Total synthesis of insect pheromones (R)-4-dodecanolide and (S)-5-hexadecanolide

Article abstract of DOI:10.1055/s-2006-950212

The asymmetric total synthesis of naturally occurring insect pheromones, (R)-4-dodecanolide and (S)-5-hexadecanolide has been achieved in a simple and efficient way with high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950212

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3270
PAPER
Total Synthesis of Insect Pheromones (R)-4-Dodecanolide and
(S)-5-Hexadecanolide1
Total
S
ynthesis of
o
Insec
t
Phero
w
mones,
(
R
)
-
4-Dod
r
ecanolid
a
e
and (
S
)-5-
v
H
exadecano
a
lide ram Sabitha,* E. Venkata Reddy, K. Yadagiri, 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 21 February 2006; revised 3 April 2006
O
O
Abstract: The asymmetric total synthesis of naturally occurring in-
sect pheromones, (R)-4-dodecanolide and (S)-5-hexadecanolide has
been achieved in a simple and efficient way with high yields.
1
(4R)-dodecanolide
Keywords: pheromone, natural product, dodecanolide, hexadecan-
olide, chiral lactones
O
O
Optically active 5- and 6-alkyl-substituted g- and d-lac-
tones are attractive building blocks in the synthesis of nat-
ural products2 and comprise of structural moieties that are
frequently present in, for example, insect pheromones,3
cardenolides,4 lignans, and flavor components.5 In addi-
tion to these important properties, they are key synthons
for several biologically important molecules. The g-lac-
tone (R)-4-dodecanolide (1) (Figure 1) is a defensive se-
cretion isolated from the pygidial glands of rove beetles,
Bledius mandibularis and Bledius spectabilis.6 It was also
produced during the bioconversion7 of soy bean fatty ac-
ids by Pencillium Roqueforti spores in the presence of an
exogenous lipase and has been used as a flavoring agent;8
it has been isolated from various fruits9 and butterfat.10
The d-lactone (S)-5-hexadecanolide (2) (Figure 1) was
isolated from the mandibular glands of the oriental hornet
Vespa orientalis;11 it is a pheromone that stimulates the
workers to construct queen cells. This lactone is also
found in some fruits, such as apricots and peaches. Both 1
2
(5S)-hexadecanolide
Figure 1
and 2 have a chiral lactone unit in their structure. Owing
to their remarkable physiological activities, several ap-
proaches leading to (R)-4-dodecanolide12 and (S)-5-
hexadecanolide12e,13 have been reported. Although a great
number of synthetic routes to the title compounds have
been published, there is still a need to explore short and ef-
ficient routes to these compounds. A continuation of our
interest in the synthesis of lactones14 prompted us to take
up the total synthesis of (R)-4-dodecanolide and (S)-5-
hexadecanolide due to their simple structure coupled with
biological activities; the results are presented herein.
The retrosynthetic analysis for the two lactones 1 and 2 is
outlined in Scheme 1.
OMOM
OH
O
H17C8
O
H17C8
COOMe
H17C8
1
3
4
OMOM
C11H23
O
O
COOH
C11H23
2
5
O
OH
THPO
OH
OTHP
C9H19
6
7
Scheme 1
SYNTHESIS 2006, No. 19, pp 3270–3274
x
x.
x
x
.
2
0
0
6
Advanced online publication: 21.08.2006
DOI: 10.1055/s-2006-950212; Art ID: Z03906SS
© Georg Thieme Verlag Stuttgart · New York

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PAPER
Total Synthesis of Insect Pheromones (R)-4-Dodecanolide and (S)-5-Hexadecanolide
3271
OH
OMOM
a
8
4
OMOM
b
c
OMe
9
O
OMOM
d
OMe
1
O
3
Scheme 2 Reagents and conditions: (a) MOMCl, i-Pr2NEt, anhyd CH2Cl2, 0 °C to r.t., 2 h, 90%; (b) 1.6 M BuLi in hexane, ClCO2Me, anhyd
THF, –78 °C, 30 min, 90%; (c) Pd/C, H2, EtOAc, 4 h, 90%; (d) PTSA, MeOH, r.t, 12 h, 80%.
