Stereoselective Synthesis of 4α-Hydroxy-8,12-Guaianolides from Santonin

Article abstract of DOI:10.1021/jo991756n

Hydroxyester 2, easily obtained from santonin (1), has been transformed into 10α-hydroxyguai-3-en-8,12-olide 6, a good intermediate for the synthesis of natural 8,12-guaianolides. Compound 6 was obtained from 2 by photochemical rearrangement of its acetyl derivative 7, stereoselective hydrogenation on Pd/C, reduction, regioselective elimination, hydrolysis, and lactonization. The synthesis of the natural guaianolides 3-5 was carried out in two sequences in which the regioselective elimination of a hydroxyl group at C₁₀ with triflic anhydride or SOCl₂ to afford, respectively, the endo or exo double bond on C₁₀ and the regioselective opening of the C₃-C₄ α-epoxide were the key steps.

Full text of DOI:10.1021/jo991756n

2138
J . Org. Chem. 2000, 65, 2138-2144
Ster eoselective Syn th esis of 4r-Hyd r oxy-8,12-Gu a ia n olid es fr om
Sa n ton in
Gonzalo Blay,† Victoria Bargues,† Luz Cardona,† Ana M. Collado,† Begon˜a Garc´ıa,†
M.Carmen Mun˜oz,‡ and J ose´ R. Pedro*,†
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universitat de Valencia, E-46100 Burjassot,
Valencia, Spain, and Departamento de F´ısica Aplicada, Universidad Polite´cnica de Valencia,
E-46022 Valencia, Spain
Received November 10, 1999
Hydroxyester 2, easily obtained from santonin (1), has been transformed into 10R-hydroxyguai-3-
en-8,12-olide 6, a good intermediate for the synthesis of natural 8,12-guaianolides. Compound 6
was obtained from 2 by photochemical rearrangement of its acetyl derivative 7, stereoselective
hydrogenation on Pd/C, reduction, regioselective elimination, hydrolysis, and lactonization. The
synthesis of the natural guaianolides 3-5 was carried out in two sequences in which the
regioselective elimination of a hydroxyl group at C10 with triflic anhydride or SOCl2 to afford,
respectively, the endo or exo double bond on C10 and the regioselective opening of the C3-C4
R-epoxide were the key steps.
Guaiane sesquiterpenes including both 6,12- and 8,12-
guaianolides make up a group of natural compounds
widely present in the plant kingdom.1 These natural
products have aroused much interest on account of their
wide spectrum of biological properties, particularly the
cytotoxic and antitumor activity associated with the
R-methylene-γ-lactone group.
Numerous syntheses of 6,12-guaianolides have been
published starting from santonin (1),1-3 a commercial
natural product. However, there are few reports concern-
ing the synthesis of 8,12-guaianolides. Barton et al. have
reported a very low yield synthesis of the 8,12-guaiano-
lide geigerin starting from artemisin, the 8R-hydroxy
derivative of santonin (1).4 The key step in these syn-
theses is the photochemical rearrangement from the
eudesmane to the guaiane framework promoted by UV
irradiation from the dienone moiety present in santonin
or artemisin.4,5
In a previous paper, we described an efficient method
for the funcionalization of C8 in santonin to give alcohol
2,6 which has been proved a good intermediate for the
synthesis of 8,12-eudesmanolides6,7 and furanoeudes-
manes.8 As 2 presents in ring A the required dienone
moiety for the photochemical rearrangement from eudes-
mane to guaiane,9 we thought that this compound could
also be useful for the synthesis of 8,12-guaianolides.
Besides, since a number of natural 8,12-guaianolides,
such as 3-5, present a hydroxyl group at C4 and different
substitution at C10, the 10R-hydroxyguai-3-en-8,12-olide
6 could be a good intermediate for the synthesis of these
compounds.
In the present work we describe the synthesis of 6
using the easily available 2 as starting material and its
transformation into the 4R-hydroxy-8,12-guaianolides
3-5. Structure 3 was reported for 8-epi-pseudoivalin, a
natural product isolated from Helichrysum dasyanthum10
† Universitat de Valencia.
‡ Universidad Polite´cnica de Valencia.
(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; 1992, 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.
(2) (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) Roberts, J . S. Nat. Prod. Rep.
1985, 2, 97. (d) 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.
(3) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R. In Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science:
Amsterdam, Vol. 21, in press.
(4) Barton, D. H. R.; Pinhey, J . T.; Wells, R. J . J . Chem. Soc. 1964,
2518.
(5) (a) Barton, D. H. R.; De Mayo, P.; Shafiq, M. J . Chem. Soc. 1957,
929. (b) Barton, D. H. R.; Levisalles, J . E. D.; Pinney, J . T. J . Chem.
Soc. 1962, 3472.
(7) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R.; Serrano, A.
Tetrahedron 1992, 48, 5265.
(8) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R.; Sa´nchez, J . J . J .
Org. Chem. 1996, 61, 3815.
(6) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R. J . Org. Chem. 1991,
56, 6172.
(9) Zimmerman, H. E.; Schuster, D. I. J . Am. Chem. Soc. 1962, 84,
4527.
10.1021/jo991756n CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/16/2000

Synthesis of 4R-Hydroxy-8,12-Guaianolides
J . Org. Chem., Vol. 65, No. 7, 2000 2139
Sch em e 1
and Apalochlamys spectabilis,11 and guaianolide 4 and
its 11,13-dehydro derivative 5 from Dittrichia graveo-
lens.12 Compound 5 has been also isolated from Fran-
coeuria crispa,13 A. spectabilis,11 and Inula anatolica.14
alcohols 10 (56%) and 11 (40%), whose elimination was
carried out in two steps and separately as they showed
clear different reactivities toward halogenation or me-
sylation. Alcohol 10 by quick mesylation with MsCl in
the presence of Et3N and later elimination with Li2CO3
in DMF afforded alkene 12 (50%). On the other hand,
treatment of its epimer 11 with POCl3 in the presence of
pyridine gave a mixture of epimeric chlorides (1H NMR)
which were subjected to elimination with Li2CO3-LiBr
to also give compound 12 (80%). In this way 12 was
obtained in 60% overall yield from 9.
Finally the hydrolysis of the ester groups and lacto-
nization were achieved by treatment with KOH in MeOH
at rt and later acidification with 2 M HCl to give the
expected guaianolide 6 in 98% yield.
With compound 6 in our hands we envisaged the
synthesis of the natural guaianolides 3-5. A 4R-OH could
be introduced from the C3-C4 double bond, while regio-
selective elimination of the C10-OH would give rise to
the endo- or exocyclic double bond. Further changes on
the γ-lactone unity would allow the obtainment of the
three natural compounds.
