Stereoselective Total Synthesis of (+)-Virol C

Article abstract of DOI:10.1055/s-2003-42465

A highly stereoselective synthesis of (+)-Virol C (1) has been achieved starting from octan-1-ol (6) using two different strategies, elimination reactions of epoxyallyl chloride 12 and epoxy chloride 16 to hydroxyenyne 2 and trans-hydroxyalkenyl chloride 4 as key reactions in route a and route b, respectively.

Full text of DOI:10.1055/s-2003-42465

PAPER
2699
Stereoselective Total Synthesis of (+)-Virol C
Stereoselective
To
o
tal Synthesis
w
of (+)-Virol
C
ravaram Sabitha,* Ch. Srinivas Reddy, Pabbaraja Srihari, Jhillu Singh Yadav
Organic Division – I, Indian Institute of Chemical Technology, Hyderabad, India
Fax +91(402)716012; E-mail: sabitha@iict.ap.nic.in
Received 1 July 2003; revised 19 August 2003
Our retrosynthetic strategy (Scheme 1) is presented as two
routes a and b. The route a involves building up the key
fragment 2 from epoxyallyl chloride 12 by elimination re-
action. Coupling of 2 with hydroxyl protected 5-bro-
mopent-4-yne-1-ol 3 would give the target molecule 1
under Cadiot–Chodkiewicz’s conditions.
Abstract: A highly stereoselective synthesis of (+)-Virol C (1) has
been achieved starting from octan-1-ol (6) using two different strat-
egies, elimination reactions of epoxyallyl chloride 12 and epoxy
chloride 16 to hydroxyenyne 2 and trans-hydroxyalkenyl chloride 4
as key reactions in route a and route b, respectively.
Key words: Virol C, stereoselective, elimination reaction, Cadiot–
Chodkiewicz coupling, Sonogashira
The route b involves coupling of alkenyl chloride 4 with
diyne 5 under Sonogashira’s conditions.
Our synthetic protocol starts from the readily available oc-
tan-1-ol (6) (Scheme 2). The Swern oxidation of 6 fol-
lowed by an in situ Wittig reaction with
(ethoxycarbonylmethylene)triphenylphosphorane led to
, -unsaturated ester 7 in 84% yield. The reduction of the
ester functionality with DIBAL furnished the , -unsatur-
ated alcohol 8 in a yield of 90%. The E-allyl alcohol 8 was
subjected to a Sharpless asymmetric epoxidation6 to af-
ford the chiral epoxide 9. The epoxy alcohol 9 was oxi-
dized to epoxy aldehyde employing Swern reaction
conditions and followed by an in situ Wittig reaction with
(ethoxycarbonylmethylene)triphenylphosphorane to give
the ester 10.
A well-known toxic plant, water hemlock, Cicuta virosa
(Umbelliferae) is widely distributed in the temperate re-
gions. The major component of the plant, cicutoxin, was
isolated in 19151 and its planar structure was reported in
1953.2 Although cicutoxin (C17H22O2) is a chemically and
pharmacologically interesting polyacetylenic alcohol, its
precise mode of pharmacological action has not been
studied because of its chemical instability.3
Virol A, B and C4 are polyacetylenic alcohol analogues of
cicutoxin which are chemically more stable than cicutoxin
and were recently isolated. The total synthesis of Virol C
has been reported and the absolute configuration of its ste-
reogenic center was assigned as ‘S’. Even though contri-
butions have been made towards the total synthesis4,5 of
this long chain polyacetylenic alcohol, the need for a sim-
ple strategic route still remains. We herein report two dif-
ferent concise, simple and efficient routes for the
stereoselective total synthesis of (+) Virol C (1) from oc-
tan-1-ol (6).
The reduction of the ester group with diisobutylalumini-
um hydride (DIBAL-H) furnished the epoxyallyl alcohol
11 in 73% yield, which was converted to the epoxyallyl
chloride 12 by treatment with CCl4/Ph3P at reflux temper-
ature. The chiral epoxyallyl chloride 12 was subjected by
known reaction conditions7 to give the key fragment,
chiral alcohol hydroxyenyne 2 exclusively as a single iso-
mer in an excellent yield. The E-stereochemistry at the
Scheme 1
SYNTHESIS 2003, No. 17, pp 2699–2704
x
x.
x
x
.
