á
/
4.24 (m, 5
H, H-3, H-4, H-5, H-6ax and H-6eq), 4.99/5.02 (s, 1 H,
nmax: 2935, 2250 (CN), 1740 (CÄ
/
O), 1380, 1230, 1130,
1
1050, 1020, 915, 800, 690 cmꢁ1; H NMR (CDCl3): d
2.10 (s, 3 H, CH3CO), 3.39 (s, 3 H, OCH3), 3.49 (d, 1 H,
H-1), 5.40/5.49 (s, 1 H, H-7), 7.40Á
/
7.58 (m, 5 H,
aromatics); 13C NMR (CDCl3): d 36.7 (C-2), 56.0/56.1
(OCH3), 64.3/64.6 (C-4), 67.9 (C-3), 68.2 (C-5), 68.5/69.3
J2,3 2.58 Hz, H-2), 3.82 (t, 1 H, Jgemꢂ
6ax), 4.07 (dd, 1 H, J3,4 2.95, J4,5 9.14 Hz, H-4), 4.25Á
4.40 (m, 2 H, H-5 and H-6eq), 4.91 (s, 1 H, H-1), 5.31 (t,
/J5,6 12.30 Hz, H-
/
(C-6), 71.3/71.4 (C-7), 97.2/97.3 (C-1), 115.7/115.8 (CÅ
N), 117.0/117.1 (CÅN), 127.0/127.3 (2 C, Cortho), 128.9
(2 C, Cmeta), 129.8 (Cpara), 133.1 (Cipso). HRMS (CI):
Calcd for C16H18N2O5: (Mꢀ
Naꢀ) 383.128334. Found:
(Mꢀ
Naꢀ) 383.126684.
/
/
1 H, J2,3 2.68 Hz, H-3), 5.63 (s, 1 H, H-7), 7.30Á7.55 (m,
/
5 H, aromatics); 13C NMR (CDCl3): d 20.8 (CH3CO),
35.2 (C-2), 55.7 (OCH3), 58.7 (C-5), 66.3 (C-3), 68.8 (C-
/
/
6), 74.4 (C-4), 97.2 (C-1), 102.1 (C-7), 116.1 (CÅN),
126.0 (2 C, Cortho), 128.2 (2 C, Cmeta), 129.2 (Cpara),
/
4.1.2. Methyl 3-O-benzyl-4,6-O-benzylidene-2-C-cyano-
2-deoxy-a- -altropyranoside (9). Methyl 4,6-O-benzyli-
-altropyranoside (4, 18.5 mg,
0.06 mmol) was azeotropically dried with anhydrous
benzene under vacuum and dissolved in dry CH2Cl2 (0.5
136.7 (Cipso), 170.2 (CÄ
/
O).
D
dene-2-cyano-2-deoxy-a-
D
4.1.4. Methyl 3,4-di-O-acetyl-2-C-cyano-6-O-
cyanophenylmethyl-2-deoxy-a-D-altropyranoside (7a/b).
Compound 6a/b (61.3 mg, 0.19 mmol) was dissolved in

M.I. Mangione et al. / Carbohydrate Research 338 (2003) 2177Á
/2183
2183
5. Pellegrinet, S. C.; Spanevello, R. A. Tetrahedron Lett.
1997, 38, 8623Á8626.
6. Poonian, M. S.; Nowoswiat, E. F. J. Org. Chem. 1980, 45,
203Á208.
7. Yang, C. O.; Wu, H. Y.; Fraser-Smith, E. B. Tetrahedron
Lett. 1992, 33, 37Á40.
dry CHCl3 (1.9 mL) and cooled at 0 8C under argon.
Dry pyridine (156 mL, 1.93 mmol), 4-(dimethylami-
no)pyridine (11.8 mg, 0.10 mmol) and Ac2O (109 mL,
1.16 mmol) were successively added to the stirred soln at
0 8C. The cooling bath was then removed and stirring
continued during 15 h at rt. The mixture was diluted
with EtOAc, washed with 10% aq CuSO4, water and
brine, dried (MgSO4) and concentrated. The crude
product was purified by flash chromatography to
furnish pure 7a/b (70.0 mg, 90%) as a colorless oil.
/
/
/
8. Azuma, A.; Nakajima, Y.; Nishizono, N.; Minakawa, N.;
Suzuki, M.; Hanaoka, K.; Kobayashi, T.; Tanaka, M.;
Sasaki, T.; Matsuda, A. J. Med. Chem. 1993, 35, 4183Á
/
4189.
9. Collins, P.; Ferrier, R. Monosaccharides. Their Chemistry
and their Roles in Natural Products; J. Wiley & Sons:
Compounds 7a/b: IR (NaCl) nmax: 3020, 2950, 2250 (CÅ
/
N), 1760 (CÄ
/
O), 1500, 1455, 1380, 1250, 1185, 1070,
1
Chichester, 1995; pp 280Á289.
/
760, 690 cmꢁ1; H NMR (CDCl3): d 1.98/2.10 (s, 3 H,
CH3CO), 3.29 (m, 1 H, H-2), 3.40/3.44 (s, 3 H, OCH3),
10. Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach, Pergamon Press, Oxford, 1983, pp. 89,
125, 144, 265.
