Facile synthesis of enantiomerically pure 2- and 2,3-disubstituted furans catalysed by mixed lewis acids: An easy route to 3-iodofurans and 3-(hydroxymethyl)furans

Article abstract of DOI:10.1002/chem.200900007

Simple and efficient syntheses, catalysed by a mixed Lewis acid system (ZrCl₄/ZnI₂), of enantiomerically pure 2- and 2,3-disubstituted furan derivatives-including important synthons such as 3-iodofuran and 3-(hydroxymethyl)furan deri

Full text of DOI:10.1002/chem.200900007

FULL PAPER
DOI: 10.1002/chem.200900007
Facile Synthesis of Enantiomerically Pure 2- and 2,3-Disubstituted Furans
Catalysed by Mixed Lewis Acids: An Easy Route to 3-Iodofurans and
3-(Hydroxymethyl)furans
Mohammad Saquib,[a] Irfan Husain,[a] Brijesh Kumar,[b] and Arun K. Shaw*[a]
Dedicated to Professor Sunil K. Talapatra on the occasion of his 75th birthday
Abstract: Simple and efficient syntheses, catalysed by a mixed Lewis acid system
(ZrCl4/ZnI2), of enantiomerically pure 2- and 2,3-disubstituted furan derivatives—
Keywords: asymmetric synthesis ·
including important synthons such as 3-iodofuran and 3-(hydroxymethyl)furan de-
chiral pool · furans · Lewis acids ·
rivatives—from commercially available 3,4,6-tri-O-acetyl-d-glucal are described.
Morita–Baylis–Hillman adducts
The transformation is achieved through a synergistic interaction between ZrCl4
and ZnI2 in catalytic amounts.
Introduction
tant enantiomerically pure compounds from sugars,[3] we
were interested in developing the synthesis of enantiomeri-
cally pure 2,3-disubstituted furans.[4]
Substituted furan motifs are present in numerous natural
products and synthetic materials, including industrial inter-
mediates, pharmaceuticals, insecticides, flavours and fragran-
ces. In addition, they are widely used as precursors in syn-
thetic chemistry.[1] Consequently, a large number of methods
for synthesizing substituted furans are known.[1a,b] Although
these methods have proved quite useful, they still have their
limitations, and so the development of newer methods that
allow for facile synthesis of substituted furans under mild
conditions, from readily accessible starting materials and
with inexpensive catalysts still remains an exceedingly active
research domain. A great deal of emphasis is at present
being placed on the synthesis of organic compounds from
renewable sources such as carbohydrates rather than from
petroleum.[2]
Our idea emanated from literature reports on a wide
array of natural products and compounds of biological sig-
nificance containing 2- or 2,3-disubstituted furans as distinc-
tive structural features.[5] Synthesis of enantiomerically pure
furans is a challenging job;[4a,b] moreover, introduction of
substitution at C-3 in a furan ring is a difficult proposition.[6]
In this context we have devised an efficient and a versatile
method for accessing various enantiomerically pure 2- and
2,3-disubstituted furans (Figure 1).
In continuation of our ongoing programme directed to-
wards the synthesis of biologically and synthetically impor-
Figure 1. Some representative examples of enantiomerically pure 2,3-dis-
ubstituted furans synthesized by our methodology.
[a] M. Saquib, I. Husain, Dr. A. K. Shaw
Division of Medicinal and Process Chemistry
Central Drug Research Institute
Lucknow-226001 (India)
Results and Discussion
E-mail: akshaw55@yahoo.com
[b] Dr. B. Kumar
Synthesis of enantiomerically pure 2-substituted furans: We
found a number of literature reports describing the synthesis
of 2-(d-glycero-1,2-dihydroxyethyl)furan (I),[7] an important
chiral building block, from unprotected glucal and galactal.[8]
Sophisticated Analytical Instrumentation Facility
Central Drug Research Institute, Lucknow-226001 (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900007.
Chem. Eur. J. 2009, 15, 6041 – 6049
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6041

have similar properties and ZrCl4 is cheaper than HfCl4 we
also tried ZrCl4/ZnI2 to examine its effect on the reaction.
The above experiment was thus conducted in the presence
of ZrCl4/ZnI2 (5:10 mol%), and provided I as the exclusive
product in 82% yield (Table 1).
This turned out to be the best reaction condition for car-
rying out this transformation. When the same reaction was
conducted at 508C with the other parameters constant the
reaction time was reduced to 10 min but the yield was de-
creased to 70% (Table 1). When the same reaction was con-
ducted in the presence either of HfCl4 or of ZnI2 alone no
reaction occurred either at room temperature or at 508C
(Table 1). Likewise, no reaction was possible in the presence
of ZrCl4 alone at room temperature, although at 508C the
reaction did occur, albeit very slowly, to furnish I in 43%
yield in 3 h (Table 1). Here it can be presumed from the
above results that some kind of synergistic effect of the
HfCl4/ZnI2 or ZrCl4/ZnI2 systems is causing the novel trans-
formation to proceed very rapidly, as we had also observed
in our earlier work,[11] although the exact mechanistic path-
way is not yet clear.
Next, to study the scope and limitations of this methodol-
ogy for the synthesis of furan I, a few more experiments
with 2,3-dideoxy-hex-2-enopyranosides containing different
alkoxy substituents at C-1 were performed (Table 2). In all
the cases the reactions proceeded smoothly and the desired
furan was obtained as the sole product. Replacement of
OiPr by OMe thus did not bring about any change in the
course of the reaction or the yield of the desired product I.
Here, though, the furan I was obtained in just 25 min in
83% yield. However, the reaction took a slightly longer
time to go to completion (45 min) when OiPr was replaced
by Oiamyl at C-1, with a decrease in the yield (71%).
However, only a limited number of reports concerning the
production of I or its protected derivatives from 2,3-di-
deoxy-hex-2-enopyranosides are available.[9] All of these lit-
erature reports described routes either only to 2-substituted
furan I or to some of its protected derivatives from 2,3-di-
deoxy-hex-2-enopyranoside. We believed that if suitable
conditions were optimized to provide I from the glycal-de-
rived isopropyl 2,3-dideoxy-a-d-erythro-hex-2-enopyrano-
side (1a), the same reaction conditions should be translata-
ble to the production of our targeted 2,3-disubstituted
furans III from II.
We therefore carried out some model experiments to
study the formation of enantiomerically pure 2-substituted
furans such as I from the hex-2-enopyranoside (Table 1).
Table 1. Optimization for the preparation of furandiol I from hex-2-eno-
pyranoside 1a.
Entry[a]
Catalyst(s) (mol%)
T
t [min]
Yield (I) [%]
1
2
3
4
5
6
7
8
9
HfCl4 (5), ZnI2 (10)
HfCl4 (5), ZnI2 (10)
ZrCl4 (5), ZnI2 (10)
ZrCl4 (5), ZnI2 (10)
HfCl4 (5)
ZnI2 (10)
HfCl4 (5)
ZnI2 (10)
ZrCl4 (5)
RT
508C
RT
508C
RT
RT
508C
508C
RT
60
20
30
10
30
30
30
30
30
180
69
65
82
70
no reaction
no reaction
no reaction
no reaction
no reaction
43
Table 2. Synthesis of furan I from different hex-2-enopyranosides 1.
10
ZrCl4 (5)
508C
[a] THF as a solvent and 0.5 mmol of 1a were used in all the experi-
ments.
Entry
Hex-2-enopyranoside
Reaction conditions
Yield (I) [%]
We first treated a solution of 1a in THF with iodine at
room temperature, which furnished a mixture of products
(TLC). This unsuccessful result might be attributable to the
joint participation of both 6-OH and 4-OH as internal nu-
cleophiles attacking at the anomeric carbon in SN2 fashion,
resulting in a mixture of products.[10]
1
2
3
1a
1b
1c
RT, 30 min
RT, 25 min
RT, 45 min
82
83
71
At this stage we decided that other Lewis acids should be
investigated for catalysis of the transformation of 1a to I.
Recently we reported the preparation of a,b-unsaturated al-
dehydes by Perlin hydrolysis of acyl- or alkyl-protected gly-
cals with catalysis by HfCl4 and ZnI2 in place of toxic
HgSO4.[11] For this current study we preferred to explore the
utility of HfCl4/ZnI2. When 1a in THF was treated with
HfCl4/ZnI2 (5:10 mol%) at RT, I was obtained exclusively in
69% yield in 60 min (Table 1). Because ZrCl4 and HfCl4
A few reactions were also conducted with hex-2-enopyra-
nosides possessing different substituents at C-6 (Scheme 1).
