First total syntheses of (Z)-15-methyl-10-hexadecenoic acid and the (Z)-13-methyl-8-tetradecenoic acid

Article abstract of DOI:10.1016/j.chemphyslip.2006.10.003

The first total syntheses for the (Z)-15-methyl-10-hexadecenoic acid and the (Z)-13-methyl-8-tetradecenoic acid were accomplished in seven steps and in 31-32% overall yields. The (trimethylsilyl)acetylene was the key reagent in both syntheses. It is proposed that the best synthetic strategy towards monounsaturated iso methyl-branched fatty acids with double bonds close to the ω end of the acyl chain is first acetylide coupling of (trimethylsilyl)acetylene to a long-chain bifunctional bromoalkane followed by a second acetylide coupling to a short-chain iso bromoalkane, since higher yields are thus obtained. Spectral data is also presented for the first time for these two unusual fatty acids with potential as biomarkers and as topoisomerase I inhibitors.

Full text of DOI:10.1016/j.chemphyslip.2006.10.003

Chemistry and Physics of Lipids 145 (2007) 37–44
First total syntheses of (Z)-15-methyl-10-hexadecenoic acid
and the (Z)-13-methyl-8-tetradecenoic acid
∗
´
Nestor M. Carballeira , Nashbly Montano, Luis F. Padilla
Department of Chemistry, University of Puerto Rico, P.O. Box 23346, San Juan, PR 00931-3346, USA
Received 19 July 2006; received in revised form 17 October 2006; accepted 18 October 2006
Available online 13 November 2006
Abstract
The first total syntheses for the (Z)-15-methyl-10-hexadecenoic acid and the (Z)-13-methyl-8-tetradecenoic acid were accom-
plished in seven steps and in 31–32% overall yields. The (trimethylsilyl)acetylene was the key reagent in both syntheses. It is
proposed that the best synthetic strategy towards monounsaturated iso methyl-branched fatty acids with double bonds close to the
␻ end of the acyl chain is first acetylide coupling of (trimethylsilyl)acetylene to a long-chain bifunctional bromoalkane followed by
a second acetylide coupling to a short-chain iso bromoalkane, since higher yields are thus obtained. Spectral data is also presented
for the first time for these two unusual fatty acids with potential as biomarkers and as topoisomerase I inhibitors.
© 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: (Z)-15-Methyl-10-hexadecenoic acid; (Z)-13-Methyl-8-tetradecenoic acid; Fatty acids; Synthesis; Biomarkers
1. Introduction
the iso C15–C17 (n − 6) series exemplified by the fatty
acids (Z)-13-methyl-8-tetradecenoic acid (1a) and the
(Z)-15-methyl-10-hexadecenoic acid (1b). Acid 1a has
not been isolated from natural sources, but the (Z)-15-
methyl-10-hexadecenoic acid (1b) has been identified
before in several organisms, such as in the siphonarid
limpet Siphonaria denticulata (Carballeira et al., 2001).
Because of the nature of the (n − 6) fatty acids 1a and 1b,
i.e., C15–C17 chain lengths and iso ramification, there
is a high probability for these compounds to be also
of bacterial origin (Kaneda, 1991). In addition, these
fatty acids remain under-explored as possible therapeu-
tic agents despite the fact that iso-branched fatty acids
with similar chain lengths have displayed considerable
topoisomerase-I inhibition and also cytotoxicity (Lee et
al., 1998; Reyes and Carballeira, 1996). Therefore, in
order to provide spectral data so as to aid in their iden-
tification in nature and to supply enough material for
further biological studies we have developed the first
total syntheses for acids 1a and 1b following a similar
Methyl-branched fatty acids are of interest as
biomarkers for alkane-utilizing bacteria in soils and
as biomarkers for sulphate-reducing bacteria, such as
Desulfovibrio species, also found in wetland sediments
(Boon et al., 1977; Boon et al., 1996). Particularly inter-
esting fatty acids for the Desulfovibrio species are the
iso methyl-branched fatty acids i-15:1 (n − 7) and i-17:1
(n − 7), which are characteristic for the Desulfovibrio
and both fatty acids seem to be biosynthetically related
by a two carbon extension of the shorter-chain C15 ana-
log (Dowling et al., 1988; Edlund et al., 1985). While the
iso C15–C17 (n − 7) series has been well studied, little is
known of another series of odd-chain fatty acids, namely
∗
Corresponding author. Tel.: +1 787 764 0000x4791;
fax: +1 787 756 8242.
E-mail address: nmcarballeira@uprrp.edu (N.M. Carballeira).
0009-3084/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.chemphyslip.2006.10.003

38
N.M. Carballeira et al. / Chemistry and Physics of Lipids 145 (2007) 37–44
synthetic sequence consisting of seven steps and using
(trimethylsilyl)acetylene as the key reagent in the syn-
theses.
2.2.2. 9-Bromo-1-[(tetrahydropyran-2-yl)oxy]nonane
(3b)
The 9-bromo-1-[(tetrahydropyran-2-yl)oxy]nonane
(3b) was obtained as a colorless oil in a 100% yield from
the reaction of 9-bromo-1-nonanol (4.06 g, 18.18 mmol)
with 2,3-dihydro-2H-pyran (41.00 mmol) and catalytic
amounts of PTSA in dichloromethane (12 mL) accord-
ing to the general procedure described above. Compound
3b presented comparable spectral data to the one
previously reported in the literature (Grube et al.,
2006).