3.70Á3.93 (m, 2 H, H-6), 4.25 (m, 1 H, H-5), 4.97 (m, 1
/
11. Williams, N. R. J. Chem. Soc., Chem. Commun. 1967,
H, H-1), 5.24 (m, 1 H, H-3), 5.30Á5.55 (m, 2 H, H-4 and
/
H-7), 7.40Á
/
7.65 (m, 5 H, aromatics); 13C NMR
20.4 (CH3CO), 34.9 (C-2), 56.1/56.2
1012Á
/
1013.
12. Inch, T. D.; Lewis, G. J. Carbohydr. Res. 1970, 15, 1Á
/10.
(CDCl3):
d
13. Sepulchre, A.-M.; Lukacs, G.; Vass, G.; Gero, S. D.
Angew. Chem., Int. Ed. 1972, 11, 148.
(OCH3), 65.1/65.4 (C-3), 66.18/66.22 (C-4), 67.9/68.6
(C-5), 67.6/68.5 (C-6), 71.0/71.1 (C-7), 97.5 (C-1), 115.8
14. Lo´pez, J. C.; Lameigne´re, E.; Burnouf, C.; Laborde, M.
A.; Ghini, A. A.; Olesker, A.; Lukacs, G. Tetrahedron
(2C, CÅ
129.0 (2 C, Cmeta), 129.9 (Cpara), 132.4 (Cipso), 169.1/
169.3/169.4/169.5 (CÄO).
/
N), 116.5 (2C, CÅ
/
N), 127.1/127.3 (2 C, Cortho),
1993, 49, 7701Á
15. Kazmi, S. N-H.; Ahmed, Z.; Khan, A. Q.; Malik, A.
Synth. Commun. 1988, 18, 151Á156.
16. Davidson, B. E.; Guthrie, R. D.; McPhail, A. T. J. Chem.
Soc., Chem. Commun. 1968, 1273Á1274.
17. Davidson, B. E.; Guthrie, R. D. J. Chem. Soc., Perkin
Trans. 1 1972, 658Á663.
18. Spanevello, R. A.; Pellegrinet, S. C. Synth. Commun. 1995,
25, 3663Á3670.
19. Watanabe, S.; Kavai, I.; Bobek, M. J. Carbohydr. Chem.
1995, 14, 685Á701.
20. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; J. Wiley & Sons: New York, 1994; pp 730Á
731.
/
7722.
/
/
Acknowledgements
/
This research was supported by the Third World
Academy of Sciences, Trieste, Italy, the International
Foundation for Science, Stockholm, Sweeden, and the
Organization for the Prohibition of Chemical Weapons,
The Hague, The Netherlands, through the grants to
AGS and RAS respectively. MIM thanks CONICET for
the award of a fellowship. Thanks are also due Dr R.
Kohli for the mass spectra, Professor M. Gonza´lez
Sierra for his assistance with the NMR spectra, and N.
Fortuna for collaboration through the Undergraduate
Research Program.
/
/
/
/
21. Wiggins, L. F. Methods Carbohydr. Chem. 1963, 2, 188Á
/
191.
22. De las Heras, F.; San Felix, A.; Calvo-Mateo, A.;
Fernandez-Resa, P. Tetrahedron 1985, 41, 3867Á
23. Inghardt, T.; Fredj, T.; Magnusson, G. J. Org. Chem.
1988, 53, 4542Á4548.
24. Kessler, H.; Griesinger, J.; Zarbock, H. R.; Loosli, J. J.
Magn. Res. 1984, 57, 331Á335.
25. Olsson, R.; Berg, U.; Frejd, T. Tetrahedron Lett. 1997, 38,
5701Á5704.
26. Nagata, W.; Yoshioka, M.; Okumura, T. J. Chem. Soc.
(C) 1970, 2365Á2377.
27. (a) Inghardt, T.; Frejd, T. J. Org. Chem. 1989, 54, 5539Á
/3873.
/
References
/
1. (a) Hall, R. H.; Bischofberger, K.; Brink, A. J.; de
Villierrs, O. G.; Jordaan, A. J. Chem. Soc., Perkin Trans.
/
1 1979, 781Á
(b) Mubarak, A.; Fraser-Reid, B. J. Org. Chem. 1980, 47,
4265Á4268.
2. Thang, T. T.; Winternitz, F.; Lagraange, A.; Olesker, A.;
Lukacs, G. Tetrahedron Lett. 1980, 21, 4495Á4498.
3. Knierzinger, A.; Vasella, A. J. Chem. Soc., Chem. Com-
mun. 1984, 26, 9Á11.
4. Pellegrinet, S. C.; Spanevello, R. A. Tetrahedron: Asym-
metry 1997, 8, 1983Á1986.
/786;
/
/
/
5543;
/
(b) Olsson, R.; Berg, U.; Frejd, T. Tetrahedron 1998, 54,
3935Á
28. Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y. J.
Org. Chem. 1996, 61, 440Á441.
/
3954; idem 1998, 54, 5424.
/
/
/