InCl3-catalyzed rapid 1,3-alkoxy migration in glycal ethers: Stereoselective synthesis of unsaturated α-O-glycosides and an α,α-(1→1)-linked disaccharide

Article abstract of DOI:10.1002/ejoc.200800453

InCl₃ catalyzes a facile stereoselective 1,3-migration of allylic ethers of glycals to afford 2-C-methylene- and 2,3-unsaturated-α- O-glycosides in high yields. The reaction is rapid (10 min), requires only 20 mol-% of the catalyst, and is compatible with acid-labile functional groups such as epoxides and acetals. This methodology provides a convenient alternative to the Ferrier rearrangement. A direct synthesis of an α,α-(1→1)- linked disaccharide derivative by a domino process is also reported. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800453

FULL PAPER
DOI: 10.1002/ejoc.200800453
InCl3-Catalyzed Rapid 1,3-Alkoxy Migration in Glycal Ethers: Stereoselective
Synthesis of Unsaturated α-O-Glycosides and an α,α-(1Ǟ1)-Linked
Disaccharide
Paramathevar Nagaraj[a] and Namakkal G. Ramesh*[a]
Dedicated to Dr. Antonius J. H. Klunder
Keywords: Carbohydrates / Glycosylation / Lewis acids / Glycosides / Disaccharides
InCl3 catalyzes a facile stereoselective 1,3-migration of allylic
ethers of glycals to afford 2-C-methylene- and 2,3-unsatu-
rated-α-O-glycosides in high yields. The reaction is rapid
(10 min), requires only 20 mol-% of the catalyst, and is com-
patible with acid-labile functional groups such as epoxides
and acetals. This methodology provides a convenient alter-
native to the Ferrier rearrangement. A direct synthesis of an
α,α-(1Ǟ1)-linked disaccharide derivative by a domino pro-
cess is also reported.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
based inactivation of ribonucleotide diphosphate re-
ductase.[9]
Introduction
The rapidly growing interest in understanding the role
of oligosaccharides in various biological processes, coupled
with the formidable task of isolating them from natural
sources, provide organic chemists with tremendous scope
for the development of new and efficient strategies for
stereoselective construction of glycosidic linkages.[1]
Furthermore, glycosides possessing additional synthetically
maneuverable functionalities offer added advantages and
allow easy access to more complex molecules. In this con-
text, 2,3-unsaturated glycosides have enjoyed widespread
applications in organic synthesis for the last four decades,
as their unsaturation allowed the introduction of a variety
of functionalities.[2] In recent years, 2-C-methylene glyco-
sides, a class of unsaturated glycosides with an exo-methyl-
ene group at C2, have gained immense importance as versa-
tile intermediates in the synthesis of natural products and
biologically important compounds such as restricticin,[3] cy-
clophellitol,[4] C-disaccharides,[5] carbohydrates from poly-
enes,[6] and ara-cyclohexenyl-adenine.[7] 2-C-Methylene hy-
droperoxides synthesized from 2-C-methylene glycosides
have been used as chiral catalysts for enantioselective epox-
idation reactions.[8] The 2-C-methylene group is also a key
structural feature of molecules involved in mechanism-
Conventionally, 2-C-methylene glycosides 2 are accessed
through Wittig reactions of the corresponding 2-keto glyco-
sides 1 [Equation (1)].[3,4,7,10] In certain cases it has been
reported that the Wittig reaction is very sensitive to the con-
ditions employed.[3,4] An alternative and simple approach
to 2-C-methylene glycosides 2 using a “New Ferrier system”
first developed by Balasubramanian et al.[11] and sub-
sequently exploited by others[12–14] generally involves an
acid-catalyzed (Lewis or Brønsted) substitution with allylic
rearrangement of 2-C-acetoxymethyl glycals 3 [Equation
(2)] or 2-C-(propargyloxymethyl)-glycals. Some of these
methodologies suffer from certain disadvantages such as
substrate instability,[15,16] longer reaction times (1–16 h),
lack of stereoselectivity in some examples, and requirement
for stoichiometric or even larger amounts of catalysts. Dur-
ing the course of our research on 2-C-substituted sugars, we
encountered a facile route to the synthesis of 2-C-methylene
glycosides through InCl3-catalyzed 1,3-alkoxy migration in
glycal ethers, which we report here. The reaction is general,
rapid, stereoselective, yielding only the α-anomers, and also
compatible with acid-labile groups such as epoxides and
acetals. A novel InCl3-catalyzed one-pot stereoselective syn-
thesis of an α,α-(1Ǟ1)-linked disaccharide has also been
accomplished.
[a] Department of Chemistry, Indian Institute of Technology –
Delhi, Hauz Khas,
New Delhi 110016, India
Results and Discussion
Fax: +91-11-26582037
E-mail: ramesh@chemistry.iitd.ac.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
In the last decade, InCl3 has found wide application as a
mild Lewis acid in organic chemistry.[17] In carbohydrate
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Table 1. Effect of Lewis acids on [1,3]-migration in ether 6a to af-
ford the 2-C-methylene glycoside 8a.
Entry
Lewis acid
mol-%
Time (min)
Yield (%)[a]
1
2
3
4
5
InCl3
20
20
20
20
20
10
10
10
10
10
88
73
69
63
(1)
(2)
ZnCl2
CAN[b]
BiCl3
BF3·Et2O
complex mixture
[a] Isolated yield after column chromatography. [b] Ceric ammo-
nium nitrate.
effecting the InCl3-mediated transformation in 10 min, re-
sulted, however, in a lower yield of the product (68%).
Intrigued by the simplicity and success, we prepared sev-
eral hitherto unknown glycal ethers[20,21] possessing diverse
functional groups (6a–g, 7a–c) from the corresponding
alcohols 4 and 5,[22] and the InCl3-mediated 1,3-migration
reaction was tested on them (Scheme 2, Table 2). In all
cases the allylic rearrangement occurred rapidly with just
20 mol-% of anhydrous InCl3, affording the corresponding
2-C-methylene glycosides (8a–g, 9a–c) exclusively as their
α-anomers in high yields. The reaction works with equal
ease in both the galactal (Entries 1–7; Table 2) and the glu-
cal series (Entries 8–10; Table 2). Comparison of a few ex-
chemistry, it is mainly used as a catalyst for glycosylation
reactions through the coupling of glycosyl donors with a
variety of nucleophiles,[12,18] and its use in a 1,3-migration
reaction, to the best of our knowledge, has not been re-
ported so far. With this background, we investigated the
reaction between 3,4,6-tri-O-benzyl-2-C-methoxymethyl ga-
lactal 6a and InCl3 (Scheme 1). When compound 6a was
initially exposed to 50 mol-% of anhydrous InCl3 in dry
CH2Cl2 at room temperature, we were pleasantly surprised
to observe that the starting material was completely con-
sumed within 10 min and that the reaction afforded an 88%
yield of a single product that was characterized as methyl
2-C-methylene-α-O-glycoside 8a. Subsequently, after few
experiments, we observed that just 20 mol-% of InCl3 was
sufficient to bring about this reaction without any change in
the reaction time, yield, or stereoselectivity. The α-anomeric
Table 2. Synthesis of glycal ethers 6 and 7 and their allylic re-
arrangement catalyzed by InCl3.
