First synthesis of the antifungal oidiolactone C from trans-communic acid: Cytotoxic and antimicrobial activity in podolactone-related compounds

Article abstract of DOI:10.1021/jo0161882

The synthesis of the fungicide oidiolactone C starting from diterpenic trans-communic acid was carried out with an overall yield of 11.7%. The key step in the process consists of a new bislactonization reaction catalyzed by Pd(II), which gives rise to the podolactone-type tetracyclic skeleton from a norlabdadienedioic acid. We also carried out a study of the structure-biological activity of different natural podolactones and their synthetic precursors. Thus, the highest cytotoxic activity was found in dienic dilactones with ether-type substitutions on C-17, whereas the closure of the γ-lactone ring is not critical for presenting a maximal antimicrobial activity.

Full text of DOI:10.1021/jo0161882

J . Org. Chem. 2002, 67, 2501-2508
2501
F ir st Syn th esis of th e An tifu n ga l Oid iola cton e C fr om
tr a n s-Com m u n ic Acid : Cytotoxic a n d An tim icr obia l Activity in
P od ola cton e-Rela ted Com p ou n d s
Alejandro F. Barrero,*,† Sime´on Arseniyadis,‡ J ose´ F. Qu´ılez del Moral,† M. Mar Herrador,†
M. Valdivia,† and D. J ime´nez†
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Instituto de Biotecnolog´ıa,
Universidad de Granada, Avda. Fuentenueva s/ n, 18071, Granada, Spain, and
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif sur Yvette, France
afbarre@goliat.ugr.es
Received October 10, 2001
The synthesis of the fungicide oidiolactone C starting from diterpenic trans-communic acid was
carried out with an overall yield of 11.7%. The key step in the process consists of a new
bislactonization reaction catalyzed by Pd(II), which gives rise to the podolactone-type tetracyclic
skeleton from a norlabdadienedioic acid. We also carried out a study of the structure-biological
activity of different natural podolactones and their synthetic precursors. Thus, the highest cytotoxic
activity was found in dienic dilactones with ether-type substitutions on C-17, whereas the closure
of the γ-lactone ring is not critical for presenting a maximal antimicrobial activity.
In tr od u ction
against Candida albicans and other related species. Also
worth mentioning are the results obtained against the
dimorphic fungus Histoplasma capsulatum, which causes
one of the most severe mycoses.9 Recently, a patent
appeared describing the production of terpenoid lactones
from Oidiodendrum griseum,10 an invention which also
provides a pharmaceutical compound, comprising terpe-
noid lactones, useful in the treatment of IL-1 (interleukin-
1) and TNF (tumor necrosis factor) mediated diseases.
Our group’s interest in this class of compound led to a
first synthetic procedure starting from a mixture of trans-
and cis-communic acids (4 and 5) obtained from the cones
of J uniperus communis.11 The main drawback of this first
method lies in the mixture of three isomers called
“communic acids” (4-6), which required a chromato-
graphic separation over silica gel impregnated with 20%
silver nitrate to eliminate mirceo-communic acid (6) to
allow use of the two-component mixture of cis- and trans-
isomers as starting material. Furthermore, some steps
in this former synthetic strategy, such as the closure of
the δ-lactone or the formation of the dienolide system,
needed improvement. With the aim of both continuing
our studies on the possible use of these compounds as
herbicides and also furthering our knowledge of the
structure-cytotoxic relationship and antimicrobial activ-
Podolactones are nor- or bisnorditerpenic compounds
isolated mainly from different plants of the genus Podocar-
pus (family Podocarpaceae);1 a number of dilactones
isolated from filamentous fungi (Oidiodendrum trunca-
tum,2 Aspergillus wentii,3 and Acrostalamus sp.4) have
also been considered as part of this group. These mol-
ecules present a wide range of biological activities: anti-
tumor,5 insecticidal,6 antifeedant,7 allelopathic,8 and
fungicidal activities9 deserving special attention. In rela-
tion to this antifungal activity, PR-1388 (1), LL-Z1271R
(2), and oidiolactone C (3) were assayed against 11
(4) Ellestad, G. A.; Evans, R. H.; Kunstmann, M. P.; Lancaster, J .
E.; Morton, G. O. J . Am. Chem. Soc. 1970, 92, 5483-5489.
(5) Hembree, J . A.; Chang, C.; McLaughlin, J . L.; Cassady, J . M.;
Watts, D. J .; Wenkert, E.; Fonseca, S. F.; De Paiva Campello, J .
Phytochemistry 1979, 18, 1691-1694.
(6) Singh, P.; Russell, G. B.; Hayashi, Y.; Gallagher, R. T.; Freder-
icksen, S. Entomol. Exp. Appl. 1979, 25, 121-127.
(7) Zhang, M.; Ying, B. P.; Kubo, I. J . Nat. Prod. 1992, 55, 1057-
1062.
strains of pathogenic yeasts, showing promising results
(8) Mac´ıas, F. A.; Simonet, A. M.; Pacheco, P. C.; Barrero, A. F.;
Cabrera, E.; J ime´nez-Gonza´lez, D. J . Agric. Food Chem. 2000, 48,
3003-3007.
* Corresponding author. Fax: + 34 958 243318.
† Universidad de Granada.
‡ Institut de Chimie des Substances Naturelles.
(9) Hosoe, T.; Nozawa, K.; Lumley, T. C.; Currah, R. S.; Fukushima,
K.; Takizawa, K.; Miyaji, M.; Kawai, K. Chem. Pharm. Bull. 1999, 47,
1591-1597.
(1) Dictionary of Terpenoids; Connolly, J . D., Hill, R. A., Eds.;
Chapman & Hall, London, UK, 1991; Vol. 2, 853-857.
(2) Andersen, N. R.; Rasmunsen, P. R. Tetrahedron Lett. 1984,
(3) Dorner, J . W.; Cole, R. J .; Springer, J . P.; Cox, R. H.; Cutler, H.;
Wicklow, D. T. Phytochemistry 1980, 19, 1157-1161.
(10) Pfizer Inc. Limited. Eur. Pat. 0 933 273 A1, 1999.
(11) Barrero, A. F.; Sa´nchez, J . F.; Elmerabet, J .; J ime´nez-Gonza´lez,
D.; Mac´ıas, F. A.; Simonet, A. M. Tetrahedron 1999, 55, 7289-7304.
10.1021/jo0161882 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/16/2002

2502 J . Org. Chem., Vol. 67, No. 8, 2002
Barrero et al.
Sch em e 1
F igu r e 1. Retrosynthetic analysis for podolactones.
Ta ble 1. Distr ibu tion of Com m u n ic Acid s in th e Con es
of Som e Con ifer s
relative proportion
species
wt %
(cis:trans:mirceo)
J . communis L.
J . thurifera L.
J . phoenicea L.