25
The synthesis of (R)-4-dodecanolide (1) began with the natural lactone {[a]D25 +36.4 (c 1, MeOH), [Lit.12d [a]D
key precursor, chiral propargyl alcohol 4,15 which was +37.5 (c 1, MeOH)]}.
prepared by a known procedure.16 The free hydroxy of the
chiral alcohol, (3R)-undec-1-yn-3-ol (4) was first protect-
The synthesis of (S)-5-hexadecanolide (2) began with the
2,3-epoxy alcohol 7 (Scheme 3). The alcohol was con-
ed as its methoxymethyl ether using Hünig’s base (i-
verted into the corresponding epoxy chloride 10 on reac-
Pr2EtN, 2 equiv) and methoxymethyl chloride (3 equiv) in
tion with triphenylphosphine in refluxing carbon
dry dichloromethane at room temperature to afford 817 in
tetrachloride in the presence of sodium hydrogen carbon-
90% yield (Scheme 2). The acetylenic compound 8 was
ate. The epoxy chloride 10 was subjected to base-induced
then subjected to methoxycarbonylation18 with methyl
opening with lithium amide in liquid ammonia at –33 °C
chloroformate (1 equiv) in the presence of 1.6 M butyllith-
and further treated with nonyl bromide leading to the
ium in hexane (1 equiv) at –78 °C to give the acetylenic
chiral acetylenic alcohol 6 directly in a one-pot procedure
ester 9 in 90% yield.
(Scheme 3).
Catalytic hydrogenation of the ester 9 using palladium on
The secondary hydroxy group of compound 6 was pro-
carbon and hydrogen in ethyl acetate afforded the saturat-
tected as its methoxymethyl ether by treatment with
ed ester 3 in 90% yield. Finally, the cyclization of com-
Hünig’s base and methoxymethyl chloride in anhydrous
dichloromethane at room temperature to afford compound
pound 3 with 4-toluenesulfonic acid in methanol afforded
the target lactone (R)-4-dodecanolide (1) by in situ depro-
11 in 98% yield. In the next step, the reduction of the triple
tection of the methoxymethyl group followed by cycliza-
bond and subsequent deprotection of the tetrahydropyra-
tion (Scheme 2). The synthetic material showed IR and 1H
nyl group of compound 11 over 10% palladium on carbon
gave 12 in 80% yield. The alcohol 12 was oxidized to the
and 13C NMR spectral data in good agreement with the
O
O
a
b
Cl
OH
THPO
THPO
7
10
OMOM
OH
c
d
OTHP
OTHP
H
19C9
H19C9
6
11
OMOM
OMOM
12
f
e
CHO
H23C11
H23C11
OH
13
2
OMOM
g
COOH
H23C11
5
Scheme 3 Reagents and conditions: (a) Ph3P, NaHCO3, CCl4, reflux, 4 h, 80%; (b) Li/liq NH3, Fe(NO3)3 (cat.), anhyd THF, C9H19Br, 8 h,
60%; (c) MOMCl, i-Pr2NEt, 0 °C to r.t., 2 h, 98%; (d) 10% Pd/C, H2, EtOH, r.t., 6 h, 80%; (e) IBX, anhyd DMSO, anhyd CH2Cl2, r.t., 2 h, 77%;
(f) NaClO2, NaH2PO4, aq DMSO, r.t., 1 h, 71%; (g) PTSA, MeOH, r.t., 12 h, 80%.
Synthesis 2006, No. 19, 3270–3274 © Thieme Stuttgart · New York

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3272
G. Sabitha et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 153.52, 94.48, 86.4, 76.62, 65.17,
aldehyde 13 in 77% yield with 2-iodoxybenzoic acid
(IBX) in anhydrous dimethyl sulfoxide and anhydrous
55.59, 52.51, 38.85, 34.83, 31.71, 29.27, 29.06, 25.57, 22.62, 14.05.
dichloromethane and then 13 was further oxidized with MS (ESI): m/z = 270 (M+).
sodium chlorite and sodium dihydrogen phosphate in
Methyl (4R)-4-(Methoxymethoxy)dodecanoate (3)
aqueous dimethyl sulfoxide to afford the corresponding
acid 5 in 71% yield.19 Finally the synthesis of target mol-
ecule 2 was achieved in 80% yield by in situ deprotection
of the methoxymethyl group and subsequent cyclization
(Scheme 3).
