A facile synthesis of both enantiomers of 6-acetoxy-5-hexadecanolide, a major component of mosquito oviposition attractant pheromones

Article abstract of DOI:10.1002/ejoc.200801134

The stereoselective synthesis of (-)-(5R,6S)-erythro-6-acetoxy-5- hexadecanolide, the major component of a mosquito oviposition attractant, pheromone, and its enantiomer are reported. The synthesis was completed over seven steps in 28% overall yield by us

Full text of DOI:10.1002/ejoc.200801134

FULL PAPER
DOI: 10.1002/ejoc.200801134
A Facile Synthesis of Both Enantiomers of 6-Acetoxy-5-hexadecanolide, a
Major Component of Mosquito Oviposition Attractant Pheromones
Surendra Singh[a] and Patrick J. Guiry*[a]
Keywords: Pheromones / Lactones / Natural products / Total synthesis
The stereoselective synthesis of (–)-(5R,6S)-erythro-6-acet-
oxy-5-hexadecanolide, the major component of a mosquito
oviposition attractant pheromone, and its enantiomer are re-
ported. The synthesis was completed over seven steps in
28% overall yield by using Sharpless asymmetric epoxid-
ation and ZrCl4-catalyzed cyclic acetal formation as the key
steps.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
key-structural unit in the mosquito attractant pheromone
1, Scheme 1.[35] The exploitation of this chemistry suggested
an alternative asymmetric retrosynthetic route of 1 to us,
Scheme 2, and now we wish to report the results of our
investigations.
Introduction
The mosquito oviposition attractant pheromones were
isolated by Laurence and Pickett from apical droplets
formed on the egg of the mosquito Culex pipens fatigans
(= quinquefasciatus).[1] The absolute configuration of the
natural pheromone was identified as (–)-(5R,6S)-6-acetoxy-
5-hexadecanolide (1), which acts as an oviposition attract-
ant pheromone by attracting other gravid females of the
same and some related species and induces them to oviposit
in the same spot where the original eggs are found.[2] This
behaviour can be used to tempt the mosquito away from
populated areas to a place where they can be readily
trapped.
Scheme 1. ZrCl4-catalyzed one-pot esterification and diacetate de-
protection.
The first synthesis of the two enantiomers of the erythro
isomer of 1 was reported by Fuganti in 1982.[3] Since then
numerous enantioselective syntheses of erythro-6-acetoxy-5-
hexadecanolide have been reported[4–33] but the develop-
ment of a short synthetic route with good overall yield was
lacking and therefore of interest. As part of our work on
the development of compounds with potential for the reso-
lution of inflammation, we recently reported the synthesis
and biological evaluation of Lipoxin A4 analogues.[34] We
have also improved the synthetic methodology for the prep-
aration of 2, a key intermediate of Lipoxin A4, and we have
found the δ-lactone 3 as a by-product which contains the
Scheme 2. Retrosynthetic route for (–)-(5R,6S)-6-acetoxy-5-hexa-
decanolide (1).
Thus, (Ϯ)-tridec-1-en-3-ol (4) was synthesized in 78%
yield by the reaction of undecanal with vinylmagnesium
bromide, Scheme 3. The (+)-(S)-1-[(R)-oxiran-2-yl]un-
decan-1-ol (5) was synthesized in 40% yield and in 97%
ee using Ti(OiPr)4, -(+)-diisopropyl tartrate and cumene
hydroperoxide as the oxidant. Unreacted (R)-tridec-1-en-3-
[a] Centre for Synthesis and Chemical Biology, School of Chemis-
try and Chemical Biology, University College Dublin,
Belfield, Dublin 4, Ireland
Fax: +353-1-716 2501
E-mail: patrick.guiry@ucd.ie
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Eur. J. Org. Chem. 2009, 1896–1901

Synthesis of Both Enantiomers of 6-Acetoxy-5-hexadecanolide
Scheme 3. Enantioselective synthesis of epoxides (+)- and (–)-5.
