Asymmetric total syntheses of (R)-(-)-argentilactone and (S)-5-hexadecanolide

Article abstract of DOI:10.1055/s-2006-942518

The simple and efficient asymmetric syntheses of (R)-(-)-argentilactone and (S)-5-hexadecanolide were achieved from the same starting material by a similar strategy. The key intermediates for both molecules were chiral 5-hydroxyalk-2-en-6-ynoates. Georg T

Full text of DOI:10.1055/s-2006-942518

PAPER
2879
Asymmetric Total Syntheses of (R)-(–)-Argentilactone and
(S)-5-Hexadecanolide
S
ynthese
s
of
(
R
)-(–
o
)-Argentilac
w
tone and(
S
)
-5-H
e
r
xadecano
a
lide varam Sabitha,* Narjis Fatima, R. Swapna, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: sabitha@iictnet.org
Received 20 April 2006; revised 5 May 2006
procedures being reported10,11 for both the racemic and
optically active forms. Most of the reported synthetic
routes for argentilactone (1) employ Wittig olefination of
the pyrancarbaldehyde with the corresponding hexyl-
idenetriphenylphosphorane to produce the (Z)-alkene
(C7–C8). In continuation of our studies on the synthesis of
naturally occurring lactones,12,13 we became interested in
the total synthesis of argentilactone (1) and hexadecano-
lide (2) by using a similar strategy. It is important to men-
tion that these two molecules 1 and 2 can be made from
the same starting material, and via two chiral 5-hydroxy-
alk-2-en-6-ynoates 3 and 4 (Scheme 1).
Abstract: The simple and efficient asymmetric syntheses of (R)-(–)-
argentilactone and (S)-5-hexadecanolide were achieved from the
same starting material by a similar strategy. The key intermediates
for both molecules were chiral 5-hydroxyalk-2-en-6-ynoates.
Key words: lactones, total synthesis, natural products, argentilac-
tone, hexadecanolide
6-Alkyl-substituted d-lactones and a,b-unsaturated d-lac-
tones (5,6-dihydro-2H-pyran-2-ones) are key structural
units of many natural products1 as well as valuable syn-
thetic intermediates to other chiral molecules of consider-
able interest. These lactones are known to exhibit a wide
range of biological activities such as plant-growth inhibi-
tion, antifeedant, antifungal, and antitumor properties,2
and comprise structural moieties frequently present in,
e.g., insect pheromones, cardenolides, and lignans.3 Ar-
gentilactone (1) belongs to this family, having an alkyl
side chain at the C6 position and with a cis double bond at
C7–C8. This lactone was first isolated in 1977 from the
rhizomes of Aristolochia argentia by Ruveda and co-
workers.4 It showed both antileishmanial5 and cytotoxic
activity6 against P-388 mouse leukemia cells. Later it was
also isolated from the methanolic extract of a Brazilian
medicinal plant, Chorisia crispiflora,6 which is one of the
folk medicines used for rheumatism and menorrhalgia.
This compound was also found to be present in the hexane
extract of Annona haematantha.5 Recently, argentilactone
was isolated as the main constituent from the essential oil
of Hyptis ovalifolia Benth,7 and showed strong in vitro an-
tifungal activity against dermatophytes. Therefore, argen-
tilactone (1) could be an interesting molecule for the
development of new drugs against dermatophytes. The
natural form of argentilactone has the R-configuration,
and is used as a starting material for the synthesis of pher-
omones.8 A d-lactone (S)-5-hexadecanolide (2) was iso-
lated from the mandibular glands of the oriental hornet,
Vespa orientalis9 as a pheromone to stimulate the workers
to construct queen cells. This lactone is also found in
some fruits, such as apricots and peaches. Both 1 and 2
have chiral lactone units in their structure.
The synthesis of argentilactone (1) (Scheme 2) began with
the known 2,3-epoxy chloride 5.14 2,3-Epoxy chloride 5
was directly converted into an alkylated chiral alkynol 614
in 81% yield in a one-pot procedure consisting of subject-
ing 2,3-epoxy chloride 5 to a base-induced opening with
lithium metal in liquid ammonia in tetrahydrofuran, and
treatment of the resultant alkynol without isolation with 1-
bromopentane at –78 °C. The spectral data of alkynol 6
was in good agreement with the assigned structure. The
secondary hydroxy group of alkynol 6 was protected as its
p-methoxybenzyl ether by reaction of alkynol 6 with p-
methoxybenzyl bromide and sodium hydride in dry tet-
rahydrofuran at room temperature; this afforded
compound 715 in 88% yield. Deprotection of the tetra-
hydropyran-2-yl group in 7 was achieved with the use of
pyridinium p-toluenesulfonate in methanol16 at room tem-
perature, affording primary alcohol 8 in 67% yield; it was
characterized by IR, 1H NMR, and mass spectroscopy.
