A facile synthesis of natural products chaetomellic acid A and 1,7(Z)-nonadecadiene-2,3-dicarboxylic acid

Article abstract of DOI:10.1021/jo020195o

Synthesis of recently isolated bioactive natural products chaetomellic acid A anhydride (1) and a novel 1,7- (Z)-nonadecadiene-2,3-dicarboxylic acid (2) have been described. Chemoselective carbon-carbon S_N2′ coupling reactions of appropriate Grignard reagents with dimethyl bromomethylfumarate (7) in diethyl ether in the presence of HMPA at room temperature furnished the corresponding diesters 8 and 15 in 60-62% yields. The formed diesters 8 and 15 on hydrolysis gave respectively the corresponding desired diacids 9 and 2 in quantitative yields. Acetic anhydride induced ring closure of diacids 9 and 2 respectively gave the chaetomellic acid A anhydride (1) and isochaetomellic acid B anhydride (16) with 38-39% overall yields in five steps.

Full text of DOI:10.1021/jo020195o

sponding dimethyl ester 15. Since chaetomellic acids are
active in their dianionic form, we felt that synthesis of
itaconic acid analogues 9 and 2 of these acids will be of
interest and useful for biological evaluation studies point
of view. The compounds containing such a exo-type or
exocyclic carbon-carbon double bonds are generally syn-
thesized by using Wittig reactions,12 coupling reactions
involving reduction of carbon-carbon triple bonds,13 and
SN2′ coupling reactions14 of appropriate substrates and
nucleophiles. Chemoselective Grignard reactions, with
preservation of substrate functional groups such as es-
ter,15,16 carboxylic acid,17 nitrile,15 and epoxide,18 are
known in the literature, and recently we have demon-
strated a chemoselective Grignard coupling reaction with
an intact preservation of the cyclic anhydride moiety.10
We have studied several Michael type addition reactions
to the carbon-carbon double bond in maleic anhydrides
and their derivatives, and they are potential starting
materials for the synthesis of natural products19 and
heterocycles.20 We planned a chemoselective SN2′ carbon-
carbon coupling reaction21 of an appropriate Grignard
reagent with bromomethylmaleic anhydride (4) and
dimethyl bromomethylfumarate (7) for an easy access to
these natural products, and we herein report the syn-
thesis of chaetomellic anhydrides 1 and 16 and novel
itaconic acid analogues 2 and 9 (Schemes 1 and 2).
Reaction of citraconic anhydride (3) with NBS/benzoyl
peroxide in carbon tetrachloride under reflux followed by
Kugelrohr distillation of the obtained oily product gave
bromomethylmaleic anhydride (4)22 in 55% yield with
98% purity (by 1H NMR). The reactions of Grignard
reagent tertadecylmagnesium bromide with highly reac-
tive monosubstituted bromoanhydride 4 in the presence/
absence of HMPA with/without copper catalyst were not
selective and yielded only 8-10% of the desired product
chaetomellic acid A anhydride (1). To obtain the selectiv-
ity, we planned for preparation of relatively less reactive
starting material dimethyl bromomethylfumarate (7),
A F a cile Syn th esis of Na tu r a l P r od u cts
Ch a etom ellic Acid A a n d 1,7(Z)-
Non a d eca d ien e-2,3-d ica r boxylic Acid †,‡
Anirban Kar and Narshinha P. Argade*,§
Division of Organic Chemistry (Synthesis),
National Chemical Laboratory, Pune 411 008, India
argade@dalton.ncl.res.in
Received March 20, 2002
Abstr a ct: Synthesis of recently isolated bioactive natural
products chaetomellic acid A anhydride (1) and a novel 1,7-
(Z)-nonadecadiene-2,3-dicarboxylic acid (2) have been de-
scribed. Chemoselective carbon-carbon SN2′ coupling reac-
tions of appropriate Grignard reagents with dimethyl bromo-
methylfumarate (7) in diethyl ether in the presence of HMPA
at room temperature furnished the corresponding diesters
8 and 15 in 60-62% yields. The formed diesters 8 and 15
on hydrolysis gave respectively the corresponding desired
diacids 9 and 2 in quantitative yields. Acetic anhydride
induced ring closure of diacids 9 and 2 respectively gave the
chaetomellic acid A anhydride (1) and isochaetomellic acid
B anhydride (16) with 38-39% overall yields in five steps.