ol was recovered in 50% yield, which when subjected to cyclisation under microwave irradiation at 80 °C. Com-
the same epoxidation protocol, albeit with (–)-diisopropyl pound 7a, thus formed in 85% yield with an epimeric ratio
tartrate, was converted into (–)-(R)-1-[(S)-oxiran-2-yl]un- of 7:3, was protected as the acetate 8a in the presence of
decan-1-ol (5) in 76% isolated yield and 90.4% ee.
acetic anhydride and a catalytic amount of DMAP (20 mol-
The epoxide (+)-5 was treated with the Grignard reagent %) in dichloromethane and triethylamine. We have investi-
derived from 2-(2-bromoethyl)-1,3-dioxane at –35 °C in gated various methods, e.g. (BBr3 in dichloromethane, 3 
THF using 20 mol-% of CuI, Scheme 4.[34,35] The 4R,5S HCl, BF3–diethyl ether, Me3SiCl and NaI, trytilium hexa-
diol 6 was converted into the methoxy-substituted tetra- fluoride phosphate) for the deprotection of the methoxy
hydropyrane 7a using ZrCl4 (10 mol-%) as the Lewis acid group but we obtained very poor yields of lactol 9 (up to
for the deprotection of the 1,3-dioxane and its subsequent 35%).
Scheme 4. Synthesis of (5R,6S)-(–)-erythro-6-acetoxy-5-hexadecanolide (1).
Eur. J. Org. Chem. 2009, 1896–1901
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1897

S. Singh, P. J. Guiry
FULL PAPER
chromatography separations were performed using Merck Kieselgel
60 (0.040–0.063 mm). HPLC analysis was performed with a
LC2010A machine equipped with a UV/Vis detector employing a
Chiracel OD column from Daicel Chemical Industries. The com-
pound 6 was synthesized according to literature report.[34,35] All
reagents were purchased from Sigma–Aldrich and used as received.
Solvents were dried immediately before use by using solvent drying
system pure solv 300-M-3.
Therefore, we prepared the benzyl ether 7b in 65% yield
from diol 6 using the same ZrCl4-catalyzed protocol under
microwave irradiation. The acetal 7b was then converted
into the acetate 8b in 97% yield and the benzyl ether depro-
tected using 10% Pd/C in THF/H2O (3:1) with an ad-
ditional trace amount of 1  HCl under 20 bar pressure of
H2 at room temp. to provide the corresponding lactol 9 in
90% isolated yield.[36] Lactol 9 was then oxidized using
PCC in dichloromethane at 50 °C to afford (5R,6S)-(–)-
erythro-6-acetoxy-5-hexadecanolide (1) in 95% yield. We
also investigated the one-pot acetal deprotection and oxi-
dation[37,38] of compound 8a in the presence of BF3–diethyl
ether and m-chloroperbenzoic acid which afforded (5R,6S)-
(–)-erythro-6-acetoxy-5-hexadecanolide (1) in 76% yield.
The spectroscopic and physical data of compound (5R,6S)-
1 were identical with the literature reports and the enantio-
meric excess (Ͼ99.9%) was determined by HPLC using a
chiralpak OD column. The opposite enantiomer was also
synthesised, starting with (R)-1-[(S)-oxiran-2-yl]undecan-1-
ol and employing the same synthetic strategy to afford
Microwave Irradiation Experiments: All microwave experiments
were performed using the CEM Discover Synthesizer possessing a
single-mode microwave cavity producing controlled irradiation at
2.45 GHz. Experiments were carried out in standard microwave
process Pyrex vials (capacity 10 mL) using the high-absorbance
level. Reaction time reflects irradiation times at the set reaction
temperature (fixed hold times).
