The first total synthesis of the marine fatty acid (±)-9-methoxypentadecanoic acid: A synthetic route towards mid-chain methoxylated fatty acids

Article abstract of DOI:10.1016/S0009-3084(03)00043-4

The marine fatty acid (±)-9-methoxypentadecanoic acid was synthesized for the first time in seven steps (7.8% overall yield) starting from commercially available 9-decen-1-ol. The key step in the synthesis was the coupling of pentylmagnesium bromide with 1-benzyloxy-9,10-epoxydecane under 1,5-cyclooctadiene copper (I) chloride catalysis. Nuclear magnetic resonance data are provided for the first time for this type of methoxylated fatty acids and the synthetic approach utilized is of general applicability since it can be used in the synthesis of other mid-chain methoxylated fatty acids. This synthetic methodology should afford sufficient quantities of these fatty acids for biological evaluation. The spectral data obtained for the title compound will also be helpful in subsequent characterizations of other mid-chain methoxylated fatty acids using nuclear magnetic resonance spectroscopy.

Full text of DOI:10.1016/S0009-3084(03)00043-4

Chemistry and Physics of Lipids 124 (2003) 63–67
The first total synthesis of the marine fatty acid
( )-9-methoxypentadecanoic acid: a synthetic route
towards mid-chain methoxylated fatty acids
Néstor M. Carballeira∗, Carlos Miranda
Department of Chemistry, University of Puerto Rico, P.O. Box 23346, San Juan 00931-3346, Puerto Rico
Received 21 February 2003; accepted 12 March 2003
Abstract
The marine fatty acid ( )-9-methoxypentadecanoic acid was synthesized for the first time in seven steps (7.8% overall yield)
starting from commercially available 9-decen-1-ol. The key step in the synthesis was the coupling of pentylmagnesium bromide
with 1-benzyloxy-9,10-epoxydecane under 1,5-cyclooctadiene copper (I) chloride catalysis. Nuclear magnetic resonance data are
provided for the first time for this type of methoxylated fatty acids and the synthetic approach utilized is of general applicability
since it can be used in the synthesis of other mid-chain methoxylated fatty acids. This synthetic methodology should afford suffi-
cient quantities of these fatty acids for biological evaluation. The spectral data obtained for the title compound will also be helpful
in subsequent characterizations of other mid-chain methoxylated fatty acids using nuclear magnetic resonance spectroscopy.
© 2003 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Algae; Fatty acids; 9-Methoxypentadecanoic acid; Synthesis
1. Introduction
triglycerides of the bacillus Helicobacter pylori
(Inamoto et al., 1995). On the other hand, the four
mid-chain methoxylated fatty acids 9-methoxypenta-
decanoic acid, 9-methoxyheptadecanoic acid, 13-me-
thoxyheneicosanoic acid, and 15-methoxytricosanoic
acid were identified in the red alga Schizymenia dubyi
collected in Sicily, Italy (Barnathan et al., 1998).
However, in all of these cases the absolute stere-
ochemistry at the methoxylated carbon was never
determined and since these compounds were only
identified by gas chromatography-mass spectrometry,
nuclear magnetic resonance spectral data for all of
these fatty acids is still lacking in the lipid literature.
In addition, there are no reported syntheses for these
saturated mid-chain methoxylated fatty acids, but a
couple of monounsaturated mid-chain methoxylated
Saturated mid-chain methoxylated fatty acids are
rare in nature, but several interesting examples have
been identified in bacteria and marine organisms. For
example, the acid-producing bacterium Thiobacillus
produces the fatty acids 10-methoxyoctadecanoic acid,
11-methoxyoctadecanoic acid, 12-methoxyeicosanoic
acid, and 13-methoxyeicosanoic acid (Kerger et al.,
1986). Some recent findings also reported the fatty
acids 11-methoxyheptadecanoic acid and 11-metho-
xynonadecanoic acid in the cholesterol esters and
∗
Corresponding author. Tel.: +1-787-764-0000x4791;
fax: +1-787-756-8242.
E-mail address: ncarball@upracd.upr.clu.edu (N.M. Carballeira).