2. Materials and methods
2.1. Instrumentation
1H NMR (300 MHz) and 13C NMR (75 MHz) were
recorded on a Bruker DPX-300 spectrometer. 1H NMR
chemical shifts are reported with respect to inter-
nal (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 ChemStation equipped with a
30 m × 0.25 mm special performance capillary column
(HP-5MS) of polymethyl siloxane crosslinked with 5%
phenyl methylpolysiloxane. IR spectra were recorded
on a Nicolet 600 FT-IR spectrophotometer (Thermo-
Nicolet, Madison, WI, USA). Elemental analyses were
performed by Galbraith Laboratories Inc., Knoxville,
Tennessee. High resolution mass spectral data was per-
formed at the Emory University Mass Spectrometry
Center.
2.3. General procedure for the first acetylide
coupling reaction
To a stirred solution of (trimethylsilyl)acetylene
(5.3–8.1 mL, 38.5–58.2 mmol) in dry THF (18.0 mL)
and under argon was added n-BuLi (2.5 M,
44.88–67.97 mmol) in hexane at −78 ◦C. After 5 min
HMPA(5.0–7.0 mL) (Caution!HMPAistoxicandsafety
precautions should be taken when handling this solvent)
and either 3a or 3b (3.94–5.42 g) were added dropwise
to the reaction mixture, maintaining the temperature at
−78 ◦C. After 24 h, the reaction mixture was quenched
with water. The organic product was extracted with
diethyl ether (2× 15 mL), dried over MgSO4, filtered,
and evaporated in vacuo, affording 4.02–4.74 g (87–98%
yield) of either 9-(trimethylsilyl)-1-[(tetrahydropyran-2
-yl)oxy]non-8-yne (4a) or 11-(trimethylsilyl)-1-[(tetra-
hydropyran-2-yl)oxy]undec-10-yne (4b). The products
4a and 4b were purified under vacuum distillation
(Kugelrohr) at 100–115 ◦C/3 mm Hg for 1 h.
2.2. General procedure for the protection of the
bromo-alcohols
To 4.00 g of either 7-bromo-1-heptanol or 9-bromo-
1-nonanol in 12 mL of dichloromethane (CH2Cl2)
was added dropwise 2,3-dihydro-2H-pyran (35.85–
41.00 mmol) and catalytic amounts of p-toluene sul-
fonic acid (PTSA). The reaction mixture was stirred
for 24 h at room temperature. The organic layer was
washed with water (2× 50 mL), NaHCO3 (3× 50 mL),
and dried over MgSO4, filtered, and evaporated in
vacuo affording 5.55–5.59 g (97–100% yield) of either
3a or 3b. The products were purified using silica
gel column chromatography eluting with hexane/ether
(9:1).
2.3.1. 9-(Trimethylsilyl)-1-[(tetrahydropyran-2-yl)oxy]-
non-8-yne (4a)
The 9-(trimethylsilyl)-1-[(tetrahydropyran-2-yl)oxy]
non-8-yne (4a) was obtained as a colorless oil in a 87%
yield from the reaction of 3a (5.42 g, 19.42 mmol) with
n-BuLi in THF (18 mL) and (trimethylsilyl)acetylene
(7 mL) according to the general procedure described
above; IR (neat) νmax 2932, 2859, 2174, 1454, 1441,
1352, 1249, 1200, 1137, 1121, 1079, 1034, 843,
760 cm−1; 1H NMR (CDCl3) δ 4.57 (1H, m), 3.86–3.73
(2H, m), 3.50–3.35 (2H, m), 2.21 (2H, t, J = 7.1 Hz, H-7),
1.91–1.52 (10H, m, –CH2–), 1.33 (6H, m), 0.12 (9H, s,
–Si(CH3)3); 13C NMR (CDCl3) δ 107.68 (s, C-2), 98.83
(d), 84.45 (s), 67.60 (t, C-1), 62.33 (t), 30.76 (t), 29.66 (t),
28.90 (t), 28.72 (t), 28.54 (t), 26.08 (t), 25.47 (t), 19.81
(t), 19.68 (t), 0.16 (q, –Si(CH3)3); GC–MS (70 eV) m/z
(relative intensity) 295 (M+ − 1, 1), 223 (1), 183 (2),
173 (6), 123 (2), 111 (2), 109 (7), 103 (15), 101 (7), 85
(100), 75 (21), 73 (55), 69 (3), 67 (10), 59 (11), 57 (9),
2.2.1. 7-Bromo-1-[(tetrahydropyran-2-yl)oxy]heptane
(3a)
The 7-bromo-1-[(tetrahydropyran-2-yl)oxy]heptane
(3a) was obtained as a colorless oil in a 97% yield from
the reaction of 7-bromo-1-heptanol (4.00 g, 20.50 mmol)
with 2,3-dihydro-2H-pyran (35.85 mmol) and catalytic
amountsofPTSAindichloromethane(12 mL)according
to the general procedure described above. Compound 3a
presented comparable spectral data to the one previously
reported in the literature (Das et al., 2006).