1
stereochemistry was confirmed by detailed H NMR NOE
studies.[19]
Scheme 1. InCl3-catalyzed 1,3-migration of ether 6a.
The facile nature of the reaction prompted us to investi-
gate the efficiency of various Lewis acids in effecting this
reaction. From Table 1, it is quite clear that while this reac-
tion has been achieved with a variety of Lewis acids – such
as anhydrous BiCl3, ZnCl2, and CAN, etc. – InCl3 was the
best among them in terms of yield. Interestingly, with
BF3·Et2O, a more popular and more commonly used Lewis
acid, only a complex mixture was obtained. Furthermore,
[a] Isolated yields after column chromatography. [b] In all cases,
only α-anomer was obtained. [c] All the reactions were performed
with 20 mol-% of anhydrous catalyst in dry CH2Cl2 at room tem-
perature over 10 min. [d] The spectroscopic data were consistent
with the literature values[11,12,13,14]. [e] Racemic epichlorohydrin was
used for the etherification, and the 1:1 diastereomeric mixtures of
6f and 7b were subjected to subsequent allylic rearrangement with-
use of CH3CN instead of CH2Cl2 as a solvent, while equally out separation. [f] A complex mixture was obtained.
Scheme 2. Synthesis of glycal ethers (6 and 7) and their InCl3-catalyzed allylic rearrangement.
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Eur. J. Org. Chem. 2008, 4607–4614

InCl3-Catalyzed Rapid 1,3-Alkoxy Migration in Glycal Ethers
amples carried out with 20 mol-% of anhydrous ZnCl2 dis- anomeric carbon (Figure 1). In the carbocation II, this spa-
played the catalytic superiority of InCl3 (Entries 1, 3, 6, 7, tial distance decreases to 2.74 Å, presumably due to the in-
and 9; Table 2).
teraction between the lone pair of electrons on the oxygen
In order to demonstrate the functional group compatibil- atom of the C-6 benzyloxy group and the positive charge
ity, ethers bearing acid-labile groups such as epoxides (6f at the anomeric carbon (Figure 1). Such an interaction
and 7b) and an acetal (6e) were synthesized and subjected would not only provide additional stability for II, but would
to the InCl3-mediated reaction. Gratifyingly, the alkoxy mi- also sterically block the β-face for attack of the nucleophile.
gration reaction occurred very readily to afford the corre- On the other hand, the spatial distance between the oxygen
sponding 2-C-methylene glycosides (8f, 9b, and 8e) in good atom of the C-3 benzyloxy group and the anomeric carbon
yields and with the acid labile groups remaining intact. In increases from 3.28 Å in 6a to 3.39 Å in carbocation II.
view of the literature background that InCl3 rapidly cata- Preliminary AM1 calculations are thus suggestive of a pos-
lyzed the rearrangement of epoxides to carbonyl com- sible involvement of the C-6 benzyloxy group in stereodi-
pounds,[23] the preference for the 1,3-migration reaction recting the glycosylation step, resulting in exclusive forma-
over the epoxide rearrangement in the case of compounds tion of α-anomers. However, detailed mechanistic investi-
6f and 7b merits special mention. It is noteworthy that gations taking the effect of solvents, temperature, reagents,
ZnCl2 failed to bring about the expected allylic rearrange-
ments of compound 6f and 7b, resulting in complex mix-
tures.
A plausible mechanism for the 1,3-migration reaction
with the observed α-stereoselectivity is given in Scheme 3.
Initial coordination of InCl3 with the side-chain alkoxy
group at C-2 of 6 (to afford intermediate I) followed by its
departure would result in the formation of a highly stabi-
lized anomeric carbocation II. It is likely that the anomeric
carbocation II would be stabilized not only by the ring oxy-
gen atom but also by the remote oxygen atom of the C-6
benzyloxy group, thereby sterically blocking the β-face for
attack of the departing alkoxy group and thus resulting in
exclusive formation of α-anomers. Stereoselective glycosyla-
tion reactions through the anchimeric assistance of remote
acyl, ester, or carbamate groups are well documented in the
literature.[24] It has also been reported that esters are better
stereodirecting agents than alkoxy groups. However, most
of these reports have dealt with saturated pyranosides, ex-
cept for the one by Srivastava et al.,[24a] who observed such
remote stereocontrol in an endocyclic unsaturated sugar. In
the present case, in order to find out whether the exclusive
formation of α-anomers in all these examples is influenced
by the remote stereocontrolling effect of the C-6 benzyloxy
group, semiempirical AM1 calculations were performed
with HyperChem.[25] First of all, AM1 calculations indicate
that the preferred low-energy conformation of compound
5
6a is H4 (with a minimum calculated energy of –7.0 kcal),
in which the (pseudo)axial C-6 benzyloxy group positions
itself close to the anomeric carbon, with a spatial distance
of 2.91 Å between the C-6 benzyloxy oxygen atom and the cation II. Hydrogens are omitted for clarity.
Figure 1. Low-energy conformations of compound 6a and carbo-
Scheme 3. Putative mechanism for stereoselective formation of α-glycosides 8 and 9.
Eur. J. Org. Chem. 2008, 4607–4614
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P. Nagaraj, N. G. Ramesh
FULL PAPER
reaction conditions, etc. into account would need to be
done to explain the observed stereoselectivity unambigu-
ously.
A novel and interesting observation was the direct syn-
thesis of an α,α-(1Ǟ1)-linked disaccharide 11 as a single
diastereomer in 80% yield in just 10 min (Scheme 4) when
alcohol 4 itself was exposed to a catalytic amount of anhy-
drous InCl3. The formation of the disaccharide was sug-
gested by the absence of any OH stretching frequency in its
IR spectrum, as well as the absence of any exchangeable
proton in its 1H NMR spectrum. This was further sup-
ported by the ESI HRMS data, which showed a peak at
879.3998 {[M + Na]+} due to the formation of the disac-
charide. The C2 symmetry of the molecule was evidenced
from its 13C NMR spectrum, which displayed signals corre-
sponding to only half the number of carbon atoms. The
α,α-anomeric stereochemistry was confirmed by detailed 1H
NMR NOE studies. It is likely that the reaction proceeds
through an initial [1,3]-migration of alcohol 4 to give the
hemiacetal 10, which could not be isolated under the reac-
tion conditions, followed by a rapid in situ glycosylation
reaction resulting directly in the stereoselective formation
of an α,α-(1Ǟ1)-linked disaccharide 11. To the best of our
knowledge, formation of an α,α-(1Ǟ1)-linked disaccharide
through such a domino process has no precedence. Given
the biological significance of trehalose {α,α-(1Ǟ1)-linked
glucoside} and its analogues,[26] the one-pot synthesis of
compound 11 reported here assumes synthetic significance.
Scheme 5. InCl3-catalyzed synthesis of 2,3-unsaturated glycosides
14 and 15.