Chaetomellic acid A anhydride (1) and chaetomellic
acid B anhydride have been recently isolated1 from Chaet-
omella acutiseta, and their dianionic forms are potent and
highly specific inhibitors of ras farnesyl-protein trans-
ferase. At present a number of FPTase inhibitors are in
human clinical trials by several companies,2 and provi-
sion of new facile synthetic approaches to these natural
products chaetomellic acid A anhydride (2-tetradecyl-3-
methylmaleic anhydride) and chaetomellic acid B anhy-
dride [(Z)-2-hexadec-7-enyl-3-methylmaleic anhydride] is
a task of current interest.3-10 Eight alternate syntheses
of 1, including three from our group,7,8,10 and two syn-
theses of chaetomellic acid B5,9 have been recently accom-
plished using elegant synthetic strategies.3-10 Very re-
cently the Watanabe’s group from Kyoto University in
J apan isolated11 a novel compound 1,7(Z)-nonadecadiene-
2,3-dicarboxylic acid (NDA, 2) from cultures of a white-
rot fungus Ceriporiopsis subvermispora as a correspond-
ing diester 15. The structural assignment of NDA (2) was
(12) (a) Mangaleswaran, S.; Argade, N. P. J . Org. Chem. 2001, 66,
5259. (b) Mangaleswaran, S.; Argade, N. P. J . Chem. Soc., Perkin
Trans. 1 2001, 1764. (c) Mangaleswaran, S.; Argade, N. P. J . Chem.
Soc., Perkin Trans. 1 2000, 3290.
(13) (a) Dulcere, J .; Mihoubi, M. N.; Rodriguez, J . J . Org. Chem.
1993, 58, 5709. (b) Tamaru, Y.; Hojo, M.; Yoshida, Z. J . Org. Chem.
1991, 56, 1099 and refs. cited therein 13a, b.
(14) (a) Ballini, R.; Bosica, G.; Livi, D. Synthesis 2001, 1519. (b)
Ballini, R.; Marcantoni, E.; Parella, S. J . Org. Chem. 1999, 64, 2954
and refs. cited therein 14a, b.
(15) Nunomoto, S.; Kawakami, Y.; Yamashita, Y. J . Org. Chem.
1983, 48, 1912.
(16) Normant, J . F.; Villieras, G.; Scott, F. Tetrahedron Lett. 1977,
18, 3236.
(17) (a) Dasgupta, S. K.; Rice, D. M.; Griffin, R. G. J . Lipid Res.
1982, 23, 197. (b) Baer, T. A.; Carney, R. L. Tetrahedron Lett. 1976,
17, 4697.
(18) (a) Nicolaou, K. C.; Duggan, M. E.; Ladduwahetty, T. Tetrahe-
dron Lett. 1984, 25, 2069. (b) Brevet, J .-L.; Mori, K. Synthesis 1992,
1007. (c) Mori, K.; Argade, N. P. Liebigs Ann. Chem. 1994, 695.
(19) (a) Deshpande, A. M.; Natu, A. A.; Argade, N. P. Synthesis 2001,
702. (b) Mhaske, S. B.; Argade N. P. J . Org. Chem. 2001, 66, 9038. (c)
Mhaske, S. B.; Argade N. P. Synthesis 2002, 323 and refs. cited therein.
(20) Argade, N. P.; Balasubramaniyan, V. Heterocycles 2000, 53, 475.
(21) (a) Silverman, G. S.; Rakita, P. E. Handbook of Grignard
Reagents, 1st ed.; Marcel Dekker: New York, 1996. (b) Lipshutz, B.
H.; Sengupta, S. Org. React. 41, 1992, 135.
1
1
done on the basis of H NMR, H-1H COSY, 13C NMR,
HMQC and HMBC NMR, and GC-MS data of corre-
† NCL Communication No. 6625.
‡ Dedicated to Dr. B. G. Hazra, OCS, NCL, Pune.
§ Fax: +91-20-5893153.
(1) Singh, S. B.; Zink, D. L.; Liesch, J . M.; Goetz, M. A.; J enkins, R.
G.; Nalin-Omstead, M.; Silverman, K. C.; Bills, G. F.; Mosley R. T.;
Gibbs, J . B.; Albers-Schonberg, G.; Lingham, R. B. Tetrahedron 1993,
49, 5917.
(2) Singh, S. B.; J ayasuriya, H.; Silverman, K. C.; Bonfiglio, C. A.;
Williamsons, J . M.; Lingham, R. B. Bioorg. Med. Chem. 2000, 8, 571.
(3) Singh, S. B. Tetrahedron Lett. 1993, 34, 6521.
(4) (a) Branchaud, B. P.; Slade, R. M. Tetrahedron Lett. 1994, 35,
4071. (b) Slade, R. M.; Branchaud, B. P. J . Org. Chem. 1998, 63, 3544.
(5) Kates, M. J .; Schauble, J . H. J . Org. Chem. 1996, 61, 4164.
(6) Ratemi, E. S.; Dolence, J . M.; Poulter, C. D.; Vederas, J . C. J .
Org. Chem. 1996, 61, 6296.
