Stereoselective synthesis of (2R,3S,4S,5R)-trans-3,4-dihydroxy-5-(4- fluorophenoxymethyl)-2-(1-N-hydroxyureidyl-3-butyn-4-yl)tetrahydrofuran and (2R,3S,4S,5R)-trans-5-ethynyl-2-(4-fluorophenoxymethyl)-3,4-O-isopropylidene tetrahydrofuran from mannose diac

Article abstract of DOI:10.1016/j.tetasy.2005.01.046

Stereoselective synthesis of pharmaceutically interesting chiral tetrahydrofurans starting from mannose diacetonide is reported. A 1,4-diol system derived from mannose diacetonide, through a Mitsunobu reaction was stereospecifically cyclized to give chira

Full text of DOI:10.1016/j.tetasy.2005.01.046

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1135–1140
Stereoselective synthesis of (2R,3S,4S,5R)-trans-3,4-
dihydroxy-5-(4-fluorophenoxymethyl)-2-(1-N-hydroxyureidyl-3-
butyn-4-yl)tetrahydrofuran and (2R,3S,4S,5R)-trans-5-ethynyl-2-
(4-fluorophenoxymethyl)-3,4-O-isopropylidene tetrahydrofuran
from mannose diacetonideI
G. V. M. Sharma,a,* Sreenivas Punna,a Lanka Hymavathi,a N. Yella Reddy,a
Palakodety Radha Krishna,a Mukund S. Chorghadeb,* and Steven V. Leyc
aD-211, Discovery Laboratory, Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bChorghade Enterprises, 14 Carlson Circle, Natick, MA 01760-4205, USA
cDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Received 15 November 2004; revised 26 January 2005; accepted 27 January 2005
Abstract—Stereoselective synthesis of pharmaceutically interestingchiral tetrahydrofurans startingfrom mannose diacetonide is
reported. A 1,4-diol system derived from mannose diacetonide, through a Mitsunobu reaction was stereospecifically cyclized to give
chiral tetrahydrofurans. Both the C-1 and C-4 centers of D-mannose are successfully exploited to install the requisite side chains.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
inga chiral tetrahydrofuran moiety, and several other
2,5-disubstituted tetrahydrofurans with biological activ-
ity have been found in nature or have been synthesized in
the laboratory.2 Pharmaceutical research aimed at the
development of new drugs based on such chiral tetra-
hydrofurans has resulted in the synthesis3 and testing
of several analogues having potential 5-LO inhibitory
activity.
Currently significant effort is being directed in both the
academic and industrial laboratories for the develop-
ment of new anti-asthmatic agents with more efficacy
and especially those that are orally active. Although sev-
eral ground-breaking advances in understanding the
pathology of asthma, and the subsequent discovery
and synthesis of new drugtargets have been reported,
the introduction of a completely safe and efficacious
drughas remained elusive. Compounds, such as 1, bear-
1
To research further on the development of new chiral
furans with potent activity, we report herein, starting
OH
N
OH
N
NH2
NH2
F
O
O
O
O
O
O
O
O
HO
OH
O
1
O
F
2
F
3
Figure 1.
q IICT Communication no. 040305.
*
Correspondingauthors. Fax: +91 40 27160387; e-mail: esmvee@iict.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.046

1136
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1135–1140
from mannose diacetonide, the first synthesis of 2 and 3,
which should be useful for buildinga library of com-
pounds in this area (Fig. 1).
MeOH at room temperature for 2 h furnished 7 (70%),
which on oxidative cleavage with NaIO4 and aq NaH-
CO3 in CH2Cl2 gave aldehyde 8 (96%). Reduction of
aldehyde 8 with NaBH4 in MeOH afforded 9 in 60%
yield. Tosylation of 9 with p-TsCl and Et3N in CH2Cl2
in the presence of DMAP (cat) at room temperature
afforded 10 (94%), which on reaction with 4-fluorophe-
nol and NaH in DMF furnished 11 (75%). Oxidative
2. Results and discussion
Retrosynthetic analysis (Scheme 1) indicated that 2
could be synthesized from 4, which in turn could be pro-
duced by a stereospecific cyclization of diol 5. Further-
more, diol 5 should be obtainable from the easily
accessible chiral startingmaterial mannose diacetonide
6. Thus, by makinguse of the lactol functionality in 6,
the diol for the cyclization could be made, while the
C-2, 3 and 4 centers were retained in 2 and 3.
7
deprotection of the PMB group in 11 usingDDQ in
aq CH2Cl2 (1:19) at room temperature afforded 12
(69%), which was converted into the urea derivative in
two steps.
