Synthesis of three marine natural sesterterpenolides from methyl isoanticopalate. First enantioselective synthesis of luffolide

Article abstract of DOI:10.1021/jo0515529

The synthesis of three marine sponge metabolites, luffolide (4), 5, and 6, are described for the first time, establishing the absolute configuration of these compounds. The key intermediate, aldehyde 17, was obtained from methyl isoanticopalate, 11. The a

Full text of DOI:10.1021/jo0515529

Synthesis of Three Marine Natural Sesterterpenolides from
Methyl Isoanticopalate. First Enantioselective Synthesis of
Luffolide
P. Basabe,* S. Delgado, I. S. Marcos, D. Diez, A. Diego, M. De Roma´n, and J. G. Urones
Departamento de Quı´mica Orga´nica, Facultad de Ciencias Qu´ımicas, Universidad de Salamanca,
Plaza de los Ca´ıdos 1-5, 37008 Salamanca, Spain
pbb@usal.es
Received July 26, 2005
The synthesis of three marine sponge metabolites, luffolide (4), 5, and 6, are described for the first
time, establishing the absolute configuration of these compounds. The key intermediate, aldehyde
17, was obtained from methyl isoanticopalate, 11. The addition of 3-furyllithium to 17 and
subsequent photochemical oxidation give the γ-hydroxybutenolide 5 and its epimer at C-16.
Sesterterpenolide 6 is obtained by dehydration of 5. From the key aldehyde 17, luffolide (4) was
obtained in six steps.
Introduction
biological properties that include antimicrobial, cytotoxic,
and antiinflammatory activities.2 They have the pyra-
nofuranone moiety, present in manoalide, as part of their
structures.
Various kinds of terpenoids bearing a γ-hydroxy-
butenolide moiety have been isolated from marine sources,
and some of them, represented by manoalide (1), have
received considerable attention because of their antiin-
flammatory activity.1
Recently Snapper et al.3 described the total synthesis
of cacospongiolides B and E and the initial study of the
mechanism of the antiinflammatory activity. Tricarbocy-
clic sesterpenoides with cheilanthane skeleton have been
obtained from Spongia species. They are exemplified by
luffolide (4), the natural compounds 5 and 6 and petro-
saspongiolides M-R (7-10) (Figure 1).
This compound is a potent inhibitor of the enzyme
phospholipase A2, which is intimately involved in the
initial step of the inflammatory response. A number of
bicarbocyclic sesterterpenoides with a carbon skeleton
reminiscent of the carbon skeleton of clerodane diterpe-
noids, such as cacospongiolide B (2) and E (3), have
* To whom correspondence should be addressed. Fax: 34 923
294574.
10.1021/jo0515529 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/15/2005
9480
J. Org. Chem. 2005, 70, 9480-9485

Three Marine Natural Sesterterpenolides
FIGURE 1. Several sesterterpenolides with a cheilanthane skeleton.
Luffolide (4) is a minor metabolite of the sponge
Luffariella sp. from Palau.4 The structure of luffolide was
determined by single-crystal X-ray analysis. Sponges of
the genus Luffariella have provided a series of sestert-
erpenes that are potent antiinflammatory agents;5 luf-
folide also inhibits hydrolysis of phosphatidylcholine by
bee venom PLA2. However the lack of a natural com-
pound had limited the study of the pharmacological
properties of luffolide.
The sesterterpenolides 5 and 6 were isolated from
marine sponge Ircinia sp.6 and show a protein kinase
inhibitor activity. Selective inhibitors of MSK 1 and
MAPKAPK-2 protein kinase are most likely to exhibit
highly specific cellular effects.
Results and Discussion
When nature provides sufficient quantity of homochiral
material, which can be used as starting material for the
synthesis of active compounds, enantioselective semisyn-
thesis is a reasonable and cheap alternative to total
synthesis. Several routes leading to a variety of enan-
tiopure bioactive terpene compounds has been developed
starting from natural chiral building blocks such as
carvone,9 sclareol,10 sclareolide,11 ent-halimic acid,12 and
zamoranic acid,13 among others.