Here the reactions also occurred in a facile manner with the
formation of the desired furans in high yields (Scheme 1).[12]
Synthesis of enantiomerically pure 2,3-disubstituted furans:
Once the methodology for the synthesis of 2-substituted
furans was established, we focused our attention on exploit-
ing the synthetic protocol for the construction of targeted
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Chem. Eur. J. 2009, 15, 6041 – 6049

Enantiomerically Pure 2- and 2,3-Disubstituted Furans
FULL PAPER
ity of the above method for the
synthesis of 2,3-disubstituted
furans, we examined the con-
struction of two other 2,3-di-
deoxy-hex-2-enopyranoside
types with reactive functionali-
ties at C-3 and their conver-
sions into the corresponding
furans. A literature survey re-
vealed that 3-iodofurans[6a,17]
and 3-(hydroxymethyl)furans[18]
are two very useful classes of
furan-based building block.
Keeping the synthetic impor-
tance of these two furan classes
in mind, we decided to prepare
3-iodo- and 3-hydroxymethyl-
substituted 2,3-dideoxy-hex-2-
enopyranosides and to convert
them into the corresponding 3-
iodo- and 3-hydroxymethyl-sub-
stituted furan derivatives by
Scheme 1. Synthesis of furans from differently C-6-substituted hex-2-enopyranosides.
2,3-disubstituted furans, working on the premise that any C-
3-substituted 2,3-dideoxy-hex-2-enopyranoside could like-
wise be converted into a furan. We therefore report here an
efficient and simple strategy to provide enantiomerically
pure 2,3-disubstituted furans III from precursors II under
mild reaction conditions. Treatment of the various C-3-alkyl-
aryl- and -alkyl-substituted 2,3-dideoxy-hex-2-enopyrano-
sides 11a–f—obtained from the corresponding MBH
(Morita–-Baylis–Hillman) adducts 10a–f[3b]—in THF in the
presence of ZrCl4/ZnI2 (5:10 mol%) at 608C led to the for-
mation of furanmethanol derivatives 12a–f in very good
yields in only 1–2.5 h (Table 3).
using the synthetic strategy described above. a-Iodination of
methyl 6-O-trimethylacetyl-2,3-dideoxy-a-d-glycero-hex-2-
enopyranosid-4-ulose (16)[19] was thus carried out to afford
methyl 6-O-trimethylacetyl-3-iodo-2,3-dideoxy-a-d-glycero-
hex-2-enopyranosid-4-ulose (17) (Scheme 3). The a-iodo de-
rivative 17 was then reduced under Luche condition to fur-
nish a 1:1 isomeric mixture of a-iodo-2,3-dideoxy-hex-2-eno-
pyranosides. The isomeric mixture was utilized without fur-
ther purification to provide the enantiomerically pure 3-io-
dofuran derivative 18 as a single product in 78% yield in
three steps from 16 (Scheme 3).
The synthesis of the enantiomerically pure 3-(hydroxyme-
thyl)furan derivative 20 was achieved from methyl 6-O-tri-
methylacetyl-3-(hydroxymethyl)-2,3-dideoxy-a-d-glycero-
hex-2-enopyranosid-4-ulose (19). This compound was pre-
pared through MBH chemistry, by treatment of a solution
of 16 in THF with aqueous formaldehyde (37%) in the pres-
ence of DMAP.[20] Reduction of 19 under Luche condition
and subsequent treatment of a THF solution of the crude
reduced product with ZrCl4/ZnI2 (5:10 mol%) led to the for-
mation of 20 in good yield (Scheme 3). It can be argued
here that the easy syntheses of the 3-iodofuran 18 and the 3-
(hydroxymethyl)furan 20 clearly show the versatility of the
present methodology.
Likewise, the methyl 6-azido-2,3,6-trideoxy-hex-2-enopyr-
anoside 14 was also completely converted under identical
reaction conditions into the corresponding azido-substituted
furanmethanol 15 in 74% yield in 1 h (Scheme 2).
It is worth mentioning here that substituted 3-aryl- or -al-
kylfuranmethanol derivatives are used as intermediates in
organic syntheses of many biologically significant com-
pounds.[13] They also serve as convenient precursors for the
synthesis of aryl-/alkyl-substituted furanmethanes[6b,14] and 3-
acylfurans.[5e,15] The synthesis of enantiomerically pure 3-
aryl- and -alkyl-substituted furanmethanols is a challenging
job.[5d] They are usually accessed through 3-lithiofurans, 3-
halofurans or furan-3-carbaldehyde, which are difficult to
synthesize and in some cases difficult to use.[5d] In contrast,
the current methodology provides a simple and efficient
method to obtain enantiomerically pure 3-substituted aryl-/
alkylfuranmethanols. To the best of our knowledge this is
the first report on transformations of MBH adducts[16] into
enantiomerically pure 2,3-disubstituted furans with well-de-
fined chiral centres.
Conclusions
In summary, we have developed an efficient and practical
method, based on the 2-(d-glycero-1,2-dihydroxyethyl)furan
core I, for the transformation of sugars into enantiomeri-
cally pure 2,3-disubstituted furans with well-defined chiral
centre(s) in very good yields, which should find wide appli-
cation for the synthesis of natural products and compounds
of biological importance. To the best of our knowledge this
Synthesis of enantiomerically pure 3-iodofurans and 3-(hy-
droxymethyl)furans: In order to show the general applicabil-
Chem. Eur. J. 2009, 15, 6041 – 6049
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6043

A. K. Shaw et al.
Table 3. Synthesis of enantiomerically pure 2,3-disubstituted furans.
adducts into furans for the first time. The use of catalytic
amounts of inexpensive ZrCl4/ZnI2, mild reaction conditions
and easy workup procedures are the key features of the
method. The crude product was found to be as pure as
column-pure product (TLC).[21] In addition, the method was
also applied to the synthesis of the enantiomerically pure 3-
iodofuran derivative 18, the synthesis of which is a methodo-
logical challenge.[17a] Further functionalization of enantio-
merically pure 3-iodofuran and 3-(hydroxymethyl)furan de-
rivatives of types 18 and 20, respectively, can be accom-
plished in various ways. They can also be utilized as building
synthons in diversity-oriented-synthesis (DOS).[22] Work to-
wards this end is currently underway in our laboratory.
Entry Hex-2-eno-pyranoside t [min] Furan
Yield [%]
1
2
3
90
86
84
79
110
Experimental Section
General remarks: Organic solvents were dried by standard methods. All
products were characterized by 1H NMR, 13C NMR, DEPT pulse se-
quence, two-dimensional homonuclear COSY (Correlation Spectrosco-
py), HSQC (Heteronuclear Single Quantum Correlation), HMBC (Het-
eronuclear Multiple Bond Correlation), IR, MS (ESI), HRMS (EI) and
HRMS (DART). Analytical TLC was performed with 2.5ꢁ5 cm plates
coated with a 0.25 mm thickness of silica gel (60 F-254), and visualization
was accomplished with CeSO4 or H2SO4/EtOH (10%) and subsequent
charring over a hot plate. Column chromatography was performed with
silica gel (60–120, 100–200). NMR spectra were recorded on Bruker
Avance DPX 200FT, Bruker Robotics and Bruker DRX 300 and 400
spectrometers at 200/300 MHz (1H) and 50/75 MHz (13C). Experiments
were recorded in CDCl3 or CDCl3+CCl4 at 258C. Chemical shifts are
given on the d scale. For 13C NMR reference, CDCl3 appeared at
77.10 ppm unless otherwise stated. IR spectra were recorded on Perkin–
Elmer 881 and Shimadzu FTIR-8210 PC spectrophotometers. Mass spec-
tra were recorded on a JEOL JMS-600H high-resolution spectrometer in
EI mode at 70 eV. Optical rotations were determined on an Autopol III
polarimeter (Rudolph Research) with a 1 dm cell and chloroform as sol-
vent; concentrations are in g/100 mL.
60
4
5
150
60
76
78
General reaction procedure for the preparation of furans from 2,3-di-
deoxy-hex-2-enopyranosides: ZrCl4 (5 mol%) and ZnI2 (10 mol%) were
added in succession to a stirred solution of the 2,3-dideoxy-hex-2-enopyr-
anoside in dry tetrahydrofuran (4–6 mL) and the reaction mixture was
stirred at the temperature and for the time specified. On completion of
the reaction (TLC), the mixture was quenched with water and extracted
with ethyl acetate (6ꢁ4 mL). The combined organic layers were washed
with brine, dried over Na2SO4 and concentrated under reduced pressure
to afford the crude product. The crude product was chromatographed to
afford pure compound.
6
120
74
Compound 4: Furan 4 was prepared
from 2,3-dideoxy-hex-2-enopyranoside
3 by the general reaction procedure
for the production of furans from 2,3-
dideoxy-hex-2-enopyranosides given
above, in 86% yield and as a syrup.
