Synthesis of (-)-(5R,6S)-6-acetoxyhexadecanolide, a mosquito oviposition attractant pheromone of Culex pipiens fatigans

Article abstract of DOI:10.1055/s-2006-950341

Asymmetric total synthesis of (-)-(5R,6S)-6-acetoxyhexadecanolide has been achieved via a key intermediate which was prepared by a Grignard reaction from an alcohol. The alcohol was easily accessed via two different routes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950341

4242
PAPER
Synthesis of (–)-(5R,6S)-6-Acetoxyhexadecanolide, a Mosquito Oviposition
Attractant Pheromone of Culex pipiens fatigans1
S
ynthesisof (–)-(5
o
R
,6
S
)-6-Ace
w
toxyhexadecanolid
r
e
avaram Sabitha,* R. Swapna, E. Venkata Reddy, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: sabitha@iictnet.org
Received 31 July 2006; revised 17 August 2006
Grignard reaction. This intermediate was synthesized by
two different routes from THP protected hex-5-en-1-ol 4
and epoxy chloride 5.
Abstract: Asymmetric total synthesis of (–)-(5R,6S)-6-acetoxy-
hexadecanolide has been achieved via a key intermediate which was
prepared by a Grignard reaction from an alcohol. The alcohol was
easily accessed via two different routes.
In route a, the THP ether 4 was epoxidized using dry
Key words: lactone, total synthesis, natural product, (–)-(5R,6S)-6- MCPBA and sodium bicarbonate in anhydrous dichlo-
acetoxyhexadecanolide, pheromone
romethane, followed by quenching with saturated sodium
sulfite to afford epoxide 6 in 96% yield. The epoxide 6
was subjected to hydrolytic kinetic resolution (HKR)7 us-
ing 0.005 equivalent of chiral Jacobsen’s (S,S)-salen
Co(III) acetate catalyst [(S,S)-N,N¢-bis(3,5-di-tert-butyl-
salicylidene)-1,2-cyclohexanediamino-Co(III) acetate,
freshly prepared from (S,S)-N,N¢-bis(3,5-di-tert-butylsali-
cylidene)-1,2-cyclohexanediamino-Co(III) chloride and
acetic acid] to afford enantio-enriched (>96% ee) epoxide
7 and the terminal diol 8 in 47% yield. The primary hy-
droxyl group of the diol 8 was protected as its p-meth-
oxybenzyl ether using 1 equivalent of PMBBr and 1.5
equivalents of NaH in anhydrous THF at 0 °C to afford the
compound 3 in 80% yield (Scheme 2).
In route b, the known epoxy chloride 57 was chosen as the
starting material. The conversion of epoxy chloride 5 to
the substituted chiral acetylenic alcohol 98 in 70% yield
was accomplished by treating compound 5 with 6 equiva-
lents of Li metal in liquid ammonia at –78 °C followed by
2 equivalents of THP protected bromoethanol. In the next
step, the reduction of the triple bond in compound 9 over
10% Pd/C and Na2CO3 in EtOAc furnished the corre-
sponding saturated compound 3 in 90% yield (Scheme 3).
Functionalized d-lactones have attracted substantial atten-
tion in recent years due to their synthetic importance as
building blocks in natural products synthesis2 and as well
as their frequent presence in structural moieties of insect
pheromones. One such example is (–)-(5R,6S)-6-acetoxy-
hexadecanolide (1), isolated by Laurence and Pickett in
1982 from the apical droplet of mosquito (Culex pipiens
fatigans) eggs.3 The substance attracts other gravid fe-
males of the same and some related mosquito species in-
ducing them to oviposit in the same spot where the
original eggs are found. These behaviors can be used to
lure the mosquito away from populated areas to a place
where they can be readily trapped. It has the ability to
transmit the West Nile Virus.4 In the last few years many
syntheses of 1 have appeared in the literature.5 Owing to
their physiological activities, much effort has been ex-
panded on the synthesis of 6-substituted d-lactones. In
continuation of our efforts on d-lactones,6 we herein re-
port the synthesis of (–)-(5R,6S)-6-acetoxyhexadecano-
lide.
