Stereoselective synthesis of chiral tetrahydrofurans with potent 5-LO inhibitory activity

Article abstract of DOI:10.1016/j.tetasy.2005.01.045

Chiral glyceraldehydes have been exploited for the design of convenient and scalable synthetic approaches to chiral tetrahydrofurans, which have potential as potent 5-lipoxygenase (5-LO) inhibitors. The synthesis of all four possible stereoisomers by a general methodology is reported; wherein the chirons derived from the glyceraldehyde derivatives on reaction with homopropargyl ether, cyclization and further reactions gave the targets.

Full text of DOI:10.1016/j.tetasy.2005.01.045

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1125–1133
Stereoselective synthesis of chiral tetrahydrofurans with potent
5-LO inhibitory activityI
G. V. M. Sharma,a,* Sreenivas Punna,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—Chiral glyceraldehydes have been exploited for the design of convenient and scalable synthetic approaches to chiral tetra-
hydrofurans, which have potential as potent 5-lipoxygenase (5-LO) inhibitors. The synthesis of all four possible stereoisomers by a
general methodology is reported; wherein the chirons derived from the glyceraldehyde derivatives on reaction with homopropargyl
ether, cyclization and further reactions gave the targets.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Bronchial asthma is characterized by both broncho con-
striction and airway inflammation, which leads to bron-
chial hyper responsiveness to various stimuli. Cysteinyl
leukotrienes (LTs) have been implicated in bronchial
constriction and submucosal odema of airways in
asthmatics.1 The relationship between inflammatory
conditions and prostaglandins, thromboxanes and
leukotrienes has been established.1 Chiral tetrahydrofu-
rans 1 and 3 have been explored for their action against
5-lipoxygenase (5-LO). These belong to the lignan fam-
ily of 2,5-disubstituted tetrahydrofurans, with diverse
substitution and a trans-juxtaposition of ring and sub-
stituents. Compound 1 is a highly selective and orally
active leukotriene modulator that works by inhibiting
the action of 5-lipoxygenase.2,3 Previously we have re-
ported several investigations aimed at optimizing the
syntheses of the target molecules.4 Herein, we report a
flexible approach for the formal synthesis of 1 and 2
and the synthesis of 3 and 4 (Fig. 1) from (S)- and
(R)-glyceraldehyde derivatives and homopropargyl alco-
hol (a C-4 synthon).
Retrosynthetic analysis, as depicted in Scheme 1, sug-
gests that 1, 2, 3 and 4 could be prepared from tetra-
hydrofurans 5, 6, 7 and 8, which, in turn could be
made from the propargylic carbinols 9 and 10 derived
from 11 and 12, respectively. Thus, the main strategy
for the synthesis of 1–4 would be to convert 11 and 12
to diastereomeric carbinols, their cyclization and further
transformations.
2.1. Synthesis of 1 and 2 from (S)-glyceraldehyde
derivative 11
Accordingly, Wittig olefination of 115 (Scheme 2) with
(carbethoxymethylene)triphenyl phosphorane in MeOH
gave 13 (85:15 cis:trans), which on hydrogenation with
PtO2 at room temperature furnished 14 in quantitative
yield. Reduction of ester 14 with LAH in THF gave alco-
hol 15 (97%), which on iodoxybenzoic acid (IBX) oxida-
tion in DMSO afforded aldehyde 16 (84%). Reaction of
16 with the lithium anion of 1-(4-methoxybenzyloxy)-3-
butyne [prepared from 1-(4-methoxybenzyloxy)-3-bu-
tyne6 and n-BuLi] in dry THF afforded 9 (55%) as an
inseparable 1:1 mixture of diastereoisomers, which was
used as such in further reactions. Carbinol 9 on treatment
with Ac2O and Et3N in CH2Cl2 at room temperature fur-
nished 17 (77%), which on hydrolysis with 60% aq AcOH
at room temperature, afforded 18 (89%). Selective tosyla-
tion of diol 18 using p-TsCl and Et3N in CH2Cl2 gave
q IICT Communication no. 040306.
*
Corresponding authors. Fax: +9140 27160387; e-mail: esmvee@
iict.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.045

1126
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1125–1133
O
O
O
O
O
O
N
NH2
NH2
N
F
1
2
F
OH
OH
O
O
O
O
O
O
NH2
N
N
NH2
F
3
F
4
OH
OH
Figure 1.
O
O
O
O
OH
OH
1
2
5
F
F
O
OH
O
O
O
O
11
OH
9
6
7
O
O
3
OH
F
F
O
O
OH
O
O
O
12
OH
O
10
O
4
OH
8
Scheme 1.
monotosylate 19 (77%), which on treatment with K2CO3
in methanol at room temperature gave the desired tetra-
hydrofuran 20 as a diastereomeric mixture. Alcohol 20
was subjected to tosylation with p-TsCl and Et3N to give
21 (78%), which on subsequent reaction with 4-fluoro-
phenol and NaH in DMF at 80 ꢁC furnished 22 (66%).
lytic hydrogenation and reduction afforded 25. IBX oxi-
dation of 25 gave 26 (84%), which on reaction with the
lithium anion of 1-(4-methoxybenzyloxy)-3-butyne in
THF gave 10 as an inseparable (1:1) mixture. Acetyl-
ation (Ac2O, Et3N) of 10 gave acetate 27, which on acid
hydrolysis (60% aq AcOH), afforded diol 28 (83%).
Selective tosylation of 28 furnished 29 (81%), which on
cyclization gave 30. Reaction of 30 with p-TsCl and
Et3N, followed by further reaction of 31 with 4-fluoro-
phenol and NaH in DMF furnished 32 (94%). Further,
oxidative deprotection of PMB in 32 with DDQ afford-
ed a separable mixture of 7 and 8 (79%; ꢀ1:1 ratio).
Treatment of tetrahydrofuran 22 with DDQ7 in
CH2Cl2–H2O (19:1 ratio) afforded the corresponding
hydroxy compounds 5 and 6, separable by column chro-
matography (silica gel, finer than 200 mesh, 20% EtOAc
in petroleum ether), in 72% overall yield (ꢀ1:1 ratio).
1
1
The splitting pattern of the –CH2OAr group in the H
In the H NMR of 8 and 7, the methylene (–CH2OAr)
NMR of 5 and 6 was found to be distinctively different.
For example, the methylene protons in cis-acetylene 6
resonated at d 3.93 and 4.05 as double doublets, while
for 5 (trans) the same protons appeared at d 3.97 as a
doublet. The conversion of these enantiomerically pure
products 5 and 6 to targets 1 and 2, is well established
in the literature4a and formally completes the synthesis
of 1 and 2.
protons resonated at d 3.99/4.11 as two double doublets
and d 3.94 (doublet), respectively, which is characteristic
of cis and trans compounds. Reaction of 7 and 8 with
N,O-bis-(phenoxycarbonyl)hydroxylamine9 in the pres-
ence of Ph3P and DIAD, under Mitsunobu10 reaction
conditions, furnished 33 and 34, respectively. Finally,
ammonolysis9 of 33 and 34 with aq NH4OH afforded
targets 3 and 4.
