Synthesis of benzophenone-containing fatty acids

Article abstract of DOI:10.1021/jo061617n

(Chemical Equation Presented) Syntheses of new benzophenone-containing fatty acids (FABPs) 1, 5, and 6 and a new route to FABP 3 are described. Combined with the known 2 and 4, these FABPs comprise a set of photoactivatable fatty acid analogues with the crosslinking site at defined distances from the carboxylic acid hydroxyl group oxygen atoms ranging from 7.9 to 25.0 A.

Full text of DOI:10.1021/jo061617n

having a benzophenone12-14 or a trifluoromethylaryldiazirine15
in the center.
Synthesis of Benzophenone-Containing Fatty
Acids
As part of a study of cellular cholesterol efflux and HDL
formation, we have been preparing benzophenone-containing
analogues of cholesterol16-18 and phospholipids19 as additional
prospective photoaffinity labeling agents. For incorporation into
the phospholipid analogues, fatty acids containing the ben-
zophenone photophore at different defined positions along the
entire hydrocarbon chain length were desired, to afford the
possibility of photocrosslinking at a range of depths within cell
membranes. This Note describes a series of six such fatty acid
benzophenone analogues (FABPs), compounds 1-6 (Figure 1).
Yonghong Gan, Pingzhen Wang, and Thomas A. Spencer*
Department of Chemistry, Dartmouth College,
HanoVer, New Hampshire 03755
taspen@dartmouth.edu
ReceiVed August 3, 2006
Syntheses of new benzophenone-containing fatty acids
(FABPs) 1, 5, and 6 and a new route to FABP 3 are
described. Combined with the known 2 and 4, these FABPs
comprise a set of photoactivatable fatty acid analogues with
the crosslinking site at defined distances from the carboxylic
acid hydroxyl group oxygen atoms ranging from 7.9 to
25.0 Å.
Photoactivatable fatty acid analogues have a long history.
Benzophenone-bearing carboxylic acid chains were first syn-
thesized by Breslow for his studies of remote functionalization
in steroids1 and subsequently for use as photochemical probes
of model membrane structures.2 At approximately the same time,
Khorana pioneered the use of photoactivatable phospholipids
containing aryl azides or diazo ketone moieties.3-5 More
recently, several other groups have used fatty acids or phos-
pholipids containing benzophenones for studies in model
membranes6-9 or for labeling membrane proteins.10,11 Of
particular note are the membrane-spanning dicarboxylic acids
FIGURE 1. Structures of benzophenone-containing fatty acids 1-6
with the distance (in Å) from the hydroxyl group oxygen atom to the
keto carbonyl group carbon atom, as measured in the fully extended
conformation by the Spartan program, shown in parentheses for each
compound.
Molecular modeling using the Spartan program indicates that
in 1-6 the photocrosslinking carbonyl carbon atom will be at
the respective distances shown in Figure 1 from the carboxylic
* To whom correspondence should be addressed. Phone: 603-646-2805.
Fax: 603-646-3946.
(1) Breslow, R.; Baldwin, S.; Flechtner, T.; Kalicky, P.; Liu, S.;
Washburn, W. J. Am. Chem. Soc. 1973, 95, 3251-3262.
(2) Czarniecki, M. F.; Breslow, R. J. Am. Chem. Soc. 1979, 101, 3675-
3676.
(3) Chakrabarti, P.; Khorana, H. G. Biochemistry 1975, 14, 5021-5033.
(4) Gupta, C. M.; Radhakrishnan, R.; Gerber, G. E.; Olsen, W. L.; Quay,
S. C.; Khorana, H. G. Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 2595-2599.
(5) Gupta, C. M.; Costello, C. E.; Khorana, H. G. Proc. Natl. Acad. Sci.
U.S.A. 1979, 76, 3139-3143.
(11) Montecucco, C.; Schiavo, G. Biochem. J. 1986, 237, 309-312.
(12) Nakatani, Y.; Yamamoto, M.; Diyizou, Y.; Warnock, W.; Dolle´,
V.; Hahn, W.; Milon, A.; Ourisson, G. Chem.-Eur. J. 1996, 2, 129-138.
