An iodocyclization approach toward diastereoselective synthesis of highly functionalized tetrasubstituted tetrahydrofurans with 2,5-trans and 2,5-cis relationships from pyranoside derived acyclic oximes

Article abstract of DOI:10.1016/j.tetasy.2007.08.030

An efficient method to obtain novel tetrasubstituted tetrahydrofurans with C2 and C5 substitution in trans- and cis-relative configurations has been reported.

Full text of DOI:10.1016/j.tetasy.2007.08.030

Tetrahedron: Asymmetry 18 (2007) 2069–2078
An iodocyclization approach toward diastereoselective synthesis of
highly functionalized tetrasubstituted tetrahydrofurans with 2,5-trans
and 2,5-cis relationships from pyranoside derived acyclic oximesI
Vikas Kumar,a Harsh Mohan Gauniyalb and Arun K. Shawa,*
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
bDivision of Sophisticated Analytical Instrumentation Facility, Central Drug Research Institute, Lucknow 226 001, India
Received 4 July 2007; accepted 30 August 2007
Abstract—An efficient method to obtain novel tetrasubstituted tetrahydrofurans with C2 and C5 substitution in trans- and cis-relative
configurations has been reported.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ods have been reported with regards to the construction
of 2,5-disubstituted THFs, while reports toward the syn-
thesis of tri- and tetra-substituted tetrahydrofurans are
few.7,8 We have recently reported new and convenient
approaches for the stereoselective synthesis of highly func-
tionalized trisubstituted THFs starting from commercially
available glycals.9,10
The stereoselective synthesis of highly functionalized tetra-
hydrofuran (THF) derivatives have received much atten-
tion in recent years owing to their widespread occurrence
in various natural products as structural units1 and also
their presence in many biologically active compounds,2
such as renealtins A and B,1a asitrocin, 2,4-cis- and trans-
asitrocinones,1b and donnaienin.1e
A
polysubstituted
Our interest in the synthesis of substituted tetrahydro-
furans motivated us to develop a new synthetic route to
afford stereochemically pure isomers of appropriately func-
tionalized tetrasubstituted THFs as novel privileged scaf-
folds. These will be further elaborated upon to a wide
variety of new chemical libraries of unnatural THFs from
a biological point of view.
THF segment is also found in trilobatin B I, a lignan
from the liverwort Bazzania trilobata (Fig. 1).3 A few liter-
ature reports on unnatural tetrasubstituted tetrahydro-
furans (THFs) II–IV, which have been used for the
development of high-affinity ligands and photoaffinity
labels for the D-fructose transporter GLUT54 and more
interestingly compound V exhibiting in vitro microbial
activity on cultures of Mycobacterium tuberculosis5 are
noteworthy (Fig. 1). The densely substituted chiral THFs
can offer a high degree of structural diversity and may be
used as intermediates for the synthesis of various bio-
dynamic compounds. Therefore, an easy access to a syn-
thetic approach capable of targeting chiral substituted
THFs is required. With this in mind, many synthetic strat-
egies have been developed to obtain these compounds and
the natural products themselves.6 Several literature meth-
Realizing the importance of the above mentioned poly-
functionalized THFs, we envisaged a new oxime substi-
tuted THF scaffold 1 containing various diversification
sites that allow amenability of the product transformation
to biologically interesting molecules. The retrosynthetic
strategy to obtain 1 is depicted in Scheme 1. It is worth not-
ing that the direct iodocyclization of aldehyde 1b0, which to
the major extent exists in hemiacetal furanoid form is not
possible. Therefore, we decided to use oxime ether 1c, a
key intermediate in this study that on iodocyclization
involving participation of C2 benzyloxy oxygen atom could
afford a stereodiversified THF-oxime of type 1 as a build-
ing block for library development. Another explicit reason
to use the oxime ether rather than alternatives in this study
q CDRI Communication No. 7140.
Corresponding author. Tel.: +91 9415403775; e-mail: akshaw55@
*
yahoo.com
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.030

2070
V. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 2069–2078
OH
OH
OH
HO
HO2C
OH
OH
OH
OH
O
HO
O
O
Trilobatin B I
OH
HO
NO2
HO
H
OH
N
H
N
O
HO
O
O2N
OH
III
II
OH
HO
NO2
OH
HO
H
N
OH
N
O
C16H33
O
O
O2N
IV
V
OH
Figure 1.
OBn
3
BnO
BnO
OH
OBn
1
5
NOR
2
5
6
RON
HO
4
I
2
6
HO
OH
1c
OBn
O 1
O
1b'
1'
1
OBn
I
O
O
HO
HO
HO
O
BnO
OH
OBn
1b'
BnO
1b
OH
1a
OMe
OMe
Scheme 1.
was its facile transformation to various functionalities such
as aldehydes,11 amines,12 nitriles,13 and amides.14 The
representative analogues of 1c can be obtained from methyl
a,D-glycopyranoside 1a.
2. Results and discussion
Methyl 6-deoxy-6-iodo-2,3-di-O-benzyl-a,D-glucopyrano-
side 2 was prepared from methyl a,D-glucopyranoside.16
Compound 2 on treatment with Zn dust in MeOH in the
presence of a catalytic amount of cyanocobalamine17
yielded cyclic hemiacetal 3 (an a- and b-mixture). Hemiac-
etal 3 on refluxing with O-benzylhydroxylamine hydrochlo-
ride13 in DCM (Scheme 2) furnished an inseparable
mixture of E- and Z-isomers of oxime 4 in an 84:16 ratio,
as determined by 1H NMR spectra, in very good yield
(Table 1, compound 4).
Although the cyclization of oxime ethers toward the synthe-
sis of aminocyclitols is known in the literature,15 to the best
of our knowledge, the iodocyclization of the sugar derived
oxime ethers of type 1c to their corresponding THFs has
not yet been reported. Herein, we report the full results of
iodocyclization of oximes 4, 5, 6, and 16 to obtain new tetra-
substituted THFs 7a–d, 8a–c, 9a,b, and 17a,b, respectively.
OBn
BnO
OBn
Zn dust, NH4Cl,
cyanocobalamine
I
RONH2.HCl
O
N
HO
BnO
Pyridine,
DCM
MeOH, rt, 1 h
HO
OR
OH
OBn
O
OBn
4. R=Bn, 5. R=Me, 6. R=H
3
2
OMe
Scheme 2.

V. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 2069–2078
Table 1. Oxime derivatives 4–6 via Scheme 2 Table 2. THF derivative 7–9 via Scheme 3
2071
Compound
Reaction condition
Ratioa (E:Z)
Yield (%)
Compound
Yield of each isomera (%)
4
5
6
Reflux, 5 h
Reflux, 3.5 h
rt, 24 h
84:16
80:20
75:25
86
81
52
a
b
c
d
7
8
9
46
40
29
27
12
9
—
2
NI
—
a Ratio of E/Z isomers of oximes was determined by 1H NMR.13
50 (a+b)
NI = not isolable.
a The geometry of each isomeric oxime was determined on the basis of
chemical shift of H10 and its J1 ,2 value.13
To obtain the desired THF, oxime 4 was subjected to an
iodocyclization reaction18 (Scheme 3). In this process, a
mixture of four stereoisomers was formed. The chromato-
graphic purification of this mixture resulted in the separa-
tion of all four isomers 7a–d in 2–46% yield (Table 2).