Conclusions
In conclusion, we report a new strategy for the synthesis
of relatively less well explored unsaturated glycosides –
namely, 2-C-methylene glycosides – for which only a few
methods are available in the literature. The reaction is
highly stereoselective, affording only the α-anomers in all
cases. This methodology, while providing a convenient al-
ternative to the Ferrier rearrangement, is also explicitly sim-
ple to perform. We have also demonstrated the synthesis of
some unique 2-C-methyleneglycosides such as 8e, 8f, and 9b
that are not accessible by the existing methods. The stereo-
selective formation of the α,α-(1Ǟ1)-linked disaccharide de-
rivative 11 in one-pot fashion is synthetically quite interest-
ing and is likely to spur further interest in this area.
Experimental Section
General Considerations: All solvents were purified by standard pro-
cedures. Thin-layer chromatography (TLC) was performed on
Merck silica gel pre-coated on aluminium plates. Flash column
chromatography was performed on 230–400 mesh silica gel. Optical
rotations were recorded on an Autopol II or an Autopol V (Ru-
dolph Research Flanders, New Jersey) instrument. All the rotations
were measured at 589 nm (sodium D line). Melting points of the
compounds are uncorrected. IR spectra were taken over the 4000–
400 cm–1 range as KBr pellets on a Nicolet (Madison, USA) FT-
IR spectrophotometer (Model protégé 460). All the 1H and 13C
Scheme 4. Domino one-pot synthesis of disaccharide 11.
An earlier report by Descotes and Martin[27] on the NMR spectra were recorded on a 300 MHz Bruker Spectrospin
DPX FT-NMR spectrometer. Chemical shifts are reported as δ val-
ues (ppm) relative to Me4Si as internal standard. Mass spectra were
recorded with a Waters Micro Mass Q-TOF or an Applied Biosys-
tems Q-Star instrument.
BF3·Et2O-catalyzed rearrangement of 3,4,6-tri-O-benzyl--
glucal 12 to the 2,3-unsaturated α-benzyl glycoside 14
prompted us to examine this reaction with InCl3 as a cata-
lyst. As in our earlier cases, treatment of 12 with 20 mol-%
of InCl3 proceeded with equal feasibility to afford 14 in Typical Procedure for the Synthesis of Ethers 6 and 7: Alcohol 4 or
64% yield, as an anomeric mixture in a 5:1 ratio.[28,29] InCl3
also mediated a rapid transformation of 3,4,6-tri-O-benzyl-
-galactal 13 into the glycoside 15 as a single anomer in
77% yield (Scheme 5).[30] Interestingly, with ZnCl2 as a cat-
alyst, the above reactions again proved to be futile. It is
worth mentioning that Ferrier rearrangements of protected
galactals are not as easy reactions as those of protected glu-
cals,[31] and the methodology reported here for the synthesis
of 2,3-unsaturated galactoside through [1,3]-alkoxy mi-
gration should prove to be synthetically attractive.
5
[22] (1.0 g, 2.2 mmol) was dissolved in dry DMF (5.0 mL), and the
mixture was cooled to 0 °C. Sodium hydride (0.131 g, 3.3 mmol,
60% in paraffin oil) was added. After 5 min, alkyl halide
(3.3 mmol) was added, and the reaction mixture was stirred at
room temperature for the specified time. After completion, the re-
action mixture was quenched with water and extracted with ethyl
acetate (4ϫ50 mL). The organic layer was washed with saturated
sodium hydrogen carbonate solution, followed by water, and was
then dried with sodium sulfate, filtered, and concentrated. Column
chromatography of the crude reaction mixture with hexane/ethyl
acetate (5:1) as an eluent afforded ethers 6 or 7, respectively.
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InCl3-Catalyzed Rapid 1,3-Alkoxy Migration in Glycal Ethers
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-methoxymethyl-
D
-
(d, J = 12.0 Hz, 1 H), 4.53–4.38 (m, 3 H), 4.29–4.25 (m, 3 H), 3.96
(t, J = 3.6 Hz, 1 H), 3.83–3.63 (m, 3 H), 3.45–3.40 (m, 2 H), 3.35
[s, 6 H, C(OMe)2] ppm. 13C NMR (75 MHz, CDCl3): δ = 143.2 (C-
1), 138.7, 138.1, 138.0, 128.3, 128.2, 127.89, 127.85, 127.69, 127.64,
127.5 (Caryl), 109.7 (C), 102.6 [CH(OCH3)2], 75.7 (OCH), 73.5
(OCH2), 73.3 (OCH2), 73.1 (OCH2),72.4 (OCH), 71.0 (OCH), 69.0
(OCH2 ), 68.7 (OCH2 ), 68.1 (OCH2), 53.7 (OCH3 ), 53.6
lyxo-hex-1-enitol (6a): Compound 6a (0.80 g, 77% yield) was ob-
tained as a colorless liquid by treatment of glycal 4 (1.0 g,
2.2 mmol) with NaH (0.131 g, 3.3 mmol) and methyl iodide
(0.213 mL, 3.3 mmol) over 4 h. [α]2D8 = +11.5 (c = 0.33, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.32–7.23 (m, aromatic, 15 H), 6.39
(s, 1 H, 1-H), 4.81 (d, J = 11.7 Hz, 1 H), 4.78 (d, J = 11.4 Hz, 1
H), 4.64 (d, J = 11.4 Hz, 1 H), 4.62 (d, J = 11.7 Hz, 1 H), 4.51 (d,
J = 12.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.26 (m, 2 H), 4.14
(OCH ) ppm. IR (KBr): ν = 2928, 2867, 1671, 1497, 1449, 1390,
˜
3
1256, 1191, 1091, 743, 699 cm–1. HRMS (ESI): calcd. for
(d, J = 11.1 Hz, 1 H), 3.96 (t, J = 3.3 Hz, 1 H), 3.80–3.78 (m, 1 C32H38O7Na [M + Na]+ 557.2515; found 557.2528.
H), 3.68 (dd, J = 10.5, 4.2 Hz, 1 H), 3.59 (d, J = 10.5 Hz, 1 H),
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-(2Ј,3Ј-epoxypropyl-
oxy)methyl-D-lyxo-hex-1-enitol (6f): Compound 6f (0.78 g, 70%
3.23 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 142.8
(C-1), 138.4, 138.0, 137.9,137.7, 128.7,128.4, 127.8, 127.7, 127.6,
127.4, 127.3 (Caryl), 109.7 (C), 75.4 (OCH), 73.2 (OCH2), 73.0
(OCH2), 72.8 (OCH2), 72.2 (OCH), 71.6 (OCH), 69.8 (OCH2), 67.8
yield) was obtained as a colorless liquid by treatment of glycal 4
(1.0 g, 2.2 mmol) with NaH (0.131 g, 3.3 mmol) and epichlorohyd-
rin (0.263 mL, 3.3 mmol) over 10 h. The spectroscopic data and
specific rotation reported are for a 1:1 mixture of diastereomers.