N.M. Carballeira et al. / Chemistry and Physics of Lipids 145 (2007) 37–44
39
55 (11). HRMS (APCI) Calcd for C17H33O2Si [M + H]+
297.2250, found 297.2239.
previously reported in the literature (Karpinska et al.,
2004). HRMS (APCI) Calcd for C14H25O2 [M + H]+
225.1855, found 225.1846.
2.3.2. 11-(Trimethylsilyl)-1-[(tetrahydropyran-2-yl)-
oxy]undec-10-yne (4b)
2.4.2. 1-[(Tetrahydropyran-2-yl)oxy]undec-10-yne
(5b)
The 11-(trimethylsilyl)-1-[(tetrahydropyran-2-yl)-
oxy]undec-10-yne (4b) was obtained as a color-
less oil in a 98% yield from the reaction of 3b
(3.94 g, 12.82 mmol) with n-BuLi in THF (18 mL)
and (trimethylsilyl)acetylene (5 mL) according to the
general procedure described above; IR (neat) νmax 2931,
2855, 2174, 1454, 1352, 1249, 1200, 1136, 1121, 1079,
The 1-[(tetrahydropyran-2-yl)oxy]undec-10-yne (5b)
was obtained as a colorless oil in a 88% yield in
the reaction of 11-(trimethylsilyl)-1-[(tetrahydropyran-
2-yl)oxy]undec-10-yne (4b) (2.18 g, 6.72 mmol) with
tetrabutylammonium fluoride (1 M) in THF (8 mL)
following the general procedure described above. Com-
pound 5b presented comparable spectral data to the one
previously reported in the literature (Cryle et al., 2005).
HRMS (APCI) Calcd for C16H29O2 [M + H]+ 253.2159,
found 253.2168.
1
1033, 843, 760 cm−1; H NMR (CDCl3) δ 4.57 (1H,
m), 3.89–3.68 (2H, m), 3.51–3.35 (2H, m), 2.20 (2H,
t, J = 7.1 Hz, H-9), 1.80–1.51 (10H, m, –CH2–), 1.31
(10H, m), 0.12 (9H, s, –Si(CH3)3); 13C NMR (CDCl3)
δ 107.75 (s, C-10), 98.83 (d), 84.30 (s, C-11), 67.66
(t, C-1), 62.33 (t), 30.76 (t), 29.72 (t), 29.39 (t), 29.00
(t), 28.76 (t), 28.59 (t), 26.20 (t), 25.48 (t), 19.83 (t,
C-9), 19.68 (t), 0.16 (q, –Si(CH3)3); GC–MS (70 eV)
m/z (relative intensity) 323 (M+ − 1, 1), 309 (1), 183
(1), 173 (6), 159 (2), 149 (2), 137 (1), 119 (3), 103
(13), 101 (12), 97 (3), 93 (1), 91 (2), 86 (5), 85 (100),
83 (5), 81 (4), 75 (18), 73 (51), 69 (4), 67 (10), 61
(2), 59 (12), 57 (9), 56 (9), 55 (11). HRMS (APCI)
Calcd for C19H37O2Si [M + H]+ 325.2552, found
325.2563.
2.5. General procedure for the second acetylide
coupling reaction
To a solution of either 5a or 5b (1.42–2.57 g,
5.64–11.45 mmol) and dry THF (12.0 mL) at 0 ◦C
n-BuLi (2.5 M, 19.73–40.01 mmol) in hexane was
added while stirring under an argon atmosphere. After
45 min 1-bromo-4-methylpentane (16.91–34.34 mmol)
in HMPA (2.5–4.5 mL) (Caution! HMPA is toxic and
safety precautions should be taken when handling this
solvent) was added to the reaction mixture and the reac-
tion was left stirring for 24 h at room temperature. After
this time the reaction mixture was quenched with water
and the organic products were extracted with hexane (1×
50 mL), dried over MgSO4, filtered and evaporated in
vacuo, affording 1.29–2.76 g (3.84–8.94 mmol) of either
13-methyl-1-[(tetrahydropyran-2-yl)oxy]tetradec-8-yne
(6a) or 15-methyl-1-[(tetrahydropyran-2-yl)oxy]hexa-
dec-10-yne (6b) in 68–78% isolated yields. The
products were purified by distilling the impuri-
ties under vacuum distillation (Kugelrohr) at 110–
120 ◦C/3 mm Hg.
2.4. General procedure for the removal of the silyl
group
To a mixture of either 4a or 4b (2.18–3.67 g,
6.72–12.38 mmol) and dry THF (8.0 mL) was
added dropwise tetrabutylammonium fluoride (1 M,
6.72–12.38 mmol) at 0 ◦C. After 48h at room temper-
ature the reaction was quenched with HCl (2 M), and
the organic layer was washed with a brine solution (1×
50 mL), dried over MgSO4, filtered, and evaporated
in vacuo, affording 1.48–2.67 g (5.89–11.91 mmol) of
the desilylated products 5a and 5b in 88–96% isolated
yields. The products were used in the next step without
further purification.