Rf =0.52 (n-hexane/ethyl acetate 3:2);
eluent for column chromatography n-
hexane/ethyl acetate 22:3; [a]D26
=
Scheme 2. Synthesis of azido-substituted furanmethanol 15 from 6-azido 2,3,6-trideoxy-hex-2-enopyranoside
14.
+40.0 (c=0.1, CHCl3); 1H NMR
(CDCl3, 300 MHz): d=7.39 (s, 1H; H-
5), 6.36–6.32 (m, 2H; H-4, H-3), 4.96
(d, J=2.2 Hz, 1H; H-1’), 4.37 (d, J=
5.7 Hz, 2H; H-2’a, H-2’b), 2.10 ppm (s, 3H; OCOCH3); 13C NMR
(CDCl3, 75 MHz): d=171.2 (OCOCH3), 152.8 (Cq; C-2), 142.5 (C-5),
110.3 (C-4), 107.2 (C-3), 66.5 (C-2’), 66.1 (C-1’), 20.8 ppm (OCOCH3); IR
(neat): n˜ =3408, 3020, 1731, 1224 cmÀ1; MS (ES): m/z: 188 [M+NH4]+,
is the first report on the synthesis of enantiomerically pure
2,3-disubstituted furans starting from hex-2-enopyranosides.
This method also demonstrates the transformation of MBH
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Enantiomerically Pure 2- and 2,3-Disubstituted Furans
FULL PAPER
21.7 (OCH
ACHTUGNTRENUN(GN CH3)2), 21.2 ppm (C-6); IR
(neat): n˜ =3424, 2258, 1641, 1382 cmÀ1
;
MS (ES): m/z: 215 [M+NH4]+, 179
[MÀH2O]+; HRMS (EI): m/z: calcd
for C10H16NO3 [M+H]+ 198.1130;
found 198.1116.
Compound 7: CeCl3·7H2O (186 mg,
0.5 mmol)
0.5 mmol) were added at 08C to
stirred solution of (340 mg,
and
NaBH4
(19 mg,
a
5
1.0 mmol) in ethanol (8 mL) and the
reaction mixture was stirred continu-
Scheme 3. Synthesis of 3-iodofurans and 3-(hydroxymethyl)furans.
ously for 50 min, with the temperature
of the reaction mixture being kept be-
tween 08C and 108C. After comple-
153 [M+HÀH2O]+; HRMS (EI): m/z: calcd for C8H9O3 [M+HÀH2O]+
tion of the reaction (TLC monitoring), excess NaBH4 was neutralized
with acetone and the solvent was removed (rotary evaporator) to afford
the crude product. NaN3 (325 mg, 5 mmol) was added to a DMF solution
(10 mL) of the dried crude product, and the reaction mixture was stirred
at 90–1008C for 2.5 h. The cooled reaction mixture was poured into an
excess of ice-cold water and extracted with dichloromethane (5ꢁ5 mL).
The combined organic layers were washed with brine, dried over Na2SO4
and concentrated under reduced pressure to yield the crude product,
which was purified by column chromatography to give pure compound 7
as a syrup (152 mg, 71%). Rf =0.62 (n-hexane/ethyl acetate 3:2); eluent
for column chromatography n-hexane/ethyl acetate 9:1; [a]3D1 =À44.70
(c=0.12, CHCl3); 1H NMR (CDCl3, 300 MHz): d=5.90 (d, J=10.1 Hz,
1H; H-3), 5.72 (td, J=10.1, 4.6, 2.3 Hz, 1H; H-2), 5.08 (s, 1H; H-1),
153.0511; found 153.0552.
Compound 5: Dry pyridine (6 mL) was added at À308C to a solution of
the ketone 2 (1.116 g, 6 mmol) in dry CH2Cl2 (15 mL), followed by drop-
wise addition, over 1 h, of
a solution of p-toluenesulfonyl chloride
(1.944 g, 10.2 mmol) in dry dichloromethane (5 mL). After addition was
complete, the reaction mixture was stirred at the same temperature for
an additional 1 h and finally kept in a refrigerator at 58C overnight. On
completion of reaction (TLC), the mixture was poured into ice-cold
water (excess) and the organic layer was separated. The aqueous layer
was extracted with dichloromethane (4ꢁ5 mL) and the combined organic
layers were washed successively with water and brine, dried over Na2SO4
and concentrated with co-distillation with toluene to remove pyridine
(rotary evaporator). Column chromatographic purification of the crude
product furnished pure compound 5 as a white solid (1.490 g, 73%). Rf =
0.58 (n-hexane/ethyl acetate 7:3); eluent for column chromatography n-
hexane/ethyl acetate 43:7); m.p. 61–648C; [a]D =À18.5 (c=0.2, CHCl3);
1H NMR (CDCl3, 300 MHz): d=7.78 (d, J=8.3 Hz, 2H; H-2’, H-6’), 7.34
(d, J=8.2 Hz, 2H; H-3’, H-5’), 6.82 (dd, J=10.3, 3.6 Hz, 1H; H-2), 6.05
(d, J=10.3 Hz, 1H; H-3), 5.30 (d, J=3.5 Hz, 1H; H-1), 4.67 (dd, J=6.0,
2.5 Hz, 1H; H-5), 4.49 (dd, J=10.8, 2.5 Hz, 1H; H-6a), 4.31 (dd, J=10.8,
4.07–3.98 (m, 2H; H-4, OCH
J=13.0, 2.7 Hz, 1H; H-6a), 3.45 (dd, J=13.0, 6.4 Hz, 1H; H-6b), 1.26 (d,
J=6.3 Hz, 3H; OCH(CH3)2), 1.17 ppm (d, J=6.1 Hz, 3H; OCH(CH3)2);
13C NMR (CDCl3, 75 MHz): d=132.6 (C-3), 127. 4 (C-2), 92.3 (C-1), 71.3
(C-5), 70.5 (OCH(CH3)2), 65.1(C-4), 52.0 (C-6), 23.5 and 21.8 ppm
(OCH
ACHTUGNERTN(NUNG CH3)2), 3.87–3.81 (m, 1H; H-5), 3.54 (dd,
G
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(CH3)2); IR (neat): n˜ =3421, 2102, 1030 cmÀ1; MS (ES): m/z: 252
[M+K]+,186 [M+HÀN2]+; HRMS (EI): m/z: calcd for C9H15N3O3 [M]+
213.1113; found 213.1118.
Compound 8: Furan 8 was obtained from 6 as a syrup in 89% yield by
the general reaction procedure given above for producing furans from
2,3-dideoxy-hex-2-enopyranosides. Rf =0.42 (n-hexane/ethyl acetate 3:2);
6.0 Hz, 1H; H-6b), 4.01 (pent., J=6.2 Hz, 1H; OCHACHTNUGTRNEG(UN CH3)2), 2.45 (s, 3H;
À
CH3 of OTs), 1.24 (d, J=6.2 Hz, 3H; OCH
N
6.2 Hz, 3H; OCH
A
eluent for column chromatography n-hexane/ethyl acetate 4:1; [a]D28
=
145.0 (ArCq; C-2), 132.7 (ArCq), 129.8 (C-2’, C-6’), 128.1 (C-3’, C-5’),
127.1 (C-3), 91.4 (C-1), 72.2 (C-5), 71.6 (OCH(CH3)2), 68.2(C-6), 23.2
+38.0 (c=0.1, CHCl3); 1H NMR (CDCl3, 300 MHz): d=7.40 (s, 1H; H-
5), 6.39–6.35 (m, 2H; H-3, H-4), 5.03 (d, J=3.1 Hz, 1H; H-1’), 2.88 (d,
J=5.97 Hz, 2H; H-2’), 2.83 ppm (brs, 1H; OH); 13C NMR (CDCl3+CCl4,
75 MHz): d=153.2 (Cq; C-2), 142.7 (C-5), 117.0 (Cq; CN), 110.6 (C-3),
107.4 (C-4), 63.7 (C-1’), 25.0 ppm (C-2’); IR (neat): n˜ =3413, 3021, 2260,
1216 cmÀ1; MS (ES): m/z: 160 [M+Na]+, 155 [M+NH4]+; HRMS (EI):
m/z: calcd for C7H8NO2 [M+H]+ 138.0555; found 138.0550.
A
ACHTUNGTRENNUNG
(CH3 of OTs), 21.8 and 21.7 ppm (OCHACHTNUTRGNEUNG(CH3)2); IR (KBr): n˜ =3446,
1695, 1651, 1350 cmÀ1
;
ESI-MS: m/z: 358 [M+NH4]+, 281 [M+HÀ
(CH3)2CHOH]+; HRMS (EI): m/z: calcd for C16H20O6S [M]+ 340.0981;
found 340.1007.