The 1D and 2D NMR experiments of the major isomer
showed the formation of a tetrasubstituted THF skeleton
but its stereochemical outcome could not be analyzed due
to the appearance of overlapping signals for H4 and H5
0
I
H5
OBn
OBn
OBn
OBn
O
N
H5
O
I
N
H4
H4
H1'
1
H3
OH
at d 4.47 ppm in H NMR spectra. Therefore, in order to
establish its stereostructure completely, it was derivatized
H1'
H2
H3
H2
OAc
to its acetyl analogue.
7c
10
1
Here, in its H NMR spectra the signals for H4 and H5
Figure 2. NOE correlations.
became separated and appeared at
d
5.44 ppm
(J4,5 = 3.63 Hz) and 4.65–4.60 ppm (multiplet), respec-
tively. The NOE and NOESY experiments allowed its
identification as 10 (Fig. 2). The transannular NOE experi-
ment19 of 10 showed that both H4 and H5 were trans to H2.
ing THF isomers 7b (2,5-trans) and 7d, (2,5-cis) showed
that they adopt similar structures. Furthermore, the stereo-
chemical results obtained in iodocyclization of oxime 4
revealed that both 7a and 7c were obtained from the E-
isomer, whereas 7b and 7d were derived from its Z-isomer.
1
The H NMR spectra of 10 showing coupling between H4
and H5 (J4,5 = 3.63 Hz) with no coupling between H3 and
H4 (J3,4 = 0.00 Hz) provided adequate evidence for the
pseudoequatorial dispositions of H3 and H4 suggesting
the torsion angle closer to 90ꢁ between them (Fig. 2).20
It can be presumed that the predominant formation of dia-
stereoisomer 7a over 7c was due to the more favored dispo-
sition of the iodine p complex at one side of the double
bond than the other side.21 While the steric crowding near
the si (upper) face of the double bond in oxime 4 favors the
re (bottom) face attack of iodine on the double bond result-
ing in 7a as the major isomer (46%), the poor yield of 7c
(12%) in this process was attributed to the si face
attack of the iodine on it (Fig. 3). The same argument
can be applied for the better yield of 7b (29%) as com-
pared to 7d (2%), both obtained from the Z-isomer of
oxime 4.
Thus, after establishing the stereostructure of 10, the major
isomer was identified as THF 7a (2,5-trans). The NOE and
NOESY experiments for compound 7c showed the cis rela-
1
tionship between H2 and H5. Its H NMR spectra showed
the appearance of a triplet at d 4.29 ppm due to proton H4
(J4,3 = J4,5 = 2.97 Hz) and a double doublet at d 4.02 ppm
due to H3 (J3,2 = 5.10 Hz, J3,4 = 2.85 Hz), clearly indicat-
ing the pseudoequatorial orientation of H3, H4, and H5
and pseudoaxial orientation of H2, and thereby showing
a slight distortion in the ring structure due to unfavorable
1,3-steric interaction between CH2I at C5 and OBn at C3. It
can be argued here that based on NOE experiments and
coupling constants between the vicinal protons as illus-
trated above, the H3–H4 torsion angle20 is greater than
90ꢁ and therefore, the stereostructure of this isomer could
be assigned as 7c (Fig. 2). The NMR spectra of the remain-
Encouraged by these results, we performed similar experi-
ments under identical conditions using O-methylhydroxyl-
amine hydrochloride and hydroxylamine hydrochloride,
respectively, with a view to test their efficacy toward the
iodocyclization reaction. The formation of four THF
BnO
BnO
OH
OH
BnO
OR
OH
OH
OBn
I2 (1.5 eq)
N
N
I
I
N
I
+
+
RO
RO
N
O
O
O
O
DCM, rt
1-2 h
OR
OH
OBn
BnO
OR
N
I
7. R=Bn, 8.R=Me, 9.R=H
Scheme 3.

2072
V. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 2069–2078
xyl amines. Here an inseparable mixture of E- and Z-iso-
R
OH
I2
H
mers (75:25) of oxime 6 was isolated in 52% yield. Its
iodocyclization furnished only two isolable diastereoiso-
mers of THF derivative 9. These two isomers were sepa-
rated by column chromatography (from TLC) but
subsequently isomerized into a mixture of two diastereoiso-
mers during evaporation of their chromatographic eluents
and identified as 9a and 9b (Tables 1 and 2).
OH
H
H
H
H
R
I2
disfavoured π-complex
H
favoured π-complex
I2
H
H
H
HO
OBn
RON
BnO
H
H
H
H
OBn
BnO
These results clearly indicated that the iodocyclization of
oximes 4–6 involved the participation of the C2 benzyloxy
oxygen atom to furnish the 2,5-trans THF scaffold as
major isomers. In order to synthesize the 2,5-cis THFs
we required a methyl a,D-glycopyranoside whose stereo-
chemistry at C2 should be opposite to that of methyl
a,D-glucopyranoside. Therefore, we identified the commer-
cially available methyl a,D-mannopyranoside 11 as a suit-
able starting material in this endeavor. Adopting similar
experimental protocols as described above to obtain THFs
7–9 from their respective oxime derivatives, the iodocycli-
zation of oxime 16 derived from 11 furnished chromato-
graphically pure 2,5-cis THF derivatives 17a and 17b
(Scheme 4). Their stereostructures were established by the
combined use of 1D and 2D NMR experiments.
OH
I2
H
RON
Top β-attack
Bottom α-attack
H
O
H
O
I
I
RON
RON
BnO
OH
7a
major isomer
OH
BnO
7c
minor isomer
Figure 3.
isomers in the case of O-methylhydroxylamine hydrochlo-
ride was also noticed in the crude H NMR spectra of 8.
1
Three isomers were separated by the column chromato-
graphy of the crude product mixture but the fourth isomer
could not be isolated from this series as its yield was negli-
gible. These isomers were identified as 8a–c by their
detailed spectral analyses and also based on the identifica-
tion of 7a–d.
Here the exclusive formation of 2,5-cis THF 17 from the
oxime 16 might be due to high diastereofacial selectivity
in electrophilic addition of iodine on the C5–C6 double
bond in 16 to form p complex. On the other hand, the pref-
erential formation of 2,5-trans THFs 7a and 7b, 8a and 8b,
and 9a and 9b over their cis-isomers may be attributed to
the moderate facial selectivity in the process of the iodocyc-
lization of oximes 4–6 (Fig. 4).22
However, when hydroxylamine hydrochloride was used the
results were different when compared to substituted hydro-
HO
HO
HO
I
Ph
PhCH(OMe)2
CSA, DMF, rt
O
O
OH
OBn
OR
O
O
O
i. I2, MeOH, 80oC
HO
RO
BnO
ii. I2, Ph3P,
Imidazole,Toluene.
11
OMe
OMe
OMe
12 R=H
14
BnBr, KOH,
toluene
Zn dust, NH4Cl
cyanocobalamine
MeOH, rt, 40 min.
13 R=Bn
reflux
BnO
OBn
BnO
OBn
OH
BnO
OH
OBn
BnONH2.HCl
I2(1.5 eq),
N
+
I
N
N
Pyridine, DCM,
reflux, 1 h
I
DCM, rt, 1 h
OBn
HO
BnO
O
O
OH
OBn
O
17b (33%)
17a (40%)
16 (anti:syn 6:1)
15
Scheme 4.