Methyl isoanticopalate, 11, obtained from sclareol14 is
an excellent precursor for the synthesis of bioactive
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The absolute configuration was not established for
compound 5 at C-16 and furthermore was isolated as
inseparable 1:1 mixture of C-25 epimers.
Petrosaspongiolides M-R have been isolated from the
New Caledonian marine sponge Petrosaspongia nigra
Bergaquist.7 Their chemical structures were determined
from spectral studies. Petrosaspongiolides are potent and
selective phospholipase A2 inhibitors. They have shown
an in vitro and in vivo potent antiinflammatory activity,
mediated by specific inhibition of secretor phospholipase
8
A2.
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J. Org. Chem, Vol. 70, No. 23, 2005 9481

Basabe et al.
SCHEME 1. Synthesis of Aldehyde 17a
a Reagents and conditions: (a) DIBAL-H, DCM, -78 °C, 2 h, 60%; (b) TPAP, NMO, DCM, sieves 4 Å, rt, 1 h, 98%; (c) p-TsOH, benzene,
80 °C, 2 h, 98%; (d) (i) LDA, HMPA, THF, -78 °C, 20 min, (ii) H2O/THF 1:3, 70%; (e) (MeOCH2Ph3)+Cl-, HMDSNa, THF, -78 °C, 1 h,
80%; (f) p-TsOH, acetone/H2O 45:1, rt,12 h, 97%.
natural compounds due to its tricycle framework and the
stereochemistry of its chiral centers.
Reaction of 15 with methoxymethylenetriphenyl-phos-
phonium chloride in the presence of NaHMDS gave a
mixture of 16a/16b at 80%. The synthesis of 17 from 16a/
16b could be achieved with p-TsOH in acetone/water. In
this way we have access to the key aldehyde 17, in an
easy repeated and scalable way.
Synthesis of Sesterterpenolides 5 and 6 from
Aldehyde 17. Once aldehyde 17 had been obtained, the
synthesis for the three natural compounds was initiated.
First of all we described the synthesis of the natural
sesterterpenolides 5 and 6.
Treatment of 17 with an excess of 3-furyllithium17
obtained by reaction of 3-bromofuran with BuLi gives a
1:1 mixture of diastereoisomers 18 and 19, which were
separated by column chromatography, as illustrated in
Scheme 2.
To determine the C-16 absolute configuration of the
furanoderivatives 18 and 19, the modified Mosher’s
method18 was applied. Compound 18 and 19 were treated
with (+)-MTPA to afford esters 18a and 19a, respectively.
Comparison between the NMR spectra of each parent
compound and its derivative, specially the δ of H-18,
confirmed the (R)-configuration for 18 at C-16 and the
(S)-configuration for 19 at the same center (Scheme 2).
In this work, methyl isoanticopalate, 11, has been
transformed for the first time into luffolide (4) and the
natural sesterterpenolides 5 and 6. In this way, a new,
easily obtained chiral starting material can be added to
the chiral pool for the synthesis of marine natural
products.
Synthesis of Aldehyde 17. The synthetic plan for the
synthesis of the above compounds was the transforma-
tions of methyl isoanticopalate, 11, into a key aldehyde,
17. This aldehyde will be the starting material for the
three compounds.
The synthesis of the aldehyde was accomplished in six
steps from methyl isoanticopalate, 11, as depicted in
Scheme 1. Reduction of the methoxycarbonyl with DIBAL
gave the alcohol 12, thence oxidized with TPAP, Ley’s oxi-
dant,15 to aldehyde 13. The key isomerization of the
12,13-double bond, in aldehyde 13, to the 13-16 position
in aldehyde 15 was carried out from aldehyde 14 following
the methodology of Arno´ et al.16 The aldehyde 14 was ob-
tained by treatment of 13 with p-TsOH/C6H6 at 80 °C.
When the kinetic enolate of 14, which had been generated
with LDA/HMPA at -78 °C, was treated with a 1:3 mix-
ture of cold water/THF the aldehyde 15 was obtained in
a 70%. The stereochemistry of aldehyde 15 was confirmed
by NOE experiments. The experimental results indicated
a clear NOE between the aldehydic proton and Me-17
and also with one of the terminal methylenic protons.