2
0
0
3
Advanced online publication: 04.11.2003
DOI: 10.1055/s-2003-42465; Art ID: Z09603SS
© Georg Thieme Verlag Stuttgart · New York

2700
G. Sabitha et al.
PAPER
Scheme 2
double bond was assigned by examining the splitting pat- termediate, trans-hydroxyalkenyl chloride 4 as a major
tern of the olefinic protons that showed large coupling product (Scheme 5).
constants. The other fragment hydroxy-protected 5-bro-
The other fragment 5 was prepared as shown in Scheme 6.
mopent-4-yn-1-ol 3 was prepared from readily available
Cross-coupling reaction of 13 with trans-1,2-dichloroeth-
pent-4-yn-1-ol (13) in two steps by protecting hydroxyl
ylene under modified Sonogashira’s conditions10 pro-
ceeded to afford the fragment 17 in good yield, which was
subsequently treated with BuLi to produce terminal diyne
group as TBDMS ether and bromination8 of terminal
alkyne group by reaction with NBS and AgNO3
(Scheme 3). The coupling reaction of 2 with 3 proceeded
18. The free hydroxyl group of 18 was protected as its tet-
smoothly under Cadiot–Chodkiewicz’s conditions9 to
rahydropyranyl (THP) derivative 5.
The final coupling reaction11 of trans-alkenyl chloride 4
give the protected enediynol 15 in a 55% yield. Finally,
removal of TBDMS group using TBAF gave (+)-Virol C
with 5 in the presence of Pd(PPh3)2Cl2 and CuI gave the
(1) (Scheme 4) in 85% yield.
desired compound 19, which on removal of THP group
gave the target molecule 1 (Scheme 7).
The physical and spectroscopic data (IR, H NMR, 13C
NMR and mass spectra) of synthetic Virol C prepared by
two routes were found to be identical in all respects with
those reported for natural product. The value of [ ]D mea-
sured for synthetic Virol {[ ]D +6.2 (c = 0.80, MeOH)} is
The synthesis of (+)-Virol C (1) was also achieved using
an alternate strategy as shown in Schemes 5– 7. The ep-
1
oxy alcohol 9, which was prepared as shown in Scheme 2,
was converted to the epoxy chloride 16 on treatment with
CCl4/Ph3P under reflux conditions in 88% yield. The
compound 16 when treated with LiNH2 in liquid NH3 at
–33 °C underwent elimination reaction to give the key in-
in accordance to the reported for the natural (+)-Virol C
{Lit.5 ([ ]D +6.4, (c = 0.82, MeOH}.
Scheme 3
Scheme 4
Synthesis 2003, No. 17, 2699–2704 © Thieme Stuttgart · New York

PAPER
Scheme 5
Stereoselective Total Synthesis of (+)-Virol C
2701
Scheme 6
Scheme 7
(E)-Dec-2-en-1-ol (8)
Crude products were purified by column chromatography on silica
gel of 60–120 mesh. IR spectra were recorded as neat thin film on
Perkin-Elmer I spectrometer. 1H and 13C NMR spectra were record-
ed on Varian Gemini 200 MHz or Avance 300 MHz spectrometers
in CDCl3 using TMS as internal standard. All solvents used were
purified by a known procedure. Petroleum ether used had bp 60–80
°C. All reactions were carried out under N2 using dry glassware.
To a solution of ester 7 (2.0 g, 10 mmol) in anhyd CH2Cl2 (25 mL)
at 0 °C was added a 20% solution of DIBAL in toluene (15 mL, 21.7
mmol) over 10 min. After the addition, the mixture was stirred for
8 h. The mixture was then quenched by the addition of sat. aq solu-
tion of sodium potassium tartrate (10 mL) and was stirred vigorous-
ly at r.t for 2 h to get a biphasic solution. The mixture was extracted
with CH2Cl2 and the combined organic extracts were dried
(Na2SO4), filtered and concentrated to give the crude alcohol which
was further purified by column chromatography (EtOAc–petroleum
ether, 2.5:7.5); yield: 1.5 g (90%).