0009-3084/03/$ – see front matter © 2003 Elsevier Science Ireland Ltd. All rights reserved.
doi:10.1016/S0009-3084(03)00043-4

64
N.M. Carballeira, C. Miranda / Chemistry and Physics of Lipids 124 (2003) 63–67
fatty acids have been synthesized, in particular those
derived from Lyngbya majuscula (Müller et al., 1995;
Mesguiche et al., 1999). Therefore, a general and
practical synthetic methodology towards saturated
mid-chain methoxylated fatty acids is needed if we
are to fully characterize these fatty acids and explore
their biological potential. In the present communi-
cation we report the first total synthesis of racemic
9-methoxypentadecanoic acid, since the absolute
stereochemistry at the asymmetric carbon in the nat-
ural fatty acid is not known. This was achieved by
a seven-step synthetic methodology that could very
well be used in the synthesis of most of the known
saturated mid-chain methoxylated fatty acids.
viously reported 1-benzyloxy-9-decene (Prugh et al.,
1986). IR (neat) ν 3063, 3028, 2926, 2851, 1641,
1493, 1453, 1360, 1100, 909, 732, 695 cm−1 13C
;
NMR (CDCl3, 75.5 MHz) δ 139.1 (d, C-2), 138.8 (s),
128.3 (d), 127.6 (d), 127.5 (d), 114.2 (t, C-1), 72.9 (t),
70.5 (t), 33.9 (t, C-3), 29.8 (t), 29.5 (t), 29.1 (t), 29.0
(t), 26.2 (t), 25.6 (t); GC-MS m/z (relative intensity)
M+ 246 (1), 161 (1), 155 (1), 147 (1), 137 (2), 118
(2), 108 (6), 107 (22), 106 (2), 105 (3), 104 (4), 95
(14), 92 (35), 91 (100), 83 (4), 81 (12), 79 (6), 77 (3),
69 (8), 67 (7), 65 (8), 55 (14).
2.3. 1-Benzyloxy-9,10-epoxydecane
Magnesium monoperoxyphthalate (MMPP) (6.12 g,
15.9 mmol) was added to a solution of 1-benzyloxy-9-
decene (0.65 g, 2.65 mmol) dissolved in ethanol. The
reaction mixture was stirred at room temperature
for 48 h. A mixture of 120 ml of hexane and water
(1:1) was added and the organic phase was separated,
dried and evaporated. The residue was purified by
silica gel chromatography using hexane–diethyl ether
(8:2) as eluent, which afforded 0.51 g (73% yield)
of 1-benzyloxy-9,10-epoxydecane. IR (neat) ν 3032,
2924, 2858, 1495, 1452, 1359, 1256, 1203, 1104,
2. Materials and methods
2.1. Instrumentation
1H NMR (300 and 500 MHz) and 13C NMR (75
and 125 MHz) were either recorded on a Bruker
DPX-300 spectrometer or a Bruker DRX-500 spec-
1
trometer. H NMR chemical shifts are reported with
respect to internal (CH3)4Si, 13C NMR chemical
shifts are reported in parts per million relative to
CDCl3 (77.0 ppm). GC/MS analyses were recorded
at 70 eV using a Hewlett-Packard 5972A MS Chem-
Station equipped with a 30 mm × 0.25 mm spe-
cial performance capillary column (HP-5MS) of
polymethyl siloxane cross-linked with 5% phenyl
methylpolysiloxane. IR spectra were recorded on a
Nicolet 600 FT-IR spectrophotometer.
911, 830, 735 cm−1; H NMR (CDCl3, 300 MHz) δ
1
7.40–7.24 (5H, m, C6H5), 4.50 (2H, s, CH2-Ph), 3.46
(2H, t, J = 6.6 Hz, H-1), 2.90 (1H, m, H-9), 2.74
(1H, A part ABX system, H-10), 2.46 (1H, B part
ABX system, J = 2.75 and 5.01 Hz, H-10), 1.61–1.26
(14H, m, CH2); 13C NMR (CDCl3, 75.5 MHz) δ
138.6 (s), 128.3 (d), 127.6 (d), 127.4 (d), 72.8 (t),
70.4 (t), 52.4 (d, C-2), 47.1 (t, C-1), 32.4 (t, C-3),
29.7 (t), 29.4 (t), 29.3 (t), 26.1 (t, C-8), 25.9 (t, C-4);
GC-MS m/z (relative intensity) M+ 262 (M+, 0.1),
245 (0.1), 161 (0.1), 153 (1), 135 (1), 133 (1), 108
(10), 107 (53), 105 (5), 104 (6), 97 (2), 95 (5), 92
(24), 91 (100), 81 (10), 79 (9), 67 (10), 55 (13).