NOR
H
H
BnO
BnO
OBn
NOR
H
x
H
I2
H
H
I2
H
H
H
BnO
OH
OH
H
H
H
16
4-6
Figure 4.

V. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 2069–2078
2073
70 eV. Optical rotations were determined on an Autopol
III polarimeter using a 1 dm cell at 28 ꢁC in chloroform
and methanol as the solvents; concentrations mentioned
are in g/100 mL.
BnO
OH
RON
I
O
4.1.1. (3R,4S,5R) 3,4-Bis(benzyloxy)-5-vinyl-tetrahydro-
furan-2-ol 3. To a magnetically stirred suspension of Zn
dust (1.36 g, 20.79 mmol) and NH4Cl (1.11 g, 20.76 mmol)
in dry methanol (35 mL) was added cyanocobalamine
(10 mg, 0.007 mmol) and allowed to stir for 10 min. After
that, a solution of 2 (1.0 g, 2.07 mmol) in dry methanol
was added and the resulting solution was further stirred till
the disappearance of starting material (TLC control, 1 h).
The reaction mixture was filtered through a Celite bed.
The filtrate was evaporated under reduced pressure. The
residue obtained was dissolved in ethyl acetate (25 mL)
and washed with a mixture of brine and water (1:1 v/v,
10 mL each). The organic layer was dried over Na2SO4
and concentrated to give 3, which was purified by column
chromatography to obtain a colorless oil (diasteromeric
mixture, 572 mg, 85%). Eluent for column chromato-
graphy: EtOAc/hexane (1/9, v/v); Rf 0.55 (1/1, EtOAc/
hexane); 1H NMR (300 MHz) d 7.38–7.22 (m, 10H),
6.12–5.92 (m, 1H), 5.51–5.24 (m, 3H), 4.65 (dd, J = 3.33,
8.22 Hz, 1H), 4.60–4.46 (m, 4H), 4.00–3.91 (m, 2H); 13C
NMR (75 MHz, CDCl3) d 137.5 (Ar qC), 134.6 (@CH),
134.0 (@CH), 129.2, 129.1, 129.0, 128.9, 128.7, 128.6,
128.5, 128.3, 128.2 (ArC), 119.3 (@CH2), 119.1 (@CH2),
101.6 (CH anomeric), 96.5 (CH anomeric), 85.5 (CH),
83.9 (CH), 83.2 (CH), 82.3 (CH), 80.5 (CH), 80.1 (CH),
73.7(CH2), 73.2 (CH2), 72.8 (CH2), 72.5 (CH2); IR (neat,
cmꢀ1) 3378, 3021, 2931, 2365, 1710, 1657, 1523, 1217,
1050; mass (ESI-MS) m/z 326; found 344 [M+NH4]+.,
326 [M]+Å, 309 [MꢀOH]+Å; EI-HRMS: calcd for
C20H22O4: 326.1518, measured 326.1539.
Figure 5. Sites of diversification.
Moreover, in all the cases, iodocyclization of inseparable
E- and Z-oxime isomers predominantly resulted 4,5-cis
THF derivatives. These results suggested that no significant
differences should be expected between the iodocyclization
of each oxime isomer.13
3. Conclusion
In conclusion, we have developed an efficient method to
obtain densely functionalized, stereochemically pure tetra-
substituted 2,5-trans-7a and 7b, 8a and 8b, and 9a and 9b
and 2,5-cis-17a and 17b THF derivatives as novel scaffolds.
Here we successfully isolated all these THF isomers and
established their stereostructure, which was not the case
in the earlier report on intramolecular cyclization reactions
of sugar derived c-hydroxyalkenes.8e The production of a
mixture is potentially problematic in such applications,
but in this study, each isomeric THF was separated from
the mixture and therefore, access to all isomers in the dis-
covery phase can be advantageous. All these THFs with
an appropriate orientation of functional groups and three
points of diversification (Fig. 5) can generate chemical
libraries for a broad spectrum of biological screening.
4. Experimental
4.1. General
4.1.2. (2S,3S,4R) 2,3-Bis(benzyloxy)-4-hydroxy hex-5-enal
O-benzyl oxime 4. To a solution of 3 (500 mg, 1.53 mmol)
in dry DCM (15 mL) were added O-benzylhydroxylamine
hydrochloride (612 mg, 2.5 equiv), pyridine (0.4 mL) and
this reaction mixture allowed to reflux. After completion
of the reaction (TLC control, 5 h), saturated aqueous solu-
tion of NaHCO3 was added to neutralize the reaction mix-
ture. The organic layer was separated, dried over Na2SO4,
and evaporated to dryness under reduced pressure to an
oily product mixture that was subjected to column chroma-
tography to obtain 4 (inseparable mixture of E- and Z-
isomers, 86%) as a colorless oil. Eluent for column chroma-
tography: EtOAc/hexane (2/23, v/v); Rf 0.45 (1/4, EtOAc/
hexane); 1H NMR (300 MHz, CDCl3) d 7.55 (d, J =
7.95 Hz, 1H, H-1, E-isomer), 7.39–7.28 (m, 10H, 10ArH),
5.83 (ddd, J = 5.67, 10.50, 17.13 Hz, 1H, H-5), 5.27 (dt,
J = 1.44, 17.25 Hz, 1H, H-6a), 5.18–5.14 (m, 3H, H-6b
and NOCH2Ph), 4.77–4.35 (m, 4H, 2 · CH2Ph), 4.32 (br
s, 1H, H-4), 4.22 (dd, J = 5.34, 7.92 Hz, 1H, H-2), 3.55
(dd, J = 3.96, 5.31 Hz, 1H, H-3), 2.45 (br s, 1H, OH);
13C NMR (75 MHz, CDCl3) d 152.0 (HC@N), 149.6
(HC@N), 138.3 (@CH), 138.0 (Ar qC), 137.9 (Ar qC),
137.8 (@CH), 137.7 (Ar qC), 128.9, 128.8, 128.7, 128.6,
128.4, 128.4, 128.3 (ArC), 117.4 (@CH2), 116.9 (@CH2),
82.8 (CH), 82.4 (CH), 77.3 (CH), 76.9 (CH2), 76.5 (CH2),
75.4 (CH2), 75.1 (CH2), 72.8 (CH), 72.7 (CH), 72.6
Organic solvents were dried by standard methods. The
oxime derivatives 4–6 and 16 were synthesized in the
laboratory. All the products were characterized by 1H,
13C, two-dimensional homonuclear COSY (correlation
spectroscopy), heteronuclear single quantum coherence
(HSQC), heteronuclear multiple bond correlation spectros-
copy (HMBC), IR, ESI-MS, and elemental analysis (C, H,
N). Analytical TLC was performed using 2.5 · 5 cm plates
coated with a 0.25 mm thickness of silica gel (60F-254), and
visualization was accomplished with CeSO4 or 10% H2SO4/
EtOH and subsequent charring over hot plate. Column
chromatography was performed using silica gel (60–120
and 100–200 mesh). NMR spectra were recorded on Bru-
ker Avance DPX 200FT, Bruker Robotics, and Bruker
DRX 300 Spectrometers at 200, 300 MHz (1H) and 50,
75 MHz (13C). Experiments were recorded in CDCl3 and
CD3OD at 25 ꢁC. Chemical shifts are given on the d scale
and are referenced to the TMS at 0.00 ppm for proton
and 0.00 ppm for carbon. For 13C NMR reference CDCl3
appeared at 77.16 ppm. IR spectra were recorded on
Perkin–Elmer 881 and FTIR-8210 PC Shimadzu Spectro-
photometers. Mass spectra were recorded on a JEOL
JMS-600H high resolution spectrometer using EI mode at

2074
V. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 2069–2078
(CH2), 72.3 (CH), 71.7 (CH2); IR (neat, cmꢀ1) 3447, 3065,
3032, 2926, 1597, 1496, 1455, 1210, 1073, 1020; mass (ESI-
MS) m/z 431; found 432 [M+1]+Å, 454 [M+Na]+Å. Elemen-
tal Anal. Calcd for C27H29NO4: C, 73.6; H, 6.9; N, 3.2.
