Design and Synthesis of 23,24-Dinoroleanolic Acid Derivatives, Novel Triterpenoid-Steroid Hybrid Molecules

Full text of DOI:10.1021/jo980525y

4846
J . Org. Chem. 1998, 63, 4846-4849
oleanolic acid (7). In our first strategy, it was ambiguous
Design a n d Syn th esis of
whether phosphorus pentachloride (PCl5) would give the
desired ring contraction product 9a in the first step
according to classical procedures.5a-d,g In our second
strategy, there were two potential problems as follows.
A Beckmann or Schmidt rearrangement on the C-3
ketone was known to give lactam 10b in addition to the
desired compound 10a .6 In addition, it was unclear
whether olefin 11 would be obtained from 10a in the
second step of this sequence. Initially, we examined the
first sequence involving ring contraction of methyl ole-
anolate (8)7 to 9a since this plan seemed to have fewer
complications than the alternative strategy.
23,24-Din or olea n olic Acid Der iva tives,
Novel Tr iter p en oid -Ster oid Hybr id
Molecu les
Tadashi Honda and Gordon W. Gribble*
Department of Chemistry, Dartmouth College,
Hanover, New Hampshire 03755-3564
Received March 19, 1998
In a previous paper, we reported that oleanolic acid
derivatives with a 1-en-3-one functionality in ring A, e.g.,
1 and 2, show significant inhibitory activity against
interferon-γ-induced nitric oxide (NO) production in
mouse macrophages.1 Mechanism studies reveal that
enones 1 and 2 suppress transcription or translation of
inducible nitric oxide synthase (iNOS) and inducible
cyclooxygenase (COX-2) genes.2 Glucocorticoids, e.g.,
hydrocortisone and dexamethasone, are also well known
to have similar activities.3 For the structure of gluco-
corticoids, a 4-en-3-one or 1,4-dien-3-one functionality in
ring A is characteristic.4 Thus, the design and synthesis
of triterpenoid-steroid hybrid molecules, i.e., 23,24-
dinoroleanolic acid derivatives 3-6, is deemed to be very
interesting from the perspective of structure-activity
relationships. We herein describe the synthesis of com-
pounds 3-6 derived from oleanolic acid (7).
Resu lts a n d Discu ssion
In the event, dehydration of methyl oleanolate (8),
derived from oleanolic acid (7) with ethereal diazo-
methane, with PCl5 in benzene and toluene gave the
desired ring contraction product 9a and an unknown
byproduct 9b [9a :9b ) 7:1].8 Although both compounds
have the same Rf value on TLC, pure 9a was obtained
as colorless needles in 63% yield by recrystallization from
acetone. This successful ring contraction led us to pursue
the first synthetic strategy as shown in Scheme 1.
For the transformation of olefin 9a into ketone 12a ,
the obvious ozonolysis cannot be used because ozone also
reacts with the C-12 olefin of oleanane triterpenoids to
give the 12R,13R-epoxide, 12-ketone,9 and 12R-hydroxy
lactone.11 Therefore, various other oxidation conditions
were examined. Oxidation of 9a with a catalytic amount
of osmium tetraoxide and 4-methylmorpholine N-oxide
in aqueous acetone12 gave a complex mixture. A catalytic
amount of ruthenium tetraoxide (RuO4) and sodium
13
metaperiodate in aqueous CH3CN and CCl4 also gave
a complex mixture. Under the conditions of a catalytic
amount of RuO4 and sodium hypochlorite in CCl4,14 9a
was recovered. However, a stoichiometric amount of
(5) (a) Voser, W.; White, D. E.; Heusser, H.; J eger, O.; Ruzicka, L.
Helv. Chim. Acta 1952, 35, 830. (b) Barton, D. H. R.; Ives, D. A. J .;
Thomas, B. R. J . Chem. Soc. 1954, 903. (c) Crabbe, P.; Ourisson, G.;
Takahashi, T. Tetrahedron 1958, 3, 279. (d) Pettit, G. R.; Dias, J . R.
Can. J . Chem. 1969, 47, 1091. (e) Kazlauskas, R.; Pinhey, J . T.; Simes,
J . J . H.; Watson, T. G. Chem. Commun. 1969, 945. (f) Shoppee C. W.;
Hughes, N. W.; Lack, R. E.; Pinhey, J . T. J . Chem. Soc. C 1970, 1443.