Resu lts a n d Discu ssion
For the synthesis of 6 (Scheme 1) the most important
step was the change from a eudesmane to a guaiane
framework by photochemical rearrangement in an acid
medium of the dienone system. Since the selective
hydrogenation of the C6-C7 double bond in the presence
of the C1-C2 double bond seemed rather difficult, we
decided to carry out this photochemical rearrangement
on the trienone system, leaving the hydrogenation of the
C6-C7 double bond for a further step. On the other hand,
since it is known15 that compound 2 in an acidic medium
suffers lactone ring closure with concomitant migration
of the double bond from C6-C7 to C7-C11, leading to a
8,12-butenolide, the C8 hydroxyl group was protected as
an acetate prior to irradiation in acetic acid.
Irradiation of an acetic acid solution of acetate 7 with
UV light16 for 9 h under argon gave the desired guaiane
8 (54%) in which the C6-C7 double bond remained
unaltered, together with a significant amount of starting
material 7 (22%). Unfortunately longer irradiation times
did not increase the yield of 8 and diminished the amount
of recovered starting material 7.
The next step was the obtainment of the saturated
ketone 9. It was carried out by hydrogenation of com-
pound 8 over 10% Pd/C in EtOH to give 9 (74%) with
high stereoselectivity. No traces of other isomers were
found in the reaction mixture. The structure and stereo-
chemistry of compound 9 has been confirmed by the X-ray
diffraction spectrum.
To form the C3-C4 double bond, the carbonyl group
had to be reduced and the resulting alcohols eliminated.
Treatment of 9 with NaBH4 afforded the two epimeric
In the first instance we attempted the synthesis of
compound 3, which presents the double bond between C1
and C10 (Scheme 2). As a tetrasubstituted double bond
would react faster toward electrophilic reagents than the
trisubstituted C3-C4, the first step was the epoxidation
of this double bond. We subjected compound 6 to various
epoxidation conditions [(m-CPBA,17 dimethyldioxirane,18
magnesium monoperphthalate (MMPP19)]. In all cases
mixtures of R- and â-epoxides were obtained in similar
ratios (1H NMR) without significant differences of ste-
reoselectivity. As MMPP afforded the higher total yield,
the reaction was carried out with this reagent, and a
mixture of â-epoxide 13 (34%) and R-epoxide 14 (53%)
was obtained. The stereochemistry of the oxirane rings
1
was assigned by H NMR on the basis of the chemical
shift of the protons on C6 with reference to those of
compound 6.20 Proton H6R appears at similar δ values
in compounds 6 (δ 1.98), 13 (δ 1.90), and 14 (δ 1.90),
whereas in compound 13 H6â shows a downfield shift to
δ 1.46 (δ 1.23 in 6) due to the deshielding effect of the
(10) J akupovic, J .; Zdero, C.; Grenz, M.; Tsichritzis, F.; Lehman,
L.; Hashemoi-Nejad, S. M.; Bholman, F. Phytochemistry 1989, 28, 1119.
(11) Zdero, C.; Bohlman, F.; King, R. M. Phytochemistry 1990, 29,
3201.
(12) Rustaiyan, A.; J akupovic, J .; Chau-Thi, T. V.; Bohlman, F.;
Sadjadi, A. Phytochemistry 1987, 26, 2603.
(13) Abdel-Mogib, M.; J akupovic, J .; Dawidar, A. M.; Metwally, M.
A.; Abou-Elzahab, M. Phytochemistry 1990, 29, 2581.
(14) Topcu, G.; O¨ ksu¨z, S. Phytochemistry 1990, 29, 3666.
(15) Cardona, L.; Garc´ıa, B.; Pedro, J . R.; Ruiz, D. Tetrahedron 1994,
50, 5527.
(16) Arigoni, D.; Bosshard, H.; Bruderer, H.; Bu¨chi, G.; J eger, O.;
Krebaum, L. J . Helv. Chim. Acta 1957, 11, 1732.
(17) Pearson, A. J .; Hsu, S. Y. J . Org. Chem. 1986, 51, 2505.
(18) Messeguer, A.; Sa´nchez-Baeza, F.; Casas, J .; Hammock, B. D.
Tetrahedron 1991, 47, 1291.
(19) Broghman, P.; Cooper, M. S.; Cunmerson, D. A.; Heaney, H.;
Thompson, N. Synthesis 1987, 1015.
(20) Ando, M.; Kusaka, H.; Ohara, H.; Takase, K.; Yamaoka, H.;
Yoshikazu, Y. J . Org. Chem. 1989, 54, 1952.

2140 J . Org. Chem., Vol. 65, No. 7, 2000
Blay et al.
Sch em e 2
oxirane ring. On the other hand, H6â shows a high-field
shift in compound 14 (δ 1.05) which can be due to steric
compression of the C4-Me with a â disposition in the
R-epoxide.
The formation of the C1-C10 double bond was achieved
regioselectively by treatment of compound 14 with triflic
anhydride (Tf2O)/pyridine in CH2Cl2 at rt21 and afforded
the expected tetrasubstituted alkene 15 in 66% yield. A
positive NOE effect between C4-Me and H6R indicated
their spatial proximity and consequently the R diposition
of the oxirane ring, as can be observed in a molecular
model of this compound.
To open the oxirane ring, compound 15 was treated
with PhSeNa/Ti(i-PrO)4/DMF22 and compound 16 was
obtained in high yield (81%). Treatment of 16 with
deactivated Raney Ni23 effected the elimination of the
phenylselenyl group and gave compound 17 in near
quantitative yield (95%).
(SOCl2/pyridine-THF/-78 °C or rt)25 afforded a mixture
of the three possible alkenes (1H NMR) (Scheme 3).
Although the major constituent was the desired 19, a
significant amount of 20 with a C9-C10 double bond was
formed, while the C1-C10 isomer could only be detected
at a trace level. To increase the formation of the exo-
methylene double bond, pyridine was substituted by more
bulky bases (Et3N, DBU) and the reaction carried out
under different conditions. The highest selectivity was
obtained with DBU (-60 °C, 20 min), which gave an 11:1
mixture of 19 (58%) and 20 (5%).
The epoxidation of 19 was carried out with MMPP19
at 0 °C and afforded R-epoxide 21 in 61% yield with only
2% of its â-isomer 22 showing a higher stereoselectivity
than the epoxidation of compound 6 to 14. A clear
deshielding effect of H6â in compound 22 (δ 1.30, 1.02
in 19) allows us to assign the stereochemistry of these
epoxides. The regioselective opening of the oxirane ring
under the previously reported conditions gave compound
24 in 50% overall yield for the two steps.
