Stereoselective Synthesis of 7,11-Guaien-8,12-olides from Santonin. Synthesis of Podoandin and (+)-Zedolactone A

Article abstract of DOI:10.1021/jo000927h

Photochemical rearrangement of hydroxy ester 2, easily obtained from santonin (1), afforded butenolide 4, a good starting material for the synthesis of 7,11-guaien-8,12-olides. Compound 4 has been transformed into compound 10, which has been used for the synthesis of podoandin (5) and (+)-zedolactone A (ent-6). Regioselective elimination of the acetyl group on C₁₀ afforded directly podoandin (5). For the synthesis of ent-6, a hydroxyl group has been regio- and stereoselectively introduced at the 4α-position through the 3α,4α-epoxide 15. The basic hydrolysis of the 10-acetyl group in compound 18 took place with concomitant intramolecular conjugated addition of the alkoxide to the butenolide moiety to give ether 19. Cleavage of the 7,10-oxido bridge via the lactone enolate afforded (+)-zedolactone A (ent-6). This synthesis has allowed for the establishment of the absolute stereochemistry of natural zedolactone A as the enantiomer of our synthetic product.

Full text of DOI:10.1021/jo000927h

J . Org. Chem. 2000, 65, 6703-6707
6703
Ster eoselective Syn th esis of 7,11-Gu a ien -8,12-olid es fr om Sa n ton in .
Syn th esis of P od oa n d in a n d (+)-Zed ola cton e A
Gonzalo Blay, Victoria Bargues, Luz Cardona, Begon˜a Garc´ıa, and J ose´ R. Pedro*
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universitat de Valencia,
E-46100 Burjassot, Valencia, Spain
jose.r.pedro@uv.es
Received J une 19, 2000
Photochemical rearrangement of hydroxy ester 2, easily obtained from santonin (1), afforded
butenolide 4, a good starting material for the synthesis of 7,11-guaien-8,12-olides. Compound 4
has been transformed into compound 10, which has been used for the synthesis of podoandin (5)
and (+)-zedolactone A (ent-6). Regioselective elimination of the acetyl group on C10 afforded directly
podoandin (5). For the synthesis of ent-6, a hydroxyl group has been regio- and stereoselectively
introduced at the 4R-position through the 3R,4R-epoxide 15. The basic hydrolysis of the 10-acetyl
group in compound 18 took place with concomitant intramolecular conjugated addition of the
alkoxide to the butenolide moiety to give ether 19. Cleavage of the 7,10-oxido bridge via the lactone
enolate afforded (+)-zedolactone A (ent-6). This synthesis has allowed for the establishment of the
absolute stereochemistry of natural zedolactone A as the enantiomer of our synthetic product.
7,11-En-8,12-olide or 8,12-furan moieties and related
functionalities such as 7,11-en-8-hydroxy-8,12-olide and
7(11),8-dien-8,12-olide are present in many natural ses-
quiterpenoids, mainly eudesmane, eremophilane, or ger-
macrane.1 Compounds with these kinds of functionalities
have considerable biological importance, as many of them
have shown antiinflammatory,2 ichtiotoxic and cytotoxic,3
seed germination inhibitory,4 or molluscicidal activities,4,5
among others. Consequently, efficient synthesis of these
compounds is a challenge which has received much
attention in the past decades.6
synthetic approach to these kinds of compounds have not
been reported in the literature, so far. This fact has
aroused our interest and, as a continuation of our
research program on the synthesis of biologically active
sesquiterpenoids,10-12 we present in this paper an ef-
ficient approach to 7,11-guaien-8,12-olides starting from
santonin (1) and its application to the synthesis of two
7,11-guaien-8,12-olides, 5 and ent-6. Structure 5 was
reported for a sesquiterpene lactone isolated from Podocar-
pus andina, which has shown molluscicidal activity
against the aquatic snail Biomphalaria glabratus and
inhibits the germination of lettuce seedlings (Lactuca
sativa).7 Structure 6 was reported for zedolactone A, a
sesquiterpene lactone isolated from the dry rhizomes of
Curcuma aeruginosa, ‘Gajutsu’ in J apan, which are used
in traditional oriental medicine as a gastrointestinal
remedy.8 This synthesis has allowed for the determina-
tion of the absolute stereochemistry of natural zedolac-
tone A as the enantiomer of our synthetic product.
In recent years the isolation of sesquiterpenes bearing
these functionalities on a guaiane skeleton from natural
sources has been the subject of several reports in the
literature.7-9 In contrast, to the best of our knowledge, a
(1) (a) Connolly, J . D.; Hill, R. A. Dictionary of Terpenoids; Chapman
and Hall: London, 1991. (b) Roberts, J . S.; Bryson, I. Nat. Prod. Rep.
1984, 1, 105. (c) Fraga, B. M. Nat. Prod. Rep. 1985, 2, 147; 1986, 3,
273; 1987, 4, 473; 1988, 5, 497; 1990, 7, 61; 1990, 7, 515; 1993, 9, 217;
1992, 9, 557; 1993, 10, 397; 1994, 11, 533; 1995, 12, 303; 1996, 13,
307; 1997, 14, 145; 1998, 15, 73; 1999, 16, 21. (d) Faulkner, D. J . Nat.
Prod. Rep. 2000, 17, 7.
(2) Endo, K.; Taguchi, F.; Hikino, H.; Yamahara, J .; Fujimura, H.
Chem. Pharm. Bull. 1979, 27, 2954.
(3) Iguchi, K.; Mori, K.; Suzuki, M.; Takahashi, H.; Yamada, Y.
Chem. Lett. 1986, 1789.