The retrosynthetic strategy for (–)-(5R,6S)-6-acetoxy-
hexadecanolide (1) is outlined in Scheme 1. The key inter-
mediate 2 was prepared from the compound 3 by a
Thus, the intermediate 3 was prepared by two different
routes as shown in Schemes 2 and 3. This was further uti-
lized for the synthesis of the target molecule 1. Accord-
O
OH
OMOM
route b
O
PMBO
O
PMBO
C
10H21
Cl
OTHP
C10H21
THPO
OH
5
1
2
3
4
OAc
route a
OTHP
Scheme 1 Retrosynthetic route for (–)-(5R,6S)-6-acetoxyhexadecanolide (1)
SYNTHESIS 2006, No. 24, pp 4242–4246
x
x.
x
x
.
2
0
0
6
Advanced online publication: 02.11.2006
DOI: 10.1055/s-2006-950341; Art ID: Z16006SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (–)-(5R,6S)-6-Acetoxyhexadecanolide
4243
O
MCPBA, NaHCO3,
OTHP
OTHP
CH2Cl2, r.t.
96%
6
4
OH
(S,S)-salen cobalt(III)
acetate (0.005 equiv),
O
HO
+
OTHP
OTHP
H2O (0.5 equiv),THF
47%
7
8
OH
PMBBr, NaH
PMBO
OTHP
anhyd THF
0 °C to r.t.
80%
3
Scheme 2
ingly, the secondary hydroxyl group of compound 3 was
protected as its methoxymethyl ether using 3 equivalents
of Hunig’s base (i-Pr2EtN) and 2 equivalents of MOMCl
in anhydrous CH2Cl2 at room temperature affording 10 in
96% yield.9 Deprotection of PMB group of compound 10
was done by treatment with 1.5 equivalents of DDQ in
CH2Cl2/H2O (9:1) to afford compound 11 in 83% yield.
Oxidation of compound 11 with IBX (o-iodoxybenzoic
acid) in DMSO–CH2Cl2 at 25 °C afforded aldehyde 12 in
80% yield (Scheme 4).
O
Li–liq NH3, Fe(NO3)3,
PMBO
Cl
Br
OTHP
5
anhyd THF, –78 °C
70%
OH
H2–Pd/C,
PMBO
EtOAc, Na2CO3
OTHP
9
90%
OH
PMBO
The aldehyde 12 was treated with the Grignard reagent
prepared from decylmagnesium bromide (freshly pre-
pared from 1-bromodecane and Mg in anhyd diethyl
ether) affording the key intermediate 2 as a major product
with anti-selectivity (80% ee) in 78% yield.10 The second-
ary hydroxyl group of compound 2 was protected by using
acetic anhydride and triethylamine in anhydrous CH2Cl2
to afford acetate 13. Deprotection of the THP group in 13
using PTSA in MeOH11 resulted in alcohol 14 in 90%
OTHP
3
Scheme 3
yield. The alcohol 14 was oxidized to aldehyde 15 using
IBX in 77% yield. The aldehyde 15 was further oxidized
with NaClO2 and NaH2PO4 in DMSO and water to afford
the corresponding acid 16 in 72% yield.12 Finally the syn-
MOMCl,
DIPEA,
OMOM
OH
OMOM
DDQ,
PMBO
PMBO
HO
OTHP
anhyd THF
0 °C to r.t.
96%
OTHP
OTHP CH2Cl2/H2O (9:1)
83%
11
10
3
OMOM
OMOM
Mg, C10H21Br,
Ac2O, Et3N,
IBX, DMSO,
H21C10
OTHP
anhyd THF
0 °C to r.t.
80%
OHC
OTHP
anhyd THF
0 °C to r.t.
77%
anhyd Et2O
0 °C to r.t.
78%
OH
12
2
OMOM
OMOM
OMOM
IBX, DMSO,
PPTS,
H21C10
H21C10
H21C10
CHO
OH
OTHP
MeOH, r.t.
90%
anhyd THF
0 °C to r.t.
77%
OAc
OAc
OAc
15
14
13
O
O
OMOM
PTSA,
anhyd benzene
NaClO2, NaH2PO4,
H21C10
H21C10
COOH
anhyd DMSO, r.t.
