A consecutive approach towards the stereoselective synthesis of trisubstituted THF domains

Article abstract of DOI:10.1016/j.tetasy.2006.12.010

A highly efficient, consecutive approach for the construction of synthetically valued, enantiomerically pure, trisubstituted THF domains 3-10 in a stereoselective manner starting from glycal derived allylic alcohols 1a-1d under Sharpless asymmetric epoxid

Full text of DOI:10.1016/j.tetasy.2006.12.010

Tetrahedron: Asymmetry 17 (2006) 3294–3299
A consecutive approach towards the stereoselective synthesis
of trisubstituted THF domainsI
Ram Sagar,a L. Vijaya Raghava Reddy,a Mohammad Saquib,a
Brijesh Kumarb and Arun K. Shawa,*
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute (CDRI), Lucknow 226 001, India
bDivision of Sophisticated Analytical Instrumentation Facility, Central Drug Research Institute (CDRI), Lucknow 226 001, India
Received 7 November 2006; accepted 7 December 2006
Abstract—A highly efficient, consecutive approach for the construction of synthetically valued, enantiomerically pure, trisubstituted
THF domains 3–10 in a stereoselective manner starting from glycal derived allylic alcohols 1a–1d under Sharpless asymmetric epoxida-
tion (SAE) conditions is reported. The reaction involves the intramolecular asymmetric ring opening (ARO) of in situ formed enantio-
pure 2,3-epoxy alcohols followed by protection of the diol.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tio- or diastereomerically enriched epoxy alcohols, are
amongst the most valuable and versatile intermediates in
organic synthesis,9 because they readily undergo regioselec-
tive ring-opening reactions.10 As a result, the Sharpless
asymmetric epoxidation has found extensive utility in the
synthesis of natural products.11 In our research on the syn-
thetic applications of glycals derived acyclic a,b-unsatu-
rated sugar aldehydes,12 commonly known as Perlin
aldehydes,13 while carrying out epoxidation studies on
these Perlin aldehyde derived allylic alcohols, it was found
that 1c, among the allylic alcohols studied was transformed
into a THF derivative, an increasingly significant motif
in natural products14 during its SAE (Fig. 1) by using
super-stoichiometric amount of catalysts [2.0 equiv
Ti(O-i-Pr)4, 2.5 equiv diethyl tartrate (DET) and 3.0 equiv
t-BuOOH].
In recent years consecutive reactions1 have received much
attention by the chemical community, because they address
fundamental principles of synthetic efficiency and reaction
design. They are more efficient and cost effective than con-
ventional stepwise transformations, as they yield complex
molecules from simple starting materials with a high
chemo-, regio- and stereoselectivity. Ideally, these reactions
occur in a consecutive fashion, by the successive addition
of reagents, without the isolation of intermediates in the
sense of a ‘one-pot synthesis’.2
Tetrahydrofurans (THFs), found in many naturally occur-
ring compounds,3,4 are of paramount importance since
these heterocycles, both naturally produced and syntheti-
cally derived, often display diverse biological activity.5
Their stereoselective synthesis with required protections is
a desired goal despite it being an elusive and challenging
objective.
H
O
SAE
OH
OH
OBn
(-)-DET
OBn
BnO
BnO
BnO
Sharpless asymmetric epoxidation (SAE) of allylic alcohols
is one of the most significant developments in the history of
asymmetric catalysis.6–8 The products of this process, enan-
BnO
ref 12b.
OH
H
OH
O
1c
SAE
OH
(+)-DET
H
OBn
q CDRI Communication No. 7064.
THF derivatives
*
Corresponding author. Tel.: +91 9415403775; e-mail: akshaw55@
yahoo.com
Figure 1.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.010

R. Sagar et al. / Tetrahedron: Asymmetry 17 (2006) 3294–3299
3295
In association with one of the projects for achieving the
synthesis of biologically important compounds, large quan-
tities of stereochemically pure 2,3,4-trisubstituted THF
derivatives are required. Very recently we have disclosed
a novel and very efficient methodology for their prepara-
tion, starting from enantiomerically pure 2,3-epoxy alco-
hols in good to very good yields.12a Here we presumed
that the increase in the yield of the 2,3-epoxy alcohols
may help in obtaining THF derivatives in a more com-
manding yield. Over the course of our study towards the
improvement of yields of 2,3-epoxy alcohols, we found a
new and efficient method for the stereoselective synthesis
of enantiopure trisubstituted THF domains whose results
are discussed below.
stirred for 45 min at 0 ꢁC to hydrolyze the tartrate ester.