Resu lts a n d Discu ssion
We have recently described the synthesis of three
8,12-guaianolides10 from alcohol 2, readily obtained from
santonin (1),13 in which photochemical rearrangement
from the eudesmane to the guaiane framework was
achieved by irradiation of the dienone moiety in the
8-acetyl derivative of compound 2.10 It is remarkable that
the C6-C7 double bond does not interfere in this rear-
rangement. On the other hand, we have also described
(4) Kubo, I.; Ying, B. P.; Castillo, M.; Brinen, L. S.; Clardy, J .
Phytochemistry 1992, 31, 1545.
(5) Delgado, G.; Garc´ıa, P. E.; Bye, R. A.; Linares, E. Phytochemistry
1991, 30, 1716.
(6) (a) Heathcock, C. H. In The Total Synthesis of Natural Products;
Apsimon, J ., Ed.; Wiley-Interscience: New York, 1973; Vol 2. (b)
Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C.
T. In The Total Synthesis of Natural Products; Apsimon, J ., Ed.; Wiley-
Interscience: New York, 1983; Vol 5. (c) Pirrung, M. C. In The Total
Synthesis of Natural Products; Goldsmith, D., Ed.; Wiley-Inter-
science: New York, 2000; Vol 11. (d) Roberts, J . S. Nat. Prod. Rep.
1985, 2, 97. (e) J enniskens, L. H. D.; Wijnberg, J . B. P. A.; de Groot,
A. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier Science: Amsterdam, 1994; Vol 14. (f) Blay, G.; Cardona, L.;
Garc´ıa, B.; Pedro, J . R. In Studies in Natural Products Chemistry; Atta-
ur-Rahman, Ed.; Elsevier Science: Amsterdam, (in press).
(7) Kubo, I.; Ying, B.-P.; Castillo, M.; Brienen, L. S.; Clardy, J .
Phytochemistry 1992, 31, 1545.
(9) (a) Rodr´ıguez, A. D.; Boulanger, A. J . Nat. Prod. 1996, 59, 653.
(b) Rodr´ıguez, A. D.; Boulanger, A. J . Nat. Prod. 1997, 60, 207.
(10) Blay, G.; Bargues, V.; Cardona, L.; Collado, A. M.; Garc´ıa, B.;
Mun˜oz, M. C.; Pedro, J . R. J . Org. Chem. 2000, 65, 2138.
(11) Blay, G.; Cardona, L.; Garc´ıa, B.; Lahoz, L.; Pedro, J . R. Eur.
J . Org. Chem. 2000, 2145-2151.
(12) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R.; Sa´nchez, J . J . J .
Org. Chem. 1996, 61, 3815.
(8) Takano, I.; Yasuda, I.; Takeya, K.; Itokawa, H. Phytochemistry
1995, 40, 1197.
(13) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R. J . Org. Chem.
1991, 56, 6172.
10.1021/jo000927h CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/09/2000

6704 J . Org. Chem., Vol. 65, No. 20, 2000
Blay et al.
Sch em e 1
that, by treatment in acidic medium (p-TsOH/benzene),
compound 2 undergoes lactonization with concomitant
migration of the C6-C7 double bond to the C7-C11
position, affording 7,11-eudesmen-8,12-olide 3 in 93%
yield.14 With these two ideas in mind we thought that
compound 4 could be prepared directly from 2. Since the
photochemical rearrangement15 is carried out in AcOH
as solvent and the lactonization to butenolide moiety is
catalyzed by acid, we expected that both of these steps
could take place in a one-pot conversion during the
irradiation. This supposition proved to be correct, and
irradiation of compound 2 for 9 h in AcOH afforded
directly the 7,11-guaien-8,12-olide 4 in 85% yield (Scheme
1). It is worth remarking that this good result stood in
contrast to the low yield (40%) that was obtained upon
irradiation of 3 in AcOH.
With compound 4 in our hands we undertook the
modification of the A ring functionalization in order to
obtain 10. From this compound we expected to prepare
podoandin (5) by regioselective elimination of the
C10-acetate group, while (+)-zedolactone A (6) could be
obtained by acetate hydrolysis followed by introduction
of a hydroxyl group at C4. The synthesis of 10 from 4
could be carried out by reduction of the enone to a
saturated ketone, reduction of the carbonyl group, and
regioselective elimination of the resulting alcohols. In the
first instance, reduction of the enone to the ketone was
attempted by hydrogenation on 5% Pd/C in acetone since
we have observed in a previous work that the C7-C11
double bond is not affected under these conditions.14
However, compound 4 showed a great resistance to
hydrogenation and was recovered unaltered. Fortunately,
a repetitive treatment of 4 with NaTeH16 gave saturated
ketone 7 in 64% yield. The positive NOE effects between
H1-H4, H15-H6R and H8-H6â confirmed the stereochem-
istry as depicted in Scheme 1. A small amount of a
tetrahydro derivative (8%) and 20% of starting material
were also isolated from the reaction mixture. Next,
treatment of 7 with NaBH4 afforded the two epimeric
alcohols 8 (55%) and 9 (34%), whose elimination was
carried out by treatment with POCl3 in the presence of
pyridine, followed by elimination of the mixture of
chlorides with Li2CO3-LiBr. This afforded regioselectively
compound 10 in 72% yield. From this compound, by
treatment with p-TsOH adsorbed on silica gel in toluene-
H2O17 at room temperature for 24 h, compound 5 was
obtained in 84% yield (Scheme 1). Its NMR spectra were
consistent with this structure and agreed with the
reported data for podoandin.7
For the synthesis of compound ent-6, the hydrolysis of
the acetate group was required. In contrast to the
easiness of the acetate elimination, its transformation
into an alcohol was troublesome. Under the usual hy-
drolytic conditions, consisting of treatment with 5%KOH/
EtOH followed by aqueous 18% HCl,10,16 a less polar
compound identified as ether 12 was obtained as the
main product (57%). This compound was obtained in a
nearly quantitative yield (97%), if the reaction was
carried out at 0 °C and reprotonated with 9% HCl. The
unexpected formation of 12 can be explained by an
intramolecular Michael addition of the C10-alkoxide,
resulting from the acetate hydrolysis, to the C7-C11
double bond conjugated with the lactone carbonyl group
(Scheme 1). Other hydrolytic conditions were also
tried without success. Thus LiOH (MeOH-H2O-THF)18
(14) Cardona, L.; Garc´ıa, B.; Pedro, J . R.; Ruiz, D. Tetrahedron 1994,
50, 5527.
