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10 2-MAG isomers can be clearly identified
by examining their signature ¹H NMR and ¹³C
NMR signals.5,6
11
Representative
Procedures for the Synthesis of 9.9-MAG (Entry l)
2-[(8-Bromooctyl)oxy]tetrahydro-2
H
-pyran (1l):
To a stirred solution of 8-bromooctan-1-ol (10.5 g, 50 mmol) in anhyd
CH2Cl2 (50 mL), DHP (5.2 mL, 57 mmol) and p-toluenesulfonic acid (PTSA, 430 mg,
2.5 mmol) were added at r.t. The reaction was stirred overnight
and then sat. aq NaHCO3 (50 mL) was added. The aqueous
layer was extracted with CH2Cl2 (50 mL). The
combined organic extracts were dried over Na2SO4 and
concentrated in vacuo. Flash chromatography on silica gel using
2% EtOAc in hexane as the eluent gave 1l
¹² as
a colorless oil in 95% yield.
2-(Octadec-9-yn-1-yloxy)tetrahydro-2
H
-pyran (2l):
To a stirred solution of 1-decyne (2.76 g, 20 mmol) in anhyd THF (50
mL), hexamethylphosphoramide (HMPA, 10 mL) and n-BuLi
(1.6 M solution in hexane, 11 mL) were slowly added at -60 ˚C.
After half an hour the reaction mixture was warmed to -20 ˚C,
and then 1l (4.1 g, 14 mmol) was added dropwise.
The reaction mixture was slowly warmed to r.t. and stirred overnight.
The reaction was quenched by addition of sat. aq NH4Cl
(50 mL) and extracted with EtOAc (3 × 50 mL). The combined
organic extracts were washed with sat. aq NaHCO3 and
brine, and then dried over Na2SO4 and filtered.
Compound 2l
¹³ was
purified by silica gel chromatography (2% EtOAc in hexane)
as a pale yellow oil in 90% yield.
Octadec-9-ynoic
Acid (3l): Freshly prepared Jones reagent (2.7 M, 10 mL) was
added dropwise to a solution of 2l (2.8 g,
8 mmol) in acetone (50 mL) while maintaining the reaction temperature
at 0-4 ˚C. Upon the disappearance of 2l, as monitored by TLC (ca. 4 h), i-PrOH (1 mL) was added to quench excessive
Jones oxidant. The chromium salt was removed by filtration and washed
thoroughly with acetone (50 mL). The filtrate was concentrated in
vacuo, and the residue was submitted to silica gel chromatography
(10-40% EtOAc in hexane) to give 3l
¹³ as
a white solid (mp 47-48 ˚C) in 95% yield.
Methyl Octadec-9-ynoate (4l): Concentrated
H2SO4 (0.1 mL, ca. 96%) was added
to a suspension of 3l (2.0 g, 7 mmol) in
MeOH (30 mL). The solution was concentrated after overnight reaction.
Purification by silica gel chromatography (2-5% EtOAc
in hexane) gave compound 4l as a light
yellow oil in 97% yield. ¹H NMR (400
MHz, CDCl3): δ = 3.67 (s, 3 H), 2.30
(t, J = 7.5 Hz, 2 H), 2.13 (t,
J = 6.9 Hz, 4 H), 1.59-1.69
(m, 2 H), 1.42-1.54 (m, 4 H), 1.17-1.42 (m, 16
H), 0.88 (t, J = 6.7 Hz, 3 H).
Methyl (
Z
)-Octadec-9-enoate (5l): Ni(OAc)2˙4H2O
(250 mg, 1 mmol) was dissolved in degassed EtOH (10 mL), followed
by the addition of 1,2-ethylenediamine (67 µL,
1
mmol). Sodium borohydride (38 mg dissolved in 950 µL EtOH
and 50 µL of 2 N aq NaOH, 1 mmol) was added and the solution
turned from blue to black in color. The catalyst was ready for use
after cessation of hydrogen release.
A flask containing 4l (1.7 g, 6 mmol) was flushed with hydrogen.
