Stereoselective syntheses of pharmaceutically relevant chiral tetrahydrofurans from (S)- and (R)-glyceraldehyde derivatives

Article abstract of DOI:10.1016/j.tetasy.2005.01.044

A practically simple and flexible method of making chiral tetrahydrofurans of therapeutic relevance is reported from glyceraldehyde derivatives as chiral synthons. One of the stereocentres is derived from glyceraldehyde derivatives, while the other one is introduced by Sharpless asymmetric epoxidation using either (+)- or (-)-DIPT.

Full text of DOI:10.1016/j.tetasy.2005.01.044

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1113–1123
Stereoselective syntheses of pharmaceutically relevant chiral
tetrahydrofurans from (S)- and (R)-glyceraldehyde derivativesI
G. V. M. Sharma,a,* Sreenivas Punna,a T. Rajendra Prasad,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—A practically simple and flexible method of making chiral tetrahydrofurans of therapeutic relevance is reported from gly-
ceraldehyde derivatives as chiral synthons. One of the stereocentres is derived from glyceraldehyde derivatives, while the other one
is introduced by Sharpless asymmetric epoxidation using either (+)- or (ꢀ)-DIPT.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
diastereoisomers 1 and 4, from (S)- and (R)-glyceralde-
hyde derivatives.
Asthma is a chronic inflammatory disease complicated
by periodic acute inflammatory changes. The role of leu-
kotrienes, the metabolites of arachidonic acid that are
produced by the action of the 5-lipoxygenase (5-LO) en-
zyme, in inflammatory and allergic responses, including
arthritis, asthma, psoriasis and thrombotic diseases, is
well recognized.1,2 Blocking either the synthesis or func-
tion of leukotrienes (LTs) has been shown to confer
therapeutic benefits on asthmatic patients. Chiral tetra-
hydrofurans are structural features in a variety of natu-
ral products,3–5 while compounds 2a and 3a and their
stereoisomers 1a and 4a (Fig. 1) have been investigated
for their inhibitory action against 5-lipoxygenase.6 Com-
pound 2a was found to be a potent and orally active leu-
kotriene modulator that works by inhibiting the action
of 5-lipoxygenase (5-LO) to block the generation of cys-
teinyl leukotrienes and LTB4. Further studies on 3a
showed a high degree of potency, excellent oral bioavail-
ability and exceptionally favourable safety profile7 over
2a. Synthetic routes for the preparation of 2 and 2a and
3 and 3a have been reported by us.8 Herein, we report a
flexible synthetic route for acetylenes 2 and 3 and their
2. Results and discussion
Retrosynthetic analysis (Scheme 1) indicates that 1–4
could be prepared from alcohols 5–8 derived from allylic
alcohols 9 and 10, while these could be envisaged from
(S)- and (R)-glyceraldehyde derivatives 11 and 12,
respectively. Thus, of the two requisite stereogenic cen-
tres, one is obtained from either the (S)- or (R)-glyceral-
dehyde derivative, while the other is introduced on the
allylic alcohol by the Sharpless asymmetric epoxidation
method using (+) and (ꢀ)-DIPT. Thus the main strategy
would be the synthesis of allylic alcohols 9 and 10 from
glyceraldehyde derivatives and their conversion into chi-
ral propargyl alcohols through the epoxy alcohols.
Alcohols 5–8 in turn afforded the target acetylenic deriv-
atives 1–4.
2.1. Synthesis of allylic alcohol 9
Accordingly, the Wittig olefination of 119 (prepared
from L-ascorbic acid) with (carbethoxymethylene)tri-
phenyl phosphorane in CH2Cl2 gave ester 13 (Scheme
2), which on catalytic hydrogenation with PtO2 at room
temperature afforded 1410 in quantitative yield. Ester 14
was reduced with LAH in THF to furnish the known
alcohol 1511 (97%), which on oxidation with IBX in
q IICT Communication no. 040304.
*
Corresponding authors. Fax: +91 40 2716 0387; e-mail: esmvee@
iict.res.in
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.044

1114
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
O
O
O
O
1, 1a
O
2, 2a
R
R
F
F
F
O
O
R
O
3, 3a
R
4, 4a
F
1-4 R = H
1a-4a R = CH2CH2N(OH)CONH2
Figure 1.
O
O
1
O
O
5
6
OH
OH
O
O
O
O
OH
O
9
11
2
O
3
4
O
7
OH
OH
O
O
O
O
OH
O
O
10
12
O
8
Scheme 1.
O
O
O
a
b, c
O
O
O
O
R
CO2Et
11
14 R = CO2Et
15 R = CH2OH
13
O
O
d
O
e, f
O
O
R
16 (84%)
17 R = CO2Et (65%)
9 R = CH2OH (98%)
Scheme 2. 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) Ph3P@CHCO2Et, benzene, reflux, 6 h; (f) DIBAL-H, dry CH2Cl2, ꢀ20 ꢁC, 2 h.
DMSO afforded aldehyde 16 (84%). Subjecting 16 to a
Wittig olefination with (carbethoxymethylene)triphenyl
phosphorane, in benzene at reflux, resulted in 17
(65%), which on selective reduction with DIBAL-H in
CH2Cl2 at ꢀ20 ꢁC furnished allylic alcohol 9 (98%).
ment with LDA at ꢀ40 ꢁC afforded 5 (95%), which on
acetylation (Ac2O, Et3N) furnished the corresponding
acetate 20 (97%). Hydrolysis of 20 with 60% aq AcOH
at room temperature gave diol 21 (73%), which on tosyl-
ation (p-TsCl, Et3N) in CH2Cl2, afforded monotosylate
22 in 71% yield.
2.2. Synthesis of (2R,5S)-cis-2-ethynyl-5-(4-fluorophen-
oxymethyl)tetrahydrofuran 1
Cyclization of tosylate 22 with K2CO3 in methanol at
room temperature afforded the 2,5-disubstituted tetra-
hydrofuran 23 (99%), which on tosylation, and further
treatment of 24 with 4-fluorophenol in the presence of
NaH in DMF at 80 ꢁC afforded 1 in 86% yield. Thus,
making use of (S)-glyceraldehyde derivative 11 and
Sharpless epoxidation with (ꢀ)-DIPT, the synthesis of
(2R,5S)-isomer 1 was successfully achieved.
Sharpless asymmetric epoxidation12 of 9 (Scheme 3)
using (ꢀ)-DIPT, Ti(OiPr)4 and cumene hydroperoxide
at ꢀ20 ꢁC, furnished (2R,3R)-epoxide 18 (76%), which
on subsequent reaction with Ph3P in CCl4 in the pres-
ence of NaHCO3 (cat) at reflux, gave 19 (68%). The
fragmentation13 of chiral epoxy chloride 19 on treat-

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
1115
O
O
O
a, b
R
O
c, d
O
OH
O
O
9
OR
18 R = OH (76%)
19 R = Cl (68%)
5 R = H (95%)
20 R = Ac (97%)
HO
RO
h, i
HO
O
e, f
g
RO
O
21R = H (73%)
OAc
22 R = Ts (71%)
23 (99%)
24 R = Ts (64%)
1 R = 4-F-C6H4 (86%)
i
˚
Scheme 3. Reagents and conditions: (a) (ꢀ)-DIPT, Ti(O Pr)4, cumene hydroperoxide, MS 4 A, CH2Cl2, ꢀ20 ꢁC, 3 h; (b) Ph3P, cat NaHCO3, CCl4,
reflux, 3 h; (c) LDA, dry THF, ꢀ40 ꢁC, 3 h; (d) Ac2O, Et3N, CH2Cl2, rt, 30 min; (e) 60% aq AcOH, rt, 12 h; (f) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (g)
K2CO3, MeOH, rt, 2 h; (h) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (i) 4-F-C6H4OH, NaH, DMF, 80 ꢁC, 5 h.
2.3. Synthesis of (2S,5S)-trans-2-ethynyl-5-(4-fluoro-
phenoxymethyl)tetrahydrofuran (2)
ingly, 12 on two sequential Wittig olefinations (Scheme
5) and further reactions were converted into 10.
Similarly, Sharpless epoxidation of allylic alcohol 9
(Scheme 4) with (+)-DIPT gave (2S,3S)-epoxide 25
(72%), which was further converted into propargyl alco-
hol 6 (83%) through the corresponding chloride 26.
Acetylation of 6 furnished acetate 27 (91%), which on
deprotection of the acetonide moiety in 27 and subse-
quent tosylation of 28 afforded 29 (89%). Treatment of
29 with K2CO3 in methanol gave tetrahydrofuran 30
(95%). Finally, tosylation of 30 followed by treatment
of 31 with 4-fluorophenol in the presence of NaH
2.5. Synthesis of (2R,5R)-trans-2-ethynyl-5-(4-fluoro-
phenoxymethyl)tetrahydrofuran 3
As described in Scheme 3, 10 on Sharpless asymmetric
epoxidation (Scheme 6) with (ꢀ)-DIPT gave epoxide
37 (69%). Fragmentation of 38 with LDA furnished 7
(80%), which on acetylation gave 39. Acetonide depro-
tection in 39 followed by tosylation of diol 40 afforded
41 (71%). Cyclization of 41 with K2CO3 in methanol
as described above afforded 42 in 75% yield. Finally,
alcohol 42 on tosylation and subsequent etherification
of 43 with 4-fluorophenol (NaH, DMF) at 80 ꢁC afford-
ed 3 in 82% yield.
1
at 80 ꢁC gave 28a in 76% yield. In the H NMR of cis-
acetylene 1 the ArOCH2-group resonated as two double
doublets (d 3.9, J = 4.6, 9.1 Hz and 4.06, J = 5.9,
9.1 Hz), while for trans-2, it resonated as a doublet at
d 3.9, J = 5.8 Hz, indicating a distinctive regiochemistry
of the C-2 and C-5 positions of ring junction. No
enhancement in the NOE was observed for 2, which
when irradiated, further indicates its trans geometry.
HPLC (Chiralcel-OD; 1 cm ID/25 cm length; 10% iso-
propanol in n-hexane; 1 mL/min) analysis of 1 and 2
confirmed their enantiomeric homogeneity.