Found: C, 73.1; H, 6.6; N, 3.6.
1H, H-2), 3.59 (dd, J = 3.63, 5.64 Hz, 1H, H-3); 13C
NMR (75 MHz, CDCl3) d 152.2 (HC@N), 150.4 (HC@N),
138.3 (@CH), 138.2 (Ar qC), 138.0 (Ar qC), 137.8 (@CH),
128.9, 128.8, 128.6, 128.5, 128.4 (ArC), 117.4 (@CH2),
116.9 (@CH2), 82.8 (CH), 82.4 (CH), 77.6 (CH), 75.6
(CH2), 75.4 (CH2), 72.9 (CH2), 72.8 (CH) 72.6 (CH), 72.3
(CH), 72.0 (CH2); IR (KBr, cmꢀ1): 3228, 2926, 1600,
1456, 1397, 1350, 1124, 1068, 1031; mass (ESI-MS) m/z
341. Found: 343 [M+2]+Å, 342 [M+1]+Å; EI-HRMS: calcd
for C20H23O4N: 341.1627, measured 341.1617.
4.1.3. (2S,3S,4R) 2,3-Bis(benzyloxy)-4-hydroxy hex-5-enal
O-methyl oxime 5. To a solution of 3 (1.0 g, 3.07 mmol)
in dry DCM (30 mL) were added O-methylhydroxylamine
hydrochloride (641 mg, 2.5 equiv), pyridine (0.8 mL) after
which this reaction mixture was allowed to reflux. After
completion of reaction (TLC control, 3.5 h), saturated
aqueous solution of NaHCO3 was added to neutralize the
reaction mixture. The organic layer was separated, dried
over Na2SO4, and evaporated to dryness under reduced
pressure to an oily product mixture that was purified by
column chromatography to yield 5 (inseparable mixture
of E and Z isomers, 880 mg, 81%), colorless oil. Eluent
for column chromatography: EtOAc/hexane (2/23, v/v);
4.1.5. General procedure for the synthesis of THF deriva-
tive. To a stirred solution of oxime (0.7 mmol) in dry
DCM (20 mL), iodine (266 mg, 1.5 equiv) was added por-
tionwise and the reaction mixture was allowed to stir at
room temperature. After completion of the reaction
(TLC control, 1–2 h), 10% aqueous Na2S2O3 was added
to neutralize the excess iodine. The organic layer was sep-
arated, dried over Na2SO4, and concentrated to dryness
to furnish a mixture of products that was subjected to puri-
fication by column chromatography to obtain 7a–d.
1
Rf 0.56 (1:4 EtOAc/hexane); H NMR (300 MHz, CDCl3)
d 7.45 (d, J = 8.01 Hz, 1H, H-1, E-isomer), 7.36–7.24 (m,
10H, ArH), 5.93–5.82 (m, 1H, H-5), 5.32 (dt, J = 1.29,
17.22 Hz, 1H, H-6a), 5.19 (dt, J = 1.20, 10.50 Hz, 1H,
H-6b), 4.80 (d, J = 11.28 Hz, 1H, CH2Ph), 4.69 (d,
J = 10.32 Hz, 1H, CH2Ph), 4.65 (d, J = 9.87 Hz, 1H,
CH2Ph), 4.46 (d, J = 11.71 Hz, 1H, CH2Ph), 4.36 (br s,
1H, H-4), 4.26 (dd, J = 5.37, 7.95 Hz, 1H, H-2), 3.92 (s,
3H, CH3), 3.58 (dd, J = 3.93, 5.22 Hz, 1H, H-3), 13C
NMR (75 MHz, CDCl3) d 151.3 (CH@N), 148.9 (CH@N),
138.4 (@CH), 138.3 (Ar qC), 138.1 (Ar qC), 137.8 (@CH),
128.9, 128.8, 128.7, 128.5, 128.4 (Ar C), 117.4, 117.0
(@CH2), 82.9 (CH), 82.4 (CH), 77.5 (CH), 75.5 (CH2),
75.2 (CH2), 72.9 (CH), 72.8 (CH2), 72.3 (CH), 71.9
(CH2), 62.7 (CH3), 62.4 (CH3); IR (neat, cmꢀ1) 3465,
3035, 2936, 1597, 1455, 1351, 1210, 1042; mass (ESI-MS)
m/z 355. Found: 378 [M+Na]+Å, 357 [M+2]+Å; 356
[M+1]+Å; 316, 254, 181, 91. Elemental Anal. Calcd for
C21H25NO4: C, 70.9; H, 7.1; N, 3.9. Found: C, 70.6; H,
7.4; N, 4.1.
4.1.6. (10E,2S,3R,4S,5R) 3-Benzyloxy-4-hydroxy-5-iodo-
methyl tetrahydrofuran-2-carbaldehyde O-benzyl oxime 7a.
Yield 46%, a colorless solid (mp 76–78 ꢁC), eluent for
column chromatography: EtOAc/hexane (3/47, v/v);
[a]D = +29.4 (c 0.18, CHCl3); Rf 0.42 (1/4 EtOAc/hexane);
1H NMR (300 MHz, CDCl3) d 7.53 (d, J = 7.68 Hz, 1H,
H-10), 7.35–7.25 (m, 10-H, 10ArH), 5.09 (s, 2H, NOCH2Ph),
4.79 (dd, J = 3.90, 7.62 Hz, 1H, H-2), 4.59–4.45 (m, 4H,
CH2Ph, H-4, H-5), 4.02 (d, J = 3.63 Hz, 1H, H-3), 3.26–
3.20 (m, 2H, H-6), 2.05 (br s, 1H, OH); 13C NMR
(75 MHz, CDCl3) d 148.5 (HC@N), 137.9 (Ar qC), 137.8
(Ar qC), 129.1, 129.0, 128.8, 128.6, 128.5, 128.1 (ArC),
86.3 (CH), 82.0 (CH), 79.5 (CH), 76.7 (CH2), 75.3 (CH),
73.1 (CH2), 1.1 (CH2I); IR (neat, cmꢀ1) 3448 , 2933, 2873,
1596, 1496, 1455, 1257, 1081, 1035; mass (ESI-MS) m/z
467; found 468 [M+1]+Å, 461, 340 [MꢀI]+Å; EI-HRMS: calcd
for C20H22NO4I: 467.0594, measured 467.0610.
