Synthesis of mayolene-16 and mayolene-18: Larval defensive lipids from the European Cabbage butterfly

Article abstract of DOI:10.1021/jo011102q

A tandem Wittig approach has been employed for the synthesis of both (11S,9Z,12Z,15Z)- and (11R,9Z,12Z,15Z)-hydroxyoctadeca-9,12,15-trienoic acid (11-hydroxylinolenic acid, 11-HLA) from (R)-glyceraldehyde acetonide. From (11R)-HLA we have prepared the corresponding palmitic acid and stearic acid esters, mayolene-16 (1) and mayolene-18 (2), insect defensive compounds recently identified from Pieris rapae larvae. In addition, we describe the synthesis of three macrocyclic oligomers (24-26) derived from (11R)-HLA.

Full text of DOI:10.1021/jo011102q

Syn th esis of Ma yolen e-16 a n d Ma yolen e-18: La r va l Defen sive
Lip id s fr om th e Eu r op ea n Ca bba ge Bu tter fly
Douglas B. Weibel, Laura E. Shevy, Frank C. Schroeder, and J errold Meinwald*
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853
circe@cornell.edu
Received November 26, 2001
A tandem Wittig approach has been employed for the synthesis of both (11S,9Z,12Z,15Z)- and
(11R,9Z,12Z,15Z)-hydroxyoctadeca-9,12,15-trienoic acid (11-hydroxylinolenic acid, 11-HLA) from
(R)-glyceraldehyde acetonide. From (11R)-HLA we have prepared the corresponding palmitic acid
and stearic acid esters, mayolene-16 (1) and mayolene-18 (2), insect defensive compounds recently
identified from Pieris rapae larvae. In addition, we describe the synthesis of three macrocyclic
oligomers (24-26) derived from (11R)-HLA.
In tr od u ction
study their biological activity, we wished to prepare
compounds 24-26 as well. We now report the synthesis
of both enantiomers of 11-HLA, mayolene-16 (1) and
mayolene-18 (2), and of the oligomeric macrolides 24-
26.
As part of our ongoing investigation of the chemical
defenses of insect larvae and pupae, we have recently
characterized a new family of biologically active lipids,
the mayolenes, from the glandular hair secretion of
larvae of the European Cabbage butterfly, Pieris rapae.1
The mayolenes consist of (11R)-HLA2 (11-HLA ) 11-
hydroxylinolenic acid) esterified with a series of homolo-
gous saturated fatty acids. The major components of this
larval defensive secretion, mayolene-16 (1) and mayolene-
18 (2), are (11R)-HLA esters of palmitic acid and stearic
acid, respectively.
Resu lts a n d Discu ssion
Because the bis-allylic hydroxyl group in 11-HLA is
particularly prone to 1,4-elimination, we sought synthe-
ses of (11R)- and (11S)-HLA compatible with the acid-
and heat-sensitive nature of the intermediates and
product. Our route utilizes two consecutive Wittig reac-
tions to construct the C9-C10 and C12-C13 cis double bonds,
and allows both enantiomers of 11-HLA to be prepared
from (R)-glyceraldehyde acetonide (9) simply by varying
the order in which the two Wittig reactions are carried
out (Scheme 1).
To prepare (11R)-HLA, the ylide derived from (3Z)-3-
hexyltriphenylphosphonium bromide (6)4 was treated
with 9,5 providing diene 10 with excellent diastereo-
selectivity (Z:E > 99:1, GC).6 Deprotection of the ac-
etonide using methanolic hydrochloric acid afforded diol
11 (Scheme 2).
Conversion of 11 to the corresponding di-tert-butyldi-
methylsilyl ether, followed by anticipated regioselective
deprotection of the primary silyl ether using HF-pyr7
surprisingly gave only the undesired product, arising
from selective removal of the secondary, allylic silyl ether.
To circumvent this problem, diol 11 was regioselectively
protected as the primary tert-butyldimethylsilyl ether 12
using TBSCl and triethylamine in the presence of DBU.8
Following the structural characterization of the may-
olenes, we were interested in synthesizing the individual
enantiomers of 11-HLA, which we needed to determine
the absolute configuration of these natural products, as
well as to provide samples of the mayolenes for further
study of their biological activity.1 At an early stage in
the course of characterizing the mayolenes, we considered
candidate structures 24-26, structural analogues of the
polyazamacrolides recently indentified from ladybird
beetle pupae.3 To establish the presence or absence of
these macrocyclic lactones in the insect secretion and to
(3) Schroeder, F. C.; Smedley, S. R.; Gibbons, L. K.; Farmer, J . J .;
Attygalle, A. B.: Eisner, T.; Meinwald, J . Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 13387.