(15) (a) Zimmerman, H. E.; Schuster, D. I. J . Am. Chem. Soc. 1962,
84, 4527. (b) Arigoni, D.; Bosshard, H.; Bruderer, H.; Bu¨chi, G.; J eger,
O.; Krebaum, L. J . Helv. Chim. Acta 1957, 11, 1732.
(16) Bargues, V.; Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R.
Tetrahedron 1998, 54, 1845.
(17) Cardona, M. L: Fernandez, I.; Garc´ıa, B.; Pedro, J . R. J . Nat.
Prod. 1990, 53, 1042.
(18) Baker, R.; Castro, J . L. J . Chem Soc. Perkin Trans. 1 1990, 47.

Synthesis of 7,11-Guaien-8,12-olides
J . Org. Chem., Vol. 65, No. 20, 2000 6705
NaOAc25 caused dehydration to guaiafurane 14.26 Only
the use of tetrapropylammonium perruthenate (TPAP)
with 4-methylmorpholine N-oxide (NMO)27 allowed com-
pound 1128 to be obtained, although in low yield (27%).
A last attempt to obtain compound 11 consisted of a retro-
Michael reaction29 on compound 12. For this purpose
compound 12 was treated with LDA (2 equiv) at -78 °C,
until disappearance of the starting material. However,
after quenching with aqueous HCl the reaction reverted
to the starting material, which was recovered (34%)
together with compound 1128 (50% yield) (Scheme 2).
Sch em e 2
Since all our attempts to obtain 11 from 10 in good
yield failed, we decided to change the order of the
reactions, introducing the hydroxyl group on C4 first and
leaving the transformation of the acetate for the last step.
To introduce the 4R-OH, we carried out the following
sequence. Compound 10 (Scheme 3) was subjected to
epoxidation with MMPP30 to give two stereoisomeric
epoxides, 15 (75%) and 16 (18%), whose stereochemistry
was deduced by comparison of their spectroscopic data
with those of related epoxides10 and NOE experiments.
The R stereochemistry of the oxirane ring in the major
epoxide 15 was inferred by the positive NOE found
among H6â and H3 and H8. Cleavage of the oxirane ring
by treatment of 15 with PhSeNa/Ti(i-PrO)4/DMF31 gave
hydroxyphenylselenide 17 in 87% yield, which by hydro-
genolysis of the C-Se bond with deactivated Raney Ni32
afforded compound 18 in quantitative yield (99%). The
transformation of compound 18 into ent-6 required hy-
drolysis of the C10-acetate group as the last step. On the
basis of the results obtained in the hydrolysis of com-
pound 10, it was also foreseeable that a similar Michael
reaction could not be avoided during saponification of the
acetate group in compound 18. Indeed, the basic hydroly-
sis of 18 afforded ether 19 in 85% yield. Finally, treat-
ment of ether 19 with LDA gave the desired compound
ent-6 in 50% yield, together with starting material 19
(45%). The spectral and physical data of synthetic ent-6
were coincident with those described for natural zedo-
lactone A isolated from C. aeruginosa.8 Our synthetic
Sch em e 3
product ent-6 showed an [R]23 in MeOH of +18.0,
D
whereas the reported value for the natural product was
-34.3. Although we do not have an explanation for the
difference in the absolute values of the optical rotations,
the opposite signs indicates that both products are
enantiomers. Because the absolute stereochemistry of our
synthetic products is established by unambiguous chemi-
cal synthesis from santonin (1) whose stereochemistry
afforded 12 (85%), while LiOOH (THF:H2O, 4:1),19 DBU
in MeOH,20 50% NH3 in MeOH,21 or 50% Triton B in
MeOH22 also gave epimerized products at C8. An alterna-
tive way was the use of reductive methods (diisobutyl-
aluminum hydride, DIBAL-H)23 to free the 10-OH. This
reagent would also reduce the lactone to lactol, which
should be reoxidized in a later step (Scheme 2). Treat-
ment of 10 with DIBAL-H at -45 °C afforded a mixture
of lactols 13 with 50% yield; however, reoxidation to the
butenolide moiety could not be achieved satisfactorily.
Swern reagent24 gave complex mixtures, while PCC/
(25) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647.
(26) Data for compound 14: oil; IR (NaCl) 3500-3300, 3040, 1650,
1570 cm-1 1Η ΝΜR (300 ΜΗz) δ 7.02 (1H, s), 5.35 (1H, br s), 2.98
;
(1H, d, J ) 16.5), 2.91 (1H, d, J ) 16.5), 1.90 (3H, d, J ) 1.5), 1.66
(3H, br s), 1.29 (3H, s).
(27) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc. Chem. Comm. 1987, 162. (b) Blay, G.; Schrijvers, R.;
Wijnberg, J . B. P. A.; de Groot, A. J . Org. Chem. 1995, 60, 2188.