The oxidation of a furan ring to a γ-hydroxybutenolide
following the Faulkner methodology19 has been used by
our group for the synthesis of several sesterter-
penolides.12a,b This reaction is easy to carry out and gives
excellent yields.
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F.; Garrido, N. M.; Urones, J. G. Tetrahedron Lett. 2003, 44, 5419-
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Marcos, I. S.; Cubillo, M. A.; Moro, R. F.; Carballares, S.; D´ıez, D.;
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5, 217-220.
The application of this reaction to compound 18 gave
5 in 75% yield, whose properties were identical to those
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Basabe, P.; Pedrero, A. B.; Garc´ıa, N.; Urones, J. G. Tetrahedron 2003,
59, 685-694. (b) Zoretic, P. A.; Fang, H.; Ribeiro, A. A.; Dubay, G. J.
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9482 J. Org. Chem., Vol. 70, No. 23, 2005

Three Marine Natural Sesterterpenolides
SCHEME 2. Synthesis of 5 and 6a
a Reagents and conditions: (a) 3-bromofurane, n-BuLi, -78 °C, 1 h, 18(41%), 19 (30%); (b) (+)-MTPA, DMAP, DCC, DCM, 12 h, 99%
(18a), 82% (19a); (c) 1O2 hν, Rose Bengal, DCM, -78 °C, 3 h, 75% (5), 74% (20), 73% (6); (d) POCl3, Py, 0 °C to rt, 4 h, 26%.
SCHEME 3. Synthesis of Luffolidea
a Reagents and conditions: (a) Ac2O, Py, rt, 12 h, 99%; (b) 1O2 hν, Rose Bengal, DCM, -78 °C, 3 h, 77%; (c) m-CPBA, DCM, rt, 1 h, 84%;
(d) BF3‚Et2O, benzene, 10 °C, 5 min, 50%; (e) p-TsOH, benzene, rt, 12 h, 50%.
of the natural compound, establishing the absolute
stereochemistry for this compound, which was hitherto
unknown.
When the photochemical oxidation was carried out
with alcohol 19 gave the product 20, the epimer of 5 at
C-16, was obtained in 77% yield.
Finally, dehydration of 19 with phosphorus oxychloride
in pyridine gave the intermediate 21, which by photo-
chemical oxidation yields the butenolide 6 with properties
identical to those of natural sesterterpenolide.
Synthesis of Luffolide 4. Finally we described the
synthesis of luffolide as illustrated in Scheme 3. The
alcohol 18 was converted in two steps to hydroxybuteno-
lide 23. The epoxidation of 23 with m-CPBA yielded a
mixture of epoxides 24a/24b. The key in the synthesis
of luffolide is the epoxide rearrangement (24a/24b) in
order to obtain the aldehydic function.
Even though the epoxidation reaction is not stereoselec-
tive, this step does not present a problem in our synthetic
strategy, because the final step is an equilibration reac-
tion of the aldehyde mixture leading to the thermodynami-
cally stable one, in which the formyl group is equatorial,
avoiding any 1,3 diaxial interaction with Me-23.
The treatment of epoxides 24a/24b with BF3‚Et2O
results in rearrangement20 to form the aldehyde 25a/25b.
(20) (a) Trost, B. M.; Shen, H. C.; Surivet, J. P. Angew. Chem., Int.
Ed. 2003, 42, 3943-3947. (b) Rickborn, B. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
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Johnson, F. H. Tetrahedron Lett. 1969, 10, 3951-3952.
J. Org. Chem, Vol. 70, No. 23, 2005 9483

Basabe et al.
a 200 W lamp. After 3 h irradiation was stopped, the pink
solution was allowed to warm to room temperature, and
saturated aqueous oxalic acid (5 mL) was added. After 30 min
of vigorous stirring, the mixture was diluted with water and
extracted with CH2Cl2. The combined organic extracts were
washed with water and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated to give a residue which
was purified by silica gel column chromatography (benzene/
The equilibration reaction of the aldehyde mixture 25a/
25b with p-TsOH yielded the aldehyde 4 (50%). Com-
parison of the H NMR of 4 with the H NMR spectra
reported in the literature4 for luffolide clearly shows that
they are identical. We reported the 13C NMR data for
luffolide and its optical rotation.