(7) Argade, N. P.; Naik, R. H. Bioorg. Med. Chem. 1996, 4, 881.
(8) Desai, S. B.; Argade, N. P. J . Org. Chem. 1997, 62, 4862.
(9) Poigny, S.; Guyot, M.; Samadi, M. J . Chem. Soc., Perkin Trans.
1 1997, 2175.
(10) Deshpande, A. M.; Natu, A. A.; Argade, N. P. J . Org. Chem.
1998, 63, 9557.
(11) Enoki, M.; Watanabe, T.; Honda, Y.; Kawahara, M. Chem. Lett.
2000, 54.
(22) Laursen, R. A.; Shen, W.-C.; Zahka, K. G. J . Med. Chem. 1971,
14, 619.
10.1021/jo020195o CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/05/2002
J . Org. Chem. 2002, 67, 7131-7134
7131

SCHEME 1a
a
Key: (i) NBS, DBP, CCl4, reflux, 8 h (55%); (ii) C14H29MgBr, Et2O, rt, 8 h (8-10%); (iii) CH3OH, H+/H2SO4, reflux, 12 h (75%); (iv) NBS, AIBN,
CCl4, reflux, 12 h (85%); (v) C14H29MgBr, Et2O, HMPA, rt, 8 h (60%); (vi) AcOH + HCl (7:3), reflux, 2 h (98%); (vii) Ac2O, reflux, 2 h (∼100%).
SCHEME 2a
a
Key: (i) LiNH2/NH3, C11H23Br, -78 °C to -33 °C to rt, 4 h (80%); (ii) H2, Lindlar Pd, quinoline, hexane, rt, 30 min (99%); (iii) p-TsCl, TEA,
DMAP, CH2Cl2, rt, 6 h (86%); (iv) LiBr, NaHCO3, acetone, rt, 15 h (85%); (v) CH3(CH2)10CHdCH(CH2)3MgBr, Et2O, HMPA, rt, 8 h (62%); (vi)
LiOH, THF + H2O (2:1), rt, 18 h (98%); (vii) Ac2O, reflux, 2 h (∼100).
which is also a more appropriate precursor for the syn-
thesis of natural dicarboxylic acid 2. The reaction of citra-
conic anhydride (3) with methanol/H2SO4 under reflux
gave the desired diester 6 in 75% yield.23 The diester 6
on treatment with NBS/AIBN in refluxing carbon tetra-
chloride underwent smooth allylic bromination and isomer-
ization of carbon-carbon double bond to yield the dim-
ethyl bromomethylfumarate (7) in 85% yield.24 An in situ
isomerization of (Z)-isomer to (E)-isomer was confirmed25
by obtaining the same product 7 from the corresponding
dimethyl methylfumarate under the same set of reaction
conditions. The unsymmetrical bromodiester 7 has five
alternate sites available for nucleophilic reactions, viz.
(i) two ester carbonyls for 1,2-additions, (ii) two sites for
Michael addition, and (iii) allylic bromo atom for nucleo-
philic substitution reaction. The freshly prepared Grig-
nard reagent from tetradecyl bromide, in the presence
of HMPA reacted in a highly chemo- and regioselective
fashion with bromodiester 7 and the exclusive Michael
addition followed by elimination of allylic bromo atom
gave the net SN2′ product 8 in 60% yield.24 The diester 8
on refluxing with glacial acetic acid plus concentrated
HCl (7:3) mixture gave the dicarboxylic acid 9 in 98%
yield. The dicarboxylic acid 9 in refluxing acetic anhy-
dride furnished the desired bioactive natural product
chaetomellic acid A anhydride (1) in nearly 100% yield.
In this reaction both the formation of cyclic anhydride 5
and gem-dialkyl-substituted exocyclic to tetrasubstituted
endocyclic carbon-carbon double bond migration took
place in one pot. In the present five-step synthesis the
chaetomellic acid A anhydride (1) was obtained in 38%
overall yield. The analytical and spectral data obtained
for 1 were in complete agreement with the reported data.1
On successful completion of synthesis of 1 via 8, we
planned for the first synthesis of recently isolated novel
dicarboxylic acid 2. The reaction of tetrahydrofurfuryl
chloride (10) with LiNH2/NH3, followed by treatment with
undecyl bromide, gave the acetylene derivative 11 in 80%
yield.26 Catalytic hydrogenation of 11 with Lindlar
catalyst gave the cis olefin 12 in 97% yield. Conversion
(24) (a) Beltaief, I.; Besbes, R.; Amor, F. B.; Amri, H.; Villieras, M.;
Villieras, J . Tetrahedron 1999, 55, 3949. (b) Amri, H.; Villieras, J .
Tetrahedron Lett. 1987, 28, 5521. (c) Loh, T.-P.; Lye, P.-L. Tetrahedron
Lett. 2001, 42, 3511. (d) Calo, V.; Lopez, L.; Pesce, G. J . Organomet.