C. sempervirens
57
35:15:50
6:3:1
1:1:0
3.7
3.3
2.3
0:1:0
ity, we communicate in this article the results concerning
new and more efficient syntheses of podolactones, includ-
ing those of the recently reported metabolite oidiolactone
C, using only trans-communic acid (4) as starting mate-
rial. We also report the results obtained from a compara-
tive study on the cytotoxic and antimicrobial activity
shown by different intermediates and final products.
Resu lts a n d Discu ssion
The preparation of bioactive podolactones such as
oidiolactone C (3) or LL-Z1271R (2) was retrosynthetically
planned as indicated in Figure 1, the starting material
being trans-communic acid (4). Access to the final prod-
noticeably more efficient than the previously reported
ozonolysis of the corresponding methyl ester.12
Oxidation of aldehyde 10 and double esterification with
diazomethane led to diester 11 with 90% yield. The next
step was to oxidize regioselectively the allylic position
C7. The best yields for the hydroxy derivative 12 (67%
yield based on 60% conversion) were obtained by using
0.5 mol of SeO2 and 2.5 mol of t-BuOOH per mol of 11.
ucts would be achieved via dilactone 7 after introducing
9-11
∆
and the appropriate functionalizations. The γ-lac-
tone ring closure was envisioned to occur through the key
intermediates 8 and 9, both possessing the ∆6 double
bond, which could be obtained respectively by selective
degradation of the side chain of 4 or by double degrada-
The elimination reactions in different acid media on
the 7-hydroxy derivative were unsuccessful. Attempts to
accomplish the regioselective elimination by derivatiza-
tion of this alcohol as an ester and subsequent treatment
with organic bases did not work satisfactorily either,
diene 14 being obtained only in low yields.
tion of the chain and the exocyclic double bond ∆8-(17)
.
With regard to the election of the natural source of the
starting material, we have studied the content in com-
munic acids of the cones of J . communis in comparison
with those of J uniperus thurifera, J uniperus phoenicea,
and Cupressus sempervirens (Mediterranean cypress), the
latter being quite abundant in Southern Spain (Table 1).
The presence of only trans-communic acid (4) in the cones
of cypress, easily isolated from the acid fraction on the
hexane extract by crystallization of its sodium salt, was
a determining factor for the selection of these cones.
A more efficient allylic elimination was acomplished
by using Pd(0) complexes on different ester deriva-
tives.13,14 When the corresponding acetate, mesylate, and
carbonate were treated with Pd(PPh3)4, only starting
material was recovered. Fortunately, exposure of trifluo-
roacetate 13 to Pd(PPh3)4 resulted in the formation of
diene 14 in an acceptable yield (72% based on 70%
conversion). In the next step of the synthetic sequence,
saponification of diester 14 was accomplished after
The first synthetic approach to the total syntheses of
the target molecules is summarized in Scheme 1 using
diene 8 as key intermediate.
The selective degradation of 4 to 10 in 60% yield was
realized via ozonolysis at low temperature; the compound
resulting from the double degradation, keto aldehyde 18,
was obtained in 10% yield, and 10% of starting material
was recovered. Starting material can be easily isolated
and recycled from crude reaction, making this procedure
(12) Barrero, A. F.; Sa´nchez, J . F.; Altarejos, J . Tetrahedron Lett.
1989, 30, 5515-5518.
(13) Takacs, J . M.; Lawson, E. C.; Clement, F. J . Am. Chem. Soc.
1997, 119, 5956-5957.
(14) Takahashi, T.; Nakagawa, M.; Minoshima, T.; Yamada, H.;
Tsuji, J . Tetrahedron Lett. 1990, 31, 4333-4336.

Synthesis of Fungicidal Podolactones
J . Org. Chem., Vol. 67, No. 8, 2002 2503
Sch em e 2
treating with sodium propanethiolate, diacid 8 being
obtained in 85% yield.
The application of the iodo lactonization method15 to 8
following the conditions described by Barrett et al.16 led
regio- and stereoselectively to 12,8-γ-lactone 19 (96%
yield). Then, with the aim of forcing the δ-lactone ring
closure between C19 and C6, we proceeded to the
selective protection of the carboxyl group at C12. The
steric hindrance of the carboxyl group at C19 explains
the selective formation of methyl monoester 15 (90%
yield) when diacid 8 was treated with MeOH in the
presence of 1,1′-carbonyldiimidazole. Iodo lactonization
of 15 under Barrett’s conditions after careful deoxygen-
ation of the reaction medium furnished the iodo deriva-
tive 16 (80% yield) along with 20% of dilactone 7.
Base-induced closure of the C12-C17 δ-lactone ring
in 16 was unsuccessfully tried using K2CO3/CH3CN/H2O
and KOH/MeOH. To achieve this conversion, silver salt-
catalyzed hydrolysis was envisioned.17 In the event,
exposure of 16 to AgNO3/H2O/acetone led to the desired
7 in 72% yield, along with alkyl nitrate 20 in 20% yield,
whereas the use of AgBF4/H2O/acetone afforded exclu-
sively dilactone 7 in 84% yield.
oxidation of conjugated dienes in the presence of Pd(II)
complexes. Although this reaction has been described
satisfactorily using catalytic amounts of Pd(II) with
benzoquinone as a reoxidant and in the presence of protic
acids,18 only a few examples of intramolecular nucleo-
philic attack of a carboxylate leading to a monolactone
have been described.19 In our case, when diacid 8 was
treated with substoichiometric Pd(II) (25%) and p-ben-
zoquinone in a mixture of acetic acid and acetone as sol-
vent, key intermediate 7 was obtained in 70% yield
(based on 80% conversion).20 This reaction constitutes the
first example described of bislactonization of conjugated
dienes. One possible pathway for this bis-cyclization is
shown in Scheme 2.
The requisite C9-C11 unsaturation was initially at-
tempted via the selenylation/oxidation protocol. To find
the best conditions for this conversion, diester 11 was
used as a model. Direct conversion to phenylselenide 22
via the corresponding lithium enolate and subsequent
addition of phenylselenenyl chloride was unsuccessful.
After a good deal of careful experimentation, it was found
that 22 could be obtained, via the corresponding silyl
ketene acetal, when 11 was treated with 5 equiv of LDA
and 7 equiv of TMSCl for 20 min and then with another
7 equiv of phenylselenenyl chloride. Application of the
very same conditions to intermediate 7 led stereoselec-
tively to 11R-phenylseleno lactone 24. Oxidation of 24 to
the corresponding selenoxide by hydrogen peroxide with
concomitant syn elimination provided dienolide 17 in 80%
overall yield. To complete the synthesis of oidiolactone
C, 17 was treated with m-CPBA. Unfortunately, this
reaction proceeded very slowly and only 5% of the target
compound was obtained. Dimethyldioxirane was found
to epoxidize 17 more efficiently, furnishing the desired
dienolide 3 in 49% yield (based on 39% conversion).