In conclusion, we have accomplished a diastereoselec-
tive synthesis of luffolide from methylisoanticopalate that
establishes this compound as an excellent source for the
synthesis of marine natural products. The usefulness of
the aldehyde 17 in marine natural γ-hydroxybutenolide
synthesis has also been demostrated.
1
1
EtOAc 9/1) to yield 5 (45 mg, 75%) as a colorless oil. [R]22
)
D
-15.5 (c ) 0.45, CHCl3), lit.6 [R]25 ) -118.65 (c ) 0.44,
D
CHCl3), (personal communication from the authors state that
the natural compounds could be decomposed). IR (film): 3364,
2931, 2846, 1751, 1645, 1458, 1387, 1131, 1040, 948, 908, 878
1
cm-1. H NMR δ major: 6.16 (1H, s), 6.00 (1H, s), 4.91 (1H,
s), 4.77 (1H, br s), 4.68 (1H, s), 4.65 (1H, br t, J ) 6.8 Hz),
2.68 (1H, br s), 2.40 (1H, br d, J ) 11.8 Hz), 2.0-1.0 (17H, m),
0.86 (3H, s), 0.83 (6H, s), 0.69 (3H, s). 1H NMR δ minor: 6.24
(1H, s), 6.00 (1H, s), 4.91 (1H, s), 4.77 (1H, br s), 4.68 (1H, s),
4.65 (1H, br t, J ) 6.8 Hz), 2.73 (1H, br s), 2.40 (1H, br d, J )
11.8 Hz), 2.0-1.0 (17H, m), 0.86 (3H, s), 0.83 (6H, s), 0.70 (3H,
s). 13C NMR δ major: 169.9, 167.8, 149.5, 117.8, 106.9, 98.0,
68.6, 60.0, 56.2, 53.8, 41.9, 40.5, 40.2, 40.1, 38.1, 37.8, 33.3,
33.3, 30.0, 23.2, 21.4, 19.0, 18.6, 16.2, 15.5. 13C NMR δ
minor: 170.6, 170.4, 149.1, 118.9, 106.9, 97.5, 68.4, 60.0, 56.2,
53.7, 41.9, 40.7, 40.2, 40.1, 38.1, 37.8, 33.3, 33.3, 29.8, 23.2,
21.4, 19.0, 18.6, 16.2, 15.5. EIMS m/z (%) 402 (M)+ (2), 362
(4), 307 (12), 154 (100), 77 (38). HRMS (EI): m/z calcd for
C25H38O4 (M)+ 402.2770, found 402.2776.
Experimental Section
17,18,19,25-Tetranor-cheilanth-13(24)-en-16-al (17). To
a 0.03 M solution of 16a/16b (102 mg, 0.33 mmol) in acetone
(11 mL) and water (0.3 mL) was added p-TsOH (330 mg, 1.7
mmol) at room temperature. After being stirred for 15 h, the
reaction mixture was diluted with water and extracted with
Et2O. The extracts were washed with 6% aqueous NaHCO3
solution and water. Evaporation of the solvent yielded the
aldehyde 17 (97 mg, 97%). IR (film): 2929, 2846, 1727, 1648,
1459,1386, 1095, 1040, 893 cm-1. H NMR δ: 9.62 (1H, dd, J
1
) 2.6, 1.2 Hz), 4.79 (1H, s), 4.37 (1H, s), 2.50-1.10 (19H, m),
0.85, 0.81, 0.80 and 0.70 (3H, s each). 13C NMR δ: 203.2, 148.0,
107.3, 59.5, 56.0, 50.8, 41.5, 40.5, 39.6, 39.3, 38.7, 37.3, 39.6,
32.9, 32.8, 22.3, 21.0, 18.6, 18.2, 15.8, 15.1. EIMS m/z (%) 302
(M)+ (18), 285 (10), 149 (20), 109 (65), 69 (100). HRMS (EI)
m/z calcd for C21H34O (M)+ 302.2610, found 302.2614.