Tridec-1-en-3-ol (4): Vinylmagnesium bromide was prepared by ad-
dition of vinyl bromide (3.88 mL, 50 mmol) to preactivated magne-
sium turnings (1.21 g, 50 mmol) in THF (50 mL) using a dry ice
condenser and stirring at room temp. for 45 min. The vinylmagne-
sium bromide solution was slowly transferred to pre-cooled unde-
cylaldehyde (9.3 mL, 45 mmol) in 20 mL of diethyl ether at –78 °C
and the resulting mixture stirred for an hour, warmed to room
(5S,6R)-(+)-erythro-6-acetoxy-5-hexadecanolide (1) in
a
95.5% ee as determined by HPLC. The optical rotation of temp., stirred for a further hour and then quenched with 2  HCl
(50 mL). The reaction mixture was extracted with diethyl ether
(50 mL). The organic phase was separated and the aqueous phase
was extracted with diethyl ether (3 ϫ 50 mL). After concentration
of the combined extracts, the resulting residue was purified by ku-
gelrohr distillation (140 °C/1 mbar) to afford the title compound as
both enantiomers is in concurrence with literature re-
ports.[3,5,10,11,33]
Conclusion
a colourless oil (7.00 g, 78%). IR (neat): ν = 3352, 2925, 2854,
˜
1
1466, 1067, 990, 920 cm–1. H NMR (400 MHz, CDCl3): δ = 5.85
In summary we have synthesised both enantiomers of
erythro-6-acetoxy-5-hexadecanolide (1) with Ͼ99% ee in a
28% overall yield of both enantiomer by using Sharpless
asymmetric epoxidation as one of the key steps. We have
also used our recently developed ZrCl4-catalyzed deprotec-
tion of 1,3-dioxane and ring closure to prepare a benzyloxy-
substituted tetrahydropyrane as the key intermediate for the
mosquito pheromone synthesis. We are currently investiga-
ting the application of this methodology in the total synthe-
sis of other natural products and the results of these studies
will be reported in due course.
(ddd, J = 17.1, 10.4, 6.2 Hz, 1 H), 5.20 (tt, J = 17.2, 1.4 Hz, 1 H),
5.08 (tt, J = 10.4, 1.4 Hz, 1 H), 4.11–4.04 (m, 1 H), 1.56–1.42 (m,
2 H), 1.30–1.20 (m, 16 H), 0.87 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 141.3, 114.5, 73.2, 37.0, 31.9, 29.6 (4 C),
29.3, 25.3, 22.7, 14.1 ppm. GCMS (ESI): calcd. for C13H26O
[M]+ 198.1984; found 198.1992.
(S)-1-[(R)-Oxiran-2-yl]undecan-1-ol (5): 4-Å molecular sieves (1.0 g)
and CH2Cl2 (30 mL) were placed in a two-necked 100-mL round-
bottomed flask, followed by addition of Ti(OiPr)4 (955 µL,
3.23 mmol) and (+)-diisopropyltartrate (883.4 µL, 4.2 mmol) at
–35 °C under nitrogen and the resulting mixture was stirred for
30 min. The tridec-1-en-3-ol (6.4 g, 32.3 mmol) was added and
stirred for 30 min, than cumene hydroperoxide (4.6 mL, 0.75 equiv.)
was added during 20 min at the same temperature and then it was
increased to –22 °C. The reaction progress was checked by TLC to
monitor the consumption of cumene hydroperoxide. The reaction
Experimental Section
General Remarks: 1H and 13C NMR spectra were recorded on
400 MHz (operating frequencies: 1H, 399.8 MHz; 13C, was completed in 30 h, then quenched with saturated sodium sul-
100.61 MHz, respectively) and 500 MHz (operating frequencies:
fate solution (3 mL). Diethyl ether (30 mL) was added and the re-
1H, 499.77 MHz; 13C, 125.67 MHz, respectively) FT spectrometers sulting mixture stirred for 3 h at room temp. The reaction mixture
at ambient temperature. Chemical shifts (δ) are given in parts per
million and coupling constants are given as absolute values ex-
pressed in Hertz. The reference values used for deuterated chloro-
form (CDCl3) were 7.26 and 77.00 ppm for 1H and 13C NMR spec-
tra, respectively. The reactions under microwave irradiations were
carried out using a CEM Discover microwave reactor. HRMS were
obtained using a Micromass/Waters LCT instrument. Infrared
spectra were recorded with a Perkin–Elmer Infrared FT spectrome-
ter. Optical rotation values were measured with a Perkin–Elmer 343
polarimeter. All optical rotations were obtained at room temp.