The above freshly prepared P-2 Ni-ethylene-diamine catalyst
(6 mL) was introduced by a gas-tight syringe. Upon the disappearance
of 4l, as monitored by TLC, the flask was
flushed with air to stop the reaction. The reaction mixture was
diluted with EtOAc (6 mL), filtered through a short pad of silica
gel, and concentrated in vacuo. The residue was purified by silica
gel chromatography (2-5% EtOAc in hexane) to provide 5l
¹4 as a light yellow
oil in 99% yield. The ratio of cis-5 to the over-reduced alkane and the corresponding trans isomer was analyzed by GC-MS (Agilent
G1800C, HP-5MS column, 30 m × 0.25 mm × 0.25 µm). ¹H
NMR (400 MHz, CDCl3): δ = 5.30-5.40
(m, 2 H), 3.67 (s, 3 H), 2.30 (t, J = 7.5
Hz, 2 H), 1.95-2.06 (m, 4 H), 1.56-1.70 (m, 2
H), 1.20-1.38 (m, 20 H), 0.88 (t, J = 6.8
Hz, 3 H).
2,3-Dihydroxypropyl (
Z
)-Octadec-9-enoate
(9.9-MAG): Compound 5l (1.5 g, 5 mmol)
was added to a two-necked flask containing DMSO (10 mL). Glycerol
(2.3 g, 25 mmol) and P1 phosphazene (137 mg, 0.5 mmol) were subsequently added.
One neck of the reaction flask was connected to a vacuum line (ca.
60 mmHg) installed in the fume hood. The reaction mixture was stirred
at r.t. overnight. Saturated aq NaHCO3 (50 mL) was added;
then the mixture was extracted with EtOAc (3 × 50 mL).
The combined organic extracts were dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was submitted to
purification by silica gel chromatography (20-60% EtOAc
in hexane) to give a white solid containing 1-MAG as the major product,
accompanied with 3% of corresponding 2-MAG, in a total
yield of 87%.
The crude product was dissolved
in MeCN at a concentration of 100 mg/mL (slight heating
if needed) and then left in the refrigerator (4 ˚C) for
crystallization. The precipitant was filtered to give 9.9-MAG with
over 99% purity. The mixture can also be purified by preparative
RP-HPLC (Atlantis dC18 column, 5 µm, 30 × 150
mm; MeCN-H2O). Three authentic samples corresponding
to the major by-products in this case: 1,3-dihydroxypropyl (Z)-octadec-9-enoate (major 2-MAG by-product),
2,3-dihydroxypropyl (E)-octadec-9-enoate
and over-reduced 2,3-dihydroxypropyl octadecanoate have been prepared
and analyzed to reassure effective HPLC analysis and purification.
The chemical purity of final products were also examined by ¹H
NMR and ¹³C NMR spectroscopic analyses.5,6,¹5 ¹H
NMR (400 MHz, CDCl3): δ = 5.29-5.39 (m,
2 H), 4.14 (d, J = 5.5 Hz, 2
H), 3.87-3.95 (m, 1 H), 3.68 (dd, J = 11.6,
3.5 Hz, 1 H), 3.57 (dd, J = 11.6,
6.1 Hz, 1 H), 3.49 (br, 2 H), 2.34 (t, J = 7.6
Hz, 2 H), 1.95-2.07 (m, 4 H), 1.56-1.67 (m, 2
H), 1.19-1.38 (m, 20 H), 0.88 (t, J = 6.7
Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 174.51,
130.17, 129.84, 70.40, 65.18, 63.58, 34.30, 32.08, 29.94, 29.88, 29.70,
29.50 (2 × C), 29.37, 29.30 (2 × C), 27.39, 27.34, 25.05,
22.86, 14.29.
12
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White PD.
Linclau B.
J.
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15 The E-double
bond isomers, if present, could be detected on the ¹³C
NMR spectra taken in CDCl3. Their olefinic carbons appeared
in the downfield region relative to those of Z-configured
1-MAGs (ca. 0.4-0.6 ppm difference).