Ethyl (E)-Dec-2-enoate (7)
To a stirred solution of oxalyl chloride (0.8 mL, 9.2 mmol) in anhyd
CH2Cl2 (60 mL) at –78 °C under N2 was added DMSO (0.70 mL,
10.0 mmol). After stirring for 5 min at the same temperature, the re-
action mixture was allowed to warm to –60 °C over 20 min where
upon alcohol 6 (1.0 g, 7.6 mmol) was added in CH2Cl2 (5 mL). The
mixture was allowed to warm to –35 °C over 20 min and stirred for
5 min at this temperature and then treated over 4 min with Et3N
(5.35 mL, 38 mmol). After 30 min, the mixture was warmed to r.t.,
then benzene (10 mL) was added followed by (ethoxycarbonylme-
thylene)triphenylphosphorane (3.2 g, 9.2 mmol) and the mixture
was stirred for overnight. The solvents were evaporated and the res-
idue was dissolved in Et2O. The Et2O layer was washed with H2O
(2 × 5 mL), brine (5 mL), dried (Na2SO4). Evaporation of the sol-
vent and purification by column chromatography (EtOAc–petro-
leum ether, 0.5:9.5) afforded pure 7 as a colorless oil; yield: 1.27 g
(84%).
IR (neat): 3343, 2925, 2855, 1643, 1432, 1379, 1216, 1002, 969
cm–1.
1H NMR (200 MHz, CDCl3): = 5.70–5.60 (m, 2 H), 4.10–4.00 (m,
2 H), 2.10–1.90 (m, 2 H), 1.40–1.20 (m, 10 H), 1.18–1.00 (br s, 1
H), 0.90 (br t, 3 H, J = 6.7 Hz).
[(2S,3S)-3-Heptyloxiranyl]methanol (9)
To a precooled (–20 °C) suspension of activated 4 Å molecular
sieves (2 g) in CH2Cl2 (50 mL) under N2 were added L-(+)-diisopro-
pyl tartrate (DIPT, 0.34 g, 1.4 mmol) and Ti(OPr-i)4 (0.36 g, 1.2
mmol) and the mixture was stirred for 15 min. To this mixture was
added 8 (1.5 g, 9.6 mmol) followed by tert-butylhydroperoxide
(TBHP, 3.8 mL, 21.0 mmol, 5.5 M in undecane) at an interval of 25
min. After 4 h, the mixture was warmed to 0 °C and quenched with
H2O (7 mL). The mixture was stirred for 0.5 h. To this mixture was
added aq 20% NaOH solution saturated with solid NaCl (2 mL) and
the mixture was vigorously stirred for 2 h. The organic layer was
separated, dried (Na2SO4), filtered and concentrated to give the
crude epoxy alcohol, which was purified by column chromatograpy
(EtOAc–petroleum ether, 3:7); yield: 1.46 g (88%); [ ]D –17.4 (c =
3.75, CHCl3).
IR (neat): 2954, 2928, 2857, 1728, 1659, 1435, 1271, 1197, 1170,
1041, 979 cm–1.
1H NMR (200 MHz, CDCl3): = 6.92 (m, 1 H), 5.80 (d, 1 H,
J = 15.6 Hz), 4.18 (q, 2 H, J = 6.7, 14.1 Hz), 2.25–2.15 (m, 2 H),
1.60–1.20 (m, 10 H), 0.90 (br t, 3 H, J = 6.4 Hz).
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G. Sabitha et al.
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IR (neat): 3419, 2925, 2856, 1461, 1219, 1032, 873 cm–1.
cation by column chromatography (EtOAc–petroleum ether,
1.5:8.5) gave 2 as a colorless oil; yield: 0.61 g (74%); [ ]D +13.5
(c = 0.62, CHCl3).
IR (neat): 3389, 3314, 2104, 1635 cm–1.
1H NMR (200 MHz, CDCl3): = 3.87–3.80 (m, 1 H), 3.65–3.55 (m,
1 H), 2.95–2.82 (m, 2 H), 1.77 (br s, 1 H), 1.60–1.20 (m, 12 H), 0.90
(br t, 3 H, J = 6.7 Hz).