2.6. Synthesis of (2S,5R)-cis-2-ethynyl-5-(4-fluorophen-
oxymethyl)tetrahydrofuran 4
Similar sequence of reactions as described for 3, except
for using (+)-DIPT for Sharpless epoxidation on allylic
alcohol 10 (Scheme 7) afforded 4. The 1H NMR of 3 and
4 were found to be similar to that of 2 and 1,
respectively.
2.4. Synthesis of allylic alcohol 10
A possible plausible mechanism for the cyclization is
shown in Scheme 8. Tosylate 22 on reaction with
K2CO3 undergoes deacetylation as well as epoxide for-
mation in situ, which on concomitant nucleophilic attack
Allylic alcohol 10 was prepared from aldehyde 12 (pre-
pared from D-mannitol) following a similar sequence
of reactions described for the preparation of 9. Accord-
O
O
O
O
a, b
R
O
c, d
OH
O
O
OR
9
25 R = OH (72%)
6 R = H (83%)
27 R = Ac (91%)
26 R = Cl (75%)
HO
RO
HO
O
h, i
e, f
RO
g
O
OAc
28R = H (66%)
29 R = Ts (89%)
30 (95%)
31 R = Ts (69%)
2 R = 4-F-C6H4 (76%)
i
˚
Scheme 4. Reagents and conditions: (a) (+)-DIPT, Ti(O Pr)4, cumene hydroperoxide, MS 4 A, CH2Cl2, ꢀ20 ꢁC, 3 h; (b) Ph3P, cat NaHCO3, CCl4,
reflux, 3 h; (c) LDA, dry THF, ꢀ40 ꢁC, 3 h; (d) Ac2O, Et3N, CH2Cl2, rt, 30 min; (e) 60% aq AcOH, rt, 12 h; (f) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (g)
K2CO3, MeOH, rt, 2 h; (h) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (i) 4-F-C6H4OH, NaH, DMF, 80 ꢁC, 5 h.

1116
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
O
O
O
a
b, c
O
O
O
O
R
CO2Et
12
32 (73%)
33 R = CO2Et (99%)
34 R = CH2OH (92%)
O
O
O
d
O
e, f
O
R
35 (81%)
36 R = CO2Et (76%)
10 R = CH2OH (88%)
Scheme 5. 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) Ph3P@CHCO2Et, benzene, reflux, 6 h; (f) DIBAL-H, dry CH2Cl2, ꢀ20 ꢁC, 2 h.
O
O
O
a, b
c, d
R
OH
O
O
O
O
10
OR
37 R = OH (69%)
38 R = Cl (88%)
7 R = H (80%)
39 R = Ac (94%)
HO
e, f
g
RO
h, i
HO
O
RO
O
43 R = Ts (70%)
OAc
42 (75%)
40 R = H (90%)
41 R = Ts (71%)
3 R = 4-F-C6H4 (82%)
i
˚
Scheme 6. Reagents and conditions: (a) (ꢀ)-DIPT, Ti(O Pr)4, cumene hydroperoxide, MS 4 A, CH2Cl2, ꢀ20 ꢁC, 3 h; (b) Ph3P, cat NaHCO3, CCl4,
reflux, 3 h; (c) LDA, dry THF, ꢀ40 ꢁC, 3 h; (d) Ac2O, Et3N, CH2Cl2, rt, 30 min; (e) 60% aq AcOH, rt, 12 h; (f) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (g)
K2CO3, MeOH, rt, 2 h; (h) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (i) 4-F-C6H4OH, NaH, DMF, 80 ꢁC, 5 h.
O
O
O
a, b
R
OH
O
O
c, d
O
O
10
44 R = OH (65%)
45 R = Cl (95%)
OR
8 R = H (94%)
46 R = Ac (83%)
HO
h, i
RO
HO
RO
e, f
g
O
O
OAc
49 (90%)
50 R = Ts (82%)
4 R = 4-F-C6H4 (60%)
47 R = H (92%)
48 R = Ts (68%)
i
˚
Scheme 7. Reagents and conditions: (a) (+)-DIPT, Ti(O P)4, cumene hydroperoxide, MS 4 A, CH2Cl2, ꢀ20 ꢁC, 3 h; (b) Ph3P, cat NaHCO3, CCl4,
reflux, 3 h; (c) LDA, dry THF, ꢀ40 ꢁC, 3 h; (d) Ac2O, Et3N, CH2Cl2, rt, 30 min; (e) 60% aq AcOH, rt, 12 h; (f) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (g)
K2CO3, MeOH, rt, 2 h; (h) p-TsCl, Et3N, CH2Cl2, rt, 8 h; (i) 4-F-C6H4OH, NaH, DMF, 80 ꢁC, 5 h.
by an oxy-anion onto epoxide gives tetrahydrofuran 23.
As similar mechanism is also appropriate for the conver-
sion of 29, 41 and 48 into the corresponding THFs 30, 42
and 49.
4. Experimental
Solvents were dried over standard drying agents and
freshly distilled prior to use. H NMR (200 MHz) spec-
1
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
10ꢀ1 deg cm2 gꢀ1. Organic solutions were dried over
anhydrous Na2SO4 and concentrated below 40 ꢁC in
vacuo.
3. Conclusion
In conclusion, the four stereoisomeric acetylenes 1–4
were prepared from allylic alcohols 9 and 10 by a flexible
approach using Sharpless asymmetric epoxidation using
(ꢀ) and (+)-DIPT, respectively. The requisite allylic
alcohols were in turn, prepared from the (S)- and (R)-
glyceraldehyde derivatives. These acetylenes serve as ad-
vanced synthetic intermediates for the successful elabo-
ration into several novel anti-asthmatic target
molecules by attachment of the appropriate hydroxy
urea derivatives.
4.1. Ethyl (2E,6R)-6,7-isopropylidenedioxy hept-2-enoate
17
A stirred solution of 15 (0.80 g, 5.0 mmol) in DMSO
(5 mL) was treated with IBX (1.47 g, 5.26 mmol) in

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
1117
O
K
HO
O
TsO
TsO
OAc
O
K
O K
22
HO
O
23
Scheme 8.
portions, while maintaining the temperature below 0 ꢁC
and then stirred at room temperature for 4 h. The reac-
tion mixture was treated with saturated NaHCO3 solu-
tion (20 mL), filtered through Celite and washed with
EtOAc (3 · 30 mL). The organic layer was separated
and washed with water (25 mL), brine (25 mL) and dried
over Na2SO4. Evaporation of the solvent gave (4R)-4,5-
isopropylidenedioxy-1-pentanal 16 (0.663 g) in 84%
yield as a yellow liquid, which was used in subsequent
experiments without any further purification.
4.02–4.12 (m, 2H, H-1), 5.61–5.71 (m, 2H, H-2, 3); 13C
NMR (CDCl3, 50 MHz): d 25.3, 26.5, 28.0, 32.7, 62.8,
68.9, 75.1, 108.3, 129.8 (2C); EIMS m/z (relative
intensity): 171 (M+ ꢀ CH3, 35.8), 93 (22.3), 67 (37.3),
55 (26.8), 43 (100); HRMS: Calculated for C9H15O3
(M+ ꢀ CH3): 171.102120; observed: 171.102195.
4.3. Synthesis of (2R,5S)-2-ethynyl-5-(4-fluorophenoxy-
methyl)tetrahydrofuran 1
4.3.1. (2R,3R,6R)-2,3-Epoxy-6,7-isopropylidenedioxyhept-
an-1-ol 18. To a stirred and cooled (ꢀ20 ꢁC) suspen-
A solution of 16 (15 g, 94.9 mmol) in benzene (200 mL)
was treated with (carbethoxymethylene)triphenyl phos-
phorane (39.6 g, 113.8 mmol) and heated at reflux for
6 h. The solvent was evaporated and the residue purified
by column chromatography (silica gel, 10% EtOAc in
hexane) to afford 17 (14 g) in 65% yield as a pale yellow
˚
sion of molecular sieves (4 A, 1.25 g) in CH2Cl2 (10 mL)
under an N2 atmosphere, (ꢀ)-DIPT (7.6 g, 32.4 mmol),
Ti(OiPr)4 (7.68 g, 27.02 mmol) and cumene hydroper-
oxide (8.22 g, 54 mmol) were added sequentially. After
20 min, the resulting mixture was treated dropwise with
a solution of 9 (5 g, 26.88 mmol) in CH2Cl2 (15 mL) and
stirred for an additional 3 h. The reaction mixture was
quenched with 10% NaOH solution saturated with
NaCl (15 mL) and filtered through Celite. Evaporation
of the solvent and purification of the residue by column
chromatography (silica gel, 50% EtOAc in hexane) gave
18 (4.15 g) in 76% yield as a colourless liquid.
[a]D = +24.3 (c 0.3, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.32, 1.38 (2s, 6H, 2 · CH3), 1.58–1.78
(m, 4H, H-4, 5), 2.84–3.01 (m, 2H, H-2, 3), 3.5 (t, 1H,
J = 6.1 Hz, H-7), 3.6 (dd, 1H, J = 4.7, 11.75 Hz, H-1),
3.85 (dd, 1H, J = 3.29, 11.75 Hz, H-10), 3.98–4.2 (m,
2H, H-6, 70); 13C NMR (CDCl3, 50 MHz): d 25.5,
26.8, 27.6, 29.6, 55.3, 58.3, 61.6, 69.1, 75.1, 108.8; EIMS
m/z (relative intensity): 187 (M+ ꢀ CH3, 14.9), 144 (85),
101 (47.7), 83 (95), 43 (100); HRMS: Calculated for
1
liquid. [a]D = ꢀ5.4 (c 1.2, CHCl3); H NMR (CDCl3,
200 MHz): d 1.3 (t, 2 · 3H, J = 6.8 Hz, CH3), 1.34, 1.4
(2s, 6H), 1.61–1.7 (m, 2H, H-5), 2.2–2.42 (m, 2H, H-
4), 3.5 (t, 1H, J = 6.8 Hz, H-7), 3.99–4.26 (m, 4H, H-6,
70, OCH2), 5.82 (td, 1H, J = 2.25, 15.75 Hz, H-2), 6.94
(dt, 1H, J = 6.8, 15.75 Hz, H-3); 13C NMR (CDCl3,
50 MHz): d 14.0, 25.4, 26.7, 28.2, 31.9, 60.0, 69.0, 74.9,
108.7, 121.7, 147.7, 166.3; EIMS m/z (relative intensity):
213 (M+ ꢀ CH3, 9), 95 (40.2), 67 (25.3), 55 (53.7), 41
(100); HRMS: Calculated for C11H17O4 (M+ ꢀ CH3):
213.112684; observed: 213.112732.