2.2. 1-Benzyloxy-9-decene
A solution of 9-decen-1-ol (0.5 g, 3.2 mmol) in
dry tetrahydrofuran (THF), was added dropwise with
stirring to a suspension of sodium hydride (0.23 g,
9.6 mmol) in 2 ml of THF at room temperature under
nitrogen. Then, 0.6 ml of benzylchloride (4.15 mmol)
was added dropwise and the resulting mixture was
heated under reflux for 16 h. Subsequently, 10 ml of
water was added, the solvent was evaporated and the
mixture was extracted with diethyl ether (2 × 80 ml).
The extracts were dried (Na2SO4), and the solvent
was evaporated. The resulting residue was purified by
distillation obtaining 0.65 g (83% yield) of the pre-
2.4. 1-Benzyloxy-9-pentadecanol
A solution of 0.3 ml (0.35 g, 2.34 mmol) of
1-bromopentane in 2 ml of THF was added drop-
wise under nitrogen to a suspension of 0.057 g
(2.34 mmol) of magnesium turnings in 0.5 ml of re-
fluxing THF. After completion of the addition the
Grignard reagent was cooled to −20 ◦C and 0.51 g
(1.95 mmol) of 1-benzyloxy-9,10-epoxydecane and

N.M. Carballeira, C. Miranda / Chemistry and Physics of Lipids 124 (2003) 63–67
65
–CH3). 13C NMR (CDCl3, 125.8 MHz) δ 138.7 (s),
128.3 (d), 127.6 (d), 127.4 (d), 81.0 (d, C-9), 72.8
(t, CH2OPh), 70.5 (t, C-1), 56.3 (q, OCH3), 34.6 (t),
33.4 (t), 29.8 (t), 29.7 (t), 29.5 (t), 29.42 (t), 29.39 (t),
26.9 (t), 26.2 (t), 25.2 (t), 22.63 (t), 22.62 (t), 14.1 (q,
–CH3). GC-MS m/z (relative intensity) M+-32 316
(5), 263 (8), 225 (1), 207 (1), 171 (3), 157 (3), 142
(3), 130 (4), 129 (41), 117 (7), 108 (3), 107 (12), 97
(30), 92 (13), 91 (100), 83 (4), 79 (5), 71 (14), 67 (5),
55 (28).
20 mg of 1,5-cyclooctadienecopper (I) chloride was
added. After stirring the reaction mixture for 16 h
at room temperature 3 ml of 1 M HCl was added
and the THF was evaporated in vacuo. The residue
was extracted with diethyl ether (2 × 80 ml) and the
combined extracts were washed with 80 ml of 2 M
KHCO3, dried (Na2SO4), and the solvent evaporated.
The resulting residue was chromatographed on silica
gel (hexane–diethyl ether, 8:2) yielding 0.56 g (87%
yield) of 1-benzyloxy-9-pentadecanol. IR (neat) ν
3450 (OH), 3024, 2921, 2845, 1453, 1365, 1273,
1104, 729 cm−1 1H NMR (CDCl3, 500 MHz) δ
;
2.6. 9-Methoxypentadecan-1-ol
7.33–7.24 (5H, m, C6H5), 4.49 (2H, s, CH2-Ph), 3.56
(1H, m, H-9), 3.45 (2H, t, J = 6.6 Hz, H-1), 1.60 (4H,
m, H-8, H-10), 1.42–1.29 (20H, m, CH2), 0.89 (3H, t,
J = 6.8 Hz, –CH3). 13C NMR (CDCl3, 125.8 MHz)
δ 138.6 (s), 128.2 (d), 127.5 (d), 127.4 (d), 72.8 (t,
CH2OPh), 71.8 (d, C-9), 70.4 (t, C-1), 37.40 (t), 37.37
(t), 31.8 (t), 29.66 (t), 29.57 (t), 29.48 (t), 29.34 (t),
29.31 (t), 26.1 (t), 25.5 (t), 22.5 (t), 14.0 (q, –CH3).