2.2. Synthesis of 3 and 4from ( R)-glyceraldehyde
derivative 12
3. Conclusion
The synthesis of 3 and 4 was initiated from 12. Thus, the
known ester 23,8 prepared from 12 (Scheme 3), on cata-
In conclusion, the synthesis of chiral furans 1–4 has been
achieved from (S)- and (R)-glyceraldehyde derivatives

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1125–1133
1127
O
CO2Et
O
e, f
O
a
b, c, d
O
O
O
O
R
11
13 (99%)
cis:trans 85:15
14 R = CO2Et (99%)
15 R = CH2OH (97%)
16 R = CHO (84%)
HO
OMPM
O
OMPM
g, h
i, j, k
RO
O
OAc
OR
9 R = H (55%)
18 R = H (89%)
19 R = Ts (77%)
17 R = Ac (77%)
2
5
ArO
O
1
1''
OH
1'
RO
l
2'
5
O
OMPM
(72%)
+
20 R = H (93%)
21 R = Ts (78%)
22 R = 4-F-C6H4 (66%)
ArO
O
2
OH
6
Ar = 4-F-C6H4
Scheme 2. Reagents and conditions: (a) Ph3P@CHCO2Et, MeOH, rt, 9 h; (b) H2, PtO2, EtOAc, rt, 4 h; (c) LiAlH4, dry THF, rt, 3 h; (d) IBX, dry
DMSO, 0 ꢁC to rt, 4 h; (e) 1-(4-methoxybenzyloxy)-3-butyne, n-BuLi, ꢁ78 ꢁC to rt, 2 h; (f) Ac2O, Et3N, CH2Cl2, rt, 0.5 h; (g) 60% aq AcOH, rt, 12 h;
(h) p-TsCl, Et3N, CH2Cl2, rt, 10 h; (i) K2CO3, MeOH, rt, 3 h; (j) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (k) 4-FC6H4OH, NaH, DMF, 80 ꢁC, 5 h; (l) DDQ, aq
CH2Cl2 (19:1), rt, 5 h.
11 and 12, respectively. The formal synthesis of 1 and 2,
and the total synthesis of 3 and 4 for a large scale prep-
aration has been well established by a flexible approach
from (S)- and (R)-glyceraldehyde derivatives and pro-
vides the data base for all four possible stereoisomers
for their evaluation.
J = 6.8 Hz, CH3), 1.3, 1.35 (2s, 6H, CH3), 3.5 (dd, 1H,
J = 5.9 Hz, H-5), 4.07 (q, 2H, J = 6.8 Hz, –OCH2),
4.27 (dd, 1H, J = 5.9 Hz, H-5a), 5.32–5.43 (m, 1H, H-
4), 5.72 (dd, 1H, J = 2.2, 11.3 Hz, H-2), 6.27 (dd, 1H,
J = 5.4, 11.3 Hz, H-3); 13C NMR (CDCl3, 50 MHz): d
13.0, 25.2, 26.3, 60.1, 69.21, 73.3, 109.4, 120.5, 149.1,
165.3; EIMS m/z (relative intensity in %): 185
(M+ꢁCH3, 15), 173 (6), 149 (23), 125 (20), 97 (45), 43
(100); HRMS: Calculated for C9H13O4 (M+ꢁCH3):
145.086469; Observed: 145.087162.
4. Experimental
Solvents were dried over standard drying agents and
freshly distilled prior to use. H NMR (200 MHz) spec-
1
4.2. Ethyl (4R)-4,5-isopropylidenedioxy-1-pentanoate 14
tra were recorded in deuteriochloroform solution with
tetramethylsilane as an internal reference 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
10ꢁ1 deg cm2 gꢁ1. Organic solutions were dried over
anhydrous Na2SO4 and concentrated below 40 ꢁC in
vacuo.
A solution of 13 (23 g, 115 mmol) in EtOAc (50 mL) was
treated with PtO2 (0.100 g, 0.44 mmol) and hydro-
genated till there was no additional consumption of
hydrogen (4 h). The reaction mixture was filtered and
concentrated to afford 14 (23 g) in 99% yield as a colour-
less liquid. [a]D = ꢁ4.0 (c 2.0, CHCl3); 1H NMR
(CDCl3, 200 MHz): d 1.25 (t, 3H, J = 6.8 Hz, CH3),
1.29, 1.32 (2s, 6H, CH3), 1.75–1.89 (m, 2H, H-3), 2.3–
2.45 (m, 2H, H-2), 3.5 (t, 1H, J = 6.5 Hz, H-5), 3.92–
4.15 (m, 4H, H-4, 5a, OCH2); 13C NMR (CDCl3,
50 MHz): d 14.0, 25.4, 26.8, 28.6, 30.2, 60.1, 68.8, 74.7,
108.7, 172.6. EIMS m/z (relative intensity in %): 203
(M++H, 23), 173 (16.4), 143 (13.4), 101 (100), 43
(97); HRMS: Calculated for C8H13O4 (M+ꢁ29):
173.081384; Observed: 1173.081619.