(g) Pettit, G. R.; Dias, J . R. J . Org. Chem. 1972, 37, 973. (h) Wolff, G.
A.; Trendel, J . M.; Albrecht, P. Tetrahedron 1989, 45, 6721.
(6) (a) Sundararamaiah, A.; Ramraj, S. K.; Lakshman Rao, K.;
Vimala Bai, V. J . Indian Chem. Soc. 1976, 53, 664. (b) Finlay, H. J .;
Honda, T.; Gribble, G. W.; Danielpour, D.; Benoit, N. E.; Suh, N.;
Williams, C.; Sporn, M. B. Bioorg. Med. Chem. Lett. 1997, 7, 1769.
(7) Frazier, D.; Noller, C. R. J . Am. Chem. Soc. 1944, 66, 1267.
(8) This ratio was determined from the integration ratio of the olefin
proton at C-12 of each compound [9a : δ 5.32 (1H, t, J ) 3.4 Hz), 9b:
δ 5.37 (1H, t)] in the 1H NMR spectrum.
The removal of the two methyl groups at C-4 from
tetracyclic and pentacyclic triterpenoids has been the
subject of a considerable number of reports.5 On the
basis of these studies, we envisioned two strategies for
the removal of the two methyl groups at C-4 from
(9) Unpublished results: Methyl 3â-acetoxyolean-12-en-28-oate was
converted into methyl 3â-acetoxy-12R,13R-epoxyolean-28-oate by ozon-
olysis in CH2Cl2 (-78 °C) followed by triethylamine,10 and this
compound was also converted into methyl 3â-acetoxy-12-oxoolean-28-
oate by ozonolysis, followed by triphenylphosphine.10.
(10) Hon, Y.; Lin, S.; Lu, L.; Chen, Y. Tetrahedron 1995, 51, 5019.
(11) Konoike, T.; Takahashi, K.; Araki, Y.; Horibe, I. J . Org. Chem.
1997, 62, 960.
* To whom correspondence should be addressed. Tel. (603) 646-3118.
Fax: (603) 646-3946. E-mail: Grib@Dartmouth.edu.
(1) Honda, T.; Finlay, H. J .; Gribble, G. W.; Suh, N.; Sporn, M. B.
Bioorg. Med. Chem. Lett. 1997, 7, 1623.
(2) Suh, N.; Honda, T.; Finlay, H. J .; Barchowsky, A.; Williams, C.;
Benoit, N. E.; Xie, Q.; Nathan, C.; Gribble, G. W.; Sporn, M. B. Cancer
Res. 1998, 58, 717.
(3) (a) O’Banion, M. K.; Winn, V. D.; Young, D. A. Proc. Natl. Acad.
Sci. U.S.A. 1992, 89, 4888. (b) Kunz, D.; Walker, G.; Eberhardt, W.;
Pfeilschifter, J . Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 255.
(4) Fieser, L. F.; Fieser, M. In Steroids; Reinhold Publishing Corp.:
New York, 1959; Chapter 19, pp 600-726.
(12) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(13) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(14) Gopal, H.; Gordon, A. J . Tetrahedron Lett. 1971, 2941.
S0022-3263(98)00525-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/18/1998

Notes
J . Org. Chem., Vol. 63, No. 14, 1998 4847
Sch em e 1a
a
Key: (a) CH2N2/Et2O/THF; (b) PCl5/PhH/toluene; (c) RuO4/CCl4; (d) AcOH/CH2Cl2; (e) MeMgBr/Et2O; (f) POCl3/pyr; (g) NaOH/H2O/
MeOH; (h) Li/DMF; (i) PhSeCl/EtOAc, 30%H2O2/THF.