Accordingly, alcohol 12 was treated with N,O-bis(phen-
yloxycarbonyl)hydroxylamine,8 Ph3P and DIAD in dry
THF under Mitsunobu6 conditions to give 13 in 99%
yield, which on subsequent ammonolysis8 with NH4OH
in MeOH afforded 14 in 66% yield. Finally, deprotection
of the acetonide in 14 with catalytic concd HCl in
MeOH at room temperature gave 2 in 78% yield, whose
structure was ascertained by spectral analysis.
Accordingly, a reaction of the lithium anion of 1-(4-
methoxybenzyloxy)-3-butyne (Scheme 2) [generated in
situ on reaction of 1-(4-methoxybenzyloxy)-3-butyne
A4 and n-BuLi] in THF with 6 gave diol 5 (43%) in a
19:1 ratio.5a,b Diol 6, on cyclization under Mitsunobu6
reaction conditions (Ph3P, DEAD) in dry THF, was
found to be completely stereospecific5c and afforded 4
(93%), by an SN2 mechanism. Acid (concd HCl) cata-
lyzed deprotection of the acetonide group in 4 in aq
Havingsuccessfully completed the synthesis of dihy-
droxy tetrahydrofuran 2, our focus was aimed at the
development of a simple synthetic route for the acetylenic
OPMB
OPMB
O
O
O
OH
O
O
OH
O
O
O
OH
2
O
O
O
O
O
O
6
5
4
Scheme 1.
9
OPMB
OPMB
b
1
O
O
O
10
OH
6
3
O
O
OH
O
O
c
O
4
OH
a
5
O
O
O
O
O
O
6
5
4
OPMB
OPMB
d, e, f
F
8
OR
HO
HO
O
9
1
R
O
5
O
O
g, h
3
4
O
O
O
O
O
O
7
8 R = CHO
11 R = PMB
12 R = H
9 R = CH2OH
10 R = CH2OTs
OR
N
F
NHR
k
i, j
O
2
O
O
O
O
13 R = COOPh
14 R = H
Scheme 2. Reagents and conditions: (a) 1-(4-methoxybenzyloxy)-3-butyne A, n-BuLi, ꢀ78 ꢁC to rt, 1 h, 43%; (b) DEAD, Ph3P, dry THF, rt, 1 h;
93%; (c) cat concd HCl, aq MeOH, rt, 2 h, 70%; (d) NaIO4, aq NaHCO3, CH2Cl2, rt, 5 h, 96%; (e) NaBH4, MeOH, rt, 1 h, 60%; (f) p-TsCl, Et3N,
CH2Cl2, rt, 8 h, 94%; (g) 4-F–C6H4OH, NaH, DMF, 80 ꢁC, 4 h, 75%; (h) DDQ, aq CH2Cl2, rt, 5 h, 69%; (i) DIAD, Ph3P, PhCOONHCOOPh, dry
THF, rt, 1 h, 99%; (j) NH4OH, MeOH, rt, 3 h, 66%; (k) cat concd HCl, aq MeOH, 24 h, 78%.

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1135–1140
1137
system 3, which would be useful for the synthesis of new
chemical entities (NCEs). As shown in Scheme 3, from
the retrosynthetic analysis, it was envisaged that 3 could
be made from 6 by the transformations as indicated.
on Varian Gemini-200 MHz spectrometer. J values are
given in hertz. Optical rotations were measured with a
JASCO DIP-370 instrument, and [a]D values are in units
of 10ꢀ1 degcm 2 gꢀ1. Organic solutions were dried over
anhydrous Na2SO4 and concentrated below 40 ꢁC in
vacuo.
introduce
CH2OAr
F
O
O
4.1. 4-(4-Methoxybenzyloxy)butyn-1-yl-2,3:5,6-di-O-iso-
propylidene-a-D-mannofuranoside 4
O
OH
O
O
convert to
acetylene
O
O
O
O
To a stirred and cooled (ꢀ78 ꢁC) solution of 1-(4-meth-
oxybenzyloxy)-3-butyne A (0.365 g, 1.92 mmol) in dry
THF (5 mL) under a nitrogen atmosphere, a solution
of n-BuLi (1.37 mL, 1.92 mmol; 1.4 M hexane solution)
was added and stirred for 30 min after which it was
warmed to room temperature. A solution of 6 (0.5 g,
1.92 mmol) in dry THF (5 mL) was added dropwise at
room temperature. After 1 h, the reaction mixture was
quenched with NH4Cl (5 mL) and extracted with EtOAc
(3 · 20 mL), washed with brine (20 mL), dried over
Na2SO4 and evaporated. The residue was purified by
column chromatography (silica gel, 20% EtOAc in hex-
ane) to afford diol 5 (0.37 g) in 43% yield as a colourless
6
3
Scheme 3.