Finally conversion of 17 into the corresponding exo-
methylene derivative 3 was achieved by Grieco’s proce-
dure.24 Treatment of the lithium enolate of 17 with
phenylselenyl chloride gave the phenylseleno derivative
18, which after oxidative syn elimination with 30% H2O2
yielded 3 in 41% overall yield. Its NMR spectra were
consistent with its structure and confirm this structure
For the synthesis of compound 4 the epimerization at
C11 was carried out by treatment of 24 with LDA at -78
°C and reprotonation of the lactone enolate with NH4Cl
at 0 °C,26 which afforded 4 in 93% yield. Its NMR spectra
were consistent with its structure and confirm the
structure of 11â,13-dihydro-1-epi-inuviscolide for the
natural product isolated from D. graveolens.12
1
for natural 8-epi-pseudoivalin as the H NMR spectral
data were identical to the reported data for the natural
product.10,11
Finally conversion of 24 into the corresponding exo-
methylene derivative by Grieco’s procedure24 afforded 5
in 45% overall yield. Its NMR spectra were consistent
with this structure and confirm 1-epi-inuviscolide as the
natural product isolated from F. crispa,13 A. spectabilis,11
and I. anatolica14 as its 1H NMR spectral data were
identical to the reported data for the natural product.
For the synthesis of compounds 4 and 5 from 6 the new
double bond should be introduced between C10 and C14.
In this case, treatment with excess SOCl2 in pyridine,
the reagent of choice in the literature,2,25 should afford
satisfactory yields for this elimination. Besides, as this
gem-disubstituted double bond would react slower toward
epoxidation than the trisubstituted C3-C4, the epoxida-
tion and the elimination could be carried out in inverse
order. Treatment of compound 6 by standard procedures
In summary, 4R-hydroxy-8,12-guaianolides 3-5 were
synthesized in enantiomerically pure forms from com-
mercially available santonin (1). For the synthesis of
these compounds a synthetic sequence has been devised
which opens a pathway for the synthesis of natural 8-oxy-
functionalized guaianes and 8,12-guaianolides and re-
lated compounds.
(21) Bargues, V.; Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R.
Tetrahedron 1998, 54, 1845.
(22) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557.
(23) Sevrin, M.; Van Ende, D.; Krief, A. Tetrahedron Lett. 1976,
2643.
(24) Grieco, P. A.; Miyashita, M. J . Org. Chem. 1974, 39, 120.
(25) (a) Marx, J . N.; McGaughey, M. S. Tetrahedron 1972, 28, 3583.
(b) Edgar, M. T.; Greene, A. E.; Crabbe´, P. J . Org. Chem. 1979, 44,
159.
(26) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R. J . Org. Chem.
1993, 58, 7204.

Synthesis of 4R-Hydroxy-8,12-Guaianolides
J . Org. Chem., Vol. 65, No. 7, 2000 2141
Sch em e 3
Ta ble 1. 13C NMR Da ta of Com p ou n d s 3-12 (δ, CDCl3)
carbon
3
4
5
6a
7
8
9
10
11a
12a
C1
C2
C3
C4
C5
C6
C7
C8
124.4b
30.1c
39.6c
80.7
54.4
26.9
45.6b
26.7c
43.2
46.1b
26.6c
42.8
51.6
33.5
124.4
141.0
48.8
26.3
44.9
81.1
48.7
72.9
40.4
179.9
9.8
153.8
127.3
186.1
130.6b
151.1b
125.3
141.8
68.1
38.5
39.5
42.1
173.7
15.2
46.1b
36.7c
207.6
160.3d
146.0d
124.7
140.2
70.5
50.7
36.9
218.6
44.1b
47.6
23.4
43.7b
72.1
33.4
83.0
42.6
175.0
12.8
26.9
9.1
51.4
36.5
72.5b
45.7c
44.3c
25.1
43.5c
72.2b
33.6
84.1
42.9
175.4
11.8
26.3
9.8
50.4
35.1
76.7
47.3
46.3
23.7
44.4
72.3
33.5
83.8
42.4
175.2
12.5
26.2
13.4
51.2
170.4
170.3
22.6
21.0
52.5
32.4
122.4
143.8
50.6b
28.2
43.5
72.2
35.1
80.4
80.5
53.9b
25.7c
51.5
54.0b
25.5c
47.3
50.5
81.9
84.7
40.8
144.2
42.3
178.7
12.4
84.7
40.5
C9
40.4c
140.2b
139.3
170.2
113.7
23.2
42.9c
82.3
C10
C11
C12
C13
C14
C15
OCH3
CH3CO
144.0
139.8
170.2
118.9d
116.1d
23.9
84.1
47.4b
173.4
15.8
22.1
8.4
42.3b
175.2
12.1
115.4
23.9
24.0
14.7
25.7
10.2
52.1
170.2
26.1
14.9
51.2
170.3
170.3
22.7
23.2
52.2
51.4
170.3
170.1
22.6
21.1
51.1
170.3
170.3
22.6
21.0
170.1
169.9
21.0
CH3CO
20.8
20.8
21.1
a
Assignment by heteronuclear 1H-13C NMR correlation. b -dThese signals may be interchanged within the corresponding spectrum.
reflections collected, θ range 2.25-24.97°, 1861 independent
reflections (Rint ) 0.0165). Final R indices were R1 ) 0.0425
and wR2 ) 0.0911 [I > 2σ(I)]. Residual electron densities were
0.285 and -0.162 e Å-3. Data were collected for a crystal of
size 0.1 × 0.1 × 0.2 mm at 293 K with a Siemens P-4
diffractometer using graphite-monochromated Mo KR radia-
tion (λ ) 0.710 73 Å) and the θ-2θ scan technique. Lorentz-
polarization and absorption corrections were applied to the
data. The structure was solved by direct methods using
SHELX86 and refined by the full-matrix least-squares method
on F2 using SHELXL93.28 All non-hydrogen atoms were refined
anisotropically.
Meth yl (11S)-8r-Acetoxy-3-oxoeu d em a -1,4,6-tr ien -12-
oa te (7). A mixture of 26 (2.46 g, 8.91 mmol), Ac2O (24 mL),
pyridine (24 mL), and a catalytic amount of DMAP was stirred
at rt for 3 h. The reaction was quenched with 2 M HCl and
then extracted with EtOAc. The combined organic layers were
washed with aqueous NaHCO3 and brine, dried with Na2SO4,
and concentrated. Chromatography of the residue (7:3 hexane/
Exp er im en ta l Section
All melting points are uncorrected. Column chromatography
was performed on silica gel (SDS, silica gel 40-60 mm). W-2
Raney Ni was prepared according to Mozingo,27 and deacti-
vated by heating the ethanolic suspension at 60 °C for 3-4
days. IR spectra were recorded as liquid films for oils and as
KBr disks for solids. Specific rotations were measured in
CHCl3. 1H and 13C NMR were measured in CDCl3; chemical
shifts are reported in parts per million and J values in hertz.
NMR were run at 200.1, 299.95, or 399.95 Mz for 1H and at
50.3, 75.43, or 100.58 MHz for 13C. The carbon type (methyl,
methylene, methine, or quaternary) was determined by DEPT
experiments. 13C NMR spectral data of compounds 3-12 are
listed in Table 1 and those of compounds 13-25 in Table 2.
Mass spectra were run by chemical ionization (with CH4).
Crystal data for 9: C20H30O7, M ) 382.44, monoclinic, P21/m,
a ) 8.726(2) Å, b ) 12.769(3) Å, c ) 9.070(2) Å, â ) 90.52(3)°,
V ) 1010.6(3) Å3, Z ) 2, µ(Mo KR) ) 0.094 mm-1, 1987
(27) (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.