15
RuO4 in CCl4 was found to afford the desired ketone
12a in 86% yield.16 Because of partial isomerization of
12a to 12b on silica gel column chromatography and,
also, because treatment of 12a with acetic acid in CH2Cl2
gave 12b in 54% yield, 12a and 12b were assigned to
have the 5R and 5â configurations, respectively,5g al-
though this assignment was not proven.
halogenolysis of 3 with lithium iodide (LiI) in DMF.20
Insertion of a double bond into the C-1 position of 3 was
accomplished by phenylselenenyl chloride in ethyl ace-
tate, followed by oxidation with hydrogen peroxide21 to
provide dienone 5 in 62% yield. In the 13C NMR
spectrum of 5, the chemical shift of the C-3 ketone was
observed at 186 ppm. This value is characteristic for a
1,4-dien-3-one functionality.22,23 Halogenolysis of 5 with
LiI in DMF gave dienone acid 6 in 78% yield.
We initially examined the introduction of the methyl
group into the C-3 carbonyl group using the pure cis
ketone 12b. However, with both methylmagnesium
bromide (MeMgBr) and methyllithium (MeLi), only the
starting material 12b was recovered in quantitative
yield.17 On the other hand, methylation of crude 12a
with MeLi in Et2O (-78 °C) gave 1318 (42% yield) and
some byproducts whose structures are unknown. More-
over, MeMgBr in Et2O at room temperature gave 13 in
69% yield as a sole product. This difference in reactivity
between 12a and 12b is not at all obvious.
Dehydration of 13 with phosphoryl chloride in pyri-
dine19 at room temperature for 1 day gave olefin 14 in
95% yield. Oxidation of 14 with a stoichiometric amount
of RuO4 in CCl4 gave 1,5-diketone 15. Without further
purification, 15 was cyclized via an aldol condensation
with sodium hydroxide5g in methanol to afford the desired
enone 3, a new triterpenoid-steroid hybrid molecule
(75% yield from 14). Three other new triterpenoid-
steroid hybrid molecules were synthesized from 3 as
follows. Enone acid 4 was prepared in 81% yield by
Studies on the biological properties of compounds 3-6
are in progress.24
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
Thomas-Hoover capillary melting point apparatus and are
uncorrected. Elemental microanalysis was performed by At-
lantic Microlab, Inc. TLC was fulfilled with Merck precoated
TLC plates (silica gel 60 F254). Flash column chromatography
was done with Select Scientific silica gel (230-400 mesh). The
standard workup method was as follows: an organic extract was
washed with saturated aqueous NaHCO3 solution (three times)
and then saturated aqueous NaCl solution (three times), dried
over anhydrous MgSO4, and filtered.
Meth yl 3-Isop r op ylid en e-A-n or olea n -12-en -28-oa te (9a ).
To a cold (ice bath) solution of methyl oleanolate (8) (2.60 g, 5.52
mmol) in benzene (350 mL) and toluene (125 mL) was added
PCl5 (3.00 g, 14.4 mmol, in 50 mL of CH2Cl2). After the mixture
was stirred in an ice bath for 30 min, saturated aqueous Na2CO3
(20) Dean, P. D. G. J . Chem. Soc. 1965, 6655.
(21) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J . Am. Chem.
Soc. 1973, 95, 6137.
(15) Nakata, H. Tetrahedron 1963, 19, 1959.
(16) Pure 12a could not be obtained because of partial isomerization
of 12a into 12b upon silica gel column chromatography.
(17) Similarily, Ruzicka5a and Ourisson5c reported that they used
drastic conditions for the introduction of a methyl group into a
lanostane triterpenoid with the same A ring moiety as 12b.
(18) Although the 1H and 13C NMR spectra showed that 13 was a
single compound, the configuration at C-3 was not determined.
(19) Paquette, L. A.; Roberts, R. A.; Drtina, G. J . J . Am. Chem. Soc.
1984, 106, 6690.
(22) Pouchert, C. J .; Behnke, J . In The Aldrich Library of 13C and
1H FT NMR Spectra, 1st ed.; Aldrich Chemical Co., Inc.: Milwaukee,
1993; Vol. 3, pp 563-617.
(23) In a 1-en-3-one and 1,3-dien-5-one functionality, the carbonyl
carbon was observed at 199-200 ppm.22.
(24) Preliminary evaluation of these compounds on an iNOS assay
revealed that compound 6 showed moderate inhibitory activity at the
1 µM level.