Accordingly, 6 (Scheme 4) on treatment with trimethyl
sulfoxonium iodide in the presence of t-BuOK in DMSO
afforded 15.9 Reaction of 15 with p-TsCl and Et3N in
CH2Cl2 gave 16, which on etherification with 4-fluoro-
phenol and NaH in dry DMF furnished 17 in 53% yield.
Acetonide deprotection in 17 with catalytic concd HCl
in aq MeOH at room temperature afforded diol 18.
Oxidative cleavage of 18 with NaIO4 in the presence
of aq NaHCO3 in CH2Cl2 gave the corresponding alde-
hyde 19 (79%). Finally, aldehyde 19 on treatment with
CBr4 and Ph3P in CH2Cl2 at room temperature afforded
dibromo derivative 20, which on n-BuLi induced double
elimination gave 3 in 77% yield, whose structure was
confirmed from a spectral study.
1
syrup. [a]D = ꢀ8.5 (c 0.9, CHCl3); H NMR (CDCl3,
200 MHz): d 1.32, 1.35, 1.40, 1.51 (4s, 12H), 2.48 (dt,
2H, J = 6.9, 2.3 Hz, H-9), 2.6–2.81 (br s, 2H, OH),
3.52 (t, 2H, J = 6.9 Hz, H-10), 3.7–3.76 (m, 1H, H-2),
3.78 (s, 3H, OCH3), 3.9–4.1 (m, 3H, H-1, 3), 4.19–4.28
(m, 1H, H-5), 4.36–4.43 (m, 1H, H-4), 4.45 (s, 2H,
OCH2), 4.61–4.71 (m, 1H, H-6), 6.82, 7.21 (2d, 4H,
J = 8.8 Hz, Ar–H). FABMS m/z (relative intensity):
473 (M+ + Na, 26), 435 (14), 133 (24), 121 (100), 57 (36).
HO
HO
O
O
O
O
O
O
O
OR
O
OH
d
b, c
Ref. 9
6
O
O
O
O
O
O
F
16 R = Ts
17 R = 4-F-C6H4
A solution of the above diol 5 (0.35 g, 0.78 mmol) in dry
THF (5 mL) was treated with Ph3P (0.813 g, 3.1 mmol)
at room temperature. After 15 min, DEAD (0.04 g,
0.234 mmol) in THF (3 mL) was added dropwise and
the mixture stirred for 1 h. The solvent was evaporated
and the residue purified by column chromatography (sil-
ica gel, 10% EtOAc in hexane) to afford 4 (0.315 g) in
93% yield as a light yellow syrup. [a]D = ꢀ11.5 (c 1.0,
CHCl3); 1H NMR (CDCl3, 200 MHz): d 1.3, 1.39,
1.46, 1.47 (4s, 12H), 2.5 (dt, 2H, J = 7.14, 2.38 Hz, H-
9), 3.54 (t, 2H, J = 7.1 Hz, H-10), 3.82 (s, 3H, OCH3),
3.84–3.91 (m, 1H, H-3), 3.98–4.15 (m, 2H, H-1), 4.28–
4.4 (m, 2H, H-2, 4), 4.49 (s, 2H, OCH2), 4.64–4.82 (m,
2H, H-5, 6), 6.88, 7.26 (2d, 4H, J = 8.8 Hz, Ar–H).
FABMS m/z (relative intensity %): 432 (M+, 18), 431
(55), 417 (53), 343 (20), 121 (100).
18
15
O
OHC
O
Br
O
e
f
g
O
3
Br
O
O
F
O
O
F
19
20
Scheme 4. Reagents and conditions: (a) (CH3)3S+OIꢀ, t-BuOK,
DMSO, rt, 1 h; (b) p-TsCl, Et3N, CH2Cl2, rt, 8 h; 57%; (c) 4-F–
C6H4OH, NaH, DMF, 80 ꢁC, 5 h, 53%; (d) cat concd HCl, aq MeOH,
rt, 2 h, 72%; (e) NaIO4, aq NaHCO3, CH2Cl2, rt, 5 h, 79%; (f) CBr4,
Ph3P, CH2Cl2, rt, 30 min, 89%; (g) n-BuLi, THF, ꢀ78 ꢁC to rt, 2 h,
77%.
3. Conclusion
In conclusion, mannose diacetonide 6 has been success-
fully utilized for the first, efficient synthesis of 2, an ana-
logue of 1. Furthermore, a key acetylenic intermediate 3
was prepared from 6, which is a very useful scaffold for
the development of a variety of chiral tetrahydrofuran
based NCEs and could lead to designed libraries of
new glycosubstances of therapeutic importance.