(16S),(25R/S)-Dihydroxy-cheilantha-13(24),17-dien-19,-
25-olide (20). Rose Bengal (1 mg) was added to a solution of
19 (8 mg, 0.02 mmol) and DIPEA (0.04 mL, 0.27 mmol) in dry
CH2Cl2 (2.5 mL) at room temperature. Anhydrous oxygen was
bubbled in for 10 min, and after that the solution was placed
under oxygen atmosphere at -78 °C and irradiated with a 200
W lamp. After 3 h irradiation was stopped, the pink solution
was allowed to warm to room temperature, and saturated
aqueous oxalic acid (5 mL) was added. After 30 min of vigorous
stirring, the mixture was diluted with water and extracted
with CH2Cl2. The combined organic extracts were washed with
water and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated to give a residue which was purified
by silica gel column chromatography (benzene/EtOAc 9/1) to
19,25-Epoxy-cheilantha-13(24),17(25),18-trien-(16R)-
ol (18) and 19,25-Epoxy-cheilantha-13(24),17(25),18-trien-
(16S)-ol (19). A solution of 3-bromofuran (0.3 mL, 3.3 mmol)
in THF (7 mL) was treated dropwise with n-BuLi (1.6 M in
hexane, 1.96 mL, 3.3 mmol) at -78 °C. After the reaction
mixture was stirred for 30 min at this temperature, a solution
of aldehyde 17 (100 mg, 0.33 mmol) in dry THF (9 mL) was
added and stirred for an additional 45 min. The reaction
mixture was treated with saturated NH4Cl aqueous solution,
warmed to room temperature and extracted with Et2O. The
organic layer was washed with brine and water and dried over
Na2SO4. The residue obtained after removal of the solvent was
purified by chromatography (Hex/EtOAc 9/1, 85/15) to yield
the diastereoisomer alcohols 18 (50 mg, 41%, R) and 19 (37
yield 20 (6 mg, 74%). [R]22 ) -54 (c ) 0.30, CHCl3). IR
D
(film): 3365, 2928, 2851, 1721, 1462, 1389, 1131, 1058 cm-1
.
1H NMR δ major: 6.15 (1H, s), 6.08 (1H, s), 4.89 (1H, s), 4.67
(1H, d, J ) 8.0 Hz), 4.51 (1H, s), 2.40 (1H, br d, J ) 11.8 Hz),
mg, 30%, S). Data for 18. [R]22 ) -11 (c ) 0.19, CHCl3). IR
D
1
2.0-0.85 (18H, m), 0.86, 0.82, 0.80 and 0.70 (3H, s each). H
(film): 3357, 2928, 2847, 1644, 1503, 1461, 1386, 1157, 1025,
1
NMR δ minor: 6.22 (1H, s), 6.03 (1H, s), 4.86 (1H, s), 4.60
(1H, d, J ) 6.4 Hz), 4.46 (1H, s), 2.40 (1H, br d, J ) 11.8 Hz),
874 cm-1. H NMR δ: 7.41 (1H, s), 7.35 (1H, s), 6.42 (1H, s),
4.87 (1H, s), 4.71 (1H, s), 4.70 (1H, t, J ) 4.8 Hz), 2.35 (1H,
ddd, J ) 12.6, 4.0, 2.5 Hz), 1.95-0.80 (17H, m), 0.84 (3H, s),
0.80 (6H, s), 0.70 (3H, s). 13C NMR δ: 148.9, 145.5, 139.6,
128.8, 108.2, 106.3, 66.2, 59.4, 56.2, 53.3, 42.0, 40.4, 39.9, 39.7,
38.1, 37.7, 33.2, 33.2, 31.8, 23.1, 21.4, 19.0, 18.6, 16.2, 15.6.