4848 J . Org. Chem., Vol. 63, No. 14, 1998
Notes
solution (50 mL) and water (100 mL) were added, and stirring
was continued at room temperature for another 30 min. After
the upper organic phase was separated, the aqueous phase was
twice extracted with a mixture of CH2Cl2 and Et2O (1:2). The
extract was combined with the original organic phase and
worked up according to the standard method. The filtrate was
evaporated in vacuo to give a solid (2.47 g). The solid was
recrystallized from acetone to afford the title compound as
colorless crystals (1.40 g, 56%). The mother liquid was evapo-
rated in vacuo to give a residue (1.02 g). The residue was
subjected to flash column chromatography [hexanes-EtOAc (10:
1)] to give an amorphous solid (670 mg). This was recrystallized
from acetone to give the title compound as colorless crystals (178
mg, 7%): mp 144-145 °C; TLC [hexane/EtOAc (10/1)] Rf 0.5;
IR (KBr) 2945, 2860, 1732 cm-1; 1H NMR (CDCl3) δ 5.32 (1H, t,
J ) 3.4 Hz), 3.64 (3H, s), 2.87 (1H, dd, J ) 3.8, 13.6 Hz) 1.75,
1.59, 1.16, 0.94, 0.91, 0.78, 0.69 (each 3H, s); 13C NMR (CDCl3)
δ 178.6, 144.5, 135.6, 122.8, 121.1, 56.1, 53.7, 51.8, 47.1, 46.1,
45.5, 44.3, 42.0, 39.5, 39.3, 34.2, 33.4, 32.9, 32.7, 31.0, 28.9, 28.2,
26.4, 25.7, 23.9, 23.4, 23.3, 23.1, 19.8, 17.3, 14.8; EIMS (70 eV)
m/z 452 [M]+ (63), 437 (16), 393 (9), 203 (100); HREIMS calcd
give an amorphous solid (246 mg). The solid was subjected to
flash column chromatography [hexanes-EtOAc (4:1)] to give the
title compound as colorless crystals (116 mg, 42%).
(b) To a solution of crude olefin 12a (316 mg, 0.74 mmol) in
anhydrous Et2O (12.5 mL) was added dropwise a solution of
MeMgBr in Et2O (3 M, 0.75 mL, 2.3 mmol) in an ice bath. The
mixture was stirred at room temperature for 30 min. To the
mixture were added saturated aqueous NH4Cl solution and
water. The aqueous mixture was extracted with a mixture of
CH2Cl2 and Et2O (1:2) three times. The extract was washed with
water (twice) and brine (twice), dried over MgSO4, and filtered.
The filtrate was evaporated in vacuo to give an amorphous solid
(313 mg). The solid was subjected to flash column chromatog-
raphy [hexanes-EtOAc (3:1)] to give the title compound as
colorless crystals (225 mg, 69%). An analytically pure sample
was obtained by recrystallization from MeOH as colorless
needles: mp 157-158 °C; TLC [hexane/EtOAc (3/1)] Rf 0.45; IR
(KBr) 3565, 2944, 2865, 1718 cm-1; 1H NMR (CDCl3) δ 5.31 (1H,
t, J ) 3.4 Hz), 3.63 (3H, s), 2.87 (1H, dd, J ) 3.9, 13.9 Hz), 1.30,
1.16, 1.00, 0.93, 0.90, 0.77 (each 3H, s); 13C NMR (CDCl3) δ 178.6,
144.5, 122.7, 79.1, 61.2, 51.8, 47.1, 46.8, 46.1, 44.6, 42.1, 41.9,
40.9, 40.3, 34.1, 33.4, 33.0, 32.6, 31.0, 30.1, 28.3, 26.5, 25.3, 23.9,
23.4, 17.7, 17.4, 15.6; CIMS (NH3) m/z 460 [M + NH4]+ (6), 443
for
C31H48O2 452.3654, found 452.3640. Anal. Calcd for
C31H48O2: C, 82.25; H, 10.69. Found: C, 82.12; H, 10.74.