Thin-layer chromatography (TLC) was carried out on aluminum
sheets precoated with silica gel 60 F254 (Merck) and either visual-
ized in a UV light or vanillin/CH3COOH and H2SO4. Column
was filtered through a pad of Celite and concentrated under vac-
uum. The epoxide was purified by column chromatography using
pentane/EtOAc (9.5:0.5Ǟ8.5:1.5) to give 2.4 g of unreacted tridec-
1-en-3-ol and 2.8 g (40%) of epoxide 5 as a solid; m.p. 25–27 °C,
ref.[5] 25–26 °C. [α]2D0 = +16.1 [c = 1, in CHCl3], ref.[5] [α]2D0 = +16.2
(c = 1.01, in CHCl ). IR (neat): ν = 3433, 2926, 2855, 1256, 1436,
˜
3
1092, 906 cm–1. H NMR (400 MHz, CDCl3): δ = 3.85–3.80 (m,
1
1 H), 3.01 (tt, J = 3.9, 3.0 Hz, 1 H), 2.81 (dd, J = 5.0, 2.8 Hz, 1
H), 2.73 (dd, J = 5.0, 4.0 Hz, 1 H), 1.84 (d, J = 2.5 Hz, 1 H), 1.60–
1.28 (m, 18 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 68.4, 54.5, 43.4, 33.4, 31.9, 29.7, 29.6 (2C), 29.5, 29.3,
25.3, 22.7, 14.1 ppm. GCMS (ESI): calcd. for C13H26O2 [M]+
214.1933; found 214.1927.
1898
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1896–1901

Synthesis of Both Enantiomers of 6-Acetoxy-5-hexadecanolide
(R)-1-[(S)-Oxiran-2-yl]undecan-1-ol (5): The synthesis of (–)-5 was
carried out according to the procedure above and the recovered
allylic alcohol was used as substrate and isolated in a 76% yield;
m.p. 25–27 °C, ref.[5] 25–26 °C. [α]2D0 = –14.6 (c = 1.0, in CHCl3,
ref.[5] [α]2D0 = –16.6 (c = 1.12, in CHCl3).
HRMS (ESI): calcd. for C17H34NaO3 [M + Na]+ 309.2406, found
309.2402.
(R)-1-[(S)-6-Benzyloxy-tetrahydro-2H-pyran-2-yl]undecan-1-ol (7b):
ZrCl4 (44.6 mg, 10 mol-%) and diol 6 (662 mg, 2 mmol) were dis-
solved in benzyl alcohol (621 µL, 6 mmol) and irradiated under
MW (150 W) at 80 °C for 6 min. The title compound 7b was puri-
fied by flash column chromatography using pentane/EtOAc
(8.5:1.5) as eluent to afford 7b as a liquid (65%) with epimeric ratio
Determination of ee Values of Epoxide 5: The epoxides (+) and
(–)-5 were converted into the corresponding (S)-1-[(R)-oxiran-2-yl]-
undecyl 2-phenoxyacetates.[39] Epoxide (+)-5 (21.4 mg, 0.1 mmol),
triethylamine (28 µL, 0.2 mmol), and DMAP (25 mol-%) were dis-
solved in THF (1 mL), followed by addition of benzoyl chloride
(12 µL, 0.1 mmol) and 2-phenoxyacetic acid (15.2 mg, 0.1 mmol)
and the resulting reaction mixture was stirred for 24 h. 5% HCl
(1 mL) was added, the mixture was extracted with ethyl acetate
(2ϫ5 mL) and the organic layer was washed with water (1 mL)
and dried with MgSO4. The solvent was removed under reduced
pressure and the crude material was purified by column chromatog-
raphy using 9:1 (pentane/EtOAc). The enantiomeric excess of the
phenoxy acetate derivative was determined by HPLC using chi-
ralpak OD column; 1 mL/min flow rate, 90:10 hexane/isopropyl
(0.72:0.28). [α]2D0 = –42.9 (c = 1.0, in CHCl ). IR (neat): ν = 3465,
˜
3
2925, 2854, 1455, 1351, 1121, 1020 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 7.30–7.15 (m, 5 H), 4.87 (d, J = 2.3 Hz, 0.72 H), 4.79
(d, J = 12.1 Hz, 0.28 H), 4.62 (d, J = 12.1 Hz, 0.72 H), 4.53 (d, J
= 12.1 Hz, 0.28 H), 4.44 (d, J = 2.0 Hz, 0.28 H), 4.41 (d, J =
12.1 Hz, 0.72 H), 3.66–3.60 (m, 1 H), 3.53–3.47 (m, 0.72 H), 3.29–
3.24 (m, 0.28 H), 1.90–1.30 (m, 10 H), 1.29–1.10 (m, 14 H), 0.80
(t, J = 6.8 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 138.3,
128.3 (2 C), 127.7 (2 C), 127.5, 96.9, 73.6, 71.6, 68.6, 32.0, 31.9,
29.8, 29.7, 29.6 (2 C), 29.3, 26.0, 23.9, 22.7, 17.6, 14.1 ppm (major
diastereomer) and 138.0, 128.3 (2C), 127.9 (2C), 127.6, 101.4, 78.9,
73.4, 70.0, 32.3, 31.3, 29.7, 29.6 (3 C), 29.3, 25.9, 21.7, 17.6,
14.1 ppm (minor diastereomer). HRMS (ESI): calcd. for
C23H38NaO3 [M + Na]+ 385.2719, found 385.2715.