4.1.4. (2S,3S,4R) 2,3-Bis(benzyloxy)-4-hydroxy hex-5-enal
oxime 6. To a solution of 3 (1.02 g, 3.13 mmol) in dry
DCM (30 mL) were added hydroxylamine hydrochloride
(544 mg, 2.5 equiv) and pyridine (0.8 mL) after which this
reaction mixture was stirred at room temperature. After
completion of reaction (TLC control, 24 h), saturated
aqueous solution of NaHCO3 was added to neutralize the
reaction mixture. The organic layer was separated, dried
over Na2SO4, and evaporated to dryness under reduced
pressure to obtain an oily product mixture. This on column
chromatographic purification furnished 6 (inseparable mix-
ture of E- and Z-isomers, 556 mg, 52%) as a colorless solid
(mp 68–71 ꢁC). Eluent for column chromatography:
EtOAc/hexane (7/43, v/v); Rf 0.43 (3:7 EtOAc/hexane,
v/v); 1H NMR (300 MHz, CDCl3) d 8.37 (br s, 1H,
@N–OH), 7.55 (d, J = 7.86 Hz, 1H, H-1), 7.35–7.31 (m,
10H, ArH), 5.84 (ddd, J = 5.58, 10.59, 16.92 Hz, 1H,
H-5), 5.31 (dt, J = 1.38, 15.87 Hz, 1H, H-6a), 5.19 (dt,
J = 1.20, 10.50 Hz, 1H, H-6b), 4.79 (d, J = 11.25 Hz, 1H,
CH2Ph), 4.68 (d, J = 8.76 Hz, 1H, CH2Ph), 4.64 (d,
J = 8.28 Hz, 1H, CH2Ph), 4.45 (d, J = 11.73 Hz, 1H,
CH2Ph), 4.36 (br s, 1H, H-4), 4.28 (dd, J = 5.73, 7.86 Hz,
4.1.7. (10E,2S,3R,4S,5R) 3-Benzyloxy-4-acetyloxy-5-iodo-
methyl tetrahydrofuran-2-carbaldehyde O-benzyl oxime 10.
Yield 72%, colorless oil, eluent for column chromato-
graphy: EtOAc/hexane (1/24, v/v); [a]D = +156.8 (c 0.19,
CHCl3) Rf 0.47 (1/9, EtOAc/hexane); 1H NMR (300
MHz, CDCl3) d 7.53 (d, J = 7.74 Hz, 1H, H-10), 7.36–
7.18 (m, 10H, ArH), 5.44 (d, J = 3.63 Hz, 1H, H-4), 5.09
(s, 2H, NOCH2Ph), 4.76 (d, J = 12.12 Hz, 1H, CH2Ph),
4.68 (dd, J = 4.11, 7.71 Hz, 1H, H-2), 4.65–4.60 (m, 1H,
H-5), 4.57 (d, J = 12.09 Hz, 1H, CH2Ph), 4.04 (d, J =
4.08 Hz, 1H, H-3), 3.29–3.15 (m, 2H, H-6), 2.10 (s, 3H,
COCH3); 13C NMR (75 MHz, CDCl3) d 170.3 (COMe),
147.9 (HC@N), 137.9 (Ar qC), 137.7 (Ar qC), 129.0,
128.9, 128.7, 128.6, 128.5, 128.3 (ArC), 84.1 (CH), 80.6
(CH), 79.6 (CH), 76.7 (CH2), 76.6(CH), 72.8 (CH2), 21.3
(CH3), ꢀ0.3 (CH2I); IR (neat, cmꢀ1) 3032, 2922, 1744,
1596, 1496, 1454, 1371, 1230, 1065, 1032; mass (ESI-MS)
m/z 509; found 511 [M+2]+Å, 510 [M+1]+Å, 382 [MꢀI]+Å.
4.1.8. (10Z,2S,3R,4S,5R) 3-Benzyloxy-4-hydroxy-5-iodo-
methyl tetrahydrofuran-2-carbaldehyde O-benzyl oxime 7b.
Yield 29%, colorless oil, eluent for column chromato-

V. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 2069–2078
2075
graphy: EtOAc/hexane (3/47, v/v); [a]D = +141.25 (c 0.16,
CHCl3); Rf 0.56 (1/4, EtOAc/hexane); 1H NMR
(300 MHz, CDCl3) d 7.35–7.21 (m, 10H, ArH), 6.91 (d,
J = 4.26 Hz, 1H, H-10), 5.30 (t, J = 3.99, 4.08 Hz, 1H, H-
2), 5.10 (s, 2H, NOCH2Ph), 4.50–4.44 (m, 3H, CH2Ph,
H-5), 4.39 (br s, 1H, H-4), 4.26 (d, J = 3.75 Hz, 1H, H-
3), 3.26–3.23 (m, 2H, H-6), 1.98 (br s, 1H, OH); 13C
NMR (75 MHz, CDCl3) d 151.2 (HC@N), 138.1 (Ar qC),
129.1, 129.0, 128.9, 128.7, 128.6, 128.4, 128.2 (ArC), 85.4
(CH), 81.9 (CH), 77.7 (CH), 77.0 (CH2), 75.3 (CH), 73.1
(CH2), 1.0 (CH2I); IR (neat, cmꢀ1) 3433, 2928, 1596,
1496, 1455, 1209, 1088, 1026; mass (ESI-MS) m/z 467;
found 468 [M+1]+Å, 454, 432, 340 [MꢀI]+Å.
4.1.9. (10E,2S,3R,4S,5S) 3-Benzyloxy-4-hydroxy-5-iodo-
methyl tetrahydrofuran-2-carbaldehyde O-benzyl oxime 7c.
Yield 12%, a colorless solid (mp 68–70 ꢁC), eluent for
column chromatography: EtOAc/hexane (3/47, v/v);
[a]D = ꢀ7.5 (c 0.16, CHCl3); Rf 0.31 (1/4 EtOAc/hexane);
1H NMR (300 MHz, CDCl3) d 7.56 (d, J = 7.71 Hz, 1H,
H-10), 7.37–7.24 (m, 10H, ArH), 5.11 (s, 2H, NOCH2Ph),
4.72 (dd, J = 5.07, 7.74 Hz, 1H, H-2), 4.52 (s, 2H, CH2Ph),
4.29 (t, J = 2.97, 1H, H-4), 4.02 (dd, J = 2.85, 5.10 Hz, 1H,
H-3), 3.93 (ddd, J = 3.63, 5.61, 9.12 Hz, 1H, H-5), 3.37–
3.26 (m, 2H, H-6), 2.12 (br s, 1H, OH); 13C NMR
(75 MHz, CDCl3) d 148.4 (HC@N), 137.8 (Ar qC), 137.7
(Ar qC), 129.1, 129.0, 128.8, 128.7, 128.6, 128.5, 128.4,
128.3, 127.9 (ArC), 86.2 (CH), 85.3 (CH), 79.4 (CH), 79.1
(CH), 76.7 (CH2), 73.0 (CH2), 6.6 (CH2I); IR (neat,
cmꢀ1) 3409, 3029, 2925, 1610, 1495, 1455, 1364, 1216,
1074, 1024; mass (ESI-MS) m/z 467; found 468 [M+1]+Å,
432, 340 [MꢀI]+Å; EI-HRMS: calcd for C20H22NO4I:
467.0594, measured 467.0548.