(4) Sandri, J .; Viala, J . J . Org. Chem. 1995, 60, 6627.
(5) J ackson, D. Y. Synth. Commun. 1998, 18, 337.
(6) For a review of the chemistry of optically active glyceraldehyde
acetonide, see: J urczak, J .; Pikul, S.; Bauer, T. Tetrahedron 1986, 42,
447.
(1) Smedley, S. R.; Schroeder, F. C.; Weibel, D. B.; Meinwald, J .;
Lafleur, K. A.; Renwick, J . A.; Rutowski, R.; Eisner, T. Proc. Natl. Acad.
Sci. U.S.A. 2002, 99, 6822.
(2) We could locate only a single reference to 11-HLA in the
literature: Hamberg, M. J . Chem. Soc., Perkin Trans. 1 1993, 3065.
(7) Baker, R.; Castro, J . L. J . Chem. Soc., Chem. Commun. 1989,
378.
10.1021/jo011102q CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/19/2002
5896
J . Org. Chem. 2002, 67, 5896-5900

Synthesis of Mayolene-16 and Mayolene-18
SCHEME 1
SCHEME 2a
The secondary hydroxyl group in silyl ether 12 was
protected as the tert-butyldiphenylsilyl ether to provide
13, followed by selective deprotection of the primary silyl
ether in the presence of PPTS, affording alcohol 14.
Interestingly, the tert-butyldiphenylsilyl group in 14 was
found to migrate slowly to the primary hydroxyl group.
Oxidation of freshly prepared 14 using tetrapropylam-
monium perruthenate/4-methylmorpholine N-oxide (TPAP/
NMO)9 afforded aldehyde 7, which was subsequently
treated with the ylide prepared from (8-carboxymethy-
loctyl)triphenylphosphonium bromide (5)10 toyield trienoate
15. Treatment of 15 with TBAF afforded alcohol 16,
which upon hydrolysis with aqueous lithium hydroxide
followed by careful neutralization, provided (11R)-HLA
(3).
To prepare (11S)-HLA, 9 was treated with the ylide
derived from 5 to afford 17 with excellent diastereo-
selectivity (Z:E > 98:2, GC). Deprotection of 17 with
methanolic hydrochloric acid afforded diol 18 (Scheme
3). Protection of the primary hydroxyl group as the tert-
butyldimethylsilyl ether gave 19. The free secondary
hydroxyl group of 19 was protected as the tert-butyl-
diphenylsilyl ether to afford 20, which was regioselec-
tively deprotected at the primary hydroxyl group to yield
alcohol 21. Oxidation of 21 with PCC provided aldehyde
8. A Wittig reaction between 8 and the ylide prepared
from 6 afforded triene 22, which was subsequently
deprotected using TBAF, to yield alcohol 23. Hydrolysis
of 23 provided (11S)-HLA (4). With synthetic samples of
optically pure (11R)- and (11S)-HLA in hand, we showed
the absolute configuration of the mayolenes to be (11R).1
a
Reagents and conditions: (a) LiHMDS, -78 °C, THF, then 9;
(b) HCl, MeOH; (c) TBSCl, Et3N, DBU, CH2Cl2; (d) TBDPSCl,
DMAP, CH2Cl2; (e) PPTS, EtOH; (f) TPAP, NMO, CH2Cl2; (g) 5,
LiHMDS, -78 °C, THF, then 7; (h) TBAF, THF; (i) LiOH, MeOH.
We next focused on a convenient esterification tech-
nique that would permit the preparation of mayolene-
16 (1) and mayolene-18 (2). We found that the synthesis
of these labile compounds could be carried out by preac-
tivating palmitic or stearic acid with 1-(3-dimethylami-
nopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)11 in
the presence of DMAP, followed by the addition of 3
(Scheme 4). To avoid elimination, we carefully neutral-
ized the reaction mixture using pH 5.75 buffer, followed
by extraction and flash chromatography on wet silica gel,
to afford pure 1 and 2. The H NMR, 13C NMR, and ESI
1
mass spectra of 1 and 2 were found to be indistinguish-
able from those determined for the natural materials,1
confirming the structures assigned to the mayolenes on
spectroscopic grounds.