Synthetic 3 was found to display identical spectroscopic
properties when compared to authentic oidiolactone C,21
Two other new approaches to facilitate the formation
of the desired dilactone were also pursued. In the first
place, it was anticipated that dilactone 7 could conceiv-
ably be derived from monoester diacid 15 via a vinylogous
epoxyde opening with concomitant ring closure and loss
of methanol, in a process mechanistically related to the
iodo lactonization. In the event, 7 was obtained directly
in 70% yield when 15 was treated with 1.1 equiv of
m-CPBA in CH2Cl2, the presence of the corresponding
monoepoxide being noticed during the reaction process.
and an optical rotation value ([R]20 -12.0; c ) 0.2,
D
CHCl3) confirmed the absolute configuration of the
natural compound (Scheme 3). Previously, we had also
reported the formation of 2 from 17.11
Alternatively, as a consequence of the close spatial
relationship between both carboxyl groups in diacid 8 and
the conjugated dienic system, the last approach to
intermediate 7 was envisioned via 1,4-regioselective
(18) Ba¨ckvall, J . E.; Vagberg, J . O. J . Org. Chem. 1988, 53, 5695-
5699.
(19) J onasson, C.; Ro¨nn, M.; Ba¨ckvall, J . E. J . Org. Chem. 2000,
67, 2122-2126.
(20) Barrero, A. F.; Qu´ılez del Moral, J . F.; Cuerva, J . M.; Cabrera,
E.; J ime´nez-Gonza´lez, D. Tetrahedron Lett. 2000, 41, 5203-5206.
(21) J ohn, M.; Krohn, K.; Flo¨rke, U.; Aust, H.-J .; Draeger, S.; Schulz,
B. J . Nat. Prod. 1999, 62, 1218-1221.
(15) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8, 171-197.
(16) Barrett, A. G. M.; Carr, R. A. E. J . Org. Chem. 1986, 51, 5840-
5846.
(17) Shimizu, T.; Hiranuma, S.; Watanabe, T.; Kirihara, M. Het-
erocycles 1994, 38, 243-245.

2504 J . Org. Chem., Vol. 67, No. 8, 2002
Barrero et al.
Sch em e 3
Sch em e 5
Sch em e 6
Sch em e 4
failed. To circumvent this problem, the proposed ap-
proach to key intermediate 27 was revised on the basis
of the easy cyclization of triol 30. Thus, there was good
reason to believe that the desired γ-lactone closure could
be accomplished via chemoselective reduction of the
lactone moiety on compound 32, which could be prepared
by saponification of the methyl ester on 28 with sodium
propanethiolate. Thus, exposure of the nonisolated in-
termediate 33 to the action of aqueous 1 N HCl at 0 °C
led to the closure to the 6,19-lactone 34 in 88% overall
yield (Scheme 6).
Oxidation of primary alcohol 34 with PDC in DMF
furnished, after esterification with diazomethane, the
corresponding methyl ester 27 with an acceptable yield
(70%). Together with 27, aldehyde 35 (8% yield) and
lactone 28 (20% yield) were obtained. The latter resulted
from the opposite cyclization to that described for the
formation of 34 with concomitant opening of the 6,19-
lactone. The completion of the synthesis of key lactone 7
only requires the allylic oxidation of the C-17 methyl with
closure of the δ-lactone. This conversion was achieved
with SeO2 in refluxing acetic acid to yield 7 in 51% yield.
Our initial proposal for the second synthetic strategy
to oidiolactone C is shown in Scheme 4. This route
commenced with the ozonolysis of trans-communic acid
4. When this compound was exposed to ozone in excess,
keto aldehyde 18 was obtained in 76% yield. Oxidation
of 18 with J ones reagent and esterification with diazo-
methane, followed by treatment with PhSeCl in EtOAc
and oxidation with H2O2, provided conjugated ketone 9
in 77% overall yield.
Αddition of MeMgBr to 9 to introduce C17 of the
podolactone skeleton was totally stereoselective and
provided lactone 28 in 84% yield (based on 90% conver-
sion). Chemoselective reduction of γ-lactone function with
LAH at 0 °C afforded diol 29 in 79% yield, which was
accompanied by reduction of the methyl ester to give triol
30 (18% yield). The latter compound was found to be acid-
labile and underwent quantitative conversion to tetrahy-
drofuran derivative 31 via a SN2′ mechanism when
subjected to chromatographic separation on silica gel
(Scheme 5).
Acetylation of diol 29 under standard conditions gave
rise to monoacetyl derivative 25. Attempts to achieve
allylic oxidation of 25 with PCC or PDC under the
conditions described by Gao et al.22 on similar substrates
(22) Gao, W. G.; Sakaguchi, K.; Isoe, S.; Ohfune, Y. Tetrahedron Lett.
1996, 37, 7071-7074.

Synthesis of Fungicidal Podolactones
J . Org. Chem., Vol. 67, No. 8, 2002 2505
Sch em e 7
activity against yeasts and comparatively (from 4 to 8
times) less effect against Gram-positive bacteria. This
comparison suggests certain structure-activity relation-
ships. Thus, the presence of the 7,9(11)-dien-12,17-olide
moiety is necessary to achieve the maximum activity
against yeasts. For molecules possessing the above-
mentioned functionalities, the closure of the γ-lactone
ring results in a remarkable lack of activity against
Gram-positive bacteria
Assays of the antitumor activity in vitro have been
achieved in some of the most representative compounds
described in the article. Four cell lines, P-388 (mouse
lymphome), A-549 (human lung carcinome), HT-29 (hu-
man colon carcinome), and MEL-28 (human melanome),
were tested following established methods.26 Results
obtained are summarized in Table 3.
After careful analysis of the results obtained from the
two described approaches to oidiolactone C, it was noticed
that an improvement to the synthesis could be achieved
if intermediate 9 of the second route was homologated
to diene 14 via the Wittig reaction or other methylenation
reactions. This homologation was finally accomplished
by treatment with the corresponding phosphorus ylide
to yield diene 14 in 80% yield. Thus, the enantiospecific
synthesis of oidiolactone C in 11 steps from 4 with 11.7%
overall yield has been acomplished, improving noticeably
the syntheses of podolactones described by Burke et al.23
and by Adinolfi et al.24
In parallel with the chemical synthesis, we evaluated
the antimicrobial activity of 18 molecules with podolac-
tone-related structures, 12 of them prepared during this
work and the rest obtained during our previous re-
search.11 These compounds were tested against selected
Gram-positive and -negative bacteria and yeasts (Table
2) following a methodology described by our group.25
Tested compounds were grouped on the basis of their
structural similarities: group I, the bicyclic trinorlab-
danes 9, 11, 13, and 14; group II, the tricyclic 12,8-olides
19, 32, and 36; group III, the tricyclic 19,6-olides 27, 34,
and 35; group IV, the tricyclic 12,17-olides 37-39; and
group V, the tetracyclic 19,6:12,17-diolides 2, 7, 17, 40,
and 41. Previously reported data on the antifungal
activity of oidiolactone C (3) (group V) are included in
Table 2.9
Con clu sion s
We have developed an efficient enantiospecific route
toward oidiolactone C starting from easily available
communic acids. The key step in this synthesis is the
totally regio- and stereoselective palladium(II) bislacton-
ization reaction, which is the first example described of
bis-cyclization in this kind of oxidation. Although differ-
ent synthetic routes to podolactones have been described
in the literature, the approach described here is more
efficient than the previous results. The study of the
antimicrobial activity of different podolactones and syn-
thetic precursors (some of them turned out to be remark-
ably active) permitted some structure-activity relation-
ships to be established.