alcohol as mobile phase and 220 nm λmax
.
Spectroscopic Data for (S)-1-[(R)-Oxiran-2-yl]undecyl-2-phenoxy
Acetate: Isolated as a colourless oil in 95% yield with 97% ee and
rt 8.2 min (minor) and rt 11.1 min (major). [α]2D0 = –8.7 (c = 0.5, in
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.36–7.24 (m, 2 H), 7.00
(t, J = 7.4 Hz, 1 H), 6.92 (dd, J = 0.9, 8.7 Hz, 2 H), 4.87 (dd, J =
5.5, 12.6 Hz, 1 H), 4.65 (s, 2 H), 3.01–2.94 (m, 1 H), 2.72 (dd, J =
4.0, 5.1 Hz, 1 H), 2.68 (dd, J = 2.6, 5.1 Hz, 1 H), 1.70 (dd, J = 6.8,
14.4 Hz, 2 H), 1.26 (s, 16 H), 0.89 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 168.5, 157.8, 129.5, 121.8, 114.6,
73.9, 65.2, 52.0, 45.2, 31.9, 31.6, 31.3, 29.6 (2 C), 29.5, 29.4, 29.3
(2 C), 24.9, 22.7, 14.1 ppm. The ee of (R)-1-[(S)-oxiran-2-yl]unde-
cyl 2-phenoxyacetate was found to be 90.4% and rt 8.2 min (major)
and rt 11.1 min (minor). [α]2D0 = +7.9 (c = 1.4, in CHCl3).
(S)-1-[(R)-6-Benzyloxy-tetrahydro-2H-pyran-2-yl]undecan-1-ol (7b):
[α]2D0 = +34.1 (c = 1.0, in CHCl3)
General Procedure for Acetyl Protection of Alcohols: Alcohol 7a–b
(1 mmol) was dried under vacuum and dissolved in CH2Cl2 (3 mL)
and triethylamine (1 mL), DMAP (24.4 mg, 0.2 mmol), and acetic
anhydride (189 µL, 2 mmol) was added. The reaction mixture was
refluxed for 2 h. The solvent was removed under reduced pressure
and the crude mixture was purified by flash column chromatog-
raphy using pentane/EtOAc (9:1) as eluent.
(S)-1-Acetoxy-[(R)-6-methoxy-tetrahydro-2H-pyran-2-yl]undecane
(8a): Compound 8a was isolated in 98% yield as a colourless liquid.
(4S,5R)-1-(1,3-Dioxan-2-yl)hexadecane-4,5-diol (6): Isolated as yel-
low solid in 85% yield; m.p. 85 °C. [α]2D0 = –3.2 (c = 1.0, in CHCl3).
