114
N.M. Carballeira et al. / Chemistry and Physics of Lipids 164 (2011) 113–117
(Carballeira et al., 2009). The latter report indicated that these iso
monounsaturated fatty acids do have antiprotozoal potential.
it will remain unexplored until enough material becomes avail-
able for such studies. However, by applying our previous developed
synthetic methodology for unsaturated iso methyl-branched fatty
acids (Carballeira et al., 2009) to the synthesis of 1 enough mate-
rial for such studies could be obtained. Therefore, in order to
unequivocally conclude the total characterization of 1, i.e., deter-
total synthesis for the (Z)-16-methyl-11-heptadecenoic acid (1).
This synthesis was accomplished following a synthetic sequence
consisting of seven steps and using (trimethylsilyl)acetylene as the
key reagent in the synthesis (Scheme 1). We also report that acid
1 displays antiprotozoal activity towards Leishmania donovani pro-
mastigotes by a mechanism that probably involves inhibition of the
leishmania DNA topoisomerase IB enzyme.
eluting with hexane/ether (9:1). The silylated alkyne 3 (Banaszak
et al., 2009) was obtained as a colorless oil 2.43 g (7.16 mmol) for a
97% yield.
2.4. 1-[(Tetrahydropyran-2-yl)oxy]dodec-11-yne (4)
To a mixture of 2.35 g (6.93 mmol) of 3 and 12.0 mL of dry THF
was added dropwise 6.93 mmol of tetrabutylammonium fluoride
(1 M) at 0 ◦C. After 24 h at room temperature the reaction was
quenched with HCl (2 M), and the organic layer was washed with
brine (1 × 20 mL), ether (1 × 20 mL), dried over MgSO4, filtered, and
evaporated in vacuo. The crude product was purified using silica
gel column chromatography eluting with hexane/ether (9:1). The
alkyne 4 was obtained as a colorless oil 1.66 g (6.22 mmol) for a 90%
yield. IR (neat) ꢀmax 3312, 2926, 2854, 1466, 1441, 1352, 1323, 1259,
1200, 1136, 1121, 1078, 1026, 988, 904, 870, 814, 721, 627 cm−1
;
1H NMR (CDCl3, 500 MHz) ı 4.55 (1H, t, J = 2.7 Hz), 3.84 (1H, m),
3.71 (1H, m), 3.49 (1H, m), 3.36 (1H, m), 2.16 (2H, dt, J = 7.1, 2.6 Hz,
H-10), 1.92 (1H, t, J = 2.6 Hz, H-12), 1.81 (2H, m), 1.70 (2H, m), 1.53
(6H, m, –CH2–), 1.27 (12H, m, –CH2–); 13C NMR (CDCl3, 125 MHz)
␦ 98.80 (d), 84.74 (s, C-11), 68.01 (d, C-12), 67.64 (t, C-1), 62.29
(t), 30.75 (t), 29.71 (t, C-2), 29.48 (t), 29.41 (t), 29.39 (t), 29.04 (t),
28.70 (t), 28.45 (t), 26.19 (t, C-3), 25.48 (t), 19.66 (t, C-10), 18.36 (t);
GC–MS (70 eV) m/z (relative intensity) 266 (M+, 1), 237 (1), 225 (1),
211 (1), 195 (1), 165 (1), 149 (1), 135 (1), 123 (1), 109 (4), 107 (2),
101 (27), 97 (2), 95 (11), 93 (4), 91 (2), 86 (6), 85 (100), 84 (10), 81
(19), 79 (9), 67 (21), 57 (9), 56 (17), 55 (28). HRMS (APCI) Calcd. for
2. Materials and methods
2.1. Instrumentation
1H NMR (500 MHz) and 13C NMR (125 MHz) were recorded
on a Bruker DRX-500 spectrometer. 1H 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).
Gas chromatography/mass spectrometry (GC/MS) analyses were
recorded at 70 eV using either a Hewlett Packard 5972A MS
ChemStation or an Agilent 5975C MS ChemStation coupled to an
Agilent 7890A GC where both instruments were equipped with a
30 m × 0.25 mm special performance capillary column (HP-5MS) of
polymethyl siloxane crosslinked with 5% phenyl methylpolysilox-
ane. IR spectra were recorded on a Nicolet Magna 750 FT-IR
spectrophotometer (Thermo-Nicolet, Madison, WI, USA). High res-
olution mass spectral data was performed at the Emory University
Mass Spectrometry Center on a thermo linear ion trap-Fourier
transform mass spectrometer (LTQ-FTMS) using atmospheric pres-
sure chemical ionization (APCI) as the probe.
C
19H35O2 [M+H]+ 267.2682, found 267.2681.