(28) (a) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467. (b)
SHELXS93, A program for the Refinement of Crystal Structures,
University of Go¨ttingen, 1993.

2142 J . Org. Chem., Vol. 65, No. 7, 2000
Ta ble 2. 13C NMR Da ta of Com p ou n d s 13-25 (δ, CDCl3)
Blay et al.
carbon
13
14
15
16a
17
18a
19
20
21
22
23a
24
25
C1
C2
C3
C4
C5
C6
C7
C8
49.7b
29.2c
63.7
67.5
45.8b
22.7c
45.8b
80.6
50.0
72.9
40.4
179.6
9.5
39.8b
28.5c
60.9
127.4b
33.4
63.5
67.0
51.6
27.0
47.9
79.3
39.2
140.2b
40.4
178.8
10.0
22.3
16.1
124.7b
39.4c
53.4d
81.2
124.4b
29.8c
39.6c
80.9
124.6b
29.8c
39.6c
81.0
48.3
36.3
48.5b
35.8
46.9b
32.0
62.3
65.9
50.2b
23.4
42.8
84.3
41.0
145.2
40.6
179.2
9.5
44.8b
33.3
64.0
66.9
45.8
22.7
46.9
84.0
40.4
144.1
43.6b
179.6
9.6
46.8b
35.2
55.7
80.3
51.2b
22.7
42.7
83.8
44.4
142.3
40.2
179.5
9.5
45.1b
26.6
43.7
80.2
53.5b
22.8
47.0
84.0
40.8
140.0
40.3
179.7
9.5
45.2b
26.7
43.5
124.0
141.0
52.4b
24.8
123.3c
137.9
50.7b
27.2
65.7
80.4
38.0b
27.4c
47.2b
82.0
54.8d
25.5
54.8
54.6
53.9b
23.5
26.1c
49.9
26.7c
58.8
48.6
47.2b
84.7
43.9
55.9
82.4
40.9
143.7
51.1
176.0
21.9
115.5
23.9
80.8
80.5
79.0
83.2
C9
41.4
72.4
40.2
180.2
10.0
40.6c
135.7b
40.4
40.1c
140.3b
40.6
39.7c
140.4b
51.0
42.6
145.2
40.5
179.7
9.5
115.2
14.8
122.6c
145.6
40.4
C10
C11
C12
C13
C14
C15
179.6
10.4
20.2
179.4
10.3
23.0
175.7
22.0
23.0
179.8
10.1
27.6
24.8
15.8
33.3
15.6
115.7
16.1
117.7
16.0
115.4
20.7
115.2
23.7
23.3
23.5
23.7
15.1
a
Aromatic carbons: for 16, δ 127.4, 129.1, 129.6, 133.7; for 18, δ 124.3, 129.0, 129.7, 138.3; for 23, δ 127.4, 128.8, 129.1, 133.8; for 25,
δ 124.0, 128.9, 129.7, 138.3. b -dThese signals may be interchanged within the corresponding spectrum.
EtOAc) gave 2.55 g (90%) of acetate 7: yellow oil; [R]19D +271.8
(c 1.7); IR (NaCl) 1737, 1648 cm-1; MS m/e 319 (M+ + 1, 72),
318 (M+, 18), 275 (25), 259 (86), 227 (37) 199 (100); HRMS
6.0, 6.8), 3.65 (3H, s), 2.51 (1H, br d, J ) 16.4), 2.47-2.55 (1H,
m), 2.35-2.20 (3H, m), 2.15 (1H, dd, J ) 6.0, 16.4), 2.15-2.05
(1H, m) 2,00 (3H, s), 1.97-1.90 (1H, m), 1.95 (3H, s), 1.48 (3H,
s), 1.37-1.33 (3H, m), 1.07 (3H, d, J ) 7.2), 1.01 (3H, d, J )
1
318.1456, C18H22O5 required 318.1467; H NMR (400 MHz) δ
7.2). Data for compound 11: yellow oil; [R]28 +34.3 (c 1.34);
6.72 (1H, d, J ) 9.7), 6.70 (1H, br s), 6.25 (1H, d, J ) 9.7),
5.70 (1H, br dd, J ) 9.8, 7.9), 3.67 (3H, s), 3.39 (1H, q, J )
7.1), 2.32 (1H, dd, J ) 6.3, 12.2), 2.04 (3H, s), 1.98 (3H, s),
1.49 (1H, dd, J ) 9.8, 12.2), 1.37 (3H, d, J ) 7.1), 1.21 (3H, s).
Met h yl (11S)-8r,10r-Dia cet oxy-3-oxo-1rH -gu a ia -4,6-
d ien -12-oa te (8). A solution of acetate 7 (748 mg, 2.35 mmol)
in AcOH (75 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 hexane/
EtOAc) to give 166 mg (22%) of starting material 7 and 479
mg (54%) of guaiane 8: yellow solid; mp 119-121 °C (hex-
D
IR (NaCl) 3500-3100, 1729 cm-1; MS m/e 383 (M+ - 1, 10),
351 (6), 334 (14), 274 (29); HRMS 383.2047, C20H31O7 (M+
-
1
1) required 383.2070; H NMR (400 MHz) δ 4.96 (1H, ddd, J
) 1.6, 5.6, 9.6), 3.83 (1H, ddd, J ) 3.4, 8.0, 8.8), 3.64 (3H, s),
2.63 (1H, ddd, J ) 6.0, 9.2, 11.2), 2.51 (1H, d, J ) 16.4), 2.52
(1H, dq, J ) 3.2, 7.6), 2.25 (1H, ddd, J ) 3.2, 9.6, 10.0), 2.23-
2.19 (1H, m), 2.03 (1H, dd, J ) 5.6, 16.8), 2.00 (3H, s), 2.00-
1.95 (1H, m), 1.95 (3H, s), 1.85 (1H, ddd, J ) 8.8, 11.2, 14.0),
1.63 (1H, ddd, J ) 3.4, 9.2, 14.0), 1.45 (3H, s), 1.40 (1H, br d,
J ) 14.4), 1.07 (3H, d, J ) 7.6), 1.03 (3H, d, J ) 7.2), 0.88
(1H, ddd, J ) 10.0, 12.4, 14.4).
ane-EtOAc); [R]21D -167.1 (c 1.52); IR (KBr) 1738, 1696 cm-1
;
MS m/e 379 (M+ + 1, 10), 319 (30), 259 (100); HRMS 379.1743
Meth yl (11S)-8r,10r-Dia cetoxy-1,5,7rH-gu a i-3-en -12-
oa te (12). F r om Com p ou n d 10. To a 0 °C precooled solution
of 3â-alcohol 10 (386 mg, 1.01 mmol) and Et3N (0.85 mL, 6.05
mmol) in CH2Cl2 (5.9 mL) and under argon was added MsCl
(360 µL, 4.43 mmol), and the resulting mixture was stirred
for 3 h. The reaction was quenched with 10% HCl aqueous to
acid pH and extracted with EtOAc. The combined organic
layers were washed with saturated aqueous NaHCO3 and
brine, dried over Na2SO4, and concentrated to give an oil which
1
(M+ + 1), C20H27O7 required 379.1757; H NMR (400 MHz) δ
6.59 (1H, s), 5.47 (1H, dd, J ) 4.1, 6.7), 4.46 (1H, br s), 3.68
(3H, s), 3.46 (1H, q, J ) 7.0), 2.98 (1H, dd, J ) 6.7, 15.0), 2.45
(1H, dd, J ) 5.3, 16.6), 2.38 (1H, d, J ) 4.0, 16.6), 2.33 (1H,
dd, J ) 4.1, 15.0), 2.07 (3H, s), 1.97 (3H, s), 1.80 (3H, d, J )
2.1), 1.36 (3H, d J ) 7.0), 1.15 (3H, s).