72%
reflux,
76%
OAc
OAc
16
1
Scheme 4
Synthesis 2006, No. 24, 4242–4246 © Thieme Stuttgart · New York

4244
G. Sabitha et al.
PAPER
temperature of the mixture began to rise. The temperature rose to
~25 °C before dropping to 15 °C, at which point H2O addition was
continued at a rate that maintained the reaction temperature near
20 °C. After 1 h, the addition was complete, the ice bath was re-
moved, and the reaction was stirred at r.t. for 24 h and then
quenched with aq sat. NaHCO3 solution. The filtrate was washed
with H2O, brine and dried (Na2SO4). The organic layer was concen-
trated to give the crude material, which after column chromatogra-
phy provided the pure product 8 (6.1 g, 47%, 96% ee) as a liquid;
[a]D25 –18.02 (c = 1.5, CHCl3).
thesis of target molecule 1 was achieved in 76% yield by
in situ deprotection of MOM group and subsequent cy-
clization by using catalytic amount of PTSA in anhydrous
benzene under reflux (Scheme 4).13 The synthetic materi-
al showed IR, 1H, 13C NMR spectral data and optical rota-
25
tion {[a]D –35.0 (c = 1.5, CHCl3)} in good agreement
with the natural lactone.
Reactions were conducted under N2 using anhyd solvents such as
CH2Cl2, THF, CCl4, benzene and EtOAc. All reactions were moni-
tored by TLC using silica-coated plates and visualizing under UV
light. Light petroleum of the distillation range 60–80 °C was used.
Yields refer to chromatographically and spectroscopically (1H, 13C)
homogeneous material. Air sensitive reagents were transferred by
syringe or cannula. Evaporation of solvents was performed at re-
IR (neat): 3403, 2940, 2867, 1121, 1073, 1028 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.54 (t, J = 3.7 Hz, 1 H), 3.90–
3.32 (m, 7 H), 1.90–1.40 (m, 12 H).
ESIMS: m/z = 241 (M+ + Na).
(2R)-1-(4-Methoxyphenoxy)-6-(tetrahydro-2H-2-pyranyl-
oxy)hexan-2-ol (3)
1
duced pressure, using a Büchi rotary evaporator. H NMR spectra
were recorded on Varian FT-200 MHz (Gemini) and Bruker
UXNMR FT-300 MHz (Avance) in CDCl3. Chemical shift values
were reported in parts per million (d) relative to tetramethylsilane
(d = 0.0) as an internal standard. Mass spectra were recorded under
electron impact at 70 eV on LC-MSD (Agilent technologies). Col-
umn chromatography was performed on silica gel (60–120 mesh)
supplied by Acme Chemical Co., India. TLC was performed on
Merck 60 F-254 silica gel plates. Optical rotations were measured
with JASCO DIP-370 polarimeter at 20 °C.
To a stirred suspension of freshly activated NaH (0.660 g, 27.0
mmol) in anhyd THF (30 mL) at 0 °C, was added dropwise alcohol
8 (4 g, 18.3 mmol) in anhyd THF (10 mL). After stirring for 30 min,
PMBBr (3.1 g, 18.3 mmol) in anhyd THF (10 mL) was added. After
completion of the reaction (3 h), the mixture was quenched with aq
sat. NH4Cl solution and extracted with EtOAc. The organic layer
was washed with H2O, brine, dried (Na2SO4) and concentrated in
vacuo. Purification of the residue by silica gel column chromatog-
raphy afforded 3 (5.4 g, 80%) as a viscous liquid.
1H NMR (CDCl3, 300 MHz): d = 7.20 (d, J = 9.0 Hz, 2 H), 6.83 (d,
J = 8.3Hz, 2 H), 4.54 (t, J = 3.0 Hz, 1 H), 4.45 (s, 2 H), 3.85–3.66
(m, 6 H), 3.51–3.20 (m, 4 H), 1.85–1.30 (m, 12 H).
2-(5-Hexenyloxy)tetrahydro-2H-pyran (4)
In a 100 mL round-bottomed flask fitted with a N2 adaptor, the hex-
5-en-1-ol (10 g, 100.0 mmol) in anhyd CH2Cl2 (80 mL) was taken
and a catalytic amount of PTSA was added. Then the mixture was
cooled to 0 °C. To this 3,4-dihydro-2H-pyran (6.5 mL, 110.0 mmol)
was added dropwise. After completion of addition, the mixture was
allowed to stir for 3 h. The mixture was diluted with CH2Cl2, and
the organic layer was washed with H2O, aq NaHCO3, and dried
(Na2SO4). Concentration under reduced pressure and purification
over silica gel column chromatography afforded pure tetrahydropy-
ranyl ether 4 (18.2 g, 95%) as a viscous liquid.