[α]2D8 = +20.0 (c = 0.22, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
7.33–7.19 (m, aromatic, 30 H), 6.38 (s, 2 H, 1-H), 4.80 (d, J =
12.0 Hz, 2 H), 4.78 (d, J = 11.4 Hz, 2 H), 4.64 (d, J = 11.4 Hz, 2
H), 4.61 (d, J = 12.0 Hz, 2 H), 4.50 (d, J = 11.7 Hz, 2 H), 4.40 (d,
J = 11.7 Hz, 2 H), 4.26–4.20 (m, 6 H), 3.96 (m, 2 H), 3.83–3.51
(m, 8 H), 3.28–3.21 (m, 2 H), 3.06 (m, 2 H), 2.71 (t, J = 4.2 Hz, 2
H), 2.51 (m, 2 H) ppm. 13C NMR(75 MHz, CDCl3): δ = 143.2 (C-
1), 143.1, 138.5, 138.0, 137.8, 128.2, 127.77, 127.71, 127.59, 127.52,
127.3 (Caryl), 109.6 (C), 75.6 (OCH), 73.3 (OCH2 ), 73.1
(OCH2),73.0 (OCH2), 72.2 (OCH), 70.9 (OCH), 69.9 (OCH2), 69.6
(OCH2), 68.8 (OCH2), 68.6 (OCH2), 68.0 (OCH2), 50.6 (OCH),
(OCH ), 56.8 (OCH ) ppm. IR (KBr): ν = 2870, 1663, 1455, 1350,
˜
2
3
1088, 952, 907, 741, 698 cm– 1 . HRMS (ESI): calcd. for
C29H32NaO5 [M + Na]+ 483.2147; found 483.2145.
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-ethoxymethyl-D-lyxo-
hex-1-enitol (6b): Compound 6b (0.74 g, 70% yield) was obtained
as a colorless liquid by treatment of glycal 4 (1.0 g, 2.2 mmol) with
NaH (0.131 g, 3.3 mmol) and ethyl iodide (0.268 mL, 3.3 mmol)
over 4 h. [α]2D8 = +13.6 (c = 0.22, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.39–7.26 (m, 15 H, aromatic), 6.44 (s, 1 H, 1-H), 4.87
(d, J = 11.7 Hz, 1 H), 4.84 (d, J = 11.7 Hz, 1 H), 4.72 (d, J =
15.0 Hz, 1 H), 4.70 (d, J = 11.7 Hz, 1 H), 4.56 (d, J = 11.7 Hz, 1
H), 4.45 (d, J = 12.0 Hz, 1 H), 4.33 (m, 1 H), 4.20 (d, J = 10.8 Hz,
1 H), 4.02 (t, J = 3.6 Hz, 1 H), 3.86 (dd, J = 10.5, 3.5 Hz, 1 H),
3.80–3.71 (m, 2 H), 3.54–3.35 (m, 3 H), 1.21 (t, J = 7.2 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 142.4 (C-1), 138.3,
137.8, 137.6, 127.9, 127.5, 127.4, 127.3, 127.2, 127.1 (Caryl), 109.9
(C), 75.2 (OCH), 73.0 (OCH2), 72.8 (2ϫOCH2), 72.7 (OCH2), 72.1
(OCH), 70.6 (OCH), 67.7 (OCH2 ), 64.5 (OCH2 ), 14.8
44.18 (OCH ), 44.12 (OCH ) ppm. IR (KBr): ν = 2922, 2863, 2361,
˜
2
2
1663, 1456, 1347, 1185, 1088, 742, 698 cm–1. HRMS (ESI): calcd.
for C31H34NaO6 [M + Na]+ 525.2253; found 525.2242.
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-benzyloxymethyl-D-
lyxo-hex-1-enitol (6g): Compound 6g (0.89g, 74% yield) was ob-
tained as a colorless low-melting solid by treatment of glycal 4
(1.0 g, 2.2 mmol) with NaH (0.131 g, 3.3 mmol) and benzyl chlo-
ride (0.381 mL, 3.3 mmol) over 4 h. [α]2D8 = +27.5 (c = 0.16, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.37–7.24 (m, aromatic, 20 H),
6.39 (s, 1 H, 1-H), 4.80 (d, J = 11.7 Hz, 1 H), 4.78 (d, J = 11.4 Hz,
1 H), 4.62 (d, J = 12.0 Hz, 1 H), 4.60 (d, J = 11.4 Hz, 1 H), 4.57
(d, J = 11.7 Hz, 1 H), 4.53–4.35 (m, 4 H), 4.27–4.24 (m, 2 H), 3.95
(t, J = 3.3 Hz, 1 H), 3.83–3.53 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 143.2 (C-1), 138.6, 138.4, 138.1, 138.0, 128.36, 128.30,
127.8, 127.7, 127.6, 127.5, 126.9 (Caryl), 110.0 (C), 75.7 (OCH), 73.6
(OCH2), 73.3 (OCH2), 73.1 (OCH2), 72.5 (OCH), 71.5 (OCH2),
(OCH CH ) ppm. IR (KBr): ν = 2969, 2863, 1663, 1489, 1454,
˜
2
3
1353, 1091, 741, 698 cm–1. HRMS (ESI): calcd. for C30H34NaO5
[M + Na]+ 497.2304; found 497.2304.
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-(prop-2Ј-enyloxy)-
methyl-D-lyxo-hex-1-enitol (6c): Compound 6c (0.76 g, 70% yield)
was obtained as a colorless liquid by treatment of glycal 4 (1.0 g,
2.2 mmol) with NaH (0.131 g, 3.3 mmol) and allyl bromide
(0.287mL, 3.3 mmol) over 5 h. [α]2D8 = +20.0 (c = 0.28, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.40–7.28 (m, aromatic, 15 H), 6.45
(s, 1 H, 1-H), 6.00–5.87 (m, 1 H), 5.30 (d, J = 17.1 Hz, 1 H), 5.21
(d, J = 10.5 Hz, 1 H), 4.87 (d, J = 12.0 Hz, 1 H), 4.86 (d, J =
11.4 Hz, 1 H), 4.71 (d, J = 11.4 Hz, 1 H), 4.69 (d, J = 12.0 Hz, 1
H), 4.57 (d, J = 12.0 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.35 (m,
2 H), 4.25 (d, J = 11.1 Hz, 1 H), 4.04–3.97 (m, 4 H), 3.64–3.56 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.0 (C-1), 138.6,
138.19, 137.9, 134.8, 128.1, 127.87, 127.81, 127.67, 127.60, 127.4
(Caryl), 116.9 (=CH2), 110.0 (C), 75.7 (OCH), 73.4 (OCH2), 73.2
(OCH2), 73.0 (OCH2), 72.3 (OCH), 71.0 (OCH), 70.3 (OCH2), 68.0
71.1 (OCH), 68.1 (OCH ), 67.9 (OCH ) ppm. IR (KBr): ν = 2903,
˜
2
2
2861, 1658, 1453, 1346, 1211, 1172, 1094, 890, 735, 690, 602,
468 cm–1. HRMS (ESI): calcd. for C35H36NaO5 [M + Na]+
559.2460; found 559.2430.