[α]2D0 = –52.3 (c = 2.5, in CHCl ). IR (neat): ν = 2927, 2855, 1731,
˜
3
1461, 1247, 1033 cm–1. 1H NMR (500 MHz, CDCl3): δ = 4.91 (ddd,
J = 9.7, 6.4, 3.6 Hz, 0.3 H), 4.87–4.81 (m, 0.7 H), 4.72 (br. s, 0.7
H), 4.28 (dd, J = 9.5, 2.0 Hz, 0.3 H), 3.74 (ddd, J = 11.6, 5.2,
2.0 Hz, 0.7 H), 3.47 (s, 0.9 H), 3.43–3.36 (m, 0.3 H), 3.34 (s, 2.1
H), 2.06 (s, 2.1 H), 2.04 (s, 0.9 H), 1.85–1.50 (m, 7 H), 1.49–1.20
(m, 17 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 170.6, 98.5, 75.8, 69.5, 54.4, 31.9, 29.9, 29.6 (3 C),
29.5 (2 C), 29.3, 26.5, 25.5, 22.7, 21.1, 17.7, 14.1 ppm (major dia-
stereomer) and 170.5, 103.5, 76.7, 75.6, 55.8, 30.9, 30.4, 29.9, 29.6
(3 C), 29.5 (2 C), 29.3, 26.6, 25.1, 21.7, 17.7, 14.1 ppm (minor dia-
stereomer). HRMS (ESI): calcd. for C19H36NaO4 [M + Na]+
351.2511, found 351.2527.
IR (neat): ν = 3306, 2915, 2848, 1408, 1355, 1297, 1149, 1072 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 4.53 (t, J = 4.7 Hz, 1 H), 4.11–
4.03 (m, 2 H), 3.92–3.84 (m, 1 H), 3.78–3.73 (m, 3 H), 2.12–2.02
(m, 2 H), 1.84–1.26 (m, 24 H), 0.88 (t, J = 7.0 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 102.2, 74.6, 74.3, 66.8 (2 C), 34.9,
31.9, 31.3, 30.1, 29.7, 29.6 (3 C), 29.3, 26.0, 25.8, 22.6, 20.3, 14.1
ppm. HRMS (ESI): calcd. for C19H39O4 [M + H]+ 331.2848; found
331.2848.
(4R,5S)-1-(1,3-Dioxan-2-yl)hexadecane-4,5-diol (6): [α]2D0 = +3.8 (c
= 1.0, in CHCl3).
(R)-1-[(S)-6-Methoxy-tetrahydro-2H-pyran-2-yl]undecan-1-ol (7a):
ZrCl4 (6.8 mg, 5 mol-%) and diol 6 (200 mg, 0.606 mmol) were dis-
solved in methanol (400 µL) and irradiated under MW (150 W) at
60 °C for 6 min. The title compound was purified by flash column
chromatography using pentane/EtOAc (8.5:1.5) as eluent to afford
it as a liquid (85%) with epimeric ratio (7:3). [α]2D0 = –52.5 (c = 1.0,
(S)-1-Acetoxy-[(R)-6-benzyloxy-tetrahydro-2H-pyran-2-yl]undecane
(8b): Compound 8b was isolated in 97% yield as a colourless liquid.