The resulting solution was extracted with ether. The
combined organic layer was dried over anhydrous sodium
sulfate and concentrated to yield an oily product.
Surprisingly, purification of the oily product furnished a
highly substituted THF domain 3 (3,6-anhydro galactitol
derivative) as the major product (38% yield) instead of
the epoxy derivative 2a which was isolated in trace
amounts only (Scheme 2).
Ti(O-i-Pr)4 (0.5 equiv.),
L-(+)-DET (0.6 equiv.),
t-BuOOH (2.0 equiv.),
O
OH
O
O
BnO
OH
2a
(traces)
H
+
H
BnO
MS 4 Å, DCM, 2.5 h
-25 ˚C to 0 ˚C, sat. citric
acid in acetone, 2 h
HO
OBn
1a
2. Results and discussion
Scheme 2. Consecutive approach towards the synthesis of THF domain.
In order to increase the yield of the epoxy alcohols, SAE of
allylic alcohols 1a–1d (Scheme 1) was repeated using differ-
ent permutations and combination of factors such as vary-
ing the ratios of the Sharpless reagents, performing the
reaction in inert atmosphere. However, neither of our
attempts was able to achieve any increment in the yields
of the 2,3-epoxy alcohols 2a–2d, except a slight change in
the time of reaction.
Encouraged by these results, attempts towards optimiza-
tion to obtain the highly substituted THF domain 3 in a
better yield by replacing the quenching reagent, a satu-
rated solution of citric acid in acetone with a solution of
citric acid in 2,2-dimethoxypropane, yielded 3 in only
24% yield along with 2,3-epoxy alcohol 2a (51%) in 4 h.
While quenching the reaction mixture with saturated citric
acid solution in 10% aqueous acetone, only 2a was
obtained in a 63% yield. However, an appreciable increase
in the yield of 3 (48%) was observed (Table 1, entry 1) when
this reaction was carried out using stoichiometric amounts
of the Sharpless reagents (Scheme 3, Path A).
Here, we anticipated that by modifying the work-up proce-
dure of the SAE of allylic alcohol would be helpful for
achieving the goal. A literature survey for the preparation
of sensitive epoxy alcohols revealed that the saturated citric
acid solution in ether: acetone (9:1) is recommended for the
removal of Ti(O-i-Pr)4 from the reaction mixture instead of
using 10% aqueous solution of tartaric acid.15 Since the
solubility of citric acid is better in acetone, we opted for
saturated citric acid in acetone instead of an ether/ether–
acetone solution of citric acid as a quenching agent.
To understand the importance of this consecutive one-pot
process, we synthesized the same THF 3 step-wise via 2a
(Scheme 3, Path B). In this case the overall yield of THF
3 obtained was 42%, whereas the above mentioned consec-
utive approach afforded the same THF domain in a 48%
yield.
Our modified work-up procedure entails additional stirring
of the reaction mixture containing 2a (TLC) obtained by
SAE of 1a using sub-stoichiometric amount of reagents
[Ti(O-i-Pr)4 (0.5 equiv) and (+)-DET (0.6 equiv)], with sat-
urated citric acid solution in acetone for 2 h, resulting in
the formation of an insoluble titanium citrate complex.15
The filtrate obtained after filtration was evaporated, dis-
solved in dichloromethane (DCM) and washed with the
minimum amount of water to remove the excess of citric
acid. The extracted organic layer was then evaporated.
The residue thus obtained was taken in ether. To it
10 mL of 4% NaOH solution in brine was added and then
Having optimized the reaction conditions and ensured the
literature precedent16 on the importance of 2,3,4-trisubsti-
tuted THF domains, a series of enantiopure allylic alcohols
1a–1d were successfully transformed into their correspond-
ing trisubstituted THF domains (Table 1) under similar
reaction conditions as described above, in acceptable yields
with >99% stereoselectivity in all cases.