To a soln of 9 (1.0 g, 3.7 mmol) in anhyd EtOAc (5 mL) was added
a catalytic amount of 10% Pd/C and the mixture was stirred at r.t.
under a H2 atmosphere for 4 h. Then the catalyst was filtered off,
washed with EtOAc, and the filtrate was concentrated under re-
duced pressure and purified by column chromatography (silica gel,
PE–EtOAc, 9:1) to afford 3 as a colorless liquid; yield: 0.91 g
(90%).
In conclusion, we have achieved simple, short and effi-
cient total syntheses of (R)-4-dodecanolide and (S)-5-
hexadecanolide in good yields by utilizing chiral acety-
lenic alcohols as key intermediates.
[a]D25 +1.5 (c 1, CHCl3).
IR (neat): 2928, 2856, 1742, 1216, 1038 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.57 (s, 2 H), 3.65 (s, 3 H), 3.56–
3.48 (m, 1 H), 3.34 (s, 3 H), 2.36 (t, J = 7.5 Hz, 2 H), 1.92–1.66 (m,
2 H), 1.47–1.27 (m, 14 H), 0.89 (t, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 174.1, 95.4, 76.6, 55.5, 51.4, 34.1,
31.8, 29.8, 29.72, 29.5, 29.2, 25.2, 22.6, 14.1.
All solvents were distilled before use. Dry solvents were prepared
according to standard procedures. All reactions were carried out un-
der a N2 atmosphere and monitored by TLC on silica gel (60–120
mesh, Merck). NMR spectra were recorded on Bruker (300 MHz
1
1H, 75 MHz 13C) and Varian (200 MHz H, 50 MHz 13C) NMR
MS (ESI): m/z = 297 (M+ + Na).
spectrometers using CDCl3 as solvent. ESI-MS were recorded with
LC-MSD-Trap-SL (Agilent technologies). IR spectra were record-
ed with FTIR (Thermo Nicolet Nexus 670 spectrophotometer).
(R)-4-Dodecanolide (1)
To a stirred soln of 3 (0.5 g, 1.8 mmol) in MeOH was added a cata-
lytic amount of PTSA under a N2 atmosphere. The mixture was
stirred at r.t. for 12 h and then quenched by addition of solid
NaHCO3, which was then filtered off and the solvent was removed
from the filtrate under reduced pressure to give a residue that was
purified by column chromatography (silica gel, PE–EtOAc, 6:4) to
afford 1 as yellow liquid; yield: 0.285 g (80%).
[a]D25 +36.4 (c 1, MeOH).
IR (neat): 2928, 2856, 1777, 1216, 1038 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.47–4.34 (m, 1 H), 2.51–2.20 (m,
4 H), 1.91–1.26 (m, 14 H), 0.88 (t, J = 6.9 Hz, 3 H).
(3R)-3-(Methoxymethoxy)undec-1-yne (8)
To a soln of 4 (1.5 g, 8.9 mmol) in anhyd CH2Cl2 (10 mL) at 0 °C
under N2 atmosphere, was added i-Pr2NEt (3.10 mL, 17.8 mmol)
dropwise and, after 5 min, MOMCl (2.71 mL, 33.8 mmol) was add-
ed dropwise. The mixture was stirred at r.t. for 2 h and then diluted
with H2O and washed with sat. aq NH4Cl and brine. The organic
phase was dried (anhyd Na2SO4) and concentrated under reduced
pressure. The residue was purified by column chromatography (sil-
ica gel, PE–EtOAc, 9:1) to afford pure 8 as a clear colorless liquid;
yield: 1.7 g (90%).
[a]D25 –13.5 (c 1, CHCl3).
IR (neat): 2929, 2858, 2235, 1252, 1031 cm–1.
13C NMR (75 MHz, CDCl3): d = 177.3, 81.0, 35.6, 31.8, 29.4, 29.3,
29.1, 28.8, 27.9, 25.2, 22.6, 14.1.
1H NMR (200 MHz, CDCl3): d = 4.90 (d, J = 6.6 Hz, 1 H), 4.53 (d,
J = 6.6 Hz, 1 H), 4.27 (td, J = 2.2, 6.6 Hz, 1 H), 3.35 (s, 3 H), 2.32
(d, J = 2.2 Hz, 1 H), 1.78–1.61 (m, 2 H), 1.50–1.23 (m, 12 H), 0.89
(t, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 94.0, 82.6, 73.3, 65.4, 55.6, 53.6,
31.8, 29.4, 29.2, 29.1, 25.2, 22.6, 14.1.
MS (ESI): m/z = 199 (M+ + 1).