1H NMR (200 MHz, CDCl3): = 6.20 (dd, 1 H, J = 5.9, 15.9 Hz),
5.67 (d, 1 H, J = 15.9 Hz), 4.17–4.12 (m, 1 H), 2.82 (d, 1 H, J = 1.8
Hz), 1.20–1.60 (m, 12 H), 0.87 (t, 3 H, J = 6.7 Hz).
Ethyl (E)-3-[(2S,3S)-3-Heptyloxiran-2-yl]prop-2-enoate (10)
To a stirred solution of oxalyl chloride (0.76 mL, 8.7 mmol) in an-
hyd CH2Cl2 (60 mL) at –78 °C under N2 was added DMSO (1.23
mL, 17.4 mmol). After stirring for 5 min at the same temperature,
the reaction mixture was allowed to warm to –60 °C over 20 min
where upon alcohol 9 (1.0 g, 5.81 mmol) was added in CH2Cl2 (5
mL). The mixture was allowed to warm to –35 °C over 20 min and
stirred for 5 min at this temperature and then treated over 4 min with
Et3N (4 mL, 29.2 mmol). After 30 min, the mixture was warmed to
r.t., then benzene (10 mL) was added followed by (ethoxycarbonyl-
methylene)triphenylphosphorane (2.4 g, 6.9 mmol). The mixture
was stirred overnight, the solvents were evaporated and the residue
was dissolved in Et2O. The mixture was washed with H2O (2 × 5
mL), brine (5 mL), and dried (Na2SO4). Evaporation of the solvent
and purification by column chromatography (EtOAc–petroleum
ether, 1:9) afforded pure 10 as a colorless oil; yield: 1.2 g (85%).
5-(tert-Butyldimethylsilyloxy)pent-1-yne (14)
To a stirred solution of pent-4-yn-1-ol (13; 1.0 g, 11.9 mmol) and
imidazole (1.21 g, 17.8 mmol) in anhyd CH2Cl2 (10 mL) at 0 °C was
added TBDMSCl (2.6 g, 17.8 mmol). The reaction mixture was
stirred at 0 °C for 20 min, warmed to r.t., and the stirring was con-
tinued for another 1 h. The reaction was quenched with sat. aq
NH4Cl solution and extracted with Et2O (3 × 40 mL). The combined
organic extracts were dried (Na2SO4) filtered and concentrated un-
der vaccum. The product was purified by column chromatography
(EtOAc–petroleum ether, 0.2:9.4) to afford 14 as a colorless oil;
yield: 2.40 g (88%).
IR (neat): 2920, 2848, 2098, 1564, 1451, 1119 cm–1.
1H NMR (300 MHz, CDCl3): = 3.64 (t, 2 H, J = 5.9 Hz), 2.21 (dt,
2 H, J = 2.7, 7.0 Hz), 1.80 (t, 1 H, J = 2.7 Hz), 1.66 (quint, 2 H,
J = 7.0 Hz), 0.84 (s, 9 H), 0.01 (s, 6 H).
IR (neat): 2923, 2850, 1658, 1456, 1221, 1037, 875 cm–1.
1H NMR (200 MHz, CDCl3): = 6.78–6.60 (dd, 1 H, J = 6.1, 17.1
Hz), 6.20–6.02 (d, 1 H, J = 17.1 Hz), 4.22 (q, 2 H, J = 7.0 Hz), 3.20
(d, 1 H, J = 6.1 Hz), 2.90–2.80 (m, 1 H), 1.70–1.25 (m, 12 H), 0.95
(br t, 3 H, J = 6.5 Hz).
5-Bromopent-4-ynyl tert-Butyldimethylsilyl Ether (3)
A solution of 14 (1.0 g, 11.9 mmol) in acetone (20 mL) was treated
with NBS (2.54 g, 14.2 mmol) and (50 mg) at r.t. After 1 h, the re-
action mixture was poured into ice-cold H2O and the precipitated
solid was filtered off and washed with EtOAc. The resulting filtrate
was washed with brine and dried (Na2SO4). Evaporation of the sol-
vent followed by column chromatography (petroleum ether) afford-
ed 3; yield: 1.6 g (84%).