Compound 6: CeCl3·7H2O (186 mg, 0.5 mmol) and NaBH4 (19 mg,
0.5 mmol) were added at 08C to
a stirred solution of 5 (340 mg,
Compound 9: Furan 9 was obtained from 7 as a syrup in 82% yield by
the general reaction procedure given above for producing furans from
2,3-dideoxy-hex-2-enopyranosides. Rf =0.50 (n-hexane/ethyl acetate 4:1);
1.0 mmol) in ethanol (8 mL), and the reaction mixture was stirred contin-
uously for 50 min, with the temperature of the reaction mixture being
kept between 08C and 108C. After completion of the reaction (TLC
monitoring), excess NaBH4 was neutralized with acetone and the solvent
was removed under reduced pressure to afford the crude product. NaCN
(255 mg, 5 mmol) was added to a DMF (10 mL) solution of the dried
crude product, and the reaction mixture was stirred at 1008C to 1108C
for 4 h (TLC monitoring). The cooled reaction mixture was poured into
an excess of ice-cold water and extracted with dichloromethane (5ꢁ
5 mL). The combined organic layers were washed with brine, dried over
Na2SO4 and concentrated under reduced pressure to yield the crude
product, which was purified by column chromatography to give pure
compound 6 as a syrup (160 mg, 81%). Rf =0.35 (n-hexane/ethyl acetate
3:2); eluent for column chromatography n-hexane/ethyl acetate 4:1;
[a]2D6 =+24.5 (c=0.2, CHCl3); 1H NMR (CDCl3, 300 MHz): d=5.91 (d,
J=10.1 Hz, 1H; H-2), 5.74 (td, J=10.1, 2.3 Hz, 1H; H-2), 5.10 (s, 1H;
eluent for column chromatography n-hexane/ethyl acetate 23:2; [a]D31
=
1
+47.26 (c=0.15, CHCl3); H NMR (CDCl3, 300 MHz): d=7.38 (t, J=0.6,
0.5 Hz, 1H; H-5), 6.36–6.31 (m, 2H; H-3, H-4), 4.82 (dd, J=7.0, 4.7 Hz,
1H; H-1’), 3.60 (dd, J=12.6, 7.0 Hz, 1H; H-2’a), 3.52 ppm (dd, J=12.6,
4.7 Hz, 1H; H-2’b); 13C NMR (CDCl3, 75 MHz): d=153.2 (Cq; C-2),
142.5 (C-5), 110.4 (C-4), 107.3 (C-3), 67.0 (C-1’), 55.0 ppm (C-2’); IR
(neat): n˜ =3399, 2106, 1220 cmÀ1; MS (ES): m/z: 136 [M+HÀH2O]+;
HRMS (EI): m/z: calcd for C6H6N3O [M+HÀH2O]+ 136.0511; found
136.0539.
Compound 10 f: TiCl4 (3.75 mmol, 0.41 mL) was added dropwise at
À788C to
a stirred solution of tetrabutylammonium iodide (TBAI,
0.5 mmol, 185 mg) in dry CH2Cl2 (20 mL). After the system had been
stirred for two minutes, a mixture containing isopropyl 6-O-acetyl-2,3-di-
deoxy-a-d-glycero-hex-2-enopyranosid-4-ulose (2.5 mmol, 570 mg) and 3-
nitrobenzaldehyde (5 mmol, 755 mg) in dry dichloromethane (10 mL)
was added. The reaction mixture was allowed to warm slowly to À308C
and stirred for 5 h. A saturated aqueous solution of NaHCO3 was added,
and the resulting mixture was filtered through a celite pad. The organic
H-1), 4.08–4.00 (m, 2H; H-4, OCH
(dd, J=16.8, 3.3 Hz, 1H; H-6a), 2.66 (dd, J=16.8, 7.1 Hz, 1H; H-6b),
1.26 (d, J=6.2 Hz, 3H; OCH(CH3)2), 1.18 ppm (d, J=6.1 Hz, 3H; OCH-
ACHTUNGTRENNUNG
(CH3)2); 13C NMR (CDCl3, 75 MHz): d=132.4 (C-3), 127.2 (C-2), 117.4
ACHTUGNRTNE(NUNG CH3)2), 3.94–3.87 (m, 1H; H-5), 2.84
AHCTUNGTRENNUNG
(Cq; CN), 92.5 (C-1), 70.6 (OCH
ACHTUGNRTNE(NUNG CH3)2), 67.8 (C-5), 66.7 (C-4), 23.6 and
Chem. Eur. J. 2009, 15, 6041 – 6049
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6045

A. K. Shaw et al.
layer was separated from the filtrate, and the aqueous layer was extract-
ed with dichloromethane (5ꢁ5 mL). The organic layers were combined,
washed with brine solution and dried over Na2SO4. The crude product
obtained after evaporation of the solvent was chromatographed to yield
pure compound 10 f as a viscous oil (476 mg, 50%). Rf =0.56 (n-hexane/
ethyl acetate 3:2); eluent for column chromatography n-hexane/ethyl
acetate 41:9; [a]D29 =À6.0 (c=0.2, CHCl3); 1H NMR (CDCl3+CCl4,
300 MHz): d=8.22 (s, 1H; H-3’), 8.11 (dd, J=8.1, 1.1 Hz, 1H; H-5’), 7.70
(d, J=7.7 Hz, 1H; H-7’), 7.50 (t, J=7.9 Hz, 1H; H-6’), 6.68–6.67 (m, 1H;
H-2), 5.64 (s, 1H; H-1’), 5.38 (d, J=3.57 Hz, 1H; H-1), 4.59 (dd, J=5.2,
2.9 Hz, 1H; H-5), 4.43 (dd, J=11.9, 2.9 Hz, 1H; H-6a), 4.35 (dd, J=11.9,
1H, H-2’b), 1.18 ppm (s, 9H; COC
d=179.1 (OCOC(CH3)3), 149.0 (Cq; C-2), 148.2 (ArCq; C-2’’), 141.9
(C-5), 132.3 (C-4’’, C-6’’), 127.0 (C-3’’, C-7’’), 124.7 (Cq; C-3), 118.7 (Cq;
(CH3)3); 13C NMR (CDCl3, 75 MHz):
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
À
CN), 111.3 (ArCq; C-5’’), 110.5 (C-4), 68.1 (C-1’’), 66.7 (C-2’), 66.5
(C-1’), 38.9 (Cq; OCOC(CH3)3), 27.1 ppm (OCOC
G
N
n˜ =3425, 2231, 1719, 1162 cmÀ1 MS (ES): m/z: 366 [M+Na]+, 325
;
[MÀH2O]+; HRMS (DART): m/z: calcd for C19H20NO4 [M+HÀH2O]+
326.1392; found 326.1402.
Compound 12c: Furan 12c was obtained as a viscous oil in 79% yield
from 2,3-dideoxy-hex-2-enopyranoside 11c by the general reaction proce-
dure given above for producing furans from 2,3-dideoxy-hex-2-enopyra-
nosides. Rf =0.42 (n-hexane/ethyl acetate 3:2); eluent for column chro-
matography n-hexane/ethyl acetate 4:1; [a]3D1 =À62.7 (c=0.20, CHCl3);
1H NMR (CDCl3+CCl4, 300 MHz): d=7.57 (d, J=8.3 Hz, 2H; H-4’’, H-
6’’), 7.47 (d, J=8.1 Hz, 2H; H-3’’, H-7’’),7.21 (d, J=1.7 Hz, 1H; H-5),
6.00 (d, J=1.7 Hz, 1H; H-4), 5.91 (s, 1H; H-1’’), 5.04 (dd, J=6.8, 4.9 Hz,
1H; H-1’), 4.41 (dd, J=11.4, 7.4 Hz, 1H; H-2’a), 4.32 (dd, J=11.4,
À
5.3 Hz, 1H; H-6b), 3.99 (pent., J=6.1 Hz, 1H; OCH
OCOCH3), 1.22 (d, J=6.2 Hz, 3H; OCH(CH3)2), 1.18 ppm (d, J=6.1 Hz,
3H; OCH
(CH3)2); 13C NMR (CDCl3+CCl4, 50 MHz): d=194.1 (C-4),
ACHTUGNTRENUN(NG CH3)2), 1.99 (s, 3H;
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
170.4 (OCOCH3), 148.5 (Cq), 143.0 (Cq), 140.6 (C-2), 138.7 (ArCq), 132.8
(C-7’), 129.4 (C-6’), 123.0 (C-5’), 121.9 (C-3’), 92.1 (C-1), 72.2 (C-5), 71.8
(OCHACHTUNGTRENNUNG(CH3)2), 69.8 (C-1’), 62.4 (C-6), 23.2 (OCOCH3), 22.0 and
20.7 ppm; IR (neat): n˜ =3428, 3021, 1738, 1532, 1216 cmÀ1; MS (ES): m/z:
397 [M+NH4]+; HRMS (EI): m/z: calcd for C18H19NO7 [MÀH2O]+
361.1161; found 361.1157.