(2S,3S)-2,3-Epoxy-7-(tetrahydro-2H-pyran-2-yloxy)heptan-1-
ol (7)
Anhyd CH2Cl2 (20 mL) was added to powdered activated 4Å mo-
lecular sieves and the suspension was cooled to –24 °C. Ti(Oi-Pr)4
(1.061 g, 3.73 mmol) and D-(–)-DET (0.770 g, 3.73 mmol) were
subsequently added with stirring and the resulting mixture was
stirred at –24 °C for 30 min, (E)-7-(tetrahydro-2H-pyran-2-
yloxy)hept-2-en-1-ol (4 g, 18.69 mmol) in anhyd CH2Cl2 (20 mL)
was added and the resulting mixture was stirred at –24 °C for a fur-
ther 30 min. 3.3 M tert-Butyl hydroperoxide in toluene (8.49 mL,
28 mmol) was then added and the resulting mixture was stirred at
–24 °C for 3 h. It was then warmed to 0 °C, quenched by addition
of H2O (6 mL) and stirred at r.t. for 1 h. 30% aq NaOH soln saturat-
ed with NaCl (6 mL) was then added and the mixture stirred vigor-
ously at r.t. for a further 30 min. The resulting mixture was washed
well with CH2Cl2. The organic phase was separated and the aqueous
phase was extracted with CH2Cl2. The combined organic layers
were washed with brine and dried (anhyd Na2SO4). The solvent was
removed under reduced pressure and the residue was purified by
column chromatography (silica gel, PE–EtOAc, 5:5) to afford 7 as
a viscous liquid; yield: 3.4 g (80%).
MS (ESI): m/z = 213 (M+ + 1).
Methyl (4R)-4-(Methoxymethoxy)dodec-2-ynoate (9)
Acetylenic compound 8 (1.0 g, 4.71 mmol) was dissolved in freshly
distilled anhyd THF (5 mL) in an oven-dried round-bottomed flask
under N2 atmosphere. The soln was then cooled to –78 °C and 1.6
M BuLi in hexane (5.89 mL, 9.43 mmol) was added. The mixture
was stirred at –78 °C for 2 h and then methyl chloroformate (0.54
mL, 7.07 mmol) in anhyd THF (5 mL) was added slowly and the
mixture was stirred at –78 °C for 2 h. The mixture was diluted with
EtOAc and washed with sat. aq NH4Cl, and brine. The organic
phase was dried (anhyd Na2SO4) and concentrated under reduced
pressure. The residue was purified by column chromatography (PE–
EtOAc, 8:2) to afford 9 as a viscous liquid; yield: 1.14 g (90%).
[a]D25 +5.6 (c 1, CHCl3).
IR (neat): 2929, 2858, 2235, 1722, 1252, 1032 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.88 (d, J = 6.7 Hz, 1 H), 4.56 (d,
J = 6.7 Hz, 1 H), 4.41 (t, J = 6.8 Hz, 1 H), 3.78 (s, 3 H), 3.38 (s, 3
H), 1.82–1.74 (m, 2 H), 1.51–1.30 (m, 12 H), 0.89 (t, J = 6.8 Hz, 3
H).
[a]D25 +13.3 (c 1, CHCl3).
IR (neat): 3438, 2960, 2856, 1049 cm–1.
Synthesis 2006, No. 19, 3270–3274 © Thieme Stuttgart · New York

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PAPER
Total Synthesis of Insect Pheromones (R)-4-Dodecanolide and (S)-5-Hexadecanolide
3273
1H NMR (200 MHz, CDCl3): d = 4.55 (t, J = 3.02 Hz, 1 H), 3.87–
3.56 (m, 4 H), 3.51–3.33 (m, 2 H), 2.92 (m, 1 H), 2.87 (m, 1 H),
1.91–1.44 (m, 12 H), 2.22 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 98.7, 67.5, 62.5, 61.9, 58.6, 55.8,
31.3, 30.6, 29.3, 25.3, 22.7, 19.5.
gel, hexane–EtOAc, 9:1) to afford pure 11 as a clear colorless liq-
uid; yield: 1.9 g (98%); 94% ee.