GC-MS m/z (relative intensity) M+ 334 (0.1), 316
(5), 249 (2), 225 (3), 207 (1), 188 (1), 161 (1), 157
(2), 151 (1), 137 (1), 125 (2), 111 (3), 107 (25), 105
(3), 104 (5), 97 (9), 95 (5), 92 (18), 91 (100), 83 (5),
81 (4), 79 (4), 69 (8), 65 (4), 57 (6), 55 (18).
A solution of 0.51 g (1.46 mmol) of 1-benzyloxy-9-
methoxypentadecane in 3 ml of methanol and 0.1 ml
of acetic acid was stirred with 50 mg of Pd/C (10%)
under H2 (1 bar) for 12 h. The reaction mixture was fil-
tered through Celite®, the solvent removed in vacuo,
and the resulting residue was chromatographed on sil-
ica gel (hexane–ether, 8:2) resulting in 0.18 g (47%
yield) of 9-methoxypentadecan-1-ol. IR (neat) ν 3383
(OH), 2931, 2861, 1460, 1375, 1281, 1196, 1097,
1
719 cm−1; H NMR (CDCl3, 500 MHz) δ 3.63 (2H,
t, J = 6.7 Hz, H-1), 3.31 (3H, s, –OCH3), 3.11 (1H,
m, H-9), 1.65 (1H, brs, –OH), 1.55 (2H, m, H-2),
1.43 (4H, m, H-8, H-10), 1.39–1.22 (18H, m, CH2),
0.89 (3H, t, J = 6.9 Hz, –CH3). 13C NMR (CDCl3,
125.8 MHz) δ 81.0 (d, C-9), 63.1 (t, C-1), 56.3 (q,
–OCH3), 33.5 (t), 33.4 (t), 32.8 (t), 32.1 (t), 29.8 (t),
29.5 (t), 29.3 (t), 25.7 (t), 25.31 (t), 25.26 (t), 24.9 (t),
22.6 (t), 14.0 (q, –CH3). GC-MS m/z (relative inten-
sity) M+-1 257 (0.1), 243 (1), 208 (1), 174 (6), 173
(52), 141 (26), 130 (9), 129 (100), 123 (8), 109 (2),
99 (3), 97 (50), 95 (8), 85 (6), 83 (5), 81 (34), 71 (45),
69 (17), 67 (21), 58 (9), 55 (60).
2.5. 1-Benzyloxy-9-methoxypentadecane
Into a two-necked round-bottom flask and under a
nitrogen atmosphere, was placed 0.56 g (1.68 mmol)
of 1-benzyloxy-9-pentadecanol in 3 ml of dimethyl
sulfoxide (DMSO). Separately, two equivalents of
NaH (0.080 g, 3.33 mmol) were dissolved in 1 ml of
DMSO and added dropwise to the reaction mixture
followed by stirring at room temperature for 1 h. An
excess of CH3I was then added, and the reaction mix-
ture was further stirred for 2 h. After this, the mixture
was diluted with 30 ml of hexane–diethyl ether (1:1)
and washed with H2O (2 × 30 ml) to remove the
DMSO. The organic phase was dried over Na2SO4,
filtered, and evaporated in vacuo, affording 0.51 g
(87% yield) of 1-benzyloxy-9-methoxypentadecane.