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-methoxymethyl-D-
arabino-hex-1-enitol (7a): Compound 7a (0.56 g, 55% yield) was
obtained as a colorless liquid by treatment of glycal 5 (1.0 g,
2.2 mmol) with NaH (0.131 g, 3.3 mmol) and methyl iodide
(0.213 mL, 3.3 mmol) over 4 h. [α]2D8 = +34.5 (c = 0.39, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.30–7.24 (m, aromatic, 15 H), 6.47
(s, 1 H, 1-H), 4.73 (d, J = 11.7 Hz, 1 H), 4.63–4.53 (m, 5 H), 4.20–
4.17 (m, 3 H), 3.89 (t, J = 6.3 Hz, 1 H), 3.80 (dd, J = 10.5, 5.7 Hz,
(OCH ), 67.7 (OCH ) ppm. IR (KBr): ν = 2861, 1662, 1456, 1348,
˜
2
2
1183, 1071, 922, 741, 698 cm–1. HRMS (ESI): calcd. for
C31H34NaO5 [M + Na]+ 509.2304; found 509.2298.
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-(2Ј,2Ј-dimethoxy- 1 H), 3.70 (dd, J = 10.5, 3.3 Hz, 1 H), 3.59 (d, J = 11.4 Hz, 1 H),
ethoxy)methyl-
D
-lyxo-hex-1-enitol (6e): Compound 6e (0.672 g,
3.25 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.7
57% yield) was obtained as a colorless liquid by treatment of glycal
(C-1), 138.4, 138.0, 137.9, 128.48, 128.42, 127.89, 127.85, 127.77,
4 (1.0 g, 2.2 mmol) with NaH (0.131 g, 3.3 mmol) and α-chloro- 127.70 (Caryl), 109.7 (C), 76.6 (OCH), 74.3 (OCH), 73.8 (OCH),
acetaldehyde dimethyl acetal (0.398 mL, 3.3 mmol) over 8 h. [α]2D8
= +97.1 (c = 0.35, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.34–
7.24 (m, aromatic, 15 H), 6.39 (s, 1 H, 1-H), 4.808 (d, J = 12.0 Hz,
1 H), 4.801 (d, J = 11.7 Hz, 1 H), 4.66 (d, J = 11.7 Hz, 1 H), 4.62
73.4 (OCH2), 73.1 (OCH2), 72.8 (OCH2), 70.0 (OCH2), 68.2
(OCH ), 56.9 (OCH ) ppm. IR (KBr): ν = 2923, 2862, 1666, 1455,
˜
2
3
1362, 1168, 1089, 740, 699 cm–1. HRMS (ESI): calcd. for
C29H32NaO5 [M + Na]+ 483.2147; found 483.2152.
Eur. J. Org. Chem. 2008, 4607–4614
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4611

P. Nagaraj, N. G. Ramesh
FULL PAPER
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-(2Ј,3Ј-epoxypropyl-
oxy)methyl-D-arabino-hex-1-enitol (7b): Compound 7b (0.624 g,
128.0, 127.7, 127.5, 127.4, 127.0 (Caryl), 111.5 (=CH2), 102.5 (C-1),
78.0 (OCH), 75.4 (OCH), 73.9 (OCH2), 73.3 (OCH2), 71.5 (OCH2),
56% yield) was obtained as a colorless liquid by treatment of glycal
5 (1.0 g, 2.2 mmol) with NaH (0.131 g, 3.3 mmol) and epichlorohy-
drin (0.263 mL, 3.3 mmol) over 8 h. The spectroscopic data and
specific rotation reported are for a 1:1 mixture of diastereomers.
[α]2D8 = +32.5 (c = 0.22, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
7.29–7.24 (m, aromatic, 30 H), 6.46 (s, 2 H, 1-H), 4.72 (d, J =
11.4 Hz, 2 H), 4.64–4.52 (m, 10 H), 4.30–4.15 (m, 6 H), 3.88 (t, J
= 5.4 Hz, 2 H), 3.79–3.64 (m, 6 H), 3.53 (m, 2 H), 3.36–3.24 (m, 2
H), 3.10 (m, 2 H), 2.75 (m, 2 H), 2.55 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 143.9 (C-1), 143.8 (C-1), 138.3, 137.9, 128.5,
128.47, 128.41, 127.8, 127.7, 127.6 (Caryl), 109.4 (C), 109.3 (C), 76.6
(OCH), 76.5 (OCH), 73.9 (OCH), 73.7 (OCH), 73.4 (OCH2), 73.0
(OCH2), 72.79 (OCH2), 72.76 (OCH2),71.2 (OCH2),69.58 (OCH2),
69.53 (OCH2), 69.4 (OCH2), 68.8 (OCH2), 68.6 (OCH2), 68.2
(OCH2), 50.9 (OCH), 50.7 (OCH), 44.36 (OCH2), 44.32
70.6 (OCH), 69.3 (OCH ), 54.7 (OCH ) ppm. IR (KBr): ν = 2910,
˜
2 3
2359, 1597, 1454, 1358, 1194, 1092, 1055, 966, 916, 740, 698 cm–1.
HRMS (ESI): calcd. for C29H32NaO5 [M + Na]+ 483.2147; found
483.2186.
Prop-2-enyl 3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-α-D-lyxo-
hexopyranoside (8c): Compound 8c (0.175g, 76% yield) was ob-
tained by treatment of ether 6c (0.230 g, 0.47 mmol) with anhyd.
InCl3 (0.020 g, 0.094 mmol) over 10 min. Colorless liquid. [α]2D8
=
1
+16 (c = 1.2, CHCl3). H NMR (300 MHz, CDCl3) δ = 7.36–7.21
(m, aromatic, 15 H), 5.97–5.84 (m, 1 H), 5.40 (s, 1 H), 5.28–5.14
(m, 4 H), 4.89 (d, J = 12.0 Hz, 1 H), 4.71 (d, J = 12.0 Hz, 1 H),
4.63 (d, J = 11.7 Hz, 1 H), 4.61 (d, J = 12.0 Hz, 1 H), 4.49–4.37
(m, 3 H), 4.19–4.09 (m, 2 H) 4.04–3.97 (m, 2 H), 3.54–3.50 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3) δ = 140.7 (C-2), 138.6, 138.3,
138.0, 134.0,128.6, 128.5, 128.3, 128.2, 128.0, 127.9, 127.6, 127.59,
127.49, 127.44, 127.0 (Caryl), 117.2 (=CH2), 111.4 (=CH2), 100.6
(C-1), 78.1 (OCH), 75.4 (OCH), 73.9 (OCH2), 73.3 (OCH2), 71.5
(OCH2), 70.7 (OCH), 69.3 (OCH2), 67.7 (OCH2) ppm. IR (KBr):
(OCH ) ppm. IR (KBr): ν = 2863, 1958, 1879, 1813, 1723, 1666,
˜
2
1487, 1456, 1361, 1253, 1169, 914, 847, 743, 699, 607, 473 cm–1.
HRMS (ESI): calcd. for C31H34NaO6 [M + Na]+ 525.2253; found
525.2249.
ν = 2917, 2862, 2359, 1597, 1492, 1455, 1358, 1149, 1093, 1022,
˜
740, 698 cm–1. HRMS (ESI) calcd. for C31H34NaO5 [M + Na]+
509.2304; found 509.2291.