4.2. (2E,6R)-6,7-Isopropylidenedioxy hept-2-ene-1-ol 9
A stirred solution of 17 (13.87 g, 60.8 mmol) in dry
CH2Cl2 (60 mL) was cooled to ꢀ20 ꢁC and treated with
a solution of DIBAL-H (17.27 g, 121.6 mmol; 2.5 M
solution in hexane) dropwise. After 2 h, the reaction
mixture was warmed to 0 ꢁC and treated dropwise with
MeOH (10 mL) to obtain a gelatinous cake. The mixture
was diluted with CH2Cl2 (100 mL) and stirred for
15 min. A solution of Na–K tartrate (90 mL) was added
dropwise and stirred for an additional 45 min. The reac-
tion mixture was filtered through Celite and washed
with CH2Cl2 (2 · 50 mL). The organic layer was washed
with water (2 · 100 mL), brine (50 mL), dried over
Na2SO4 and evaporated to give 9 (11 g) in 98% yield
C9H15O4
187.096634.
(M+ ꢀ CH3):
187.097034;
observed:
4.3.2. (2S,3R,6R)-1-Chloro-2,3-epoxy-6,7-isopropyliden-
edioxy heptane 19. A stirred mixture of 18 (3.8 g,
18.8 mmol), Ph3P (7.4 g, 28.3 mmol) and NaHCO3
(0.6 g) in CCl4 (50 mL) was heated at reflux for 3 h.
The solvent was evaporated and the residue purified
by column chromatography (silica gel, 20% EtOAc in
hexane) to give 19 (2.8 g) in 68% yield as a colourless
1
liquid. [a]D = +8.2 (c 0.7, CHCl3); H NMR (CDCl3,
1
as a colourless liquid. [a]D = ꢀ13.2 (c 2.5, CHCl3); H
200 MHz): d 1.31, 1.36 (2s, 6H, 2 · CH3), 1.63–1.72
(m, 4H, H-4, 5), 2.8–2.9 (m, 1H, H-2), 2.91–3.02 (m,
1H, H-3), 3.32–3.68 (m, 3H, H-1, 7), 3.95–4.19 (m,
2H, H-6, 70); 13C NMR (CDCl3, 50 MHz): d 25.6,
NMR (CDCl3, 200 MHz):
d 1.16, 1.2 (2s, 6H,
2 · CH3), 1.46–1.74 (m, 2H, H-5), 1.79–1.98 (m, 1H,
OH), 2.02–2.19 (m, 2H, H-4), 3.36–3.78 (m, 3H, H-6, 7),

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G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
26.9, 27.6, 29.6, 44.5, 57.0, 58.3, 69.2, 75.1, 109.1; EIMS
m/z (relative intensity): 205 (M+ ꢀ CH3, 35.8), 145 (23),
83 (61), 72 (98), 43 (100); HRMS: Calculated for
C9H14ClO3 (M+ ꢀ CH3): 205.063147; observed:
205.062719.
1), 2.57 (br s, 2H, OH), 3.35–3.5 (m, 1H, H-7), 3.57–
3.8 (m, 2H, H-6, 70), 5.32–5.47 (m, 1H, H-3); CIMS
m/z (relative intensity): 187 (M+ + H, 74.6), 127
(59.7), 109 (35.8), 81 (56.7), 43 (100); HRMS Calcu-
lated for C9H15O4 (M+ + H): 187.097034; observed:
187.096547.
4.3.3. (3R,6R)-3-Hydroxy-6,7-isopropylidenedioxy-hept-
1-yne 5. To freshly prepared LDA [prepared from
diisopropyl amine (4.6 g, 45.45 mmol) and n-BuLi
(2.91 g, 45.54 mmol; 1.4 N hexane solution)] in THF
(10 mL), a solution 19 (2.5 g, 11.36 mmol) in THF
(20 mL) was added at ꢀ40 ꢁC. After 3 h, the reaction
was quenched with aq NH4Cl solution (40 mL) and di-
luted with CH2Cl2 (50 mL). The organic layer was sepa-
rated, washed with water (3 · 20 mL), brine (200 mL),
dried over Na2SO4, concentrated in vacuo and the resi-
due purified by column chromatography (silica gel,
15% EtOAc in hexane) to furnish 5 (2.0 g) in 95% yield
4.3.6. (3R,6R)-3-Acetoxy-6-hydroxy-7-p-toluenesulfonyl-
oxy-hept-1-yne 22. A solution of 21 (1.1 g, 5.9 mmol)
and Et3N (1.19 g, 11.82 mmol) in CH2Cl2 (20 mL) was
cooled to 0 ꢁC, treated with p-TsCl (1.12 g, 5.91 mmol)
and stirred at room temperature for 8 h. The reaction
mixture was diluted with CH2Cl2 (20 mL) and washed
with water (20 mL), brine (20 mL), dried over Na2SO4,
evaporated and the residue obtained was purified by col-
umn chromatography (silica gel, 10% EtOAc in hexane)
to furnish 22 (1.42 g) in 71% yield as a yellow syrup.
[a]D = +28.1 (c 1.0, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.35–1.68 (m, 3H, H-4, OH), 1.68–2.0 (m,
2H, H-5), 2.08 (s, 3H, CH3), 2.4 (d, 1H, J = 2.4 Hz, H-
1), 2.46 (s, 3H, Ar–CH3), 3.79–4.06 (m, 3H, H-6, 7),
5.35 (td, 1H, J = 4.8, 7.2 Hz, H-3), 7.36 (d, 2H,
J = 7.2 Hz, Ar–H), 7.8 (d, 2H, J = 7.2 Hz, Ar–H).
FABMS m/z (relative intensity): 341 (M+ + H, 13.8),
281 (50), 155 (54.1), 133 (52.7), 109 (100). HRMS: Cal-
culated for C16H21O6S (M+ + H): 341.105885; observed:
341.104916.
1
as a pale yellow liquid. [a]D = ꢀ3.0 (c 2.2, CHCl3); H
NMR (CDCl3, 200 MHz): d 1.32, 1.39 (2s, 6H,
2 · CH3), 1.64–1.94 (m, 4H, H-4, 5), 2.19–2.21 (br s,
1H, OH), 2.39 (d, 1H, J = 2.3 Hz, H-1), 3.5 (t, 1H,
J = 5.7 Hz, H-7), 3.96–4.16 (m, 2H, H-6, 70), 4.34–4.45
(m, 1H, H-3); 13C NMR (CDCl3, 50 MHz): d 25.4,
26.6, 28.8, 33.5, 61.3, 69.0, 72.7, 75.3, 84.7, 108.7; EIMS
m/z (relative intensity): 169 (M+ ꢀ CH3, 22.3), 109
(20.8), 81 (37.3), 55 (35.8), 43 (100); HRMS: Calculated
for C9H13O3 (M+ ꢀ CH3): 169.086469; observed:
169.086140.
4.3.7. (2R,5S)-5-Ethynyl-2-(hydroxymethyl)tetrahydro-
furan 23. To a solution of 22 (0.6 g, 1.76 mmol) in
MeOH (10 mL) at room temperature, K2CO3
(0.536 g, 3.88 mmol) was added and the mixture stirred
for 2 h. It was then treated with NH4Cl solution
(10 mL), MeOH evaporated and the residue extracted
with EtOAc (3 · 20 mL). The organic layer was washed
with water (10 mL), brine (10 mL), dried over Na2SO4
and evaporated. The residue obtained was purified by
column chromatography (silica gel, 20% EtOAc in hex-
ane) to furnish 23 (0.22 g) in 99% yield as a colourless
4.3.4. (3R,6R)-3-Acetoxy-6,7-isopropylidenedioxy-hept-
1-yne 20. A solution of 5 (1.8 g, 9.8 mmol) and Et3N
(3.95 g, 39.2 mmol) in CH2Cl2 (15 mL) at 0 ꢁC was
treated with Ac2O (1.2 g, 11.7 mmol) and stirred at
room temperature for 30 min. The reaction mixture was
diluted with CH2Cl2 (50 mL) and washed with water
(20 mL), brine (20 mL) and dried over Na2SO4. Evapo-
ration of the solvent and purification of the residue by
column chromatography (silica gel, 10% EtOAc in hex-
ane) gave 20 (2.15 g) in 97% yield as a yellow liquid.
[a]D = +37.5 (c 2.1, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.3, 1.39 (2s, 6H, 2 · CH3), 1.64–2.0 (m,
4H, H-4, 5), 2.06 (s, 3H, CH3), 2.4 (d, 1H, J = 2.0 Hz,
H-1), 3.5 (t, 1H, J = 5.7 Hz, H-7), 3.95–4.13 (m, 2H,
H-6, 70), 5.31–5.41 (m, 1H, H-3); 13C NMR (CDCl3,
50 MHz): d 20.8, 25.5, 26.8, 28.8, 30.7, 63.3, 69.1, 73.7,
75.1, 80.7, 108.9, 169.6; EIMS m/z (relative intensity):
211 (M+ ꢀ CH3, 29.8), 169 (11.9), 91 (22.3), 72 (23),
43 (100); HRMS: Calculated for C11H15O4
(M+ ꢀ CH3): 211.097034; observed: 211.095947.