The oxidation of the primary hydroxy group in alcohol 8
with pyridinium dichromate in dichloromethane afforded
aldehyde 917 in 64% yield. Aldehyde 9 underwent Still’s
modification of the Horner–Wadsworth–Emmons18 reac-
tion in the presence of sodium hydride and bis(2,2,2-tri-
fluoroethyl) (methoxycarbonylmethyl)phosphonate in dry
tetrahydrofuran at –78 °C; this gave a,b-unsaturated ester
3, predominantly as the Z-isomer, as characterized by 1H
and 13C NMR spectroscopy, in 85% yield. In the 1H NMR
spectrum, resonances at d 5.83, a doublet of triplets
(J = 1.8, 11.5 Hz), and at d 6.38, a doublet of triplets
(J = 6.8, 11.5 Hz), confirmed the Z-geometry of the dou-
ble bond. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone in
dichloromethane–water (CH2Cl2–H2O, 9:1)19 was used to
deprotect ether 3, removing the p-methoxybenzyl group,
and giving secondary alcohol 10 in 55% yield. The cy-
clization of hydroxy ester 10 was achieved in refluxing
The important biological activities of argentilactone (1)
and hexadecanolide (2) have led to a number of synthetic
SYNTHESIS 2006, No. 17, pp 2879–2884
x
x.
x
x
.
2
0
0
6
Advanced online publication: 25.07.2006
DOI: 10.1055/s-2006-942518; Art ID: Z08006SS
© Georg Thieme Verlag Stuttgart · New York

2880
G. Sabitha et al.
PAPER
O
O
O
O
8
7
(S)-hexadecanolide (2)
R-(–)-argentilactone (1)
OBn
OPMB
CO2Et
CO2Me
THPO
4
3
O
Cl
5
Scheme 1 Retrosynthetic strategy for (R)-(–)-argentilactone and (S)-5-hexadecanolide from the same starting material
benzene containing catalytic amount of p-toluenesulfonic chloride 5 was subjected to base-induced opening by lith-
acid,20 to afford lactone 11 in 68% yield. Finally, the par- ium amide in liquid ammonia at –78 °C, and treated with
tial hydrogenation of the triple bond over 5% palladium– 1-bromononane to give the chiral alkynol 12 directly in a
calcium carbonate gave the target molecule, (R)-(–)-ar- one-pot procedure in 70% yield. The secondary hydroxy
gentilactone (1), in 60% yield, and with optical rotation group of alkynol 12 was protected as its benzyl ether by
25
[a]D –19.5 (c 0.5, EtOH) {Lit.4 [a]D25 –21.1 (c 2.25, treatment of alkynol 12 with sodium hydride and benzyl
EtOH)}. The optical purity of the product was estimated bromide in dry tetrahydrofuran15 at room temperature;
1
to be 86%. The H and 13C NMR, IR, and mass spectro- this gave benzyl ether 1315 in 96% yield. Subsequently,
scopic data of this synthesized compound were identical deprotection of the tetrahydropyran-2-yl group by use of
to those of the natural product.