4.1. Ethyl (2Z,4R)-4,5-isopropylidenedioxy-2-pentenoate
13
A solution of 11 (15 g, 115.4 mmol) in MeOH (150 mL)
at 10 ꢁC was treated with (carbethoxymethylene)triphe-
nyl phosphorane (48.1g, 138.4 mmol) in portions. After
stirring at room temperature for 9 h, the solvent was
evaporated and the residue purified by column chroma-
tography (silica gel, 10% EtOAc in petroleum ether) to
give 13 (23 g) in 99% yield (85:15 cis:trans) as a pale yel-
low liquid. Compound cis-13: [a]D = ꢁ116.3 (c 0.71,
CHCl3); 1H NMR (CDCl3, 200 MHz): d 1.2 (t, 3H,
4.3. (2R)-1,2-Isopropylidenedioxy-5-pentanol 15
A suspension of LAH (4.93 g, 130.4 mmol) in THF
(50 mL) was cooled to 0 ꢁC and treated dropwise with

1128
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1125–1133
O
CO2Et
O
e, f
O
a
b, c, d
O
O
O
O
R
24 R = CO2Et (99%)
25 R = CH2OH (95%)
23
12
26 R = CHO (84%)
HO
OMPM
O
OMPM
i, j, k
RO
O
g, h
OAc
OR
28 R = H (83%)
29 R = Ts (81%)
10 R = H (57%)
27 R = Ac (87%)
ArO
O
OH
RO
l
O
7
OMPM
(79%)
+
30 R = H (98%)
31 R = Ts (65%)
32 R = 4-F-C6H4 (94%)
2
5
ArO
1'
2'
O
1''
OH
8
Ar = 4-F-C6H4
m
m
ArO
ArO
n
O
3 (56%)
R
33 (76%)
n
O
4 (62%)
R
34 (68%)
Ar = 4-F-C6H4; R = N(OCOOPh)COOPh
Scheme 3. Reagents and conditions: (a) Ph3P@CHCO2Et, CH2Cl2, rt, 9 h; (b) H2, PtO2, EtOAc, rt, 4 h; (c) LiAlH4, dry THF, rt, 3 h; (d) IBX, dry
DMSO, 0 ꢁC to rt, 4 h; (e) 1-(4-methoxybenzyloxy)-3-butyne, n-BuLi, ꢁ78 ꢁC to rt, 2 h; (f) Ac2O, Et3N, CH2Cl2, rt, 0.5 h; (g) 60% aq AcOH, rt, 12 h;
(h) p-TsCl, Et3N, CH2Cl2, rt, 10 h; (i) K2CO3, MeOH, rt, 3 h; (j) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (k) 4-FC6H4OH, NaH, DMF, 80 ꢁC, 5 h; (l) DDQ, aq
CH2Cl2 (19:1), rt, 5 h; (m) DIAD, Ph3P, PhCOONHCOOPh, dry THF, 0 ꢁC to rt, 1h; (n) NH 4OH, MeOH, rt, 3 h.
a solution of 14 (22 g, 108.9 mmol) in THF (75 mL). The
reaction mixture was warmed to room temperature,
allowed to stir for 3 h and then treated with a saturated
solution of Na2SO4 (15 mL). After stirring for an addi-
tional 30 min, it was filtered through Celite and washed
with EtOAc (3 · 75 mL). The combined organic layers
were washed with NaCl solution (2 · 25 mL) and evap-
orated to give 15 (17 g) in 97% yield as a colourless
5.25 mmol) in portions. The reaction mixture was
stirred at room temperature for 4 h, treated with
saturated aq NaHCO3 solution (15 mL), filtered
through Celite and washed with solvent ether
(3 · 30 mL). Two layers were separated and the organic
layer washed with water (15 mL), brine (15 mL) and
dried over Na2SO4. Evaporation of solvent gave (4R)-
4,5-isopropylidenedioxy-1-pentanal 16 (0.663 g) in 84%
yield as a yellow liquid, which was used as such for fur-
ther reaction.
1
liquid. [a]D = ꢁ10.3 (c 0.75, CHCl3); H NMR (CDCl3,
200 MHz): d 1.35, 1.4 (2s, 6H), 1.6–1.75 (m, 4H, H-3, 4),
1.92 (br s, 1H, OH), 3.5 (t, 1H, J = 6.1Hz, H-1), 3.6–
3.72 (m, 2H, H-5), 3.98–4.16 (m, 2H, H-1a, 2); 13C
NMR (CDCl3, 50 MHz): d 25.6, 26.8, 29.0, 30.1, 62.4,
69.4, 75.9, 108.8; EIMS m/z (relative intensity in %):
145 (M+ꢁCH3, 13.4), 85 (32), 72 (18), 57 (13.4), 43
(100); HRMS: Calculated for C7H13O3 (M+ꢁCH3):
145.086468; Observed: 145.087162.
A stirred solution of 1-(4-methoxybenzyloxy)-3-butyne
(4.47 g, 23.50 mmol) in dry THF (10 mL) at ꢁ78 ꢁC
was treated with n-BuLi (16.78 mL, 23.5 mmol, 1.4 M
hexane solution). After 30 min, a solution of 16
(3.10 g, 19.60 mmol) in THF (10 mL) was added
dropwise at ꢁ78 ꢁC and stirred at room temperature
for 2 h. The reaction mixture was quenched with aq
NH4Cl solution (25 mL) and EtOAc (50 mL) then
added and stirred for 10 min. The aqueous layer was
separated and extracted with EtOAc (2 · 50 mL). The
combined organic layers were dried over Na2SO4,
evaporated and the residue purified by column
4.4. (2R,5RS)-5-Hydroxy-1,2-isopropylidenedioxy-9-
(4-methoxybenzyloxy)non-6-yne 9
A stirred solution of 15 (0.80 g, 5.00 mmol) in dry
DMSO (5 mL) at 0 ꢁC was treated with IBX (1.47 g,

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1125–1133
1129
chromatography (silica gel, 25% EtOAc in petroleum
ether) to furnish 9 (3.75 g) in 55% yield as a pale yellow
syrup. [a]D = ꢁ13.4 (c 0.7, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.35, 1.40 (2s, 6H, –CH3) 1.60–1.87 (m, 5H,
H-3, 4, –OH), 2.49 (dt, 2H, J = 2.10, 8.60 Hz, H-8),
3.44–3.58 (m, 3H, H-1, 9), 3.80 (s, 3H, Ar–OCH3),
3.95–4.15 (m, 2H, H-1a, 2), 4.30–4.42 (m, 1H, H-5),
4.46 (s, 2H, –OCH2–Ar), 6.85, 7.22 (2d, 4H,
J = 7.50 Hz, Ar–H); FABMS m/z (relative intensity in
%): 348 (M+, 12), 347 (40), 289 (26), 189 (100); HRMS:
Calculated for C20H27O5 (M+ꢁH): 347.185849. Found:
347.185567.
4.7. (2R,5RS))-5-Acetoxy-2-hydroxy-9-(4-methoxybenz-
yloxy)-1-(p-toluenesulfonyloxy)non-6-yne 19
A solution of 18 (1.00 g, 2.85 mmol) in CH2Cl2 (15 mL)
containing Et3N (1.59 mL, 11.40 mmol) was cooled to
0 ꢁC and treated with p-TsCl (0.65 g, 3.41mmol) and
stirred at room temperature for 10 h. The reaction mix-
ture was diluted with CH2Cl2 (25 mL) and washed with
water (2 · 20 mL). The organic layer was dried over
Na2SO4, evaporated and purified the residue by column
chromatography (silica gel, 25% EtOAc in petroleum
ether) to afford 19 (1.10 g) in 77% yield as a yellow syr-
up. [a]D = ꢁ8.7 (c 0.7, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.45–1.90 (m, 4H, H-3, 4), 2.04 (s, 3H,
–OAc), 2.40–2.52 (m, 5H, H-8, –CH3), 3.52 (t, 2H,
J = 6.97 Hz, H-9), 3.80 (s, 3H, Ar–OCH3), 3.82–4.18
(m, 3H, H-1, 2), 4.45 (s, 2H, –OCH2–Ar), 5.32 (t, 1H,
J = 10.00 Hz, H-5), 6.83, 7.22 (2d, 4H, J = 7.44 Hz,
Ar–H), 7.32, 7.78 (2d, 4H, J = 8.30 Hz, Ar–H).