(28) Data for compound 11: oil; IR (NaCl) 3560-3300, 1730 cm-1
;
1Η ΝΜR (300 ΜΗz) δ 5.39 (1H, br s), 4.95 (1H, br dd, J ) 5.4, 6.5),
2.92 (1H, dd, J ) 3.9, 13.8), 2.70-2.60 (1H, m), 2.49 (1H, dd, J ) 8.4,
15.6), 2.42 (1H, dd, J ) 6.5, 15.2), 2.30-2.22 (2H, m), 2.07 (1H, dd, J
) 7.2, 13.8), 2.00 (1H, br dd, J ) 5.4, 15.2), 1.83 (3H, d, J ) 2.1), 1.74
(3H, d, J ) 1.8), 1.27 (3H, s).
(19) (a) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6147. (b) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow,
R. L. J . Am. Chem. Soc. 1990, 112, 4011.
(20) Baptistella, L. H. B.; dos Santos, J . F.; Ballabio, K. C.; Marsaioli,
A. J . Synthesis 1989, 436.
(29) Magnus P.; Booth, J .; Diorazio, L.; Donohoe, T.; Lynch, V.;
Magnus, N.; Mendoza, J .; Pye, P.; Tarrant, J . Tetrahedron 1996, 52,
14103.
(21) Neilson, T.; Werstiuk, E. S. Can. J . Chem 1971, 49, 493.
(22) Marshall, J . A.; Hinkle, K. W. J . Org. Chem. 1996, 61, 4247.
(23) Yoon, N. M.; Gyoung, Y. S. J . Org. Chem. 1985, 50, 2443.
(24) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (b)
Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978, 43, 2480.
(30) Broghman, P.; Cooper, M. S.; Cunmerson, D. A.; Heaney, H.;
Thompson, N. Synthesis 1987, 1015.
(31) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557.
(32) Sevrin, M.; Van Ende, D.; Krief, A. Tetrahedron Lett. 1976,
2643.

6706 J . Org. Chem., Vol. 65, No. 20, 2000
Blay et al.
has been established by X-ray analysis,33 we can conclude
that the absolute stereochemistry of natural product
isolated from C. aeruginosa is (1S,4S,8R,10S)-4,10-dihy-
droxyguai-7(11)-en-8,12-olide.
55%) and 9 (325 mg, 34%). Data for compound 8: solid; mp
118-120 °C (hexanes-EtOAc); [R]21 +81.6 (c 0.98); IR (KBr)
D
3530-3400, 1735, 1680 cm-1; MS m/e 277 (M+ + C2H5 - AcOH,
6), 266 (6), 249 (100), 231 (51), 230 (17); HRMS 277.1807,
1
C
17H25O3 (M+ + C2H5 - AcOH) required 277.1803; H NMR
In summary, an efficient procedure for the preparation
of compound 10 from santonin (1) has been developed.
Compound 10 opens a pathway for the synthesis of
natural 7,11-guaien-8,12-olides and compounds with
related functionalities. As an example of the usefulness
of this method, two 7,11-guaien-8,12-olides, 5 and ent-6,
have been synthesized in enantiomerically pure form, and
as a consequence of the synthesis of ent-6, the absolute
stereochemistry of natural zedolactone A has been es-
tablished.
(250 MHz) δ 4.94 (1H, br d, J ) 7.1), 4.22 (1H, td, J ) 3.0,
7.2), 2.91 (1H, ddd, J ) 4.6, 8.6, 12.9), 2.63 (1H, dd, J ) 3.6,
13.2), 2.52 (1H, d, J ) 16.6), 2.40-2.20 (2H, m), 2.28 (1H, dd,
J ) 7.1, 16.6), 2.10-1.90 (1H, m), 1.90-1.75 (2H, m), 1.79 (6H,
br s), 1.49 (3H, s), 1.09 (3H, d, J ) 7.0); 13C NMR (200 MHz)
δ 175.3, 170.1, 161.8, 121.9, 84.6 (C), 80.5, 73.1, 48.6, 43.3 (CH),
36.3, 33.2 (CH2), 27.4 (CH3), 23.3 (CH2), 22.2, 10.1, 8.0 (CH3).
Data for compound 9: oil; [R]20 +44.6 (c 1.30); IR (NaCl)
D
3530-3410, 1752, 1736, 1676 cm-1; MS m/e 277 (M+ + C2H5
- AcOH, 7), 250 (16), 249 (100), 231 (75), 230 (18); HRMS
277.1804, C17H25O3 (M+ + C2H5 - AcOH) required 277.1803;
1H NMR (250 MHz) δ 4.92 (1H, br d, J ) 7.2), 3.96 (1H, ddd,
J ) 3.3, 6.4, 9.4), 3.25 (1H, ddd, J ) 4.0, 8.2, 12.2), 2.66 (1H,
dd, J ) 2.5, 10.7), 2.55 (1H, d, J ) 16.4), 2.20 (1H, dd, J ) 7.2,
16.4), 2.10-1.90 (3H, m), 1.80 (6H, br s), 1.90-1.60 (2H, m),
1.49 (3H, s), 1.12 (3H, d, J ) 6.5); 13C NMR (200 MHz) δ 174.9,
169.9, 160.9, 122.4, 84.1 (C), 80.3, 77.2, 48.0, 47.5, 44.0 (CH),
35.2, 33.0 (CH2), 27.0 (CH3), 22.9 (CH2), 22.1, 13.9, 8.0 (CH3).