pyridinium p-toluenesulfonate in methanol16 furnished
primary alcohol 14 in 96% yield. Alcohol 14 was oxidized
to the corresponding aldehyde, which, without isolation,
was further treated with the two-carbon Wittig ylide
By a similar strategy, (S)-5-hexadecanolide was synthe-
sized in a short procedure, also starting from 2,3-epoxy
chloride 5. The procedure is shown in Scheme 3. Epoxy
OH
O
a
b
OTHP
Cl
THPO
C5H11
5
6
OPMB
OPMB
OTHP
c
d
OH
C5H11
C5H11
8
7
OPMB
OPMB
f
CHO
e
CO2Me
C5H11
C5H11
9
3
O
O
OH
g
O
h
O
CO2Me
C5H11
argentilactone (1)
C5H11
C5H11
11
10
Scheme 2 Synthesis of (R)-(–)-argentilactone. Reagents and Conditions: (a) Li/liq NH3, Fe(NO3)3 (cat.), Me(CH2)4Br, dry THF, 81%; (b)
NaH, PMBBr, THF, 0 °C to r.t., 88%; (c) PPTS, MeOH, r.t., 67%; (d) PDC, CH2Cl2, reflux, 3–4 h, 64%; (e) (F3CCH2O)2P(O)CH2CO2Me, NaH,
THF, 1 h, 85%; (f) DDQ, CH2Cl2–H2O, r.t., 2.5 h, 55%; (g) PTSA, benzene, reflux, 2 h, 68%; (h) 5% Pd–CaCO3, quinoline, EtOAc, H2, r.t,
2 h, 60%.
Synthesis 2006, No. 17, 2879–2884 © Thieme Stuttgart · New York

PAPER
Syntheses of (R)-(–)-Argentilactone and (S)-5-Hexadecanolide
2881
OH
O
a
b
OTHP
Cl
THPO
C9H19
5
12
OBn
OBn
c
d
OH
OTHP
C9H19
C9H19
14
13
O
OBn
e
CO2Et
O
C11H23
C9H19
4
5-(S)-hexadecanolide (2)
Scheme 3 Synthesis of (S)-5-hexadecanolide. Reagents and Conditions: (a) Li/liq NH3, Fe(NO3)3 (cat.), Me(CH2)8Br, dry THF, 70%; (b)
NaH, BnBr, THF, 0 °C to r.t., 98%; (c) PPTS, MeOH, r.t., 96%; (d) (COCl)2, DMSO, Et3N, Ph3P=CHCO2Et, CH2Cl2, –78 °C, 70%; (e) 10%
Pd/C (cat.), H2, EtOH, 12 h, 70%.
g, 81.6 mmol) followed at –78 °C, and the resulting grey suspension
was stirred for 30 min. Epoxide 5 (3 g, 13.6 mmol) in dry THF (25
mL) was added to this over 15 min, and the mixture was then stirred
for 2 h at the same temperature. Then 1-bromopentane (4.13 mL,
32.6 mmol) was added dropwise to the mixture. The mixture was
stirred at the same temperature for 6 h, and the reaction was
quenched by the addition of solid NH4Cl; then the NH3 was allowed
to evaporate. The reaction mixture was extracted with H2O and
EtOAc. The combined organic layers were washed with H2O (1 ×
50 mL) and brine (1 × 50 mL), and dried (anhyd Na2SO4). The sol-
vent was removed under reduced pressure. The residue was purified
by column chromatography (silica gel, PE–EtOAc, 6:4); this gave
pure 6 as a clear, colorless liquid.
(ethoxycarbonylmethylene)triphenylphosphorane, to fur-
nish the a,b-unsaturated ester 421 in 70% yield.
Finally, the synthesis of target molecule 2 was completed
in a single-pot four-reaction sequence. Treatment of ester
4 over 10% palladium–carbon in ethanol under hydrogen
yielded (S)-5-hexadecanolide (2) in 70% yield, by in situ
removal of the benzyl protecting group, saturation of the
double and triple bonds, followed by cyclization
(Scheme 3). The synthetically obtained compound
showed IR, 1H, and 13C NMR spectral data and an optical
rotation {[a]D25 –27.10 (c 1, CHCl3)} in good agreement
with those of the natural lactone.
Yield: 2.8 g (81%); [a]D25 –6.72 (c 1, CHCl3).
IR (neat): 3420, 3933, 2362, 1617, 1352, 1032, 772 cm–1.
In summary, we have demonstrated efficient, scalable,
and stereoselective total syntheses of (R)-argentilactone
and (S)-5-hexadecanolide in eight and five steps, respec-
tively, in good yields by utilizing chiral 5-hydroxyalk-2-
en-6-ynoates as key intermediates.