4.5. (2R,5RS)-5-Acetoxy-1,2-isopropylidenedioxy-9-(4-
methoxybenzyloxy)non-6-yne 17
A
solution of 9 (3.50 g, 10.05 mmol) and Et3N
(4.18 mL, 30.16 mmol) in CH2Cl2 (20 mL) containing
DMAP (0.1equiv) at 0 ꢁC was treated with Ac2O
(1.13 mL, 12.06 mmol) dropwise and stirred at room
temperature for 30 min. The reaction mixture was treat-
ed with saturated aq NH4Cl solution (20 mL), diluted
with CH2Cl2 (50 mL) and the organic layer separated.
It was washed with water (2 · 30 mL), brine (40 mL)
and dried over Na2SO4. Evaporation of the solvent
and purification of the residue by column chromatogra-
phy (silica gel, 25% EtOAc in petroleum ether) gave 17
4.8. (2S,5RS)-2-(Hydroxymethyl)-5-(1-(4-methoxybenz-
yloxy-3-butyn-4-yl)tetrahydrofuran 20
A solution of compound 19 (1.45 g, 2.87 mmol) in
MeOH (20 mL) at room temperature was treated with
K2CO3 (0.87 g, 6.30 mmol) and stirred for 3 h. It was
treated with aq NH4Cl solution (20 mL), evaporated
MeOH and the residue extracted with EtOAc
(3 · 50 mL). The organic layer was washed with water
(2 · 50 mL), brine (40 mL), dried over Na2SO4 and
evaporated. The obtained residue was purified by col-
umn chromatography (silica gel, 25% EtOAc in petro-
leum ether) to afford 20 (0.776 g) in 93% yield as a
colourless liquid. [a]D = ꢁ19.7 (c 1.0, CHCl3); 1H
NMR (200 MHz, CDCl3): d 1.80–2.25 (m, 4H, H-3, 4),
2.48 (dt, 2H, J = 0.72, 7.14 Hz, H-200), 3.52 (t, 3H,
J = 7.39 Hz, H-10, 100) 3.60–3.78 (m, 1H, H-10a), 3.78
(s, 3H, Ar–OCH3), 3.95–4.10, 4.10–4.25 (2m, 1H, H-
2), 4.44 (s, 2H, –OCH2–Ar), 4.50–4.61, 4.61–4.71 (2m,
1H, H-5), 6.82, 7.22 (2d, 4H, J = 9.00 Hz, Ar–H);
FABMS m/z (relative intensity in %): 313 (M++Na,
65), 289 (M+ꢁH, 100), 259 (20), 241 (30), 182 (30),
154 (75), 137 (95); HRMS: Calculated for C17H21O4
(M+ꢁH): 289.143984. Found: 289.143748.
(3.02 g) in 77% yield as
a pale yellow liquid.
[a]D = ꢁ12.5 (c 1.0, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.25, 1.40 (2s, 6H, –CH3), 1.45–2.00
(m, 4H, H-3, 4), 2.05 (s, 3H, –OAc), 2.46 (d, 2H,
J = 1.30, 6.90 Hz, H-8), 3.30–3.82 (m, 6H, H-1, 9, Ar–
OCH3), 3.88–4.25 (m, 2H, H-1a, 2), 4.42 (s, 2H, –
OCH2–Ar), 5.29–5.45 (m, 1H, H-5), 6.84, 7.22 (2d,
4H, J = 8.90 Hz, Ar–H); FABMS m/z (relative intensity
in %): 413 (M++Na, 10), 389 (M+ꢁ1, 15), 375
(M+ꢁCH3, 20), 331 (10), 272 (10), 215 (15), 121 (100),
43 (15); HRMS: Calculated for C22H29O6 (M+ꢁH):
389.196414. Found: 389.195793.
4.6. (2R,5RS)-5-Acetoxy-1,2-dihydroxy-9-(4-methoxy-
benzyloxy)non-6-yne 18
A mixture of 17 (1.60 g, 4.10 mmol) and 60% aq AcOH
(15 mL) was stirred at room temperature for 12 h. The
reaction mixture was neutralized with solid NaHCO3,
saturated aq NaHCO3 solution (pH 7) and extracted
with EtOAc (3 · 50 mL). The combined organic layers
were evaporated and the residue purified by filtration
through a small pad of silica gel with 50% EtOAc in
petroleum ether solvent system to afford diol 18
4.9. (2S,5RS)-5-(1-(4-Methoxybenzyloxy-3-butyn-4-yl)-
2-(p-toluenesulfonyloxymethyl)tetrahydrofuran 21
A solution of 20 (0.77 g, 2.65 mmol) and Et3N (1.10 mL,
7.95 mmol) in CH2Cl2 (10 mL) was treated with p-TsCl
(0.61g, 3.20 mmol) and stirred at room temperature for
8 h. Work-up and purification as described for 19 gave
21 (0.92 g) in 78% yield as a light yellow syrup.
[a]D = +7.2 (c 0.9, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.85–2.22 (m, 4H, H-3, 4), 2.28–2.35 (m,
5H, H-200, Ar–CH3), 3.50 (t, 2H, J = 7.10 Hz, H-100),
3.80 (s, 3H, Ar–OCH3), 3.98 (d, 1H, J = 4.80 Hz, H-
10), 4.00–4.12 (m, 1H, H-10a), 4.15–4.22 (m, 1H, H-2),
4.44 (s, 2H, –OCH2–Ar), 4.45–4.62 (m, 1H, H-5), 6.84,
7.22 (2d, 4H, J = 8.80 Hz, Ar–H), 7.30, 7.80 (2d, 4H,
J = 8.20 Hz, Ar–H); FABMS m/z (relative intensity in
%): 467 (M++Na, 55), 444 (M+, 65), 443 (M+ꢁH, 80),
413 (15), 336 (25), 255 (50), 214 (60).
(1.28 g) in 89% yield as
a pale yellow syrup.
[a]D = ꢁ10.2 (c 0.8, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.50–2.00 (m, 4H, H-3, 4), 2.05 (s, 3H,
–OAc), 2.50 (dt, 2H, J = 1.20, 6.80 Hz, H-8), 3.30–3.82
(m, 7H, H-1, 9, –OCH3), 4.09 (t, 1H, J = 6.50 Hz, H-
2), 4.45 (s, 2H, –OCH2–Ar), 5.30–5.44 (m, 1H, H-5),
6.85, 7.22 (2d, 4H, J = 9.00 Hz, Ar–H); FABMS m/z
(relative intensity in %): 373 (M++Na, 40), 349
(M+ꢁH, 18), 335 (M+ꢁCH3, 45), 290 (15), 241 (20),
121 (100), 91 (5), 69 (8), 55 (10); HRMS: Calculated
for C18H23O6 (M+ꢁCH3): 335.149464. Found:
335.149249.