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR spectra were
measured at 300 or 400 MHz. 13C NMR spectra were measured
at 75 or 100 MHz. Microanalyses were recorded at the
Servicios Te´cnicos (UGR). Chromatography was performed
with flash-grade silica gel. All air- and water-sensitive reac-
tions were performed in flasks flame-dried under a positive
flow of argon and conducted under an atmosphere of argon.
Dry THF was obtained by distillation under argon from
sodium-benzophenone ketyl. Methylene chloride, N,N-dim-
ethylformamide (DMF), and diisopropylamine were distilled
from calcium hydride. Dried cones were extracted as described
elsewhere,27 and their composition in communic acids was
calculated after column chromatography of the decerated
extract. trans-Communic acid (4) was isolated from C. sem-
pervirens cones as follows: 2 kg of air-dried cypress cones were
extracted with hexane in a Soxhlet apparatus, the resulting
extract was defatted by precipitation at low temperature. The
defatted extract (100 g) was dissolved in 300-400 mL of
hexane and treated with 2 N NaOH to obtain 49.5 g of a white
solid. This precipitate was composed mainly of 4 (2.3%).
Meth yl 13,14,15,16-Tetr a n or la bd -8(17)-en e-12,19-d io-
a te (11). A solution of 4 (3.0 g, 9.9 mmol) in 50 mL of CH2Cl2,
cooled at -78 °C, was subjected to a stream of O2/O3 (30 nL/h)
for 1.5 h. Then, argon was bubbled through for 10 min and 3
mL of dimethyl sulfide was added. The mixture was stirred
for 6 h at room temperature and then concentrated under
vacuum. Purification by column chromatography afforded
alkene 10 (1725 mg, 66%),12 ketone 18 (266 mg, 10%), and 300
mg of starting material (10%).
An analysis of the results led to the following conclu-
sions. Structural groups I-III lack activity. In group IV,
maximum activity is shown by compound 38, which was
selective against Gram-positive bacteria and yeasts. In
group V, three molecules (2, 17, and 41) show a relevant
(23) Burke, S. D.; Kort, M. E.; Strickland, S.; Organ, H. M.; Silks,
L. A., III. Tetrahedron Lett. 1994, 35, 1503-1506.
(24) Adinolfi, M.; Mangoni, L.; Barone, G.; Laonigro, G. Gazz. Chim.
Ital. 1973, 103, 1271-1279.
(25) Barrero, A. F.; Oltra, J . E.; Herrador, M. M.; Cabrera, E.;
Sa´nchez, J . F.; Qu´ılez, J . F.; Rojas, F. J .; Reyes, J . F. Tetrahedron.
1993, 49, 141-150.
(26) Bergeron, R. J .; Davanaugh, P. F., J r.; Kline, S. J .; Hughes, R.
G., J r.; Elliot, G. T.; Porter, C. W. Biochem. Biophys. Res. Commun.
1984, 121, 848-854.
(27) De Pascual Teresa, J .; San Feliciano, A.; Barrero, A. F. Anal.
Quı´m. 1973, 69, 1065.

2506 J . Org. Chem., Vol. 67, No. 8, 2002
Ta ble 2. An tim icr obia l Activity of Selected Com p ou n d s, MIC (µg/m L)a
Barrero et al.
Gram-positive bacteriab
Gram-negative bacteriac
yeastsd
A
B
C
D
E
F
G
H
I
9
>100
>100
>100
>100
>100
>100
>100
>100
>100
<50
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
25-50
<6.25
>100
<3.12
group I
11
13
14
19
32
36
27
34
35
37
38
39
2
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
group II
group III
group IV
50-100
>100
50-100
>100
>100
<25
>100
<25
<6.25
>100
<3.12
>100
25-50
25-50
25-50
<3.12
<3.12
<3.12
50-100
50-100
50-100
<3.12
12-25
50-100
50-100
>100
>100
>100
>50
>100
>100
>100
>100
>100
>50
>100
>100
>100
>100
>100
>50
>100
>100
25-50
<3.12
>25
>25
>25
7
>100
>25
>25
>25
>100
>25
>25
>25
>100
>25
>25
>25
>100
<12.5
>25
<6.25
32
group V
17
40
41
3
<6.25
<3.12
>25
>25
<6.25
<3.12
16
a
b
The most promising results are in italic type. A, Enterococcus faecalis S 48; B, Bacillus subtilis CECT 397; C, Staphylococcus aureus
ATCC 8. c D, Salmonella typhymurium LT 2; E, Escherichia coli; F, Proteus s. G, Candida albicans CECT 1394; H, Saccharomyces
d
cerevisiae; I, Cryptococum neoformans.
°C; [R]20 -2.3 (c ) 0.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ
Ta ble 3. Cytotoxic Activity of Selected Com p ou n d s, IC50
D
(µg/m L)a
5.55 (t, J ) 3.0 Hz, 1H), 5.23 (br s, 1H), 4.87 (d, J ) 1.7 Hz,
1H), 3.62 (s, 3H), 3.58 (s, 3H), 2.69 (br d, J ) 11.1 Hz, 1H),
P-388
A-549
HT-29
MEL-28
2.54 (dd, J ) 15.9, 3.8 Hz, 1H), 2.33 (dd, J ) 15.9, 11.2 Hz,
1H), 2.28 (br s, 1H), 2.26 (d, J ) 3.0 Hz, 1H), 2.21 (br d, 13.5
Hz, 1H), 1.79 (m, 1H), 1.77 (br d, 1H), 1.63 (br d, J ) 12.6 Hz,
1H), 1.55 (m, 1H), 1.26 (ddd, J ) 13.2, 13.3, 4.1 Hz, 1H), 1.15
2
0.12
0.5
2.5
20
2
10
0.12
0.5
5
20
2
0.25
1
10
0.25
1
20
17
36
37
38
39
40
41
>20
>20
(s, 3H), 1.12 (ddd, J ) 13.5, 13.5, 4.0 Hz, 1H), 0.52 (s, 3H); 13
C
5
2
NMR (100 MHz, CDCl3) δ 177.2, 173.1, 156.5 (q, J (13C,19F) )
42 Hz), 142.9, 114.6 (q, J (13C,19F) ) 284 Hz), 114.3, 80.4, 51.8,
51.5, 49.4, 47.0, 43.8, 39.2, 38.5, 37.8, 30.5, 29.9, 28.5, 19.8,
12.0; IR (film) 1784, 1732, 1657, 874 cm-1; HRFABMS calcd
for C20H27O6F3Na [M + Na]+ 443.1657, found 443.1656. Anal.