1
liquid. [a]D = +20.0 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 1.89–2.38 (m, 4H, H-3, 4), 2.4 (br s, 1H,
OH), 2.46 (d, 1H, J = 2.2 Hz, acetylenic), 3.55 (dd,
1H, J = 4.5, 11.25 Hz, OCH2), 3.72 (dd, 1H, J = 4.0,
11.25 Hz, OCH2), 4.0–4.15 (m, 1H, H-2), 4.52–4.66
(m, 1H, H-5); 13C NMR (CDCl3, 50 MHz): d 26.6,
29.6, 33.6, 64.6, 68.3, 73.0, 80.7; EIMS m/z (relative
intensity): 125 (M+ ꢀ H, 8), 95 (74.6), 67 (100), 53
(40), 41 (80); HRMS: Calculated for C7H9O2
(M+ ꢀ H): 125.060255; observed: 125.060322.
4.3.8. (2R,5S)-5-Ethynyl-2-(p-toluenesulfonyloxymethyl)-
tetrahydrofuran 24.
4.3.5. (3R,6R)-3-Acetoxy-6,7-dihydroxy-hept-1-yne 21.
A
A
solution of 23 (0.22 g,
solution of 20 (2 g, 8.8 mmol) in 60% aq AcOH
(20 mL) was stirred at room temperature for 12 h.
The reaction mixture was neutralized with saturated
NaHCO3 solution. It was extracted with EtOAc
(3 · 50 mL), after which the organic layer was evapo-
rated and the residue filtered through a small pad of
silica gel with 50% EtOAc in hexane to afford 21
1.75 mmol) and Et3N (0.35 g, 3.5 mmol) in CH2Cl2
(5 mL) was treated with p-TsCl (0.354 g, 1.86 mmol)
and stirred at room temperature for 8 h. It was worked-
up and purified as described for 22 to give 24 (0.33 g) in
64% yield as a yellow syrup. [a]D = +10.0 (c 0.5, CHCl3);
1H NMR (CDCl3, 200 MHz): d 1.84–2.11 (m, 4H, H-3,
4) 2.32 (d, 1H, J = 2.1 Hz, acetylenic), 2.45 (s, 3H, CH3),
3.92–4.2 (m, 3H, H-2, OCH2), 4.48–4.58 (m, 1H, H-5),
7.34 (d, 2H, J = 7.6 Hz, Ar–H), 7.8 (d, 2H, J = 7.6 Hz,
Ar–H); CIMS m/z (relative intensity): 281 (M+ + H,
100), 109 (49.2), 117 (31.3), 81 (7.0), 43 (100); HRMS:
(1.2 g) in 73% yield as
a
colourless syrup.
[a]D = +53.2 (c 1.2, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.5–1.7 (m, 2H, H-4), 1.75–2.05 (m, 2H,
H-5), 2.14 (s, 3H, OAc), 2.45 (d, 1H, J = 2.01 Hz, H-

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
1119
Calculated for C14H17O4S (M+ + H): 281.084756; ob-
served: 281.083610.
intensity in %): 205 (M+ ꢀ CH3, 3), 127 (7), 101 (22),
72 (28), 43 (100).
4.4.3. (3S,6R)-3-Hydroxy-6,7-isopropylidenedioxy-hept-
1-yne 6. To freshly prepared LDA [prepared from
diisopropyl amine (2.3 g, 23.6 mmol) and n-BuLi
(15.7 mL, 23.6 mmol; 1.5 N hexane solution)] in THF
(6 mL), a solution of 26 (1.5 g, 5.9 mmol) in THF
(10 mL) was added at ꢀ40 ꢁC. After 3 h, it was worked-
up and purified as described for 5 to furnish 6 (1.0 g) in
83% yield as a pale yellow liquid. [a]D = ꢀ21.0 (c 1.0,
4.3.9. (2R,5S)-2-Ethynyl-5-(4-fluorophenoxymethyl)tetra-
a stirred suspension of NaH
hydrofuran 1. To
(0.032 g, 1.33 mmol) in DMF (3 mL), a solution of 24
(0.33 g, 1.1 mmol) in DMF (3 mL) was added and
heated at 80 ꢁC for 5 h. The reaction mixture was cooled
to room temperature and treated with NH4Cl solution.
It was extracted with ether (2 · 10 mL) and the organic
layer washed with water (2 · 10 mL), brine (10 mL) and
dried over Na2SO4. Evaporation of solvent and purifica-
tion of residue by column chromatography (silica gel,
7% EtOAc in hexane) afforded 1 (0.21 g) in 86% yield
1
CHCl3); H NMR (CDCl3, 200 MHz): d 1.34, 1.4 (2s,
6H, 2 · CH3), 1.64–1.9 (m, 4H, H-4, 5), 2.49 (d, 1H,
J = 2.3 Hz, H-1), 2.55–2.7 (br s, 1H, OH), 3.52 (t, 1H,
J = 5.8 Hz, H-7), 3.98–4.16 (m, 2H, H-6, 7a), 4.35–4.49
(m, 1H, H-3). EIMS m/z (relative intensity in %): 169
(M+ ꢀ CH3, 25), 109 (25), 72 (33), 43 (100); HRMS:
Calculated for C9H13O3 (M+ ꢀ CH3): 169.086469;
found: 169.086817.
1
as a colourless liquid. [a]D = +16.0 (c 1.0, CHCl3); H
NMR (CDCl3, 200 MHz): d 1.88–2.32 (m, 4H, H-3, 4),
2.41 (d, 1H, J = 2.3 Hz, acetylenic), 3.9 (dd, 1H,
J = 4.6, 9.1 Hz, OCH2), 4.06 (dd, 1H, J = 5.9, 9.1 Hz,
OCH2), 4.22–4.36 (m, 1H, H-5), 4.58–4.69 (m, 1H, H-
2), 6.75–7.02 (m, 4H, Ar–H); 13C NMR (CDCl3,
50 MHz): d 28.2, 33.1, 68.5, 71.2, 72.9, 76.3, 83.7,
115.4, 115.6, 115.8, 115.9, 154.9, 159.6; EIMS m/z (rela-
tive intensity): 220 (M+, 10.4), 125 (14.9), 95 (94), 67
(100), 41 (59.7); HRMS: Calculated for C13H13FO2
(M+): 220.089958; observed: 220.089497.
4.4.4. (3S,6R)-3-Acetoxy-6,7-isopropylidenedioxy-hept-1-
yne 27. A solution of 6 (1.0 g, 5.43 mmol) and Et3N
(2.74 g, 27.15 mmol) in CH2Cl2 (10 mL) at 0 ꢁC was
treated with Ac2O (0.665 g, 6.52 mmol) and stirred at
room temperature for 30 min. Worked-up and purified
as described for 20 to give 27 (1.1 g) in 91% yield as a
yellow liquid. [a]D = ꢀ51.5 (c 1.0, CHCl3); 1H NMR
(CDCl3, 200 MHz): d 1.32, 1.39 (2s, 6H, 2 · CH3),
1.46–2.01 (m, 4H, H-4, 5), 2.08 (s, 3H, CH3), 2.41 (d,
1H, J = 2.3 Hz, H-1), 3.5 (t, 1H, J = 6.9 Hz, H-70),
3.98–4.14 (m, 2H, H-6, 70), 5.31–5.42 (m, 1H, H-3).
EIMS m/z (relative intensity in %): 211 (M+ ꢀ CH3,
72), 169 (28), 109 (40), 72 (67), 43 (100); HRMS: Calcu-
lated for C11H15O4 (M+ ꢀ CH3): 211.097034; found:
211.097445.
4.4. Synthesis of (2S,5S)-2-ethynyl-5-(4-fluorophenoxy-
methyl)tetrahydrofuran 2
4.4.1. (2S,3S,6R)-2,3-Epoxy-6,7-isopropylidenedioxyhep-
tan-1-ol 25. To a stirred and cooled (ꢀ20 ꢁC) suspen-
˚
sion of molecular sieves (4 A, 0.55 g) in CH2Cl2
(10 mL) under an N2 atmosphere, (+)-DIPT (4.0 g,
17.41 mmol), Ti(OiPr)4 (4.12 g, 14.51 mmol) and
cumene hydroperoxide (4.4 g, 29.0 mmol) were added
sequentially. After 20 min, the resulting mixture was
treated with a solution of 9 (2.7 g, 14.51 mmol) in
CH2Cl2 (10 mL) and stirred for an additional 3 h.
Work-up and purification as described for 18 gave 25
(2.1 g) in 72% yield as a colourless liquid. [a]D = ꢀ26.9
4.4.5. (3S,6R)-3-Acetoxy-6,7-dihydroxy-hept-1-yne 28.
A
solution of 27 (1.1 g, 4.86 mmol) in 60% aq AcOH
(10 mL) was stirred at room temperature for 12 h.
Work-up and purification as described for 21 afforded
28 (0.6 g) in 66% yield as
a colourless syrup.
1
(c 1.1, CHCl3); H NMR (CDCl3, 200 MHz): d 1.32,
[a]D = ꢀ46.3 (c 1.0, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.45–1.7 (m, 2H, H-4), 1.75–2.05 (m, 2H,
H-5), 2.09 (s, 3H, –OAc), 2.4 (br s, 3H, H-1, OH),
3.32–3.5 (m, 1H, H-7), 3.52–3.8 (m, 2H, H-6, 7a), 5.3–
5.44 (m, 1H, H-3); EIMS m/z (relative intensity in %):
155 (M+ ꢀ CH3, 3), 113 (3), 95 (60), 67 (63), 43 (100);
HRMS: Calculated for C8H11O3 (M+ ꢀ CH3):
155.070819; 155.071352.
1.38 (2s, 6H, 2 · CH3), 1.58–1.79 (m, 4H, H-4, 5), 2.3–
2.52 (br s, 1H, OH), 2.84–3.0 (m, 2H, H-2, 3), 3.5 (t,
1H, J = 6.1 Hz, H-7), 3.6 (dd, 1H, J = 4.5, 12.0 Hz, H-
1), 3.85 (dd, 1H, J = 3.3, 11.2 Hz, H-10), 3.98–4.2 (m,
2H, H-6, 70); EIMS m/z (relative intensity in %): 187
(M+ ꢀ CH3, 7), 143 (27), 101 (25), 83 (63), 43 (100);
HRMS: Calculated for C9H15O4 (M+ ꢀ CH3):
187.097034; found: 187.097403.