[α]2D0 = –38.1 (c = 1.0, in CHCl ). IR (neat): ν = 2925, 2855, 1743,
˜
3
1458, 1239, 1024 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.37–7.26
(m, 5 H), 4.97–4.93 (m, 1 H), 4.90–4.84 (m, 1 H), 4.72 (d, J =
11.9 Hz, 0.75 H), 4.61 (d, J = 12.0 Hz, 0.25 H), 4.47 (d, J =
11.0 Hz, 0.75 H), 4.43 (dd, J = 11.0, 2.1 Hz, 0.25 H), 3.85 (ddd, J
= 11.6, 5.2, 1.8 Hz, 0.75 H), 3.39 (ddd, J = 11.2, 6.2, 1.9 Hz, 0.25
H), 2.08 (s, 0.75 H), 2.06 (s, 2.25 H), 1.90–1.60 (m, 6 H), 1.50–1.20
(m, 18 H), 0.89 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (126 MHz,
in CHCl ). IR (neat): ν = 3465, 2925, 2854, 1440, 1355, 1121,
˜
3
1020 cm–1. 1H NMR (500 MHz, CDCl3): δ = 4.74 (br. s, 0.7 H),
4.34 (dd, J = 9.5, 2.1 Hz, 0.3 H), 3.69 (br. s, 0.3 H), 3.68–3.62 (m,
0.7 H), 3.60 (br. s, 0.7 H), 3.48 (s, 0.9 H), 3.38–3.36 (m, 0.3 H),
3.35 (s, 2.1 H), 2.04 (br. s, 0.3 H), 1.95 (br. s, 0.7 H), 1.86–1.39 (m,
8 H), 1.38–1.18 (m, 16 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR CDCl3): δ = 170.6, 138.2, 128.3 (2 C), 127.7 (2 C), 127.5, 96.6, 75.8,
(125 MHz, CDCl3): δ = 98.8, 73.6, 71.3, 54.5, 32.0, 31.9, 29.7 (2
C), 29.6 (3 C), 29.3, 26.0, 23.9, 22.7, 17.5, 14.1 ppm (major dia-
stereomer) and 103.5, 78.8, 73.4, 55.9, 32.3, 31.9, 31.1, 29.7 (2 C),
29.6 (3 C), 25.9, 22.7, 21.7, 17.5, 14.1 ppm (minor diastereomer).
69.9, 68.4, 31.9, 30.0, 29.6 (3 C), 29.5 (2 C), 29.3, 26.5, 25.5, 22.7,
21.1, 17.8, 14.1 ppm (major diastereomer); 170.5, 137.9, 128.3 (2
C), 128.0 (2 C), 127.6, 101.1, 76.8, 75.6, 69.7, 31.0, 30.4, 29.6 (3
C), 29.5 (2 C), 29.3, 26.6, 25.2, 21.8, 21.1, 17.8, 14.1 ppm (minor
Eur. J. Org. Chem. 2009, 1896–1901
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1899

S. Singh, P. J. Guiry
FULL PAPER
diastereomer). HRMS (ESI): calcd. for C25H40NaO4 [M + Na]+
427.2824, found 427.2823.
Acknowledgments
(R)-1-Acetoxy-[(S)-6-benzyloxy-tetrahydro-2H-pyran-2-yl]undecane
(8b): [α]2D0 = +44.2 (c = 1.0, in CHCl3).
We express our gratitude to the Irish Research Council for Science,
Engineering and Technology (IRCSET) for a post-doctoral fellow-
ship, granted to S. Singh. We also acknowledge the facilities pro-
vided by the Centre for Synthesis and Chemical Biology (CSCB),
funded by the Higher Education Authority’s Programme for Re-
search in Third-Level Institutions (PRTLI). We are grateful to Dr.
Jimmy Muldoon and Dr. Dilip Rai of the CSCB for NMR and
mass spectra, respectively.
(S)-1-Acetoxy-[(R)-6-hydroxy-tetrahydro-2H-pyran-2-yl]undecane
(9): Compound 8b (202.1 mg, 0.5 mmol) was dissolved in THF/
H2O (4 mL, 3:1) and 10% Pd/C (20 mg) was added under a blanket
of nitrogen. The reaction mixture was pressurized with 20 bar H2
in an autoclave. The reaction was monitored by TLC using pen-
tane/EtOAc (8:2) as eluent and after 24 h the reaction mixture was
filtered through a pad of Celite and washed with EtOAc (100 mL).
The solvent was removed under vacuum and the crude material
was purified by flash column chromatography using pentane/
EtOAc (8.5:1.5) as eluent to give compound 9 in 90% yield as a
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colourless liquid. [α]2D0 = –40.1 (c = 1.5, in CHCl ). IR (neat): ν =
˜
3
2926, 2856, 1728, 1372, 1248, 1028 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 5.32 (br. s, 0.5 H), 4.95–4.84 (m, 1 H), 4.70 (ddd, J =
9.1, 6.1, 2.0 Hz, 0.5 H), 4.00 (ddd, J = 11.7, 4.4, 2.1 Hz, 0.5 H),
3.49 (ddd, J = 7.1, 5.0, 1.7 Hz, 0.5 H), 2.77 (d, J = 6.1 Hz, 0.5 H),
2.38–2.30 (m, 0.5 H), 2.07 (2s, 3 H), 1.91–1.83 (m, 1 H), 1.72–1.58
(m, 5 H), 1.41–1.25 (m, 18 H), 0.88 (t, J = 6.9 Hz, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 170.8, 170.7, 96.7, 92.0, 77.3, 75.7,
75.5, 69.9, 32.7, 31.9, 29.9, 29.6 (3 C), 29.5 (2 C), 29.3, 26.2, 26.0,
25.5 (2 C), 22.7, 21.7, 21.2, 17.1, 14.1 ppm. HRMS (ESI): calcd.