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-C-benzyloxymethyl-D-
arabino-hex-1-enitol (7c): Compound 7c (0.82 g, 70% yield) was ob-
tained as a colorless liquid by treatment of glycal 5 (1.0 g,
2.2 mmol) with NaH (0.131 g, 3.3 mmol) and benzyl chloride
(0.381 mL, 3.3 mmol) over 4 h. [α]2D8 = +36.1 (c = 0.10, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.31–7.25 (m, aromatic, 20 H), 6.50
(s, 1 H, 1-H), 4.75 (d, J = 11.4 Hz, 1 H), 4.66–4.63 (m, 3 H), 4.60–
4.52 (m, 3 H), 4.39 (d, J = 11.7 Hz, 1 H), 4.34–4.24 (m, 3 H), 3.94
(t, J = 5.4 Hz, 1 H), 3.76 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 143.6 (C-1), 138.3, 138.2, 137.88, 137.85, 128.6, 128.3,
128.2, 128.1, 128.0, 127.75, 127.73, 127.6, 127.5, 127.4 (Caryl), 109.5
(C), 76.4 (OCH), 74.0 (OCH), 73.7 (OCH),73.3 (OCH2), 72.9
(OCH2 ),72.6 (OCH2 ), 70.8 (OCH2 ) 68.1 (OCH2 ), 67.5
Prop-2-ynyl 3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-α-D-lyxo-
hexopyranoside (8d): Compound 8d (0.165 g, 83% yield) was ob-
tained by treatment of ether 6d (0.200 g, 0.413 mmol) with anhyd.
InCl3 (0.018 g, 0.082 mmol) over 10 min. Colorless liquid. [α]2D8
=
+20.8 (c = 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.36–
7.20 (m, aromatic,15 H), 5.45 (s, 1 H, 1-H), 5.38 (s, 1 H), 5.31 (s,
1 H), 4.90 (d, J = 12.0 Hz, 1 H), 4.71 (d, J = 12.0 Hz, 1 H), 4.64
(d, J = 12.0 Hz, 1 H), 4.61 (d, J = 12.0 Hz, 1 H), 4.46 (d, J =
12.0 Hz, 1 H), 4.44–4.37 (m, 2 H), 4.23 (m, 2 H), 4.09 (t, J =
6.6 Hz, 1 H), 3.98 (m, 1 H), 3.54 (m, 2 H), 2.39 (t, J = 2.4 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3) δ = 140.0 (C-2), 138.5, 138.3,
137.9, 128.4, 128.38, 128.34, 128.1, 127.9, 127.7, 127.6, 127.55,
127.51, 127.0 (Caryl), 112.4 (=CH2), 100.1 (C-1), 79.0 (C), 78.0
(=CH), 75.2 (OCH),74.5 (OCH2), 74.0 (OCH2), 73.4 (OCH2), 71.6
(OCH2), 71.1 (OCH), 69.1 (OCH2), 54.0 (OCH2) ppm. IR (KBr):
(OCH ) ppm. IR (KBr): ν = 2860, 1664, 1456, 1361, 1169, 1067,
˜
2
740, 697 cm–1. HRMS (ESI): calcd. for C35H36NaO5 [M + Na]+
559.2460; found 559.2467.
General Procedure for InCl3-Mediated [1,3]-Migrations in Glycal
Ethers 6 and 7 to form 8 and 9: Glycal ether 6 or 7 (1 mmol) was
dissolved in dry CH2Cl2 (5 mL) and dried with activated molecular
sieves (4 Å) in order to remove any moisture if present. The solu-
tion was then transferred by syringe to a dry three-necked round-
bottomed flask (flame-dried and cooled under argon). Anhydrous
InCl3 (0.2 mmol) was added to the reaction mixture in one lot, and
the reaction was allowed to proceed under argon. After 10 min,
the reaction mixture was quenched with water and extracted with
chloroform (3ϫ50 mL). The combined organic layer was washed
with water, dried with sodium sulfate, filtered, and concentrated.
The crude product was purified by column chromatography with
hexane/ethyl acetate (5:1) mixture as an eluent to provide 2-C-
methylene glycosides 8 or 9, respectively.
ν = 2919, 2861, 1636, 1455, 1358, 1092, 1028, 740, 696 cm–1
.
˜
HRMS (ESI): calcd. for C31H32NaO5 [M + Na]+ 507.2140; found
507.2139.
(2Ј,2Ј-Dimethoxy)ethyl 3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-
α-D-lyxo-hexopyranoside (8e): Compound 8e (0.18 g, 64% yield)
was obtained by treatment of ether 6e (0.280 g, 0.524 mmol) with
anhyd. InCl3 (0.022 g, 0.104 mmol) over 10 min. Colorless liquid.
[α]2D8 = +9.3 (c = 0.6, CHCl3). 1H NMR (300MHz, CDCl3): δ =
7.36–7.21 (m, aromatic, 15 H), 5.41 (s, 1 H, 1-H), 5.26 (s, 1 H),
5.22 (s, 1 H), 4.89 (d, J = 11.7 Hz, 1 H), 4.70 (d, J = 12.0 Hz, 1
H), 4.63–4.57 (m, 2 H), 4.53 (t, J = 5.4 Hz, 1 H), 4.48–4.37 (m, 3
H), 4.15 (t, J = 6.3 Hz, 1 H), 3.98 (m, 1 H), 3.66 (dd, J = 11.1,
6.3 Hz, 1 H), 3.59–3.49 (m, 3 H), 3.35 (s, 3 H, OCH3), 3.32 (s, 3
H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.6 (C-2),
138.6, 138.4, 138.0, 128.48, 128.44, 128.3, 128.1, 127.8, 127.7,
127.5, 127.1 (Caryl), 111.9 (=CH2), 102.6 (C-1), 101.9 (OCH), 78.0
(OCH), 75.3 (OCH), 74.0 (OCH2), 73.4 (OCH2), 71.6 (OCH2), 70.8
(OCH), 69.4 (OCH), 66.8 (OCH2 ), 53.9 (OCH3 ), 53.7
Methyl 3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-α-D-lyxo-hexo-
pyranoside (8a): Compound 8a (0.22 g, 88% yield) was obtained by
treatment of ether 6a (0.250 g, 0.54 mmol) with anhyd. InCl3
(0.022 g, 0.108 mmol) over 10 min. Colorless liquid. [α]2D8 = +5.6 (c
= 0.53, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.36–7.23 (m,
aromatic, 15 H), 5.43 (s, 1 H), 5.28 (s, 1 H), 5.10 (s, 1 H, 1-H), 4.91
(d, J = 11.7 Hz, 1 H), 4.72 (d, J = 12.0 Hz, 1 H), 4.65 (d, J =
13.5 Hz, 1 H), 4.61 (d, J = 13.5 Hz, 1 H), 4.45 (d, J = 11.7 Hz, 1
(OCH ) ppm. IR (KBr): ν = 2918, 1633, 1496, 1454, 1403, 1358,
˜
3
1325, 1192, 1107, 1072, 1031, 973, 919, 738, 697 cm–1. HRMS
(ESI): calcd. for C32H38NaO7 [M + Na]+ 557.2515; found 557.2540.