In the early stages of characterizing the larval Pieris
defensive secretion, spectroscopic evidence had suggested
that macrocyclic lactones such as 24-26, admixed with
several fatty acids, might be important constituents. We
therefore investigated conditions for the macrolactoniza-
tion of (11R)-HLA to afford authentic samples of the
corresponding mono- and oligomeric macrolides. While
macrolactonization of (11R)-HLA using 2-chloro-1-meth-
ylpyridinium iodide,12 2,2′-dipyridyl disulfide,13 and DCC/
DMAP/DMAP-HCl14 furnished only elimination prod-
(8) Kim, S.; Chang, H. Bull. Chem. Soc. J pn. 1985, 58, 3669.
(9) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
Chem. Commun. 1987, 1625. (b) Ley, S. V.; Norman, J .; Griffith, W.
P.; Marsden, S. P. Synthesis 1994, 639.
(10) Tranchepain, I.; Le Berre, F.; Dure´ault, A.; Le Merrer, Y.;
Depezay, J . C. Tetrahedron Lett. 1989, 45, 2057.
(11) Sheehan, J . C.; Cruickshank, P. A.; Boshart, G. L. J . Org. Chem.
1961, 26, 2525.
J . Org. Chem, Vol. 67, No. 17, 2002 5897

Weibel et al.
SCHEME 3a
SCHEME 5a
a
Reagents and conditions: (a) iPr2NEt, 2,4,6-trichlorobenzoyl
chloride, benzene, then DMAP.
a
Reagents and conditions: (a) (a) LiHMDS, -78 °C, THF, then
9; (b) HCl, MeOH; (c) TBSCl, Et3N, DBU, CH2Cl2; (d) TBDPSCl,
DMAP, CH2Cl2; (e) PPTS, EtOH; (f) PCC, NaOAc, CH2Cl2; (g) 6,
LiHMDS, -78 °C, THF, then 8; (h) TBAF, THF; (i) LiOH, MeOH.
groups from cyanobacterial blooms, has been reported.
Only by employment of 2,4,6-trichlorobenzoyl chloride/
Et3N/DMAP was successful macrolactonization of the
appropriate precursor to mueggelone accomplished.17
Chromatography of the macrolactonization products
formed from (11R)-HLA provided samples of pure 24-
26, along with the tetramer, and a sample of a pentamer
admixed with small amounts of the tetramer and higher
SCHEME 4a
1
oligomers. The H NMR spectra of macrolides 24-26 are
readily distinguishable from each other and from the
natural secretion. While the 1H NMR spectra of the
tetramer and pentamer are virtually indistinguishable,
and resemble some relevant portions of the 1H NMR
spectra of O-acyl derivatives of the acyclic monomer
(11R)-HLA, the C-11 proton chemical shift value in these
macrolides is clearly upfield of the corresponding C-11
proton in O-acyl derivatives of (11R)-HLA, indicating that
none of these macrolides are present in the glandular hair
secretion.
In summary, we have described a concise route to both
enantiomers of 11-HLA from (R)-glyceraldehyde ac-
a
(12) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49.
(13) Corey, E. J .; Nicolaou, K. C. J . Am. Chem. Soc. 1974, 96, 5614.
(14) Boden, E. P.; Keck, G. E. J . Org. Chem. 1985, 50, 2394.
(15) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
(16) (a) Papendorf, O.; Ko¨nig, G. M.; Wright, A. D.; Chorus, I.;
Oberemm, A. J . Nat. Prod. 1997, 60, 1298. (b) Stierle, D. B.; Stierle,
A. A.; Bugni, T.; Loewen, G. J . Nat. Prod. 1998, 61, 251.
(17) (a) Ishigami, K.; Motoyoshi, H.; Kitahara, T. Tetrahedron Lett.
2000, 41, 8897. (b) Motoyoshi, H.; Ishigami, K.; Kitahara, T. Tetrahe-
dron 2001, 57, 3899.
Reagents and conditions: (a) EDCI, DMAP, CH2Cl2, then 3.
ucts, we found that 2,4,6-trichlorobenzoyl chloride/Et3N/
DMAP15 yielded predominantly the desired macrolides
24-26 (Scheme 5), along with small amounts of tet-
rameric and pentameric macrolides. Similar experience
during the total synthesis of mueggelone,16 an allylic 10-
membered macrolide independently isolated by two
5898 J . Org. Chem., Vol. 67, No. 17, 2002

Synthesis of Mayolene-16 and Mayolene-18
solution of 13 (795 mg, 1.56 mmol) in ethanol (20 mL). After
being stirred for 6.5 h at 55 °C, the solution was cooled to rt,
diluted with brine (40 mL), and extracted with CH2Cl2 (100
mL). Organic extracts were combined, dried (MgSO4), filtered,
and concentrated under vacuum. Flash chromatography (10:1
hexane/ethyl acetate) of the residual oil provided 14 (565 mg,
92%) as a clear oil.