[a]D25 +8.31 (c 1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 4.90 (d, J = 6.7 Hz, 1 H), 4.56 (t,
J = 3.3 Hz, 1 H), 4.50 (d, J = 6.7 Hz, 1 H), 4.26 (t, J = 5.9 Hz, 1 H),
3.88–3.66 (m, 2 H), 3.51–3.37 (m, 2 H), 3.34 (s, 3 H), 2.19 (td,
J = 1.7, 6.7 Hz, 2 H), 1.73 –13 (m, 26 H), 0.89 (t, J = 6.7 Hz, 3 H,).
MS (ESI): m/z = 303 (M+ + 1).
(2R,3S)-1-Chloro-2,3-epoxy-7-(tetrahydro-2H-pyran-2-
yloxy)heptane (10)
13C NMR (75 MHz, CDCl3): d = 98.8, 93.8, 78.4, 67.3, 65.7, 62.2,
55.5, 35.8, 31.8, 30.7, 29.6, 29.4, 29.2, 29.1, 28.8, 28.6, 25.5, 22.6,
22.1, 19.5, 18.6, 14.1.
To a stirred soln of 7 (3.0 g, 13.04 mmol) in anhyd CCl4 (20 mL)
was added Ph3P (5.22 g, 19.56 mmol) and NaHCO3 (1.095 g, 13.04
mmol). The resulting mixture was vigorously refluxed for 4 h. The
solids were removed by filtered and washed with Et2O. The solvent
was removed from the filtrate under reduced pressure and the resi-
due was purified by column chromatography (silica gel, PE–
EtOAc, 9:1) to afford 10 as a viscous liquid; yield: 2.5 g (80%).
[a]D25 +8.02 (c 1, CHCl3).
IR (neat): 2940, 2866, 1029 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.54 (t, J = 3.2 Hz, 1 H), 3.84–
3.67 (m, 2 H), 3.61 (m, 2 H), 3.33 (m, 2 H), 2.29 (m, 1 H), 2.82 (m,
1 H), 1.92 –1.42 (m, 12 H).
MS (ESI): m/z = 383 (M+ + 1).
(5S)-5-(Methoxymethoxy)hexadecan-1-ol (12)
To a soln of 11 (1.8 g, 4.7 mmol) in anhyd EtOH (5 mL) was added
a catalytic amount of 10% Pd/C and the mixture was stirred at r.t.
under a H2 atmosphere for 6 h. Then the catalyst was filtered off and
washed with EtOAc and the filtrate was concentrated under reduced
pressure and purified by column chromatography (silica gel, PE–
EtOAc, 6:4) to afford 12 as a colorless liquid; yield: 1.14 g (80%).
[a]D25 +5.51 (c 1, CHCl3).
IR (neat): 3432, 2925, 2854, 1461, 1040 cm–1.
13C NMR (75 MHz, CDCl3): d = 98.7, 67.2, 61.8, 59.3, 56.8, 48.2,
31.7, 30.6, 29.3, 25.4, 22.7, 19.5.
MS (ESI): m/z = 249 (M+ + 1).
1H NMR (300 MHz, CDCl3): d = 4.60 (s, 2 H), 3.62 (t, J = 6.1 Hz,
2 H), 3.49 (m, 1 H), 3.35 (s, 3 H), 1.59–1.34 (m, 26 H), 0.89 (t,
J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 95.3, 77.5, 62.5, 55.4, 34.2, 33.9,
(5R)-1-(Tetrahydro-2H-pyran-2-yloxy)hexadec-6-yn-5-ol (6)
To freshly distilled NH3 (50 mL) in a 100-mL two-necked, round-
bottomed flask fitted with a cold finger condenser was added a cat-
alytic amount of Fe(NO3)3, followed by the addition of Li metal
pieces (0.508 g, 72.5 mmol) at –33 °C and the resulting grey-col-
ored suspension was stirred for 30 min. To this soln was added 10
(2.4 g, 9.6 mmol) in anhyd THF (10 mL) over a period of 15 min.
The mixture was then stirred at this temperature for 2 h. Then, nonyl
bromide (5.8 mL, 30.2 mmol) was added dropwise to the mixture
and it was stirred at this temperature for 6 h. The reaction was
quenched by the addition of solid NH4Cl and then NH3 was allowed
to evaporate. The mixture was extracted with H2O and EtOAc. The
combined organic layers were washed with H2O (1 ×), and brine,
and dried (anhyd Na2SO4); the solvent was removed under reduced
pressure. The residue was purified by column chromatography (sil-
ica gel, PE–EtOAc, 6:4) to afford pure 6 as a clear colorless liquid;
yield: 1.92 g (60%); 94% ee.