However, in the case of 1d where the reaction was carried
out by using (À)-DET, the corresponding 2,3-epoxy alco-
OR3
OR3
R4O
R4O
SAE in presence of
L-(+)-DET, 60-70%
OH
OH
O
R2
R2
R1
R1
2
1
2a. R1=OBn, R2=R3=H, R4=Bn
2b. R1=R3=H, R2=OBn, R4=Bn
2c. R1=OBn, R2=H, R3=R4=Bn
2d. R1=H, R2=OBn, R3=R4=Bn
1a. R1=OBn, R2=R3=H, R4=Bn
1b. R1=R3=H, R2=OBn, R4=Bn
1c. R1=OBn, R2=H, R3=R4=Bn
1d. R1=H, R2=OBn, R3=R4=Bn
Scheme 1. Sharpless asymmetric epoxidation.

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R. Sagar et al. / Tetrahedron: Asymmetry 17 (2006) 3294–3299
Table 1. Results of synthesis of THF domains from glycal derived allylic alcohols
Entry
1
Reactant
Reagent/time (h)
(+)-DET/4.5
Major product
Minor product
OH
O
O
OH
O
O
O
H
1a
H
HO
OBn
HO
OBn
3a (4%)
3 (48%)
OH
OH
OH
O
H
O
O
H
2
3
1b
1c
(+)-DET/4.5
(+)-DET/14
OBn
HO
OBn
HO
4a (5%)
4 (51%)
OH
O
O
O
O
H
H
BnO
OBn
BnO
OBn
5a (10%)
5 (55%)
OH
O
OH
O
O
O
4
1d
(+)-DET/11
H
H
BnO
6a (10%)
OBn
BnO
6 (40%)
OBn
H
H
O
O
OH
OH
O
5
6
7
1a
1b
1c
(À)-DET/4.5
(À)-DET/4.5
(À)-DET/14
OH
OBn
O
HO
HO
OBn
7 (48%)
7a (5%)
H
H
O
O
O
OH
OBn
O
HO
HO
OBn
8 (46%)
8a (5%)
H
H
O
O
OH
O
OH
OBn
O
BnO
BnO
9 (52%)
OBn
9a (10%)
hol 2e was isolated as the major product in a 76% yield
along with traces of 10.
OH
OH
BnO
BnO
Path B
ref.12b
OH
OH
O
H
H
BnO
O
BnO
H
OBn
2a
1a
Ti(O-i-Pr)4 (1.0 equiv.),
L-(+)-DET (1.2 equiv.),
t-BuOOH (2.0 equiv.),
MS 4 Å, DCM, 2.5 h
-25 ˚C to 0 ˚C and
BnO
O
O
OH
O
PhNHNH2.HCl,
BnO
OBn
BnO
2e
Path A
C2H5OH, reflux, 2 h.
(ref. 12a)
sat. citric acid in acetone, 2 h
OH
OH
O
O
O
OMe
O
Thus, the above results led us to argue that the insoluble
titanium citrate complex formed during work-up, probably
induces the C3 selectivity leading to intramolecular nucleo-
philic asymmetric ring opening (ARO) of the epoxide at C3
involving the participation of the C-(6)-benzyloxy oxygen
atom followed by protection of the terminal vicinal diol
by acetone to afford 3.
OMe
H
H
CSA, rt, 2 h
OBn
HO
HO
OBn
3a
Path A (48%)
Path B (3 steps, 42%, )
Scheme 3. Consecutive and stepwise synthesis of THF domain 3.

R. Sagar et al. / Tetrahedron: Asymmetry 17 (2006) 3294–3299
3297
3. Conclusion
collected was concentrated. The residue obtained was dis-
solved in Et2O (20 mL) and stirred with 4% NaOH in brine
solution (10 mL) at 0 ꢁC for 0.75 h to hydrolyze and
remove excess diethyl tartrate. Afterwards, the ether layer
was separated, washed with brine, dried over Na2SO4
and concentrated to afford the crude product. This was
purified by column chromatography to furnish pure THF
3 (141 mg, 48%) and 3a (10 mg, 4%). A similar reaction
protocol was adopted for compounds 1b, 1c and 1d using
(+)- and (À)-DET.