2.5.1. 13-Methyl-1-[(tetrahydropyran-2-yl)oxy]-
tetradec-8-yne (6a)
The 13-methyl-1-[(tetrahydropyran-2-yl)oxy]tetra-
dec-8-yne (6a) was obtained as a colorless oil in a
78% yield from the reaction of 1-[(tetrahydropyran-
2-yl)oxy]non-8-yne (5a) (2.57 g, 11.45 mmol) with
1-bromo-4-methylpentane (34.34 mmol) in HMPA
(4.5 mL) and n-BuLi (40.01 mmol) according to the gen-
eral procedure described above; IR (neat) νmax 2932,
2857, 1466, 1441, 1384, 1366, 1352, 1261, 1201,
1137, 1121, 1078, 1034, 905, 869, 815 cm−1; 1H NMR
(CDCl3) δ 4.57 (1H, m), 3.86–3.70 (2H, m), 3.51–3.35
2.4.1. 1-[(Tetrahydropyran-2-yl)oxy]non-8-yne
(5a)
The 1-[(tetrahydropyran-2-yl)oxy]non-8-yne (5a)
was obtained as a colorless oil in a 96% yield in
the reaction of 9-(trimethylsilyl)-1-[(tetrahydropyran-
2-yl)oxy]non-8-yne (4a) (3.68 g, 12.38 mmol) with
tetrabutylammonium fluoride (1 M) in THF (8 mL)
following the general procedure described above. Com-
pound 5a presented comparable spectral data to the one

40
N.M. Carballeira et al. / Chemistry and Physics of Lipids 145 (2007) 37–44
(2H, m), 2.14 (4H, m), 1.84–1.45 (13H, m, –CH2–), 1.34
(8H, m, –CH2–), 0.87 (6H, d, J = 6.6 Hz, –CH(CH3)2);
13C NMR (CDCl3) δ 98.83 (d), 80.31 (s), 80.16 (s), 67.63
(t, C-1), 62.32 (t), 38.20 (t, C-12), 30.77 (t), 29.71 (t, C-
2), 29.09 (t), 29.01 (t), 28.79 (t), 27.64 (d, C-13), 27.06
(t), 26.16 (t, C-3), 25.49 (t), 22.57 (q, C-14, C-15), 19.68
(t), 18.72 (t, C-10), 18.36 (t, C-7); GC–MS (70 eV) m/z
(relative intensity) 308 (M+, 1), 223 (1), 195 (1), 193
(1), 179 (1), 123 (2), 121 (3), 111 (1), 109 (7), 107
(3), 101 (14), 97 (2), 95 (12), 93 (5), 91 (3), 85 (100),
81 (15), 79 (9), 77 (3), 69 (18), 67 (21), 57 (10), 55
(22).
2.6.1. 13-Methyl-8-tetradecyn-1-ol (7a)
The 13-methyl-8-tetradecyn-1-ol (7a) was obtained
as a colorless oil in a 91% yield from the reaction
of 13-methyl-1-[(tetrahydropyran-2-yl)oxy]tetradec-8-
yne (2.69 g, 8.73 mmol) with catalytic amounts of PTSA
in methanol (10 mL) according to the general pro-
cedure described above; IR (neat) νmax 3360 (OH,
broad), 2927, 2856, 1466, 1434, 1384, 1367, 1333,
1
1117, 1058, 725 cm−1; H NMR (CDCl3) δ 3.63 (2H,
t, J = 6.6 Hz, H-1), 2.12 (4H, m, H-7, H-10), 1.60–1.45
(7H, m, –CH2–), 1.35 (8H, m, –CH2–), 0.86 (6H, d,
J = 6.6 Hz, –CH(CH3)2); 13C NMR (CDCl3) δ 80.34
(s), 80.10 (s), 62.99 (t, C-1), 38.19 (t, C-12), 32.71
(t, C-2), 29.01 (t), 28.91 (t), 28.74 (t), 27.60 (d, C-
13), 27.02 (t, C-11), 25.61 (t), 22.56 (q, C-14, C-15),
18.98 (t, C-10),18.70 (t, C-7); GC–MS (70 eV) m/z
(relative intensity) 224 (M+, 1), 209 (1), 150 (5), 135
(6), 125 (2), 124 (8), 123 (8), 122 (4), 121 (20), 119
(1), 111 (6), 110 (10), 109 (54), 108 (9), 107 (19),
105 (4), 98 (11), 97 (12), 96 (24), 95 (66), 94 (16),
93 (34), 91 (17), 85 (5), 84 (6), 83 (17), 82 (57),
81 (85), 80 (31), 79 (59), 78 (6), 77 (21), 71 (8), 70
(14), 69 (100), 68 (42), 67 (90), 66 (11), 65 (14), 63
(2), 59 (1), 57 (19), 56 (12), 55 (81), 54 (36). HRMS
(APCI) Calcd for C15H29O [M + H]+ 225.2213, found
225.2213.