(2S,3Z,6Z)-2-[(ter t-Bu tyldiph en ylsilyl)oxy]-3,6-n on adien -
1-a l (7). Powdered, activated 4 Å molecular sieves (375 mg),
4-methylmorpholine N-oxide (132 mg, 1.13 mmol), and tetra-
propylammonium perruthenate (13 mg, 0.037 mmol) were
added to a stirred solution of 14 (297 mg, 0.75 mmol) in CH2-
Cl2 (5 mL). After being stirred for 35 min at rt, the solution
was filtered through a small pad of SiO2, which was subse-
quently washed with CH2Cl2. The combined CH2Cl2 washes
were concentrated under vacuum. Flash chromatography (50:1
hexane/ethyl acetate) of the residual oil provided 7 (240 mg,
81%) as a clear oil.
(11R,9Z,12Z,15Z)-11-[(ter t-Bu tyld ip h en ylsilyl)oxy]oc-
ta d eca -9,12,15-tr ien oic Acid Meth yl Ester (15). A 1.0 M
solution of lithium bis(trimethylsilyl)amide (0.76 mL, 1.07
mmol) in THF was added dropwise to a solution of 5 (584 mg,
1.15 mmol) in THF (8 mL) and HMPA (1 mL) at -78 °C. After
the solution was stirred at -78 °C for 45 min, a solution of 7
(300 mg, 0.76 mmol) in THF (2 mL) was added dropwise. The
solution was stirred for 1 h at -78 °C, subsequently stirred
for 3 h at 0 °C, and then quenched by slow addition of a
saturated aqueous solution of NH4Cl (10 mL). THF was
removed under vacuum and the resulting oil extracted with
CH2Cl2 (50 mL). Combined organic extracts were dried (Mg-
SO4), filtered, and concentrated under vacuum. Flash chro-
matography (30:1 hexane/ethyl acetate) of the residual oil
provided 15 (229 mg, 55%) as a bright yellow oil.
(11R,9Z,12Z,15Z)-11-Hyd r oxyocta d eca -9,12,15-tr ien o-
ic Acid Meth yl Ester (16). A 1.0 M solution of tetrabuty-
lammonium fluoride (0.32 mL, 0.32 mmol) in THF was added
dropwise to a stirred solution of 15 (118 mg, 0.21 mmol) in
THF (1.0 mL). The solution was stirred for 4.5 h at rt, then
poured into brine (5 mL), and extracted with CH2Cl2 (20 mL).
Combined organic extracts were dried (MgSO4), filtered, and
concentrated under vacuum. Flash chromatography (4:1 hex-
ane/ethyl acetate) of the residual oil provided 16 (65.8 mg, 99%)
as a clear oil.
(11R,9Z,12Z,15Z)-11-Hyd r oxyocta d eca -9,12,15-tr ien o-
ic a cid (3). A solution of 16 (11.0 mg, 0.035 mmol) in CH3OH
(0.25 mL) was treated with an aqueous solution of LiOH (0.400
mL, 3 M) and stirred for 3.5 h at 50 °C. The cloudy solution
was cooled to rt and carefully titrated to pH 6.0 with 0.25 M
aqueous HCl. THF was removed under vacuum and the
residue dissolved in ether (1.0 mL), dried (Na2SO4), filtered,
and concentrated under vacuum. Flash chromatography (2:1
hexane/ethyl acetate) of the residual oil provided 3 (10.0 mg,
95%) as a clear oil: [R]D +6.4 (c 1.60, CH3OH); Rf ) 0.44 (1:1
hexane/ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 5.40-5.52
(m, 5 H), 5.27-5.34 (m, 2 H), 2.81-2.97 (m, 2 H), 2.34 (t, J )
7.4 Hz, 2 H), 2.02-2.21 (m, 4 H), 1.66 (app quintet, J ) 7.2
Hz, 2 H), 1.28-1.42 (m, 8 H), 0.99 (t, J ) 7.5 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 179.3, 132.7, 132.4, 131.5, 131.1,
130.4, 126.6, 64.0, 34.2, 29.7, 29.24, 29.22, 29.1, 27.9, 26.2, 24.8,
20.8, 14.4; IR (neat, cm-1) 3886, 3658, 3012, 2962, 2930, 2856,
1710, 1462, 1412, 1248, 1070; MS (ESI+) m/z 294 (294 calcd
for C18H30O3); MS (ESI-) m/z 293; MS/MS (ESI-) daughter
ions of m/z 293, m/z 275, 197, 95.