IR (neat) ν 3024, 2927, 2839, 1437, 1278, 1114,
2.7. 9-Methoxypentadecanal
To a stirred solution of 9-methoxypentadecan-1-ol
(0.18 g, 0.68 mmol) in 10 ml of CH2Cl2 was slowly
added pyridinium chlorochromate (0.42 g, 1.98 mmol)
at room temperature. After 12 h, the reaction mixture
was filtered through Florisil and washed with diethyl
ether (3 × 15 ml). Evaporation of the solvent afforded
0.15 g (90% yield) of 9-methoxypentadecanal. IR
(neat) ν 2929, 2854, 1735, 1458, 1376, 1290, 1115,
749 cm−1; H NMR (CDCl3, 500 MHz) δ 7.34–7.25
1
(5H, m, C6H5), 4.50 (2H, s, CH2-Ph), 3.46 (2H, t,
J = 6.6 Hz, H-1), 3.31 (3H, s, –OCH3), 3.11 (1H, m,
H-9), 1.73 (2H, m, H-2), 1.61 (4H, m, H-8, H-10),
1.35–1.22 (18H, m, CH2), 0.88 (3H, t, J = 6.8 Hz,
1
1099, 948 cm−1; H NMR (CDCl3, 500 MHz) δ 9.7

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N.M. Carballeira, C. Miranda / Chemistry and Physics of Lipids 124 (2003) 63–67
(1H, brt, J = 1.7 Hz, CHO), 3.30 (3H, s, –OCH3),
3.10 (1H, m, H-9), 2.40 (2H, dt, J = 7.4 and 1.7 Hz,
H-2), 1.61 (2H, m, H-3), 1.42 (4H, m, H-8, H-10),
1.35–1.25 (16H, m, CH2), 0.86 (3H, t, J = 6.6 Hz,
–CH3). 13C NMR (CDCl3, 125.8 MHz) δ 200.6 (s,
C-1), 81.0 (d, C-9), 56.3 (q, –OCH3), 33.5 (t), 33.4
(t), 32.8 (t), 32.1 (t), 29.8 (t), 29.6 (t), 29.3 (t), 25.7 (t),
25.31 (t), 25.26 (t), 25.0 (t), 22.6 (t), 14.0 (q, –CH3).
GC-MS m/z (relative intensity) M+-1 255 (0.1), 224
(1), 172 (10), 171 (90), 139 (8), 130 (8), 129 (100),
121 (16), 111 (3), 98 (6), 97 (61), 95 (21), 93 (11),
85 (3), 83 (6), 81 (10), 79 (9), 71 (24), 69 (26), 67
(16), 57 (11), 55 (65).
2.8. 9-Methoxypentadecanoic acid
To a solution of 9-methoxypentadecanal (0.15 g,
0.61 mmol) in t-butyl alcohol was added a solution
of NaClO2 (0.22 g, 2.5 mmol) and NaH2PO4 (0.35 g,
3 mmol) as buffer in 3 ml of water over a period of
10 min. The reaction mixture was stirred at room tem-
perature for 12 h. The mixture was diluted with water
and extracted with diethyl ether (3 × 20 ml). The
combined extracts were dried over Na2SO4 and con-
centrated. The resulting crude product was purified by
phase transfer with an aqueous solution of NaHCO3
and ether. Acidification of the aqueous phase and ex-
traction with diethyl ether afforded 0.66 g (40% yield)
of the previously reported 9-methoxypentadecanoic
acid (Barnathan et al., 1998). 1H NMR (CDCl3,
300 MHz) δ 3.31 (3H, s, –OCH3), 3.12 (1H, m, H-9),
2.35 (2H, t, J = 7.5 Hz, H-2), 1.63 (2H, m, H-3),
1.43 (4H, m, H-8, H-10), 1.40–1.25 (16H, m, CH2),
0.89 (3H, t, J = 6.6 Hz, –CH3). 13C NMR (CDCl3,
75.5 MHz) δ 177.0 (s, C-1), 81.0 (d, C-9), 56.3 (q,
–OCH3), 33.5 (t), 33.4 (t), 32.8 (t), 32.1 (t), 29.8 (t),
29.6 (t), 29.2 (t), 25.7 (t), 25.31 (t), 25.26 (t), 24.9 (t),
22.7 (t), 14.1 (q, –CH3). GC-MS m/z (relative inten-
sity) M+-1 271 (0.1), 240 (1), 188 (6), 187 (53), 169
(9), 155 (62), 137 (14), 130 (9), 129 (100), 119 (5),
113 (2), 109 (16), 97 (54), 95 (18), 93 (4), 71 (35),
69 (19), 67 (14), 60 (12), 57 (7), 55 (66).