Calcd for C20H27O6F3: C, 57.14; H, 6.43. Found: C, 57.19; H,
6.79.
20
>10
>20
>10
0.12
>20
>10
0.12
>10
0.1
0.1
a
The most promising results are in italic type.
Alkene 10 was oxidized and esterified as previously de-
scribed11 to give 11 (1800 mg, 90%).
To a solution of 157 mg (0.37 mmol) of 13 in 2 mL of dry
toluene was added 51 mg (0.37 mmol) of K2CO3 and 80 mg
(0.074 mmol) of Pd(PPh3)4. The reaction mixture was heated
at 60 °C for 6.5 h. Then, it was diluted with t-BuOMe and
cool water was added. The organic layer was separated and
washed with brine and concentrated. The residue was purified
by column chromatography (hexane/t-BuOMe 85:15) to give
56 mg (50%, 72% based on recovered starting material) of 14
Dim eth yl 7r-Hyd r oxy-13,14,15,16-tetr a n or la bd -8(17)-
en e-12,19-d ioa te (12). To an ice-chilled stirred suspension
of SeO2 (73 mg, 0.65 mmol) in CH2Cl2 (1 mL) was added
t-BuOOH (5.5 M) in hexane (0.47 mL, 2.6 mmol). The mixture
was stirred for 30 min and alkene 11 (400 mg, 1.3 mmol) in
CH2Cl2 (10 mL) was added dropwise. After stirring for 2 h at
5-10 °C, the mixture was diluted and washed with water. The
organic layer was separated, dried over Na2SO4, and concen-
trated. The residue was purified by column chromatography
using hexane: t-BuOMe to give 168 mg (40%; 66% based on
recovered starting material) of 12 as a colorless oil: [R]20D -2.3
as colorless crystals: mp 82-84 °C; [R]20 -23.0 (c ) 0.6,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.10 (m, 2H), 4.86 (d, J
) 1.6 Hz, 1H), 4.67 (br s, 1H), 3.67 (s, 3H), 3.58 (s, 3H), 2.68
(br d, J ) 9.2 Hz, 1H), 2.53 (dd, J ) 16.2, 3.4 Hz, 1H), 2.35
(dd, J ) 16.2, 9.4 Hz, 1H), 2.26 (br s, 1H), 2.22 (br d, J ) 13.4
Hz, 1H), 1.82 (qt, J ) 13.7, 3.7 Hz, 1H), 1.58 (m, 2H), 1.27 (s,
3H), 1.19 (m, 1H), 1.07 (ddd, J ) 13.5, 13.5, 4.2 Hz, 1H), 0.48
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.8, 174.1, 145.2,
129.0, 128.0, 110.2, 55.2, 51.6, 51.1, 48.6, 43.3, 38.0, 37.0, 36.9,
30.8, 27.7, 19.5, 11.7; IR (film) 1740, 1719, 1637, 1597, 885,
698 cm-1; HRFABMS calcd for C18H26O4Na [M + Na]+ 329.1729,
found 329.1730.
1
(c ) 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 4.97 (s, 1H),
4.59 (s, 1H), 4.37 (br s, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 2.90 (br
d, J ) 11.6 Hz, 1H), 2.51 (dd, J ) 16.0, 4.0 Hz, 1H), 2.36 (dd,
J ) 16.0, 11.6 Hz, 1H), 2.15 (m, 2H), 2.04 (dd, J ) 12.9, 2.9
Hz, 1H), 1.97 (br s, 1H), 1.79 (m, 1H), 1.62 (br d, J ) 12.4 Hz,
1H), 1.53 (m, 1H), 1.25 (ddd, J ) 13.2, 12.8, 3.2 Hz, 1H), 1.15
(s, 3H), 1.10 (ddd, J ) 13.5, 13.5, 4.0 Hz, 1H), 0.50 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 177.7, 174.1, 149.9, 108.9, 73.2, 51.6,
51.2, 48.1, 45.8, 43.8, 39.5, 38.7, 38.0, 31.9, 30.2, 28.5, 19.8,
11.7; IR (film) 3470, 3078, 2947, 1722, 1648 cm-1; HRFABMS
calcd for C18H28O5Na [M + Na]+ 347.1834, found 347.1836.
13,14,15,16-Tetr an or labda-6,8(17)-dien e-12,19-dioic Acid
(8). To a solution of 14 (160 mg, 0.53 mmol) in 9 mL of DMF
was added 470 mg (4.8 mmol) of sodium propanothiolate. The
reaction was stirred at 50 °C for 24 h. The mixture was
recooled at 0 °C and diluted with t-BuOMe. Cool water was
added, then the mixture was acidified to pH 2 with 2 N HCl
and extracted with t-BuOMe. The combined extracts were
dried over Na2SO4 and concentrated in a vacuum. Purification
by flash chromatography (hexane/t-BuOMe 1:1) gave 125 mg
Dim eth yl 13,14,15,16-Tetr a n or la bd a -6,8(17)-d ien e-12,-
19-d ioa te (14). To a solution of 1000 mg (3.1 mmol) of 12 and
415 mg (3.4 mmol) of DMAP in 10 mL of CH2Cl2 was added
dropwise 0.9 mL (6.2 mmol) of TFAA at 0 °C. After stirring
45 min at room temperature, the mixture was diluted with
t-BuOMe and then cool water was added. The organic layer
was separated, washed with 2 N HCl and brine, dried with
Na2SO4, and concentrated. The residue was purified by column
chromatography (hexane/t-BuOMe 4:1) to afford 1116 mg
(86%) of trifluoroacetate 13 as a colorless solid: mp 99-101
(0.45 mmol, 85%) of 8 as white solid: mp 190 °C; [R]20 -10.0
D
(c ) 0.3, CHCl3); 1H NMR (300 MHz, acetone-d6) δ 6.18 (br d,
J ) 10.2 Hz, 1H), 6.08 (ddd, J ) 10.2, 3.1, 3.1 Hz, 1H), 4.86
(br s, 1H), 4.76 (br s, 1H), 2.63 (br d, J ) 9.2 Hz, 1H), 2.57

Synthesis of Fungicidal Podolactones
J . Org. Chem., Vol. 67, No. 8, 2002 2507
(ddd, J ) 16.2, 3.2, 3.2 Hz, 1H), 2.31 (ddd, J ) 16.1, 9.3, 3.5
Hz, 1H), 2.27 (br s, 1H), 2.19 (br d, J ) 13.3 Hz, 1H), 1.90 (qq,
J ) 13.8, 3.7 Hz, 1H), 1.71 (m, 1H), 1.56 (m, 1H), 1.30 (s, 3H),
1.25 (m, 1H), 1.12 (ddd, J ) 13.5, 13.5, 4.1 Hz, 1H), 0.62 (s,
3H); 13C NMR (75 MHz, acetone-d6) δ 180.5, 177.8, 147.2,
130.6, 129.1, 110.7, 56.2, 50.2, 44.3, 39.3, 38.3, 38.3, 32.0, 28.6,
20.8, 12.6; IR (film) 3300-2500 (wide band), 1700, 1643, 1600,
883, 691, 723 cm-1; HRFABMS calcd for C16H20O4Na3 [M -
2H + 3Na]+ 345.1055, found 345.1056.