2.5.2. 15-Methyl-1-[(tetrahydropyran-2-yl)oxy]-
hexadec-10-yne (6b)
The 15-methyl-1-[(tetrahydropyran-2-yl)oxy]hexa-
dec-10-yne (6b) was obtained as a colorless oil in a
68% yield from the reaction of 1-[(tetrahydropyran-
2-yl)oxy]undec-10-yne (5b) (1.29 g, 3.84 mmol) with
1-bromo-4-methylpentane (16.91 mmol) in HMPA
(2.5 mL) and n-BuLi (19.73 mmol) according to the gen-
eral procedure described above; IR (neat) νmax 2937,
2856, 1467, 1366, 1255, 1201, 1140, 1121, 1080, 1033,
904, 869, 815 cm−1; 1H NMR (CDCl3) δ 4.57 (1H, m),
3.86–3.70 (2H, m), 3.50–3.35 (2H, m), 2.12 (4H, m),
1.76–1.48 (13H, m), 1.29 (12H, m, –CH2–), 0.87 (6H,
d, J = 6.6 Hz, –CH(CH3)2); 13C NMR (CDCl3) δ 98.83
(d), 80.10 (s), 80.11 (s), 67.67 (t, C-1), 62.33 (t), 38.19
(t, C-14), 30.77 (t), 29.73 (t, C-2), 29.43 (t), 29.14 (t),
28.82 (t), 27.63 (t), 27.06 (d, C-15), 26.21 (t), 25.48 (t),
22.57 (q, C-16, C-17), 19.68 (t), 18.99 (t, C-12), 18.73 (t,
C-9); GC–MS (70 eV) m/z (relative intensity) 336 (M+,
1), 251 (1), 149 (1), 137 (2), 123 (2), 121 (2), 111 (1), 109
(8), 107 (3), 105 (1), 101 (22), 96 (4), 95 (13), 93 (4), 91
(3), 85 (100), 81 (15), 79 (8), 77 (3), 71 (2), 69 (20), 67
(22), 65 (2), 57 (11), 56 (10), 55 (23); analysis calculated
for C22H40O2: C, 78.51; H, 11.98; found: C, 79.12; H,
12.67.
2.6.2. 15-Methyl-10-hexadecyn-1-ol (7b)
The 15-methyl-10-hexadecyn-1-ol (7b) was obtained
as a colorless oil in an 88% yield from the reaction
of 15-methyl-1-[(tetrahydropyran-2-yl)oxy]hexadec-
10-yne (1.24 g, 3.67 mmol) with catalytic amounts of
PTSA in methanol (10 mL) according to the general
procedure described above; IR (neat) νmax 3360 (OH,
broad), 2932, 2856, 1467, 1386, 1366, 1320, 1058 cm−1
;
1H NMR (CDCl3) δ 3.63 (2H, t, J = 6.6 Hz, H-1), 2.12
(4H, m, H-9, H-12), 1.55–1.45 (7H, m, –CH2–), 1.29
(12H, m, –CH2–), 0.87 (6H, d, J = 6.6 Hz, –CH(CH3)2);
13C NMR (CDCl3) δ 80.29 (s), 80.20 (s), 63.05 (t,
C-1), 38.19 (t, C-14), 32.77 (t, C-2), 29.48 (t), 29.36
(t), 29.12 (t), 29.08 (t), 28.81 (t), 27.63 (d, C-15), 27.05
(t), 25.70 (t), 22.56 (q, C-16, C-17), 18.99 (t, C-12),
18.72 (t, C-9); GC–MS (70 eV) m/z (relative intensity)
252 (M+, 1), 237 (1), 196 (1), 178 (1), 163 (1), 153 (1),
151 (1), 149 (3), 137 (2), 136 (3), 135 (7), 121 (11),
111 (5), 110 (12), 109 (59), 107 (12), 97 (10), 96 (29),
95 (62), 94 (10), 93 (23), 91 (11), 83 (17), 82 (54), 81
(77), 80 (20), 79 (40), 77 (14), 70 (11), 69 (100), 68
(37), 67 (81), 65 (10), 57 (16), 55 (75), 54 (31). HRMS
(APCI) Calcd for C17H33O [M + H]+ 253.2526, found
253.2525.
2.6. General procedure for the removal of the
tetrahydropyranyl protecting group
To a mixture of methanol (10.0 mL) and either 6a or
6b (1.23–2.69 g, 3.67–8.73 mmol) was added catalytic
amounts of PTSA and the reaction mixture was stirred
at 35 ◦C for 24 h. After this time the organic extract was
washed with a saturated solution of sodium bicarbonate
(3× 50 mL), dried over MgSO4, filtered, and evapo-
rated in vacuo, affording 0.82–1.79 g (3.24–7.96 mmol)
of the alkynols 7a and 7b for 88–91% yields. The prod-
uct was used in the next step without further purifi-
cation.

N.M. Carballeira et al. / Chemistry and Physics of Lipids 145 (2007) 37–44
41
1504, 1467, 1384, 1366, 1120, 1058, 805, 722 cm−1; 1H
NMR (CDCl3) δ 5.34 (2H, m, H-10, H-11), 3.63 (2H,
t, J = 6.6 Hz, H-1), 2.00 (5H, m, H-9, H-12, H-15), 1.70
(1H, brs, –OH), 1.58–1.50 (2H, m, H-2), 1.28 (16H, m,
–CH2–), 0.86 (6H, d, J = 6.6 Hz, –CH(CH3)2); 13C NMR
(CDCl3) δ 129.93 (d), 129.85 (d), 63.03 (t, C-1), 38.63
(t, C-14), 32.79 (t, C-2), 29.73 (t), 29.56 (t), 29.46 (t),
29.41(t), 29.26(t), 27.87(d, C-15), 27.54(t, C-12), 27.42
(t, C-9), 27.18 (t), 25.73 (t, C-3), 22.61 (q, C-16, C-17);
GC–MS (70 eV) m/z (relative intensity) 254 (M+, 1), 236
(3), 208 (1), 180 (1), 165 (1), 151 (2), 137 (5), 123 (11),
111 (8), 110 (15), 109 (22), 97 (21), 96 (45), 95 (46),
83 (36), 82 (75), 81 (50), 71 (10), 70 (18), 69 (80), 68
(34), 67 (55), 57 (42), 56 (56), 55 (100), 54 (31); analysis
calculated for C17H34O: C, 80.24; H, 13.47; found: C,
79.63; H, 12.37.