(E)-3-[(2S,3S)-3-Heptyloxiran-2-yl]prop-2-en-1-ol (11)
To a solution of Ester 10 (1.0 g, 4.1 mmol) in anhyd CH2Cl2 (25 mL)
at 0 °C was added an 1.3 M solution of DIBAL in hexane (1.7 mL,
10.3 mmol) over 10 min. After the addition, the mixture was stirred
for 2 h for completion of the reaction. The reaction was quenched
by the addition of aq sat. solution of sodium potassium tartrate (6
mL) and the mixture was stirred vigorously at r.t for 2 h to get a bi-
phasic solution. The mixture was extracted with CH2Cl2 and the or-
ganic extracts were dried (Na2SO4), filtered and concentrated to
give the crude alcohol, which was purified by column chromatogra-
phy (EtOAc–petroleum ether, 3:7); yield: 0.60 g (73%); colorless
liquid.
IR (neat): 2916, 2863, 1592, 1448, 1193, 1142, 1035 cm–1.
1H NMR (200 MHz, CDCl3): = 3.66 (t, 2 H, J = 5.9 Hz), 2.34 (t,
2 H, J = 2.7 Hz), 1.70 (quint, 2 H, J = 4.9 Hz), 0.97 (s, 9 H), 0.01
(s, 6 H).
(8S,9E)-17-(tert-Butyldimethylsilyloxy)heptadec-9-ene-11,13-
diyn-8-ol (15)
IR (neat): 1730, 1660, 970, 1130 cm–1.
A solution of NH2OH·HCl (363 mg, 5.6 mmol) in H2O (0.4 mL), aq
70% ethylamine solution (3.5 mL), CuCl (26 mg, 0.26 mmol) and
MeOH (17.9 mL) were placed in a round bottom flask. Air was
completely replaced by N2. While stirring, alkyne 2 (0.450 mg, 2.8
mmol) was added in one portion and to the resulting yellow suspen-
sion was added the bromoalkyne 3 (0.5 g, 11.2 mmol) over a period
of 30 min while maintaining the temp at 40 °C. After 1 h, the reac-
tion was quenched with a sat.aq solution of KCN (2 mL), and to this
was added sat. aq NH4Cl solution and extracted with Et2O. The
Et2O layer was washed with brine, dried (Na2SO4) and concentrated
under vacuum. The residue was purified by column chromatogra-
phy (EtOAc–petroleum ether, 0.6:9.4)to afford 15 as a colorless liq-
uid; yield: 0.5 g (50%).
1H NMR (200 MHz, CDCl3): = 6.10–5.94 (m, 1 H), 5.52–5.40 (m,
1 H), 4.18 (d, 2 H, J = 6.9 Hz), 3.09 (dd, 1 H, J = 3.1, 8.9 Hz), 2.80
(m, 1 H), 1.60–1.20 (m, 12 H), 0.90 (t, 3 H, J = 6.6 Hz).
(E)-3-[(2S,3S)-3-Heptyloxiran-2-yl]prop-2-enyl Chloride (12)
To a solution of alcohol 11 (1.0 g, 5 mmol) in anhyd CCl4 (20 mL)
was added Ph3P (1.59 g, 6.0 mmol) and a pinch of NaHCO3. The re-
action mixture was refluxed for 5 h. The solvent was evaporated and
the residue was extracted with Et2O. The Et2O layer was washed
with brine, and dried (Na2SO4). Evaporation of the solvent followed
by column chromatography (EtOAc–petroleum ether, 0.7:9.3) af-
forded epoxy chloride 12 as a colorless oil; yield: 0.85 g (85%).
IR (neat): 2927, 2854, 1640, 1467, 1265, 1120 cm–1.
IR (neat): 3433, 2234, 1602, 1457, 1054, 950 cm–1.
1H NMR (200 MHz, CDCl3): = 6.05–5.95 (m, 1 H), 5.40–5.60 (m,
1 H), 4.00 (d, 2 H, J = 6.8 Hz), 3.10 (dd, 1 H, J = 3.1, 8.8 Hz), 2.80–
2.70 (m, 1 H), 1.60–1.20 (m, 12 H), 0.90 (br t, 3 H, J = 6.2 Hz).