10r-Acet oxy-1,5rH ,8â H-gu a ia -3,7(11)-d ien -8,12-olid e
(10). To a solution of the mixture of alcohols obtained in the
previous step (755 mg, 2.45 mmol) and pyridine (2.02 mL,
24.90 mmol) in benzene (24.5 mL) at room temperature and
under argon was added POCl3 (562 µL, 6.05 mmol), and the
solution was heated at reflux for 35 min. After this time, the
mixture was cooled to room temperature, quenched with
aqueous NH4Cl, and extracted with EtOAc. Usual workup
afforded an oil which was suspended with LiBr (432 mg, 4.90
mmol) and Li2CO3 (547 mg, 7.35 mmol) in DMF (28.8 mL),
and the suspension was heated under argon at 100 °C for 2 h
and 15 min. The reaction mixture was cooled to room temper-
ature, quenched with aqueous saturated NH4Cl, and extracted
with EtOAc. After the usual workup, chromatography (8:2
hexane/EtOAc) afforded 511 mg (72%) of compound 10: oil;
Exp er im en ta l Section 34
10r-Acet oxy-3-oxo-1rH ,8âH -gu a ia -4,7(11)-d ien -8,12-
olid e (4). A solution of compound 2 (750 mg, 2.71 mmol) in
AcOH (30 mL) under argon was irradiated with a 400 W UV
lamp for 9 h. Removal of the solvent at reduced pressure
afforded an oil which was chromatographed (6:4 to 4:6 hex-
anes-EtOAc) to give 700 mg (85%) of compound 4: solid; mp
162 °C dec (hexanes-EtOAc); [R]25 +13.6 (c 1.03); IR (KBr)
D
1756, 1727, 1639 cm-1; MS m/e 304 (M+, 2), 262 (66), 244 (100),
215 (26), 204 (16); HRMS 304.1319, C17H20O5 (M+) required
304.1310; 1H NMR (400 MHz) δ 4.82 (1H, br dd, J ) 5.4, 11.6),
3.94-3.86 (1H, m), 3.84 (1H, br d, J ) 20.1), 3.50 (1H, br d, J
) 20.1), 2.85 (1H, dd, J ) 5.4, 12.8), 2.48 (1H, t, J ) 12.3),
2.43 (2H, d, J ) 4.0), 1.99 (3H, s), 1.88 (3H, t, J ) 1.6), 1.77
(3H, br d, J ) 1.2), 1.20 (3H, s); 13C NMR (200 MHz) δ 206.1,
172.9, 170.0, 164.3, 157.1, 140.0, 125.6, 82.0 (C), 78.6, 49.5
(CH), 43.9, 37.2, 28.9 (CH2), 22.1, 19.8, 8.6, 8.3 (CH3).
10r-Ac e t o x y -3-o x o -1,5rH ,8âH -g u a i-7(11)-e n -8,12-
olid e (7). A suspension of tellurium powder (1.60 g, 12.3 mmol)
and NaBH4 (1.14 g, 29.5 mmol) in deoxigenated EtOH (33 mL)
was refluxed under argon for 1 h. After this time, the resulting
deep purple solution was cooled to 0 °C and a solution of 1.8
mL of glacial AcOH in 6.7 mL of EtOH was added, followed
by a solution of 4 (934 mg, 3.07 mmol) in 5.5 mL of EtOH and
11 mL of benzene. The resulting mixture was stirred at room
temperature for 3 days. After this time, the reaction flask was
open to air, water added, and the mixture stirred for 1 h. The
reaction mixture was filtered through Celite, washed with
brine, dried, and concentrated to give a residue which was
subjected to the same reaction conditions. Chromatography
of the oil obtained (7:3 to 3:7 hexane/EtOAc) separated starting
material 4 (187 mg, 20%), a tetrahydro derivative (75 mg, 8%),
and 602 mg (64%) of ketone 7: solid; mp 120-122 °C
[R]22 +44.4 (c 1.08); IR (NaCl) 1757, 1735, 1690 cm-1; MSEI
D
m/e 290 (M+, 1), 246 (31), 230 (100), 228 (29), 215 (31); HRMS
290.1530, C17H22O4 (M+) requiered 290.1518; 1H NMR (200
MHz) δ 5.36 (1H, br s), 5.00-4.90 (1H, m), 3.25 (1H, dt, J )
7.9, 10.1), 2.81 (1H, dd, J ) 4.0, 13.5), 2.52 (1H, dd, J ) 3.6,
16.0), 2.55-2.30 (1H, m), 2.35 (1H, dd, J ) 6.6, 16.0), 2.30-
2.20 (2H, m), 2.01 (1H, t, J ) 13.5), 1.83 (3H, s), 1.81 (3H, s),
1.72 (3H, d, J ) 1.2), 1.53 (3H, s); 13C NMR (200 MHz) δ 174.9,
169.9, 160.6, 143.0 (C), 123.7 (CH), 121.7, 84.2 (C), 80.0, 49.7,
47.9 (CH), 35.1, 32.4 (CH2), 26.8 (CH3), 26.3 (CH2), 22.2, 14.9,
8.0 (CH3).
5rH,8âH-Gu a ia -1(10),3,7(11)-tr ien -8,12-olid e (P od oa n -
d in , 5). To a solution of compound 10 (29 mg, 0.10 mmol) in
water-saturated toluene (2.2 mL) was added previously pre-
(hexanes-EtOAc); [R]25 +12.3 (c 1.46); IR (KBr) 1740, 1724,
D
17
1680 cm-1; MS m/e 306 (M+, 0.3), 264 (11), 246 (100), 217 (13);
pared p-TsOH-SiO2 (159 mg). The mixture was stirred at
1
HRMS 306.1463, C17H22O5 (M+) required 306.1467; H NMR
room temperature for 24 h and filtered through silica gel
(EtOAc), and the solvent was removed in vacuo to give 19 mg
(400 MHz) δ 4.96 (1H, br d, J ) 7.6), 3.42 (1H, ddd, J ) 5.2,
8.4, 13.2), 2.69 (1H, dd, J ) 3.6, 13.2), 2.62 (1H, d, J ) 16.5),
2.53 (1H, quint, J ) 7.2), 2.45-2.35 (1H, m), 2.36 (1H, dd, J
) 8.4, 17.2), 2.15 (1H, dd, J ) 7.6, 16.5), 2.06 (1H, dd, J )
13.2, 17.2), 1.86 (3H, s), 1.84 (3H, d, J ) 2.0), 1.69 (1H, dd, J
) 10.4, 13.2), 1.55 (3H, s), 1.12 (3H, d, J ) 7.2); 13C NMR (200
MHz) δ 215.5, 174.5, 169.8, 159.3, 123.1, 83.5 (C), 79.9, 50.5,
44.7, 41.1 (CH), 36.6, 32.7 (CH2), 27.4 (CH3), 22.4 (CH2), 21.9,
9.3, 8.0 (CH3).