1H NMR (300 MHz, CDCl3): d = 3.77–3.67 (m, 1 H), 3.58–3.66 (t,
J = 6.0 Hz, 1 H), 3.11–3.25 (m, 1 H), 2.88–3.05 (m, 1 H), 2.81–2.72
(m, 1 H), 2.68–2.56 (m, 1 H), 2.05 (br s, OH, 1 H), 1.34–1.27 (td,
J = 2.2, 7.5 Hz, 2 H), 1.5–2.0 (m, 8 H,), 1.2–1.4 (m, 6 H), 0.01–0.06
(t, J = 6.2 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 98.83, 80.71, 64.65, 64.53, 62.12,
Reactions were conducted under a N2 atmosphere in anhydrous sol-
vents such as CH2Cl2, THF, CCl4, benzene, and EtOAc. All reac-
tions were monitored by TLC on silica-coated plates (Merck 60 F-
254) and with visualization under UV light. Light PE of the distilla-
tion range 60–80 °C was used. Yields refer to chromatographically
and spectroscopically (1H, 13C NMR) homogeneous material. Air-
sensitive reagents were transferred by syringe or double-ended nee-
dle. Evaporation of solvents was performed at reduced pressure, us-
ing a Buchi rotary evaporator.1H NMR spectra were recorded on
Varian FT-200 MHz (Gemini) and Bruker UXNMR FT-300 MHz
(Avance) instruments, and CDCl3 was the solvent. Chemical shift
values (d) were reported in ppm relative to tetramethylsilane (d 0.0)
as internal standard. Mass spectra were recorded under electron im-
pact at 70 eV on an LC-MSD (Agilent Technologies) instrument.
Column chromatography was performed on silica gel (60–120
mesh) supplied by Acme Chemical Co., India. Optical rotations
were measured with a JASCO DIP-370 polarimeter at 20 °C.
61.94, 37.39, 30.99, 30.49, 28.31, 25.31, 22.11, 19.35, 18.62, 13.88.
MS (EI, 70 eV): m/z = 254 [M + Na]+.
2-{(R)-3-[(4-Methoxybenzyl)oxy]dec-4-ynyloxy}tetrahydro-
2H-pyran (7)
Alcohol 6 (0.8 g, 3.1 mmol) in dry THF (10 mL) was added drop-
wise to a stirred suspension of freshly activated NaH (0.223 g, 9.3
mmol) in dry THF (30 mL) at 0 °C. After the mixture had stirred for
30 min, PMBBr (0.636 g, 3.1 mmol) in dry THF (10 mL) was add-
ed. After completion of the reaction (3 h), the mixture was quenched
with sat. aq NH4Cl soln and extracted with EtOAc. The organic lay-
er was washed with H2O and brine soln, dried (anhyd Na2SO4), and
concentrated in vacuo; purification by column chromatography (sil-
ica gel) afforded 7 as a viscous liquid.
Yield: 1.03 g (88%); [a]D25 +21.72 (c 1, CHCl3).
IR (neat): 3418, 1615, 1513, 1353, 1248, 1121, 1034, 772, 618 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.27–7.19 (m, 2 H), 6.87–6.79 (d,
J = 8.3 Hz, 2 H), 4.67 (d, J = 11.2 Hz, 1 H), 4.55 (m, 1 H), 4.40 (t,
J = 11.2 Hz, 1 H), 4.2 (m, 1 H), 3.78 (s, 3 H), 3.52–3.38 (m, 2 H),
(R)-1-(Tetrahydro-2H-pyran-2-yloxy)dec-4-yn-3-ol (6)
To freshly distilled NH3 (50 mL) in a 100-mL two-neck round-bot-
tomed flask fitted with a cold-finger condenser was added a catalyt-
ic amount of Fe(NO3)3. The piecewise addition of Li metal (0.244
Synthesis 2006, No. 17, 2879–2884 © Thieme Stuttgart · New York

2882
G. Sabitha et al.
PAPER
2.30–2.17 (td, J = 7.2, 5.6 Hz, 2 H), 2.06–1.29 (m, 2 H), 1.3–1.5 (m,
14 H), 0.92 (t, J = 7.2 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 141.80, 129.93, 129.70, 129.62,
114.25, 113.73, 113.69, 98.89, 98.68, 76.57, 73.79, 70.32, 70.16,
65.56, 64.96, 63.34, 62.14, 55.25, 36.02, 30.58, 25.46, 19.47, 14.08.
(m, 1 H), 3.79 (s, 3 H), 3.69 (s, 3 H), 3.07–3.01 (dt, J = 2.0, 6.8 Hz,
2 H), 2.26–2.19 (dt, J = 2.0, 6.9 Hz, 2 H), 1.59–1.30 (m, 6 H), 0.96–
0.89 (t, J = 6.7 Hz, 3 H).