4.9 Hz, 1H; H-2’b), 1.15 ppm (s, 9H;
COC
(CH3)3), 149.2 (Cq; C-2),
(CH3)3); 13C NMR
ACHTUNGTRENNUNG
À
(CDCl3+CCl4, 50 MHz): d=179.0 ( OCOC
N
146.9(ArCq; C-2’’), 141.5 (C-5), 126.8 (C-3’’, C-7’’, CF3), 125.6 (C-4’’ or C-
6’’), 125.5 (C-4’’ or C-6’’), 125.4 (ArCq; C-5’’), 125.1 (Cq; C-3), 110.9 (C-
Compound 11 f: CeCl3·7H2O (112 mg, 0.3 mmol) and NaBH4 (11 mg,
0.3 mmol) were added at 08C to a stirred solution of 10 f (227 mg,
0.6 mmol) in ethanol (7 mL) and the reaction mixture was stirred contin-
uously for 130 min, with the temperature of the reaction mixture being
kept below 58C. After completion of the reaction (TLC), excess NaBH4
was neutralized with acetone and the solvent was removed under reduced
pressure to afford the crude product, which after column chromatography
yielded 11 f as a viscous oil (190 mg, 83%). Rf =0.44 (n-hexane/ethyl ace-
tate 1:1); eluent for column chromatography n-hexane/ethyl acetate 19:6;
[a]2D9 =+30.5 (c=0.20, CHCl3); 1H NMR (CDCl3, 300 MHz): d=8.23 (s,
1H; H-3’), 8.14–8.10 (m, 1H; H-5’), 7.71 (d, J=7.7 Hz, 1H; H-7’), 7.52 (t,
J=7.9 Hz, 1H; H-6’), 5.57 (s, 1H; H-2), 5.47 (s, 1H; H-1’), 5.11 (d, J=
2.7 Hz, 1H; H-1), 4.41 (dd, J=12.2, 4.4 Hz, 1H; H-6a), 4.27 (brs, 1H;
OH), 4.18 (dd, J=12.2, 2.0 Hz, 1H; H-6b), 4.05–3.93 (m, 3H; H-4, H-5
4), 68.4 (C-1’’), 66.7 (C-2’), 66.6 (C-1’), 39.0 (OCOCACHTNUGTRNEG(UN CH3)3), 27.2 ppm
(OCOCACHTNUGRTNEUNG
(CH3)3); IR (neat): n˜ =3432, 3020, 1722, 1216 cmÀ1; MS (ES):
m/z: 387 [M+H]+; HRMS (DART): m/z: calcd for C19 H20F3O4
[M+HÀH2O]+ 369.1313; found 369.1296.
Compound 12d: Furan 12d was obtained as a viscous oil in 76% yield
from 2,3-dideoxy-hex-2-enopyranoside 11d by the general reaction pro-
cedure given above for producing furans from 2,3-dideoxy-hex-2-enopyr-
anosides. Rf =0.44 (n-hexane/ethyl acetate 7:3); eluent for column chro-
matography n-hexane/ethyl acetate 22:3; [a]2D8 =+5.6 (c=0.5, CHCl3);
1H NMR (CDCl3, 300 MHz): 7.27 (d, J=1.6 Hz, 1H; H-5), 6.29 (d, J=
1.6 Hz, 1H; H-4), 5.05 (dd, J=7.4, 4.7 Hz, 1H; H-1’), 4.77–4.72 (m, 1H;
H-1’’), 4.41(dd, J=11.4, 7.6 Hz, 1H; H-2’a), 4.30 (dd, J=4.4, 11.3 Hz, 1H,
H-2’b), 1.76–1.68 (m, 2H; H-2’’), 1.24 (brs, 14H; H-3’’ to H-9’’), 1.17 (s,
À
9H; OCOC
75 MHz): d=178.9 ( OCOCACTHNUGTNRE(UNG CH3)3), 148.6 (Cq; C-2), 141.4 (C-5), 125.9
(CH3)3), 0.88–0.84 ppm (m, 3H; H-10’’); 13C NMR (CDCl3,
ACHTUNGTRENNUNG
and OCH
ACHTUNGTRENNUNG(CH3)2), 3.86 (brs, 1H; OH), 2.03 (s, 3H; OCOCH3), 1.21 (d,
J=6.2 Hz, 3H; OCHACHTUNGTRENNUNG(CH3)2), 1.13 ppm (d, J=6.1 Hz, 3H; OCHACHTUGNTRENUN(GN CH3)2);
À
13C NMR (CDCl3, 50 MHz): 172.1 (OCOCH3), 148.4 (Cq), 143.7 (Cq),
141.9 (Cq), 132.4 (C-7’), 129.4 (C-6’), 126.3 (C-2), 122.6 (C-5’), 122.3 (C-
(Cq; C-3), 109.7 (C-4), 67.1 (C-1’’), 66.8 (C-2’), 66.1 (C-1’), 38.9 (Cq;
À
OCOC
9’’), 27.1 ( OCOC
N
3’), 93.1 (C-1), 75.6 (C-1’), 70.8 (OCH
A
1216 cmÀ1; MS (ES): m/z: 351 [M+HÀH2O]+, 339 [MÀC2H5]+; HRMS
(DART): m/z: calcd for C21H35O4 [M+HÀH2O]+ 351.2535; found
351.2544.
(C-6), 23.5 (OCOCH3), 22.0 and 20.8 ppm (OCHACHTUNGTRENNUNG
3457, 3021, 1730, 1217 cmÀ1
;
MS (ES): m/z: 404 [M+Na]+, 399
[M+NH4]+; HRMS (DART): m/z: calcd for C18H27N2O8 [M+NH4]+
399.1767; found 399.1751.
Compound 12e: Furan 12e was obtained as a viscous oil in 78% yield
from 2,3-dideoxy-hex-2-enopyranoside 11e by the general reaction proce-
dure given above for producing furans from 2,3-dideoxy-hex-2-enopyra-
nosides. Rf =0.64 (n-hexane/ethyl acetate 3:2); eluent for column chro-
matography n-hexane/ethyl acetate 21:4; [a]3D0 =À139.7 (c=0.2, CHCl3);
1H NMR (CDCl3, 300 MHz): d=7.95 (d, J=8.1 Hz, 1H; H-4’’), 7.88 (d,
J=7.7 Hz, 1H; H-7’’), 7.67 (t, J=7.7 Hz, 1H; H-6’’), 7.47 (t, J=7.7 Hz,
1H; H-5’’), 7.24 (s, 1H; H-5), 6.50 (s, 1H; H-1’’), 5.96 (d, J=1.5 Hz, 1H;
H-4), 5.17 (dd, J=7.1, 4.9 Hz, 1H; H-1’), 4.54–4.47 (m, 1H; H-2’a), 4.36
À
Compound 12a: Furan 12a was obtained in 86% yield from 2,3-dideoxy-
hex-2-enopyranoside 11a as a viscous oil by the general reaction proce-
dure given above for producing furans from 2,3-dideoxy-hex-2-enopyra-
nosides. Rf =0.56 (n-hexane/ethyl acetate 18:7); eluent for column chro-
matography n-hexane/ethyl acetate 3:2; [a]2D8 =À15.4 (c=0.26, CHCl3);
1H NMR (CDCl3, 300 MHz): d=8.19 (d, J=8.7 Hz, 2H; H-4’’, H-6’’#),
7.59 (d, J=8.6 Hz, 2H; H-3’’, H-7’’), 7.28 (d, J=1.6 Hz, 1H; H-5), 6.06
(d, J=1.6 Hz, 1H; H-4), 6.02 (s, 1H; H-1), 5.14–5.10 (m, 1H; H-1’), 4.46
(dd, J=11.6, 7.2 Hz, 1H; H-2’a), 4.39 (dd, J=11.6, 4.5 Hz, 1H; H-2’b),
(dd, J=11.4, 4.7 Hz, 1H; H-1’b), 1.18 ppm (s, 9H; COC
(CH3)3);
1.19 ppm (s, 9H; COCACHTUNGTRENNUNG
(CH3)3); 13C NMR (CDCl3, 75 MHz): d=179.2
13
À
C NMR (CDCl3, 50 MHz): d=179.1 ( OCOC
A
À
( OCOC
G
3’’), 147.9 (Cq; C-2), 141.8 (C-5), 137.8 (ArCq; C-3’’), 133.8 (C-6’’), 128.9
(C-7’’), 128.7 (C-5’’),124.7 (C-4’’), 123.2 (Cq; C-3), 110.2 (C-4), 68.1 (C-
C-2’’), 141.9 (C-5), 127.1 (C-3’’, C-7’’), 124.7 (Cq; C-3), 123.7 (C-4’’, C-6’’),
À
110.4 (C-4), 67.9 (C-1’’), 66.7 (C-2’), 66.5 (C-1’), 38.9 (Cq; OCOCACHTNUTGRNEUNG(CH3)3),
1’’), 66.5 (C-2’), 66.0 (C-1’), 64.5
(C-1’’), 38.9 (Cq; OCOC
E
27.1 ppm (OCOCACHTUNGTRENNUNG
(CH3)3); IR (neat): n˜ =3404, 1733, 1243 cmÀ1; MS (ES):
27.1 ppm ( OCOC
(CH3)3); IR (neat): n˜ =3420, 1721, 1527, 1162 cmÀ1
À
m/z: 386 [M+Na]+, 346 [M+HÀH2O]+; HRMS (DART): m/z: calcd for
MS (ES): m/z: 345 [MÀH2O]+; HRMS (DART): m/z: calcd for
C18H20NO6 [M+HÀH2O]+ 346.1290; found 346.1283.