In summary, this report describes a facile and mild proto-
col for stereoselective synthesis of highly substituted enan-
tiomerically pure THF domains directly from allylic
alcohols derived from their respective glycals under SAE
condition. Moreover, this consecutive approach circum-
vent the need to isolate the intermediate 2,3-epoxy alcohol
and thereby shows significant ‘cost/time benefits’ by reduc-
ing the amount of solvents, reagents, adsorbents and
energy.
4.2.1. (2S,3S,4S,5R)-1,2-O-Isopropylidine-3,6-anhydro-4-O-
benzyl-D-galactitol 3. Sticky solid, eluent for column
chromatography: EtOAc/hexane (1/4, v/v), [a]D = +14.0
(c 0.100, CHCl3); Rf 0.35 (3/7 EtOAc/hexane); IR (neat,
cmÀ1): 3320 (O–H str), 3069, 3031 (@C–H str), 2987,
2931, 2876 (–C–H str), 1603, 1498, 1458 (C@C str), 1373
(C–H def. of CH3), 1210, 1050 (C–O str); 1H NMR
(300 MHz, CDCl3): d 7.35–7.27 (m, 5H, ArH), 4.65 (br s,
2H, CH2Ph), 4.39–4.32 (m, 2H) 4.13–4.07 (m, 3H), 3.99–
3.94 (m, 2H), 3.72 (d, J = 9.9 Hz, 1H), 1.43 (s, 3H, CH3),
1.37 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 138.1
(Ar qC), 128.6, 127.9, 127.7 (ArC), 108.9 (qC), 84.1
(CH), 81.3 (CH), 75.0 (CH), 74.3 (CH2), 73.6 (CH), 72.6
(CH2), 67.1 (CH2), 26.8 and 25.6 (2 · CH3); mass (ESI-
MS) m/z 294; found 295 [M+1]+Å, 255, 237 [MÀC3H7O]+Å,
207, 181; EI-HRMS: (M+H) calcd for C16H22O5+H,
295.1545; found 295.1546.
4. Experimental
4.1. General
Organic solvents were dried by standard methods. Ti(O-i-
Pr)4, (+)-diethyl L-tartrate, (À)-diethyl D-tartrate and
6.0 M solution of t-BuOOH in nonane were purchased
from Aldrich chemical co. Allylic alcohols 1a–1d were syn-
thesized in the laboratory. All the products were character-
1
ized by H, 13C, IR, ESI-MS and EI-HRMS (C, H, O).
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 and subse-
quent charring over a hot plate. Column chromatography
was performed using silica gel (60–120 and 100–200 mesh).
NMR spectra were recorded on Bruker Avance DPX 200
FT, Bruker Robotics and Bruker DRX 300 Spectrometers
at 200, 300 MHz (1H) and 50, 75 MHz (13C). Experiments
were recorded in CDCl3 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 refer-
ence, CDCl3 appeared at 77.4 ppm, unless otherwise stated.
IR spectra were recorded on Perkin–Elmer 881 and FTIR-
8210 PC Shimadzu Spectrophotometers. Mass spectra were
recorded on a JEOL JMS-600H high-resolution spectro-
meter using EI mode at 70 eV. Optical rotations were
determined on an Autopol III polarimeter using a 1 dm cell
at 28 ꢁC in chloroform as the solvent; concentrations men-
tioned are in g/100 mL.