2.5. 16-Methyl-1-[(tetrahydropyran-2-yl)oxy]heptadec-
11-yne (5)
To a solution of 1.54 g (5.77 mmol) of 4 and 11.2 mL of THF at
0 ◦C, 1.87 mL (20.2 mmol) of n-BuLi (2.5 M) in hexane was added
while stirring under an argon atmosphere. After 45 min, 2.87 mL
of HMPA was added. After additional 15 min, 2.56 mL (17.3 mmol)
of 1-bromo-4-methylpentane was added to the reaction mixture
and the reaction was left stirring for 24 h at room temperature.
After this time the reaction mixture was quenched with water and
the organic product was extracted with ether (2 × 25 mL), dried
over MgSO4, filtered, and evaporated in vacuo. The crude prod-
uct was purified using silica gel column chromatography eluting
with hexane/ether (9:1). The product 5 was obtained as colorless
oil 2.02 g (5.75 mmol) for a 99% yield. IR (neat) ꢀmax 2926, 2854,
1466, 1441, 1383, 1366, 1352, 1259, 1200, 1128, 1121, 1078, 1032,
2.2. 10-Bromo-[(tetrahydropyran-2-yl)oxy]decane (2)
To 2.00 g of 10-bromo-1-decanol in 15 mL of chloroform (CHCl3)
was added dropwise 16.9 mmol of 3,4-dihydro-2H-pyran (DHP)
and catalytic amounts of p-toluenesulphonic acid (pTSA). The reac-
CHCl3 (1 × 20 mL), and dried over MgSO4, filtered, and evaporated
in vacuo. The crude product was purified using silica gel column
chromatography eluting with hexane/ether (9:1). The pure prod-
uct 2 (Banaszak et al., 2009) was obtained as a colorless oil 2.35 g
(7.32 mmol) for a 100% yield.
984, 905, 870, 814, 743 cm−1 1H NMR (CDCl3, 500 MHz) ı 4.56 (1H,
;
t, J = 2.7 Hz), 3.85 (1H, m), 3.72 (1H, m), 3.49 (1H, m), 3.37 (1H, m),
2.11 (4H, m, H-10, H-13), 1.81 (2H, m), 1.69 (2H,m), 1.51 (7H, m,
–CH2–), 1.26 (16H, m, –CH2–), 0.86 (6H, d, J = 6.6 Hz, –CH(CH3)2);
13C NMR (CDCl3, 125 MHz) ı 98.79 (d), 80.22 (s), 80.19 (s), 67.64
(t, C-1), 62.27 (t), 38.18 (t, C-15), 30.75 (t), 29.72 (t, C-2), 29.51 (t),
29.46 (t), 29.44 (t), 29.12 (t), 28.81 (t), 27,61 (d, C-16), 27.04 (t, C-3),
26.20 (t), 25.48 (t), 22.54 (q, C-17, C-18), 19.65 (t), 18.98 (t, C-13),
18.71 (t, C-10); GC–MS (70 eV) m/z (relative intensity) 350 (M+, 1),
294 (1), 279 (1), 277 (1), 265 (1), 221 (1), 207 (1), 195 (1), 165 (1),
151 (1), 149 (2), 138 (1), 137 (2), 135 (3), 123 (6), 121 (5), 111 (3),
109 (27), 107 (6), 101 (24), 96 (12), 95 (31), 93 (9), 86 (6), 85 (100),
84 (20), 83 (18), 82 (20), 81 (34), 79 (15), 69 (41), 68 (12), 67 (32),
57 (13), 56 (14), 55 (46). HRMS (APCI) Calcd. for C23H43O2 [M+H]+
351.3257, found 351.3255.
2.3. 12-(Trimethylsilyl)-1-[(tetrahydropyran-2-yl)oxy]dodec-
11-yn (3)
To a stirred solution of 3.04 mL (22.0 mmol) of (trimethylsi-
lyl)acetylene in 9.5 mL of dry THF and under argon was added
2.36 mL (25.6 mmol) of n-BuLi (2.5 M) in hexane at −78 ◦C. After
2 min, 3.36 mL of HMPA and 2.35 g (7.32 mmol) of 2 was added 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 brine solution (2 × 20 mL), diethyl ether
(2 × 20 mL), dried over MgSO4, filtered, and evaporated in vacuo.
The product was purified using silica gel column chromatography
2.6. 16-Methylheptadec-11-yn-1-ol (6)
To a mixture of methanol (20.0 mL) and 1.94 g (6.36 mmol) of
5 was added catalytic amounts of pTSA and the reaction mix-
ture was stirred at 35 ◦C for 48 h. After this time the organic