(13) Diyizou, Y. L.; Genevois, A.; Lazrak, T.; Wolff, G.; Nakatani, Y.;
Ourisson, G. Tetrahedron Lett. 1987, 28, 5743-5746.
(14) Yamamoto, M.; Warnock, W. A.; Milon, A.; Nakatani, Y.; Ourisson,
G. Angew. Chem., Int. Ed. Engl. 1993, 32, 259-261.
(15) Delfino, J. M.; Schreiber, S. L.; Richards, F. M. J. Am. Chem. Soc.
1993, 115, 3458-3474.
(16) Spencer, T. A.; Wang, P.; Li, D.; Russel, J. S.; Blank, D. H.;
Huuskonen, J.; Fielding, P. E.; Fielding, C. J. J. Lipid Res. 2004, 45, 1510-
1518.
(17) Gan, Y.; Blank, D. H.; Ney, J. E.; Spencer, T. A. J. Org. Chem.
2006, 71, 5864-5869.
(18) Gan, Y.; Spencer, T. A. J. Org. Chem. 2006, 71, 5870-5875.
(19) Wang, P.; Blank, D. H.; Spencer, T. A. J. Org. Chem. 2004, 69,
2693-2702.
(6) Gogoll, A.; Scha¨fer, H. J. Liebigs Ann. Chem. 1987, 589-596. Gogoll,
A.; Scha¨fer, H. J. Liebigs Ann. Chem. 1987, 597-606.
(7) Markovic, D. Z.; Durand, T.; Patterson, L. K. Photochem. Photobiol.
1990, 51, 389-394.
(8) Markovic, D. Z.; Patterson, L. K. Photochem. Photobiol. 1993, 58,
329-334.
(9) Lala, A. K.; Kumar, E. R. J. Am. Chem. Soc. 1993, 115, 3982-
3988.
(10) Page, M. G. P.; Rosenbusch, J. P. Biochem. J. 1986, 235, 651-
661.
10.1021/jo061617n CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/10/2006
J. Org. Chem. 2006, 71, 9487-9490
9487

SCHEME 1. Synthesis of 1a
SCHEME 2. Synthesis of 3a
a Reagents and conditions: (a) Mg, Et2O, ∆, 1 h; (b) 7, Et2O, rt,
overnight; (c) PCC, CH2Cl2, rt, 7 h; (d) O3, acetone, -50 °C, 15 min; (e)
Jones reagent at 0 °C, then rt, overnight.
a Reagents and conditions: (a) Mg, THF, ∆, 2 h, â-propiolactone, CuCl,
THF, 0 °C, rt, 1 h; (b) MeOH, H2SO4, ∆, overnight; (c) AlCl3, -15 °C, rt,
overnight; (d) 9-BBN, THF, 0 °C, rt, 4 h; (e) 14, Pd(dppf)Cl2, Cs2CO3,
AsPh3, DMF, H2O, THF, ∆, overnight; (f) NaOH, EtOH, H2O, rt, overnight.
acid oxygen atom, which is assumed to be approximately at
the membrane surface.
SCHEME 3. Synthesis of 5a
Among the series 1-6, three have previously been described
in the literature. Markovic et al.7,8 have reported an efficient
two-step synthesis of compound 2, which we have not attempted
to improve. Lala and Kumar9 have reported the preparation of
3, but we have developed the more efficient route described
below. We have previously described in detail an improved
synthesis of compound 4.19 Herein are described efficient
syntheses of the new FABPs 1, 5, and 6, as well as the improved
route to 3.
Synthesis of 1. When initial Friedel-Crafts approaches, such
as reaction of 4-n-decyl benzoyl chloride with methyl phenyl-
acetate, were unexpectedly disappointing, the route depicted in
Scheme 1 was adopted. 4-n-Decylbenzaldehyde (7) was pre-
pared from 1-phenyl-n-decane by the method of Osman20 and
treated with the Grignard reagent derived from 1-allyl-4-
bromobenzene (8), prepared by the method of Parr et al.,21 to
afford benzhydrol 9 in 41% yield. Successive conversions of 9
with PCC to give 10 in 92% yield and of 10 by oxidative
ozonolysis to give a 59% yield of 1 completed the synthesis.