C18H20NO6 [M+HÀH2O]+ 346.1290; found 346.1280.
Compound 12b: Furan 12b was obtained as a viscous oil in 84% yield
from 2,3-dideoxy-hex-2-enopyranoside 11b by the general reaction pro-
cedure given above for producing furans from 2,3-dideoxy-hex-2-enopyr-
anosides. Rf =0.31 (n-hexane/ethyl acetate 7:3); eluent for column chro-
matography n-hexane/ethyl acetate 3:1; [a]2D9 =+18.0 (c=0.20, CHCl3);
1H NMR (CDCl3, 300 MHz): d=7.63 (d, J=8.3 Hz, 2H; H-4’’, H-6’’),
7.52 (d, J=8.3 Hz, 2H; H-3’’, H-7’’), 7.27 (d, J=1.8 Hz, 1H; H-5), 6.05
(d, J=1.8 Hz, 1H; H-4), 5.97 (s, 1H; H-1’’), 5.10 (dd, J=6.8, 4.6 Hz, 1H;
H-1’), 4.44 (dd, J=11.5, 7.2 Hz, 1H, H-2’a), 4.38 (dd, J=11.5, 4.6 Hz,
Compound 12 f: Furan 12 f was obtained as a viscous oil in 74% yield
from 2,3-dideoxy-hex-2-enopyranoside 11 f by the general reaction proce-
dure given above for producing furans from 2,3-dideoxy-hex-2-enopyra-
nosides. Rf =0.52 (n-hexane/ethyl acetate 1:1); eluent for column chroma-
tography n-hexane/ethyl acetate 7:3; [a]3D1 =+33.3 (c=0.12, CHCl3);
1H NMR (CDCl3, 300 MHz): d=8.28 (s, 1H; H-3’’), 8.12 (dd, J=8.1,
1.2 Hz, 1H; H-5’’), 7.73 (d, J=7.7 Hz, 1H; H-7’’), 7.51 (t, J=7.9 Hz, 1H;
H-6’’), 7.28 (d, J=1.8 Hz, 1H; H-5), 6.09 (d, J=1.8 Hz, 1H; H-4), 6.01 (s,
1H; H-1’’), 5.12 (dd, J=6.8, 4.9 Hz, 1H; H-1’), 4.46–4.35 (m, 2H; H-2’a,
6046
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6041 – 6049

Enantiomerically Pure 2- and 2,3-Disubstituted Furans
FULL PAPER
H-2’b), 2.08 ppm (s, 3H; OCOCH3); 13C NMR (CDCl3, 75 MHz): d=
171.5 (OCOCH3), 148.7 (ArCq; C-4’’), 148.4 (Cq; C-2), 145.1 (ArCq; C-
2’’), 142.1 (C-5), 132.5 (C-7’’), 129.5 (C-6’’), 124.9 (Cq; C-3), 122.6 (C-5’’),
121.3 (C-3’’), 110.5 (C-4), 67.9 (C-1’’), 66.7 (C-2’), 66.4 (C-1’), 20.9 ppm
(OCOCH3); IR (neat): n˜ =: 3408, 3020, 1601, 1215 cmÀ1; MS (ES): m/z:
303 [MÀH2O]+; HRMS (EI): m/z: calcd for C13H10NO4 [MÀC2H5O3]+
244.0610; found 244.0573.
6.09 (d, J=1.7 Hz, 1H; H-4), 5.97 (s, 1H; H-1’), 4.99 (t, J=5.6 Hz, 1H;
H-1’), 3.72–3.59 (m, 2H; H-2’a, H-2’b), 3.53 (brs, 1H; OH), 3.49 ppm
(brs, 1H; OH); 13C NMR (CDCl3, 75 MHz): d=149.0 (Cq; C-2), 148.0
(ArCq; C-2’’), 141.9 (C-5), 132.4 (C-4’’, C-6’’), 127.0 (C-3’’, C-7’’), 124.8
(Cq; C-3), 118.7 (Cq; CN), 111.4 (ArCq; C-5’’), 110.6 (C-4), 68.3 (C-1’’),
67.0 (C-1’), 55.2 ppm (C-2’); IR (KBr): n˜ =3403, 2231, 2105, 1251 cmÀ1
;
MS (ES): m/z: 256 [MÀN2]+, 239 [M+HÀN2ÀH2O]+; HRMS (DART):
m/z: calcd for C14H11N2O2 [M+HÀN2-H2O]+ 239.0820; found 239.0815.
Compound 13: TiCl4 (3 mmol, 0.33 mL) was added dropwise at À788C to
a stirred solution of TBAI (0.4 mmol, 148 mg) in dry CH2Cl2 (20 mL).
After the system had been stirred for two minutes, a mixture containing
methyl 6-O-p-toluenesulfonyl-2,3-dideoxy-a-d-glycero-hex-2-enopyrano-
sid-4-ulose (2.0 mmol, 624 mg) and 4-cyanobenzaldehyde (4 mmol,
524 mg) in dry CH2Cl2 (10 mL) was added. The reaction mixture was al-
lowed to warm slowly to À308C and stirred for 8 h for the reaction. A sa-
turated aqueous solution of NaHCO3 was added, followed by filtration
through a celite pad. The organic layer was separated from the filtrate,
and the aqueous layer was extracted with dichloromethane (5ꢁ5 mL).
The combined organic layers were washed with brine solution and dried
over Na2SO4. The crude product obtained after evaporation of solvent
was chromatographed to yield pure compound 13 as a glassy solid
(360 mg, 41%). Rf =0.29 (n-hexane/ethyl acetate 3:2); eluent for column
chromatography n-hexane/ethyl acetate 19:6; [a]2D9 =À2.0 (c=0.4,
CHCl3); 1H NMR (CDCl3+CCl4, 300 MHz): d=7.68 (d, J=8.2 Hz, 2H;
H-2’’, H-6’’), 7.53 (d, J=8.2 Hz, 2H; H-4’, H-6’), 7.42 (d, J=8.2 Hz, 2H;
H-3’, H-7’), 7.30 (d, J=8.1 Hz, 2H; H-3’’, H-5’’), 6.79 (d, J=2.9 Hz, 1H;
H-2), 5.52 (s, 1H; H-1’), 5.12 (d, J=3.6 Hz, 1H; H-1), 4.47 (dd, J=4.6,
2.8 Hz, 1H; H-5), 4.35–4.25 (m, 2H; H-6a, H-6b), 3.41 (s, 3H; OMe),
2.43 ppm (s, 3H; CH3 of OTs); 13C NMR (CDCl3+CCl4, 50 MHz): d=
192.3 (C-4), 146.1 (Cq), 144.9 (Cq), 139.8 (C-2), 139.1 (Cq), 132.8 (Cq),
132.2 (C-4’, C-6’), 129.9 (C-3’’, C-5’’), 128.0 (C-2’’, C-6’’), 127.5 (C-3’, C-
7’), 118.4 (CN), 111.8 (Cq; C-5’), 94.5 (C-1), 72.1 (C-5), 69.2 (C-1’), 68.0
(C-6), 56.7 (OCH3), 21.7 ppm (CH3 of OTs); IR (neat): n˜ =3405, 3021,
1691, 1216 cmÀ1; MS (ES): m/z: 424 [MÀHÀH2O]+; HRMS (EI): m/z:
calcd for C22H19NO6S [MÀH2O]+ 425.0933; found 425.0929.