Meth yl 3-Oxo-A-n or olean -12-en -28-oate (12a). To a stirred
suspension of ruthenium dioxide dihydrate (240 mg, 1.42 mmol)
in CCl4 (25 mL) was added a solution of sodium metaperiodate
(2.40 g, 11.2 mmol) in water (25 mL) in an ice bath. After the
mixture was stirred for 1 h in an ice bath, the lower yellow
solution containing RuO4 (ca. 0.7-0.8 mmol) was separated. To
a solution of olefin 9a (300 mg, 0.663 mmol) in CCl4 (15 mL),
which was covered with water (9 mL), was added the yellow
solution of RuO4, which was prepared as described above. The
mixture was stirred at room temperature for 2 h. After the
water layer was separated, 2-propanol (1 mL) was added to the
mixture. An insoluble matter was removed by filtration through
Celite. The filtrate was dried over MgSO4 and filtered. The
filtrate was evaporated in vacuo to afford the crude title
compound as an amorphous solid (244 mg, 86%): TLC [hexane/
EtOAc (5/1)] Rf 0.43; 1H NMR (CDCl3) δ 5.33 (1H, t, J ) 3.3
Hz), 3.62 (3H, s), 2.88 (1H, dd, J ) 4.4, 14.2 Hz), 1.17, 0.93,
0.90, 0.81, 0.78 (each 3H, s); 13C NMR (CDCl3) δ 217.0, 178.4,
144.9, 122.1, 62.0, 51.8, 47.0, 46.4, 46.0, 42.2, 41.9, 41.5, 40.6,
36.7, 34.8, 34.1, 33.4, 32.6, 31.7, 31.0, 28.2, 26.4, 24.8, 23.9, 23.3,
17.3, 17.0, 14.8; EIMS (70 eV) m/z 426 [M]+ (57), 367 (55), 203
(100); HREIMS calcd for C28H42O3 426.3134, found 426.3133.
This material was used for the next reaction without further
purification.
[M + H]+ (35), 425 (100); HRCIMS (NH3) calcd for C29H46O3
+
H 443.3525, found 443.3519. Anal. Calcd for C29H46O3: C,
78.68; H, 10.47. Found: C, 78.57; H, 10.53.
Meth yl 3-Meth yl-A-n or olea n -3,12-d ien -28-oa te (14). To
a solution of alcohol 13 (221 mg, 0.50 mmol) in dry pyridine (4.5
mL) was added dropwise POCl3 (1.1 mL) in an ice bath. The
mixture was stirred at room temperature overnight. It was
poured into ice-water and acidified with 6 M aqueous HCl. The
mixture was extracted with a mixture of CH2Cl2 and Et2O (1:2)
three times and worked up according to the standard method.
The filtrate was evaporated in vacuo to give the title compound
as a crystalline solid (201 mg, 95%). An analytically pure sample
was obtained by recrystallization from MeOH as colorless
needles: mp 170-171 °C; TLC [hexane/EtOAc (10/1)] Rf 0.51;
IR (KBr) 2940, 2830, 1729 cm-1; 1H NMR (CDCl3) δ 5.36 (1H, t,
J ) 3.4 Hz), 3.64 (3H, s), 2.88 (1H, dd, J ) 3.9, 13.7 Hz) 1.60,
1.11, 0.94, 0.93, 0.90, 0.85 (each 3H, s); 13C NMR (CDCl3) δ 178.6,
143.9, 142.2, 125.9, 123.2, 51.8, 49.8, 47.2, 46.4, 46.1, 42.2, 42.1,
42.0, 39.9, 35.6, 34.2, 33.4, 32.6, 32.0, 31.0, 28.2, 26.0, 25.4, 23.9,
23.5, 20.0, 19.7, 16.0, 13.9; EIMS (70 eV) m/z 424 [M]+ (87), 409
(48), 365 (19), 162 (100); HREIMS calcd for C29H44O2 424.3341,
found: 424.3343. Anal. Calcd for C29H44O2: C, 82.02; H, 10.44.
Found: C, 81.94; H, 10.52.
Meth yl 23,24-Din or -3-oxoolea n -4,12-d ien -28-oa te (3). To
a solution of olefin 14 (85 mg, 0.20 mmol) in CCl4 (5 mL), which
was covered with water (3 mL), was added a yellow solution of
RuO4 in CCl4 (8 mL), which was prepared from ruthenium
dioxide dihydrate (66 mg, 0.39 mmol) and sodium metaperiodide
(528 mg, 2.5 mmol) according to the same method as for 12a .
The mixture was stirred at room temperature for 1 h. After the
water layer was separated, 2-propanol (0.2 mL) was added to
the mixture. An insoluble matter was removed by filtration
through Celite. The filtrate was dried over MgSO4 and filtered.