Synthesis of 3. 7-Octenoic acid (11) was prepared by a new
method from 5-bromo-1-pentene (12) and â-propiolactone in
92% yield by the procedure of Watson and Wagener22 (Scheme
2), in a type of reaction also used in the syntheses of 5 and 6
described below. After esterification of 11 to methyl 7-octenoate
(13) in 94% yield, Suzuki coupling23 with 4-bromo-4′-n-butylben-
zophenone (14), prepared by Friedel-Crafts reaction of n-butyl-
benzene and 4-bromobenzoyl chloride,24 gave a 75% yield of
keto ester 15,9 which was saponified in 82% yield to afford 3.
Synthesis of 5. 13-Tetradecenoic acid (16), prepared by the
method of Watson and Wagener,22 was esterified in 98% yield
to give 17 which was coupled23 with 4-bromo-4′-methylben-
zophenone (18), prepared, as before,19 by the method of
a Reagents and conditions: (a) MeOH, H2SO4, ∆, overnight; (b) 9-BBN,
THF, 0 °C, rt, 4 h; (c) 18, Pd(dppf)Cl2, Cs2CO3, AsPh3, DMF, H2O, THF,
∆, overnight; (d) NaOH, EtOH, H2O, rt, overnight.
Nakatani et al.,25 to give 19. Crude 19 was saponified to afford
5 in 70% yield from 17 (Scheme 3).
Synthesis of 6. Methyl 13-tetradecenoate (17) was also used
in the synthesis of 6 shown in Scheme 4. Olefin cross-metathesis
of 17 with 4-phenyl-1-butene (20) using the Grubbs first-
generation catalyst, by the procedure of Boyle et al.,26 gave key
intermediate 21 in 87% yield as a mixture judged to be ca. 8:1
trans/cis on the basis of precedent27 and the 13C NMR chemical
shifts for the allylic carbon atoms.28 Hydrogenation of 21 over
10% Pd/C gave 99% of 22, which was condensed with p-toluyl
chloride to give 99% of 23. Saponification of 23 afforded a
95% yield of 6.
Thus, the six FABPs with their photophores at the positions
shown in Figure 1 are all now available for incorporation into
(20) Osman, M. A. HelV. Chim. Acta 1982, 65, 2448-2449.
(21) Parr, W.; Grohmann, K.; Ha¨gele, K. Liebigs Ann. Chem. 1974, 655-
666.
(22) Watson, M. D.; Wagener, K. B. Macromolecules 2000, 33, 5411-
5417.
(23) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014-
11015.
(24) Agzamova, K. D.; Yuldashev, Kh. Yu.; Nuriddinova, M. eds:
Abdurasuleva, A. R. Sint. Reakts. Sposobn. Org. Soedin. 1983, 22-27.
(25) Nakatani, K.; Dohno, C.; Nakamura, T.; Saito, I. Tetrahedron Lett.
1998, 39, 2779-2782.
(26) Boyle, T. P.; Bremner, J. B.; Coates, J. A.; Keller, P. A.; Pyne, S.
G. Tetrahedron 2005, 61, 7271-7276.
(27) O’Leary, D. J.; Blackwell, H. E.; Washenfelder, R. A.; Grubbs, R.
H. Tetrahedron Lett. 1998, 39, 7427-7430.
(28) Batchelor, J. G.; Cushley, R. J.; Prestegard, J. H. J. Org. Chem.
1974, 39, 1698-1705.
9488 J. Org. Chem., Vol. 71, No. 25, 2006

SCHEME 4. Synthesis of 6a
concd H2SO4) was added at 0 °C, and the resulting mixture was
stirred overnight at room temperature, quenched with 2-propanol,
and filtered. Most of the solvent was removed under reduced
pressure, and a solution of 2 N NaOH was added to the residue to
adjust the pH to ca. 12. The aqueous layer was washed with ether,
then reacidified and extracted with ethyl acetate. The organic layer
was washed with brine, dried, filtered, and evaporated to give 1.1
g of residue which was purified by chromatography with 9:1 to
1:1 hexane/ethyl acetate to give 310 mg (59%) of 1 (mp 61-64.5
°C). Recrystallization from hexane gave 1: mp 71.5-73.0 °C; 1H
NMR δ 7.82 (d, J ) 8.1 Hz, 2H), 7.77 (d, J ) 8.1 Hz, 2H), 7.45
(d, J ) 8.1 Hz, 2H), 7.32 (d, J ) 8.1 Hz, 2H), 3.79 (s, 2H), 2.72
(t, J ) 7.8 Hz, 2H), 1.69 (m, 2H), 1.32 (m, 14H), 0.92 (t, J ) 6.6
Hz, 3H); 13C NMR δ 196.4, 177.2, 148.6, 137.9, 137.2, 135.2,
130.65, 130.61, 129.6, 128.6, 41.3, 36.3, 32.2, 31.4, 29.9, 29.9,
29.7, 29.6, 29.5, 22.9, 14.4. Anal. Calcd for C25H32O3: C, 78.91;
H, 8.48. Found: C, 78.65; H, 8.46.