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G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1125–1133
4.10. (2RS,5S)-5-(4-Fluorophenoxymethyl)-2-(1-(4-meth-
oxybenzyloxy)-3-butyn-4-yl)tetrahydrofuran 22
153 (25), 139 (78), 95 (80), 55 (90), 43 (100); HRMS:
Calculated for C15H17FO3 (M+): 264.116173. Found:
264.117053.
To a stirred suspension of NaH (0.13 g, 3.15 mmol, 60%
w/w dispersion in miner oil) and 4-fluorophenol (0.29 g,
2.50 mmol) in DMF (5 mL), a solution of 21 (0.94 g,
2.10 mmol) in DMF (3 mL) was added and allowed to
stir at 80 ꢁC for 5 h. The reaction mixture was cooled
to room temperature and treated with aq NH4Cl
solution (10 mL). It was extracted with solvent ether
(3 · 20 mL) and the combined organic layers washed
with water (2 · 20 mL), brine (20 mL) and dried over
Na2SO4. Evaporation of the solvent and purification
of the residue by column chromatography (silica gel,
5% EtOAc in petroleum ether) afforded 22 (0.536 g)
in 66% yield as a pale yellow liquid. [a]D = ꢁ9.2 (c
0.8, CHCl3); 1H NMR (200 MHz, CDCl3): d 1.80–
2.35 (m, 4H, H-3, 4), 2.50 (dt, 2H, J = 1.02, 6.70 Hz,
H-20), 3.52 (t, 2H, J = 7.10 Hz, H-10), 3.80 (s, 3H, Ar–
OCH3), 3.81–3.95 (m, 2H, H-100), 4.00–4.15 (m, 1H,
H-5), 4.48 (s, 2H, –OCH2–Ar), 4.55–4.65, 4.65–4.80
(2m, 1H, H-2), 6.70–7.00 (m, 6H, Ar–H), 7.20–7.25
(m, 2H, Ar–H); FABMS m/z (relative intensity in %):
384 (M+, 5), 383 (M+ꢁH, 20), 243 (100), 183 (25),
165 (20), 91 (10), 69 (25), 55 (32); HRMS: Calculated
for C23H24FO4 (M+ꢁH): 383.165863. Found:
383.164866.
4.12. Ethyl (4S)-4,5-isopropylidenedioxy-1-pentanoate 24
A solution of 23 (20.0 g, 0.10 mol) in EtOAc (75 mL)
was treated with PtO2 (0.10 g) and subjected to hydro-
genation at 40 psi pressure for 4 h. Work-up as de-
scribed for 14 afforded 24 (20.0 g) in 99% yield as a
1
colourless liquid. [a]D = +5.0 (c 2.2, CHCl3); H NMR
(200 MHz, CDCl3): d 1.28 (t, 3H, J = 7.10 Hz, –CH3),
1.30, 1.45 (2s, 6H, –CH3), 1.80–1.95 (m, 2H, H-3),
2.38–2.50 (m, 2H, H-2), 3.52 (t, 1H, J = 7.10 Hz, H-
5), 4.00–4.20 (m, 4H, H-4, 5a, –OCH2–). Anal. Calcd
for C10H18O4: C, 59.39; H, 8.97. Found : C, 58.99; H,
8.92.
4.13. (2S)-1,2-Isopropylidenedioxy-5-pentanol 25
A
cooled (0 ꢁC) suspension of LiAlH4 (3.74 g,
0.099 mol) in dry THF (75 mL) was treated dropwise
with a solution of 24 (20.00 g, 0.099 mol) in dry THF
(100 mL). After 3 h, work-up and purification as de-
scribed for 15 gave 25 (15.05 g) in 95% yield as a colour-
less liquid. [a]D = +1 2.1 c( 2.2, CHCl3). 1H NMR
(200 MHz, CDCl3): d 1.30, 1.40 (2s, 6H, –CH3), 1.60–
1.80 (m, 5H, H-3, 4, –OH), 3.50 (t, 1H, J = 8.30 Hz,
H-1), 3.60–3.70 (m, 2H, H-5), 4.00–4.18 (m, 2H, H-1a,
2); 13C NMR (50 MHz, CDCl3): d 25.5, 26.7, 28.9,
30.0, 62.2, 69.3, 76.3, 108.8; EIMS: 145 (M+ꢁCH3);
HRMS: Calculated for C7H13O3 (M+ꢁCH3):
145.086469. Found: 145.086081.
4.11. (2S,5S)-trans-5-(4-Fluorophenoxymethyl)-2-(1-
hydroxy-3-butyn-4-yl)tetrahydrofuran 5 and (2R,5S)-cis-
5-(4-fluorophenoxymethyl)-2-(1-hydroxy-3-butyn-4-yl)-
tetrahydrofuran 6
To
a stirred solution of compound 22 (0.45 g,
1.17 mmol) in CH2Cl2–H2O (19:1) (10 mL), DDQ
(0.4 g, 1.75 mmol) was added at 0 ꢁC and allowed to stir
for 5 h at room temperature. Saturated aq NaHCO3
solution (10 mL) was added to the reaction mixture
and extracted with CHCl3 (2 · 25 mL). The combined
organic layers were washed with brine (30 mL), dried
over Na2SO4, evaporated and residue purified by col-
umn chromatography (silica gel, finer than 200 mesh,
20% EtOAc in petroleum ether) to give 5 and 6 overall
in 72% yield. First eluted was 6 (0.11 g) as a colourless
syrup. [a]D = +1 4.3 (c 0.8, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.76–2.30 (m, 4H, H-3, 4), 2.45
(dt, 2H, J = 1.20, 6.75 Hz, H-20), 3.70 (t, 2H, J =
6.40 H-10), 3.93 and 4.05 (2dd, 2H, J = 6.40,
9.60 Hz, H-100), 4.15–4.36 (m, 1H, H-5), 4.56–4.69
(m, 1H, H-2), 6.78, 7.02 (m, 4H, Ar–H); FABMS: m/z
(relative intensity in %) 264 (M+, 50), 153 (35), 139
(80), 95 (90), 77 (75), 55 (90), 43 (100); HRMS:
Calculated for (M+) C15H17FO3: 264.116173. Found:
264.116018.
4.14. (2S,5R/S)-5-Hydroxy-1,2-isopropylidenedioxy-9-
(4-methoxybenzyloxy)non-6-yne 10
A stirred solution of 25 (0.80 g, 5.0 mmol) in dry
DMSO (5 mL) at 0 ꢁC was treated with IBX (1.47 g,
5.25 mmol) and stirred at room temperature for 4 h.