Compound 17: A solution of iodine (2.150 g, 8.4 mmol) in CCl4/pyridine
(1:1, 8 mL) was added dropwise under argon at 08C to a solution of
sugar enone 16 (484 mg, 2 mmol) in CCl4/pyridine (1:1, 8 mL). Subse-
quently the reaction mixture was allowed to warm to 158C and stirred
for 3 h 30 min. On completion of reaction (TLC), the reaction mixture
was diluted with ether (40 mL) and washed successively with water
(20 mL), HCl (1n, 2ꢁ20 mL), water (20 mL) and saturated sodium thio-
sulfate solution (10 mL). The worked-up product was dried over Na2SO4,
filtered and concentrated under reduced pressure to provide crude prod-
uct (724 mg) as a syrup that could be used as such for further reactions
without column purification. An analytical sample of crude product was
chromatographed to afford pure compound 17 as a syrup. Rf =0.52 (n-
hexane/ethyl acetate 4:1); eluent for column chromatography n-hexane/
ethyl acetate 97:3; [a]D29 =+46.39 (c=0.34, CHCl3); 1H NMR (CDCl3,
300 MHz): d=7.57 (d, J=3.8 Hz, 1H; H-2), 4.99 (d, J=3.8 Hz, 1H; H-
1), 4.81 (dd, J=5.4, 2.7 Hz, 1H; H-5), 4.54 (dd, J=11.9, 2.7 Hz, 1H; H-
6a), 4.44 (dd, J=11.9, 5.5 Hz, 1H; H-6b), 3.50(s, 3H; OMe), 1.18 ppm (s,
9H; OCOC
(OCOC(CH3)3), 152.5 (C-2), 102.6 (Cq; C-3), 96.0 (C-1), 73.0 (C-6), 63.0
(C-5), 56.6 (OCH3), 38.8 (OCOCCAHTUNGRTEN(UNNG CH3)3), 27.1 ppm (OCOCACHTNGURTENU(NG CH3)3); IR
(CH3)3); 13C NMR (CDCl3, 50 MHz): d=187.2 (C-4), 177.9
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(neat): n˜ =3402, 1730, 1219 cmÀ1; MS (ES): m/z: 349 [MÀHÀH2O]+;
HRMS (DART): m/z: calcd for C12H18IO5 [M+H]+ 369.0198; found
369.0178.
Compound 18: A solution of iodine (427 mg, 1.68 mmol) in CCl4/pyridine
(1:1, 1 mL) was added dropwise under argon at 08C to a solution of the
sugar enone 16 (96 mg, 0.4 mmol) in CCl4/pyridine (1:1, 1 mL). Subse-
quently the reaction mixture was allowed to warm to 158C and stirred
for 3 h 30 min. After the completion of reaction (TLC) the reaction mix-
ture was diluted with ether (5 mL) and washed successively with water
(3 mL), HCl (1n, 2ꢁ3 mL), water (3 mL) and saturated sodium thiosul-
fate solution (2 mL). The organic layer was dried over Na2SO4, filtered
and concentrated under reduced pressure to afford the crude product
(147 mg) as a syrup. CeCl3·7H2O (74 mg, 0.2 mmol) and NaBH4 (8 mg,
0.2 mmol) were added at 08C to the crude product dissolved in ethanol
(6 mL). The reaction mixture was stirred continuously for 75 min, with
the temperature of the reaction mixture being kept below 58C. After
completion of the reaction (TLC monitoring), excess NaBH4 was neutral-
ized with acetone and the reaction mixture was concentrated under re-
duced pressure. The inorganic impurities present in the crude product
were removed by washing with CH2Cl2 (3ꢁ5 mL). The combined wash-
ings were concentrated under reduced pressure. The obtained dried
crude product (136 mg) was dissolved in THF, and ZrCl4 (5 mg,
0.02 mmol) and ZnI2 (12 mg, 0.04 mmol) were added in succession. The
resulting reaction mixture was stirred at 508C for 3 h. On completion of
the reaction (TLC), the mixture was quenched with water and extracted
with ethyl acetate (6ꢁ2 mL). The combined organic layers were washed
with brine, dried over Na2SO4 and concentrated under reduced pressure
to yield the crude product, which was chromatographed to yield pure
compound 18 as an yellow oil (105 mg, 78% over three steps). Rf =0.50
(n-hexane/ethyl acetate 3:2); eluent for column chromatography n-
hexane/ethyl acetate 19:1; [a]2D8 +15.5 (c=0.18, CHCl3); 1H NMR
(CDCl3, 300 MHz): d=7.40 (d, J=1.9 Hz, 1H; H-5), 6.46 (d, J=1.9 Hz,
1H; H-4), 5.05 (dd, J=12.2, 5.5 Hz, 1H; H-1’), 4.45 (dd, J=11.3, 7.1 Hz,
1H; H-2’a), 4.29 (dd, J=11.3, 5.2 Hz, 1H; H-2’b), 2.46 (d, J=5.6 Hz, 1H;
Compound 14: CeCl3·7H2O (150 mg, 0.4 mmol) and NaBH4 (15 mg,
0.4 mmol) were added at 08C to
a stirred solution of 13 (355 mg,
0.8 mmol) in ethanol (7 mL) and the reaction mixture was stirred contin-
uously for 2 h, with the temperature of the reaction mixture being kept
below 108C. After completion of the reaction (TLC monitoring), excess
NaBH4 was neutralized with acetone and the solvent was removed under
reduced pressure to afford the crude product (416 mg). NaN3 (260 mg,
4 mmol) was added to a DMF solution of the dried crude product
(10 mL) and the reaction mixture was stirred at 908C to 1008C for 2.5 h.
The cooled reaction mixture was poured into excess of ice-cold water
and extracted with dichloromethane (5ꢁ5 mL). The combined organic
layers were washed with brine, dried over Na2SO4 and concentrated
(rotary evaporator) to yield crude product, which was purified by column
chromatography to give pure compound 14 as a white solid. (125 mg,
49% in two steps). M.p. 98–1008C; Rf =0.43 (n-hexane/ethyl acetate
3:2); eluent for column chromatography n-hexane/ethyl acetate 65:35;
1
[a]3D1 =+136.03 (c=0.2, CHCl3); H NMR (CDCl3, 300 MHz): d=7.62 (d,
J=8.3 Hz, 2H; H-4’, H-6’), 7.50 (d, J=8.2 Hz, 2H; H-3’, H-7’), 5.60 (s,
1H; H-2), 5.39 (s, 1H; H-1’), 4.89 (d, J=2.4 Hz, 1H; H-1), 4.28 (brs, 1H;
OH), 4.05 (d, J=8.9 Hz, 1H; H-4), 3.90–3.84 (m, 2H; H-5 and OH),
3.49–3.34 ppm (m, 5H; H-6a, H-6b, OCH3); 13C NMR (CDCl3+CCl4,
50 MHz): 146.7 (Cq; C-3), 142.5 (Cq; C-2’), 132.3 (C-4’, C-6’), 127.0 (C-3’,
C-7’), 125.7 (C-2), 118.5 (Cq; CN), 111.3 (Cq; C-5’), 95.5 (C-1), 75.7 (C-
1’), 71.1 (C-5), 65.4 (C-4), 56.0 (OCH3), 51.5 ppm (C-6); IR (KBr): n˜ =
3398, 3018, 2232, 2103, 1216 cmÀ1; MS (ES): m/z: 339 [M+Na]+, 291
[M+HÀCN]+; HRMS (EI): m/z: calcd for C15H15N4O3 [M+HÀH2O]+
299.1144; found 299.1122.
Compound 15: Azidofuran 15 was obtained as a white solid in 74% yield
from 2,3,6-trideoxy-hex-2-enopyranoside 14 by the general reaction pro-
cedure given above for producing furans from hex-2-enopyranosides.
M.p. 89–918C; Rf =0.48 (n-hexane/ethyl acetate 3:2); eluent for column
chromatography n-hexane/ethyl acetate 4:1; [a]2D8 =+15.00 (c=0.1,
CHCl3); 1H NMR (CDCl3, 300 MHz): d=7.63 (d, J=8.3 Hz, 2H; H-4’’,
H-6’’), 7.53 (d, J=8.2 Hz, 2H; H-3’’, H-7’’), 7.29 (d, J=1.7 Hz, 1H; H-5),
OH), 1.18 ppm (s, 9H; COC
178.5 (OCOC(CH3)3), 152.5 (Cq; C-2), 143.9 (C-5), 117.9 (C-4), 65.8 (C-
2’), 65.4 (C-1’), 64.5(Cq, C-3), 38.9 (OCOC(CH3)3), 27.1 ppm (OCOC-
(CH3)3); 13C NMR (CDCl3, 75 MHz): d=
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(CH3)3); IR (neat): n˜ =3449, 3021, 1723, 1216 cmÀ1; MS (ES): m/z: 377
[M+K]+, 356 [M+NH4]+, 337 [MÀH]+; HRMS (DART): m/z: calcd for
C11H16IO4 [M+H]+ 339.0093; found 339.0077.