4.2. 4-(4-Methoxybenzyloxy)butyn-1-yl 2,3-O-isopropyl-
idene-a-D-mannofuranoside 7
A solution of 4 (0.3 g, 0.69 mmol) in aq MeOH (5:1,
6 mL) was treated with concd HCl (0.1 mL) at 0 ꢁC
and stirred at room temperature for 2 h. The reaction
mixture was treated with solid NaHCO3 to neutralize
the acid, filtered and washed with EtOAc (2 · 15 mL).
The organic layer was dried over Na2SO4, evaporated
and the residue obtained purified by column chromato-
graphy (silica gel, 20% EtOAc in hexane) to afford 7
(0.19 g) in 70% yield as a pale yellow syrup. [a]D = ꢀ10
4. Experimental section
Solvents were dried over standard dryingagents and
freshly distilled prior to use. H NMR (200 MHz) spec-
tra were recorded in deuteriochloroform and DMSO-d6
solutions with tetramethylsilane as an internal reference
1
1
(c 0.2, CHCl3); H NMR (CDCl3, 200 MHz): d 1.31,

1138
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1135–1140
1.4 (2s, 6H), 2.48 (dt, 2H, J = 6.97, 2.3 Hz, H-9), 3.52 (t,
2H, J = 6.97 Hz, H-10), 3.6–3.75 (m, 1H, H-2), 3.81 (s,
3H, OCH3), 3.82–4.04 (m, 3H, H-1, 5), 4.46 (s, 2H,
OCH2), 4.65–4.76 (m, 2H, H-3, 4), 4.78–4.86 (m, 1H,
H-6), 6.85, 7.22 (2d, 4H, J = 9.0 Hz, Ar–H). FABMS
m/z (relative intensity %): 415 (M+ + Na, 10), 121 (22),
95 (40), 69 (64), 55 (100).
4.5. 4-(4-Methoxybenzyloxy)butyn-1-yl-2,3-O-isopropyl-
idene-5-(4-fluorophenyl)-a-D-lyxo-furanoside 11
A suspension of NaH (0.006 g, 0.28 mmol) in DMF
(1 mL) at 0 ꢁC was treated sequentially with a solution
of 4-fluorophenol (0.031 g, 0.28 mmol) in DMF (2 mL)
followed by a solution of 10 (0.12 g, 0.23 mmol) in
DMF (2 mL) and stirred at 80 ꢁC for 4 h. The reaction
mixture was cooled to 0 ꢁC, treated with a saturated
solution of NH4Cl (5 mL) and extracted with ether
(3 · 20 mL). The organic layer was dried over Na2SO4
and evaporated to give 11 (0.08 g) in 75% yield as a pale
yellow syrup. [a]D = ꢀ35.8 (c 2.7, CHCl3); 1H NMR
(CDCl3, 200 MHz): d 1.32, 1.49 (2s, 6H), 2.50 (dt, 2H,
J = 7.14, 2.8 Hz, H-8), 3.53 (t, 2H, J = 7.6 Hz, H-9),
3.81 (s, 3H, OCH3), 3.98–4.36 (m, 3H, H-1, 2), 4.46 (s,
2H, OCH2), 4.68–4.90 (m, 3H, H-3, 4, 5), 6.78–7.02
(m, 6H, Ar–H), 7.22 (d, 2H, J = 9.0 Hz, ArH).
4.3. 4-(4-Methoxybenzyloxy)butyn-1-yl-2,3-O-isopropyl-
idene-a-D-lyxo-furanoside 9
A solution of 7 (0.17 g, 0.43 mmol) in CH2Cl2 (5 mL)
containingsaturated NaHCO solution (0.1 mL) was
3
treated with NaIO4 (0.185 g, 0.86 mmol) portionwise
at 0 ꢁC and stirred at room temperature for 5 h. Solid
Na2SO4 (0.5 g) was added, the mixture stirred for an
additional 15 min, filtered and the solvent evaporated
to afford 4-(4-methoxybenzyloxy)butyn-1-yl-2,3-O-iso-
propylidene-a-D-lyxo-pentadialdo-1,4-furanoside
(8;
4.6. 4-Hydroxybutyn-1-yl 2,3-O-isopropylidene-5-(4-
fluorophenyl)-a-D-lyxo-furanoside 12
0.15 g) in 96% yield as a pale yellow syrup, that was
immediately used for further reaction without additional
purification.