H), 4.43–4.39 (m, 2 H), 4.09 (t, J = 6.3 Hz, 1 H), 3.97 (m, 1 H), 2Ј,3Ј-Epoxypropyl 3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-α-D-
3.62–3.54 (m, 2 H), 3.38 (s, 3 H, OMe) ppm. 13C NMR (75 MHz,
CDCl3): δ = 140.7 (C-2), 138.5, 138.3, 138.0, 128.4, 128.3, 128.2,
lyxo-hexopyranoside (8f): Compound 8f (0.19 g, 70% yield) was ob-
tained by treatment of ether 6f (0.270 g, 0.53 mmol) with anhyd.
4612
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4607–4614

InCl3-Catalyzed Rapid 1,3-Alkoxy Migration in Glycal Ethers
InCl3 (0.022 g, 0.106 mmol) over 10 min. Colorless liquid; the spec-
troscopic data and specific rotation reported are for a 1:1 mixture
of diastereomers. [α]2D8 = +7.5 (c = 0.4, CHCl3). 1H NMR
(300MHz, CDCl3): δ = 7.37–7.21 (m, aromatic, 30 H) 5.42 (s, 2
H),5.27 (s, 2 H), 5.24 (s, 1 H), 5.23 (s, 1 H), 4.90 (d, J = 11.7 Hz,
2 H), 4.73–4.58 (m, 6 H), 4.50–4.37 (m, 6 H), 4.14 (d, J = 4.2 Hz,
2 H), 3.97–3.69 (m, 4 H), 3.63–3.47 (m, 6 H), 3.18–3.16 (m, 2 H),
2.77–2.73 (m, 2 H), 2.58–2.55 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3) δ = 140.4 (C-2), 138.5, 138.3, 138.0, 128.3, 128.0, 127.6,
127.5, 127.0 (Caryl), 111.9 (2ϫ=CH2), 101.8 (C-1), 101.5 (C-1), 77.9
(OCH), 75.3 (OCH), 74.0 (OCH2), 73.3 (OCH2), 71.6 (OCH2), 70.8
(OCH), 70.7 (OCH), 69.4 (OCH2), 69.2 (OCH2), 68.3 (OCH2), 67.5
Supporting Information (see also the footnote on the first page of
this article): Spectral data for compounds 6d, 8b, 8g, 9a, 9c, 14, 15
1
(p. S4–S6), copies of H and 13C NMR spectra (p. S7–S52).
Acknowledgments
We are grateful to the Council of Scientific and Industrial Re-
search, New Delhi, India for financial support. PN thanks CSIR,
India and IIT Delhi for a research fellowship. We also thank Dr.
N. Pant, Department of Chemistry, IIT-Delhi for his assistance in
performing AM1 calculations.
(OCH ), 50.5 (OCH), 50.2 (OCH), 44.5 (OCH ) ppm. IR (KBr): ν
˜
2
2
= 2919, 2861, 1635, 1491, 1456, 1358, 1249, 1206, 1092, 740,
697 cm–1. HRMS (ESI): calcd. for C31H34NaO6 [M + Na]+
525.2253; found 525.2255.
[1] For very recent reviews on glycosylation methods see: a)
A. F. G. Bonget, A. V. Demchenko, Carbohydr. Res. 2007, 342,
374–406; b) P. Fügedi, in Organic Chemistry of Sugars, CRC
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2Ј,3Ј-Epoxypropyl 3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-α-D-
arabino-hexopyranoside (9b): Compound 9b (0.130 g, 56% yield)
was obtained by treatment of allyl ether 7b (0.230 g, 0.45 mmol)
with anhyd. InCl3 (0.020 g, 0.090 mmol) over 10 min. Colorless li-
quid; the spectroscopic data and specific rotation reported are for
a 1:1 mixture of diastereomers. [α]2D8 = +10.5 (c = 0.40, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.41–7.16 (m, aromatic, 30 H) 5.33
(s, 2 H), 5.23–5.19 (m, 4 H), 4.89 (d, J = 10.8 Hz, 2 H),4.76 (m, 4
H), 4.62–4.44 (m, 8 H), 3.98 (m, 2 H), 3.88–3.49 (m, 10 H), 3.20–
3.19 (m, 2 H), 2.81 (t, J = 5.4 Hz, 2 H), 2.79–2.61 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3) δ = 141.9 (C-2), 138.2, 138.0, 128.7,
128.5, 128.3, 128.3, 127.9, 127.8, 127.6 (Caryl), 111.1 (2ϫ=CH2),
101.6 (C-1), 101.5 (C-1), 81.0 (OCH), 77.9 (OCH), 75.0 (OCH2),
73.5 (OCH2), 73.46 (OCH2), 73.43 (OCH2), 71.78 (OCH2), 71.70
(OCH), 68.8 (OCH2), 68.7 (OCH), 68.3 (OCH2), 67.4 (OCH2), 50.5
(OCH), 50.2 (OCH), 44.67 (OCH2), 44.62 (OCH2) ppm. IR (KBr):
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[14] For a very recently reported AuCl3-catalyzed Ferrier-type re-
arrangement of 2-C-(propargyloxy)-methylglycals see: S. Kash-
yap, S. R. Vidadala, S. Hotha, Tetrahedron Lett. 2007, 48,
8960–8962.
ν = 2921, 2862, 1633, 1455, 1359, 1258, 1208, 1105, 1029, 740,
˜
697 cm–1. HRMS (ESI): calcd. for C31H34NaO6 [M + Na]+
525.2253; found 525.2259.
3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-α-
3,4,6-Tri-O-benzyl-2-deoxy-2-C-methylene-α-
D
-lyxo-hexopyranosyl
D-lyxo-hexopyranoside
(11): Alcohol 4 (0.280 g, 0.673 mmol) was dissolved in dry CH2Cl2
(4 mL), and the mixture was dried with activated molecular sieves
(4 Å) in order to remove any moisture if present. The solution was
then transferred by syringe to a dry three-necked round-bottomed
flask (flame-dried and cooled under argon). Anhydrous InCl3
(0.028 g, 0.134 mmol) was added to the mixture, and the reaction
was allowed to proceed under argon. After 10 min, the reaction
mixture was quenched with water and extracted with chloroform
(3ϫ50 mL). The combined organic layer was washed with water,
dried with sodium sulfate, filtered, and concentrated. The crude
product was purified by column chromatography with a hexane/
ethyl acetate (5:1) mixture as an eluent to provide compound 11
(0.140 g, 80% yield) as a colorless liquid. [α]2D8 = +33.7 (c = 0.64,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.41–7.26 (m, aromatic,
15 H), 5.56 (s, 1 H), 5.39 (s, 1 H), 5.32 (s, 1 H), 4.93 (d, J = 12.0 Hz,
1 H), 4.69 (d, J = 12.0 Hz, 1 H), 4.66 (d, J = 12.0 Hz, 1 H), 4.62
(d, J = 12.0 Hz, 1 H), 4.450 (d, J = 11.7 Hz, 1 H), 4.43 (d, J =
11.7 Hz, 1 H), 4.34 (d, J = 2.1 Hz, 1 H), 4.12 (t, J = 6.6 Hz, 1 H),
4.01 (d, J = 1.8 Hz, 1 H), 3.59–3.56 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 140.3 (C-2), 138.5, 138.3, 138.0, 128.7,
128.5, 128.3, 128.1, 127.6, 127.57, 127.51, 127.0 (Caryl), 111.4
(=CH2), 97.04 (C-1), 77.8 (OCH), 75.2 (OCH), 74.0 (OCH2), 73.3
(OCH2), 71.4 (OCH2), 71.2 (OCH), 69.2 (OCH2) ppm. IR (KBr):
[15] One difficulty often encountered by us is the purification of 2-
C-(acetoxylmethyl)-glycals 3. They tend to rearrange or decom-
pose during chromatographic purification over silica gel, some-
times resulting in poor yields. If purified very carefully, they
do not have shelf-lives of more than a couple of days even at
low temperatures; see also ref. 16.