(2R)-1-(4-methoxyphenoxy)-6-(tetrahydro-2H-2-pyranyl-
oxy)hex-3-yn-2-ol (9)
To a freshly distilled liquid ammonia (50 mL) in 100 mL two-neck
round-bottomed flask fitted with a cold finger condenser was added
a catalytic amount of Fe(NO3)3, followed by the piecewise addition
of Li metal (1.9 g, 272.7 mmol) at –78 °C, and the resulting gray
colored suspension was stirred for 30 min. To this was added epoxy
chloride 5 (11 g, 45.4 mmol) in anhyd THF (10 mL) over a period
of 15 min. The mixture was then stirred for 2 h at the same temper-
ature. After 2 h, THP protected bromoethanol (20.5 g, 90.8 mmol)
was added dropwise to the mixture. The reaction was stirred at the
same temperature for 6 h, and quenched by the addition of solid
NH4Cl, and then the ammonia was allowed to evaporate. The mix-
ture was partitioned between H2O and EtOAc and the aqueous layer
was extracted with EtOAc. The combined organic layers were
washed once with H2O, and brine, and dried (Na2SO4). The solvent
was removed under reduced pressure. The residue was purified by
silica gel column chromatography eluting with petroleum–EtOAc
(6:4) to afford the pure 9 as a clear colorless liquid (10.6 g, 70%);
[a]D25 –1.2 (c = 1.5, CHCl3).
1H NMR (CDCl3, 300MHz): d = 5.84–5.71 (m, 1 H), 5.02–4.90 (m,
2 H), 4.55 (t, J = 3.2 Hz, 1 H), 3.50–3.30 (m, 2 H), 2.15–2.03 (m, 2
H), 1.88–1.4 (m, 12 H).
2-[4-(2-Oxiranyl)butoxy]tetrahydro-2H-pyran (6)
To a suspension of NaHCO3 (5.8 g, 70.0 mmol) in CH2Cl2 (60 mL)
was added the compound 4 (13 g, 70.0 mmol) in CH2Cl2 (30 mL)
under N2. Then, dry MCPBA (14.3 g, 80.0 mmol) was added in
small portions to the mixture at 0 °C. It was stirred at r.t. for 10 h
until completion of the reaction (TLC monitoring). The mixture was
diluted with CH2Cl2 and the CH2Cl2 layer was washed with a solu-
tion of Na2SO3 followed by aq 5% NaHCO3 solution and H2O. The
organic layer was dried (Na2SO4) and concentrated to dryness under
reduced pressure. The residue was purified by silica gel chromatog-
raphy to afford the pure epoxide 6 (14.1 g, 96%) as a viscous liquid.
IR (neat): 3425, 2941, 2867, 1513, 1248, 1032 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.2 (d, J = 8.6 Hz, 2 H), 6.83 (d,
J = 8.6 Hz, 2 H), 4.60 (t, J = 3.2 Hz, 1 H), 4.50 (d, J = 3.5 Hz, 2 H),
3.85–3.66 (m, 6 H), 3.51–3.40 (m, 4 H), 2.48 (td, J = 5.2, 1.8 Hz, 2
H), 1.68–1.30 (m, 6 H).
1H NMR (CDCl3, 300 MHz): d = 4.55 (t, J = 3.2 Hz, 1 H), 3.87–3.67
(m, 2 H), 3.52–3.32 (m, 2 H), 2.86 (m, 1 H), 2.70 (m, 1 H), 2.42 (m,
1 H), 1.88–1.42 (m, 12 H).
ESIMS: m/z = 357 (M+ + Na).