4.2.2. (2S,3S,4R,5R)-1,2-O-Isopropylidine-3,6-anhydro-4-
O-benzyl-D-glucitol 4.ꢀ Solid, mp 56–58 ꢁC, eluent for
column chromatography: EtOAc/hexane (9/41, v/v),
[a]D = À12.0 (c 0.100, CHCl3); Rf 0.44 (3/7 EtOAc/hex-
ane); IR (KBr, cmÀ1): 3431 (O–H str), 3030 (@C–H str),
2925, 2861 (–CH str), 1660, 1590, 1454 (C@C str), 1367
1
(C–H def. of CH3), 1093 (C–O str); H NMR (300 MHz,
CDCl3): d 7.39–7.33 (m, 5H, ArH), 4.73 (d, J = 11.4 Hz,
1H, CH2Ph), 4.62 (d, J = 11.4 Hz, 1H, CH2Ph), 4.23 (dd,
J = 10.6 Hz and J = 5.3 Hz, 1H), 4.14–3.97 (m, 4H),
3.92–3.87 (m, 2H), 3.74 (dd, J = 9.4 Hz and J = 5.0 Hz,
1H), 2.76 (br d, J = 5.9 Hz, 1H, OH), 1.46 (s, 3H, CH3),
1.38 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 137.5
(Ar qC), 128.9, 128.6, 128.5 (ArC), 110.0 (qC), 82.6
(CH), 80.1 (CH), 76.1 (CH), 73.1 (CH2), 72.8 (CH2), 70.6
(CH), 66.9 (CH2), 26.9 and 25.4 (2 · CH3); mass (ESI-
MS) m/z 294; found 295 [M+1]+Å, 269, 237 [MÀC3H7O]+Å,
207, 181; EI-HRMS: (M+H) calcd for C16H22O5+H,
295.1545; found 295.1533.
4.2. General procedure for the preparation of THF domains
A solution of Ti(O-i-Pr)4 (0.30 mL, 1.0 mmol) and L-(+)-
diethyl tartrate (0.20 mL, 1.2 mmol) in DCM (5 mL) was
stirred at À25 ꢁC for 0.5 h in the presence of MS 4 A. To
˚
this mixture, a solution of compound 1a (328 mg, 1.0 mmol)
in DCM (5 mL) was added and the mixture stirred at the
same temperature. After 0.5 h of stirring a 6.0 M solution
of t-BuOOH in nonane (0.34 mL, 2.0 mmol) was added
and the temperature of the reaction raised to 0 ꢁC and left
to stir until the disappearance of the starting material
(TLC). A saturated citric acid solution in acetone
(15 mL) was added to quench the reaction at 0 ꢁC and stir-
red for another 2 h. The titanium-citrate complex formed
was filtered through a Celite pad. The filtrate obtained
was concentrated to dryness under reduced pressure. This
residue was dissolved in DCM and washed with the
minimal amount (1 · 5 mL) of water to remove excesses
of citric acid in the mixture. The combined organic layer
4.2.3. (2S,3S,4S,5R)-1,2-O-Isopropylidine-3,6-anhydro-4,5-
di-O-benzyl-D-galactitol 5. Oil, eluent for column chro-
matography: EtOAc/hexane (1/9, v/v), [a]D = +5.95 (c
0.235, CHCl3); Rf 0.58 (1/4 EtOAc/hexane); IR (neat,
cmÀ1): 3064, 3032 (@C–H str), 2925, 2854 (–CH str),
1600, 1495, 1456 (C@C str), 1371 (C–H def. of CH3),
1
1068 (C–O str); H NMR (300 MHz, CDCl3): d 7.37–7.27
(m, 10H, ArH), 4.60–4.47 (m, 4H, 2 · CH2Ph), 4.36 (dd,
ꢀ The appearance of the –OH signal in the 1H NMR spectra may be due to
some non-covalent type of interaction(s) between the syn related –OH
and –OBn groups.

3298
R. Sagar et al. / Tetrahedron: Asymmetry 17 (2006) 3294–3299
J = 12.9 Hz and J = 6.4 Hz, 1H), 4.12–3.94 (m, 6H), 3.82
(d, J = 9.1 Hz, 1H), 1.42 (s, 3H, CH3), 1.37 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): d 138.3, 138.0 (Ar qC),
128.9, 128.8, 128.7, 128.1, 128.0, 127.9 (ArC), 109.1 (qC),
82.5 (CH), 82.0 (2 · CH), 73.5 (CH), 72.6 (CH2), 72.3
(CH2), 71.7 (CH2), 67.6 (CH2), 27.0 and 25.7 (2 · CH3);
mass (ESI-MS) m/z 384; found 385 [M+1]+Å, 353
[MÀCH2OÀ1]+Å, 294 [MÀCH2Ph+1]+Å, 243, 181; EI-
HRMS: (M+H) calcd for C23H28O5+H, 385.2015; found
385.2048.
qC), 128.9, 128.5, 128.4 (ArC), 109.4 (qC), 81.8 (CH),
79.4 (CH), 74.7 (CH2), 74.0 (CH), 73.1 (CH2), 71.8 (CH),
67.5 (CH2), 27.1 and 25.8 (2 · CH3); mass (ESI-MS) m/z
294; found 295 [M+1]+Å, 288, 237 [MÀC3H7O]+Å, 202
[MÀCH2PhÀ1]+Å, 181; EI-HRMS: (M+H) calcd for
C16H22O5+H, 295.1545; found 295.1555.