Ma yolen e-16 (1) [(11S,9Z,12Z,15Z)-11-H exa d eca n oyl-
oxyocta d eca -9,12,15-tr ien oic Acid ]. A solution of palmitic
acid (14.4 mg, 0.056 mmol) in CH2Cl2 (0.25 mL) was treated
with DMAP (6.9 mg, 0.056 mmol) and EDCI (10.7 mg, 0.056).
The resulting cloudy solution was stirred for 10 h at rt followed
by the addition of a solution of 3 (15.0 mg, 0.051 mmol) in
CH2Cl2 (0.10 mL). After the solution was stirred for 12 h, the
solvent was removed under vacuum. The residue was dissolved
in NaOAc buffer (10 mL, 0.4 M, pH 5.75) and extracted with
etonide (9) and the Wittig reagents prepared from phos-
phonium ylides 5 and 6. From (11R)-HLA, we have
prepared mayolene-16 (1) and mayolene-18 (2), both of
which exhibit strong insect-deterrent activity in bio-
assays.1 To facilitate chemical characterization of the
Pieris rapae secretion, we also synthesized several mac-
rolides derived from (11R)-HLA. These macrolides turned
out not to be part of the larval armamentarium.
Exp er im en ta l Section
Gen er a l In for m a tion . All commercially available reagents
were used without further purification. Solvents were either
used as purchased or distilled using common practices where
appropriate. All reactions were carried out under dry nitrogen.
TLC was performed using 2.5 × 7.5 cm plates precoated with
silica gel (200 µm), and spots were visualized by anisaldehyde.
Silica gel (60 Å) was used for flash column chromatography.
An aliquot of aqueous ammonium hydroxide was added to
solutions of mayolene-16 (1) and mayolene-18 (2) prior to
positive ion electrospray mass spectrometry.
(4S,1′Z,4′Z)-2,2-Dim eth yl-4-h ep ta -1,4-d ien -1-yl-1,3-d iox-
ola n e (10). A 1.0 M solution of lithium bis(trimethylsilyl)-
amide (4.22 mL, 4.22 mmol) in THF was added dropwise over
30 min to a stirred solution of 6 (1.96 g, 4.61 mmol) in THF (8
mL) at 0 °C. After being stirred for 30 min at 0 °C, the deep
orange solution was cooled to -78 °C, and to the solution was
added dropwise a solution of 9 (500 mg, 3.84 mmol) in THF (3
mL). The solution was stirred for 3 h at 0 °C, at which time
the reaction was quenched by slow addition of a saturated
aqueous NH4Cl solution (30 mL). After brief stirring, the
yellow liquid was extracted with CH2Cl2 (45 mL). Combined
organic extracts were dried (MgSO4), filtered, and concentrated
under vacuum. Flash chromatography (30:1 hexane/ethyl
acetate) of the residual orange oil provided 10 (520 mg, 69%)
as a clear oil.
(2S,3Z,6Z)-3,6-Non adien e-1,2-diol (11). Concentrated aque-
ous hydrochloric acid (3.3 mL) was added dropwise to a stirred
solution of 10 (2.03 g, 10.3 mmol) in methanol (30 mL) at 0
°C. After the solution was stirred for 4 h at 0 °C, the pH was
adjusted to 7 by slow addition of an aqueous NH4OH solution
(25%, v/v). After methanol was removed under vacuum, the
solution was diluted with water (15 mL) and extracted with
ether (110 mL). Combined organic extracts were dried (Mg-
SO4), filtered, and concentrated under vacuum. Flash chro-
matography (1:1 hexane/ethyl acetate) of the residual yellow
oil provided 11 (1.45 g, 90%) as a light yellow oil.
(2S,3Z,6Z)-1-[(ter t-Bu tyldim eth ylsilyl)oxy]-3,6-n on adien -
2-ol (12). Triethylamine (0.045 mL, 0.33 mmol), DBU (0.010
mL, 0.065 mmol), and tert-butyldimethylsilyl chloride (50 mg,
0.33 mmol) were added to a stirred solution of 11 (51 mg, 0.33
mmol) in CH2Cl2 (0.5 mL). After being stirred for 6 h at rt,
the solution was washed with 10 mL of ice cold aqueous HCl
(5%, v/v) and extracted with CH2Cl2 (40 mL). The combined
organic layers were washed with a saturated aqueous NaHCO3
solution (15 mL), dried (MgSO4), filtered, and concentrated
under vacuum. Flash chromatography (15:1 hexane/ethyl
acetate) of the residual oil provided 12 (75 mg, 85%) as a clear
oil.