8-[4-(4-n-Butylbenzoylphenyl)]octanoic Acid (3). To a solution
of 432 mg (2.77 mmol) of 13 in 4 mL of THF was added 6.0 mL
of 0.5 M 9-BBN dropwise at 0 °C. The mixture was stirred at room
temperature for 4 h, then transferred via syringe to a mixture of
796 mg (2.51 mmol) of 14,24 411 mg (0.50 mmol) of Pd(dppf)Cl2,
2.46 g (7.56 mmol) of Cs2CO3, and 154 mg (0.50 mmol) of AsPh3
in 6.5 mL of DMF, 1.5 mL of H2O, and 6.5 mL of THF. The
resulting mixture was heated at reflux overnight and then passed
through a short pad of celite with 100 mL of ether. The organic
layer was washed with brine, dried, filtered, and evaporated to give
2.1 g of brown oil which was purified by chromatography with
10:1 hexane/EtOAc to give 741 mg (75%) of methyl 8-[4-(4-n-
butylbenzoylphenyl)]octanoate (15) as a colorless oil: 1H NMR δ
7.75 (m, 4H), 7.29 (m, 4H), 3.69 (s, 3H), 2.70 (m, 4H), 2.33 (t, J
) 7.5 Hz, 2H), 1.67 (m, 6H), 1.40 (m, 8H), 0.97 (t, J ) 7.5 Hz,
3H); 13C NMR δ 196.6, 174.5, 148.1, 148.0, 135.7, 135.6, 130.5,
130.5, 128.5, 128.5, 51.7, 36.2, 36.0, 34.3, 33.6, 31.3, 29.4, 29.3,
29.3, 25.2, 22.6, 14.2. To a solution of 313 mg (0.79 mmol) of 15
in 5 mL of ethanol was added a solution of 342 mg (8.6 mmol) of
NaOH in 10 mL of H2O. The mixture was stirred at room
temperature overnight and evaporated, and the residue was acidified
to pH ) 1 with concd HCl and extracted with EtOAc. The organic
layer was washed with brine, dried, filtered, and evaporated to give
480 mg of residue which was purified by chromatography with
4:1 hexane/EtOAc to give 246 mg (82%) of 3 as a white solid:
a Reagents and conditions: (a) RuCl2(dCHPh)(PCy3)2, CH2Cl2, ∆,
overnight; (b) 10% Pd/C, hexane, H2, rt, overnight; (c) p-toluyl chloride,
CH2Cl2, AlCl3, rt, overnight; (d) NaOH, EtOH, H2O, rt, overnight.
phospholipid analogues or for other biochemical applications.
FABP 4 has already been incorporated into photoactivatable
phosphatidylcholine analogues19 for projected studies of reverse
cholesterol transport and HDL formation, and similar analogues
will be prepared from the other five FABPs.