(2R)-6-(Tetrahydro-2H-2-pyranyloxy)hexane-1,2-diol (8)
A mixture of (S,S)-Jacobsen catalyst [(S,S)-N-N¢-bis(3,5-di-tert-bu-
tylsalicylidene)-1,2-cyclohexanediamino-Co(III) acetate] (195 mg,
0.32 mmol, 0.005 equiv) in CH2Cl2 and AcOH (39 mg, 0.65 mmol,
0.01 equiv) was stirred while open to the air for 1 h at r.t. The sol-
vent was removed by rotary evaporation, and the brown residue was
dried under vacuum. Epoxide 6 (13 g, 65 mmol, 1 equiv) was added
in one portion, and the stirred mixture was cooled in an ice-water
bath. H2O (65 mg, 35 mmol, 0.55 equiv) was slowly added until the
(2R)-1-(4-Methoxyphenoxy)-6-(tetrahydro-2H-2-pyranyl-
oxy)hexan-2-ol (3)
To a solution of compound 9 (10 g, 29.9 mmol), and Na2CO3 (6.2
g, 59.8 mmol) in anhyd EtOAc (5 mL) was added a catalytic amount
of Pd/C (10%) and the mixture was stirred at r.t. under H2 atmo-
sphere for 6 h. Then the catalyst was filtered off, washed with
EtOAc, and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography elut-
Synthesis 2006, No. 24, 4242–4246 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-(5R,6S)-6-Acetoxyhexadecanolide
4245
ing with petroleum ether–EtOAc (6:4) to afford compound 3 as a
colorless liquid (9.0 g, 90%).
ter column chromatography provided the pure product 2 (3.6 g,
78%) as a liquid; [a]D25 –8.04 (c = 1.5, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 7.20 (d, J = 9.0 Hz, 2 H), 6.83 (d,
J = 8.3 Hz, 2 H), 4.54 (t, J = 3.0 Hz, 1 H), 4.45 (s, 2 H), 3.85–3.66
(m, 6 H), 3.51–3.20 (m, 4 H), 1.85–1.30 (m, 12 H).
IR (neat): 3469, 2926, 2854, 1460, 1141, 1034 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.63 (ABq, J = 6.5 Hz, 2 H), 4.53
(t, J = 3.1 Hz, 1 H), 3.86–3.65 (m, 2 H), 3.51–3.27 (m, 7 H), 1.70–
1.22 (m, 30 H), 0.90 (t, J = 6.5 Hz, 3 H).
2-{[(5R)-5-(Methoxymethoxy)-6-(4-methoxyphenoxy)hex-
yl]oxy}tetrahydro-2H-pyran (10)
ESIMS: m/z = 425 (M+ + Na).
To solution of compound 3 (4.3 g, 12.72 mmol) in anhyd CH2Cl2
(10 mL) at 0 °C under N2, was added i-Pr2NEt (6.6 mL, 38.16
mmol) dropwise and after 5 min MOM-Cl (3.6 mL, 38.16 mmol)
was added dropwise. After stirring for 2 h at r.t., the mixture was di-
luted with H2O. Aq sat. NH4Cl solution was added, the layers were
separated and the organic layer was dried (Na2SO4). The residue
was purified on silica gel column and eluted with hexane–EtOAc
(9:1) to afford the pure compound 10 as a clear colorless liquid (4.6
g, 96%); [a]D25 –3.28 (c = 1.5, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 7.2 (d, J = 9.0 Hz, 2 H), 6.81 (d,
J = 8.3 Hz, 2 H), 4.65 (ABq, J = 6.7 Hz, 2 H), 4.54 (t, J = 3.0 Hz, 1
H), 4.43 (s, 2 H), 3.85–3.64 (m, 6 H), 3.50–3.28 (m, 7 H), 1.85–1.30
(m, 12 H).
(1S)-1-[(1R)-1-(Methoxymethoxy)-5-(tetrahydro-2H-pyranyl-
oxy)pentyl]undecyl Acetate (13)
To a stirred solution of compound 2 (1.6g, 4.9 mmol) in anhyd
CH2Cl2 (3 mL) was added Et3N (1.1 mL, 7.9 mmol) followed by
Ac2O (0.56 mL, 5.9 mmol) and a catalytic amount DMAP at 0 °C.
The mixture was stirred for 1 h and then diluted with CH2Cl2. The
organic layer was washed successively with H2O, aq 5% NaHCO3
solution, brine and dried (Na2SO4). Evaporation of the solvent un-
der reduced pressure followed by column chromatography using
silica gel (60–120 mesh) afforded the acetate 13 (1.6 g, 92%) as a
colorless liquid; [a]25D –1.94 (c = 1.5, CHCl3).