10r-Acetoxy-3â-h yd r oxy-1,4,5r H,8âH-gu a i-7(11)-en -8,-
12-olid e (8) a n d 10r-Acet oxy-3r-h yd r oxy-1,4,5rH ,8âH -
gu a i-7(11)-en -8,12-olid e (9). A solution of 7 (950 mg, 3.10
mmol) in MeOH (63 mL) was treated with NaBH4 (348 mg,
9.12 mmol) at 0 °C. After 20 min the reaction was quenched
with aqueous NH4Cl. The usual workup and chromatography
(4:6 to 2:8 hexane/EtOAc) separated compounds 8 (525 mg,
(84%) of 5: solid: mp 113-114 °C (hexanes-EtOAc); [R]21
D
+38.4 (c 1.02); IR (KBr) 1745, 1664 cm-1; MS m/e 231 (M+
+
1, 100), 230 (M+, 31), 229 (M+ - 1, 17), 213 (13); HRMS
230.1316, C15H18O2 (M+) required 230.1307; 1H NMR (400
MHz) δ 5.49 (1H, br s), 4.55 (1H, br d, J ) 12.0), 3.10-2.90
(3H, m), 2.87 (1H, br d, J ) 11.6), 2.62 (1H, dd, J ) 3.6, 12.8),
2.23 (1H, t, J ) 12.8), 1.90-1.70 (1H, m), 1.84 (3H, br s), 1.78
(6H, br s); 13C NMR (200 MHz) δ 174.3, 163.5, 142.9, 140.6
(C), 124.2 (CH), 122.7, 121.3 (C), 79.3, 49.6 (CH), 39.6, 36.8,
31.2 (CH2), 21.9, 14.9, 8.2 (CH3).
7r,10r-E p oxy-1,5,11rH,8âH-gu a i-3-en -8,12-olid e (12).
Compound 10 (33 mg, 0.11 mmol) in EtOH (0.5 mL) was added
to a solution of 5% aqueous KOH (6.4 mL), and the mixture
was stirred at room temperature for 1 h. After diluting with
EtOAc and cooling to 0 °C, the reaction was quenched with
9% aqueous HCl and extracted with EtOAc in the usual way.
Removal of the solvent afforded 27 mg (97%) of compound 12:
solid; mp 127-129 °C (hexanes-EtOAc); [R]18D +20.4 (c 0.78);
IR (KBr) 3034, 1777, 1374 cm-1; MS m/e 249 (M+ + 1, 100),
248 (M+, 21), 231 (59), 203 (33), 175 (38); HRMS 248.1418,
(33) Kitabayashi, C.; Matsuura, Y.; Tanaka, N.; Katsube, Y.; Mat-
suura, T. Acta Crystallogr. 1985, 41, 1779.
(34) For
a general description of the experimental procedures
employed in this research, see ref 10.

Synthesis of 7,11-Guaien-8,12-olides
J . Org. Chem., Vol. 65, No. 20, 2000 6707
1
C15H20O3 (M+) required 248.1412; H NMR (400 MHz) δ 5.34
(hexanes-EtOAc); [R]26 +60.8 (c 1.25); IR (KBr) 3500-3400,
D
(1H, br s), 4.42 (1H, dd, J ) 2.4, 7.2), 2.91-2.85 (1H, m), 2.50-
2.40 (1H, m), 2.44 (1H, q, J ) 7.6), 2.42 (1H, dd, J ) 7.2, 14.0),
2.31 (1H, dd, J ) 7.6, 8.4), 2.13 (1H, dd, J ) 8.8, 14.4), 1.82
(1H, br d, J ) 17.2), 1.77 (1H, d, J ) 14.4), 1.71 (3H, br s),
1.52 (1H, ddd, J ) 1.2, 2.4, 14.0), 1.29 (3H, s), 1.25 (3H, d, J
) 7.6); 13C NMR (200 MHz) δ 177.9, 140.7 (C), 125.2, 85.5 (CH),
85.1, 84.4 (C), 44.2, 44.0, 43.0 (CH), 40.7, 34.1, 28.4 (CH2), 26.0,
14.9, 8.1 (CH3).
1730, 1683 cm-1; MS m/e 337 (M+ + C2H5, 1), 249 (40), 231
(100), 230 (18); HRMS 337.2011, C17H24O5 (M+ + C2H5 required
337.2015; 1H NMR (400 MHz) δ 4.94 (1H, dt, J ) 1.6, 7.2),
3.50 (1H, ddd, J ) 3.0, 8.7, 12.3), 2.71 (1H, br d, J ) 8.8), 2.62
(1H, br d, J ) 16.0), 2.27 (1H, dd, J ) 7.2, 16.0), 1.90-1.70
(5H, m), 1.84 (3H, d, J ) 2.4), 1.79 (3H, s), 1.53 (3H, s), 1.60-
1.45 (1H, m), 1.38 (3H, s); 13C NMR (200 MHz) δ 174.9, 169.9,
160.2, 122.8, 84.1, 81.5 (C), 80.2, 51.1, 48.0 (CH), 37.1, 33.1
(CH2), 27.2, 25.3 (CH3), 24.8, 24.0 (CH2), 22.2, 8.1 (CH3).