Experimental Section
(4-Allylphenyl)-(4-decylphenyl)-methanol (9). To a mixture of
0.49 g (20.1 mmol) of magnesium in 10 mL of dry ether was added
a solution of 2.64 g (13.4 mmol) of 8 in 10 mL of dry ether. After
the mixture had been heated at reflux for 1 h, a solution of 1.1 g
(4.46 mmol) of 7 in 10 mL of dry ether was added dropwise. The
resulting mixture was stirred overnight at room temperature, diluted
with 50 mL of saturated NH4Cl, and extracted with ether. The
organic layer was washed with brine, dried, filtered, and evaporated
to give 2.9 g of residue which was purified by chromatography
with 10:1 pentane/ether to give 0.66 g (41%) of 9 as a colorless
oil: 1H NMR δ 7.31 (m, 4H), 7.21 (m, 4H), 6.02 (m, 1H), 5.83 (s,
1H), 5.13 (m, 2H), 3.42 (d, J ) 6.9 Hz, 2H), 2.63 (t, J ) 7.8 Hz,
2H), 2.28 (brs, 1H), 1.64 (m, 2H), 1.34 (m, 14H), 0.94 (t, J ) 6.6
Hz, 3H); 13C NMR δ 142.6, 142.1, 141.5, 139.6, 137.6, 128.9,
128.8, 126.9, 126.8, 116.1, 76.2, 40.2, 35.9, 32.2, 31.8, 30.0, 29.9,
29.8, 29.7, 23.0, 14.4. Anal. Calcd for C26H36O: C, 85.66; H, 9.95.
Found: C, 85.85; H, 9.91.
(4-Allylphenyl)-(4-decylphenyl)-methanone (10). To a solution
of 580 mg (1.59 mmol) of 9 in 10 mL of CH2Cl2 was added 515
mg (2.39 mmol) of PCC. The mixture was stirred at room
temperature for 7 h and then passed through a short pad of neutral
alumina column with CH2Cl2. The solvent was evaporated to give
590 mg of residue which was purified by chromatography with
25:1 hexane/ethyl acetate to give 503 mg (92%) of colorless oily
10: 1H NMR δ 7.78 (m, 4H), 7.32 (m, 4H), 6.02 (m, 1H), 5.16
(m, 2H), 3.51 (d, J ) 6.6 Hz, 2H), 2.72 (t, J ) 7.8 Hz, 2H), 1.69
(m, 2H), 1.31 (m, 14H), 0.92 (t, J ) 6.6 Hz, 3H); 13C NMR δ
196.5, 148.3, 145.1, 136.7, 136.2, 135.5, 130.6, 130.5, 128.7, 128.6,
116.9, 40.4, 36.3, 32.2, 31.5, 29.9, 29.8, 29.7, 29.6, 29.57, 23.0,
14.4. Anal. Calcd for C26H34O: C, 86.13; H, 9.45. Found: C, 86.15;
H, 9.56.
1
mp 37.2-39.8 °C; H NMR δ 7.76 (m, 4H), 7.32 (m, 4H), 2.71
(m, 4H), 2.39 (t, J ) 7.5 Hz, 2H), 1.67 (m, 6H), 1.42 (m, 8H),
0.98 (t, J ) 7.5 Hz, 3H); lit.9 1H NMR δ 8.02 (d, 4H), 7.29 (d,
4H), 2.67 (t, J ) 7.5 Hz, 4H), 2.37 (t, J ) 7.5 Hz, 2H), 1.65 (m,
6H), 1.35 (m, 8H), 0.94 (t, J ) 7.2 Hz, 3H); 13C NMR δ 196.7,
180.3, 148.2, 148.0, 135.7, 135.6, 130.5, 130.5, 128.5, 128.5, 36.2,
36.0, 33.6, 31.3, 29.3, 29.3, 29.2, 24.9, 22.6, 14.2.
Methyl 14-(4-(4-Methylbenzoyl)phenyl)tetradecanoate (19).
To a solution of 0.83 g (3.45 mmol) of 17 in 5 mL of THF was
added 8.2 mL of 0.5 M 9-BBN at 0 °C. The mixture was stirred at
room temperature for 4 h, then transferred via syringe to a mixture
of 1.21 g (4.40 mmol) of 18, prepared by the method of Nakatani
et al.,25 412 mg (0.50 mmol) of Pd(dppf)Cl2, 4.15 g (13 mmol) of
Cs2CO3, and 153 mg (0.5 mmol) of AsPh3 in a mixture of 8 mL of
THF, 2 mL of H2O, and 8 mL of DMF. The resulting mixture was
heated at reflux overnight, passed through a short pad of Celite,
and washed with 100 mL of hexane/ethyl acetate. The organic layer
was washed with water and brine, dried, and evaporated to give
2.15 g of brown oily 19. Crystallization of a small sample from
hexane/ethyl acetate afforded colorless 19: mp 51.9-52.8 °C; 1H
NMR δ 7.75 (m, 4H), 7.30 (m, 4H), 3.69 (s, 3H), 2.71 (t, J ) 7.5
Hz, 2H), 2.47 (s, 3H), 2.33 (t, J ) 7.5 Hz, 2H), 1.66 (m, 4H), 1.31
(m, 18H); 13C NMR δ 196.6, 174.6, 148.2, 143.2, 135.6, 135.5,
130.5, 129.2, 128.5, 51.7, 36.3, 34.4, 31.5, 29.9, 29.9, 29.8, 29.8,
29.7, 29.7, 29.6, 29.5, 29.4, 25.2, 21.9. Anal. Calcd for C29H40O3:
C, 79.77; H, 9.23. Found: C, 79.52; H, 9.04.