1H NMR (300 MHz, CDCl3): = 6.23 (dd, 1 H, J = 6.0, 15.9 Hz),
5.70 (d, 1 H, J = 15.9 Hz), 4.17–4.09 (m, 1 H), 3.68 (t, 2 H, J = 6.0
Hz), 2.41 (t, 2 H, J = 7.2 Hz), 1.73 (quint, 2 H, J = 6.8 Hz), 1.57–
1.24 (m, 12 H), 0.90 (m, 12 H).
(E,5S)-Dodec-3-en-1-yn-5-ol (2)
To a stirred solution of LDA at –78 °C [prepared from BuLi (8.6
mL, 13.7 mmol, 1.6 M solution in hexane and i-Pr2NH (1.94 mL,
13.8 mmol] at 0 °C in THF–HMPA (5:1, 10 mL) was added 12 (1.0
g, 4.6 mmol) and the mixture was stirred for 2 h. The mixture was
quenched with sat. aq NH4Cl solution and gently warmed to r.t.
Et2O was added and the organic layer was separated, washed with
brine, dried (Na2SO4), filtered and concentrated in vacuum. Purifi-
(E,10S)-Heptadec-8-ene-4,6-diyne-1,10-diol (1, Virol)
To compound 15 (0.10 g, 0.274 mmol) in anhyd THF (3 mL) was
added an 1% solution of TBAF in THF (0.55 mL, 0.546 mmol)
dropwise at 0 °C and the mixture was stirred for 30 min. H2O (2
mL) was added and the mixture was extracted with EtOAc. The or-
ganic extracts were washed with brine, dried (anhyd Na2SO4).
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Stereoselective Total Synthesis of (+)-Virol C
2703
Evaporation of the solvent was followed by purification of the resi-
due obtained by column chromatography (EtOAc–petroleum ether,
2:8); 0.06 g (85%); [ ]D +6.2 (c = 0.80, MeOH) {Lit.5 [ ]D +6.4
(c = 0.82, MeOH).
1H NMR (200 MHz, CDCl3): = 6.43 (d, 1 H, J = 13.9 Hz), 5.87 (d,
1 H, J = 13.9 Hz), 3.72 (t, 2 H, J = 5.8 Hz), 2.48–2.38 (m, 2 H),
1.85–1.70 (m, 2 H), 1.37 (br s, 1 H).
Hepta-4,6-diyn-1-ol (18)
IR (neat): 3334, 2927, 2856, 2235, 1625, 1461, 1296, 1058, 955,
782, 660 cm–1.
To HMPA (1.70 mL, 11.4 mmol) in THF (10 mL) was added a 2.5
M solution of BuLi in hexane (4.6 mL, 11.4 mmol) at –35 °C under
N2. After 1 h, the chloro compound 17 (0.2 g, 1.9 mmol) was added
slowly over 10 min and the stirring was continued for further 4 h.
The reaction mixture was quenched with sat. aq NH4Cl solution and
was extracted with EtOAc. The organic layer was washed by brine,
dried (Na2SO4) filtered and concentrated under reduced pressure to
yield the crude product, which was purified by column chromatog-
raphy (EtOAc–petroleum ether, 2:8); colorless liquid; yield: 0.175
g (85%).
1H NMR (200 MHz, CDCl3): = 6.22 (dd, 1 H, J = 16, 5.9 Hz, C-
9), 5.62 (d, 1 H, J = 16 Hz, C-8), 4.10 (m, 1 H, C-10), 3.68 (t, 2 H,
J = 6.4 Hz, C-1), 2.43 (t, 2 H, J = 6.6 Hz, C-3), 1.92 (m, 2 H, C-11),
1.80 (quint, 2 H, J = 6.6 Hz, C-2), 1.05–1.60 (m, 10 H, C-12 to C-
16), 0.84 (t, 3 H, J = 6.6 Hz, C-17).
13C NMR (75 MHz, CDCl3): = 148.8, 108.5, 83.4, 74.6, 73.3, 72.0,
65.5, 61.2, 36.8, 31.7, 30.8, 29.4, 29.1, 25.1, 22.5, 16.0, 14.0.
MS (EI): m/z = 262 (M+).