Meth yl (11S)-8r,10r-Dia cetoxy-3-oxo-1,4,5,7rH-gu a ia n -
12-oa te (9). A solution of 8 (1.36 g, 3.60 mmol) in absolute
EtOH (38 mL) was hydrogenated over 10% Pd/C (322 mg) for
2 h and 30 min. After this time, the catalyst was removed by
filtration through a pad of silica gel, the filtrate concentrated
in vacuo, and the residue chromatographed (9:1 to 6:4 hexane/
EtOAc) to give 1.01 g (74%) of compound 9: solid; mp 143-
1
according to H NMR analysis consisted mainly of the mesyl
derivative. A suspension of the oil and Li2CO3 (620 mg, 8.40
mmol) in DMF (26 mL) was heated under argon at 100 °C for
2 h. The reaction mixture was cooled, quenched with aqueous
saturated NH4Cl, and extracted with EtOAc. After the usual
workup, chromatography (9:1 hexane/EtOAc) gave 178 mg
144 °C (hexane-EtOAc); [R]22 -8.2 (c 1.47); IR (KBr) 1729
D
cm-1; MS m/e 323 (M+ - AcO, 4), 263 (100), 231 (10); HRMS
(50%) of 12: pale yellow oil; [R]26 +95.5 (c 1.57); IR (NaCl)
D
1
323.1863, C18H27O5 (M+ - AcO) required 323.1858; H NMR
1735 cm-1; MS m/e 307 (M+ - AcO, 1), 263 (6), 247 (100), 187
(22); HRMS 307.1898, C18H27O4 (M+ - AcO) required 307.1909;
1H NMR (400 MHz) δ 5.27 (1H, br s), 5.00 (1H, ddd, J ) 2.8,
5.2, 10.4), 3.65 (3H, s), 2.69 (1H, ddd, J ) 6.4, 7.2, 8.0), 2.60-
2.50 (3H, m), 2.43 (1H, td, J ) 2.8, 10.4), 2.18 (1H, dd, J )
5.2, 16.0), 2.22-2.14 (1H, m), 2.10-2.00 (1H, m), 2.00 (3H, s),
1.96 (3H, s), 1.68 (3H, br s), 1.50 (3H, s), 1.50-1.54 (1H, m),
1.15-1.04 (1H, m), 1.07 (3H, d, J ) 6.8).
(400 MHz) δ 4.98 (1H, ddd, J ) 1.2, 5.6, 10.4), 3.62 (3H, s),
2.68 (1H, ddd, J ) 5.2, 8.4, 12.8), 2.61 (1H, dddd, J ) 2.0, 5.2,
7.2, 12.8), 2.55 (1H, br d, J ) 17.0), 2.52 (1H, dq, J ) 3.2, 7.2),
2.45 (1H, dq, J ) 6.8, 7.2), 2.35 (1H, td, J ) 3.2, 10.4), 2.29
(1H, dd, J ) 8.4, 18.8), 2.03 (3H, s), 1.97 (1H, dd, J ) 5.6,
17.0), 1.95 (3H, s), 1.89 (1H, dd, J ) 12.8, 18.8), 1.49 (3H, s),
1.37 (1H, br d), 1.06 (3H, d, J ) 7.2), 1.00 (3H, d, J ) 6.8),
0.84 (1H, ddd, J ) 10.4, 12.8, 15.2).
F r om Com p ou n d 11. To a solution of 3R-alcohol 11 (67
mg, 0.173 mmol) and pyridine (0.14 mL, 1.73 mmol) in benzene
(1.7 mL) at rt and under argon was added POCl3 (39 µL, 0.415
mmol), and the mixture was heated at reflux for 35 min. After
this time, the mixture was cooled at rt, quenched with aqueous
NH4Cl, and extracted with EtOAc. Usual workup afforded an
oil which by 1H NMR analysis consisted of a mixture of two
epimeric chlorides.
Meth yl (11S)-8r,10r-Dia cetoxy-3â-h yd r oxy-1,4,5,7rH-
gu a ia n -12-oa te (10) a n d Meth yl (11S)-8r,10r-Dia cetoxy-
3r-h yd r oxy-1,4,5,7rH-gu a ia n -12-oa te (11). A solution of 9
(1.01 g, 2.65 mmol) in MeOH (54 mL) was treated with NaBH4
(298 mg, 7.88 mmol) at 0 °C. After 20 min the reaction was
quenched with aqueous NH4Cl. The usual workup and chro-
matography (8:2 to 5:5 hexane/EtOAc) separated two com-
pounds, â-alcohol 10 (570 mg, 56%) and R-alcohol 11 (408 mg,
40%). Data for compound 10: solid; mp 131-132 °C (hexane-
A suspension of this oil, LiBr (30 mg, 0.343 mmol), and Li2-
CO3 (38 mg, 0.510 mmol) in DMF (2 mL) was heated under
argon at 100 °C for 2 h and 15 min. The reaction mixture was
cooled at rt, quenched with aqueous saturated NH4Cl, and
extracted with EtOAc. After the usual workup, chromatogra-
EtOAc); [R]26D +62.3 (c 1.51); IR (KBr) 3580-3560, 1724 cm-1
;
MS m/e 383 (M+ - 1, 9), 351 (5), 334 (13), 274 (28); HRMS
383.2065, C20H31O7 (M+ - 1) required 383.2070; 1H NMR (400
MHz) δ 5.00 (1H, br dd, J ) 6.0, 10.4), 4.14 (1H, br dd, J )

Synthesis of 4R-Hydroxy-8,12-Guaianolides
J . Org. Chem., Vol. 65, No. 7, 2000 2143
phy (9:1 hexane/EtOAc) afforded 50 mg (80%) of compound
12 with features identical to those of the compound obtained
from 10.