4r-H yd r oxy-7r,10r-ep oxy-1,5,11rH ,8âH -gu a ia n -8,12-
olid e (19). From compound 18 (36 mg, 0.115 mmol) and
according to the procedure for the synthesis of 12 (reaction
time 3 h) was obtained compound 19 (26 mg, 85%): solid; mp
10r-Acetoxy-3r,4r-ep oxy-1,5rH,8âH-gu a i-7(11)-en -8,12-
olid e (15) a n d 10r -Acetoxy-3â,4â-ep oxy-1,5rH,8âH-gu a i-
7(11)-en -8,12-olid e (16). To a solution of compound 11 (119
mg, 0.41 mmol) in MeOH (3.5 mL) was added MMPP (243 mg,
0.49 mmol), and the mixture was stirred overnight at room
temperature. The reaction was quenched with saturated
aqueous NaHCO3 and extracted with CH2Cl2, and the organic
layers were washed with aqueous 10% Na2S2O3 and brine and
dried over Na2SO4. The usual workup and chromatography
(5:5 to 3:7 hexane/EtOAc) afforded 92 mg (75%) of compound
15 and 22 mg (18%) of compound 16. Data for compound 15:
135-136 °C (hexanes-EtOAc); [R]18 -21.9 (c 1.28); IR (KBr)
D
3345, 1772, 1376 cm-1; MS m/e 267 (M+ + 1, 15), 249 (100),
248 (20), 231 (19), 175 (12); HRMS 267.1591, C15H23O4 (M+
+
1) required 267.1596; 1H NMR (400 MHz) δ 4.52 (1H, dd, J )
1.6, 6.8), 2.58-2.49 (1H, m), 2.50 (1H, q, J ) 7.2), 2.46 (1H,
dd, J ) 6.8, 15.4), 2.23 (1H, td, J ) 3.6, 14.1), 2.20 (1H, q, J )
10.8), 2.00-1.90 (1H, m), 1.80-1.70 (1H, m), 1.66 (1H, br d, J
) 15.4), 1.56 (1H, br s), 1.47 (1H, d, J ) 10.8), 1.33 (3H, s),
1.26 (3H, d, J ) 7.2), 1.25 (3H, s), 1.20-1.15 (2H, m); 13C NMR
(200 MHz) δ 177.6, 85.2 (C), 86.9 (CH), 84.0, 80.7 (C), 45.1,
44.4, 44.1 (CH), 41.0, 38.7 (CH2), 27.7 (CH3), 27.0, 25.7 (CH2),
23.5, 7.9 (CH3).
foam; [R]26 +55.7 (c 1.94); IR (KBr) 1737, 1734, 1687 cm-1
;
D
MS m/e 307 (M+ + 1, 3), 275 (53), 248 (85), 247 (58), 246 (100),
229 (87); HRMS 307.1545, C17H23O5 (M+ + 1) required
307.1545; 1H NMR (400 MHz) δ 4.93 (1H, br d, J ) 7.2), 3.30
(1H, s), 2.87 (1H, ddd, J ) 5.6, 6.8, 12.0), 2.82 (1H, dd, J )
3.2, 13.2), 2.67 (1H, br d, J ) 16.4), 2.17 (1H, ddd, J ) 3.2,
5.6, 13.2), 2.10 (1H, dd, J ) 7.2, 16.4), 2.04 (1H, dd, J ) 6.8,
13.6), 1.93 (1H, t, J ) 13.2), 1.85 (3H, d, J ) 2.0), 1.79 (3H, s),
1.52 (3H, s), 1.50 (3H, s), 1.55-1.49 (1H, m); 13C NMR (200
MHz) δ 174.6, 169.4, 159.1, 122.8, 83.2 (C), 79.9 (CH), 64.5
(C), 60.0, 43.3, 41.9 (CH), 33.4, 28.1 (CH2), 27.2 (CH3), 24.7
4r-H yd r oxy-7r,10r-ep oxy-1,5,11rH ,8âH -gu a ia n -8,12-
olid e [(+)-Zed ola cton e A] (en t-6). To a solution of LDA
prepared from i-Pr2NH (0.2 mL, 1.5 mmol), THF (2.5 mL), and
1.6 M n-BuLi in hexane (0.94 mL, 1,5 mmol) at -78 °C under
argon was added via syringe a solution of compound 19 (11
mg, 0.041 mmol) in THF (0.3 mL). The mixture was stirred at
-78 °C for 1 h, and then the reaction was quenched with an
aqueous solution of NH4Cl, the system was opened, and the
temperature allowed to rise to room temperature. The usual
workup and chromatrography (1:9 hexane/EtOAc) afforded 5
mg (45%) of starting material 19 and 5.5 mg (50%) of
(CH2), 22.0, 15.5, 7.9 (CH3). Data for compound 16: oil; [R]24
D
+14.5 (c 1.10); IR (NaCl) 1744, 1736 cm-1; MS m/e 307 (M+
+
1, 6), 248 (39), 247 (100), 246 (39), 229 (39); HRMS 307.1549,
1
C
17H23O5 (M+ + 1) required 307.1545; H NMR (200 MHz) δ
4.84 (1H, br dd, J ) 6.6, 9.7), 3.35-3.22 (1H, m), 3.28 (1H, s),
2.88-2.76 (2H, m), 2.47-2.36 (2H, m), 2.10-1.95 (3H, m), 1.90
(3H, s), 1.80 (3H, br s), 1.47 (3H, s), 1.43 (3H, s); 13C NMR
(200 MHz) δ 174.0, 169.9, 160.8, 122.9, 84.4 (C), 79.3 (CH),
68.9 (C), 64.4, 47.6, 44.3 (CH), 42.9, 29.6, 23.8 (CH2), 22.9, 22.5,
16.2, 8.1 (CH3).