A mixture of 11 (0.08 g, 0.17 mmol) and DDQ (0.047 g,
0.21 mmol) in aq CH2Cl2 (10 mL; 1:19) was stirred at
room temperature for 5 h. The reaction mixture was treat-
ed with saturated NaHCO3 solution (5 mL) and diluted
with CH2Cl2 (10 mL). The organic layer was separated
and washed with water (3 · 10 mL), brine (10 mL) and
dried over Na2SO4. Evaporation of the solvent and puri-
fication of the residue by column chromatography (silica
gel, 20% EtOAc in hexane) afforded 12 (0.04 g) in 69%
yield as a pale yellow syrup. [a]D = ꢀ18.5 (c 2.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 1.31, 1.46 (2s, 6H), 1.8–
2.1 (br s, 1H, OH), 2.40–2.5 (m, 2H, H-8), 3.70 (t, 2H,
J = 6.8 Hz, H-9), 4.04–4.36 (m, 3H, H-1, 2), 4.70–4.88
(m, 3H, H-3, 4, 5), 6.80–7.02 (m, 4H, Ar–H).
To a stirred solution of the above alcohol 8 (0.15 g,
0.41 mmol) in MeOH (10 mL) NaBH4 (0.015 g,
0.41 mmol) was added at 0 ꢁC and stirred at room tem-
perature for 1 h. MeOH was evaporated, residue dis-
solved in water (10 mL) and extracted with EtOAc
(2 · 20 mL). The organic layer was washed with water
(2 · 10 mL), dried over Na2SO4, evaporated and the
residue obtained purified by column chromatography
(silica gel, 25% EtOAc in hexane) to afford 9 (0.09 g)
in 60% yield as a pale yellow syrup. [a]D = +8.0 (c
1
0.4, CHCl3); H NMR (CDCl3, 200 MHz): d 1.3, 1.45
(2s, 6H), 2.48 (dt, 2H, J = 6.9, 2.32 Hz, H-8), 3.5 (t,
2H, J = 6.9 Hz, H-9), 3.81 (s, 3H, OCH3), 3.84–3.93
(m, 2H, H-2, 3), 3.95–4.09 (m, 1H, H-4), 4.45 (s, 2H,
OCH2), 4.66–4.80 (m, 3H, H-1, 6), 6.85, 7.22 (2d,
4H, J = 8.8 Hz, Ar–H). FABMS m/z (relative intensity
%): 385 (M+ + Na, 4), 361 (4), 121 (50), 69 (74), 55
(100).
4.7. 4-N,O-Bis-(phenoxycarbonyl)hydroxylamine-1-butyn-
yl-2,3-O-isopropylidene-5-(4-fluorophenyl)-a-D-lyxo-
furanoside 13
To a stirred and cooled (0 ꢁC) solution of 12 (0.3 g,
0.9 mmol),
N,O-bis(phenoxycarbonyl)hydroxylamine
4.4. 4-(4-Methoxybenzyloxy)butyn-1-yl-2,3-O-isopropyl-
idene-5-(p-toluenesulfonyl)-a-D-lyxo-furanoside 10
(0.36 g, 1.35 mmol) and Ph3P (0.37 g, 1.44 mmol) in
CH2Cl2 (8 mL), DIAD (0.29 g, 1.44 mmol) was added
dropwise. After stirringat room temperature for 1 h,
the solvent was evaporated and residue purified by col-
umn chromatography (silica gel, 15% EtOAc in hexane)
to afford 13 (0.5 g) in 99% yield as a pale yellow syrup.
[a]D = ꢀ3.5 (c 0.6, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.3, 1.49 (2s, 6H), 2.7–2.81 (m, 2H, H-8),
4.0–4.52 (m, 5H, H-1, 2, 9), 4.7–4.82 (m, 3H, H-3, 4,
5), 6.76–7.02 (m, 4H, Ar–H), 7.16–7.5 (m, 10H, ArH);
FABMS m/z (relative intensity %): 614 (M+ + Na, 7),
592 (M+ + H, 35), 591 (M+, 18), 576 (M+ꢀCH3, 7),
274 (100). HRMS: Calculated for C32H31FNO9:
592.198285; found: 592.195641.
A solution of 9 (0.09 g, 0.25 mmol) and Et3N (0.14 mL,
1 mmol) in CH2Cl2 (5 mL) at 0 ꢁC was treated with p-
TsCl (0.043 g, 0.25 mmol) and stirred at room tempera-
ture for 8 h. The reaction mixture was diluted with
CH2Cl2 (20 mL), washed with water (2 · 15 mL), dried
over Na2SO4, evaporated and the residue purified by
column chromatography (silica gel, 15% EtOAc in hex-
ane) to afford 10 (0.12 g) in 94% yield as a pale yellow
syrup. [a]D = ꢀ57 (c 0.3, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.22, 1.32 (2s, 6H), 2.35–2.53 (m, 5H, H-
8, Ar–CH3), 3.5 (t, 2H, J = 6.9 Hz, H-9), 3.8 (s, 3H,
OCH3), 4.05–4.2 (m, 2H, H-2, 3), 4.20–4.35 (m, 1H,
H-4), 4.45 (s, 2H, OCH2), 4.58–4.70 (m, 3H, H-1, 6),
6.85 (d, 2H, J = 8.8 Hz, ArH), 7.16–7.36 (m, 4H, Ar–
H), 7.80 (d, 2H, J = 8.8 Hz, ArH). FABMS m/z (relative
intensity %): 516 (M+, 12), 515 (15), 155 (10), 121 (100),
91 (30).