137.8 (Ar qC), 129.6, 129.1, 128.6, 128.3, 128.1 (ArC),
86.3 (CH), 82.0 (CH), 79.5 (CH), 75.3 (CH), 73.1 (CH2),
62.4 (CH3), 1.1 (CH2I); IR (KBr, cmꢀ1) 3421, 2937, 2820,
1594, 1458, 1385, 1351, 1276, 1108, 1033; mass (ESI-MS)
m/z 391; found 393 [M+2]+Å, 392 [M+1]+Å, 264 [MꢀI]+Å;
EI-HRMS: calcd for C14H18NO4I: 391.0281, measured
391.0266.
4.1.12. (10Z,2S,3R,4S,5R)-3-Benzyloxy-4-hydroxy-5-iodo-
methyltetrahydrofuran-2-carbaldehyde O-methyl oxime 8b.
Yield 27%, colorless oil, eluent for column chromatogra-
phy: EtOAc/toluene (1/19, v/v); [a]D = +69.8 (c 0.41,
CHCl3); Rf 0.58 (1/4 EtOAc/toluene); 1H NMR (300
MHz, CDCl3) d 7.41–7.28 (m, 5H, ArH), 6.89 (d, J =
4.38 Hz, 1H, H-10), 5.26 (t, J = 4.14, 4.08 Hz, 1H, H-2),
4.58 (d, J = 2.4 Hz, 1H, CH2Ph), 4.53–4.47 (m, 1H, H-5),
4.43 (br s, 1H, H-4), 4.28 (d, J = 3.84 Hz, 1H, H-3), 3.88
(s, 3H, OCH3), 3.30–3.27 (m, 2H, H-6), 2.07 (br s, 1H,
OH); 13C NMR (75 MHz, CDCl3) d 150.6 (HC@N),
138.1 (Ar qC), 129.0, 128.8, 128.7, 128.5, 128.3 (ArC),
85.2 (CH), 81.9 (CH), 77.4 (CH), 75.3 (CH), 73.1 (CH2),
62.6 (CH3), 1.02 (CH2I); IR (Neat, cmꢀ1) 3434, 2933,
2820, 1596, 1457, 1384, 1352, 1209, 1077, 1044; mass
(ESI-MS) m/z 391; found 393 [M+2]+Å, 392 [M+1]+Å, 264
[MꢀI]+Å.
4.1.13. (10E,2S,3R,4S,5S)-3-Benzyloxy-4-hydroxy-5-iodo-
methyl tetrahydrofuran-2-carbaldehyde O-methyl oxime 8c.
Yield 9%, colorless oil, eluent for column chromatography:
EtOAc/toluene (1/19, v/v); [a]D = ꢀ11.1 (c 0.18, CHCl3);
Rf 0.36 (1/4, EtOAc/toluene); 1H NMR (300 MHz,
CDCl3) d 7.48 (d, J = 7.80 Hz, 1H, H-10), 7.39–7.28 (m,
5H, ArH), 4.71 (dd, J = 5.01, 7.80 Hz, 1H, H-2), 4.57 (s,
2H, OCH2Ph), 4.32 (t, J = 2.85 Hz, 1H, H-4), 4.05 (dd,
J = 2.64, 4.95 Hz, 1H, H-3), 3.95 (ddd, J = 3.51, 5.61,
8.82 Hz, 1H, H-5), 3.88 (s, 3H, OCH3), 3.39–3.28 (m, 2H,
H-6), 2.30 (br s, 1H, OH); 13C NMR (75 MHz, CDCl3) d
147.7 (HC@N), 137.8 (Ar qC), 129.2, 128.6, 128.4 (ArC),
86.3 (CH), 85.5 (CH), 79.4 (CH), 79.2 (CH), 73.0 (CH2),
62.4 (CH3), 6.7 (CH2I); IR (KBr, cmꢀ1) 3437, 2926, 2856,
1595, 1458, 1382, 1351, 1040; mass (ESI-MS) m/z 391;
found 393 [M+2]+Å, 392 [M+1]+Å, 264 [MꢀI]+Å; EI-HRMS:
calcd for C14H18O4NI: 391.0281, measured 391.0231.
4.1.10. (10Z,2S,3R,4S,5S) 3-Benzyloxy-4-hydroxy-5-iodo-
methyl tetrahydrofuran-2-carbaldehyde O-benzyl oxime 7d.
Yield 2%, colorless oil, eluent for column chromatography:
EtOAc/hexane (3/47, v/v); [a]D = +114.0 (c 0.05, CHCl3);
Rf 0.47 (1/4 EtOAc/hexane); 1H NMR (300 MHz,
CDCl3): d 7.35–7.27 (m, 10H, ArH), 6.93(d, J = 4.38 Hz,
1H, H-10), 5.18 (t, J = 4.32 Hz, 1H, H-2), 5.11 (s, 2H,
NOCH2Ph), 4.46 (s, 2H, CH2Ph), 4.29 (br s, 1H, H-4),
4.17 (dd, J = 1.32, 4.26 Hz, 1H, H-3), 4.01–3.95 (m, 1H,
H-5), 3.34–3.30 (m, 2H, H-6), 1.83 (br s, 1H, OH); 13C
NMR (75 MHz) d 150.3 (HC@N), 138.1 (Ar qC), 129.0,
128.8, 128.6, 128.5, 128.3 (Ar qC), 86.5 (CH), 85.8 (CH),
79.8 (CH), 77.8 (CH), 77.1 (CH2), 73.2 (CH2), 6.1
(CH2I); IR (neat, cmꢀ1) 3448, 3019, 2928, 1645, 1457,
1368, 1218, 1080, 1033; mass (ESI-MS) m/z 467; found
468 [M+1]+Å, 454, 432, 340 [MꢀI]+Å.
4.1.11. (10E,2S,3R,4S,5R)-3-Benzyloxy-4-hydroxy-5-iodo-
methyl tetrahydrofuran-2-carbaldehyde O-methyl oxime 8a.