[16] Such a rearrangement on furanose-derived 2-C-(acetoxyme-
thyl)-glycals has already been reported. See: a) J. Wolf, C. Mon-
neret, R. Pontikis, J.-C. Florent, Eur. J. Org. Chem. 1998, 2417–
2423; b) R. Pontikis, J. Wolf, C. Monneret, J.-C. Florent, Tetra-
hedron Lett. 1995, 36, 3523–3526.
ν = 2918, 2864, 1642, 1491, 1455, 1358, 1246, 1208, 1095, 956,
˜
740, 696 cm–1. HRMS (ESI): calcd. for C56H58NaO9 [M + Na]+
897.3979; found 897.3998.
Eur. J. Org. Chem. 2008, 4607–4614
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4613

P. Nagaraj, N. G. Ramesh
FULL PAPER
[17] For reviews: a) F. Fringuelli, O. Piermatti, F. Pizzo, L. Vaccaro,
Curr. Org. Chem. 2003, 7, 1661–1689; b) R. Ghosh, Ind. J.
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2000, 2347–2356.
[18] For some recent examples see: a) J. S. Yadav, B. V. S. Reddy,
M. Sreenivas, G. Satheesh, Synthesis 2007, 1712–1716; b) S. K.
Das, K. A. Reddy, V. L. N. R. Krovvidi, K. Mukkanti, Car-
bohydr. Res. 2005, 340, 1387–1392; c) S. B. Boga, K. K. Balas-
ubramanian, ARKIVOC 2004, VIII, 87–102; d) R. Ghosh, A.
Chakroborty, S. Maiti, ARKIVOC 2004, XIV, 1–9.
I. A. I. Ali, E. S. H. El Ashry, R. R. Schmidt, Eur. J. Org.
Chem. 2003, 4121–4131; e) A. V. Demchenko, E. Rousson, G.-
J. Boons, Tetrahedron Lett. 1999, 40, 6523–6526; f) J. Hirsch,
M. Koósˇ, P. Kovácˇ, Carbohydr. Res. 1998, 310, 145–149 and
references cited in these articles.
[25] Geometry optimization and AM1 calculations were performed
with HyperChem. version 7.5: HyperChem professional 7.5.
Hypercube, Inc. 1115 NW 4th St., Gainesville, FL 32601, USA.
The minimum energies reported for compound 6a and cation
II were based on conformational search.
[19] Irradiation of the signal at δ = 5.10 ppm due to H-1 of 8a [26] For some very recent reports on the synthesis and structural
resulted in an enhancement of the signal due to one of the exo-
methylene olefinic protons at δ = 5.28 ppm and vice versa. This
confirms that that anomeric proton of 8a is in the equatorial
position and that the methoxy group is in the axial position.
For details of the assignment of anomeric configurations of
similar compounds by NOE experiments, see: N. G. Ramesh,
K. K. Balasubramanian, Tetrahedron 1995, 51, 255–272.
[20] Unlike the 2-C-(acetoxymethyl)-glycals 3, all ethers 6a–g, 7a–c
reported in this manuscript are relatively stable and can be
stored in a refrigerator for longer times.
aspects of trehalose analogues see: a) H.-M. Kim, Y.-K. Chang,
S.-I. Ryu, S.-G. Moon, S.-B. Lee, J. Mol. Catal. B 2007, 49,
98–103; b) R. Namme, T. Mitsugi, H. Takahashi, S. Ikegami,
Eur. J. Org. Chem. 2007, 3758–3764; c) F. L. Lin, H. H. Van,
C. R. Bertozzi, Carbohydr. Res. 2007, 342, 2014–2030; d) F. Al-
berto, V. A. Chapa, X. Chen, A. J. Diaz, P. S. Cremer, J. Am.
Chem. Soc. 2007, 129, 10567–10574.
[27] G. Descotes, J.-C. Martin, Carbohydr. Res. 1977, 56, 168–172.
[28] Guthrie et al. obtained an anomeric mixture of 14 under the
conditions reported by Descotes in ref. 27. Please see: R. D.
Guthrie, R. W. Irvine, Carbohyr. Res. 1980, 82, 225–236.
[29] For the synthesis of 14 by a Ferrier-type rearrangement, see:
a) S. Kashyap, S. Hotha, Tetrahedron Lett. 2006, 47, 2021–
2023; b) H. Kim, H. Men, C. Lee, J. Am. Chem. Soc. 2004,
126, 1336–1337.
[30] For an InCl3-catalyzed Ferrier-type rearrangement of an allylic
carbonate to 15, within 2 min under microwave irradiation at
150 °C, see H.-C. Lin, C.-C. Chang, J.-Y. Chen, C.-H. Lin, Tet-
rahedron Asymm. 2005, 16, 297–301.
[21] While our work was in progress, 2-C-(propargyloxymethyl)-gal-
actal (6d) was reported by Hotha et al.; see ref. 14.
[22] Alcohols 4 and 5 were each prepared in two steps from the
readily available tri-O-benzyl--galactal and tri-O-benzyl--
glucal, respectively, by Vilsmeier–Haack formylation followed
by reduction. See: N. G. Ramesh, K. K. Balasubramanian, Tet-
rahedron Lett. 1991, 32, 3875–3878 and also refs. 11–14, 19.
[23] For InCl3-promoted rearrangements of epoxides to carbonyl
compounds: B. C. Ranu, U. Jana, J. Org. Chem. 1998, 63,
8212–8216.
[24] a) R. N. de Oliveira, A. C. N. de Melo, R. M. Srivastava, D.
Sinou, Heterocycles 2006, 68, 2607–2613; b) N. Ustyuzhanina,
B. Komarova, N. Zlotina, V. Krylov, A. Gerbst, Y. Tsvetkov,
N. Nifantiev, Synlett 2006, 921–923; c) C. de Meo, M. N. Ka-
mat, A. V. Demchenko, Eur. J. Org. Chem. 2005, 706–711; d)
[31] a) A. A.-H. Abdel-Rahman, G. A. Winterfeld, M. Takhi, R. R.
Schmidt, Eur. J. Org. Chem. 2002, 713–717; b) B. Shanmuga-
sundaram, A. K. Bose, K. K. Balasubramanian, Tetrahedron
Lett. 2002, 43, 6795–6798.
Received: May 7, 2008
Published Online: August 5, 2008
4614
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4607–4614