Chem. 1988, 353, 405.
(25) As a control experiment, we treated dimethyl maleate with
NBS/AIBN in refluxing CCl4 and obtained exclusively the correspond-
ing dimethyl fumarate in quantitative yield, proving that our condition
employed for allylic bromination of 6 is also sufficient for isomerization
of carbon-carbon double bond in these systems.
(23) Brown, P. M.; Spiers, D. B.; Whalley, M. J . Chem. Soc. 1957,
2882.
7132 J . Org. Chem., Vol. 67, No. 20, 2002

Dim eth yl Br om om eth ylfu m a r a te (7).24 A mixture of 6
(4.74 g, 30 mmol), N-bromosuccinimide (8.00 g, 45 mmol), and
catalytic amount of AIBN (200 mg, 1.22 mmol) in carbon
tetrachloride (150 mL) was gently refluxed for 12 h in a 250 mL
round-bottom flask. The mixture was left overnight at room
temperature and then filtered. The residue was washed with
CCl4 (25 mL × 2), and the combined organic layer was washed
with water (50 mL × 2) and brine (50 mL) and then dried over
Na2SO4 and concentrated in vacuo to furnish thick yellow oil,
which was purified by chromatography on silica gel column using
petroleum ether/ethyl acetate (9:1) to give the desired bromo
diester 7: 6.05 g (85% yield); thick oil; 1H NMR (CDCl3, 200 MHz)
of 12 to corresponding tosylate 13 (86%) followed by
displacement of OTs with LiBr in acetone at room
temperature gave the required (Z)-hexadeca-4-enyl bro-
mide (14) in 85% yield. The overall yield of 14 in four
steps was 57%. The freshly prepared Grignard reagent
from 14, in the presence of HMPA, chemo- and regiose-
lectively coupled with bromodiester 7 to yield SN2′
product 15 with 62% yield. The diester 15 on LiOH-
induced hydrolysis followed by acidification gave the
desired novel natural product 1,7(Z)-nonadecadiene-2,3-
dicarboxylic acid (2) in 98% yield. In the present four-
step synthesis the natural product 2 was obtained with
39% overall yield. The analytical and spectral data
obtained for the corresponding dimethyl ester 15 were
in complete agreement with reported data.11 The dicar-
boxylic acid 2 in refluxing acetic anhydride gave isocha-
etomellic acid B anhydride 16 in quantitative yield.
In summary, we have demonstrated the ninth synthe-
sis of bioactive natural product Chaetomellic acid A
anhydride (1) with 38% overall yield in five-step and the
first four-step synthesis of very recently isolated natural
product 1,7(Z)-nonadecadiene-2,3-dicarboxylic acid (2)
with 39% overall yield. In both above-mentioned coupling
reactions with 7, the chemo- and regioselective attack of
the Grignard reagents on vinylic carbon in absence of
copper catalyst is interesting and useful. It was also
possible to couple the above Grignard reagents under
similar reaction conditions without using HMPA to
obtain 8 and 15 with 48 to 50% yields. We also feel that
such type of migration of trisubstituted carbon-carbon
double bond to gem-disubstituted carbon-carbon double
bond with the loss of conjugation with one of the ester
carbonyls is noteworthy. The present studies also provide
a useful general approach for the synthesis of compounds
containing such exo-type or exocyclic carbon-carbon
double bonds27 for stucture-activity relationship studies.
1
δ 3.83 (s, 3H), 3.88 (s, 3H), 4.72 (s, 2H), 6.83 (s, 1H); H NMR
(CCl4, 200 MHz) δ 3.87 (s, 3H), 3.93 (s, 3H), 4.70 (s, 2H), 6.79
(s, 1H); 13C NMR (CDCl3, 50 MHz) δ 22.1, 51.7, 52.5, 127.9,
142.4, 164.5, 164.7; MS (m/e) 238, 236, 206, 204, 179, 177, 125,
98, 68, 59; IR (Neat) νmax 1730, 1726, 1643 cm-1. Anal. Calcd
for C7H9BrO4: C, 35.47; H, 3.83. Found: C, 35.59; H, 3.72.
Dimethyl methylfumarate (4.74 g, 30 mmol) with same set of
reaction conditions furnished 7 in 86% yield.
4-Hexa d ecyn -1-ol (11). Lithium (1.05 g, 150 mmol) in the
presence of ferric nitrate (50 mg) was dissolved in freshly
distilled ammonia (250 mL) at - 78 °C (disappearance of blue
color). To this freshly prepared lithium amide solution was added
tetrahydrofurfuryl chloride (6.03 g, 50 mmol) during 10 min
time, and the reaction mixture was stirred for 3 h at - 33 °C.