Scheme 1. Synthesis of racemic 9-methoxypentadecanoic acid. (i)
NaH, THF, BzCl; (ii) MMPP, EtOH, 48 h; (iii) C5H11MgBr, THF,
1,5-cyclooctadienecopper (I) chloride, −20 ◦C; (iv) NaH, CH3I,
DMSO, 2 h; (v) Pd/C (10%), H2, CH3OH-CH3CO2H; (vi) PCC,
CH2Cl2, 12 h; and (vii) NaClO2, NaH2PO4, H2O, 12 h.
epoxydecane with pentyl magnesium bromide to gen-
erate the mid-chain hydroxylated 1-benzyloxy-9-pen-
tadecanol (Scheme 1). This approach seems to be
general, inasmuch as it can be used to generate other
biosynthetically related mid-chain methoxylated fatty
acids, such as the 11-methoxyheptadecanoic acid
(Inamoto et al., 1995) by just chaining the terminal
epoxide and Grignard reagent chain-lengths. There-
fore, our synthesis started with 9-decen-1-ol, which
was converted to the already reported 1-benzyloxy-9-
decene through the reaction of the alcohol with benzyl
chloride. The double bond was effectively epoxidized
3. Results and discussion
The synthesis of ( )-9-methoxypentadecanoic acid
(1) was based on the opening of 1-benzyloxy-9,10-

N.M. Carballeira, C. Miranda / Chemistry and Physics of Lipids 124 (2003) 63–67
67
with MMPP in ethanol in a 73% yield. MMPP
turned out to be more efficient than the classical
m-chloroperoxybenzoic acid (m-CPBA) in epoxidiz-
ing these long chain alkenes, since the latter reagent
only afforded moderate to low yields at long reaction
times. In the next step towards the total synthesis of
(1) the 1-benzyloxy-9,10-epoxydecane was opened
with 1-pentylmagnesium bromide assisted by cat-
alytic amounts of 1,5-cyclooctadiene copper (I) chlo-
ride (Cook et al., 1969; Küchler et al., 1991), which
afforded the desired 1-benzyloxy-9-pentadecanol in
an 87% yield. The use of the catalyst turned out to be
essential since in the absence of the copper catalyst
no coupling was observed. The 1-benzyloxy-9-penta-
decanol was readily methylated with NaH and CH3I
in DMSO, which afforded in an 87% yield, the
1-benzyloxy-9-methoxypentadecane. Deprotection of
the primary alcohol was achieved using hydrogen and
catalytic amounts of 10% Pd/C for 12 h resulting in a
47% yield of 9-methoxypentadecan-1-ol (Scheme 1).
Final oxidation to the acid was accomplished by first
oxidizing the alcohol to the aldehyde with pyridinium
chlorochromate (90% yield) and then oxidizing the
aldehyde to the desired 9-methoxypentadecanoic acid
(1) with NaClO2 in t-butyl alcohol and NaH2PO4 as
buffer. The overall yield for the seven steps of this
synthesis was 7.8%.
The most significant absorption in the NMR spec-
trum of the ( )-9-methoxypentadecanoic acid (1)
was observed for the carbons and hydrogens bear-
ing the methoxy functionality. For example, the
methoxy protons resonated at δ 3.31 ppm and the
methoxy carbon was observed at δ 56.3 ppm, while
the methine hydrogen resonated at δ 3.12 ppm and
the methine carbon at δ 81.0 ppm. These 1H and
13C NMR displacements seem to be characteris-
tic for saturated mid-chain methoxylated fatty acids
and useful as a future reference for other similar
analogs.
( )-9-methoxypentadecanoic acid (1) was achieved
in a 7.8% overall yield, and nuclear magnetic res-
onance spectral data for (1) is reported for the first
time in the literature.
Acknowledgements
This work was supported by the SCORE program
of the National Institutes of Health (NIH) under Grant
No. SO6GM08102. C. M. thanks the Puerto Rico EP-
SCoR (NSF) program for a doctoral fellowship. The
technical assistance of Marlene Cotto, an undergradu-
ate student sponsored by the UPR NIH-RISE program,
is appreciated.
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In summary, a general and practical synthetic
methodology towards saturated mid-chain fatty acids
is reported, the total synthesis of the marine fatty acid