4.8. 4-N-Hydroxyureidyl-1-butynyl 2,3-O-isopropylidene-
5-(4-fluorophenyl)-a-D-lyxo-furanoside 14
To a solution of 13 (0.5 g, 0.88 mmol) in MeOH
(15 mL), NH4OH (10 mL) was added and stirred at

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1135–1140
1139
room temperature for 3 h. MeOH was evaporated,
diluted with water (10 mL), extracted with CH2Cl2
(3 · 10 mL) and dried over Na2SO4. Evaporation of
solvent and purification of residue by column chroma-
tography (silica gel, 40% EtOAc in hexane) afforded 14
(5 mL) and stirred at 80 ꢁC for 5 h. Work-up and puri-
fication (silica gel, 5% EtOAc in hexane) as described
for 11 gave 17 (1.5 g) in 53% yield as a pale syrup. IR
(neat): 2984, 1585, 1180, 1015, 835 cmꢀ1; [a]D = ꢀ11.25
(c 1, CHCl3); 1H NMR (CDCl3, 200 MHz): d 1.40,
1.47, 1.56 (3s, 12H), 3.98–4.15 (m, 5H, H-1, 3, 7),
4.30–4.41 (m, 2H, H-2, 6), 4.81–4.95 (m, 2H, H-4, 5),
6.75–6.84 (m, 2H, Ar–H), 6.9–7.05 (m, 2H, Ar–H);
FABMS m/z (relative intensity in %): 369 (M+ + H,
40), 311(30), 185 (26), 125 (100), 101 (100).
(0.218 g) in 66% yield as
a pale yellow syrup.
[a]D = +65.5 (c 1.0, CHCl3); 1H NMR (CDCl3, 200
MHz): d 1.32, 1.46 (2s, 6H), 2.48–2.60 (m, 2H, H-8),
3.55–3.85 (m, 2H, H-9), 4.05–4.42 (m, 3H, H-1, 2),
4.72–4.90 (m, 3H, H-3, 4, 5), 5.31–5.52 (br s, 2H,
NH2), 6.80–7.05 (m, 4H, Ar–H); FABMS m/z (relative
intensity %): 395 (M+ + H, 5), 279 (7), 176 (5), 154
(13), 54 (14). HRMS: Calculated for C19H24FN2O6:
395.161840; found: 395.159948.
4.12. 3,6-Anhydro-4,5-O-isopropylidene-7-(4-fluorophen-
yl)-D-glycero-D-mannoheptitol 18
A solution of 17 (1.11 g, 3.01 mmol) in aq MeOH (5:1,
10 mL) was treated with concd HCl (0.2 mL) at 0 ꢁC and
stirred at room temperature for 4 h. Work-up and purifica-
tion (silica gel, 50% EtOAc in hexane) as described for 7
afforded 18 (0.71 g) in 72% yield as a pale yellow syrup.
4.9. (2R,3S,4S,5R)-trans-3,4-Dihydroxy-5-(4-fluorophen-
oxymethyl)-2-(1-N-hydroxyureidyl-3-butyn-4-yl)tetrahy-
drofuran 2
To a cooled (0 ꢁC) and stirred solution of 14 (0.05 g,
0.126 mmol) in MeOH (9 mL) catalytic concd HCl (1
drop) was added followed by water (1 mL) and stirred
at room temperature for 24 h. Solid NaHCO3 was added
to neutralize the reaction mixture and solvent evapo-
rated. It was filtered and washed with ethyl acetate
(2 · 10 mL). The combined organic layers were dried
over Na2SO4, concentrated and purified by column chro-
matography (silica gel, EtOAc) to afford 2 (0.035 g) in
IR (neat): 3241, 3010, 1572, 1150, 1030, 900 cmꢀ1
;
[a]D = ꢀ11.33 (c 0.7, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.3, 1.55 (2s, 6H), 2.0 (br s, 2H, OH), 3.6–
3.85 (m, 2H, 7), 3.92 (m, 1H, H-3), 4.0 (d, 2H,
J = 4.54 Hz, H-1), 4.05–4.1 (m, 1H, H-2), 4.32–4.4 (m,
1H, H-6), 4.85–5.0 (m, 2H, H-4, 5), 6.73–6.85 (m, 2H, Ar–
H), 6.9–7.05 (m, 2H, Ar–H); FABMS m/z (relative intensity
in %): 329 (M+ + H, 8), 271(6), 109 (22), 69 (54), 57 (100).