1H NMR (CDCl3, 400 MHz): d = 4.92 (m, 1 H), 4.63 (ABq, J = 6.5
Hz, 2 H), 4.54 (t, J = 3.1 Hz, 1 H), 3.84–3.66 (m, 2 H), 3.54–3.30
(m, 6 H), 2.05 (s, 3 H), 1.70–1.22 (m, 30 H), 0.88 (t, J = 6.5 Hz, 3
H).
(2R)-2-(Methoxymethoxy)-6-(tetrahydro-2H-2-pyranyl-
oxy)hexan-1-ol (11)
13C NMR (CDCl3, 75 MHz): d = 170.7, 98.8, 96.5, 78.0, 74.5, 67.3,
62.3, 55.8, 31.8, 30.7, 30.3, 29.9, 29.8, 29.9, 29.8, 29.5, 29.5, 29.5,
29.3, 25.5, 25.4, 22.6, 21.1, 19.5, 14.1.
To a stirred solution of compound 10 (4.0g, 10.4 mmol) in CH2Cl2
(4.5 mL) and H2O (0.5 mL) was added DDQ (2.3 g, 10.4 mmol) at
r.t. The mixture was stirred for 2.5 h at r.t. before being quenched
by the addition of aq sat. NaHCO3 (10 mL). The layers were sepa-
rated and the aqueous layer was extracted with CH2Cl2 (2 ×). The
combined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The crude product was purified by column chromatography
on silica gel to give the compound 11 (2.3 g, 83%) as a pure yellow
oil; [a]D25 –17.41 (c = 1.5, CHCl3).
IR (neat): 3455, 2941, 1120, 1033 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.79–4.53 (m, 3 H), 3.95–3.29 (m,
10 H), 1.85–1.30 (m, 12 H).
ESIMS: m/z = 467 (M+ + Na).
(1S)-1-[(1R)-5-Hydroxy-1-(methoxymethoxy)pentyl]undecyl
Acetate (14)
To a stirred solution of compound 13 (1.6 g, 3.6 mmol) in MeOH
(30 mL) was added a catalytic amount of PPTS. The mixture was
stirred at r.t. for about 2 h and then MeOH was removed under re-
duced pressure. The crude residue was purified by silica gel column
chromatography to afford 14 (1.16 g, 90%) as a viscous liquid;
[a]D25 –0.73 (c = 1.5, CHCl3).
ESIMS: m/z = 285 (M+ + Na).
IR (neat): 3448, 2926, 2854, 1737, 1239, 1035 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.96 (m, 1 H), 4.65 (ABq, J = 6.5
Hz, 2 H), 3.70–3.36 (m, 6 H), 2.08 (s, 3 H), 1.80–1.23 (m, 22 H),
0.90 (t, J = 6.7 Hz, 3 H).
(2R)-2-(Methoxymethoxy)-6-(tetrahydro-2H-2-pyranyl-
oxy)hexanal (12)
To an ice-cooled solution of iodoxybenzoic acid (4.3 g, 15.2 mmol)
in DMSO (4 mL) was added a solution of alcohol 11 (2.0 g, 7.6
mmol) in anhyd CH2Cl2 (10 mL). After stirring for 2 h at r.t., the
mixture was filtered through a Celite pad and washed with Et2O.
The combined organic layers were washed with H2O, brine, dried
(Na2SO4) and concentrated in vacuo. The crude product was puri-
fied by column chromatography on silica gel eluted with petroleum
ether–EtOAc (8:2) to afford the aldehyde 12 as a viscous liquid
(1.58 g, 80%)
ESIMS: m/z = 383 (M+ + Na).
(1S)-1-[(1R)-1(Methoxymethoxy)-5-oxypentyl]undecyl Acetate
(15)
To an ice-cooled solution of iodoxybenzoic acid (1.16 g, 4.1 mmol)
in DMSO (4 mL) was added a solution of alcohol 14 (1.0 g, 2.7
mmol) in anhyd CH2Cl2 (10 mL). After stirring for 2 h at r.t., the
mixture was filtered through a Celite pad and washed with Et2O.