Methyl (Z,R)-5-Hydroxydodec-2-en-6-ynoate (10)
To a stirred soln of ester 3 (0.12 g, 0.3 mmol) in CH2Cl2 (4.5 mL)
and H2O (0.5 mL) was added DDQ (0.081 g, 0.3 mmol) at r.t. The
mixture was stirred for 2.5 h at r.t. before being quenched by the ad-
dition of sat. aq NaHCO3 (10 mL). The layers were separated and
the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The com-
bined organic extracts were dried (anhyd Na2SO4) and then concen-
trated in vacuo. The crude product was purified by column
chromatography (silica gel); this gave ester 10 as a pure yellow oil.
MS (EI, 70 eV): m/z = 374 [M + Na]+.
(R)-3-[(4-Methoxybenzyl)oxy]dec-4-yn-1-ol (8)
A cat. amount of PPTS was added to a stirred soln of 7 (3.25 g, 8.6
mmol) in MeOH (30 mL). The mixture was stirred at r.t. for ca. 2 h,
and then the MeOH was removed under reduced pressure. The
crude residue was purified by column chromatography (silica gel);
this gave 8 as a viscous liquid.
Yield: 1.7 g (67%); [a]D25 +53.5 (c 1, CHCl3).
IR (neat): 3416, 1617, 1219, 772, 617 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25–7.18 (d, J = 9.0 Hz, 2 H),
6.85–6.80 (d, J = 8.3 Hz, 2 H), 4.71–4.39 (AB q, J = 11.3 Hz, 2 H),
4.24 (m, 1 H), 3.80 (s, 3 H), 3.88–3.64 (m, 2 H), 2.28–2.21 (dt,
J = 1.5, 6.8 Hz, 2 H), 1.97–1.89 (q, J = 5.2, 10.5 Hz, 2 H), 1.61–1.49
(m, 2 H), 1.44–1.23 (m, 4 H), 0.93 (t, J = 6.8 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 159.33, 129.65, 113.85, 87.54,
78.25, 70.14, 67.25, 60.30, 55.25, 38.24, 31.06, 29.69, 28.38, 22.16,
18.67, 14.10.
Yield: 0.44 g (55%).
IR (neat): 3417, 1618, 1353 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.45–6.39 (m, 1 H), 5.94–5.90 (td,
J = 1.5 Hz, 1 H), 4.51–4.43 (m, 1 H), 3.72 (s, 3 H), 3.05–2.97 (m, 2
H), 2.23–2.14 (td, J = 5.2, 6.7 Hz, 2 H), 2.06 (br s, OH, 1 H), 1.57–
1.23 (m, 6 H), 0.91 (t, J = 6.7 Hz, 3 H).
(R)-6-(Hept-1-ynyl)-5,6-dihydro-2H-pyran-2-one (11)
To a stirred soln of ester 10 (1.0 g, 4.4 mmol) in dry benzene (10
mL) was added a cat. amount of PTSA under a N2 atmosphere. The
mixture was refluxed for 2 h, the solvent was removed under vacu-
um, and the reaction was quenched with aq NaHCO3. The aqueous
layer was extracted with EtOAc (2 × 20 mL), dried (anhyd Na2SO4),
and concentrated in vacuo. The crude product was purified by col-
umn chromatography (silica gel); this gave lactone 11 as a yellow
liquid.
Yield: 0.58 g (68%); [a]D25 +24.5(c 0.5, CHCl3).
IR (neat): 2930, 1730, 1617, 1381, 1243, 1053, 816, 760, 617 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.84 (m, 1 H), 6.08–6.02 (dt,
J = 1.5, 2.2 Hz, 1 H), 5.18–5.12 (m, 1 H), 2.66–2.60 (m, 2 H), 2.2–
2.26 (td, J = 5.2, 1.5, 2 H), 1.59–1.21 (m, 6 H), 0.97–0.91 (t, J = 6.9,
3 H).
MS (EI, 70 eV): m/z = 292 [M + H]+.
(R)-3-[(4-Methoxybenzyl)oxy]dec-4-ynal (9)
PDC (0.972 g, 2.5 mmol) was added to a soln of 8 (0.5 g, 1.7 mmol)
in CH2Cl2 (20 mL) at 0 °C and the mixture was refluxed for 3–4 h.