The filtrate was evaporated in vacuo to afford the crude methyl
3-methyl-3,5-dioxo-3,5-seco-A-norolean-12-en-28-oate (15) as an
amorphous solid (78 mg): TLC [hexane/EtOAc (3/1)] Rf 0.31; 1H
NMR (CDCl3) δ 5.40 (1H, t, J ) 3.5 Hz), 3.64 (3H, s), 2.91 (1H,
dd, J ) 3.9, 13.7 Hz), 2.14, 1.17, 1.10, 0.94, 0.93, 0.91 (each 3H,
s); 13C NMR (CDCl3) δ 216.9, 209.0, 178.4, 143.6, 123.1, 51.9,
50.0, 47.4, 45.7, 43.0, 42.2, 40.6, 39.6, 38.9, 35.7, 34.2, 33.4, 32.4,
32.3, 31.0, 30.32, 30.27, 28.0, 25.4, 24.9, 23.8, 23.4, 21.5, 17.4.
This material was used for the next reaction without further
purification. To a solution of diketone 15 (100 mg) in MeOH
(10 mL) was added 10% aqueous NaOH solution. The mixture
was heated under reflux for 1 h. After removal of MeOH, water
was added to the mixture. The aqueous mixture was extracted
with a mixture of CH2Cl2 and Et2O (1:2) three times. The extract
was washed with saturated aqueous NH4Cl solution (three
times) and then saturated aqueous NaCl solution (three times),
dried over anhydrous MgSO4, and filtered. The filtrate was
evaporated in vacuo to give the crude title compound as a
crystalline solid (84 mg, 75% from 14). An analytically pure
sample was obtained by recrystallization from MeOH as colorless
Meth yl 3-oxo-A-n or -5-â-olea n -12-en -28-oa te (12b). To a
solution of crude olefin 12a (635 mg, 1.49 mmol) in CH2Cl2 (63
mL) was added AcOH (14 mL). The mixture was stirred at room
temperature overnight. After it was washed with water (three
times), it was worked up according to the standard method. The
filtrate was evaporated in vacuo to give a solid (612 mg). The
solid was subjected to flash column chromatography [hexanes-
EtOAc (5:1)] to give the title compound as a crystalline solid
(341 mg, 54%). An analytically pure sample was obtained by
recrystallization from MeOH as colorless needles: mp 189-190
°C; TLC [hexane/EtOAc (5/1)] Rf 0.53; IR (KBr) 2962, 2856, 1724
1
cm-1; H NMR (CDCl3) δ 5.35 (1H, t, J ) 3.5 Hz), 3.62 (3H, s),
2.86 (1H, dd, J ) 4.0, 14.0 Hz) 1.24, 1.02, 0.91, 0.88, 0.81 (each
3H, s); 13C NMR (CDCl3) δ 221.6, 178.4, 144.1, 122.4, 58.1, 51.8,
47.2, 45.9, 42.3, 42.2, 41.4, 38.9, 36.2, 35.6, 34.1, 33.4, 32.5, 31.0,
27.8, 27.0, 25.5, 25.2, 24.9, 23.8, 23.4, 17.4, 16.4; EIMS (70 eV)
m/z 426 [M]+ (58), 367 (25), 366 (22), 203 (100); HREIMS calcd
for
C28H42O3 426.3134, found 426.3122. Anal. Calcd for
C
28H42O3: C, 78.83; H, 9.92. Found: C, 78.79; H, 9.91.
Meth yl 3-Hydr oxy-3-m eth yl-A-n or olean -12-en -28-oate (13).
(a ) To a solution of crude olefin 12a (264 mg, 0.62 mmol) in
anhydrous Et2O (9.6 mL) was added dropwise a solution of MeLi
in Et2O (1.4 M, 0.70 mL, 0.98 mmol) in a dry ice-acetone bath.