The combined organic layers were washed with H2O, brine, and
dried (Na2SO4), then concentrated in vacuo. The crude product was
purified by column chromatography on silica gel eluted with petro-
leum ether–EtOAc (8:2) to afford to the aldehyde 15 as a viscous
liquid (0.800 g, 77%); [a]D25 –12.7 (c = 1.5, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 9.58 (s, 1 H), 4.69 (ABq, J = 6.7
Hz, 2 H), 4.54 (t, J = 3.0 Hz, 1 H), 3.86–3.65 (m, 2 H), 3.51–3.27
(m, 6 H), 1.85–1.30 (m, 12 H).
(5R,6S)-5-(Methoxymethoxy)-1-(tetrahydro-2H-2-pyranyl-
oxy)hexadecan-6-ol (2)
IR (neat): 3450, 2926, 2854, 1738, 1461, 1372, 1239, 1031 cm–1.
To a suspension of Mg (1.37 g, 28.5 mmol) in anhyd Et2O (50 mL),
was added dropwise 1-bromodecane (11.8 mL, 28.5 mmol) under
N2 at 0 °C. The mixture was allowed to stir for 0.5 h at r.t. To this
Grignard reagent, was added aldehyde 12 (3.0 g, 5.7 mmol) in an-
hyd Et2O (10 mL) at 10 °C. The mixture was stirred for 5–6 h and
then quenched with aq sat. NH4Cl solution and filtered over Celite.
The filtrate was washed with H2O, brine and dried (Na2SO4). The
organic layer was concentrated to give the crude material, which af-
1H NMR (CDCl3, 300 MHz): d = 9.77 (s, 1 H), 4.95 (m, 1 H), 4.64
(ABq, J = 7.0 Hz, 2 H), 3.62–3.32 (m, 4 H), 2.46 (td, J = 5.4, 1.5
Hz, 2 H), 2.08 (s, 3 H), 1.80–1.23 (m, 22 H), 0.90 (t, J = 6.7 Hz, 3
H),
13C NMR (CDCl3, 75 MHz): d = 201.9, 170.5, 96.6, 77.9, 74.3, 55.9,
43.6, 31.8, 29.8, 29.6, 29.4, 29.6, 29.2, 25.7, 25.5, 22.6, 21.0, 18.3,
18.0, 14.0.
ESIMS: m/z = 381 (M+ + Na).
Synthesis 2006, No. 24, 4242–4246 © Thieme Stuttgart · New York

4246
G. Sabitha et al.
PAPER
(5R,6S)-6-(Acetyloxy)-5-(methoxymethoxy)hexadecanoic Acid
(16)
References
(1) IICT Communication No. 060715.
To a stirred solution of compound 15 (0.7 g, 1.95 mmol) in DMSO
(5 mL) was added an aq solution of NaH2PO4 (0.305 g, 1.95 mmol)
dropwise at 0 °C. To this well-stirred mixture at 0 °C was added aq
NaClO2 (0.175 g, 1.95 mmol) solution and the mixture was allowed
to stir for 1 h at r.t. To the mixture was added aq 5% NaHCO3 solu-
tion. The organic phase extracted into CH2Cl2 and the aqueous
phase was acidified with conc. HCl. The organic layer was filtered
through the small pad of Celite and the filtrate was concentrated un-
der reduced pressure. The crude product was purified by column
chromatography on silica gel eluting with petroleum ether–EtOAc
(5:5) to afford 16 as a colorless oil (0.520 g, 72%); [a]D25 –16.1
(c = 1.5, CHCl3).
(2) (a) Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach; Pergamon: Oxford, 1983. (b) Gravier-
Pelletier, C.; Saniere, M.; Charvet, I.; Le Merrer, Y.;
Depezay, J. C. Tetrahedron Lett. 1994, 35, 115.
(c) Sakamoto, A.; Yamamoto, Y.; Oda, J. J. Am. Chem. Soc.
1987, 109, 7188.
(3) Laurence, B. R.; Pickett, J. A. J. Chem. Soc., Chem.
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(4) Anderson, J. F.; Andreadis, T. G.; Vossbrinck, C. R.; Tirrell,
S.; Wakem, E. M.; French, R. A.; Garmendia, A. E.; Van
Kruinigen, H. J. Science 1999, 286, 2331.