13,14,15,16-Tetr an or labda-6,8(17)-dien e-12,19-dioic Acid
12-Meth yl Ester (15). To a solution of 400 mg (1.44 mmol) of
diacid 8 in 8 mL of dry t-BuOMe were added 3.5 mL of dry
MeOH, 800 mg (4.9 mmol) of carbonyldiimidazole, and 4 Å
molecular sieves. The reaction was stirred at room tempera-
ture for 24 h. Then, the solvent was removed under vacuum
and the residue diluted with water, acidified to pH 2 with 2 N
HCl, and extracted with t-BuOMe. The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The resulting crude
product was purified by column chromatography (hexane/t-
remaining residue was purified by column chromatography
(t-BuOMe/EtOAc 9:1) to afford 13 mg (70%) of 7.
Meth od D. Diacid 8 (100 mg, 0.36 mmol) was dissolved in
1.2 mL of acetone and 0.3 mL of glacial AcOH. To this solution
were added 58 mg (0.54 mmol) of p-benzoquinone and 20 mg
(0.09 mmol) of Pd(OAc)2. The mixture was stirred at room
temperature for 7 d. Removal of the solvent and column
chromatography of the residue afforded 56 mg (56%, 70%
based on recovered starting material) of 7.
13,14,15,16-Tetr a n or la bd a -7,9(11)-d ien e-(19,6â),(12,17)-
d iolid e (17). A solution of LDA (8 mmol) was prepared by
adding n-butyllithium (3.2 mL of a 2.5 M solution in hexane,
8 mmol) to diisopropylamine (2.2 mL, 16 mmol) in THF (5 mL)
at -78 °C. The resulting solution was stirred for 20 min, and
dilactone 7 (430 mg, 1.56 mmol) in THF (10 mL) was added
dropwise. The resulting mixture was stirred for 20 min and
1.3 mL (10.4 mmol) of TMSCl was added dropwise at -78 °C.
After further stirring for 20 min at -60 °C, 2 g of PhSeCl (10.4
mmol) in THF (5 mL) was added dropwise. The mixture was
allowed to warm over 1 h. The mixture was then diluted with
t-BuOMe and quenched with the dropwise addition of 5%
NH4Cl. The organic layer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The result-
ing selenide was used in the next reaction without purification.
The selenide was redissolved in 50 mL of CH2Cl2, and 3.5
mL of 30% H2O2 and 3.5 mL of pyridine were added. The
mixture was stirred for 5 min at reflux. After being cooled to
room temperature, the reaction was diluted with t-BuOMe and
washed with 2 N HCl and brine. The organic layer was dried
over Na2SO4 and concentrated under reduced pressure, and
the resulting crude product was purified by flash chromatog-
raphy to afford 345 mg (80%) of 17. Its spectral data are
identical to those previously reported.11 HRFABMS calcd for
BuOMe 7:3) to afford 378 mg (90%) of 15 as white solid: mp
1
88-90 °C; [R]20 -16.7 (c ) 0.6, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 6.11 (s, 2H), 4.87 (d, J ) 1.8 Hz, 1H), 4.69 (br s, 1H),
3.68 (s, 3H), 2.68 (br d, J ) 9.0 Hz, 1H), 2.53 (dd, J ) 16.2, 3.4
Hz, 1H), 2.37 (dd, J ) 16.2, 9.3 Hz, 1H), 2.28 (br s, 1H), 2.20
(br d, J ) 13.6 Hz, 1H), 1.85 (qt, J ) 13.7, 3.6 Hz, 1H), 1.60
(m, 2H), 1.33 (s, 3H), 1.08 (ddd, J ) 13.6, 13.6, 4.2 Hz, 1H),
0.86 (m, 1H), 0.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 183.0,
174.5, 145.3, 128.9, 128.6, 110.6, 55.3, 51.9, 48.8, 43.4, 38.4,
37.1, 37.0, 31.0, 28.1, 19.6, 12.1; IR (film) 3550-2500 (wide
band), 1736, 1695, 1640, 1599, 886, 700 cm-1; HRFABMS calcd
for C17H24O4Na [M + Na]+ 315.1572, found 315.1572.
Met h yl 17-Iod o-13,14,15,16-t et r a n or la b d -7-en -19,6â-
olid e-12-oa te (16). To a solution of I2 (106 mg, 0.4 mmol) in
dry deoxygenated acetonitrile (2 mL) was added at -20 °C
dropwise a solution of monoacid 15 (40 mg, 0.14 mmol) in 4
mL of acetonitrile. The reaction mixture was stirred at -20
°C for 5 h. The mixture was then diluted with t-BuOMe,
washed with saturated Na2S2O3 and brine, dried over Na2SO4,
and concentrated under reduced pressure to afford 60 mg of a
crude mixture that showed the presence of dilactone 7 along
with compound 16 in a 1:4 ratio. This mixture was not purified
due to the instability of the allylic iodide. Compound 16: 1H
NMR (400 MHz, CDCl3) δ 6.25 (dd, J ) 4.4, 2.5 Hz, 1H), 4.80
(m, 1H), 4.02 (d, J ) 9.7 Hz, 1H), 3.95 (d, J ) 9.7 Hz, 1H),
3.74 (s, 3H), 2.83 (m, 1H), 2.55 (dd, J ) 16.4, 7.3 Hz, 1H), 2.41
(dd, J ) 16.4, 4.5 Hz, 1H), 2.11 (m, 1H), 1.85 (d, J ) 5.1 Hz,
1H-5), 1.71 (m, 1H), 1.53 (m, 2H), 1.34 (m, 2H), 1.33 (s, 3H),
0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 181.7, 173.7, 144.2,
123.5, 72.9, 52.4, 50.7, 46.2, 42.6, 34.1, 33.0, 30.9, 28.0, 24.1,
C
16H18O4Na [M + Na]+ 297.1103, found 297.1104.