The mixture was stirred in a dry ice-acetone bath for 1 h. To
the mixture was added saturated aqueous NH4Cl solution (6
mL). After the upper organic layer, separated, the aqueous layer
was extracted with a mixture of CH2Cl2 and Et2O (1:2) three
times. The extract was combined with the original organic layer
and washed with water (twice) and brine (twice), dried over
MgSO4, and filtered. The filtrate was evaporated in vacuo to
needles: mp 195-196 °C; [R]23 +157 ° (c 0.31, CHCl3); TLC
D

Notes
J . Org. Chem., Vol. 63, No. 14, 1998 4849
[hexane/EtOAc (3/1)] Rf 0.38; UV (EtOH) λmax (log ꢀ) 240.2 (4.19)
(EtOH) λmax (log ꢀ) 242.9 (4.19) nm; IR (KBr) 2947, 2854, 1728,
nm; IR (KBr) 2946, 2856, 1729, 1667, 1612 cm-1 1H NMR
;
1
1658, 1622, 1600 cm-1; H NMR (CDCl3) δ 6.97 (1H, d, J ) 9.8
(CDCl3) δ 5.73 (1H, s), 5.36 (1H, t, J ) 3.5 Hz), 3.63 (3H, s),
2.89 (1H, dd, J ) 4.0, 13.6 Hz) 1.22, 1.10, 0.94, 0.91, 0.88 (each
3H, s); 13C NMR (CDCl3) δ 199.7, 178.4, 172.4, 143.9, 123.9,
122.2, 51.8, 47.1, 46.0, 45.9, 42.5, 41.8, 39.6, 38.8, 37.7, 34.1,
33.7, 33.3, 32.5, 32.2, 30.9, 30.0, 27.9, 25.6, 23.9, 23.8, 23.3, 18.6,
16.5; EIMS (70 eV) m/z 438 [M]+ (58), 379 (62), 203 (100);
HREIMS calcd for C29H42O3 438.3134, found 438.3136. Anal.
Calcd for C29H42O3: C, 79.41; H, 9.65. Found: C, 79.31; H, 9.68.
23,24-Din or -3-oxoolea n -4,12-d ien -28-oic Acid (4). A mix-
ture of enone 3 (58 mg, 0.13 mmol) and LiI (300 mg, 2.2 mmol)
in dry DMF (1.0 mL) was heated under reflux for 5 h. The
mixture was acidified with 5% aqueous HCl and then extracted
with a mixture of CH2Cl2 and Et2O (1:2) three times. The extract
was worked up according to the standard method. The filtrate
was evaporated in vacuo to give a solid (61 mg). The solid was
subjected to flash column chromatography [hexanes-EtOAc (1.5:
1)] to give the title compound as an amorphous solid (46 mg,
Hz), 6.11 (1H, dd, J ) 2.0, 9.8 Hz), 6.10 (1H, s), 5.35 (1H, t, J )
3.5 Hz), 3.63 (3H, s), 2.89 (1H, dd, J ) 4.2, 13.7 Hz) 2.55 (1H,
m), 1.26, 1.02, 1.01, 0.91, 0.87 (each 3H, s); 13C NMR (CDCl3) δ
186.6, 178.3, 170.5, 156.5, 144.5, 126.0, 124.1, 121.8, 51.9, 47.1,
45.7, 43.9, 43.0, 42.7, 41.8, 39.9, 34.9, 34.0, 33.3, 32.4, 30.9, 30.1,
28.1, 25.6, 25.2, 23.8, 23.2, 20.2, 17.1; EIMS (70 eV) m/z 436
[M]+ (100), 421 (11), 377 (53); HREIMS calcd for C29H40O3
436.2977, found 436.2973. Anal. Calcd for C29H40O3‚1/4H2O: C,
78.96; H, 9.25. Found: C, 79.09; H, 9.37.
23,24-Din or -3-oxoolea n -1,4,12-tr ien -28-oic Acid (6).
A
mixture of dienone 5 (58 mg, 0.13 mmol) and LiI (300 mg, 2.2
mmol) in dry DMF (1.0 mL) was heated under reflux for 5 h.
The mixture was acidified with 5% aqueous HCl and then
extracted with a mixture of CH2Cl2 and Et2O (1:2) three times.
The extract was worked up according to the standard method.