(2S,3Z,6Z)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-[(ter t-bu -
tyld ip h en ylsilyl)oxy]-3,6-n on a d ien e (13). DMAP (440 mg,
3.60 mmol) and tert-butyldiphenylsilyl chloride (0.93 mL, 3.60
mmol) were added to a stirred solution of 12 (487 mg, 1.80
mmol) in CH2Cl2 (10 mL). After being stirred for 18 h at rt,
the solution was diluted with brine (25 mL) and extracted with
CH2Cl2 (75 mL). Organic extracts were combined, dried
(MgSO4), filtered, and concentrated under vacuum. Flash
chromatography (60:1 hexane/ethyl acetate) of the residual oil
provided 13 (816 mg, 89%) as a clear oil.
(2S,3Z,6Z)-2-[(ter t-Bu tyldiph en ylsilyl)oxy]-3,6-n on adien -
1-ol (14). PPTS (196 mg, 0.78 mmol) was added to a stirred
J . Org. Chem, Vol. 67, No. 17, 2002 5899

Weibel et al.
ether. Combined organic extracts were dried (MgSO4), filtered,
and concentrated under vacuum. Flash chromatography (5:1
hexane/ethyl acetate) of the residual oil provided 1 (16.0 mg,
59%) as a white solid: [R]D -1.5 (c 0.84, CH2Cl2); Rf ) 0.47
14, J 3ax,4ax ) 11.5, J 3ax,4eq ) 2.5, 1 H, 3-Hax), 1.80 (m, 1 H, 4-Hax),
1.78 (m, J 9eq,9ax ) 13, J 10,9eq ) 4.5, 1 H, 9-Heq), 1.20-1.52 (m,
7 H), 0.97-1.07 (m, 2 H), 0.90 (t, J 7′,6′ ) 7.5, 3 H, 7′-H); 13C
NMR (126 MHz, benzene-d6) δ 173.1 (C-2), 136.7 (C-10), 132.6
(C-2′), 132.5 (C-5′), 128.7 (C-1′), 128.7 (C-11), 126.9 (C-4′), 64.9
(C-12), 36.2 (C-3), 29.8 (C-5), 27.0 (C-8), 26.5 (C-3′), 25.6 (C-
9), 24.9 (C-6), 24.6 (C-7), 22.1 (C-4), 20.7 (C-6′), 14.3 (C-7′);
MS (ESI) m/z 277 (277 calcd for C18H29O2 (M + H+)).
Da ta for (10Z,22Z)-12,24-Di[(1Z,4Z)-Hep ta -1,4-d ien yl]-
1,13-dioxacyclotetr aeicosa-10,22-dien e-2,14-dion e (25): 1H
NMR (500 MHz, benzene-d6) δ 6.76 (m, J 12,11 ) J 12,1′ ) 8.7, 2
H, 12-H), 5.60 (m, J 1′,2′ ) 11, J 1′,12 ) 8.7, 2 H, 1′-H), 5.58 (m,
J 10,11 ) 10.8, J 11,12 ) 8.7, 2 H, 11-H), 5.49 (m, J 1′,2 ) 11, J 2′,3′
) 7.4, 2 H, 2′-H), 5.42 (m, J 10,11 ) 10.8, J 10,9b ) 12, J 10,9a ) 5,
2 H, 10-H), 5.40-5.47 (m, 4 H, 4′-H and 5′-H), 3.02-3.15 (m,
4 H, 3′-H), 2.55 (m, J 9a,9b ) 13, J 10,9b ) 9, 2 H, 9-Hb), 2.18 (t,
J 3,4 ) 7.2, 4 H, 3-H), 1.95 (m, J 9a,9b ) 13, J 10,9a ) 5, 2 H, 9-Ha),
2.05 (m, J 6′,7′ ) 7.5, 4 H, 6′-H), 1.63-1.72 (m, 2 H, 4-Hb), 1.45-
1.53 (m, 2 H, 1-Ha), 1.12-1.43 (m, 16 H), 0.91 (t, J 7′,6′ ) 7.5, 6
H, 7′-H); 13C NMR (126 MHz, benzene-d6) δ 172.1 (C-2), 134.6
(C-10), 132.8 (C-5′), 132.0 (C-2′), 128.5 (C-1′), 128.0 (C-11),
126.8 (C-4′), 65.9 (C-12), 34.6 (C-3), 29.35 (C-8), 29.3 (C-5), 28.8
(C-6), 28.8 (C-7), 27.9 (C-9), 26.7 (C-3′), 25.3 (C-4), 20.9 (C-6′),
14.4 (C-7′); MS (ESI) m/z 553 (553 calcd for C36H57O4 (M +
H+)).