till no evolution of H2 was observed (75 min). To this solution
were added via syringe AcOH (25 µL, 0.440 mmol), compound
15 (56 mg, 0.224 mmol) in DMF (3.6 mL), and Ti(i-PrO)4 (140
µL, 0.539 mmol), and the mixture was stirred for 7 h. After
this time, the reaction was quenched with water and extracted
with EtOAc. Usual workup and chromatography (7:3 hexane/
EtOAc) yielded hydroxy selenide 16 (68 mg, 81%): yellow oil;
IR (NaCl) 3600-3200, 3057, 1764 cm-1; 1H NMR (300 MHz) δ
7.60-7.50 (2H, m), 7.40-7.30 (3H, m), 3.99 (1H, td, J ) 3.0,
10.5), 3.42 (1H, dd, J ) 7.8, 12.3), 2.86 (1H, dd, J ) 7.5, 15.0),
2.68 (1H, quint, J ) 7.8), 2.59 (1H, dd, J ) 3.0, 14.1), 2.45-
2.25 (3H, m), 2.13 (1H, ddd, J ) 2.4, 7.8, 10.5, 12.0), 1.91 (1H,
dt, J ) 2.4, 12.6), 1.68 (3H, s), 1.17 (3H, s), 1.16 (3H, d, J )
7.8), 1.20-1.10 (1H, m).
4r-Hyd r oxy-5,7,11rH,8âH-gu a i-1(10)-en -8,12-olid e (17).
Hydroxy selenide 16 (18 mg, 0.044 mmol) in MeOH (5 mL)
was treated with deactivated ethanolic W-2 Raney Ni27 (1 mL,
ca. 750 mg) at rt. After 1 h the mixture was filtered through
a short plug of silica gel with EtOAc to remove the catalyst
and to yield compound 17 (11 mg, 95%): solid; mp 91-94 °C;
[R]20D -53.3 (c 1.05); IR (KBr) 3520-3300, 1765 cm-1; MS m/e
250 (M+, 90), 235 (25), 232 (100); HRMS 250.1571, C15H23O4
required 250.1569; 1H NMR (400 MHz) δ 3.98 (1H, td, J )
3.2, 10.4), 2.70 (1H, quint, J ) 7.6), 2.56 (1H, dd, J ) 3.2, 14.4),
2.52-2.42 (1H, m), 2.48 (1H, br dd, J ) 10.8, 14.4), 2.28 (1H,
br d, J ) 12.0), 2.27-2.17 (1H, m), 2.22 (1H, dddd, J ) 2.4,
7.6, 10.8, 12.0), 1.81 (1H, dt, J ) 2.4, 12.8), 1.73 (3H, br s),
1.73-1.68 (2H, m), 1.22 (3H, s), 1.16 (3H, d, J ) 7.6), 1.05
(1H, q, J ) 12.0).
10r-Hyd r oxy-1,5,7,11rH,8âH-gu a i-3-en -8,12-olid e (6).
Compound 12 (637 mg, 1.74 mmol) was added to a solution of
KOH (2.9 g, 52.2 mmol) in MeOH (13.9 mL), and the mixture
was stirred at rt for 2 h. Addition of a 2 M HCl solution to
acid pH and usual workup and chromatography (6:4 hexane/
EtOAc) afforded 426 mg (98%) of guaianolide 6: solid; mp
114-117 °C (hexane-EtOAc); [R]27 -65.1 (c 1.66); IR (KBr)
D
3350-3320, 1766 cm-1; MS m/e 251 (M+ + 1, 2), 233 (100);
HRMS 251.1637, C15H23O3 (M+ + 1) required 251.1647); 1H
NMR (400 MHz) δ 5.34 (1H, br s), 4.15 (1H, ddd, J ) 4.4, 10.8,
12.4), 2.90 (1H, br ddd, J ) 6.4, 9.2, 9.6), 2.66 (1H, quint, J )
7.6), 2.56 (1H, ddd, J ) 3.2, 8.8, 9.2), 2.51 (1H, ddquint, J )
2.4, 3.2, 16.8), 2.43 (1H, dd, J ) 4.4, 12.4), 2.45-2.35 (1H, m),
2.29 (1H, td, J ) 7.6, 10.8), 1.98 (1H, dd, J ) 6.6, 13.6), 1.81
(1H, t, J ) 12.4), 1.62 (3H, br s), 1.23 (1H, ddd, J ) 9.6, 10.8,
13.6), 1.16 (3H, d, J ) 7.6), 1.12 (3H, s).
3â,4â-Ep oxy-10r-h yd r oxy-1,5,7,11rH,8âH-gu a ia n -8,12-
olid e (13) a n d 3r,4r-Ep oxy-10r-h yd r oxy-7,11rH,8âH-gu a -
ia n -8,12-olid e (14). To a solution of compound 6 (101 mg,
0.404 mmol) in MeOH (2.6 mL) was added MMPP (238 mg,
0.485 mmol), and the mixture was stirred at rt for 5 h. 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.
After the usual workup and chromatography (6:4 to 4:5
hexane/EtOAc), 37 mg (34%) of compound 13 and 57 mg (53%)
of compound 14 were isolated. Data for compound 13: solid;
11â-P h en ylselen yl-4r-h yd r oxy-5,7rH ,8âH -gu a i-1(10)-
en -8,12-olid e (18). To a solution of LDA prepared from i-Pr2-
NH (31 µL, 0.226 mmol), THF (0.3 mL), and 1.6 M n-BuLi in
hexane (139 µL, 0.219 mmol) at -78 °C under argon was added
via syringe a solution of compound 17 (16 mg, 0.062 mmol) in
THF (0.3 mL). The mixture was stirred at -78 °C for 1 h, and
then a solution of PhSeCl (44 mg, 0.219 mmol) in THF (0.6
mL) and HMPA (36 µL) was added. The mixture was stirred
for an additional 1 h and 30 min at -78 °C, and then the
temperature was allowed to rise to -30 °C. After 2 h at this
temperature the reaction was quenched with 0.85 mL of
aqueous 9% HCl and extracted with EtOAc. Usual workup and
chromatography (7:3 to 5:5 hexane/EtOAc) afforded 3.4 mg
(21%) of starting material 17 and 14 mg (56%) of phenylsele-
nolactone 18: yellow solid; mp 170-172 °C (hexane-EtOAc);
mp 119-121 °C (hexane-EtOAc); [R]20 -87.4 (c 1.83); IR
D
(KBr) 3500, 1765, 1200 cm-1; MS m/e 267 (M+ + 1, 17), 249
(99), 231 (96), 203 (100), 191 (56), 189 (46); HRMS 267.1597,
1
C
15H23O4 (M+ + 1) required 267.1596; H NMR (300 MHz) δ
4.15 (1H, ddd, J ) 3.6, 10.8, 12.0), 3.22 (1H, d, J ) 1.5), 2.66
(1H, quint, J ) 7.8), 2.46-2.34 (3H, m), 2.27 (1H, dd, J ) 1.5,
15.6), 2.10 (1H, ddd, J ) 7.8, 10.2, 10.8), 1.97 (1H, ddd, J )
1.5, 10.2, 15.6), 1.90 (1H, br dd, J ) 3.9, 13.8), 1.72 (1H, t, J
) 12.0), 1.46 (1H, dt, J ) 10.2, 13.8), 1.35 (3H, s), 1.19 (3H, s),
1.17 (3H, d, J ) 7.8). Data for compound 14: solid; mp 131-
132 °C (hexane-EtOAc); [R]20 -14.7 (c 1.63); IR (KBr) 3479,
D
1756, 1212 cm-1; MS m/e 267 (M+ + 1, 10), 249 (100), 231 (65),
203 (29), 189 (19); HRMS 267.1598, C15H23O4 (M+ + 1) required
1
267.1596; H NMR (400 MHz) δ 4.24 (1H, dt, J ) 8.4, 10.8),
1
3.29 (1H, br s), 3.25 (1H, dddd, J ) 1.2, 8.4, 10.8, 13.6), 2.66
(1H, dq, J ) 7.6, 8.4), 2.38 (1H, ddd, J ) 5.6, 6.4, 11.6), 2.31
(1H, dd, J ) 8.4, 15.6), 2.21 (1H, ddd, J ) 6.4, 6.8, 12.0), 2.00
(1H, dd, J ) 6.8, 13.6), 1.94 (1H, dd, J ) 8.4, 15.6), 1.90 (1H,
ddd, J ) 1.2, 5.6, 12.0), 1.42 (3H, s), 1.35 (1H dd, J ) 12.0,
13.6), 1.28 (3H, s), 1.15 (3H, d, J ) 7.6), 1.05 (1H, dt, J ) 11.6,
13.6).