The filtrate was evaporated in vacuo to give a solid (60 mg). The
solid was subjected to flash column chromatography [hexanes-
EtOAc (1:1)] to give the title compound as a crystalline solid
(43 mg, 78%). An analytically pure sample was obtained by
recrystallization from MeOH as colorless needles: mp >290 °C
81%): [R]23 +150 ° (c 0.28, CHCl3); TLC [hexane/EtOAc (1/1)]
D
Rf 0.42; UV (EtOH) λmax (log ꢀ) 240.7 (4.11) nm; IR (KBr) 3100
(br), 2942, 2851, 1722, 1694, 1673, 1650, 1617 cm-1 1H NMR
;
(CDCl3) δ 5.76 (1H, s), 5.37 (1H, t, J ) 3.4 Hz), 2.88 (1H, dd, J
) 3.9, 13.7 Hz) 1.24, 1.12, 0.99, 0.94, 0.91 (each 3H, s); 13C NMR
(CDCl3) δ 199.8, 184.2, 172.4, 143.8, 124.0, 122.5, 47.0, 46.0, 42.6,
41.5, 39.7, 38.9, 37.7, 34.1, 33.7, 33.3, 32.6, 32.2, 31.0, 30.0, 27.9,
25.7, 23.9, 23.8, 23.2, 18.7, 16.6, 14.5; EIMS (70 eV) m/z 424
[M]+ (52), 409 (13), 378 (88), 363 (38), 203 (100); HREIMS calcd
for C28H40O3 424.2977, found 424.2982. Anal. Calcd for C28H40O3‚
1/2H2O C, 77.56; H, 9.53. Found: C, 77.64; H, 9.50.
dec; [R]23 +106 ° (c 0.32, CHCl3); TLC [hexane/EtOAc (1/1)] Rf
D
0.27; UV (EtOH) λmax (log ꢀ) 243.7 (4.11) nm; IR (KBr) 3130 (br),
2940, 2865, 1724, 1654, 1611 cm-1; 1H NMR (CDCl3) δ 6.99 (1H,
d, J ) 10.0 Hz), 6.16 (1H, dd, J ) 2.0, 10.0 Hz), 6.13 (1H, s),
5.37 (1H, t, J ) 3.5 Hz), 2.87 (1H, dd, J ) 4.3, 13.6 Hz) 2.54
(1H, m), 1.28, 1.06, 1.05, 0.93, 0.90 (each 3H, s); 13C NMR
(CDCl3) δ 186.8, 184.0, 170.5, 156.7, 144.3, 126.1, 124.2, 122.0,
46.9, 45.8, 44.0, 43.0, 42.8, 41.5, 40.0, 35.0, 34.0, 33.3, 32.5, 30.9,
30.1, 28.1, 25.6, 25.2, 23.8, 23.1, 20.2, 17.1; EIMS (70 eV) m/z
422 [M]+ (67), 376 (55), 361 (15), 161 (100); HREIMS calcd for
C28H38O3 422.2821, found: 422.2821. Anal. Calcd for C28H38O3‚
1/3H2O C, 78.46; H, 9.09. Found: C, 78.72; H, 9.07.
Meth yl 23,24-Din or -3-oxoolea n -1,4,12-tr ien -28-oa te (5).
To a solution of enone 3 (44 mg, 0.10 mmol) in EtOAc (2.5 mL)
was added phenylselenenyl chloride (29 mg, 0.15 mmol). The
mixture was stirred at room temperature for 5 h. The mixture
was washed with water (0.55 mL). After removal of water, THF
(0.95 mL) and 30% aqueous H2O2 solution (0.09 mL) were added
to the mixture. Then, the mixture was stirred for 1 h. After
the mixture was diluted with EtOAc (10 mL), it was worked up
according to the standard method. The filtrate was evaporated
in vacuo to give a crystalline solid (46 mg). The solid was
subjected to flash column chromatography [hexanes-EtOAc (2.5:
1)] to give the title compound as a crystalline solid (27 mg, 62%).
An analytically pure sample was obtained by recrystallization
Ack n ow led gm en t . This investigation was sup-
ported by funds from the Norris Cotton Cancer Center.
We thank Dr. Mary K. Young and Mr. Ron New (UC
Riverside) for the mass spectra and Professor David A.
Evans and Mr. Brett D. Allison (Harvard University)
for the optical rotation measurements.
from MeOH as colorless needles: mp 184-185 °C dec; [R]23
D
+107° (c 0.28, CHCl3); TLC [hexane/EtOAc (2/1)] Rf 0.42; UV
J O980525Y