7r,8r-Epoxy-13,14,15,16-tetr an or labd-9(11)-en e-(19,6â),-
(12,17)-d iolid e (3). To a solution of dimethyldioxirane in
acetone (10 mL) was added 25 mg (0.09 mmol) of dienediolide
17. The mixture was stirred at room temperature for 24 h and
concentrated in a vacuum. The resulting crude was redissolved
in CH2Cl2, dried over Na2SO4, and concentrated under reduced
pressure. Purification by flash chromatography (hexane/t-
BuOMe, 4:6) afforded 5 mg (0.017 mmol, 19%, 49% based on
recovered starting material) of 3. The spectral data for 3 are
identical to those reported in the literature for oidiolactone
C.21 [R]20 -12.0 (c ) 0.2, CHCl3).
D
Dim eth yl 8-Oxo-13,14,15,16,17-p en ta n or la bd -6-en e-12,-
19-d ioa te (9). A solution of 4 (3.0 g, 9.9 mmol) in 50 mL of
CH2Cl2 cooled at -78 °C was bubbled with a steam of O2/O3
(30 nL/h) for 3 h. Then, argon was bubbled for 10 min and 6
mL of dimethyl sulfide was added. The mixture was stirred
for 6 h at room temperature and then concentrated under
reduced pressure. Purification by column chromatography
afforded ketone 18 (1712 mg, 65%) and alkene 10 (392 mg,
15%).
18.2, 18.0, 7.0; HRCIMS calcd for
419.0719, found 419.0718.
C
17H24O4I [M + H]+
13,14,15,16-Tet r a n or la b d -7-en e-(19,6â),(12,17)-d iolid e
(7). Meth od A. The mixture 16 + 7 (29 mg ≈ 0.07 mmol, ratio
4:1) was dissolved in 1 mL of acetone and 2 mL of water. To
this solution were added 0.05 mL (0.28 mmol) of collidine and
36 mg (0.21 mmol) of AgNO3. The reaction was stirred at 60
°C for 2 h. Then, the solvent was removed under vacuum and
the remaining residue was diluted with water and extracted
with t-BuOMe and EtOAc. The combined organic layers were
washed with 1 N HCl, brine, dried over Na2SO4, and concen-
trated under reduced pressure. The resulting crude product
was purified by column chromatography (hexane/t-BuOMe 6:4)
to afford 5 mg (20%) of the corresponding nitrate derivative
and 14 mg (72%) of 7.20
Meth od B. When the mixture 16 + 7 was heated under
the same conditions of lactonization employed in the previous
experiment but using AgBF4, only the formation of 7 (84%)
was observed.
Meth od C. To a solution of 20 mg (0.07 mmol) of monoacid
15 in 3 mL of CH2Cl2 cooled at 0 °C was added 19 mg (0.075
mmol) of m-CPBA. The reaction mixture was stirred for 4.5
h, and during this time, the temperature increased to 0 °C.
Then, the solvent was removed under vacuum and the
Following the same procedure described for 10,12 compound
18 was oxidized and esterified to give the corresponding methyl
ester in 90% yield.
To a solution of 1 g (3.22 mmol) of this intermediate in 40
mL of EtOAc was added 1 g (5.23 mmol) of PhSeCl. The
mixture was allowed to stir at room temperature for 60 h, and
then the solvent was evaporated. The resulting selenide was
redissolved in 40 mL of CH2Cl2, and 0.55 mL of 30% H2O2 and
0.64 g of pyridine were added. The mixture was stirred for 15
min at room temperature and 15 min at reflux. After being
cooled to room temperature, the reaction was diluted with CH2-
Cl2 and washed with 2 N HCl, saturated aqueous NaHCO3,
and brine. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure and the resulting crude
product purified by flash chromatography (hexane/t-BuOMe
7:3) to afford 858 mg (86%) of 9 as colorless crystals: mp
60-62 °C; [R]20D -1040 (c ) 0.45, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.31 (dd, J ) 10.6, 2.1 Hz, 1H), 6.01 (dd, J ) 10.6,
3.2 Hz, 1H), 3.68 (s, 3H), 3.61 (s, 3H), 2.87 (dd, J ) 8.1, 4.2
Hz, 1H), 2.72 (dd, J ) 16.3, 8.1 Hz, 1H), 2.50 (dd, J ) 3.2, 2.1
Hz, 1H), 2.30 (br d, J ) 14.0 Hz, 1H), 2.19 (dd, J ) 16.3, 4.2

2508 J . Org. Chem., Vol. 67, No. 8, 2002
Barrero et al.
Hz, 1H), 1.72 (m, 1H), 1.55 (m, 2H), 1.35 (m, 1H), 1.34 (s, 3H),
1.15 (ddd, J ) 13.5, 13.5, 4.0 Hz, 1H), 0.59 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 198.9, 176.4, 173.9, 149.3, 126.8, 57.7, 55.6,
51.9, 51.8, 43.3, 43.2, 37.4, 37.0, 27.7, 27.7, 19.0, 12.2; HR-
FABMS calcd for C17H24O5Na [M + Na]+ 331.1521, found
331.1512.
resulting mixture was stirred at room temperature for 30 min.
The layers were separated, and the aqueous layer was
extracted with EtOAc. Purification by flash chromatography
(hexane/t-BuOMe 3:7) afforded 1262 mg (88%) of 34 as
colorless crystals: mp 78-80 °C; [R]20 -8.5 (c ) 1.1, CHCl3);
D
1H NMR (300 MHz, acetone-d6) δ 5.74 (1H, m), 4.84 (m, 1H),
3.71 (m, 1H), 3.54 (m, 2H), 1.98 (m, 2H), 1.84 (t, J ) 1.5 Hz,
3H), 1.69-1.21 (m, 7H), 1.25 (s, 3H), 0.78 (s, 3H); 13C NMR
(75 MHz, acetone-d6) δ_182.3, 145.6, 119.9, 74.0, 63.3, 51.4,
48.2, 43.4, 34.9, 34.0, 30.5, 29.0, 24.1, 22.2, 18.8, 18.6; IR (film)
3441 (wide band), 1767, 1646, 848, 799 cm-1; HRFABMS calcd
for C16H24O3Na [M + Na]+ 287.1623, found 287.1622.