The progress of the reaction was monitored by TLC. Removal of the
solvent afforded a gummy material, which was filtered through
Celite with Et2O and concentrated. The residue was purified by col-
umn chromatography (PE–EtOAc); this gave 9 as a liquid.
Yield: 0.323 g (64%); [a]D25 +24.72 (c 1, CHCl3).
IR (neat): 3419, 2931, 1616, 772 cm–1.
13C NMR (CDCl3, 50 MHz): d = 162.99, 149.09, 121.50, 115.76,
1H NMR (300 MHz, CDCl3): d = 9.90 (s, 1 H), 7.84 (d, 2 H), 7.01
(d, 2 H), 4.42–4.47 (AB q, J = 11.3 Hz, 2 H), 3.92 (s, 3 H), 4.12 (m,
1 H), 2.76–2.66 (dd, J = 8.3, 1.5 Hz, 1 H), 2.62–2.58 (dd, J = 5.2,
1.5 Hz, 1 H), 2.30–2.21 (t, J = 6.0 Hz, 2 H), 1.63–1.30 (m, 6 H),
0.99–0.91 (t, J = 6.8 Hz, 3 H).
67.59, 30.93, 30.66, 29.67, 27.90, 22.10, 18.56, 13.90.
MS (EI, 70 eV): m/z = 192 [M + H]+..
(Z,R)-6-[Hept-1-enyl]-5,6-dihydro-2H-pyran-2-one [(R)-Argen-
tilactone; 1]
MS (EI, 70 eV): m/z = 288 [M + H]+.
To a soln of lactone 11 (0.3 g, 1.5 mmol) in EtOAc, quinoline and
the Lindlar catalyst (5% Pd/CaCO3) were added, and the mixture
was stirred at r.t. under a H2 atmosphere for 6 h. After completion
of the reaction, the mixture was filtered, and the solvent was re-
moved under reduced pressure. The crude product was purified by
column chromatography (silica gel); this gave 1 as a colorless liq-
uid.
Yield: 0.18 g (60%); [a]D25 –19.5 (c 0.5, CHCl3).
IR (neat): 2361, 1721, 1381, 1243, 1022, 816, 772 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.88–6.80 (ddd, J = 3.0, 5.4, 9.8
Hz, 1 H), 6.05–5.99 (ddd, J = 1.3, 2.4, 9.8 Hz, 1 H), 5.69–5.48 (m,
2 H), 5.23–5.13 (ddd, J = 4.7, 8.0, 10.3 Hz, 1 H), 2.43–2.31 (m, 2
H), 2.02–2.01 (m, 2 H), 1.47–1.20 (m, 6 H), 0.90 (t, J = 6.6 Hz, 3 H).
Methyl (Z,R)-5-[(4-Methoxybenzyl)oxy]dodec-2-en-6-ynoate
(3)
To a stirred suspension of NaH (0.82 g, 3.4 mmol) in dry THF (20
mL) at 0 °C under N2 was added bis(2,2,2-trifluoroethyl) (methox-
ycarbonylmethyl)phosphonate (0.594 g, 1.8 mmol) in dry THF (10
mL). After the mixture had stirred for 30 min at 0 °C, it was cooled
to –78 °C, and then a soln of aldehyde 9 (0.5 g, 1.7 mmol) in dry
THF (20 mL) was added dropwise. After stirring for 1 h, the mixture
was diluted with Et2O (5 mL) and the reaction was quenched by the
slow addition of H2O (4 mL). The layers were separated, and the
aqueous phase was extracted with Et2O (2 × 10 mL). The organic
extract was washed with brine soln, dried (anhyd Na2SO4), and con-
centrated in vacuo. The crude product was purified by column chro-
matography (silica gel); this gave a,b-unsaturated ester 3 as a
viscous liquid.
13C NMR (CDCl3, 50 MHz): d = 164.23, 144.85, 135.63, 126.44,
121.67, 73.78, 31.39, 29.94, 29.07, 27.76, 22.49, 13.97.
Yield: 0.419 g (85%).
MS (EI, 70 eV): m/z = 194 [M + H]+.