4.2.7. (2R,3R,4S,5R)-1,2-O-Isopropylidine-3,6-anhydro-4,5-
di-O-benzyl-D-galactitol 9. Oil, eluent for column chro-
matography: EtOAc/hexane (1/9, v/v), [a]D = À7.7 (c
0.220, CHCl3); Rf 0.58 (3/7 EtOAc/hexane); IR (neat,
cmÀ1): 3065, 3032 (@C–H str), 2925, 2860 (–C–H str),
1597, 1456 (C@C str), 1372 (C–H def. of CH3), 1213 and
4.2.4. (2S,3S,4R,5R)-1,2-O-Isopropylidine-3,6-anhydro-4,5-
di-O-benzyl-D-glucitol 6. Oil, eluent for column chroma-
tography: EtOAc/hexane (2/23, v/v), [a]D = À23.6 (c
0.165, CHCl3); Rf 0.61 (1/4 EtOAc/hexane); IR (neat,
cmÀ1): 3064 (@CH str), 2925, 2857 (–CH str), 1495, 1456
(C@C str), 1373 (C–H def. of CH3), 1148, 1066 (C–O
1
1069 (C–O str); H NMR (300 MHz, CDCl3): d 7.38–7.27
(m, 10H, ArH), 4.64–4.46 (m, 4H, 2 · CH2Ph), 4.18–3.89
(m, 7H), 3.86 (dd, J = 8.0 Hz and J = 2.3 Hz, 1H), 1.46
(s, 3H, CH3), 1.35 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d 138.2, 138.0 (Ar qC), 128.8, 128.1, 128.0, 127.3
(ArC), 109.7 (qC), 85.4 (CH), 84.5 (CH), 83.4 (CH), 75.8
(CH), 72.1 and 71.8 (2 · CH2), 71.4 (CH2), 67.7 (CH2),
27.2 and 25.6 (2 · CH3); mass (ESI-MS) m/z 384; found
385 [M+1]+Å, 353 [MÀCH2OÀ1]+Å, 295 [MÀCH2Ph+2]+Å,
278 [MÀOCH2Ph+1]+Å, 243, 207, 181; EI-HRMS:
(M+H) calcd for C23H28O5+H, 385.2015; found 385.1991.
1
str); H NMR (300 MHz, CDCl3): d 7.38–7.26 (m, 10H,
ArH), 4.68–4.57 (m, 4H, 2 · CH2Ph), 4.10 (dd,
J = 11.1 Hz and J = 5.7 Hz, 1H), 4.03–3.98 (m, 4H),
3.94–3.84 (m, 3H), 1.40 (s, 3H, CH3), 1.34 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): d 138.2 (Ar qC), 128.8,
128.7, 128.5, 128.2, 128.1 (ArC), 109.9 (qC), 82.8 (CH),
78.2 (CH), 77.3 (CH), 76.1 (CH), 72.3 and 72.2
(2 · CH2), 70.2 (CH2), 66.5 (CH2), 26.7 and 25.3
(2 · CH3); mass (ESI-MS) m/z 384; found 385 [M+1]+Å,
345, 181; EI-HRMS: (M+H) calcd for C23H28O5+H,
385.2015; found 385.1974.