1
(3:1 hexane/ethyl acetate); H NMR (500 MHz, benzene-d6) δ
6.74-6.80 (m, 1 H), 5.58-5.64 (m, 2 H), 5.48-5.54 (m, 2 H),
5.41-5.46 (m, 2 H), 3.12-3.20 (m, 1 H), 3.02-3.12 (m, 1 H),
2.28-2.36 (m, 1 H), 2.16-2.25 (m, 3 H), 2.04-2.12 (m, 4 H),
1.47-1.64 (m, 4 H), 1.12-1.37 (m, 32 H), 0.93 (m, 3 H), 0.92
(t, J ) 7.2 Hz, 3 H); 13C NMR (100 MHz, benzene-d6) δ 179.2,
172.3, 133.9, 132.9, 132.0, 128.0, 127.8, 126.7, 66.3, 34.5, 34.0,
32.3, 30.16, 30.15, 30.13, 30.12, 30.11, 30.10, 30.08, 30.00,
29.81, 29.80, 29.7, 29.5, 29.2, 28.3, 26.7, 25.3, 24.9, 23.1, 20.9,
14.4, 14.3; HRMS (ESI) m/z 550.4812 (550.4835 calcd for
C
34H64NO4 (M + NH4+)).
Mayolen e-18 (2) [(11S,9Z,12Z,15Z)-11-Octadecan oyloxy-
octa d eca -9,12,15-tr ien oic Acid ]. A solution of stearic acid
(21.2 mg, 0.074 mmol) in CH2Cl2 (0.30 mL) was treated with
DMAP (9.1 mg, 0.074 mmol) and EDCI (14.3 mg, 0.074). The
resulting cloudy solution was stirred for 12 h at rt followed by
the addition of a solution of 3 (20.0 mg, 0.068 mmol) in CH2-
Cl2 (0.10 mL). After the solution was stirred for 15 h, the
solvent was removed under vacuum. The residue was dissolved
in NaOAc buffer (10 mL, 0.4 M, pH 5.75) and extracted with
ether. Combined organic extracts were dried (MgSO4), filtered,
and concentrated under vacuum. Flash chromatography (5:1
hexane/ethyl acetate) of the residual oil provided 2 (22.4 mg,
59%) as a white solid: [R]D -1.4 (c 0.90, CH2Cl2); Rf ) 0.51
Da ta for (10Z,22Z,34Z)-12,24,36-Tr i[(1Z,4Z)-h ep ta -1,4-
d ien yl]-1,13,25-tr ioxa cycloh exa tr ia con ta -10,22,34-tr ien e-
1
2,14,26-tr ion e (26): H NMR (500 MHz, benzene-d6) δ 6.77
1
(3:1 hexane/ethyl acetate); H NMR (500 MHz, benzene-d6) δ
(m, J 12,11 ) J 12,1′ ) 8.8, 3 H, 12-H), 5.61 (m, J 1′,2′ ) 11, J 1′,12
)
6.74-6.80 (m, 1 H), 5.58-5.64 (m, 2 H), 5.48-5.54 (m, 2 H),
5.41-5.46 (m, 2 H), 3.12-3.20 (m, 1 H), 3.02-3.12 (m, 1 H),
2.28-2.36 (m, 1 H), 2.16-2.25 (m, 3 H), 2.04-2.12 (m, 4 H),
1.57-1.64 (m, 4 H), 1.12-1.37 (m, 36 H), 0.93 (m, 3 H), 0.92
(t, J ) 7.2 Hz, 3 H); 13C NMR (100 MHz, benzene-d6) δ 179.2,
172.3, 133.9, 132.9, 131.9, 128.0, 127.8, 126.7, 66.3, 34.5, 34.0,
32.3, 30.18, 30.16, 30.14, 30.11, 30.10, 30.09, 30.01, 29.82,
29.80, 29.59, 29.29, 28.2, 26.6, 25.3, 24.9, 23.1, 20.9, 14.4, 14.3;
HRMS (ESI) m/z 578.5138 (578.5148 calcd for C36H68NO4 (M
+ NH4+)).