IR (neat): 3418, 2932, 1722, 1605, 1513, 1440, 1172, 1083, 1034,
823, 772 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25–7.20 (d, J = 8.2 Hz, 2 H),
6.84–6.79 (d, J = 8.7 Hz, 2 H), 6.38 (dt, J = 6.8, 11.5 Hz, 1 H), 5.83
(dt, J = 1.8, 11.5 Hz, 1 H), 4.69–4.37 (AB q, J = 11.3 Hz, 2 H), 4.1
(R)-1-(Tetrahydro-2H-pyran-2-yloxy)tetradec-4-yn-3-ol (12)
To freshly distilled NH3 (50 mL) in a 100-mL two-neck round-bot-
tomed flask fitted with a cold-finger condenser was added a catalyt-
ic amount of Fe(NO3)3. The piecewise addition of Li metal (0.380
Synthesis 2006, No. 17, 2879–2884 © Thieme Stuttgart · New York

PAPER
Syntheses of (R)-(–)-Argentilactone and (S)-5-Hexadecanolide
2883
g, 54.5 mmol) followed at –78 °C, and the resulting grey suspension
was stirred for 30 min. Epoxide 5 (2 g, 9.09 mmol) in dry THF (10
mL) was added to this over 15 min, and the mixture was then stirred
for 2 h at the same temperature. Then 1-bromononane (3.76 g, 18.2
mmol) was added dropwise. The mixture was stirred at the same
temperature for 6 h, and the reaction was quenched by the addition
of solid NH4Cl; then the NH3 was allowed to evaporate. The reac-
tion mixture was extracted with H2O and EtOAc. The combined or-
ganic layers were washed with H2O (1 × 30 mL) and brine (1 × 30
mL), and dried (anhyd Na2SO4). The solvent was removed under re-
duced pressure. The residue was purified by column chromatogra-
phy (silica gel, PE–EtOAc, 6:4); this gave pure 12 as a clear,
colorless liquid.
was added slowly. After 45 min, Et3N (2.6 mL, 18.9 mmol) was
added and the mixture was allowed to warm to 0 °C, and stirred for
15 min at 0 °C. (Ethoxycarbonylmethylene)triphenylphosphorane
(2.2 g, 6.3 mmol), dissolved in dry CH2Cl2 (10 mL), was added
slowly and the mixture was stirred for 6 h at r.t. and then the reaction
was quenched with H2O. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (2 × 75 mL). The com-
bined organic layers were washed with H2O and brine and dried (an-
hyd Na2SO4). The solvent was removed in vacuo and the residue
was purified by column chromatography (silica gel); this gave a,b-
unsaturated ester 4 as a viscous liquid.
Yield: 0.86 g (70%); [a]D25 +50.60 (c 1, CHCl3).
IR (neat): 3030, 2927, 2855, 2230, 1721, 1657, 1171, 738, 698 cm–1.
Yield: 1.8 g (70%).
1H NMR (300 MHz, CDCl3): d = 7.33–7.26 (m, 5 H, Ar), 6.94 (dt,
J = 6.8, 15.8 Hz, 1 H), 5.85 (d, J = 15.8 Hz, 1 H), 4.75 (d, J = 12.1
Hz, 1 H), 4.46 (d, J = 12.1 Hz, 1 H), 4.17 (q, J = 6.7 Hz, 2 H), 4.12–
4.09 (m, 1 H), 2.62–2.56 (m, 2 H), 2.24 (td, J = 1.5, 6.8 Hz, 2 H),
1.58–48 (m, 2 H), 1.43–1.27 (m, 15 H), 0.89 (t, J = 6.7 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 166.29, 143.98, 137.87, 130.19,
128.36, 128.04, 127.98, 127.69, 123.79, 87.89, 70.29, 67.38, 60.17,
38.90, 31.89, 29.50, 29.30, 29.15, 28.89, 28.72, 28.66, 22.67, 18.71,
14.29, 14.08.
1H NMR (300 MHz, CDCl3): d = 4.75 (d, J = 12.0 Hz, 1 H), 4.56 (t,
J = 3.7 Hz, 1 H), 4.22 (m, 1 H), 3.81 (m, 2 H), 3.47 (m, 2 H), 2.23
(td, J = 2.2, 6.7 Hz, 2 H), 158–1.48 (m, 2 H), 1.43–1.27 (m, 19 H),
0.88 (t, J = 6.7 Hz, 3 H).
MS (EI, 70 eV): m/z = 333 [M+ + Na].