After all the tetrahydrofurfuryl chloride was consumed (by TLC),
n-undecyl bromide (11.75 g, 50 mmol) in THF (10 mL) was added
dropwise to the stirred and cooled reaction mixture at - 33 °C.
It was then stirred for additional 0.5 h and allowed to reach
room temperature. The residue was treated with saturated
ammonium chloride solution and extracted with ether (50 mL
× 5); the combined organic layer was washed with water (50
mL × 2) and brine (50 mL) and then dried over Na2SO4 and
concentrated in vacuo to furnish thick oil, which was purified
by chromatography on silica gel column using petroleum ether/
ethyl acetate (8:2) to give pure 11: 9.53 g (80% yield); thick oil;
1H NMR (CDCl3, 200 MHz) δ 0.87 (t, J ) 8 Hz, 3H), 1.25 (bs,
16H), 1.43 (quintet, J ) 6 Hz, 2H), 1.73 (quintet, J ) 8 Hz, 2H),
1.89 (bs, 1H), 2.05-2.20 (m, 2H), 2.20-2.35 (m, 2H), 3.74 (t, J
) 6 Hz, 2H); 13C NMR (CDCl3, 50 MHz) δ 14.0, 15.4, 18.7, 22.6,
28.9-29.6 (7 carbons), 31.6, 31.9, 61.9, 79.2, 81.0; MS (m/e) 238,
226, 209, 184, 153, 111, 97, 83, 67, 55; IR (CHCl3) νmax 3423,
2400, 1215 cm-1. Anal. Calcd for C16H30O: C, 80.61; H, 12.68.
Found: C, 80.57; H, 12.70.
4(Z)-Hexa d ecen -1-ol (12). To a solution of 11 (9.52 g, 40
mmol) in hexane (150 mL) were added Lindlar palladium
catalyst (800 mg) and quinoline (2 mL). The reaction mixture
was vigorously stirred at room temperature under slightly
positive pressure until hydrogen absorption ceased (0.5 h). The
mixture was filtered, and filtrate was concentrated in vacuo. The
residue was chromatographed over silica gel using petroleum
ether/ethyl acetate (8:2) to give 12: 9.51 g (99% yield), thick oil;
1H NMR (CDCl3, 200 MHz) δ 0.88 (t, J ) 6 Hz, 3H), 1.26 (bs,
18H), 1.51 (bs, 1H), 1.64 (quintet, J ) 8 Hz, 2H), 2.04 (quintet,
J ) 6 Hz, 2H), 2.14 (quintet, J ) 6 Hz, 2H), 3.67 (t, J ) 6 Hz,
2H), 5.30-5.50 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 13.9, 22.6,
23.6, 27.2, 29.3-29.6 (7 carbons), 31.9, 32.7, 62.5, 128.8, 130.7;
MS (m/e) 240, 222, 194, 152, 109, 96, 82, 68, 55; IR (neat) νmax
3354, 1465 cm-1. Anal. Calcd for C16H32O: C, 79.93; H, 13.41.
Found: C, 79.91; H, 13.44.
Exp er im en ta l Section
Melting points are uncorrected. Column chromatographic
separations were carried out on silica gel (60-120 mesh).
Commercially available citraconic anhydride, methyl fumaric
acid, undecyl bromide, tetradecyl bromide, magnesium turnings,
HMPA, tertrahydrofurfuryl chloride, lithium ribbon, Lindlar
catalyst, quinoline, p-toluenesulfonyl chloride, DMAP, lithium
bromide, and acetic anhydride were used.
Dim eth yl Meth ylm a lea te (6). A solution of 3 (4.48 g, 40
mmol) in methanol (40 mL) and H2SO4 (0.5 mL) mixture was
refluxed for 12 h under nitrogen. The reaction mixture was
concentrated in vacuo. The residue was diluted with water and
extracted with ethyl acetate (20 mL × 3). The combined organic
layer was washed with water (20 mL) and brine and dried over
Na2SO4. Concentration of organic layer in vacuo followed by
silica gel column chromatographic purification of the crude
product using petroleum ether/ethyl acetate (9:1) as eluent
furnished pure diester 6: 4.74 g (75% yield); thick oil; 1H NMR
(CDCl3, 200 MHz) δ 2.04 (bs, 3H), 3.70 (s, 3H), 3.81 (s, 3H), 5.84
4(Z)-Hexa d ecen e 1-Tosyla te (13). p-Toluenesulfonyl chlo-
ride (11.47 g, 60 mmol) was added to a solution of 12 (7.20 g, 30
mmol), anhydrous triethylamine (9.09 g, 90 mmol), and DMAP
(75 mg) in anhydrous dichloromethane (150 mL) with stirring
and ice cooling. Stirring was continued for 6 h at room temper-
ature. The reaction mixture was then poured into ice water and
extracted with dichloromethane (50 mL × 3). The combined
organic extracts were washed with water and brine, dried over
Na2SO4 and concentrated in vacuo. The residue was chromato-
graphed over silica gel using petroleum ether/ethyl acetate (9:
1) to give 13: 10.13 g (86% yield), thick oil; 1H NMR (CDCl3,
200 MHz) δ 0.88 (t, J ) 6 Hz, 3H), 1.26 (bs, 18H), 1.69 (quintet,
J ) 8 Hz, 2H), 1.95 (quintet, J ) 8 Hz, 2H), 2.06 (quintet, J )
(bs, 1H); IR (Neat) νmax 1736, 1726, 1655 cm-1
.