Yield 40%, a colorless solid (mp 59–62 ꢁC), eluent for
column chromatography: EtOAc/toluene (1/19, v/v);
[a]D = +60.0 (c 0.28, CHCl3); Rf 0.45 (1/4 EtOAc/toluene);
1H NMR (300 MHz, CDCl3) d 7.47 (d, J = 7.65 Hz, 1H,
H-10), 7.41–7.28 (m, 5H, ArH), 4.81 (dd, J = 3.87,
7.62 Hz, 1H, H-2), 4.67–4.56 (m, 2H, OCH2Ph), 4.53–
4.48 (m, 2H, H-4, H-5), 4.08 (d, J = 3.63 Hz, 1H, H-3),
3.89 (s, 3H, OCH3), 3.30–3.27 (m, 2H, H-6), 2.02 (br s,
1H, OH), 13C NMR (75 MHz, CDCl3) d 147.8 (HC@N),
4.1.14. Mixture of 10E- and 10Z-(2S,3R,4S,5R) 3-benzyloxy-
4-hydroxy-5-iodomethyl
tetrahydrofuran-2-carbaldehyde
oximes 9a and 9b. Yield 50%, colorless oil, eluent for col-
umn chromatography: EtOAc/toluene (2/23, v/v); Rf 0.34,
1
0.55 (3/7, EtOAc/toluene); H (300 MHz, CDCl3): d 7.82
(br s, 0.7H, @N–OH), 7.52 (d, J = 7.47 Hz, 0.63H, H-10,
E-isomer), 7.39–7.28 (m, 5H, ArH), 6.94 (d, J = 4.32 Hz,
0.37H, H-10, Z-isomer), 5.35 (t, J = 4.05 Hz, 0.5H, H-2,
Z-isomer), 4.81 (dd, J = 3.96, 7.53 Hz, 0.7H, H-2, E-iso-
mer), 4.61–4.57 (m, 2H, CH2Ph), 4.54–4.43 (m, 2H, H-4,
H-5), 4.34 (d, J = 3.69 Hz, 0.56H, H-3, Z-isomer), 4.07 (d,
J = 3.96 Hz, 0.73H, H-3, E-isomer), 3.30–3.25 (m, 2H, H-
6); 13C (75 MHz, CDCl3) d 151.9 (HC@N), 149.5 (HC@N),
138.1 (Ar qC), 137.8 (Ar qC), 129.2, 129.0, 128.7, 128.5,
128.3, 128.2 (ArC), 86.3 (CH), 85.4 (CH), 82.1 (CH), 81.9
(CH), 79.5 (CH), 77.1 (CH), 75.4 (CH) 75.3 (CH), 73.3
(CH2), 73.1 (CH2), 0.9 (CH2I); IR (neat, cmꢀ1) 3414,
2926, 1596, 1459, 1383, 1352, 1094; mass (ESI-MS) m/z

2076
V. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 2069–2078
377; found 378 [M+1]+Å, 250 [MꢀI]+Å; EI-HRMS: calcd for
4.27 mmol), and imidazole (612 mg, 8.99 mmol) were
added. The resultant reaction mixture was stirred at
50 ꢁC till the disappearance of the starting material (TLC
control, 1 h). The reaction mixture was cooled to room
temperature, diluted with methanol, and the solvent was
removed under reduced pressure. To the residue obtained
was added 10% aqueous Na2S2O3 solution (30 mL) and
extracted with CH2Cl2 (3 · 15 mL). The combined organic
layer was dried and evaporated to dryness. The Ph3PO was
precipitated with anhydrous diethyl ether. The resulting
solution was decanted and evaporated to dryness under re-
duced pressure. The crude product was purified by column
chromatography to give 14 (1.2 g, 85% from 13) as a color-
less oil, eluent for column chromatography: EtOAc/tolu-
ene (1/24, v/v); [a]D = ꢀ2.8 (c 0.25, CHCl3); Rf 0.57 (1/4,
EtOAc/toluene); 1H NMR (300 MHz, CDCl3) d 7.37–
7.28 (m, 10H), 4.80 (d, J = 1.5 Hz, 1H), 4.67–4.38 (m,
4H, 2 · CH2Ph), 3.84 (br d, J = 8.58 Hz, 1H), 3.79 (dd,
J = 1.92, 2.97 Hz, 1H) 3.68–3.62 (m, 2H), 3.52 (td,
J = 2.04, 8.76 Hz, 1H), 3.41 (s, 3H), 3.33–3.26 (m, 1H),
2.33 (d, J = 1.59 Hz, 1H); 13C NMR (75 MHz, CDCl3) d
138.1 (Ar qC), 137.9 (Ar qC), 128.7, 128.5, 128.1, 127.9
(ArC), 99.3 (CH), 79.5 (CH), 73.8 (CH), 72.8 (CH2), 72.2
(CH), 71.7 (CH2), 70.6 (CH), 55.3 (CH3), 6.7 (CH2); IR
(neat, cmꢀ1) 3447, 3033, 2925, 1654, 1458, 1201, 1120,
1071; mass (ESI-MS) m/z 484; found 502 [M+NH4]+Å,
342 [MꢀIꢀMe]+Å, 279, 181.
C13H16O4NI: 377.0124, measured 377.0165.
4.1.15. Methyl 4,6-O-benzylidene-a-D-mannopyranoside 12.
To a solution of methyl a,D-mannopyranoside 11 (5.0 g,
25.8 mmol) in DMF (40 mL) were added benzaldehyde
dimethylacetal (4.6 mL, 1.2 equiv) and camphorsulfonic
acid (0.60 g, 2.58 mmol). The reaction mixture was allowed
to stir at room temperature until completion of the reaction
(TLC control, 24 h). Later, the reaction mixture was
neutralized with triethylamine and DMF was evaporated
under reduced pressure. The residue obtained was purified
by column chromatography to give 12 (3.48 g, 48%) as a
white solid. Eluent for column chromatography: EtOAc/
hexane (1/1, v/v); [a]D = +74.5 (c 2.1, MeOH); Rf 0.48
1
(EtOAc); H NMR (300 MHz, CD3OD+CDCl3) d 7.53–
7.49 (m, 2H), 7.40–7.35 (m, 3H), 5.61 (s, 1H), 4.71 (s,
1H), 4.27–4.22 (m, 4H), 3.96–3.93 (m, 2H), 3.41 (s, 3H),
2.01 (s, 0.8H); 13C NMR (75 MHz, CD3OD+CDCl3) d
137.2 (Ar qC), 128.7, 127.8, 126.0 (ArC), 101.9 (CH),
101.8 (CH), 78.6 (CH), 70.7 (CH), 68.5 (CH2), 67.9 (CH),
63.2 (CH), 54.5 (CH3); IR (KBr, cmꢀ1) 3455, 3007, 2937,
2903, 1653, 1459, 1218, 1128, 1028; mass (ESI-MS) m/z
282; found 300 [M+NH4]+Å.
4.1.16. Methyl-2,3-di-O-benzyl-4,6-benzylidene-a,D-manno-
pyranoside 13. To a solution of 12 (1.30 g, 4.61 mmol) in
dry toluene (16 mL) were added KOH (1.08 g, 19.3 mmol)
and benzyl bromide (2.30 mL, 19.3 mmol) in succession.
This reaction was then allowed to reflux until its comple-
tion (TLC control, 1 h). The reaction mixture was diluted
with toluene (60 mL) and washed with water. The organic
layer was evaporated to an oil. The oil was twice dissolved
in toluene and the solvent was evaporated to dryness. The
residue obtained was purified by column chromatography
to give 13 (1.46 g, 69%) as a colorless oil. Eluent for column
chromatography: EtOAc/hexane (1/9, v/v); [a]D = +32.8 (c
0.35, CHCl3); Rf 0.46 (1/4, EtOAc/hexane); 1H NMR
(200 MHz, CDCl3) d 7.45–7.17 (m, 15H, ArH), 5.57 (s,
1H), 4.78–4.69 (m, 4H), 4.61 (d, J = 3.69 Hz, 1H), 4.22–
4.13 (m, 2H), 3.86 (dt, J = 3.22 Hz, 2H), 3.77–3.68 (m,
2H), 3.24 (s, 3H); 13C NMR (75 MHz, CDCl3) d 138.9 (Ar
qC), 138.3 (Ar qC), 137.9 (Ar qC), 128.9, 128.5, 128.4,
128.3, 128.2, 127.9, 127.6, 126.2 (ArC), 101.6 (CH), 100.6
(CH), 79.3 (CH), 76.5 (CH), 76.4 (CH), 73.7 (CH2), 73.2
4.1.18. (3S,4S,5R)-3,4-Bis(benzyloxy)-5-vinyl-tetrahydro-
furan-2-ol 15. To a stirred suspension of Zn dust
(1.35 g, 20.65 mmol) and NH4Cl (1.10 g, 20.56 mmol) in
dry methanol (35 mL) was added a catalytic amount of
cyanocobalamine (10 mg, 0.007 mmol) and the resulting
mixture was allowed to stir for 10 min. To the stirring mix-
ture, methanolic solution of 14 (980 mg, 2.02 mmol) was
added and the stirring was continued until the disappear-
ance of the starting material (TLC control, 30 min.). The
reaction mixture was filtered through a Celite bed and
the filtrate was evaporated under reduced pressure. The
residue was dissolved in ethyl acetate (25 mL) and washed
with a mixture of brine and water (1:1 v/v, 10 mL each).