2-[(R)-3-(Benzyloxy)tetradec-4-ynyloxy]tetrahydro-2H-pyran
(13)
Alcohol 12 (2 g, 6.0 mmol) in dry THF (10 mL) was added drop-
wise to a stirred suspension of freshly activated NaH (0.31 g, 12.9
mmol) in dry THF (50 mL) at 0 °C, under a N2 atmosphere. After
the mixture had stirred for 30 min at 0 °C, BnBr (1.21 g, 7.0 mmol)
was added dropwise. The mixture was stirred for 6 h at 0 °C, and
quenched with sat. KBr soln. The layers were separated and the
aqueous layer was extracted with EtOAc (2 × 100 mL). The com-
bined organic layers were washed with H2O and brine soln and then
dried (anhyd Na2SO4). The solvent was removed in vacuo and the
residue was purified by column chromatography (silica gel); this
gave 13 as a viscous liquid.
MS (EI, 70 eV): m/z = 384 [M+].
(S)-6-Undecyl-5,6-dihydro-2H-pyran-2-one [(S)-5-Hexadecan-
olide; 2]
A cat. amount of Pd/C (10%) was added to a soln of ester 4 (0.5 g,
1.3 mmol) in dry EtOH (5 mL), and the mixture was stirred at r.t.
under a H2 atmosphere for 6 h. Then the mixture was filtered,
washed with EtOAc, and the filtrate was concentrated under re-
duced pressure and purified by column chromatography (silica gel,
PE–EtOAc, 6:4); this gave 2 as a colorless liquid.
Yield: 0.23 g (70%); [a]D25 –27.10 (c 1, CHCl3).
IR (neat): 2921, 2852, 1727, 1465, 1251, 1044 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.27–4.19 (m, 1 H) 2.60–2.35 (m,
2 H), 1.95–1.26 (m, 24 H), 0.89 (t, J = 6.1 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 171.97, 80.59, 35.85, 31.89, 29.62,
29.59, 29.54, 29.48, 29.46, 29.41, 29.30, 27.79, 24.91, 22.67, 18.48,
14.08.
Yield: 2.52 g (98%).
1H NMR (300 MHz, CDCl3): d = 7.31–7.25 (m, 5 H, Ar), 4.75 (d,
J = 12.1 Hz, 1 H), 4.75 (d, J = 12.1 Hz, 1 H), 4.45 (d, J = 12.1 Hz,
1 H), 4.56 (t, J = 3.7 Hz, 1 H,), 4.22 (m, 1 H), 3.81 (m, 2 H), 3.47
(m, 2 H), 2.23 (td, J = 2.2, 6.7 Hz, 2 H) 1.58–1.48 (m, 2 H), 1.43–
1.27 (m, 19 H), 0.88 (t, J = 6.7 Hz, 3 H).
MS (EI, 70 eV): m/z = 423 [M+ + Na].
MS (EI, 70 eV): m/z = 255 [M+ + 1].
(R)-3-(Benzyloxy)tetradec-4-yn-1-ol (14)
A cat. amount of PPTS was added to a stirred soln of 13 (2 g, 5.0
mmol) in MeOH (10 mL) under a N2 atmosphere. After stirring for
12 h at r.t., the mixture was quenched with solid NaHCO3, which
was removed by filtration. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(silica gel, PE–EtOAc, 6:4); this gave 14 as a yellow liquid.
Acknowledgement
N.F. thanks the IICT (IICT Communication No: 060301) and R.S.
thanks the CSIR for financial support.
Yield: 1.5 g (96%); [a]25D +74.52 (c 1, CHCl3).
References
1H NMR (300 MHz, CDCl3): d = 7.31–7.25 (m, 5 H, Ar), 4.79 (d,
J = 1.3 Hz, 1 H), 4.45 (d, J = 11.3 Hz, 1 H), 4.27 (m, 1 H), 3.69–
3.67 (m, 2 H), 2.22 (td, J = 2.2, 6.7 Hz, 2 H), 2.13 (m, 1 H), 1.98 (q,
J = 6.1 Hz, 2 H), 1.61–1.22 (m, 14 H), 0.88 (t, J = 6.7 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 137.70, 128.48, 128.42, 128.02,
127.78, 126.93, 87.61, 78.11, 70.49, 68.07, 60.24, 38.18, 31.87,
29.50, 29.26, 29.08, 28.86, 28.65, 22.64, 18.67, 14.08.
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Synthesis 2006, No. 17, 2879–2884 © Thieme Stuttgart · New York