1
78% yield as a syrup. [a]D = +14.2 (c 1.0, CHCl3); H
4.13. (2R,5R) 5-(1,10-Dibromoethylen-2-yl)–2-(4-fluoro-
phenoxymethyl)-3,4-O-isopropylidene tetrahydrofuran 20
NMR (DMSO, 200 MHz): d 2.30–2.48 (m, 2H, H-20),
3.80–4.15 (m, 4H, H-1), 4.18–4.31 (m, 2H, H-3, 4),
5.01–5.12 (m, 3H, H-5), 5.30 (d, 1H, J = 4.88 Hz, H-2),
6.30 (s, 2H, NH2), 6.80–6.99 and 7.0–7.19 (2m, 4H,
Ar–H), 9.38 (s, 1H, N–OH); FABMS m/z (relative inten-
sity in %): 355 (M+ + H, 7), 339 (5), 281 (9.5), 221 (12.9),
109 (100). Anal. Calcd for C16H19FN2O6: C, 54.24; H,
5.40. Found: C, 54.21; H, 5.38.
A solution of 18 (0.74 g, 2.25 mmol) in CH2Cl2 (10 mL)
containingsaturated NaHCO
solution (1.2 mL)
3
was treated with NaIO4 (0.48 g, 2.25 mmol) portionwise
at 0 ꢁC and stirred at room temperature for 5 h. Work-
up and purification as described for 8 afforded 2,3-
O-isopropylidene-5-(4-fluorophenyl)-D-glycero-D-lyxo-
pentanedialdo-1,4-furanoside 19 (0.53 g) in 79% yield as
a pale yellow syrup, which was used as such for further
reaction immediately.
4.10. 3,6-Anhydro-1,2:4,5-di-O-isopropylidene-7-(p-tolu-
enesulfonyl)-D-glycero-D-mannoheptitol 16
A solution of 15 (3.68 g, 13.4 mmol) and Et3N (5.6 mL,
40.29 mmol) in CH2Cl2 (40 mL) at 0 ꢁC, was treated with
p-TsCl (3.83 g, 20.14 mmol) and stirred at room temper-
ature for 8 h. Work-up and purification (silica gel, 15%
EtOAc in hexane) as described for 10 afforded 16
(3.3 g) in 57% yield as a pale yellow syrup. IR (neat):
2950, 1580, 1210, 1175, 1005, 825 cmꢀ1; [a]D = +9.7 (c
A solution of Ph3P (2.32 g, 8.8 mmol) in CH2Cl2 (5 mL)
was treated with a solution of CBr4 (1.03 g, 4.4 mmol) in
CH2Cl2 (5 mL) at 0 ꢁC dropwise. After 15 min, a solu-
tion of 19 (0.53 g, 1.77 mmol) in CH2Cl2 (5 mL) was
added and stirred at the same temperature for 30 min.
The solvent was evaporated and the residue subjected
to column chromatography (silica gel, 15% EtOAc in
hexane) to afford 20 (0.69 g) in 89% yield as a pale yellow
1
1.0, CHCl3); H NMR (CDCl3, 200 MHz): d 1.27, 1.31,
1.37, 1.43 (4s, 12H), 2.48 (s, 3H), 3.75–3.88 (m, 2H, H-
7), 3.90–4.10 (m, 3H, H-1, 3), 4.10–4.19 (m, 1H, H-6),
4.20–4.31 (m, 1H, H-2), 4.60–4.80 (m, 2H, H-4, 5), 7.33
(d, J = 8.7 Hz, 2H, Ar–H), 7.75 (d, J = 8.7 Hz, 2H, Ar–
H); FABMS m/z (relative intensity in %): 429 (M+ + H,
38), 371 (12), 155 (30), 91 (46), 57 (100).
syrup. IR (neat): 2995, 1590, 1410, 1130, 890 cmꢀ1
;
[a]D = ꢀ80 (c 0.5, CHCl3); 1H NMR (CDCl3,
300 MHz): d 1.34, 1.51 (2s, 6H), 3.91–4.11 (m, 2H),
4.29–4.35 (m, 1H), 4.74–4.91 (m, 3H, H-3, 4, 5), 6.58
(d, 1H, J = 7.5 Hz, H-6), 6.78–6.82 (m, 2H, Ar–H),
6.90–6.97 (m, 2H, Ar–H); FABMS m/z (relative intensity
in %): 453 (M+ + H, 12), 147 (12), 125 (16), 95 (44), 81
(50), 69 (62), 59 (100).