4.2.8. (2R,3R,4R,5R)-1,2-O-Isopropylidine-3,6-anhydro-4,5-
di-O-benzyl-D-glucitol 10. Oil, eluent for column chroma-
tography: EtOAc/hexane (2/23, v/v), [a]D = +14.0 (c 0.121,
CHCl3); Rf 0.62 (1/4 EtOAc/hexane); IR (neat, cmÀ1): 3043
(@CH str), 2933 (–CH str), 1625, 1463 (C@C str), 1367 (C–
H def. of CH3), 1072 (C–O str); 1H NMR (300 MHz,
CDCl3): d 7.42–7.28 (m, 10H, ArH), 4.85 (d, J = 11.6 Hz,
1H, CH2Ph), 4.73 (d, J = 11.6 Hz, 1H, CH2Ph), 4.61 (d,
J = 11.9 Hz, 1H, CH2Ph), 4.53 (d, J = 11.9 Hz, 1H,
CH2Ph), 4.41 (dd, J = 13.0 Hz and J = 6.4 Hz, 1H),
4.19–4.06 (m, 3H), 3.98–3.88 (m, 4H), 1.43 (s, 3H, CH3),
1.38 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 138.8
(Ar qC), 128.8, 128.6, 128.3, 128.2, 127.9 (ArC), 110.1
(qC), 81.7 (CH), 79.7 (CH), 77.4 (CH), 74.2 (CH), 73.9
and 72.8 (2 · CH2), 69.4 (CH2), 67.1 (CH2), 27.0 and
25.7 (2 · CH3); mass (ESI-MS) m/z 384; found 385
[M+1]+Å, 345, 221, 181; EI-HRMS: (M+H) calcd for
C23H28O5+H, 385.2015; found 385.1989.
4.2.5. (2R,3R,4S,5R)-1,2-O-Isopropylidine-3,6-anhydro-4-
O-benzyl-D-galactitol 7. Oil, eluent for column chroma-
tography: EtOAc/hexane (1/4, v/v), [a]D = +47.29 (c
0.148, CHCl3); Rf 0.34 (3/7 EtOAc/hexane); IR (neat,
cmÀ1): 3436 (O–H str), 3032 (@CH str), 2985, 2926 (–CH
str), 1655, 1456 (C@C str), 1376 (C–H def. of CH3),
1256, 1214 and 1069 (C–O str); 1H NMR (300 MHz,
CDCl3): d 7.40–7.29 (m, 5H, ArH), 4.67 (d, J = 11.7 Hz,
1H, CH2Ph), 4.57 (d, J = 11.7 Hz, 1H, CH2Ph), 4.37 (dt,
J = 6.8 Hz and J = 3.3 Hz, 1H), 4.23 (br s, 1H), 4.10 (dd,
J = 8.5 Hz and J = 7.4 Hz, 1H), 3.93 (br s, 4H), 3.61 (dd,
J = 8.6 Hz and J = 6.3 Hz, 1H), 1.45 (s, 3H, CH3), 1.36
(s, 3H, CH3); 13C NMR (50 MHz, CDCl3): d 137.9 (Ar
qC), 128.9, 128.4, 128.3 (ArC), 110.3 (qC), 85.5 (CH),
85.1 (CH), 75.8 (CH), 75.0 (CH and CH2), 72.2 (CH2),
66.6 (CH2), 26.4 and 25.0 (2 · CH3); mass (ESI-MS) m/z
294; found 295 [M+1]+Å, 237 [MÀC3H7O]+Å, 202
[MÀCH2PhÀ1]+Å, 181; EI-HRMS: (M+H) calcd for
C16H22O5+H, 295.1545; found 295.1553.
4.2.9. (2R,3S)-4,5,6-Tri-O-benzyl-2,3-epoxy-D-glucitol 2e.
Oil, eluent for column chromatography: EtOAc/hexane (3/
22, v/v), [a]D = À6.5 (c 0.108, CHCl3), Rf 0.50 (3/7 EtOAc/
hexane); IR (neat, cmÀ1): 3426 (O–H str), 3062, 3030
(@CH str), 2925, 2869 (–CH str), 1604, 1495, 1455 (C@C
str), 1211 (C–O str of epoxides), 1097 (C–O str); 1H
NMR (300 MHz, CDCl3): d 7.36–7.25 (m, 15H, ArH),
4.74–4.53 (m, 6H, 3 · CH2Ph), 3.79–3.64 (m, 5H), 3.52–
3.47 (m, 1H), 3.21 (dd, J = 4.0 Hz and J = 2.2 Hz, 1H,
H-3), 3.14 (ddd (o), J = 4.6 Hz and J = 2.5 Hz, 1H, H-2);
13C NMR (75 MHz, CDCl3): d 138.6, 138.5 (Ar qC),
128.7, 128.2, 128.0 (ArC), 79.4 (CH), 76.9 (CH), 73.9,
73.8, 73.0 (3 · CH2), 69.7 (CH2), 61.9 (CH2), 56.0 (C-3),
55.5 (C-2); mass (ESI-MS) m/z 434; found 435 [M+1]+Å,
343 [MÀCH2Ph]+Å, 181; elemental analysis calcd for
C27H30O5Æ0.5H2O (443.55) C, 73.11; H, 7.04. Found: C,
72.80; H, 6.56.