4.4.6. (3S,6R)-3-Acetoxy-6-hydroxy-7-p-toluenesulfonyl-
oxy-hept-1-yne 29. A solution of 28 (0.6 g, 3.22 mmol)
and Et3N (0.975 g, 9.66 mmol) in CH2Cl2 (10 mL) was
treated with p-TsCl (0.737 g, 3.87 mmol) at 0 ꢁC and
stirred at room temperature for 8 h. Work-up and puri-
fication as described for 22 afforded 29 (0.94 g) in 89%
yield as a colourless syrup. [a]D = ꢀ37.2 (c 1.3, CHCl3);
1H NMR (CDCl3, 200 MHz): d 1.51–2.0 (m, 5H, H-4, 5,
–OH), 2.08 (s, 3H, CH3), 2.4 (d, 1H, J = 2.3 Hz, H-1),
2.48 (s, 3H, Ar–CH3), 3.8–4.06 (m, 3H, H-6, 7), 5.35
(td, 1H, J = 4.8, 7.2 Hz, H-3), 7.36 (d, 2H, J = 7.9 Hz,
Ar–H), 7.8 (d, 2H, J = 7.9 Hz, Ar–H); FABMS m/z (rel-
ative intensity in %): 341 (M+ + H, 18), 327 (33), 281
4.4.2. (2R,3S,6R)-1-Chloro-2,3-epoxy-6,7-isopropylidene-
dioxy heptane 26. A stirred mixture of 25 (1.9 g,
9.4 mmol), Ph3P (3.7 g, 14.1 mmol) and NaHCO3
(0.3 g) in CCl4 (25 mL) was heated at reflux for 3 h.
Work-up and purification as described for 19 gave 26
(1.5 g) in 75% yield as a colourless liquid. [a]D = +12.9
1
(c 1.2, CHCl3); H NMR (CDCl3, 200 MHz): d 1.32,
1.39 (2s, 6H, 2 · CH3), 1.58–1.72 (m, 4H, H-4, 5), 2.8–
2.9 (m, 1H, H-2), 2.91–3.02 (m, 1H, H-3), 3.32–3.68
(m, 3H, H-1, 7), 3.94–4.16 (m, 2H, H-6, 7a). 13C
NMR (CDCl3, 50 MHz): d 25.5, 26.9, 28.1, 30.3, 44.9,
57.2, 57.2, 58.6, 69.2, 75.5, 109.1; EIMS m/z (relative

1120
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
(51), 207 (61), 136 (54), 55 (100); HRMS: Calculated for
C16H21O6S (M+ + H): 341.105885; 341.104171.
4.4.11. Ethyl (4S)-4,5-isopropylidenedioxy-1-pentanoate
33. A solution of 32 (50 g, 0.250 mol) in EtOAc
(50 mL) was treated with PtO2 (0.15 g) and subjected
to hydrogenation at 40 psi for 4 h. Work-up and purifi-
cation as described for 14 gave 33 (50 g) in 99% yield as
a colourless liquid. [a]D = +5.0 (c 2.2, CHCl3); 1H NMR
4.4.7. (2S,5S)-5-Ethynyl-2-(hydroxymethyl)tetrahydro-
furan 30. To a solution of 29 (0.9 g, 2.64 mmol) in
MeOH (15 mL) at room temperature, K2CO3 (0.805 g,
5.83 mmol) was added and the mixture was stirred for
2 h. Work-up and purification as described for 23 fur-
nished 30 (0.4 g) in 95% yield as a colourless liquid.
[a]D = ꢀ10.5 (c 1.0, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.50–2.3 (m, 4H, H-3, 4), 2.4 (br s, 1H,
OH), 2.42 (d, 1H, J = 2.2 Hz, acetylenic), 3.5 (dd, 1H,
J = 4.5, 11.3 Hz, OCH2), 3.75 (dd, 1H, J = 3.3,
11.35 Hz, OCH2), 4.16–4.34 (m, 1H, H-2), 4.6–4.74
(m, 1H, H-5); EIMS m/z (relative intensity in %): 126
(M+, 10), 95 (82), 67 (100), 53 (53), 41 (81); Anal. Calcd
for C7H10O2: C, 66.65; H, 7.99. Found: C, 66.60; H, 6.9.
(CDCl3, 200 MHz):
d
1.28 (t, 3H, J = 7.1 Hz,
OCH2CH3), 1.30 and 1.45 (2s, 6H, 2 · CH3), 1.8–1.95
(m, 2H, H-3, 30), 2.38–2.5 (m, 2H, H-2,20), 3.52 (dd,
1H, J = 7.1 Hz, H-5), 4.0–4.2 (m, 4H, H-4, 5a,
OCH2CH3).
4.4.12. (2S)-1,2-Isopropylidenedioxy-5-pentanol 34.
A
suspension of LAH (16.9 g, 0.44 mol) in THF
(300 mL) at 0 ꢁC was treated with a solution of 33
(90 g, 0.44 mol) in THF (200 mL). After 3 h, it was
worked-up and purified as described for 15 to provide
34 (65.5 g) in 92% yield as a colourless liquid.
[a]D = +14.2 (c 2.2, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.3, 1.4 (2s, 6H, 2 · CH3), 1.6–1.8 (m,
5H, H-3, 4, OH), 3.5 (t, 1H, J = 8.3 Hz, H-1), 3.6–3.7
(m, 2H, H-5), 4.0–4.18 (m, 2H, H-10, 2); 13C NMR
(CDCl3, 50 MHz): d 25.5, 26.7, 28.9, 30.0, 62.2, 69.3,
76.3, 108.8; EIMS m/z (relative intensity in %): 145
(M+ ꢀ CH3); EI-HRMS: Calculated for C7H13O3
(M+ ꢀ CH3): 145.086469: found: 145.086081.
4.4.8. (2S,5S)-5-Ethynyl-2-(p-toluenesulfonyloxymethyl)-
A
tetrahydrofuran 31.
solution of 30 (0.33 g,
2.6 mmol) and Et3N (0.263 g, 7.8 mmol) in CH2Cl2
(10 mL) was treated with p-TsCl (0.499 g, 2.6 mmol)
at 0 ꢁC and the mixture stirred at room temperature
for 8 h. Work-up and purification as described for 22
gave 31 (0.59 g) in 69% yield as a colourless syrup.
[a]D = ꢀ7.0 (c 1.0, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.64–2.0 (m, 4H, H-3, 4) 2.22 (d, 1H,
J = 2.1 Hz, acetylenic), 2.35 (s, 3H, CH3), 3.72–4.05
(m, 3H, H-2, OCH2), 4.28–4.48 (m, 1H, H-5), 7.34
(d, 2H, J = 7.6 Hz, Ar–H), 7.8 (d, 2H, J = 7.6 Hz,
Ar–H); EIMS m/z (relative intensity in %): 279
(M+ ꢀ H, 30), 167 (75), 149 (100), 113 (25), 57 (19).
4.4.13. Ethyl (2E,6S)-6,7-isopropylidenedioxy hept-2-eno-
ate 36. A stirred solution of alcohol 34 (20 g,
0.125 mol) in DMSO (60 mL) at 0 ꢁC was treated with
IBX (38.5 g, 0.137 mol) in portions and allowed to stir
at room temperature for 4 h. Work-up and purification
as described for 16 gave (4S)-4,5-isopropylidenedioxy-1-
pentanal 35 (16.0 g) in 81% yield as a light yellow liquid.
1H NMR (CDCl3, 200 MHz): d 1.3, 1.35 (2s, 6H, CH3),
1.6–2.1 (m, 2H, H-3), 2.6 (t, 2H, J2,3 = 6.2 Hz, H-2), 3.5
(t, 1H, J4,5 = 6.2 Hz, H-5), 3.98–4.2 (m, 2H, H-4, 5a), 9.8
(s, 1H, CHO).
4.4.9. (2S,5S)-2-Ethynyl-5-(4-fluorophenoxymethyl)tetra-
hydrofuran 2. To a stirred suspension of NaH (0.041 g,
1.71 mmol) in DMF (3 mL), a solution of 31 (0.32 g,
1.1 mmol) in DMF (3 mL) was added and heated at
80 ꢁC for 5 h. Work-up and purification as described
for 1 afforded 2 (0.19 g) in 76% yield as a colourless
liquid. [a]D = ꢀ21.5 (c 1.1, CHCl3), [a]D8a = ꢀ23.0 (c
A solution of aldehyde 35 (24 g, 0.15 mol) in benzene
(250 mL) was treated with (carbethoxymethylene)triphe-
nyl phosphorane (57.8 g, 0.167 mmol) and heated at re-
flux for 6 h. Work-up and purification as described for
17 afforded 36 (26.3 g) in 76% yield as a pale yellow
1
1.1, CHCl3); H NMR (CDCl3, 200 MHz): d 1.8–2.34
(m, 4H, H-3, 4), 2.38 (d, 1H, J = 2.3 Hz, acetylenic),
3.9 (d, 2H, J = 5.8 Hz, –OCH2), 4.36–4.51 (m, 1H, H-2),
4.64–4.78 (m, 1H, H-5), 6.75–7.02 (m, 4H, Ar–H); 13C
NMR (CDCl3, 50 MHz): d 27.3, 33.4, 68.5, 70.6, 72.8,
76.3, 115.4, 115.5, 115.9, 154.9, 159.7; EIMS m/z (rela-
tive intensity in %): 220 (M+, 21), 125 (10), 112 (30),
95 (100), 67 (78), 43 (61); HRMS: Calculated for
C13H13FO2 (M+): 220.089958. Found: 220.090477.