IR (KBr) 3489, 3060, 1745 cm-1; H NMR (200 MHz) δ 7.59
(2H, d, J ) 7.4), 7.45-7.25 (3H, m), 4.20 (1H, td, J ) 3.3, 9.9),
2.56 (1H, dd, J ) 3.3, 14.0), 1.74 (3H, br s), 1.52 (3H, s), 1.27
(3H, s).
4r-H yd r oxy-5,7rH ,8âH -gu a i-1(10),11(13)-d ie n -8,12-
olid e (3). To a 0 °C precooled solution of phenylselenolactone
18 (20 mg, 0.048 mmol) in THF (0.5 mL) was added 30% H2O2
(12 µL), and the mixture was stirred at 0 °C for 10 min and
then at rt for 30 min. The reaction was quenched with brine
and extracted with EtOAc, and after usual workup the oil
obtained was chromatographed (7:3 to 5:5 hexane/EtOAc) to
give 9 mg (74%) of compound 3: white solid; mp 88-92 °C
3r,4r-Ep oxy-5,7,11rH,8âH-gu a i-1(10)-en -8,12-olid e (15).
To a solution of compound 14 (64 mg, 0.241 mmol) and pyridine
(0.21 mL, 2.487 mmol) in CH2Cl2 (5.5 mL) at 0 °C and under
argon was added via syringe triflic anhydride (Tf2O) (127 µL,
0.747 mmol), and the mixture was stirred at rt for 29 h.
Additional portions of 0 °C precooled pyridine (0.1 mL) and
Tf2O (64 µL, 0.374 mmol) were added at 5, 8, and 23 h of
reaction time. The reaction was quenched with aqueous
saturated NaHCO3, and after usual workup (CH2Cl2) and
chromatography (8:2 to 4:6 hexane/EtOAc) 39 mg (66%) of
compound 15 was isolated: solid; mp 60-62 °C (hexane-
(hexane-EtOAc); [R]24 -7.6 (c 1.29); IR (KBr) 3590-3196,
D
1765 cm-1; MS m/e 249 (M+ + 1, 67), 248 (M+, 36), 231 (100),
203 (50); HRMS 248.1411, C15H20O2 required 248.1412; 1H
NMR (400 MHz) δ 6.16 (1H, d, J ) 3.6), 5.48 (1H, d, J ) 2.8),
3.78 (1H, td, J ) 3.6, 10.4), 2.65-2.52 (3H, m), 2.48-2.44 (1H,
m), 2.35 (1H, br d, J ) 11.6), 2.22-2.18 (2H, m), 1.74 (3H, br
s), 1.66-1.58 (2H, m), 1.21 (3H, s), 1.10 (1H, br q, J ) 12.0).
1,5,7,11rH,8âH-Gu a i-3,10(14)-d ien -8,12-olid e (19) a n d
7,11rH,8âH-Gu a i-3,9(10)-d ien -8,12-olid e (20). To a -60 °C
precooled solution of 6 (200 mg, 0.75 mmol) in THF (1.6 mL)
under Ar were added 0.72 mL (4.66 mmol) of DBU and 0.79
mL (10.30 mmol) of SOCl2. After being stirred at this temper-
ature for 18 min, the reaction was quenched with a precooled
mixture of ether and water and extracted with ether, and the
combined organic layers were washed with Na2CO3 and brine.
Chromatography of the resulting oil (1:0 to 7:3 hexane/EtOAc)
yielded 108 mg (58%) of compound 19 and 9.5 mg (5%) of its
isomer 20. Data for compound 19: white solid; mp 86-88 °C
EtOAc); [R]20 -46.7 (c 1.59); IR (KBr) 1772, 1203 cm-1; MS
D
m/e 249 (M+ + 1, 100), 248 (M+, 23), 231 (32), 220 (14), 203
1
(17); HRMS 248.1418, C15H20O3 required 248.1412; H NMR
(400 MHz) δ 3.87 (1H, td, J ) 2.4, 10.4), 3.39 (1H, br s), 2.70
(1H, quint, J ) 7.6), 2.67 (1H, br d, J ) 16.4), 2.63 (1H, br d,
J ) 12.4), 2.51 (1H, br dd, J ) 10.4, 14.0), 2.43 (1H, br d, J )
16.4), 2.42 (1H, dd, J ) 2.4, 14.0), 2.31 (1H, dddd, J ) 2.8,
7.6, 10.4, 12.4), 1.78 (1H, ddd, J ) 2.0, 2.8, 12.4), 1.68 (3H, br
s), 1.44 (3H, s) 1.25-1.12 (1H, m), 1.14 (3H, d, J ) 7.6).
3â-P h en ylselen yl-4r-h yd r oxy-5,7,11rH,8âH-gu a i-1(10)-
en -8,12-olid e (16). NaBH4 (36 mg, 0.962 mmol) was added
in portions to a solution of PhSeSePh (272 mg, 0.870 mmol)
in DMF (2.2 mL) under Ar at rt, and the mixture was stirred
(hexane-ether); [R]19 -19.5 (c 1.23); IR (KBr) 1769 cm-1
;
D

2144 J . Org. Chem., Vol. 65, No. 7, 2000
Blay et al.