for C18H34NaO4 [M + Na]+ 337.2355, found 337.2351.
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[α]2D0 = +43.9 (c = 1.5, in CHCl3).
27, 4011–4014.
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(–)-(5R,6S)-6-Acetoxyhexadecanolide 1: Compound
9 (100 mg,
0.32 mmol) was oxidized using PCC (207 mg, 3 equiv.), Celite
(30 mg) and sodium acetate (79 mg, 3 equiv.) in 5 mL of CH2Cl2 at
50 °C for 2 h. The reaction progress was monitored by TLC using
pentane/EtOAc (7:3) as an eluent. The reaction mixture was passed
through a pad of Celite and concentrated under reduced pressure.
The reaction mixture was purified by flash column chromatography
using pentane/EtOAc (8:2) as an eluent to afford compound 1 as
an oil in 95% yield. The enantiomeric excess was determined using
chiralpak OD column, flow rate 1 mL/min and 96:4 hexane/isopro-
pyl alcohol as mobile phase at 220 nm λmax. The retention time is
13.23 min (5S,6R) and 14.78 min (5R,6S). [α]2D0 = –35.4 (c = 0.85,
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in CHCl , ee, Ͼ99.9%). IR (neat): ν = 2925, 2854, 1744, 1371,
˜
3
1230, 1052 cm–1. 1H NMR (500 MHz, CDCl3): δ = 4.98 (dt, J =
5.0, 7.8 Hz, 1 H), 4.35 (ddd, J = 3.3, 4.6, 11.0 Hz, 2 H), 2.66–2.55
(m, 1 H), 2.50–2.40 (m, 1 H), 2.08 (s, 3 H), 2.02–1.76 (m, 2 H),
1.74–1.52 (m, 4 H), 1.40–1.16 (m, 16 H), 0.88 (t, J = 7.0 Hz, 1 H)
ppm. 13C NMR (126 MHz, CDCl3): δ = 170.8, 170.5, 80.5, 74.3,
31.9, 29.6 (2 C), 29.5 2 C, (), 29.4 (2 C), 29.3, 25.3, 23.5, 22.6, 21.0,
18.2, 14.1 ppm. HRMS (ESI): calcd. for C18H31NaO4 [M – H]–
311.2222, found 311.2230.
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Other Method: To a solution of acetal 8a (35.1 mg, 0.1 mmol) in
CH2Cl2 (5 mL) at 0 °C were added m-chloroperbenzoic acid
(25.8 mg, 0.15 mmol) and BF3·OEt2 (16.5 µL, 0.13 mmol) sequen-
tially. After stirred at room temperature for 30 min, the mixture
was cooled to 0 °C and Et3N (69.6 µL, 0.5 mmol) was added drop-
wise. The mixture was stirred at 0 °C for 30 min, then concentrated,
and the resulting residue was purified by column chromatography
using pentane/EtOAC (8:2) to give the (5R,6S)-6-acetoxyhexade-
canolide 1 (27 mg, 76%) as a liquid.
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(+)-(5R,6S)-6-Acetoxyhexadecanolide 1: [α]2D0 = +38.5 (c = 1.0, in
CHCl3, ee, 95.5%).
Supporting Information (see also the footnote on the first page of
1
this article): Relevant H, 13C NMR spectra and HPLC traces are
included.
1900
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1896–1901

Synthesis of Both Enantiomers of 6-Acetoxy-5-hexadecanolide
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Received: November 14, 2008
Published Online: March 5, 2009
Eur. J. Org. Chem. 2009, 1896–1901
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1901