4-(4-Decylbenzoyl)phenyl Acetic Acid (1). Through a solution
of 500 mg (1.38 mmol) of 10 in 20 mL of acetone was bubbled O3
for 30 min at -50 °C, followed by N2 for 15 min. A solution of
Jones reagent (500 mg of CrO3 in 1.5 mL of H2O and 0.49 mL of
J. Org. Chem, Vol. 71, No. 25, 2006 9489

14-(4-(4-Methylbenzoyl)phenyl)tetradecanoic Acid (5). The
2.15 g of crude 19 prepared as just described was dissolved in 10
mL of ethanol and diluted with a solution of 2.50 g (62 mmol) of
NaOH in 20 mL of H2O. The resulting mixture was stirred at room
temperature overnight and evaporated, and the residue was acidified
to pH ) 1 with concd HCl and extracted with CH2Cl2. The organic
layer was washed with brine, dried, filtered, and evaporated to give
1.87 g of white solid which was crystallized from hexane/ethyl
acetate to give 1.02 g (70% over two steps) of colorless 5: mp
16-[4-(4-Methyl Benzoyl) Phenyl] Hexadecanoic Acid Methyl
Ester (23). To a solution of 0.86 g (2.48 mmol) of 22 in 10 mL of
CH2Cl2 was added 0.5 mL (3.72 mmol) of p-toluyl chloride at -5
°C, followed by 0.55 g (4.10 mmol) of AlCl3 in two portions. The
resulting mixture was stirred at room temperature overnight,
quenched with 100 mL of saturated NaHCO3 solution, and extracted
with CH2Cl2. The organic layer was washed with brine, dried, and
evaporated to give 1.4 g of residue which was purified by
chromatography with 10:1 hexane/EtOAc to give 1.14 g (99%) of
23 as a white solid, which was recrystallized from hexane/ethanol
to give 23: mp 57.7-59.1 °C; 1H NMR δ 7.76 (m, 4H), 7.30 (m,
4H), 3.70 (s, 3H), 2.69 (t, J ) 7.5 Hz, 2H), 2.47 (s, 3H), 2.33 (t,
J ) 7.5 Hz, 2H), 1.65 (m, 4H), 1.31 (m, 22H); 13C NMR δ 196.6,
174.6, 148.2, 143.2, 135.6, 135.5, 130.5, 129.2, 128.5, 51.7, 36.3,
34.4, 31.5, 29.9, 29.9, 29.8, 29.7, 29.7, 29.6, 29.5, 29.4, 25.2, 21.9.
Anal. Calcd for C31H44O3: C, 80.13; H, 9.54. Found: C, 79.99; H,
9.61.
16-[4-(4-Methyl Benzoyl) Phenyl] Hexadecanoic Acid (6). To
a solution of 0.92 g (1.98 mmol) of 23 in 5 mL of ethanol was
added a solution of 1.21 g (30 mmol) of NaOH in 10 mL of H2O.
The mixture was stirred at room temperature overnight and
evaporated, and the residue was acidified to pH ) 1 with concd
HCl and extracted with EtOAc. The organic layer was washed with
brine, dried, filtered, and evaporated to give 0.89 g of residue which
was crystallized from hexane to give 0.85 g (95%) of colorless 6:
mp 80.1-81.8 °C; 1H NMR δ 7.75 (m, 4H), 7.30 (m, 4H), 2.71 (t,
J ) 7.5 Hz, 2H), 2.47 (s, 3H), 2.38 (t, J ) 7.5 Hz, 2H), 1.67 (m,
4H), 1.31 (m, 22H); 13C NMR δ 196.6, 179.7, 148.2, 143.2, 135.6,
135.5, 130.5, 129.2, 128.5, 36.3, 34.2, 31.5, 29.9, 29.9, 29.8, 29.7,
29.7, 29. 6, 29.5, 29.3, 24.9, 21.9. Anal. Calcd for C30H42O3: C,
79.96; H, 9.39. Found: C, 79.74; H, 9.59.