The organic layer was dried over Na2SO4 and concentrated
to an oil, which after column chromatographic purification
yield 15 (diastereomeric mixture, 510 mg, 77%) as a color-
less oil. Eluent for column chromatography: EtOAc/tolu-
(CH2), 69.0 (CH2), 64.2 (CH), 54.9 (CH3); IR (neat, cmꢀ1
)
ene (3/47, v/v); Rf 0.43 (1/1, EtOAc/toluene); H NMR
1
3064, 3033, 2917, 1606, 1455, 1376, 1210, 1125, 1058; mass
(200 MHz, CDCl3) d 7.37–7.32 (m, 10H, ArH), 6.17–5.99
(m, 1H), 5.42–5.25 (m, 3H), 4.79–4.57 (m, 4H), 4.37–4.26
(m, 1H), 4.04 (t, J = 3.88 Hz, 1H), 3.92 (t, J = 4.20 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 138.2 (Ar qC), 138.0
(Ar qC), 137.6 (Ar qC), 137.5 (Ar qC), 134.9 (@CH),
134.7 (@CH), 128.6, 128.5, 128.4, 128.1, 127.9, 127.8,
127.7 (ArC), 118.7 (@CH2), 100.2 (CH), 95.8 (CH), 83.6
(CH), 81.3 (CH), 81.1 (CH), 79.3 (CH), 79.2 (CH), 78.9
(CH), 74.0 (CH2), 73.1 (CH2), 72.6 (CH2), 72.1 (CH2); IR
(neat, cmꢀ1) 3459, 3031, 2926, 2367, 1743, 1651, 1508,
1456, 1245, 1145, 1091, 1036; mass (ESI-MS) m/z 326;
found 349 [M+NH4]+Å, 326 [M]+Å, 309, 291.
(ESI-MS) m/z 462; found 463 [M+1]+Å, 431 [MꢀOMe]+Å.
4.1.17. Methyl-2,3-di-O-benzyl 6-deoxy-6-iodo-a,D-manno-
pyranoside 14. To a solution of 13 (1.35 g, 2.92 mmol) in
dry methanol (36 mL) was added iodine (274 mg,
1.08 mmol) and the reaction mixture was heated at 80 ꢁC.
After the disappearance of 13, the reaction mixture was
cooled to rt, 10% aqueous Na2S2O3 solution was added
to it and the solution was evaporated to an oil, which
was subsequently dissolved in water and extracted with
CH2Cl2 (3 · 15 mL). The combined organic layer was dried
over anhydrous Na2SO4 and evaporated to an oil (1.14 g),
which was further used without purification. The oil
(1.14 g) was dissolved in toluene (35 mL) and to this solu-
tion I2 (1.15 g, 4.53 mmol), triphenylphosphine (1.12 g,
4.1.19. (2R,3S,4R) 2,3-Bis(benzyloxy)-4-hydroxy hex-5-enal
O-benzyl oxime 16. To a solution of 15 (380 mg,
1.17 mmol) in dry DCM (12 mL) were added O-benzyl-

V. Kumar et al. / Tetrahedron: Asymmetry 18 (2007) 2069–2078
2077
hydroxylamine hydrochloride (466 mg, 2.92 mmol) and
(CH2) 74.7 (CH), 71.7 (CH2), 0.1 (CH2); IR (neat, cmꢀ1
)
pyridine (0.3 mL) and this reaction mixture was allowed
to reflux. After completion of the reaction (TLC control,
1 h), saturated aqueous solution of NaHCO3 was added
to neutralize the reaction mixture. The organic layer was
separated, dried over Na2SO4, and evaporated to dryness
under reduced pressure. The residue obtained was purified
by column chromatography to obtain 16 (inseparable
mixture of E- and Z-isomers, 485 mg 97%). Colorless oil,
eluent for column chromatography: EtOAc/toluene (3/97,
3430, 3064, 3033, 2925, 1603, 1455, 1365, 1091, 1024; mass
(ESI-MS) m/z 467; found 468 [M+1]+Å, 454, 432, 340
[MꢀI]+Å.
Acknowledgments
We are thankful to Anup K. Pandey for technical assis-
tance, and S. Kanojiya and SAIF, CDRI, for providing
spectral data. V.K. thanks CSIR, New Delhi, for financial
support. This research project was partly funded by ICMR
(Reference: IRIS Cell No. 2004-02220), New Delhi.
1
v/v); Rf 0.61 (3/7, EtOAc/toluene); H NMR (300 MHz,
CDCl3) d 7.39 (d, J = 8.01 Hz, 1H, H-1, E-isomer),
7.36–7.23 (m, 10H, ArH), 5.88 (ddd, J = 5.34, 10.56,
17.25 Hz, 1H, H-5), 5.31 (dt, J = 1.53, 17.28 Hz, 1H, H-
6a), 5.20 (dt, J = 1.44, 10.38 Hz, 1H, H-6b), 5.13 (s, 2H,
NOCH2Ph), 4.71–4.33 (m, 4H, 2 · CH2Ph), 4.24 (br dd,
J = 5.1, 10.05 Hz, 1H, H-4), 4.15 (dd, J = 6.15, 7.95 Hz,
1H, H-2), 3.62 (dd, J = 4.71, 6.09 Hz, 1H, H-3), 2.68 (d,
J = 6.9 Hz, 1H, OH); 13C NMR (75 MHz, CDCl3) d
150.3 (HC@N), 148.7 (HC@N), 137.7 (Ar qC), 137.6 (Ar
qC), 137.4 (Ar qC), 137.3 (@CH), 137.0 (@CH), 128.6,
128.4, 128.3, 128.2, 128.1, 128.0 (ArC), 117.4 (@CH2),
117.0 (@CH2), 82.3 (CH), 81.7 (CH), 76.9 (CH), 76.6
(CH2), 76.3 (CH2), 74.4 (CH2), 73.8 (CH2), 72.4 (CH2),
72.2 (CH), 72.0 (CH), 71.8 (CH), 71.3 (CH2); IR (KBr,
cmꢀ1) 3469, 3065, 3032, 2923, 2366, 1636, 1454, 1366,
1207, 1077; mass (ESI-MS) m/z 431; found 454
[M+Na]+Å, 432 [M+1]+Å.
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methyl tetrahydrofuran-2-carbaldehyde O-benzyl oxime
17a. Yield 40%, a white solid (mp 82–84 ꢁC), eluent for
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[a]D = +61.9 (c 0.36, CHCl3); Rf 0.63 (1/4 EtOAc/toluene);
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