Meth yl 13,14,15,16-Tetr a n or la bd -6-en e-12,8â-olid e-19-
oa te (28). To a stirred solution of 710 mg (2.3 mmol) of 9 in
20 mL of dry THF was added 1.8 mL (2.5 mmol) of MeMgBr
(1.4 M in hexane) dropwise. After 20 min, the reaction was
diluted with t-BuOMe and quenched by addition of saturated
aqueous NH4Cl at 0 °C. The organic layer was subsequently
washed with brine, dried (Na2SO4), and evaporated. The crude
mixture was purified by flash chromatography using CH2Cl2/
t-BuOMe 9:1 as eluent to give 564 mg (84%) of 28 as colorless
Meth yl 13,14,15,16-Tetr a n or la bd -7-en e-19,6â-olid e-12-
oa te (27). To a solution of 330 mg of alcohol 34 (1.24 mmol)
in 22 mL of DMF were added 4671 mg (12.4 mmol) of PDC
and 4 Å molecular sieves. The reaction was stirred at room
temperature for 21 h. Water was added and the resulting
mixture was extracted with t-BuOMe. The combined extracts
were washed with brine, dried over Na2SO4, and filtered. The
solution that resulted was esterified with CH2N2 in t-BuOMe
and concentrated in a vacuum. The residue was purified by
flash chromatography (hexane/t-BuOMe 4:1) to afford 272 mg
(75%) of 27, together with 26 mg (8%) of the corresponding
aldehyde, which could be further oxidized, and 54 mg (15%)
of lactone 28, which could also be recycled. Methyl ester 27
crystals: mp 116-118 °C; [R]20 -13.0 (c ) 0.9, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 6.40 (dd, J ) 10.3, 1.7 Hz, 1H), 5.82
(dd, J ) 10.3, 3.0 Hz, 1H), 3.61 (s, 3H), 2.78 (dd, J ) 18.2, 8.9
Hz, 1H), 2.42 (d, J ) 18.2 Hz, 1H), 2.28 (br d, J ) 13.5 Hz,
1H), 1.94 (d, J ) 8.9 Hz, 1H), 1.87 (t, J ) 2.4 Hz, 1H), 1.79
(qt, J ) 14.0, 3.6 Hz, 1H), 1.66 (br d, J ) 13.0 Hz, 1H), 1.51
(m, 1H), 1.38 (s, 3H), 1.27 (s, 3H), 1.03 (ddd, J ) 13.5, 13.5,
4.0 Hz, 1H), 0.96 (ddd, J ) 13.3, 13.3, 4.1 Hz, 1H), 0.62 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 176.9, 176.3, 130.9, 125.8,
82.2, 53.1, 51.8, 51.6, 43.1, 37.6, 37.4, 36.1, 30.9, 28.2, 27.9,
18.7, 11.8; IR (film) 1764, 1724, 1657, 700, 724 cm-1; HR-
FABMS calcd for C17H24O4Na [M + Na]+ 315.1572, found
315.1571.
was isolated as colorless crystals: mp 79-81 °C; [R]20 -2.0
D
1
(c ) 1.2, CHCl3); H NMR (400 MHz, CDCl3) δ 5.78 (m, 1H),
4.83 (m, 1H), 3.69 (s, 3H), 2.58 (m, 1H), 2.34 (s, 1H), 2.32 (s,
1H), 2.09 (m, 1H), 1.81 (d, J ) 5.1 Hz, 1H), 1.71 (m, 1H), 1.70
(d, J ) 1.1 Hz, 3H), 1.51 (m, 3H), 1.30 (m, 1H), 1.29 (s, 3H),
0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.3, 174.4, 143.3,
119.2, 73.4, 52.0, 50.8, 47.5, 42.8, 33.7, 33.4, 31.4, 28.0, 24.0,
21.4, 18.5, 18.0; IR (film) 1767, 1736, 1651, 826 cm-1; HR-
FABMS calcd for C17H24O4Na [M + Na]+ 315.1572, found
315.1572. Anal. Calcd for C17H24O4: C, 69.62; H, 8.82. Found:
C, 69.86; H, 8.42.
13,14,15,16-Tetr a n or la bd -6-en e-12,8â-olid e-19-oic Acid
(32). To a solution of methyl ester 28 (1900 mg, 6.5 mmol) in
100 mL of DMF was added 3185 mg (32.0 mmol) of sodium
propanethiolate. The mixture was stirred at 50 °C for 15 h.
Cool water was added, then the mixture was acidified to pH 2
with 2 N HCl and extracted with t-BuOMe. The combined
extracts were washed with brine, dried over Na2SO4, and
concentrated in a vacuum. Purification by flash chromatog-
raphy (hexane/t-BuOMe 1:1) gave 1500 mg (5.4 mmol, 83%)
13,14,15,16-Tet r a n or la bd -7-en e-(19,6â),(12,17)-d iolid e
(7). Meth od E. To a solution of 473 mg (1.6 mmol) of methyl
ester 27 in 17 mL of glacial AcOH was added 355 mg of SeO2
(3.2 mmol). The mixture was stirred at reflux for 30 min. The
reaction was then diluted with t-BuOMe and washed with
saturated NaHCO3 and brine. The mother liquors were
neutralized and reextracted with EtOAc. The combined organic
layers were dried over Na2SO4 and concentrated in a vacuum.
Purification by flash chromatography afforded 225 mg (51%)
of dilactone 7 identical to that prepared above.
of 32 as white solid: mp 220-222 °C; [R]20 -15.0 (c ) 1.0,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 6.45 (dd, J ) 10.3, 1.8
Hz, 1H), 5.87 (dd, J ) 10.3, 3.0 Hz, 1H), 2.82 (dd, J ) 18.2,
8.9 Hz, 1H), 2.47 (d, J ) 18.2 Hz, 1H), 2.29 (br d, J ) 13.5 Hz,
1H), 1.98 (d, J ) 8.8 Hz, 1H), 1.92 (t, J ) 2.4 Hz, 1H), 1.84
(qt, J ) 13.9, 3.4 Hz, 1H), 1.72 (br d, J ) 13.0 Hz, 1H), 1.55
(m, 1H), 1.42 (s, 3H), 1.36 (s, 3H), 1.08 (ddd, J ) 13.5, 13.5,
4.1 Hz, 1H), 1.00 (ddd, J ) 13.3, 13.2, 4.0 Hz, 1H), 0.75 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 182.8, 176.3, 130.6, 126.1,
82.3, 53.2, 51.9, 43.0, 37.6, 37.0, 36.4, 30.9, 28.24, 28.19, 18.7,
12.0; IR (film) 3625-2590 (wide band), 1750, 1693, 721 cm-1
;
Ack n ow led gm en t. This research was supported by
the Spanish Direccio´n General de Investigacio´n Cien-
t´ıfica y Te´cnica (DGICYT; Proyecto PB 98-1365).
HRFABMS calcd for C16H22O4Na [M + Na]+ 301.1416, found
301.1416.
12-H y d r o x y -13,14,15,16-t e t r a n o r la b d -7-e n e -19,6â-
olid e (34). A suspension of 1400 mg (37 mmol) of LiAlH4 in
60 mL of THF was cooled to 0 °C. A solution of acid 32 (1500
mg, 5.4 mmol) in THF (70 mL) was added dropwise. After
complete addition, the mixture was stirred at 0 °C for 9 h.
The reaction was diluted with t-BuOMe and the pH of the
reaction adjusted to 2 by the dropwise addition of 1 N HCl.The
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra for all new compounds that appear as title
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
J O0161882