EIMS m/z (%) 370 (M)+ (27), 337 (7), 259 (23), 191 (69), 137
(33), 197 (61), 69 (100). HRMS (EI): m/z calcd for C25H38O2
(M)+ 370.2872, found 370. 2876. Data for 19. [R]22D ) -48 (c
) 0.1, CHCl3). IR (film): 3397, 3076, 2929, 2849, 1644, 1458,
1386, 1160, 1025, 878 cm-1. 1H NMR δ: 7.38 (2H, s), 6.41 (1H,
s), 4.85 (1H, s), 4.67 (1H, d, J ) 8.8 Hz), 4.47 (1H, s), 2.42
(1H, ddd, J ) 12.6, 4.0, 2.5 Hz), 2.10-0.90 (17H, m), 0.85 (3H,
s), 0.83 and 0.81 (3H, s each), 0.69 (3H, s). 13C NMR δ: 148.9,
143.2, 138.4, 130.2, 108.4, 106.1, 65.2, 60.1, 56.3, 52.7, 42.0,
40.7, 40.1, 39.4, 38.1, 37.7, 33.3, 33.2, 32.6, 23.3, 21.4, 19.0,
18.6, 16.1, 15.6. EIMS m/z (%) 370 (M)+ (13), 256 (11), 191
(17), 153 (52), 107 (55), 77 (100). HRMS (EI): m/z calcd for
C25H38O2 (M)+ 370.2872, found 370. 2869.
2.10-0.85 (18H, m), 0.86, 0.82, 0.80 and 0.70 (3H, s each). 13
C
NMR δ major: 171.4, 170.0, 148.3, 117.3, 106.5, 97.1, 66.7,
60.1, 56.3, 52.1, 41.9, 40.7, 40.1, 39.6, 38.0, 37.8, 33.3, 33.3,
30.3, 23.1, 21.4, 18.9, 18.6, 16.2, 15.6. 13C NMR δ minor:
171.4, 169.9, 148.4, 117.7, 106.3, 97.5, 66.7, 60.1, 56.3, 52.2,
41.9, 40.7, 40.1, 39.6, 38.0, 37.8, 33.3, 33.3, 30.1, 23.1, 21.4,
18.9, 18.6, 16.2, 15.6. EIMS m/z (%) 402 (M)+ (12), 384 (42),
362 (35), 154 (100), 77 (65). HRMS (EI): m/z calcd for C25H38O4
(M)+ 402.2770, found 402.2765.
25-Hydroxy-cheilantha-13(24),15,17-trien-19,25-olide (6).
Rose Bengal (2 mg) was added to a solution of 21 (8 mg, 0.023
mmol) and DIPEA (0.05 mL, 0.24 mmol) in dry CH2Cl2 (3 mL)
at room temperature. Anhydrous oxygen was bubbled in for
10 min, and after that the solution was placed under oxygen
atmosphere at -78 °C and irradiated with a 200 W lamp. After
3 h irradiation was stopped, the pink solution was allowed to
warm to room temperature, and saturated aqueous oxalic acid
(5 mL) was added. After 30 min of vigorous stirring, the
mixture was diluted with water and extracted with CH2Cl2.
The combined organic extracts were washed with water and
dried over anhydrous Na2SO4. After filtration, the solvent was
evaporated to give a residue which was purified by silica gel
column chromatography (Hex/EtOAc 8/2) to yield 6 (6.5 mg,
(16R),(25R/S)-Dihydroxy-cheilantha-13(24),17-dien-19,-
25-olide (5). Rose Bengal (3 mg) was added to a solution of
18 (16 mg, 0.04 mmol) and DIPEA (0.07 mL, 0.42 mmol) in
dry CH2Cl2 (4 mL) at room temperature. Anhydrous oxygen
was bubbled in for 10 min, and after that the solution was
placed under oxygen atmosphere at -78 °C and irradiated with
9484 J. Org. Chem., Vol. 70, No. 23, 2005

Three Marine Natural Sesterterpenolides
73%) as a colorless oil. [R]22 ) -36.4 (c ) 0.25, CHCl3), lit.6
and water. Evaporation of the dried extract gave the mixture
of epoxides derivatives 24a/24b (10 mg, 84%). IR (film): 3337,
2933, 1744, 1657, 1579, 1458, 1388, 1236, 1129, 1048, 951, 897
D
[R]25D ) -36.09 (c ) 0.53, CHCl3). UV (EtOH) λmax (log ꢀ) 202
(3.50), 264 (3.80) nm. IR (film): 3357, 2925, 2851, 1747, 1645,
1458, 1387, 1129, 969 cm-1. 1H NMR δ: 6.59 (1H, dd, J ) 16.0,
10.2 Hz), 6.31 (1H, d, J ) 16.0 Hz), 6.26 (1H, s), 5.86 (1H, s),
4.77 (1H, s), 4.40 (1H, s), 2.47 (1H, br d, J ) 10.2 Hz), 2.45
(1H, br d, J ) 18.0 Hz), 2.06 (1H, td, J ) 18.0, 4.8 Hz), 1.85-
1.00 (14H, m), 0.87 (3H, s), 0.85 (6H, s), 0.80 (3H, s). 13C NMR
δ: 170.9, 161.1, 149.1, 144.4, 123.0, 116.0, 108.7, 97.5, 62.9,
59.7, 57.2, 42.9, 42.4, 40.4, 40.3, 38.4, 36.9, 33.7, 33.8, 22.5,
21.9, 19.2, 19.0, 16.8, 16.5; HRMS (EI): m/z calcd for C25H36O3
(M)+ 384.2656, found 384.2650.