4.2.6. (2R,3R,4R,5R)-1,2-O-Isopropylidine-3,6-anhydro-4-
O-benzyl-D-glucitol 8.ꢀ Solid mp 90–92 ꢁC, eluent for
column chromatography: EtOAc/hexane (9/41, v/v),
[a]D = +4.95 (c 0.101, CHCl3); Rf 0.43 (3/7 EtOAc/hex-
ane); IR (KBr, cmÀ1): 3441 (O–H str), 2925 (–CH str),
1597, 1454 (C@C str), 1366 (C–H def. of CH3), 1067 (C–
1
O str); H NMR (300 MHz, CDCl3): d 7.40–7.33 (m, 5H,
ArH), 4.87 (d, J = 11.1 Hz, 1H, CH2Ph), 4.67 (d,
J = 11.2 Hz, 1H, CH2Ph), 4.42–4.31 (m, 2H), 4.14–4.09
(m, 2H), 3.97 (dd, J = 8.4 Hz and J = 6.1 Hz, 1H), 3.88–
3.81 (m, 2H), 3.70 (dd, J = 9.2 Hz and J = 5.5 Hz, 1H),
2.81 (br d, J = 8.4 Hz, 1H, OH), 1.45 (s, 3H, CH3), 1.39
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 137.8 (Ar

R. Sagar et al. / Tetrahedron: Asymmetry 17 (2006) 3294–3299
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4.3. Procedure for the synthesis of 3a from 2a
To a solution of epoxy alcohol 2a (500 mg, 1.45 mmol) in
absolute alcohol (10 mL), a catalytic amount of phenyl
hydrazine hydrochloride (14.46 mg, 0.10 mmol) was added
and the mixture was stirred at reflux temperature for 2 h.
After completion of the reaction (TLC), the reaction mix-
ture was cooled to room temperature and neutralized with
an excess of saturated K2CO3 solution. The organic layer
was evaporated under reduced pressure and aqueous layer
was extracted with ethyl acetate (3 · 15 mL). The combined
organic layers were washed with brine, dried over sodium
sulfate, filtered and evaporated to yield the crude product,
which was purified by silica gel column chromatography
(silica gel, 3/97 MeOH/CHCl3) to afford the pure tetra-
hydrofuran derivative 3a (299 mg, 81%) as a white shiny solid.
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4.4. Procedure for the synthesis of 3 from 3a
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To a solution of 3a (299 mg, 1.18 mmol) in acetone (5 mL),
2,2-dimethoxy propane (0.17 mL, 1.42 mmol) and a cata-
lytic amount of (1S)-(+)-10-camphorsulfonic acid (27 mg,
0.01 mmol) were added. The mixture was stirred at room
temperature for 2 h. Sodium bicarbonate was added and
stirring was continued until the solution reached pH 6.
The mixture was filtered through celite, the filter was
washed with acetone and the solvent was removed in vacuo.
The residue was partitioned between DCM and water. The
aqueous layer was extracted with DCM (3 · 10 mL). The
organic extracts were dried over anhydrous sodium sulfate
and concentrated under reduced pressure to give a residue,
which was subjected to column chromatography to afford
THF 3 (258 mg, 75%).
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Acknowledgments
We are thankful to Sophisticated Analytical Instru-
mentation Facility, CDRI, for providing spectral data
and Mr. A. K. Pandey for technical assistance. R.S. and
L.V.R.R. thank the CSIR and M.S. to DOD, New Delhi,
for financial support.
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`
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