2.7. General procedure for the catalytic
hydrogenation of the alkynes
Into a 25 mL two-necked round-bottomed flask were
placed dry hexane, the alkyne, quinoline (1 mL), and pal-
ladium in activated carbon (Lindlar’s catalyst). One of
the necks was capped with a rubber septum and the other
was connected via tygon tubing to a 25 mL graduated
pipet ending in a 150 mL beaker with distilled water.
While stirring at room temperature a 20 mL syringe
with needle was used to withdraw air from the system
and to draw water up into the graduated pipet to the
0.0 mL mark. Hydrogen was then introduced into the
system using a balloon filled with hydrogen attached to
a hose barb-to-luer lock adapter with a stopcock and a
needle. The reaction mixture consumed 51.0–54.3 mL
of hydrogen during 1 h. The mixture was filtered and
the solvent removed in vacuo obtaining 0.47–0.51 g
(1.99–2.07 mmol) of the desired alkenols 8a and 8b
accounting for 94–96% yields. The alkenols were puri-
fied under vacuum distillation (Kugelrohr) by removing
impurities at 110 ◦C/3 mm Hg.
2.8. General procedure for the oxidation of the
alcohols
To a solution of pyridinium dichromate (8.7–
10.1 mmol) and 2 mL of dimethylformamide (DMF) was
added under argon (or nitrogen) a solution of the alco-
hol (1.7–2.0 mmol) in 12 ml of DMF and the reaction
mixture was left stirring at room temperature for 24 h.
After this time, the mixture was washed with water (3×
15 mL), hexane (1× 15 mL), dried over MgSO4, fil-
tered, and evaporated in vacuo affording 1.1–1.2 mmol
of the corresponding carboxylic acids in 63%
yields.
2.7.1. (Z)-13-Methyl-8-tetradecen-1-ol (8a)
The (Z)-13-methyl-8-tetradecen-1-ol (8a) was
obtained as a colorless oil in a 94% yield from the
catalytic hydrogenation, using Lindlar’s catalyst, of 13-
methyl-8-tetradecyn-1-ol (0.50 g, 2.22 mmol) according
to the general procedure described above; IR (neat)
νmax 3360 (OH, broad), 3005, 2927, 2856, 1660, 1465,
1384, 1366, 1117, 1058, 724 cm−1; H NMR (CDCl3)
1
δ 5.34 (2H, m, H-8, H-9), 3.63 (2H, t, J = 6.6 Hz, H-1),
2.00 (5H, m, H-7, H-10, H-13), 1.70 (1H, brs, –OH),
1.68–1.55 (2H, m, H-2), 1.31 (12H, m, –CH2–), 0.86
(6H, d, J = 6.6 Hz, –CH(CH3)2); 13C NMR (CDCl3) δ
129.99 (d), 129.75 (d), 63.03 (t, C-1), 38.62 (t, C-12),
32.74 (t, C-2), 29.65 (t), 29.29 (t), 29.21 (t), 27.86 (d,
C-13), 27.52 (t, C-10), 27.41 (t, C-7), 27.14 (t), 25.68
(t), 22.60 (q, C-14, C-15); GC–MS (70 eV) m/z (relative
intensity) 226 (M+, 1), 208 (3), 180 (1), 152 (2), 137
(4), 124 (7), 123 (10), 111 (5), 110 (15), 109 (23), 97
(16), 96 (45), 95 (53), 83 (32), 82 (80), 81 (61), 79 (10),
69 (74), 68 (40), 67 (73), 57 (40), 56 (53), 55 (100), 54
(39).