1
cm-1. H NMR δ: 6.13-6.04 (2H, m), 5.58 (1H, m), 2.76 (1H,
br s), 2.58 (1H, m) 2.11 (3H, s), 1.96-1.00 (19H, m), 0.88 (3H,
s), 0.82 (6H, s), 0.77 (3H, s). EIMS m/z (%) 461 (M + 1)+ (3),
307 (18), 154 (100), 89 (31).
To a stirred solution of 24a/24b (15 mg, 0.032 mmol) in dry
benzene (3 mL) at 10 °C was added BF3‚Et2O (0.001 mL) under
argon. The mixture was stirred up to 10 °C over 5 min and
was poured into water (2 mL). This solution was removed by
extraction with Et2O (3 × 100 mL). The organic layer was
washed with an aqueous solution of NaHCO3 10% and water,
dried over Na2SO4 and concentrated under reduced pressure
to give 25a/25b (7.5 mg, 50%). IR (film): 2925, 2853, 1801,
(16R)-Acetoxy-(25R/S)-hydroxy-cheilantha-13(24)17-
dien-19,25-olide (23). Rose Bengal (8 mg) was added to a
solution of 22 (41 mg, 0.099 mmol) and DIPEA (0.26 mL, 1.03
mmol) in dry CH2Cl2 (15 mL) at room temperature. Anhydrous
oxygen was bubbled in for 10 min, and after that the solution
was placed under oxygen atmosphere at -78 °C and irradiated
with a 200 W lamp. After 3 h irradiation was stopped, the pink
solution was allowed to warm to room temperature, and
saturated aqueous oxalic acid (8 mL) was added. After 30 min
of vigorous stirring, the mixture was diluted with water and
extracted with CH2Cl2. The combined organic extracts were
washed with water and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated to give a residue which
was purified by silica gel column chromatography (Hex/EtOAc
8/2) to yield 23 (34 mg, 77%) as a colorless oil. [R]22D ) -9.05
(c ) 0.53, CHCl3). IR (film): 3367, 2928, 2847, 1744, 1647,
1
1719, 1657, 1459, 1374, 1226, 1155, 1048, 998, 878 cm-1. H
NMR δ: 9.97 (1H, s), 9.44 (1H, d, J ) 4 Hz), 6.15-5.95 (2H,
m), 5.50 (1H, m), 2.13 (3H, s), 2.15-0.90 (20H, m), 0.87 (3H,
s), 0.85 (3H, s), 0.83 (3H, s), 0.81 (3H, s). EIMS m/z (%) 461
(M + 1)+ (5), 284 (22), 256 (42), 185 (15), 129 (28).
To a solution of aldehyde 25a/25b (4 mg, 0.0086 mmol) in
dry benzene (0.6 mL) was added pTsOH (20 mg, 0.11 mmol),
and the mixture was stirred 12 h. Then, saturated aqueous
NaHCO3 was added. The organic phase was separated and the
aqueous phase was extracted with EtOAc. Extracts were
washed with brine and dried. Evaporation of the solvent
yielded the aldehyde 4 (2 mg, 50%) as an amorphous white
solid, mp 130-132 °C, lit.4 mp 123 °C (CDCl3). [R]22 ) -4.3
D
1458, 1386, 1234, 1129, 1025, 950, 889 cm-1 1H NMR δ
.