Chem. Eur. J. 2009, 15, 6041 – 6049
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6047

A. K. Shaw et al.
Compound 19: Aqueous HCHO (37%, 5 mmol, 0.5 mL) and 4-dimethy-
laminopyridine (DMAP, 0.4 mmol, 48 mg) was added to a stirred solution
of 16 (1.5 mmol, 363 mg) in dry THF (6 mL). The resulting reaction mix-
ture was allowed to stir at room temperature for 19 h. On completion of
reaction (TLC) it was acidified with HCl (1.5n) and extracted with di-
chloromethane (5ꢁ4 mL). The combined organic layers were washed
successively with aqueous solution of NaHCO3 and brine, dried over
Na2SO4 and concentrated under reduced pressure to furnish crude prod-
uct, which was chromatographed to yield pure compound 19 as an yellow
oil (175 mg, 43%) Rf =0.40 (n-hexane/ethyl acetate 3:2); eluent for
column chromatography n-hexane/ethyl acetate 39:11; [a]3D1 =+37.5 (c=
Chemistry, Vol. 15 (Eds.: G. W. Gribble, T. L. Gilchrist), Pergamon
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2002, 13, 49; h) D. S. Mortensen, A. L. Rodriguez, K. E. Karlson, J.
Sun, B. S. Katzenellenbogen, J. A. Katzenellenbogen, J. Med. Chem.
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therein; j) B. Gabriele, G. Salerno, E. Lauria, J. Org. Chem. 1999,
64, 7687; k) B. A. Keay, P. W. Dibble in Comprehensive Heterocyclic
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try 2008, 19, 1372, and references therein; b) M. Saquib, M. K.
Gupta, R. Sagar, Y. S. Prabhakar, A. K. Shaw, R. Kumar, P. R.
Maulik, A. N. Gaikwad, S. Sinha, A. K. Srivastava, V. Chaturvedi,
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130, 4097; b) H.-K. Yim, H. N. C. Wong, J. Org. Chem. 2004, 69,
2892; c) J. Mꢂndez-Andino, L. A. Paquette, Org. Lett. 2000, 2, 4095.
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Jung, J. Nat. Prod. 2008, 71, 869; b) K. Pudhom, D. Sommit, N. Su-
wankitti, A. Petsom, J. Nat. Prod. 2007, 70, 1542; c) W. K. Jeon,
J. H. Lee, H. K. Kim, A. Y. Lee, S. O. Lee, Y. S. Kim, S. Y. Ryu, S. Y.
Kim, Y. J. Lee, B. S. Ko, J. Ethnopharmacol. 2006, 106, 62; d) X. L.
Hou, H. Y. Cheung, T. Y. Hon, P. L. Kwan, T. H. Lo, S. Y. Tong,
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1
0.32, CHCl3); H NMR (CDCl3, 300 MHz): d=6.85–6.84 (m, 1H; H-2), d
5.21 (d, J=3.4 Hz, 1H; H-H-1), 4.63 (dd, J=5.7, 2.6 Hz, 1H; H-5), 4.55
(dd, J=11.9, 2.6 Hz, 1H; H-6a), 4.43 (dd, J=11.9, 5.7 Hz, 1H; H-6b),
4.33 (s, 2H; H-1’), 3.52 (s, 3H; OMe), 1.18 ppm (s, 9H; OCOC
13C NMR (CDCl3, 75 MHz): d=194.2 (C-4), 178.1 (OCOC
(CH3)3, 138.3
(C-2), 137.2 (Cq; C-3), 94.5 (C-1), 72.5(C-5), 62.7(C-6), 59.4 (C-1’), 56.6
(OMe), 38.8 (OCOC(CH3)3), 27.1 ppm (OCOC(CH3)3); IR (neat): n˜ =
ACHTUGNRTNE(NUNG CH3)3);
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
3382, 3021, 1730, 1217 cmÀ1; MS (ES): m/z: 295 [M+Na]+, 273 [M+H]+,
272 [M]+; HRMS (DART): m/z: calcd for C13H24NO6 [M+NH4]+
290.1603; found 290.1586.
Compound 20: CeCl3·7H2O (37 mg, 0.1 mmol) and NaBH4 (4 mg,
0.1 mmol) were added at À58C to a stirred solution of 19 (54 mg,
0.2 mmol) in ethanol (3 mL) and the reaction mixture was stirred contin-
uously for 45 min, with the temperature of the reaction mixture being
kept around 08C. After completion of the reaction (TLC monitoring),
excess NaBH4 was neutralized with acetone and solvent was removed
under reduced pressure to afford the crude product (75 mg). The dried
crude product was dissolved in THF, and ZrCl4 (3 mg, 0.01 mmol) and
ZnI2 (6 mg, 0.02 mmol) were then added in succession. The reaction mix-
ture was stirred at 508C for 2 h 50 min. On completion of the reaction
(TLC) the mixture was quenched with water and extracted with ethyl
acetate (6ꢁ2 mL). The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated under reduced pressure to yield the
crude product, which was purified by column chromatography to furnish
the pure compound 20 as an oil (37 mg, 77% in two steps). Rf =0.43 (n-
hexane/ethyl acetate 1:1); eluent for column chromatography n-hexane/
ethyl acetate 4:1; [a]D31 =+28.8 (c=0.2, CHCl3); 1H NMR (CDCl3,
300 MHz): d=7.30 (d, J=1.7 Hz, 1H; H-5), 6.34 (d, J=1.7 Hz, 1H; H-
4), 5.05 (dd, J=6.9, 4.9 Hz, 1H; H-1’), 4.62 (d, J=12.8 Hz, 1H; H-1’’a),
4.57 (d, J=12.8 Hz, 1H; H-1’’b), 4.42 (dd, J=11.4, 7.0 Hz, 1H; H-2’a),
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´
´
´
Ed. 2004, 43, 5991; e) J. E. Kaminska, K. Smigielski, D. Lobodzin-
ska. J. Gꢃra, Tetrahedron: Asymmetry 2000, 11, 1211.
4.36 (dd, J=11.5, 4.9 Hz, 1H; H-2’b), 1.18 ppm (s, 9H; OCOC
13C NMR (CDCl3, 75 MHz): d=178.9 (OCOC
(CH3)3), 149.5 (Cq; C-2),
141.6 (C-5), 122.2 (Cq; C-3), 111.4 (C-4), 66.4 (C-2’), 65.7 (C-1’), 56.3 (C-
ACHTUGNRTNE(NUNG CH3)3);
[8] a) J. S. Yadav, B. V. S. Reddy, A. V. Madhavi, J. Mol. Catal. A 2005,
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AHCTUNGTRENNUNG
1’’), 38.9 (OCOCACHTUNGTRENNUNG(CH3)3), 27.1 ppm ((OCOCCAHUTNGTRENN(UGN CH3)3); IR (neat): n˜ =3409,
3020, 1724, 1216 cmÀ1; MS (ES): m/z: 243 [M+H]+, 242 [M]+; HRMS
(DART): m/z: calcd for C12H17O4 [M+HÀH2O]+ 225.1126; found
225.1137.
[10] Marco-Contelles et al. reported the synthesis of (2R)1-[tert-(butylsi-
lylphenyl)-oxy]-2-furanylethanol from propargyl-6-O-2,3-dideoxy-a-
d-hex-2-enopyranoside in presence of iodine in THF see ref. [9b].
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copyranosides 3, 6 and 7 were obtained via the route delineated in
Scheme 1, see B. Fraser-Reid, A. Mclean, E. W. Usherwood, M.
Yunker, Can. J. Chem. 1970, 48, 2877.
Acknowledgements
We are thankful to SAIF, CDRI for providing spectral data and to Mr.
A. K. Pandey for technical assistance. Mohammad Saquib and Irfan
Husain thank CSIR, India for the financial assistance. We also acknowl-
edge ICMR, India for providing financial support (Grant no. 58/7/2004-
BMS). The CDRI communication number is 7573.
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6048
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 6041 – 6049

Enantiomerically Pure 2- and 2,3-Disubstituted Furans
FULL PAPER
1
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Received: January 2, 2009
Published online: May 5, 2009
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Chem. Eur. J. 2009, 15, 6041 – 6049
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6049