2.8.1. (Z)-13-Methyltetradec-8-enoic acid (1a)
The (Z)-13-methyltetradec-8-enoic acid (1a) was
obtained as a colorless oil in a 63% yield from
the reaction of (Z)-13-methyltetradec-8-en-1-ol
(0.46 g, 2.0 mmol) and pyridinium dichromate (3.8 g,
10.1 mmol) in DMF according to the general procedure
described above; IR (neat) νmax 3500–2500, 3004,
2925, 2854, 1708 (C O), 1462, 1412, 1384, 1366,
1
1169, 1116, 909, 732 cm−1; H NMR (CDCl3) δ 5.34
(2H, m, H-8, H-9), 2.34 (2H, t, J = 7.5 Hz, H-2), 2.00
(5H, m, H-7, H-10, H-13), 1.56 (2H, m, H-3), 1.35 (10
H, m, –CH2–), 0.86 (6H, d, J = 6.6 Hz, –CH(CH3)2);
13C NMR (CDCl3) δ 179.38 (s, C-1), 130.11 (d), 129.61
(d), 38.63 (t, C-12), 33.93 (t, C-2), 29.49 (t, C-6), 28.94
(t, C-5), 28.85 (t, C-4), 27.88 (d, C-13), 27.53 (t, C-10),
27.43 (t, C-7), 27.09 (t), 24.63 (t), 22.61 (q, C-14, C-15);
GC–MS (70 eV) m/z (relative intensity) 240 (M+, 8),
222 (3), 207 (1), 185 (2), 179 (3), 167 (9), 161 (2), 149
(6), 143 (1), 137 (4), 129 (2), 125 (5), 123 (7), 115 (3),
111 (11), 109 (10), 101 (5), 98 (12), 97 (21), 87 (4), 85
2.7.2. (Z)-15-Methyl-10-hexadecen-1-ol (8b)
The (Z)-15-methyl-10-hexadecen-1-ol (8b) was
obtained as a colorless oil in a 96% yield from
the catalytic hydrogenation, using Lindlar’s catalyst,
of 15-methyl-10-hexadecyn-1-ol (0.51 g, 1.99 mmol)
according to the general procedure described above; IR
(neat) νmax 3360 (OH, broad), 3005, 2926, 2854, 1622,

42
N.M. Carballeira et al. / Chemistry and Physics of Lipids 145 (2007) 37–44
(8), 84 (25), 83 (33), 81 (23), 73 (14), 71 (13), 70 (31),
69 (97), 67 (34), 60 (15), 57 (52), 55 (100). HRMS
(ESI) Calcd for C15H29O2 [M + H]+ 241.2168, found
241.2163.
et al., 2004). In this particular synthesis the synthetic
approachinvolvedtheinitialcouplingofthe(trimethylsi-
lyl)acetylene to a short-chain iso bromoalkane resulting
in a volatile iso-alkyne followed, after removal of the
silyl protecting group, by a second acetylide coupling to
a longer chain bromoalkane bearing a functional group
(e.g., a protected alcohol) that could later be transformed
into a carboxylic acid. The advantage of this strategy
is that a 100% Z stereoselectivity was obtained for the
double bond, i.e., after Lindlar hydrogenation of the
resulting internal alkyne. However, still a synthetic lim-
itation to this approach is that the initial short-chain
iso-alkane (in the example giving above the 6-methyl-1-
heptyne) is quite volatile, and the yields for the second
alkyne-bromide coupling reaction were rather low (33%
yields). Therefore, we envisioned that by reversing the
coupling order, i.e., initial coupling of the (trimethylsi-
lyl)acetylene to a long-chain bifunctional bromoalkane
followed by a second acetylide coupling to a short-
chain iso bromoalkane would result in higher yields
for the second acetylide coupling reaction (Carballeira
et al., 2007). This is the strategy we are reporting
herein for the seven-step syntheses of the fatty acids
(Z)-13-methyl-8-tetradecenoic acid (1a) and the (Z)-
15-methyl-10-hexadecenoic acid (1b), as outlined in
Scheme 1.
Both syntheses started with commercially available
(Aldrich) bromo-alcohols, i.e., the 7-bromo-1-heptanol
(2a) and the 9-bromo-1-nonanol (2b), which were pro-
tected with 3,4-dihydro-2H-pyran (DHP) in the presence
of p-toluenesulfonic acid (PTSA) affording the corre-
sponding dihydropyranyl protected alcohols 3a and 3b,
respectively, in 97–100% isolated yields. The bromo
dihydropyranyl protected alcohols 3a and 3b were
then submitted to the first acetylide coupling reac-
tion with the versatile reagent (trimethylsilyl)acetylene
using n-BuLi in THF-HMPA affording the trimethylsi-
lyl acetylenic derivatives 4a and 4b in 87–98% yields,
respectively. Deprotection of the terminal trimethylsi-
lyl group with tetrabutylammonium fluoride (TBAF)
afforded the terminal alkynes 5a and 5b in 87–96%
yields. A second acetylide coupling with 4-methyl-1-
bromopentane using n-BuLi, THF-HMPA at −10 ◦C
resulted in the iso-branched alkynes 6a and 6b in
68–78% isolated yields (Scheme 1). Deprotection of
the dihydropyranyl group with PTSA in methanol at
35 ◦C for 24 h afforded the 13-methyl-8-tetradecyn-
1-ol (7a) and the 15-methyl-10-hexadecyn-1-ol (7b)
in 88–91% isolated yields. Catalytic hydrogenation,
under Lindlar’s conditions of 7a and 7b, afforded
the cis-alkenols (Z)-13-methyl-8-tetradecen-1-ol (8a)
and (Z)-15-methyl-10-hexadecen-1-ol (8b) in 94–96%
2.8.2. (Z)-15-Methylhexadec-10-enoic acid (1b)
The (Z)-15-methylhexadec-10-enoic acid (1b) was
also obtained as a colorless oil in a 63% yield
from the reaction of (Z)-15-methylhexadec-10-en-1-ol
(0.44 g, 1.7 mmol) and pyridinium dichromate (2.28 g,