1
77.2-78.2 °C; H NMR δ 7.75 (m, 4H), 7.30 (m, 4H), 2.71 (t, J
) 7.5 Hz, 2H), 2.47 (s, 3H), 2.38 (t, J ) 7.5 Hz, 2H), 1.66 (m,
4H), 1.31 (m, 18H); 13C NMR δ 196.6, 179.7, 148.2, 143.2, 135.6,
135.5, 130.5, 129.2, 128.5, 36.3, 34.2, 31.5, 29.9, 29.8, 29.7, 29.7,
29.6, 29.5, 29.3, 24.9, 21.9. Anal. Calcd for C28H38O3: C, 79.58;
H, 9.06. Found: C, 79.63; H, 8.98.
16-Phenylhexadec-13-enoic Acid Methyl ester (21). According
to the procedure of Boyle et al.,26 to a solution of 2.47 g (1.03
mmol) of 17 and 5.44 g (4.12 mmol) of 20 in 80 mL of CH2Cl2
was added 422 mg (0.52 mmol) of bis(tricyclohexylphosphonium)-
benzylidene ruthenium(IV) dichloride (Grubbs catalyst I). The
resulting mixture was heated at reflux overnight, cooled, and
evaporated to give 7.83 g of residue which was purified by
chromatography with 60:1 hexane/EtOAc to give 3.10 g (87%) of
colorless oily 21 as a 8:1 trans/cis mixture according to 1H NMR:
1H NMR δ 7.29 (m, 2H), 7.22 (m, 3H), 5.48 (m, 1.76H), 5.44 (m,
0.24H), 3.70 (s, 3H), 2.71 (t, J ) 7.5 Hz, 2H), 2.34 (t, J ) 7.5 Hz,
4H), 2.02 (br, 2H), 1.66 (m, 2H), 1.31 (br, 16H); 13C NMR δ 174.6,
142.5, 131.4, 131.0, 129.5, 128.9, 128.7, 128.5, 128.4, 126.0, 125.9,
51.7, 36.4, 36.3, 34.7, 34.4, 32.8, 29.9, 29.8, 29. 8, 29.7, 29.5, 29.4,
29.4, 27.5 (weak), 25.2. Anal. Calcd for C23H36O2: C, 80.18; H,
10.53. Found: C, 79.98; H, 10.57.
16-Phenyl Hexadecanoic Acid Methyl Ester (22). To 1.32 g
(3.84 mmol) of 21 in 15 mL of hexane was added 140 mg of 10%
Pd/C. The mixture was stirred at room temperature under a balloon
of H2 overnight, then passed through a short pad of silica gel with
ether. The filtrate was evaporated to give 1.32 g (99%) of 22, which
was crystallized from hexane/ethanol to give 22: mp 40.5-41.8
Acknowledgment. This research was supported by Grant
HL 67294 from the National Institutes of Health.
Supporting Information Available: General experimental
methods, preparations of known compounds 7, 8, 11, 13, 14, and
16-18, 1H and 13C NMR spectra of all compounds except 8,
and atom coordinates for molecular modeling of compounds 1-6.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
°C; H NMR δ 7.31 (m, 2H), 7.21 (m, 3H), 3.70 (s, 3H), 2.64 (t,
J ) 7.5 Hz, 2H), 2.34 (t, J ) 7.5 Hz, 2H), 1.65 (m, 4H), 1.32 (br,
22H); 13C NMR δ 174.6, 143.2, 128.7, 128.5, 125.8, 51.7, 36.3,
34.4, 31.8, 29.9, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 25.2. Anal. Calcd
for C23H38O2: C, 79.71; H, 11.05. Found: C, 79.78; H, 11.11.
JO061617N
9490 J. Org. Chem., Vol. 71, No. 25, 2006