(5) Selected examples of few previous approaches:
(a) Ikishima, H.; Sekiguchi, Y.; Ichikawa, Y.; Kotsuki, H.
Tetrahedron 2006, 62, 311. (b) Sun, B.; Peng, L.; Chen, X.;
Li, Y.; Li, Y.; Yamasaki, K. Tetrahedron: Asymmetry 2005,
16, 1305. (c) Dhotare, B.; Goswami, D.; Chattopadhyay, A.
Tetrahedron Lett. 2005, 46, 6219. (d) Anderson, J. F.;
Andreadis, T. G.; Vossbrinck, C. R.; Tirrell, S.; Wakem, E.
M.; French, R. A.; Garmendia, A. E.; Van Kruiningen, H. J.
Science 1999, 286, 2331. (e) Bonini, C.; Checconi, M.;
Righi, G.; Rossi, L. Tetrahedron 1995, 51, 4111.
(f) Coutrot, Ph.; Grison, C.; Bômont, C. Tetrahedron Lett.
1994, 35, 8381. (g) Mori, K. In The Total Synthesis of
Natural Products, Vol. 9; ApSimon, J., Ed.; Wiley: New
York, 1992. (h) Kotsuki, H.; Kadota, I.; Ochi, M. J. Org.
Chem. 1990, 55, 4417. (i) Mori, K. Tetrahedron 1989, 45,
3233.
(6) (a) Sabitha, G.; Fatima, N.; Swapna, R.; Yadav, J. S.
Synthesis in press. (b) Sabitha, G.; Reddy, E. V.; Yadagiri,
K.; Yadav, J. S. Synthesis in press. (c) Sabitha, G.;
Sudhakar, K.; Reddy, N. M.; Rajkumar, M.; Yadav, J. S.
Tetrahedron Lett. 2005, 46, 6567. (d) Sabitha, G.;
Bhikshapathi, M.; Yadav, J. S. Synth. Commun. in press.
(7) Tokunaga, M.; Larrow, J. F.; Kukiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936.
IR (neat): 3447, 2925, 2854, 1738, 1460, 1372, 1238, 1030 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.94 (m, 1 H), 4.64 (ABq, J = 6.2
Hz, 2 H), 3.53 (m, 1 H), 3.37 (s, 3 H), 2.36 (t, J = 6.7 Hz, 2 H), 2.08
(s, 3 H), 1.80–1.23 (m, 22 H), 0.88 (t, J = 6.7 Hz, 3 H).
ESIMS: m/z = 397 (M+ + Na).
(–)-(5R,6S)-6-Acetoxyhexadecanolide (1)
To a stirred solution of compound 16 (0.4 g, 1.06 mmol) in anhyd
benzene (10 mL) was added a catalytic amount of PTSA under N2.
The mixture was refluxed for 2 h and the solvent was removed un-
der vacuum, and then quenched with aq NaHCO3 solution. The
aqueous layer was extracted with EtOAc (2 ×), dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel to give the lactone 1 (0.25 g, 76%);
[a]D25 –35 (c = 1.5, CHCl3).
IR (neat): 2925, 2854, 1737, 1461, 1372, 1238, 1027 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.94 (m, 1 H), 4.30 (m, 1 H), 2.66–
2.18 (m, 2 H), 2.07 (s, 3 H), 1.98–1.22 (m, 22 H), 0.89 (t, J = 6.8
Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 170.9, 170.6, 80.4, 74.3, 31.8, 29.9,
29.6, 29.5, 29.5, 29.4, 29.3, 29.2, 25.3, 23.4, 22.6, 20.9, 18.3, 14.0.
ESIMS: m/z = 313 (M+ + 1).
(8) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M.
Tetrahedron 1990, 46, 7033.
(9) Li, L.-S.; Wu, Y.-L. Tetrahedron 2002, 58, 9049.
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8381.
(11) Corey, E. J.; Knolle, J. J. Am. Chem. Soc. 1978, 100, 1942.
(12) Sugai, T.; Mori, K. Agric. Biol. Chem. 1984, 48, 2497.
(13) Dale, L. B.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc.
2001, 123, 4161.
Acknowledgment
R.S. and E.V.R. thank CSIR for the financial support.
Synthesis 2006, No. 24, 4242–4246 © Thieme Stuttgart · New York