1
liquid. [a]D = +6.9 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 1.28 (t, 3H, J = 6.75 Hz, CH3), 1.32, 1.38
(2s, 6H, 2 · CH3), 1.6–1.8 (m, 2H, H-5), 2.2–2.45 (m,
2H, H-4), 3.5 (t, 1H, J = 6.75 Hz, H-7), 3.95–4.25 (m,
4H, H-6, 7a, OCH2), 5.8 (d, 1H, J = 15.7 Hz, H-2),
6.91 (dt, 1H, J = 7.8, 15.7 Hz, H-3); EIMS m/z (relative
intensity in %): 213 (M+ ꢀ CH3, 65%), 125 (55%), 93
(20%), 81 (35%), 69 (100%).
4.4.10. Ethyl (2EZ,4S)-4,5-isopropylidenedioxy-2-pent-
enoate 32. A solution of 12 in CH2Cl2 (250 mL) was
treated with (carbethoxymethylene)triphenyl phospho-
rane (61.9 g, 0.179 mol) below 10 ꢁC and stirred at room
temperature for 9 h. Work-up and purification as des-
cribed for 13 afforded 32 (53 g) in 73% yield as a colour-
less liquid. [a]D = +109.8 (c 1.0, CHCl3); 1H NMR
4.4.14. (2E,6S)-6,7-Isopropylidenedioxy hept-2-ene-1-ol
10. A stirred solution of 36 (15 g, 65.7 mmol) in dry
CH2Cl2 (80 mL) at ꢀ20 ꢁC was treated with a solution
of DIBAL-H (66 mL, 134 mmol; 2 M solution in hex-
ane) dropwise. After 2 h, work-up and purification as
described for 9 gave 10 (10.8 g) in 88% yield as a colour-
less liquid. [a]D = +12.8 (c 2.1, CHCl3); 1H NMR
(CDCl3, 200 MHz): d 1.35, 1.40 (2s, 6H, 2 · CH3),
1.4–1.8 (m, 2H, H-5), 2.05–2.3 (m, 2H, H-4), 3.5 (t,
1H, J = 7.95 Hz, H-7), 3.95–4.2 (m, 4H, H-1, 6, 70),
(CDCl3, 200 MHz):
d
1.2 (t, 3H, J = 7.1 Hz,
OCH2CH3), 1.3, 1.35 (2s, 6H, 2 · CH3), 3.48 (dd, 1H,
J = 6.1 Hz, H-5), 4.05 (q, 2H, J = 7.1 Hz, OCH2CH3),
4.25 (dd, 1H, J = 8.0 Hz, H-5a), 5.3–5.40 (m, 1H, H-
4), 5.72 (dd, 1H, J = 2.3, 11.0 Hz, H-2), 6.72 (dd, 1H,
J = 6.1, 12.2 Hz, H-3).

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
1121
5.65–5.72 (m, 2H, H-2, 3); 13C NMR (CDCl3, 50 MHz):
d 25.60, 26.81, 28.26, 32.96, 63.20, 69.19, 75.38, 108.63,
129.68, 131.47; EIMS m/z (relative intensity in %): 171
(M+ ꢀ CH3, 45%), 101 (25%), 93 (50%), 67 (80%), 55
(50%), 43 (100%); EI-HRMS: Calculated for C9H15O3
(M+ ꢀ CH3): 171.102120; found: 171.102318.
(11.3 g, 112 mmol) in CH2Cl2 (50 mL) containing
DMAP (catalytic) at 0 ꢁC was treated with Ac2O
(5.7 g, 56.2 mmol) and stirred at room temperature for
30 min. Work-up and purification as described for 20
gave 39 (7.9 g) in 94% yield as a pale yellow liquid.
[a]D = +48.6 (c 1.0, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.34, 1.4 (2s, 6H), 1.6–2.05 (m, 4H, H-4,
5), 2.1 (s, 3H, OAc), 2.42 (d, 1H, J = 2.3 Hz, H-1),
3.52 (t, 1H, J = 5.8 Hz, H-7), 4.0–4.15 (m, 2H, H-6,
70), 5.38 (dt, 1H, J = 5.7, 2.5 Hz, H-3); 13C NMR
(CDCl3, 50 MHz): d 20.33, 25.20, 26.50, 28.53, 30.45,
62.87, 80.55, 108.40, 168.98. EIMS m/z (relative inten-
sity in %): 211 (M+ ꢀ CH3, 21%), 109(16%), 91(20%),
43(100%); EI-HRMS Calculated for C11H15O4
(M+ ꢀ CH3): 211.097034; found: 211.096451.
4.5. Synthesis of (2R,5R)-2-ethynyl-5-(4-fluorophenoxy-
methyl)tetrahydrofuran 3
4.5.1. (2R,3R,6S)-2,3-Epoxy-6,7-isopropylidenedioxy hep-
tan-1-ol 37. To a stirred and cooled (ꢀ20 ꢁC) suspen-
˚
sion of molecular sieves (4 A, 3 g) in CH2Cl2 (10 mL)
under an N2 atmosphere, (ꢀ)-DIPT (28.7 g, 122 mmol)
in CH2Cl2 (50 mL), Ti(OiPr)4 (28.9 g, 122 mmol) and
cumene hydroperoxide (31 g, 0.204 mmol; 80% solution
in cumene) were added sequentially. After 20 min, the
resulting mixture was treated with a solution of 10
(19 g, 102 mmol) in CH2Cl2 (50 mL). The reaction mix-
ture, after 3 h, was worked-up and purified as de-
scribed for 18 to furnish 37 (14.2 g) in 69% yield as a
colourless liquid. [a]D = +26.2 (c 0.5, CHCl3); 1H
4.5.5. (3R,6S)-3-Acetoxy-6,7-dihydroxy-hept-1-yne 40.
A
mixture of compound 39 (7.9 g, 34.9 mmol) in 60% aq
AcOH (60 mL) was stirred at room temperature for 12
h. Work-up and purification as described for 28 gave
40 (5.85 g) in 90% yield as a pale yellow liquid.
[a]D = +44.4 (c 1.0, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.45–1.62 (m, 2H, H-4), 1.7–2.0 (m, 2H,
H-5), 2.05 (s, 3H, OAc), 2.45 (d, 1H, J = 1.5 Hz, H-1),
3.38 (dt, 1H, J = 6.5, 7 Hz, H-7), 3.5–3.8 (m, 2H, H-6,
70), 5.35 (dt, 1H, J = 2.8, 5.1 Hz, H-3); 13C NMR
(CDCl3, 50 MHz): d 20.87, 28.17, 30.73, 63.57, 66.55,
71.52, 73.91, 80.86, 170.04.
NMR (CDCl3, 200 MHz):
d 1.34, 1.4 (2s, 6H,
2 · CH3), 1.5–1.8 (m, 4H, H-4, 5), 2.35 (br s, 1H,
OH), 2.85–3.0 (m, 2H, H-2, 3), 3.35–3.75 (m, 2H, H-
1, 7), 3.75–3.90 (m, 1H, H-1), 3.98–4.18 (m, 2H, H-6,
70); 13C NMR (CDCl3, 50 MHz): d 25.59, 26.86,
28.25, 30.04, 55.81, 58.55, 61.75, 69.27, 75.71, 108.94;
EIMS m/z (relative intensity in %): 187 (M+ ꢀ CH3,
20%), 143 (35%), 101 (50%), 83 (90%), 43 (100%); EI-
HRMS: Calculated for C9H15O4 (M+ ꢀ CH3):
187.097034; found: 187.096129.
4.5.6. (3R,6S)-3-Acetoxy-6-hydroxy-7-p-toluenesulfonyl-
oxy-hept-1-yne 41. A solution of 40 (5.9 g, 31.7 mmol)
and Et3N (6.38 g, 63.4 mmol) in CH2Cl2 (50 mL) at 0 ꢁC
was treated with p-TsCl (6.0 g, 31.5 mmol) and stirred at
room temperature for 8 h. Work-up and purification as
described for 22 gave 41 (7.65 g) in 71% yield as a yellow
4.5.2. (2S,3R,6S)-1-Chloro-2,3-epoxy-6,7-isopropylidene-
dioxy heptane 38. A stirred mixture of 37 (10.9 g,
53.9 mmol), Ph3P (21.2 g, 80.9 mol) and NaHCO3 (2 g)
in CCl4 (100 mL) was heated at reflux for 3 h. Work-
up and purification was done as described for 19 gave
38 (10.4 g) in 88% yield as a colourless liquid.
[a]D = ꢀ17.9 (c 0.5, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.35, 1.4 (2s, 6H, 2 · CH3), 1.62–1.72 (m,
4H, H-4, 5), 2.85–3.05 (m, 2H, H-2, 3), 3.4–3.6 (m,
3H, H-1, 7), 4.0–4.20 (m, 2H, H-6, 70); EIMS m/z (rela-
tive intensity in %): 205 (M+ ꢀ CH3, 50%), 145 (10%),
101 (30%), 81 (40%), 72 (90%), 43 (100%).
1
syrup. [a]D = +35.3 (c 0.6, CHCl3); H NMR (CDCl3,
200 MHz): d 1.5–1.65 (m, 2H, H-4), 1.7–2.1 (m, 2H, H-
5), 2.10 (s, 3H, OAc), 2.4 (d, 1H, J = 2.2 Hz, H-1); 2.55
(s, 3H, Ar–CH3), 3.8–4.05 (m, 3H, H-6, 7), 5.35 (dt, 1H,
J = 1.1, 5.4 Hz, H-3), 7.35, 7.8 (2d, 4H, J = 7.9 Hz, Ar–H).