(c ) 0.25, CHCl3). IR (film): 3367, 2925, 2851, 1751, 1720,
1459, 1372, 1232, 1133, 1040, 963, 736 cm-1. 1H NMR δ: 9.45
(1H, d, J ) 4.4 Hz), 6.06 (1H, br s), 5.97 (1H, s), 5.29 (1H, dd,
J ) 10.8, 2.7 Hz), 2.35-0.80 (20H, m), 2.12 (3H, s), 0.87 (3H,
s), 0.85 (3H, s), 0.83 (3H, s), 0.81 (3H, s). 13C NMR δ: 204.2,
171.1, 168.9, 166.2, 118.8, 97.7, 70.6, 58.9, 56.3, 52.7, 47.3, 41.9,
40.3, 39.8, 38.3, 37.5, 33.3, 33.2, 32.3, 26.8, 21.4, 20.8, 18.6,
18.5, 18.2, 16.2, 14.8. EIMS m/z (%) 461 (M + 1)+ (12), 282
(35), 289 (56), 185 (15), 154 (12). HRMS (EI): m/z calcd for
C27H40O6 (M + 1)+ 461.2858, found 461.2860.
major: 6.04 (1H, s), 5.90 (1H, d, J ) 9.4 Hz), 5.38 (1H, dd, J
) 9.2, 6.2 Hz), 5.06 (1H, d, J ) 9.4 Hz), 4.93 (1H, s), 4.62 (1H,
s), 2.39 (1H, br d, J ) 11.8 Hz), 2.11 (3H, s), 2.0-0.96 (17H,
1
m), 0.86 (3H, s), 0.79 (6H, s), 0.69 (3H, s). H NMR δ minor:
6.12 (1H, m), 6.09 (1H, s), 5.51 (1H, dd, J ) 9.2, 6.2 Hz), 4.87
(1H, s), 4.62 (1H, s), 2.38 (1H, br d, J ) 11.8 Hz), 2.08 (3H, s),
2.0-0.96 (17H, m), 0.86 (3H, s), 0.79 (6H, s), 0.69 (3H, s). 13
C
NMR δ major: 171.6, 170.4, 168.2, 147.6, 119.6, 107.6, 99.3,
69.3, 60.2, 56.3, 52.8, 42.1, 40.7, 40.2, 40.1, 38.2, 38.0, 33.7,
33.5, 28.9, 23.3, 21.6, 21.2, 19.2, 18.8, 16.4, 15.6. 13C NMR δ
minor: 171.6, 170.4, 168.2, 148.1, 120.2, 107.2, 98.6, 69.3,
60.1, 56.3, 52.4, 42.1, 40.7, 40.2, 40.1, 38.2, 38.0, 33.5, 33.5,
28.9, 23.3, 21.6, 21.2, 19.2, 18.8, 16.4, 15.6. EIMS m/z (%) 445
(M + 1)+ (8), 427 (10), 367 (18), 289 (12), 191 (22), 154 (98), 69
(100). HRMS (EI): m/z calcd for C27H40O5 (M + 1)+ 445.2909,
found 445.2911.
Acknowledgment. The authors thank the CICYT
for financial support (BQU 2002-02049) and Junta de
Castilla y Leon for a doctoral fellowship to S.D. and
M.D.R. The authors also thank to Dr. Stephen Marsden
(University of Leeds) for NMR spectra of the compound
6.
(13S),(16R)-Acetoxy-(25R,S)-hydroxy-16-oxo-cheilanth-
17-en-19,25-olide (4). To an ice-cooled solution of 23 (11 mg,
0.026 mmol) in dry CH2Cl2 (0.7 mL) was added m-CPBA (18
mg, 0.1 mmol). The reaction mixture was stirred at room
temperature for 1 h, diluted with water and extracted with
Et2O. The organic layer was washed successively with 10%
aqueous solution of Na2SO3, 6% aqueous solution of NaHCO3
Supporting Information Available: Copies of 1H and 13
C
NMR spectra This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0515529
J. Org. Chem, Vol. 70, No. 23, 2005 9485