IR (neat): 3360, 2927, 2856, 1643, 1455, 1242, 1056, 912 cm–1.
1H NMR (200 MHz, CDCl3): = 3.73 (t, 2 H, J = 5.9 Hz), 2.40 (t,
2 H, J = 8.2 Hz), 1.89 (s, 1 H), 1.80 (m, 2 H).
Anal. Calcd for C17H26O2: C, 77.82; H, 9.99. Found: C, 77.71; H,
9.93.
(2S,3S)-2-(Chloromethyl)-3-heptyloxirane (16)
2-(Hepta-4,6-diynyloxy)tetrahydro-2H-pyran (5)
To alcohol 9 (1.2 g, 6.9 mmol) in anhyd CCl4 (20 mL) under N2 was
added TPP (2.2 g, 8.3 mmol) and a catalytic amount of NaHCO3
(0.15 g) and the mixture was refluxed for 6 h. The solvent was evap-
orated and the crude product was chromatographed (EtOAc–petro-
leum ether, 0.5:9.5); yield: 1.15 g (88%); [ ]D –9.6 (c = 3.75,
CHCl3).
To alcohol 18 (0.12 g, 0.9 mmol) in CH2Cl2 (5 mL) at 0 °C was add-
ed a catalytic amount of p-TsOH (0.005 g) followed by dihydropy-
ran (0.093 g, 1.1 mmol) over 10 min. The mixture was stirred for 3
h. The mixture was quenched by the addition of aq sat. solution of
NaHCO3 (2 mL) and the organic layer was separated, dried
(Na2SO4), filtered, and concentrated. The crude product was puri-
fied by column chromatography (EtOAc–petroleum ether, 0.5:9.5);
colorless oil; yield: 0.160 g (90%).
IR (neat): 2928, 2857, 1462, 1377, 1266, 1068, 927, 875 cm–1.
1H NMR (200 MHz, CDCl3): = 3.59 (dd, 1 H, J = 5.2, 11.9 Hz),
3.38 (dd, 1 H, J = 5.9, 11.9 Hz), 2.96–2.88 (m, 1 H), 2.83–2.76 (m,
1 H), 1.62–1.20 (m, 12 H), 0.90 (br t, 3 H, J = 6.7 Hz).
IR (neat): 2926, 2853, 1588, 1454, 1190, 1129, 1031 cm–1.
1H NMR (200 MHz, CDCl3): = 4.60 (t, 1 H, J = 2.9 Hz), 3.92–3.76
(m, 2 H), 3.52–3.38 (m, 2 H), 2.40 (t, 2 H, J = 6.7 Hz), 1.92–1.78
(m, 3 H), 1.66–1.47 (m, 6 H).
(E,3S)-1-Chlorodec-1-en-3-ol (4)
To a freshly prepared LiNH2 (0.06 g, 2.6 mmol) in liquid NH3 (35
mL) at –33 °C was added the epoxy chloride 16 (0.5 g, 2.6 mmol)
in anhyd THF (3 mlL), and the mixture was stirred for 2 h. After
quenching the mixture with solid NH4Cl, ammonia was allowed to
evaporate. The residue was partitioned between H2O and Et2O. The
ethereal layer was washed with H2O, dried (Na2SO4), filtered, and
evaporated. Purification of the crude by column chromatography
(EtOAc–petroleum ether, 1:9) gave pure alcohol 4 as a colorless oil;
yield: 0.33 g (65%) + 0.15 g (30%) of cis product; [ ]D +7.0 (c =
4.0, CHCl3) for trans isomer.
(8S,E)-17-(Tetrahydro-2H-pyran-2-yloxy)heptadec-9-ene-
11,13-diyn-8-ol (19)
To a mixture of chloro compound 4 (0.05 g, 0.26 mmol), CuI (0.005
g, 0.02 mmol), alkyne 5 (0.075 g, 0.39 mmol) and piperidine (0.045
g, 0.52 mmol) in benzene (3 mL) under N2 was added Pd(PPh3)2Cl2
and the mixture was stirred for 2 h. The mixture was diluted with
Et2O, quenched with sat. aq NH4Cl solution. The organic layer was
washed with brine, dried (Na2SO4), concentrated and chromato-
graphed (EtOAc–petroleum ether, 0.5:9.5) to afford the pure prod-
uct as a colorless oil; yield: 0.018 g (20%).