33.2, 31.8, 29.8, 29.5, 29.3, 29.2, 22.5, 21.4, 14.1.
MS (ESI): m/z = 325 (M+ + Na).
(5S)-5-(Methoxymethoxy)hexadecanal (13)
To an ice-cooled soln of 2-iodoxybenzoic acid (2.3 g, 8.2 mmol) in
DMSO (5 mL) was added a soln of alcohol 12 (1.0 g, 3.3 mmol) in
anhyd CH2Cl2 (10 mL). The mixture was stirred at r.t. for 2 h and
then filtered through a Celite pad and washed with Et2O. The com-
bined organic filtrates were washed with H2O and brine, dried (an-
hyd Na2SO4), and concentrated in vacuo. The crude product was
purified by column chromatography (silica gel, PE–EtOAc, 8:2) to
afford aldehyde 13 as a viscous liquid; yield: 0.764 g (77%); 93%
ee.
[a]D25 +9.82 (c 1, CHCl3).
IR (neat): 2927, 2855, 1726, 1460, 1035 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.76 (t, J = 2.2 Hz, 1 H), 4.59 (AB
q, J = 6.8 Hz, 2 H) 3.51 (m, 1 H), 3.34 (s, 1 H), 2.43 (td, J = 1.5, 7.5
Hz, 2 H), 1.62–1.26 (m, 26 H), 0.88 (t, J = 6.7 Hz, 3 H).
[a]D25 +24.4 (c 1, CHCl3).
IR (neat): 3432, 2925, 2854, 2230, 1465, 1050 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.54 (t, J = 3.3 Hz, 1 H), 4.26 (t,
J = 5.9 Hz, 1 H), 3.86–3.66 (m, 2 H), 3.51–3.37 (m, 2 H), 2.20 (td,
J = 1.6, 6.7 Hz, 2 H), 1.72–1.13 (m, 26 H), 0.89 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 93.7, 82.1, 78.5, 67.1, 63.5, 62.2,
35.8, 32.8, 31.6, 29.5, 29.3, 29.2, 29.1, 28.8, 28.6, 25.3, 22.7, 22.6,
19.5, 18.6, 14.1.
13C NMR (75 MHz, CDCl3): d = 202.3, 95.4, 77.1, 55.4, 43.8, 34.2,
33.6, 31.9, 29.7, 29.6, 29.3, 25.2, 22.6, 17.9, 14.1.
MS (ESI): m/z = 323 (M+ + Na).
(5S)-5-(Methoxymethoxy)hexadecanoic Acid (5)
Compound 13 (0.6 g, 2 mmol) was dissolved in DMSO (5 mL) and
to this was added dropwise NaH2PO4⋅2H2O (0.363 g, 2.3 mmol) in
H2O (5 mL) at 0 °C. To this well-stirred mixture at 0 °C was added
NaClO2 (0.209 g, 2.3 mmol) in H2O (5 mL) and it was stirred at r.t.
for 1 h. To the mixture was added 5% NaHCO3. The aqueous phase
was acidified with concd HCl and the organic phase was extracted
into CH2Cl2. The combined organic extracts were then filtered
through a small pad of Celite and filtrate was concentrated under re-
duced pressure. The crude product was purified by column chroma-
tography (silica gel, PE–EtOAc, 5:5) to afford 5 as colorless oil;
yield: 0.505 g (80%).
MS (ESI): m/z = 339 (M+ + 1).
(5R)–5-(Methoxymethoxy)-1-(tetrahydro-2H-pyran-2-
yloxy)hexadec-6-yne (11)
To soln of 6 (1.8 g, 5.3 mmol) in anhyd CH2Cl2 (10 mL) at 0 °C un-
der N2 atmosphere, was added i-Pr2NEt (4.3 mL, 26 mmol) drop-
wise and, after 5 min, MOMCl (1.03 mL, 13 mmol) was added
dropwise. The mixture was stirred at r.t. for 2 h and then diluted
with H2O, washed with sat. aq NH4Cl and brine. The organic phase
was dried (anhyd Na2SO4) and concentrated under reduced pres-
sure. The residue was purified by column chromatography (silica
[a]D25 +5.49 (c 1, CHCl3).
IR (neat): 2926, 2854, 1710, 1461, 1038 cm–1.
Synthesis 2006, No. 19, 3270–3274 © Thieme Stuttgart · New York