Dim eth yl Meth ylfu m a r a te. Repetition of above experimen-
tal procedure with methylfumaric acid (5.20 g, 40 mmol) yielded
the dimethyl methylfumarate in same yield; thick oil; 1H NMR
(CDCl3, 200 MHz) δ 2.24 (d, J ) 2 Hz, 3H), 3.72 (s, 3H), 3.76 (s,
3H), 6.73 (q, J ) 2 Hz, 1H); IR (Neat) νmax 1734, 1724, 1645
cm-1
.
(26) Rao, A. V. R.; Ravichandran, K.; Reddy, N. L. Synth. Commun.
1984, 14, 779.
(27) (a) Keogh, M. F.; Zurita, M. E. Phytochemistry 1977, 16, 134.
(b) Huneck, S.; Yoshimura, I. Identification of Lichen Substances, 1st
ed.; Springer-Verlag: Berlin, Heidelberg, 1996.
J . Org. Chem, Vol. 67, No. 20, 2002 7133

8 Hz, 2H), 2.45 (s, 3H), 4.03 (t, J ) 6 Hz, 2H), 5.15-5.45 (m,
2H), 7.35 (d, J ) 8 Hz, 2H), 7.79 (d, J ) 8 Hz, 2H); 13C NMR
(CDCl3, 50 MHz) δ 13.9, 21.4, 22.5, 22.9, 27.0, 28.8-29.5 (8
carbons), 31.8, 69.9, 127.2, 127.7, 129.6, 131.5, 133.5, 144.4; MS
(m/e) 222, 194, 173, 155, 124, 109, 91, 68; IR (neat) νmax 1598,
1465, 1365, 1176 cm-1. Anal. Calcd for C23H38O3S: C, 70.00; H,
9.71. Found: C, 70.03; H, 9.67.
residue was chromatographed over silica gel using petroleum
ether/ethyl acetate (6:4) to give 9: 479 mg (98% yield); mp 98-
99 °C (benzene); 1H NMR (CDCl3, 200 MHz) δ 0.88 (t, J ) 8 Hz,
3H), 1.26 (bs, 24H), 1.60-1.85 (m, 1H), 1.85-2.10 (m, 1H), 3.40
(t, J ) 8 Hz, 1H), 5.84 (s, 1H), 6.55 (s, 1H), 7.35-8.30 (bs, 2H);
13C NMR (CDCl3, 75 MHz) δ 14.0, 22.6, 27.4, 29.3-29.6 (9
carbons), 30.7, 31.9, 46.6, 129.4, 137.7, 171.6, 179.3; IR (Nujol)
4(Z)-Hexa d ecen e 1-Br om id e (14). To a solution of 13 (9.85
g, 25 mmol) in dry acetone (150 mL) were added NaHCO3 (21.0
g, 250 mmol) and anhydrous lithium bromide (15.23 g, 175
mmol). The reaction mixture was stirred for 15 h at room
temperature and then diluted with ether (100 mL) and filtered
through Celite. The organic solution was concentrated in vacuo,
and the residue was diluted with ether (75 mL). The ether layer
was washed with water, 5% Na2S2O3 solution, saturated aquous
NaHCO3 solution, and brine, dried over Na2SO4, and concen-
trated in vacuo. The residue was chromatographed over silica
gel using petroleum ether to give 14: 6.44 g (85% yield); thick
oil; 1H NMR (CDCl3, 200 MHz) δ 0.88 (t, J ) 6 Hz, 3H), 1.26
(bs, 18H), 1.91 (quintet, J ) 8 Hz, 2H), 2.05 (quintet, J ) 6 Hz,
2H), 2.20 (quintet, J ) 6 Hz, 2H), 3.41 (t, J ) 8 Hz, 2H), 5.20-
5.55 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 14.1, 22.7, 25.7, 27.3,
29.3-29.7 (7 carbons), 31.9, 32.7, 33.2, 127.3, 131.8; MS (m/e)
304, 302, 205, 181, 164, 162, 150, 148, 137, 111, 97, 83, 69; IR
(Neat) νmax 1465, 1224 cm-1. Anal. Calcd for C16H31Br: C, 63.36;
H, 10.30. Found: C, 63.39; H, 10.27.