Work-up as described for 16 gave (4S)-4,5-isopropyl-
idenedioxy-1-pentanal 26 (0.663 g) in 84% yield as a yel-
low liquid.
A stirred solution of 1-(4-methoxybenzyloxy)-3-butyne
(1.0 g, 5.30 mmol) in dry THF (5 mL) at ꢁ78 ꢁC was
treated with n-BuLi (3.80 mL, 5.30 mmol; 1.4 M hexane
solution). After 30 min, a solution of 26 (0.60 g,
3.80 mmol) in dry THF (5 mL) was added dropwise
and stirred for 2 h at room temperature. Work-up and
purification by column chromatography (silica gel,
25% EtOAc in petroleum ether) as described for 9 fur-
nished 10 (0.75 g) in 57% yield as a pale yellow syrup.
[a]D = +11.0 (c 1.0, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.35, 1.40 (2s, 6H, –CH3) 1.64–1.85 (m, 5H,
H-3, 4, –OH), 2.50 (dt, 1H, J = 2.10, 8.60 Hz, H-8),
3.45–3.58 (m, 3H, H-1, 9), 3.80 (s, 3H, Ar–OCH3),
3.98–4.18 (m, 2H, H-1a, 2), 4.32–4.44 (m, 1H, H-5),
4.46 (s, 2H, –OCH2–Ar–), 6.85, 7.25 (2d, 4H,
J = 7.50 Hz, Ar–H); FABMS m/z (relative intensity in
%): 348 (M+, 12), 347 (40), 289 (26), 189 (100); HRMS:
Calculated for C20H27O5 (M+ꢁH): 347.185849. Found:
347.185567.
Second eluted was 5 (0.113 g) as a white solid, mp 73–
76 ꢁC; lit.4a 77–79 ꢁC. [a]D = ꢁ32.8 (c 1.0, CHCl3); lit.4a
[a]D = ꢁ34.0 (c 1.8, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.64–2.40 (m, 4H, H-6, 7), 2.53 (dt, 2H,
J = 1.48, 6.66 Hz, H-20), 3.75 (t, 2H, J = 6.6 Hz, H-10),
3.97 (d, 2H, J = 5.30 Hz, H-100), 4.40–4.62 (m, 1H, H-
5), 4.70–4.85 (m, 1H, H-2), 6.80, 7.08 (m, 4H, Ar–H);
FABMS m/z (relative intensity in %): 264 (M+, 68),

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1125–1133
1131
4.15. (2S,5RS)-5-Acetoxy-1,2-isopropylidenedioxy-9-
(4-methoxybenzyloxy)non-6-yne 27
(0.451g) in 98% yield as a yellow syrup. [ a]D = +23.3
(c 1.85, CHCl3); H NMR (200 MHz, CDCl3): d 1.87–
1
2.26 (m, 4H, H-3, 4), 2.26–2.42 (br s, 1H, –OH), 2.49
(dt, 2H, J = 1.15, 7.69 Hz, H-2), 3.40–3.60 (m, 3H, H-
10, 100), 3.62–3.78 (m, 1H, H-1a), 3.80 (s, 3H, –OCH3),
3.98–4.12, 4.12–4.30 (2m, 1H, H-2), 4.48 (s, 2H,
–OCH2–), 4.52–4.62, 4.62–4.73 (2m, 1H, H-5), 6.86,
7.25 (2d, 4H, J = 8.46 Hz, Ar–H); FABMS m/z (relative
intensity in %): 313 (M++Na, 65), 289 (M+ꢁH, 100),
259 (20), 241 (30), 182 (30), 154 (75), 137 (95); HRMS:
Calculated for C17H21O4 (M+ꢁH): 289.143984. Found:
289.143748.
A solution of 10 (0.70 g, 2.01mmol) and Et 3N (0.84 mL,
6.03 mmol) in CH2Cl2 (10 mL) containing DMAP
(0.1equiv) at 0 ꢁC was treated with Ac2O (0.23 mL,
2.41mmol) and stirred at room temperature for
30 min. Work-up and purification by column chroma-
tography (silica gel, 5% EtOAc in petroleum ether) as
described for 17 afforded 27 (0.68 g) in 87% yield as a
pale yellow syrup. [a]D = +9.5 (c 1.0, CHCl3); 1H
NMR (200 MHz, CDCl3): d 1.36, 1.42 (2s, 6H, –CH3),
1.60–2.00 (m, 4H, H-3, 4), 2.10 (s, 3H, –OAc), 2.51
(dt, 2H, J = 2.17, 8.20 Hz, H-8), 3.45–3.60 (m, 3H, H-
1, 9), 3.82 (s, 3H, Ar–OCH3), 3.96–4.14 (m, 2H, H-1a,
2), 4.48 (s, 2H, –OCH2–Ar), 5.32–5.45 (m, 1H, H-5),
6.86, 7.25 (2d, 4H, J = 7.60 Hz, Ar–H); FABMS m/z
(relative intensity in %): 413 (M++Na, 4), 391(6), 337
(19), 253 (10), 143 (100).
4.19. (2R,5RS)-5-(4-Methoxybenzyloxy)-3-butyn-4-yl)-2-
(p-toluenesulfonyloxymethyl)tetrahydrofuran 31
A solution of 30 (0.45 g, 1.55 mmol) and Et3N (0.65 mL,
4.65 mmol) in CH2Cl2 (10 mL) was treated with p-TsCl
(0.32 g, 1.70 mmol). After 8 h, work-up and purification
by column chromatography (silica gel, 25% EtOAc in
petroleum ether) as described for 21 gave 31 (0.448 g)
in 65% yield as a yellow syrup. [a]D = ꢁ3.5 (c 1.9,
4.16. (2S,5RS)-5-Acetoxy-1,2-dihydroxy-9-(4-methoxy-
benzyloxy)non-6-yne 28
1
CHCl3); H NMR (200 MHz, CDCl3): d 1.74–2.21 (m,
A mixture of 27 (0.80 g, 2.05) and 60% aq AcOH (8 mL)
was stirred at room temperature for 12 h. Work-up and
purification as described for 18 afforded 28 (0.595 g) in
4H, H-3, 4), 2.39–2.49 (m, 2H, H-200), 2.50 (s, 3H, Ar–
CH3), 3.50 (t, 2H, J = 8.10 Hz, H-100), 3.79 (s, 3H, Ar–
0
OCH3), 3.97 (d, 1H, J = 4.91Hz, H-1 ), 4.02–4.15 (m,
1
83% yield as a syrup. [a]D = +6.5 (c 1.0, CHCl3); H
1H, H-10a), 4.20–4.30 (m, 1H, H-2), 4.44 (s, 2H,
–OCH2ꢁAr–), 4.50–4.60 (m, 1H, H-5), 6.82 (d, 2H,
J = 7.90 Hz, Ar–H), 7.16–7.38 (m, 4H, Ar–H), 7.79 (d,
2H, J = 7.90 Hz, Ar–H); FABMS m/z (relative intensity
in %): 467 (M++Na, 2), 443 (M+ꢁH, 3), 121 (100), 107
(10), 91 (27), 55 (34); HRMS: Calculated for C24H24O6S
(M+ꢁH): 443.152830. Found: 443.152732.