8.8, 3 H, 1′-H), 5.60 (m, J 10,11 ) 10.8, J 11,12 ) 8.8, 3 H, 11-H),
5.51 (m, J 1′,2′ ) 11, J 2′,3′ ) 7.4, 3 H, 2′-H), 5.48 (m, J 10,11
)
10.8, J 10,9b ) 9, J 10,9a ) 5, 3 H, 10-H), 5.40-5.48 (m, 6 H, 4′-H
and 5′-H), 3.04-3.17 (m, 6 H, 3′-H), 2.42 (m, J 9a,9b ) 13, J 10,9b
) 12, 3 H, 9-Hb), 2.19 (t, J 3,4 ) 7.2, 6 H, 3-H), 2.14 (m, J 9a,9b
)
13, J 10,9a ) 5, 3 H, 9-Ha), 2.07 (m, J 6′,7′ ) 7.5, 6 H, 6′-H), 1.53-
1.64 (m, 6 H, 4-H), 1.14-1.38 (m, 24 H), 0.94 (t, J 7′,6′ ) 7.5, 9
H, 7′-H); 13C NMR (126 MHz, benzene-d6) δ 172.0 (C-2), 134.1
(C-10), 132.8 (C-5′), 131.9 (C-2′), 128.3 (C-1′), 127.8 (C-11),
126.7 (C-4′), 66.1 (C-12), 34.5 (C-3), 29.6 (C-8), 29.3 (C-6), 29.2
(C-5), 29.1 (C-7), 28.2 (C-9), 26.6 (C-3′), 25.2 (C-4), 20.8 (C-6′),
14.3 (C-7′); MS (ESI) m/z 830 (830 calcd for C54H85O6 (M +
H+)).
Ma cr olid es 24-26. A solution of 3 (28.5 mg, 0.097 mmol)
i
in benzene (2.0 mL) was treated with Pr2NEt (86.0 uL, 0.48
mmol) and 2,4,6-trichlorobenzoyl chloride (75.0 uL, 0.48). The
resulting solution was stirred for 3 h at rt and then rapidly
cannulated into a solution of DMAP (177 mg, 1.45 mmol) in
benzene (25 mL). After being stirred for 14 h, the solution was
diluted with ether (25 mL), filtered through Celite, and
concentrated under vacuum. Flash chromatography (CH3CN)
of the residual oil on C-18-modified silica gel provided 24 (11.8
mg, 44%), 25 (9.5 mg), and 26 (2.2 mg) as clear oils.
Ack n ow led gm en t. This work was supported in part
by the NIH (Grant GM 53830 and Training Grant GM
08500). We thank Dr. Athula Attygalle, Cornell Mass
Spectrometry Facility, for providing us with mass
spectrometric analyses.
Da ta for (10Z)-12-[(1Z,4Z)-Hep ta -1,4-d ien yl]-1-oxa cy-
clod od ec-10-en -2-on e (24): 1H NMR (500 MHz, benzene-d6)
Su p p or tin g In for m a tion Ava ila ble: Analytical data for
compounds 7 and 10-16, experimental procedures and ana-
lytical data for compounds 4, 8, and 17-23, and spectroscopic
data of the naturally occurring mixture of mayolenes. This
material is available free of charge via the Internet at
http://pubs.acs.org.
δ 6.60 (m, J 12,11 ) J 12,1′ ) 8.2, 1 H, 12-H), 5.63 (m, J 10,11
)
10.8, J 11,12 ) 8.2, 1 H, 11-H), 5.39-5.49 (m, 2 H, 4′-H and 5′-
H), 5.49-5.57 (m, 2 H, 1′-H and 2′-H), 5.35 (m, J 10,11 ) 10.8,
J 10,9ax ) 12, J 10,9eq ) 4.5, 1 H, 10-H), 3.10-3.20 (m, 2 H, 3′-H),
2.39 (m, J 9eq,9ax ) 13, J 10,9ax ) 12, J 9ax,
) 11.7, J 9ax,8eq ) 3,
8ax
1 H, 9-Hax), 2.15 (ddd, J 3ax,3eq ) 14, J 3eq,4ax ) 2.5, J 3eq,4eq ) 7.5,
1 H, 3-Heq), 2.05 (m, J 6′,7′ ) 7.5, 2 H, 6′-H), 2.02 (ddd, J 3ax,3eq
)
J O011102Q
5900 J . Org. Chem., Vol. 67, No. 17, 2002