Dim eth yl 1-Hep ta d ecen e-2,3-d ica r boxyla te (8). A fresh
solution of n-tetradecylmagnesium bromide in ether was pre-
pared as follows. A solution of n-tetradecyl bromide (2.49 g, 9
mmol) in LAH-dried ether (10 mL) was added at room temper-
ature to magnesium turnings (648 mg, 27 mmol) in ether (10
mL) under argon with constant stirring in three equal portions
at an interval of 10 min. The reaction mixture was further
stirred at room temperature for 4 h. TLC of the reaction mixture
in n-pentane showed quantitative conversion of the halide in to
the Grignard reagent. This freshly generated Grignard reagent
was added dropwise to a solution of HMPA (2.69 g, 15 mmol)
and 7 (711 mg, 3 mmol) in anhydrous ether (15 mL) at room
temperature. The reaction mixture was further stirred at room
temperature for 8 h. The reaction was quenched by the addition
of a saturated ammonium chloride solution (20 mL) and ether
(10 mL). The reaction mixture was extracted with ether (20 mL
× 3), the combined ethereal extracts were washed with water
and brine, dried with Na2SO4 and concentrated in vacuo. The
residue was chromatographed over silica gel using petroleum
ether/ethyl acetate (9.5:0.5) to give 8: 637 mg (60% yield); thick
oil; 1H NMR (CDCl3, 200 MHz) δ 0.86 (t, J ) 6 Hz, 3H), 1.24
(bs, 24H), 1.50-2.00 (m, 2H), 3.49 (t, J ) 8 Hz, 1H), 3.67 (s,
3H), 3.75 (s, 3H), 5.74 (s, 1H), 6.35 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 14.0, 22.6, 27.4, 29.2-29.5 (9-carbons), 31.3, 31.8, 46.5,
51.8, 51.9, 126.3, 138.6, 166.6, 173.6; IR (Neat) νmax 1738, 1728,
1630 cm-1. Anal. Calcd for C21H38O4: C, 71.14; H, 10.80.
Found: C, 71.10; H, 10.73.
ν
max 1703, 1693, 1628 cm-1. Anal. Calcd for C19H34O4: C, 69.90;
H, 10.50. Found: C, 69.93; H, 10.37.
1,7(Z)-Non a d eca d ien e-2,3-d ica r boxylic Acid (2). Aquous
lithium hydroxide solution (230 mg in 2 mL water) was added
to a solution of 15 (570 mg, 1.50 mmol) in tetrahydrofuran (4
mL), and the reaction mixture was stirred for 18 h at room
temperature. The reaction mixture was then concentrated in
vacuo, and the residue was diluted with ethyl acetate (50 mL)
and acidified to pH 2 with 2 N hydrochloric acid. The organic
layer was separated and the aquous layer was further extracted
with ethyl acetate (10 mL × 3). The combined organic layer was
washed with water and brine, dried over Na2SO4, and concen-
trated in vacuo. The residue was chromatographed over silica
gel using petroleum ether/ethyl acetate (6:4) to give 2: 520 mg
(98% yield); thick oil; 1H NMR (CDCl3, 200 MHz) δ 0.88 (t, J )
6 Hz, 3H), 1.26 (bs, 18H), 1.40 (quintet, J ) 6 Hz, 2H), 1.65-
1.85 (m, 1H), 1.85-2.20 (m, 5H), 3.43 (t, J ) 8 Hz, 1H), 5.36 (m,
2H), 5.85 (s, 1H), 6.55 (s, 1H), 8.72 (bs, 2H); 13C NMR (CDCl3,
75 MHz) δ 14.0, 22.6, 26.8, 27.3, 27.5, 29.2, 29.3 (6 carbons),
29.8, 31.9, 46.8, 128.7, 129.6, 130.8, 137.5, 171.5, 179.2; MS (m/
e) 352, 334, 316, 306, 295, 277, 261, 239, 221, 193, 179, 151,
126, 112, 97, 81, 67; IR (neat) νmax 2683, 1713, 1699, 1628 cm-1
.
Anal. Calcd for C21H36O4: C, 71.55; H, 10.29. Found: C, 71.47;
H, 10.37.
2-Tetr a d ecyl-3-m eth ylm a leic An h yd r id e (Ch a etom ellic
Acid A An h yd r id e, 1). A solution of 9 (326 mg, 1 mmol) in
acetic anhydride (5 mL) was refluxed for 2 h, and the reaction
mixture was allowed to reach room temperature, concentrated
under vacuo at 50 °C, and diluted with ethyl acetate (20 mL).