4.5.7. (2R,5R)-trans-5-Ethynyl-2-(hydroxymethyl)tetra-
hydrofuran 42. A solution of 41 (7.7 g, 22.6 mmol) in
MeOH (50 mL) at room temperature was treated with
K2CO3 (9.3 g, 67.3 mmol) and stirred for 2 h. Work-up
and purification as described for 23 afforded 42
(2.14 g) in 75% yield as a colourless liquid. [a]D = +8.2
4.5.3. (3R,6S)-3-Hydroxy-6,7-isopropylidenedioxy-hept-
1-yne 7. To a solution of LDA [prepared from diiso-
propylamine (16.6 g, 160 mmol) and n-BuLi (109 mL,
0.165 mol; 1.5 N hexane solution)] in THF (50 mL), a
solution of 38 (10.3 g, 47.1 mmol) in THF (25 mL) was
added at ꢀ40 ꢁC. After 3 h, work-up and purification
as described for 5 gave 7 (6.9 g) in 80% yield as a yellow
1
(c 1.0, CHCl3); H NMR (CDCl3, 200 MHz): d 1.98–
2.35 (m, 4H, H-3, 4), 2.42 (d, 1H, J = 2.3 Hz, acetylenic),
3.6 (d, 2H, J = 4.7 Hz, OCH2), 4.18–4.3 (m, 1H, H-2),
4.65–4.75 (m, 1H, H-5); EIMS m/z (relative intensity
in %): 125 (M+ ꢀ H, 10%), 95 (60%), 81 (35%), 67
(75%), 53 (65%), 43 (100%); EI-HRMS: Calculated for
(M+ ꢀ H) C7H9O2: 125.060255; found: 125.060025.
1
liquid. [a]D = +23.0 (c 1.0, CHCl3); H NMR (CDCl3,
200 MHz): d 1.3, 1.36 (2s, 6H, 2 · CH3), 1.62–1.88 (m,
4H, H-4, 5), 2.35 (d, 1H, J = 2.3 Hz, H-1), 3.5 (t, 1H,
J = 4.7 Hz, H-7), 3.95–4.15 (m, 2H, H-6, 70), 4.3–4.45
(m, 1H, H-3); EIMS m/z (relative intensity in %): 169
(M+ ꢀ CH3, 30%), 109 (15%), 82 (25%), 73 (40%), 44
(100%).
4.5.8. (2R,5R)-trans-5-Ethynyl-2-(p-toluenesulfonyloxy-
methyl)tetrahydrofuran 43. A solution of 42 (2.1 g,
16.6 mmol), Et3N (6.06 g, 60 mmol) in CH2Cl2
(20 mL) was treated with p-TsCl (3.8 g, 20 mmol) and
stirred at room temperature for 8 h. Work-up and puri-
fication as described for 22 gave 43 (3.26 g) in 70% yield
1
4.5.4. (3R,6S)-3-Acetoxy-6,7-isopropylidenedioxy-hept-1-
yne 39. A solution of 7 (6.9 g, 37.5 mmol) and Et3N
as a yellow syrup. [a]D = +5.4 (c 1.0, CHCl3); H NMR
(CDCl3, 200 MHz): d 1.8–2.25 (m, 4H, H-3, 4), 2.35 (d,

1122
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
1H, J = 2.2 Hz, acetylenic), 2.45 (s, 3H, Ar–CH3), 4.0 (d,
2H, J = 4.6 Hz, OCH2), 4.2–4.35 (m, 1H, H-2), 4.5–4.62
(m, 1H, H-5), 7.32 and 7.75 (2d, 4H, J = 9.0 Hz, Ar–H).
70); 13C NMR (CDCl3, 50 MHz): d 25.5, 26.8, 27.5,
29.5, 44.4, 57.1, 58.3, 69.1, 75.0, 108.8.
4.6.3. (3S,6S)-3-Hydroxy-6,7-isopropylidenedioxy-hept-
1-yne 8. To a solution of LDA [prepared from diiso-
propylamine (11.8 g, 114.5 mmol) and n-BuLi (70 mL,
109 mmol; 1.5 N hexane solution)] in THF (100 mL), a
solution of 45 (6.0 g, 27.4 mmol) in THF (20 mL) was
added at ꢀ40 ꢁC. After 3 h, work-up and purification
as described for 5 furnished 8 (4.7 g) in 94% yield as
4.5.9. (2R,5R)-trans-2-Ethynyl-5-(p-fluorophenoxymethyl)-
tetrahydrofuran 3. To a stirred suspension of NaH
(0.55 g, 23.1 mmol) in DMF (10 mL) at 0 ꢁC, 4-fluoro-
phenol (1.74 g, 15.5 mmol) was added. After 15 min
a solution of 43 (3.25 g, 11.6 mmol) in DMF (10 mL)
was added and heated at 80 ꢁC for 5 h. Work-up and
purification as described for 1 afforded 3 (2.08 g) in
82% yield as a colourless liquid. [a]D = +18.4 (c 1.0,
CHCl3); 1H NMR (CDCl3, 200 MHz): d 1.80–2.35
(m, 4H, H-3, 40), 2.40 (d, 1H, J = 2.2 Hz, acetylenic),
3.95 (d, 2H, J = 5.4 Hz, OCH2), 4.45 (quin, 1H,
J = 4.3 Hz, H-2), 4.70–4.82 (m, 1H, H-5), 6.70–7.0 (m,
4H, Ar–H); 13C NMR (CDCl3, 50 MHz): d 27.51,
33.09, 68.51, 70.53, 72.94, 77.01, 115.42, 115.64,
115.87, 116.10, 116.25, 154.89, 159.63; EIMS m/z (rela-
tive intensity in %): 220 (M+, 20), 125 (10%), 112 (10%),
95 (100%), 81 (10%), 55 (20%), 67 (55%), 43 (80%); EI-
HRMS: Calculated for (M+) C13H13FO2: 220.089958;
found; 220.089897.
1
a yellow liquid. [a]D = +2.6 (c 1.54, CHCl3); H NMR
(CDCl3, 200 MHz): d 1.35, 1.4 (2s, 6H, 2 · CH3) 1.6–
198 (m, 4H, H-4, 5), 2.4 (d, 1H, J = 1.86 Hz, H-1), 3.5
(t, 1H, J = 6.9 Hz, H-7), 3.98–4.2 (m, 2H, H-6, 70),
4.3–4.45 (m, 1H, H-3); 13C NMR (CDCl3, 50 MHz): d
25.62, 26.84, 29.09, 33.85, 61.83, 69.24, 72.92, 75.55,
84.66, 109.01; EIMS m/z (relative intensity in %): 169
(M+ ꢀ CH3, 30%), 109 (25%), 81 (60%), 72 (25%), 55
(80%), 43 (100%); HRMS: Calculated for C9H13O3
(M+ ꢀ CH3): 169.086469: found: 169.086063.
4.6.4. (3S,6S)-3-Acetoxy-6,7-isopropylidenedioxy-hept-1-
yne 46. A solution of 8 (3.9 g, 21.7 mmol) and Et3N
(7.76 g, 76.9 mmol) in CH2Cl2 (40 mL) containing
DMAP (catalytic) at 0 ꢁC was treated with Ac2O
(3.65 mL, 38.48 mmol) and stirred at room temperature
for 30 min. Work-up and purification as described for 20
gave 46 (4.15 g) in 83% yield as a pale yellow liquid.
[a]D = ꢀ30.5 (c 1.9, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.25, 1.35 (2s, 6H), 1.5–1.9 (m, 4H, H-4,
5), 2.02 (s, 3H, OCH3), 2.35 (d, 1H, J = 2.3 Hz, H-1),
3.45 (t, 1H, J = 6.5 Hz, H-7), 3.9–4.1 (m, 2H, H-6, 70),
5.25–5.4 (m, 1H, H-3); 13C NMR (CDCl3, 50 MHz): d
20.54, 25.58, 26.89, 29.71, 30.88, 63.88, 69.12, 73.81,
75.99, 80.80, 108.93, 169.87.
4.6. Synthesis of (2S,5R)-2-ethynyl-5-(4-fluorophenoxy-
methyl)tetrahydrofuran 4
4.6.1. (2S,3S,6S)-2,3-Epoxy-6,7-isopropylidenedioxy hep-
tan-1-ol 44. To a stirred and cooled (ꢀ20 ꢁC) suspen-
˚
sion of molecular sieves (4 A, 4 g), in CH2Cl2 (15 mL)
under N2 atmosphere, (+)-DIPT (18.1 g, 77.4 mmol)
in CH2Cl2 (20 mL), Ti(OiPr)4 (19.1 mL, 64.54 mmol)
and cumene hydroperoxide (19.6 mL, 103 mmol; 80%
solution in cumene) were added sequentially. After
20 min, it was treated with a solution of 10 (12 g,
64.5 mmol) in CH2Cl2 (30 mL) dropwise and stirred
for further 3 h at the same temperature. Work-up and
purification as described for 18 furnished 44 (8.55 g)
in 65% yield as a colourless liquid. [a]D = ꢀ20.1 (c 3.0,
4.6.5. (3S,6S)-3-Acetoxy-6,7-dihydroxy-hept-1-yne 47.
A
mixture of 46 (4.1 g) in 60% aq AcOH (20 mL) was
stirred at room temperature for 12 h. Work-up and
purification as described for 21 afforded 47 (3.1 g) in
92% yield as a pale yellow liquid. [a]D = ꢀ49.6 (c 0.5,
CHCl3); 1H NMR (CDCl3, 200 MHz): d 1.5–1.65 (m,
2H, H-4), 1.75–2.10 (m, 2H, H-5), 2.10 (s, 3H, OAc),
2.45 (d, 1H, J = 2.7 Hz, H-1), 3.42 (dd, 1H, J = 6.3,
6.8 Hz, H-7), 3.55–3.78 (m, 2H, H-6, 70), 5.38 (dt, 1H,
J = 2.7, 5.0 Hz, H-3); 13C NMR (CDCl3, 50 MHz): d
20.87, 28.17, 30.73, 63.57, 66.55, 71.52, 73.91, 80.86, 170.04.
1
CHCl3); H NMR (CDCl3, 200 MHz): d 1.35, 1.4 (2s,
6H, 2 · CH3), 1.45–1.85 (m, 5H, H-4, 5, OH), 2.85–
3.05 (m, 2H, H-2,3), 3.5 (t, 1H, J = 6.5 Hz, acetylenic),
3.65 (dd, 1H, J = 4.08, 12.2 Hz, H-1), 3.9 (dd, 1H,
J = 3.06, 12.2 Hz, H-10), 3.98–4.2 (m, 2H, H-6, 70);
13C NMR (CDCl3, 50 MHz): d 25.33, 26.31, 27.33,
29.87, 55.34, 58.41, 61.83, 69.12, 75.13, 100.84. EIMS
m/z (relative intensity in %): 187 (M+ ꢀ CH3, 45%),
143 (15%), 101 (30%), 83 (95%), 43 (100%); EI-HRMS:
Calculated for (M+ ꢀ CH3) C9H15O4: 187.097034;
found: 187.096927.