8.7 mmol) in DMF according to the general procedure
described above; IR (neat) νmax 3500–2500, 3003, 2924,
2853, 1708 (C O), 1463, 1412, 1384, 1366, 1117, 1089,
1027, 807, 784, 732 cm−1; 1H NMR (CDCl3) δ 5.34 (2H,
m, H-10, H-11), 2.34 (2H, t, J = 7.5 Hz, H-2), 2.01 (5H,
m, H-9, H-12, H-15), 1.61 (2H, m, H-3), 1.29 (14H, m,
–CH2–), 0.86 (6H, d, J = 6.6 Hz, –CH(CH3)2); 13C NMR
(CDCl3) δ 179.43 (s, C-1), 129.97 (d), 129.81 (d), 38.63
(t, C-14), 33.96 (t, C-2), 29.70 (t), 29.30 (t), 29.20 (t),
29.04 (t), 27.87 (d, C-15), 27.54 (t), 27.42 (t), 27.16 (t),
24.68 (t), 22.61 (q, C-16, C-17); GC–MS (70 eV) m/z
(relative intensity) 268 (M+, 6), 250 (4), 235 (1), 213
(2), 207 (2), 195 (5), 177 (3), 165 (2), 161 (1), 151 (3),
149 (1), 143 (1), 137 (4), 129 (3), 125 (6), 123 (5), 115
(3), 111 (13), 109 (7), 101 (4), 98 (12), 97 (24), 95 (14),
87 (4), 85 (8), 84 (22), 83 (36), 81 (19), 73 (12), 71 (11),
70 (29), 69 (85), 67 (28), 60 (18), 57 (51), 55 (100);
analysis calculated for C17H32O2: C, 76.06; H, 12.02;
O, 11.92; found: C, 76.46; H, 12.05; O, 12.25.
3. Results and discussion
Several synthetic approaches have been employed in
the synthesis of monounsaturated iso methyl-branched
fatty acids with double bonds close to the ␻ end of
the acyl chain (Reyes and Carballeira, 1996; Carballeira
et al., 2004). A reported methodology employs the
Wittig strategy where the best combination for gener-
ating the cis double bond was using the phosphonium
salt of a short-chain iso methyl-branched bromoalkane
and a long-chain aldehyde bearing a functional group
for further transformation into a carboxylic acid. This
approach was used in the synthesis of the (Z)-15-
methylhexadec-11-enoic acid (Reyes and Carballeira,
1996). The synthetic limitations to this approach were
the low yields (50%) in the Wittig coupling and obtain-
ing Z/E mixtures, which can be a serious limitation when
only the Z isomer is desired.
A more recent approach aiming at a 100% Z
selectivity involves the use of the versatile reagent
(trimethylsilyl)acetylene, as exemplified in the synthesis
of the (Z)-14-methyl-9-pentadecenoic acid (Carballeira

N.M. Carballeira et al. / Chemistry and Physics of Lipids 145 (2007) 37–44
43
Scheme 1. Synthesis of (Z)-13-methyltetradec-8-enoic acid (1a) and (Z)-15-methylhexadec-10-enoic acid (1b).
yields. Final oxidation of the alcohols with pyridinium
dichromate in dimethylformamide (DMF) resulted in the
formation of the desired acids 1a and 1b, both in 63%
yields (Scheme 1). The overall total yields for the seven
steps, in both syntheses, were 31–32%.
lyl)acetylene is first coupled to a long-chain bifunctional
bromoalkane (87–98% yields) followed by a second
acetylide coupling to a short-chain iso-bromoalkane
(68–78% yields). Complete spectral data is also provided
for the first time for the acids 1a and 1b. The synthetic
methodology presented herein will also certainly furnish
enough material for systematic bioassay studies.
Acids 1a and 1b presented comparable spectral data
that confirmed their structures. The iso methyl branch-
ing was easily identified by both 1H NMR and 13C NMR
spectrometry as well as by infrared spectroscopy (IR).
In the 1H NMR spectra both terminal isopropyl methyl
groups appeared as a doublet at δ 0.86 ppm, while in
13C NMR both methyl groups resonated at δ 22.6 ppm.
The IR was more characteristic since the terminal iso-
propyl group was observed as a doublet at 1384 and
1366 cm−1. The presence of the olefinic hydrogens was
Acknowledgements
This work was supported by a grant from the SCORE
program of the National Institutes of Health (Grant No.
S06GM08102). L.F. Padilla thanks the NIH-MARC pro-
gram for an undergraduate fellowship. We thank Fred
Strobel (Emory University) for the high resolution mass
spectral data.
1
easily detected in the H NMR spectra by the olefinic
signals at δ 5.34 ppm. The 13C NMR spectra were most
informative since both allylic methylene carbons res-
onated at δ 27.4 and 27.5 ppm, confirming the presence
of the cis double bond. The cis double bond stereochem-
istry was also further confirmed by IR since a strong
absorption at 732 cm−1 was observed for both acids. The
carboxylic acid carbonyl was observed in 13C NMR at
δ 179.4 ppm and in IR at 1708 cm−1. The mass spectra
of both acids 1a and 1b presented a base peak at m/z 55
and the typical McLafferty rearrangement at m/z 60.
In summary, we have shown that higher yields are
indeed obtained in the synthesis of monounsaturated iso
methyl-branched fatty acids with double bonds close
to the ␻ end of the acyl chain when (trimethylsi-
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