NMR (200 MHz, CDCl3): d 1.46–1.65 (m, 2H, H-3),
1.69–2.00 (m, 2H, H-4), 2.09 (s, 3H, –OAc), 2.02–2.26
(br s, 2H, –OH), 2.50 (dt, 2H, J = 2.08, 8.17 Hz, H-8),
3.30–3.46 (m, 1H, H-1), 3.46–3.78 (m, 4H, H-1, 2, 9),
3.80 (s, 3H, Ar–OCH3), 4.45 (s, 2H, –OCH2–Ar–),
5.30–5.42 (m, 1H, H-5), 6.82, 7.20 (d, 4H, J = 7.20 Hz,
Ar–H); FABMS m/z (relative intensity in %): 335
(M+ꢁCH3, 12), 215 (5), 183 (28), 154 (64), 107 (100);
HRMS: Calculated for C18H23O6 (M+ꢁCH3):
335.149464. Found: 335.149249.
4.20. (2RS,5R)-5-(4-Fluorophenoxymethyl)-2-(1-(4-meth-
oxybenzyloxy-3-butyn-4-yl)tetrahydrofuran 32
To a stirred suspension of NaH (0.04 g, 1.08 mmol, 60%
w/w dispersion in mineral oil) in DMF (3 mL), a solu-
tion of 31 (0.40 g, 0.9 mmol) in DMF (3 mL) was added,
followed by the addition of 4-fluorophenol (0.121 g,
1.08 mmol) in DMF (2 mL) and heated at 80 ꢁC for
5 h. Work-up and purification by column chromatogra-
phy (silica gel, 5% EtOAc in petroleum ether) as de-
scribed for 22 afforded 32 (0.325 g) in 94% yield as a
4.17. (2S,5RS)-5-Acetoxy-2-hydroxy-9-(4-methoxybenz-
yloxy)-1-(p-toluenesulfonyloxy)non-6-yne 29
A solution of 28 (0.60 g, 1.71 mmol) and Et3N (0.72 mL,
5.14 mmol) in CH2Cl2 (30 mL) at 0 ꢁC was treated with
p-TsCl (0.327 g, 1.71 mmol) and stirred at room temper-
ature for 10 h. Work-up and purification by column
chromatography (silica gel, 20% EtOAc in petroleum
ether) as described for 19 afforded 29 (0.69 g) in 81%
1
colourless syrup. [a]D = +6.9 (c 1.0, CHCl3); H NMR
(200 MHz, CDCl3): d 1.82–2.29 (m, 4H, H-3, 4), 2.42–
2.58 (m, 2H, H-20), 3.45–3.59 (m, 2H, H-10), 3.81(s,
3H, –OCH3), 3.85–3.96 (m, 2H, H-100), 4.00–4.14 (m,
1H, H-5), 4.47 (s, 2H, –OCH2–Ar), 4.66–4.76, 4.76–
4.82 (2m, 1H, H-2), 6.76–7.0 (m, 6H, Ar–H), 7.18–7.23
(m, 2H, Ar–H); FABMS m/z (relative intensity in %):
384 (18), 383 (69), 369 (10), 313 (20), 121 (100); HRMS:
Calculated for C23H24FO4 (M+ꢁH): 383.165863.
Found: 383.164866.
1
yield as yellow syrup. [a]D = +1 0.6 (c 0.45, CHCl3); H
NMR (200 MHz, CDCl3): d 1.52–1.98 (m, 4H, H-3, 4),
1.98 (s, 3H, –OAc), 2.41–2.56 (m, 5H, H-8, Ar–CH3),
3.34–3.72 (m, 2H, H-9), 3.80 (s, 3H, –OCH3), 3.94–4.2
(m, 3H, H-1, 2), 4.45 (s, 2H, Ar–OCH2–), 5.26–5.42
(m, 1H, H-5), 6.82, 7.21 (2d, 4H, J = 7.90 Hz, Ar–H),
7.26–7.30 (m, 2H, Ar–H), 7.62–7.82 (m, 2H, Ar–H).
4.18. (2R,5RS)-2-(Hydroxymethyl)-5-(1-(4-methoxybenz-
yloxy)-3-butyn-4-yl)tetrahydrofuran 30
4.21. (2R,5R)-trans-5-(4-Fluorophenoxymethyl)-2-
(1-hydroxy-3-butyn-4-yl)tetrahydrofuran 7 and (2S,5R)-
cis-5-(4-fluorophenoxymethyl)-2-(1-hydroxy-3-butyn-4-
yl)tetrahydrofuran 8
To a solution of 29 (0.80 g, 1.58 mmol) in MeOH
(15 mL), K2CO3 (0.482 g, 3.49 mmol) was added and
stirred at room temperature for 3 h. Work-up and puri-
fication by column chromatography (silica gel, 25%
EtOAc in petroleum ether) as described for 20 gave 30
A mixture of 32 (0.30 g, 0.78 mmol) and DDQ (0.212 g,
0.937 mmol) in aq CH2Cl2 (10 mL, 1:19) was stirred at

1132
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1125–1133
room temperature for 5 h. It was worked-up and puri-
fied by column chromatography (silica gel, 200 mesh,
20% EtOAc in petroleum ether) as described for 5 and
6 to give 7 and 8 as a colourless syrup in 79% overall
yield. First eluted was 8 (0.11 g) [a]D = ꢁ12.8 (c 0.7,
495 (15), 459 (28), 313 (90), 291 (75), 191 (40), 176
(32). Analysis for C29H26FNO7: found: C, 66.85; H,
5.23.
4.24. (2R,5R)-trans-5-(4-Fluorophenoxymethyl)-2-(1-N-
hydroxyureidyl-3-butyn-4-yl)tetrahydrofuran 3
1
CHCl3); H NMR (200 MHz, CDCl3): d 1.88–2.38 (m,
4H, H-3, 4), 2.51(dt, 2H, J = 1.31, 6.66 Hz, H-20),
3.75 (t, 2H, J = 6.66 Hz, H-10), 3.99, 4.11 (2dd, 2H,
J = 5.83, 10.1 Hz, H-100), 4.25–4.42 (m, 1H, H-5), 4.61–
4.76 (m, 1H, H-2), 6.84–7.10 (m, 4H, Ar–H); FABMS
m/z (relative intensity in %): 264 (M+, 50), 153 (35),
139 (80), 95 (90), 77 (75), 55 (90), 43 (100); HRMS: Cal-
culated for (M+) C15H17FO3: 264.116173. Found:
264.116018.