4.6.6. (3S,6S)-3-Acetoxy-6-hydroxy-7-p-toluenesulfonyl-
oxy-hept-1-yne 48. A solution of 47 (4.3 g, 23.1 mmol)
and Et3N (4.65 g, 46.2 mmol) in CH2Cl2 (50 mL) at 0 ꢁC
was treated with p-TsCl (4.4 g, 23.1 mmol) and stirred at
room temperature for 8 h. Work-up and purification as
described for 22 gave 48 (5.34 g) in 68% yield as a yellow
4.6.2. (2R,3S,6S)-1-Chloro-2,3-epoxy-6,7-isopropylidene-
dioxy heptane 45. A stirred mixture of 44 (6.0 g,
29.69 mmol), Ph3P (9.69 g, 36.98 mmol) and NaHCO3
(0.8 g) in CCl4 (30 mL) was heated at reflux for 3 h.
Work-up and purification as described for 19 gave 45
(6.1 g) in 95% yield as a colourless liquid. [a]D = ꢀ10.2
1
syrup. [a]D = ꢀ28.1 (c 2.0, CHCl3); H NMR (CDCl3,
200 MHz): d 1.5–1.65 (m, 2H, H-4), 1.7–2.08 (m, 2H,
H-5), 2.10 (s, 3H, OAc), 2.43 (d, 1H, J = 1.86 Hz, H-1)
2.55 (s, 3H, Ar–CH3), 2.60 (br s, 1H, OH), 3.8–4.05
(m, 3H, H-6, 7, 70), 5.35 (dt, 1H, J = 1.3, 6.9 Hz, H-3),
7.35, 7.80 (2d, 4H, J = 7.9 Hz, Ar–H); 13C NMR
(CDCl3, 50 MHz): d 20.87, 21.67, 27.92, 30.40, 63.25,
68.88, 73.83, 73.96, 127.95, 129.96, 145.12.
1
(c 3.0, CHCl3); H NMR (CDCl3, 200 MHz): d 1.35,
1.4 (2s, 6H, 2CH3), 1.6–1.82 (m, 4H, H-4, 5), 2.85–
3.05 (m, 2H, H-2, 3), 3.35–3.55 (m, 2H, H-1, 7), 3.62
(dd, 1H, J = 4.5, 11.2 Hz, H-10) 3.2–3.98 (m, 2H, H-6,

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 16 (2005) 1113–1123
1123
anes and Leukotrienes. In Pathobiology of the Endothelial
Cell; Noaawl, H., Vogel, M. J., Eds.; Academic: New
York, 1982; p 287; (e) Pinkard, N. The ÔNewÕ Chemical
Mediators of Inflammation. In Current Topics in Inflam-
mation and Infection; Majno, G., Cotran, R. S., Eds.;
Williams; Wilkins: Baltimore, 1982; p 38.
4.6.7.
(2S,5R)-cis-5-Ethynyl-2-(hydroxymethyl)tetra-
hydrofuran 49. A solution of 48 (3.67 g, 10.77 mmol)
in MeOH (50 mL) at room temperature was treated with
K2CO3 (3.2 g, 23.18 mmol) and stirred for 2 h. Work-up
and purification as described for 23 gave 49 (1.22 g) in
90% yield as a colourless liquid. [a]D = ꢀ18.2 (c 1.2,
2. (a) Dahlen, S.-E.; Bjork, J.; Arfors, K.-E.; Hammarstrom,
S.; Lindgren, J.-A.; Samuelsson, B. Proc. Natl. Acad. Sci.
U.S.A. 1981, 78, 3887–3891; (b) Weiss, J. W.; Drazen, J. M.;
Coles, N.; McFadden, E. R., Jr.; Weller, P. F.; Corey, E. J.;
Lewis, R. A.; Austen, K. F. Science 1982, 216, 196–
198.
3. Westley, J. W. In Polyether Antibiotics: Naturally Occur-
ring Acid Ionophores; Marcel Dekker: New York, 1982;
Vols. I and II.
4. Cave, A.; Cortes, D.; Figadere, B.; Hocquemiller, R.;
Laprevote, O.; Laurens, A.; Leboeuf, M. In Phytochemical
Potential of Tropical Plants: Recent Advances in Phyto-
chemistry; Downum, K. R., Romeo, J., Stafford, H. H. A.,
Eds.; Plenum: New York, 1993; 27.
1
CHCl3); H NMR (CDCl3, 200 MHz): d 1.9–2.38 (m,
4H, H-3, 4), 2.45 (d, 1H, J = 2.1 Hz, acetylenic), 3.55
(dd, 1H, J = 6.3, 12.75 Hz, OCH2), 3.72 (dd, 2H,
J = 3.8, 12.75 Hz, OCH2), 4.0–4.18 (m, 1H, H-2),
4.55–4.65 (m, 1H, H-5); 13C NMR (CDCl3, 50 MHz):
d 26.6, 29.64, 64.62, 68.33, 73.11, 80.7, 83.92; EIMS m/
z (relative intensity in %): 125 (M+ ꢀ H, 45%), 95
(15%), 81 (10%), 67 (80%), 53 (60%), 43 (100%); EI-
HRMS: Calculated for (M+ ꢀ H) C7H9O2: 125.060255;
found: 125.060105.
4.6.8.
(2S,5R)-cis-5-Ethynyl-2-(p-toluenesulfonyloxy-
methyl)tetrahydrofuran 50. A solution of 49 (1.3 g,
10.3 mmol) and Et3N (5.2 g, 51.5 mmol) in CH2Cl2
(25 mL) was treated with p-TsCl (2.39 g, 12.57 mmol)
and stirred at room temperature for 8 h. Work-up and
purification as described for 22 gave 50 (2.36 g) in 82%
yield as a yellow syrup. [a]D = ꢀ12.9 (c 1.4, CHCl3);
1H NMR (CDCl3, 200 MHz): d 1.8–2.25 (m, 4H, H-3,
4), 2.35 (d, 1H, J = 2.2 Hz, acetylenic), 2.45 (s, 3H,
Ar–CH3), 3.95–4.20 (m, 3H, H-2, OCH2), 4.55–4.60
(m, 1H, H-5), 7.32 and 7.8 (2d, 4H, J = 9.0 Hz, Ar–H).
5. Klein, E.; Rojahn, W. Tetrahedron 1965, 21, 2353–
2358.
6. (a) Cai, X.; Cheah, S.; Chen, S. M.; Eckman, J.; Ellis, J.;
Fisher, R.; Fura, A.; Grewal, G.; Scannell, R. T.; Yaeger,
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.; Fura, A.; Qian, C.;
U.S. Patent 5750565, 1998.
7. (a) Cai, X.; Hwang, S.; Killan, D.; Shen, T. Y. U.S. Patent
5,648,486, 1997; (b) Cai, X.; Grewal, G.; Hussion, S.;
Fura, A.; Biftu, T. U.S. Patent 5,681,966, 1997.
8. (a) Gurjar, M. K.; Murugaiah, A. M. S.; Radha Krishna,
P.; Ramana, C. V.; Chorghade, M. S. Tetrahedron:
Asymmetry 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.
9. (a) Jung, M. E.; Shaw, T. J. J. Am. Chem. Soc. 1980, 102,
6304–6311; (b) Abushnab, E.; Venishetti, P.; Leiby, R. W.;
Singh, H. K.; Mikkilineni, A. B.; Wu, D. C.-J.; Saibaba,
R.; Panzica, P. J. Org. Chem. 1988, 53, 2598–2602,
Aldehyde 11 was prepared form the corresponding diol
reported in Ref. 9 by oxidative cleavage with NaIO4.
10. Angehrn, P.; Buchmann, S.; Funk, C.; Goetschi, E.;
Gmuender, H.; Hebeisen, P.; Kostrewa, D.; Link, H.;
Luebbers, T.; Masciadri, R.; Nielsen, J.; Reindl, P.;
Ricklin, F.; Hoffman, A. S.; Thiel, F.-P. J. Med. Chem.
2004, 47, 1487–1513.
4.6.9. (2S,5R)-cis-2-Ethynyl-5-(4-fluorophenoxymethyl)-
tetrahydrofuran 4. To a stirred suspension of NaH
(0.57 g, 23.86 mmol) in DMF (5 mL), a solution of
50 (3.34 g, 11.92 mmol) in DMF (5 mL) was added,
followed by the addition of 4-fluorophenol (1.74 g,
15.5 mmol) in DMF (5 mL) and heated at 80 ꢁC for
5 h. Work-up and purification as described for 1 gave
4
(1.57 g) in 60% yield as a colourless liquid.
[a]D = ꢀ15.1 (c 1.2, CHCl3); 1H NMR (CDCl3,
200 MHz): d 2.0–2.35 (m, 4H, H-3, 4), 2.45 (d, 1H,
J = 2.2 Hz, acetylenic), 3.92 (dd, 1H, J = 4.5, 9.0 Hz,
OCH2), 4.0 (dd, 1H, J = 4.5, 9.0 Hz, OCH2), 4.35 (quin,
1H, J = 4.6 Hz, H-5), 4.65 (m, 1H, H-2), 6.85–7.05 (m,
4H, Ar–H); 13C NMR (CDCl3, 50 MHz): d 28.24,
33.1, 68.45, 72.9, 79.9, 83.8, 71.28, 115.43, 115.52,
115.68, 115.89, 154.91, 159.66; EIMS m/z (relative inten-
sity in %): 220 (M+, 30), 112 (25%), 95 (100%), 67 (70%),
43 (30%); HRMS: Calculated for C13H13O2 (M+):
220.089958; found; 220.089905.
Acknowledgements
Two of the authors (S.P. and T.R.P.) acknowledge
CSIR, New Delhi, India for the financial support.
11. Koert, U.; Wagner, H.; Stein, M. Tetrahedron Lett. 1994,
35, 7629–7632.
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