compound ent-6: oil; [R]23 +18.0 (c 0.30, MeOH); IR (NaCl)
D
3417, 1736, 1677 cm-1; MS m/e 267 (M+ + 1, 100), 249 (56),
231 (89), 177 (35), 107 (22); HRMS 267.1589, C15H23O4 (M+
+
1
1) required 267.1596; H NMR (400 MHz, CDCl3) δ 4.91 (1H,
br d, J ) 5.0), 2.72 (1H, dd, J ) 3.6, 12.4), 2.73-2.69 (1H, m),
2.32 (1H, dd, J ) 6.8, 16.0), 2.08 (1H, dd, J ) 2.8, 16.0), 1.98
(1H, ddd, J ) 3.6, 5.6, 13.6), 1.91-1.75 (3H, m), 1.82 (3H, d,
J ) 2.0), 1.75-1.69 (1H, m), 1.60 (2H, br s), 1.54-1.45 (1H,
m), 1.39 (3H, s), 1.23 (3H, s); 1H NMR (400 MHz, pyridine-d5)
δ 6.01 (1H, br d, J ) 8.0), 5.12 (1H, ddd, J ) 2.0, 3.1, 7.2),
5.10 (1H, br s), 3.27 (1H, dt, J ) 8.0, 11.2), 2.78 (1H, dd, J )
3.7, 12.4), 2.52-2.40 (1H, m), 2.44 (1H, dd, J ) 7.2, 15.6), 2.18
(1H, dd, J ) 3.1, 15.6), 2.08-1.98 (2H, m), 1.97 (1H, dd, J )
12.4, 13.2), 1.92-1.88 (1H, m), 1.83 (3H, d, J ) 2.0), 1.68-
1.56 (1H, m), 1.52 (3H, s), 1.33 (3H, s); 13C NMR (250 MHz,
CDCl3) δ 175.0, 160.7, 122.9 (C), 81.7 (CH), 80.5, 73.5 (C), 51.6,
51.1 (CH), 37.5, 36.3 (CH2), 32.0, 25.1 (CH3), 24.9, 24.6 (CH2),
8.1 (CH3); 13C NMR (400 MHz, pyridine-d5) δ 175.6, 162.5,
122.0 (C), 81.3 (CH), 80.7, 72.5 (C), 52.9, 51.5 (CH), 38.5, 37.9
(CH2), 31.6 (CH3), 25.6 (CH3), 25.3 (CH2), 25.2, 8.2 (CH3).
10r-Acetoxy-3â-p h en ylselen yl-4r-h yd r oxy-1,5rH,8âH-
gu a i-7(11)-en -8,12-olid e (17). NaBH4 (39 mg, 1.03 mmol) was
added in portions to a solution of PheSeSePh (290 mg, 0.86
mmol) in DMF (2.3 mL) under Ar at room temperature for 2
h. To this solution were added via syringe AcOH (24 µL, 0.42
mmol), compound 15 (77 mg, 0.25 mmol) in DMF (4 mL), and
Ti(i-PrO)4 (150 µL, 0.48 mmol), and the mixture was stirred
for 22 h. After this time, the reaction was quenched with water
and extracted with EtOAc. Usual workup and chromatography
(5:5 hexane/EtOAc) afforded 6 mg (8%) of 15 and hydroxy
selenide 17 (99 mg, 87%): solid; mp 154-155 °C (hexanes-
EtOAc); IR (KBr) 3550-3350, 1735, 1684 cm-1; 1H NMR (200
MHz) δ 7.58-7.55 (2H, m), 7.30-7.23 (3H, m), 4.85 (1H, br t,
J ) 5.2), 3.54 (1H, dd, J ) 7.7, 10.7), 3.22 (1H, dt, J ) 8.1,
12.2), 2.80 (1H, dd, J ) 3.9, 11.7), 2.60 (1H, dd, J ) 6.6, 14.5),
2.40-2.20 (4H, m), 1.84 (3H, s), 1.85-1.95 (1H m), 1.80 (3H,
d, J ) 1.5), 1.50 (3H, s), 1.38 (3H, s); 13C NMR (200 MHz) δ
174.6, 169.9, 160.6 (C), 133.3 (CH), 129.8 (C), 129.1, 127.3
(CH), 123.0, 83.5, 81.9 (C), 79.4, 52.7, 49.0, 45.7 (CH), 39.0,
35.0 (CH2), 24.4 (CH3), 24.2 (CH2), 22.5, 22.2, 7.9 (CH3).
10r-Acetoxy-4r-h yd r oxy-1,5rH,8âH-gu a i-7(11)-en -8,12-
olid e (18). Hydroxy selenide 17 (42 mg, 0.09 mmol) in EtOH
(0.7 mL) was treated with deactivated ethanolic W-2 Raney
Ni35 (0.9 mL, ca. 0.5 g) at room temperature. After 30 min the
mixture was filtered through a short plug of silica gel (EtOAc)
to yield compound 18 (28 mg, 99%): solid, mp 165-167 °C
Ack n ow led gm en t. Financial support from Euro-
pean Commission (FAIR CT96-1781) and from Direcio´n
General de Investigacio´n Cient´ıfica y Te´cnica (DGICYT,
Grant PB 94-0985) is gratefully acknowledged. One of
us (V.B.) is specially thankful to Conselleria de Cultura,
Educacio´ i Ciencia (Generalitat Valenciana) for a grant.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 4-10, 12, and 15-19 .This material is
available free of charge via the Internet at http://pubs.acs.org.
(35) (a) Mozingo, R. Organic Syntheses; Wiley & Sons: New York,
1955; Collect. Vol III, p 181. (b) W-2 Raney Ni was deactivated by
heating the ethanolic suspension at 60 °C for 3-4 days.
J O000927H