4.11. 3,6-Anhydro-1,2:4,5-di-O-isopropylidene-7-(4-fluoro-
phenyl)-D-glycero-D-mannoheptitol 17
4.14. (2R,3S,4S,5R)-trans-5-Ethynyl-2-(4-fluorophen-
oxymethyl)-3,4-O-isopropylidene tetrahydrofuran 3
A solution of 4-fluorophenol (0.95 g, 8.44 mmol) in
DMF (2 mL) was added to a suspension of NaH
(0.611 g, 25.4 mmol) in DMF (3 mL) at 0 ꢁC and then
treated with a solution of 16 (3.3 g, 7.7 mmol) in DMF
A solution of 20 (0.65 g, 1.47 mmol) in THF (5 mL) was
cooled to ꢀ78 ꢁC and treated with n-BuLi (1.7 mL,

1140
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1135–1140
D.; Wypij, D. M.; Yeh, C. G.; Young, M. A.; Yu, S. X.
Abstracts of Papers of the American Chemical Society, 1997,
214, 214-MEDI; (b) Sajjat, H. Md.; Grace, Y. C. Drugs
Future 1996, 21, 933; (c) Cai, X.; Hwang, S.; Killan, D.;
Shen, T. Y. U.S. Patent 5,648,486, 1997; (d) Cai, X.;
Grewal, G.; Hussion, S; Fura, A.; Biftu, T. U.S. Patent
5,681,966, 1997.
3.22 mmol; 2.0 M hexane solution). After 1 h, the reac-
tion mixture was warmed to room temperature and stir-
red for an additional 1 h. It was then quenched with
NH4Cl solution (5 mL) and extracted with EtOAc
(2 · 25 mL), dried over Na2SO4 and evaporated. The
residue obtained was purified by column chromatogra-
phy (silica gel, 20% EtOAc in hexane) to afford 3
(0.32 g) in 77% yield as a pale yellow syrup. IR (neat):
3110, 2942, 1570, 1130, 830 cmꢀ1; [a]D = ꢀ45.6 (c 0.4,
3. (a) Gurjar, M. K.; Murugaiah, A. M. S.; Radha Krishna,
P.; Ramana, C. V.; Chorghade, M. S. Tetrahedron: Asym-
metry 2003, 14, 1363–1370; (b) Dixon, D. J.; Ley, S. V.;
Reynolds, D. J.; Chorghade, M. S. Synth. Commun. 2000,
30, 1955–1961; (c) Gurjar, M. K.; Muralikrishna, L.;
Sridhar Reddy, B.; Chorghade, M. S. Synthesis 2000, 557–
560; (d) Chorghade, M. S.; Gurjar, M. K.; Adhikari, S.;
Sadalapure, K.; Lalitha, S. V. S.; Murugaiah, A. M. S.;
Radha Krishna, P. Pure Appl. Chem. 1999, 71, 1071–1074;
(e) Chorghade, M. S.; Sadalapure, K.; Adhikari, S.; Lalitha,
S. V. S.; Murugaiah, A. M. S.; Radha Krishna, P.; Sridhar
Reddy, B.; Gurjar, M. K. Carbohydr. Lett. 2000, 3, 405–
410; (f) Cai, X.; Chorghade, M. S.; Fura, A.; Grewal, S. G.;
Jauregui, K. A.; Lounsbury, H. A.; Scannell, R. T.; Grace
Yeh, C.; Young, M. A.; Yu, S.; Guo, L.; Moriarty, R. M.;
Raju, P.; Rao, M. S.; Rajesh, K. S.; Song, Z.; Staszewski, J.
P.; Sudershan, M. T.; Yang, S. Org. Process Res. Dev. 1999,
3, 73–76.
1
CHCl3); H NMR (CDCl3, 200 MHz): d 1.39, 1.59 (2s,
6H), 2.54 (d, 1H, J = 1.5 Hz, H-7), 4.0 (t, 2H,
J = 3.48 Hz, H-1, 10), 4.35 (m, 1H, H-2), 4.79–4.90 (m,
3H, H-3, 4, 5), 6.70–6.80 (m, 2H, Ar–H), 6.85–6.95
(m, 2H, Ar–H); FABMS m/z (relative intensity in %):
293 (M+ + H, 10), 259 (50), 191 (10), 71 (20), 57 (100).
Acknowledgements
Three of the authors (S.P., L.H. and Y.R.) acknowledge
CSIR, New Delhi, India for the financial support.
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