IR (neat): 3344, 2956, 2928, 2857, 1638, 1466, 1219, 1130, 1018,
809 cm–1.
1H NMR (200 MHz, CDCl3): = 6.20 (dd, 1 H, J = 1.3, 13.3 Hz),
5.93 (dd, 1 H, J = 6.7, 13.3 Hz), 4.16–4.07 (m, 1 H), 1.58–1.23 (m,
12 H), 0.90 (br t, 3 H, J = 7.2 Hz).
13C NMR (200 MHz, CDCl3): = 136.3, 119.4, 71.1, 37.0, 31.7,
29.3, 29.1, 25.1, 22.5, 13.9.
MS (EI): m/z 155 (M+ – Cl).
IR (neat): 3462, 3409, 2926, 2853, 1619,1588, 1454, 1350, 1198,
1129, 1072, 1031, 795 cm–1.
1H NMR (300 MHz, CDCl3): = 6.23 (dd, 1 H, J = 6.0, 15.7 Hz),
5.69 (d, 1 H, J = 15.7 Hz), 4.57 (t, 1 H, J = 3.6 Hz), 4.18–4.09 (m,
1 H), 3.86–3.74 (m, 2 H), 3.53–3.40 (m, 2 H), 2.45 (t, 2 H,
J = 7.3Hz), 1.90–1.75 (m, 2 H), 1.69–1.45 (m, 6 H), 1.32–1.19 (m,
12 H), 0.88 (t, 3 H, J = 6.1 Hz).
(E)-7-Chlorohept-6-en-4-yn-1-ol (17)
(E,10S)-Heptadec-8-ene-4,6-diyne-1,10-diol (1, Virol)
To a solution of 19 (0.015 g, 0.043 mmol) in MeOH (4 mL) was
added p-TsOH·H2O (ca.2mg) and the mixture was stirred for 0.5 h.
The mixture was quenched with aq sat. solution of NaHCO3 (1 mL)
and MeOH was evaporated under reduced pressure. The mixture
was extracted with EtOAc and the organic layer was dried (Na2SO4)
and concentrated under reduced pressure. The product was purified
by column chromatography (EtOAc–petroleum ether, 2:8) to fur-
nish 1 as a colorless liquid; yield: 0.010 g (90%). The compound
was characterized by spectral data such as 1H NMR, 13C NMR, IR
and mass spectroscopy, and the data were compared with the au-
thentic sample data prepared by route a and found to be identical in
all aspects.
To alkyne 13 (1.0 g, 11.9 mmol), piperidine (1.87 g, 22 mmol) and
dichloroethylene (5.77 g, 59.4 mmol) in benzene (5 mL) was added
Pd(PPh3)4 (0.687 g, 0.6 mmol) and CuI (0.22 g, 1.1 mmol) under N2.
The mixture was stirred at r.t for 6 h and diluted with anhyd Et2O
(25 mL). The reaction was quenched by the addition of aq sat. solu-
tion of NH4Cl. The organic layer was extracted with Et2O, washed
with brine, dried (Na2SO4) filtered and concentrated. The crude
product was purified by column chromatography (EtOAc–petro-
leum ether, 1:9) to afford 18 as a colorless oil; yield: 1.38 g (80%).
IR (neat): 3461, 3290, 2950, 2224, 1429, 1230, 1051, 921 cm–1.
Synthesis 2003, No. 17, 2699–2704 © Thieme Stuttgart · New York

2704
G. Sabitha et al.
PAPER
(5) Stefani, H. A.; Menezer, P. H.; Costa, I. M.; Silva, D. O.;
Acknowledgment
Petragnani, N. Synlett 2002, 1335.
ChSR thank UGC and PSH thank CSIR, New Delhi for the award
of fellowships.
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J. Am. Chem. Soc. 1982, 103, 464.
(7) Yadav, J. S.; Barma, D. K.; Dutta, D. Tetrahedron Lett.
1997, 38, 4479.
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Synthesis 2003, No. 17, 2699–2704 © Thieme Stuttgart · New York