The organic layer was washed with water and brine, dried with
Na2SO4, and concentrated in vacuo. The residue was chromato-
graphed over silica gel using petroleum ether/ethyl acetate (9.5:
0.5) to give 1: 308 mg (∼100% yield); thick oil; 1H NMR (CDCl3,
200 MHz) δ 0.88 (t, J ) 7 Hz, 3H), 1.15-1.45 (bs, 22H), 1.46-
1.69 (m, 2H), 2.07 (s, 3H), 2.45 (t, J ) 7 Hz, 2H); 13C NMR
(CDCl3, 50 MHz) δ 9.6, 14.3, 22.9, 24.6, 27.7, 29.0-31.0 (9
carbons), 32.1, 140.6, 144.9, 166.0, 166.4; MS (m/e) 308, 290, 191,
150, 126, 91, 81, 69; IR (neat) νmax 1770, 1680 cm-1. Anal. Calcd
for C19H32O3: C, 73.98; H, 10.46. Found: C, 73.73; H, 10.39.
(Z)-2-Hexa d eca -4-en yl-3-m eth ylm a leic An h yd r id e (Iso-
ch a etom ellic Acid B An h yd r id e, 16). It was prepared simi-
larly from 2 (352 mg, 1 mmol) and acetic anhydride (5 mL) as
described above to obtain the corresponding anhydride 16: 333
1
mg (∼100% yield); thick oil; H NMR (CDCl3, 200 MHz) δ 0.88
(t, J ) 6 Hz, 3H), 1.26 (bs, 18H), 1.65 (quintet, J ) 8 Hz, 2H),
1.90-2.25 (m, 4H), 2.08 (s, 3H), 2.47 (t, J ) 8 Hz, 2H), 5.20-
5.55 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 9.4, 14.0, 22.6, 26.9,
27.3, 27.5, 29.3, 29.5 (5 carbons), 29.6, 31.9, 127.7, 131.8, 140.5,
144.5, 165.8, 166.2; MS (m/e) 334, 289, 278, 266, 223, 205, 165,
149, 126, 97, 83, 69, 57; IR (Neat) νmax 1767, 1740, 1460, 1271
cm-1. Anal. Calcd for C21H34O3: C, 75.41; H, 10.25. Found: C,
75.35; H, 10.33.
Dim eth yl 1,7(Z)-Non a d eca d ien e-2,3-d ica r boxyla te (15).
Repetition of above procedure using (Z)-hexadeca-4-enylmag-
nesium bromide [prepared from 14 (2.73 g, 9 mmol) and
magnesium (648 mg, 27 mmol)] and 7 (711 mg, 3 mmol) gave
1
the corresponding diester 15: 707 mg (62% yield); thick oil; H
NMR (CDCl3, 200 MHz) δ 0.88 (t, J ) 6 Hz, 3H), 1.26 (bs, 18H),
1.35 (quintet, J ) 6 Hz, 2H), 1.66 (m, 1H), 1.80-2.15 (m, 5H),
3.51 (t, J ) 8 Hz, 1H), 3.68 (s, 3H), 3.77 (s, 3H), 5.34 (m, 2H),
5.76 (s, 1H), 6.37 (s, 1H); 13C NMR (CDCl3, 50 MHz) δ 14.0, 22.6,
26.8, 27.2, 27.5, 29.3, 29.6 (6 carbons), 30.8, 31.9, 46.4, 51.9, 52.0,
126.6, 128.8, 130.6, 138.4, 166.6, 173.6; MS (m/e) 380, 348, 320,
289, 261, 236, 193, 158, 140, 126, 107, 93, 79, 67; IR (Neat) νmax
1740, 1726, 1630, 1458, 1437 cm-1. Anal. Calcd for C23H40O4:
C, 72.59; H, 10.59. Found: C, 72.67; H, 10.53.
1-Hep ta d ecen e-2,3-d ica r boxylic Acid (9). Concentrated
hydrochloric acid (3 mL) was added to a solution of 8 (531 mg,
1.50 mmol) in acetic acid (7 mL), and the reaction mixture was
refluxed for 2 h. The reaction mixture was then cooled and
concentrated in vacuo, and the residue was diluted with ethyl
acetate (30 mL). The ethyl acetate layer was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. The
Ack n ow led gm en t. A.K. thanks CSIR, New Delhi,
for the award of a research fellowship. N.P.A. thanks
Department of Science and Technology, New Delhi, for
financial support. We thank Dr. K. N. Ganesh, Head,
Division of Organic Chemistry (Synthesis), for constant
encouragement.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of 1, 2, 8, 9, 15, 16. Mass spectra of 1, 2, 15, 16.
Experimental procedure and data for 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O020195O
7134 J . Org. Chem., Vol. 67, No. 20, 2002