To a stirred solution of 33 (0.30 g, 0.572 mmol) in
MeOH (10 mL), NH4OH solution (10 mL) was added
at room temperature. After 6 h, it was extracted with
CH2Cl2 (3 · 20 mL) and washed with 5% NaOH solu-
tion (40 mL). The aqueous phase was cooled and acidi-
fied with concd HCl to pH 7–8. The resulting solid was
filtered and washed with water. The crude product
(solid) was dissolved in MeOH and heated at reflux with
carbon (0.10 g) for 1 h. The solution was filtered and
concentrated under vacuum to give 3 (0.104 g) in
56% yield as a gummy syrup. [a]D = +43.9 (c 0.5,
Second eluted was 7 (0.117 g) as a colourless syrup.
Compound 7: [a]D = +31.9 (c 0.7, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.78–2.38 (m, 4H, H-3, 4), 2.49
(dt, 2H, J = 1.25, 6.66 Hz, H-20), 3.70 (t, 2H,
J = 7.50 Hz, H-10), 3.94 (d, J = 5.0 Hz, 2H, H-100),
4.36–4.53 (m, 1H, H-5), 4.65–4.82 (m, 1H, H-2), 6.75,
7.05 (m, 4H, Ar–H); FABMS: 264 (M+, 68), 153 (25),
139 (78), 95 (80), 55 (90), 43 (100); HRMS: Calculated
for C15H17FO3 (M+): 264.116173. Found: 264.117053.
1
CHCl3); H NMR (200 MHz, CDCl3): d 1.70–1.90 (m,
1H, H-4), 1.90–2.12 (m, 1H, H-4a), 2.12–2.38 (m, 2H,
H-3), 2.55 (dt, 2H, J = 0.80, 8.00 Hz, H-20), 3.70 (t,
2H, J = 6.40 Hz, H-10), 3.83–4.06 (m, 2H, H-100), 4.4–
4.55 (m, 1H, H-5), 4.68–4.80 (m, 1H, H-2), 5.30–5.50
(br s, 2H, –NH2), 6.78–7.05 (m, 4H, Ar–H), 8.10–8.22
(br s, 1H, OH); IR (KBR): 3438, 3193, 2941, 1626,
1508 cmꢁ1; EIMS m/z (relative intensity in %): 323
(M++H, 7), 280 (100), 264 (55). Anal. Calcd for
C16H19FN2O4: C, 59.62; H, 5.94. Found: C, 59.57; H,
5.89.
4.22. (2R,5R)-trans-5-(4-Fluorophenoxymethyl)-2-
(1-N,O-bis(phenoxycarbonyl)hydroxylamino-3-butyn-4-
yl)tetrahydrofuran 33
To a stirred solution of 7 (0.26 g, 1.0 mmol), N,O-bis-
phenoxycarbonyl-hydroxylamine (0.409 g, 1.50 mmol)
and Ph3P (0.26 g, 0.99 mmol) in CH2Cl2 (10 mL), DIAD
(0.30 g, 1.50 mmol) was added dropwise at 0 ꢁC and stir-
red at room temperature 1h. The reaction mixture was
filtered through a silica gel column using CH2Cl2 as elu-
ent and evaporated the solvent in vacuum to give 33
(0.39) in 76% yield as a pale yellow oil. [a]D = +1 4.6 (c
4.25. (2S,5R)-cis-5-(4-Fluorophenoxymethyl)-2-(1-N-
hydroxyureidyl-3-butyn-4-yl)tetrahydrofuran 4
To a stirred solution of 34 (0.25 g, 0.48 mmol) in MeOH
(5 mL), NH4OH solution (10 mL) was added at room
temperature and stirred for 6 h. Work-up as described
for 3 gave a solid, which was dissolved in MeOH and
heated at reflux with carbon (0.10 g) for 1 h, filtered
and concentrated in vacuo to give 4 (0.096 g) in 62%
yield. [a]D = ꢁ51.0 (c 0.5, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.80–2.35 (m, 4H, H-3, 4), 2.60
(dt, 2H, J = 0.60, 6.80 Hz, H-2), 3.60–3.90 (m, 3H, H-
10, 100), 4.0 (dd, 1H, J = 4.50, 9.00 Hz, H-10a), 4.24 (t,
1H, J = 6.70 Hz, H-5), 4.45–4.64 (m, 1H, H-2), 6.70–
7.03 (m, 4H, Ar–H). EIMS m/z (relative intensity in
%): 323 (M++H, 10), 280 (100), 264 (65) Analysis for
C16H19FN2O4: found: C, 59.58; H, 5.93.
1
0.5, CHCl3); H NMR (200 MHz, CDCl3): d 1.73–2.40
(m, 4H, H-3, 4), 2.70 (t, 2H, J = 7.50 Hz, H-20), 3.88
(d, 2H, J = 5.0 Hz, H-10), 4.0 (t, J = 8.8 Hz, 2H, H-10),
4.30–4.52 (m, 1H, H-5), 4.62–4.80 (m, 1H, H-2), 6.70–
7.02 (m, 4H, Ar–H), 7.10–7.55 (m, 10H, Ar–H);
FABMS m/z (relative intensity in %): 520 (M++H, 25),
519 (M+, 10), 459 (48), 363 (10), 291 (30), 191 (100),
175 (60). Anal. Calcd for C29H26FNO7: C, 66.92; H,
5.23. Found: C, 66.90; H, 5.22.
4.23. (2S,5R)-cis-5-(4-Fluorophenoxymethyl)-2-(1-N,O-
bis(phenoxycarbonyl)hydroxylamino-3-butyn-4-yl)tetra-
hydrofuran 34
References
To a stirred solution of 8 (0.264 g, 1.00 mmol), N,O-
bis(phenoxycarbonyl)hydroxylamine (0.409 g, 1.50 mmol),
and Ph3P (0.393 g, 1.50 mmol) in CH2Cl2 (10 mL)
DIAD (0.30 g, 1.50 mmol) was added dropwise at
0 ꢁC. After 1h, it was worked-up as described for 33
to give 34 (0.352 g) in 68% yield as a pale yellow oil.
[a]D = ꢁ11.2 (c 0.5, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.85–2.25 (m, 4H, H-3, 4), 2.70 (d, 2H,
J = 0.88, 6.36 Hz, H-20), 3.80–4.15 (m, 4H, H-10, 100),
4.15–4.35 (m, 1H, H-5), 4.52–4.68 (m, 1H, H-2), 6.72–
6.98 (m, 4H, Ar–H), 7.08–7.48 (m, 10H, Ar–H);
FABMS m/z (relative intensity in %): 518 (M+ꢁH, 55),
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