MS m/e 233 (M+ + 1, 100), 232 (M+, 35), 187 (19), 159 (57);
compound 24 (14 mg, 80%): solid; mp 105-107 °C (EtOAc);
1
HRMS 232.1475, C15H20O2 required 232.1463; H NMR (400
[R]22 -94.6 (c 1.12); IR (KBr) 3600-3230, 3062, 1777 cm-1
;
D
MHz) δ 5.38 (1H, br s), 5.02 (1H, s), 4.91 (1H, s), 3.95 (1H,
ddd, J ) 3.6, 10.8, 11.2), 3.08 (1H, ddd, J ) 6.0, 8.4, 9.2), 2.98
(1H, dd, J ) 3.6, 11.6), 2.71 (1H, ddd, J ) 3.6, 9.2, 11.6), 2.66
(1H, quint, J ) 7.6), 2.49 (1H, ddq, J ) 1.6, 8.4, 16.0), 2.34
(1H, ddq, J ) 2.0, 6.0, 16.0), 2.21 (1H, dd, J ) 10.2, 11.6), 2.18
(1H, br ddd, J ) 7.6, 10.8, 13.6), 1.71 (1H, ddd, J ) 1.2, 3.6,
11.2), 1.65 (3H, br s), 1.13 (3H, d, J ) 7.6), 1.02 (1H, ddd, J )
11.2, 11.6, 13.6). Data for compound 20: white solid; mp 54-
MS m/e 250 (M+, 4), 235 (6), 232 (100), 192 (21); HRMS
1
250.1565, C15H22O3 required 250.1569; H NMR (400 MHz) δ
5.08 (1H, s), 5.02 (1H, s), 3.97 (1H, td, J ) 4.4, 11.2), 3.04 (1H,
dd, J ) 4.4, 11.6), 3.00 (1H, br dd, J ) 8.4, 10.4), 2.65 (1H, dq,
J ) 7.6, 8.0), 2.12 (1H, dd, J ) 11.2, 11.6), 2.20-2.08 (2H, m),
1.92-1.80 (1H, m), 1.85-1.60 (4H, m), 1.16 (3H, d J ) 8.0),
1.13 (3H, s), 1.02 (1H, ddd, J ) 10.8, 12.8, 13.2).
4r-Hydr oxy-1,5,7rH,8,11âH-gu ai-10(14)-en -8,12-olide (4).
To a solution containing 14 mg (0.058 mmol) of compound 24
in THF (0.4 mL) cooled to -78 °C was added 0.7 mL (0.290
mmol) of a solution of LDA prepared as reported for the
synthesis of 18. The resulting mixture was stirred at -78 °C
for 15 min, and then the temperature was allowed to rise to 0
°C. After being stirred for 2 h, the reaction was quenched at 0
°C with an aqueous saturated solution of NH4Cl. Usual workup
yielded 13.4 mg (93%) of compound 4: colorless oil; [R]20D +7.1
(c 0.85); IR (NaCl) 3650-3150, 3087, 1767 cm-1; MS m/e 250
56 °C (hexane-ether); [R]18 -41.8 (c 0.91); IR (KBr) 1775,
D
1646 cm-1; MS m/e 233 (M+ + 1, 100), 232 (M+, 12), 178 (48),
159 (53); HRMS 232.1451, C15H20O2 required 232.1463; 1H
NMR (400 MHz) δ 5.74 (1H, s), 5.37 (1H, s), 4.66 (1H, br d, J
) 10.4), 2.78 (1H, dt, J ) 7.2, 11.6), 2.67 (1H, dq, J ) 7.6,
8.0), 2.47 (1H, br dd, J ) 7.2, 14.4), 2.29 (1H, ddd, J ) 4.4,
7.2, 14.8), 2.17 (1H, ddd, J ) 8.0, 10.4), 2.04 (1H, br dd, J )
11.6, 14.4), 1.97 (1H, dd, J ) 4.4, 13.8), 1.81 (3H, s), 1.72 (3H,
s), 1.25-1.10 (1H, m), 1.17 (3H, d, J ) 8.0).
3r,4r-E p oxy-1,5,7,11rH ,8âH -gu a i-10(14)-en -8,12-olid e
(21) a n d 3â,4â-Ep oxy-1,5,7,11rH,8âH-gu a i-10(14)-en -8,12-
olid e (22). To a 0 °C precooled solution of compound 19 (94
mg, 0.40 mmol) in MeOH (2.58 mL) was added MMPP (239
mg, 0.48 mmol). The mixture was stirred at this temperature
for 24 h, and additional portions of MMPP (15-20 mg) were
added at 19 and 21 h. After usual workup the solid obtained
was purified by chromatography (9:1 to 7:3 hexane/EtOAc) to
separate â-epoxide 22 (2 mg, 2%) and R-epoxide 21 (61 mg,
61%). Data for compound 21: solid; mp 51-53 °C (hexane-
(M+, 11), 235 (13), 232 (100), 192 (47); HRMS 250.1569,
1
C
15H22O3 required 250.1569; H NMR (400 MHz) δ 5.07 (1H,
s), 5.03 (1H, s), 3.78 (1H, ddd, J ) 4.4, 10.8, 11.2), 3.03 (1H,
dd, J ) 4.4, 12.0), 2.96-3.05 (1H, m), 2.26 (1H, dq, J ) 7.2,
11.6), 2.14 (1H, dd, J ) 11.2, 12.0), 2.15-2.06 (1H, m), 1.92-
1.80 (1H, m), 1.84-1.60 (5H, m), 1.23 (3H, d, J ) 7.2), 1.14
(3H, s), 1.07 (1H, ddd, J ) 10.8, 12.8, 13.2).
11â-P h e n y ls e le n y l-4r-h y d r o x y -1,5,7rH ,8âH -g u a i-
10(14)-en -8,12-olid e (25). By the same procedure used in the
synthesis of 18, from compound 24 (17 mg, 0.069 mmol) were
obtained 4.4 mg (25%) of starting material 24 and 13 mg (47%)
of 25: pale yellow solid, mp 155-157 °C (hexane-EtOAc); IR
(KBr) 3600-3200, 3065, 1768 cm-1; 1H NMR (200 MHz) δ 7.59
(2H, dd, J ) 1.7, 8.5), 7.40-7.25 (3H, s), 5.11 (1H, s), 5.04 (1H,
s), 4.20 (1H, td, J ) 4.6, 10.8), 3.05 (1H, dd, J ) 4.6, 11.8),
3.10-2.90 (1H, m), 2.20-2.05 (2H, m), 2.00-1.50 (6H, m), 1.48
(3H, s), 1.19 (3H, s), 1.30-1.10 (1H, m).
EtOAc); [R]20 -74.9 (c 0.94); IR (NaCl) 1775, 1199 cm-1; MS
D
m/e 249 (M+ + 1, 100), 248 (M+, 15), 231 (58), 203 (32); HRMS
1
248.1403, C15H20O3 required 248.1412; H NMR (400 MHz) δ
4.98 (1H, br d, J ) 1.6), 4.89 (1H, br d, J ) 2.0), 3.89 (1H, td,
J ) 2.8, 10.4), 3.31 (1H, s), 2.94 (1H, dd, J ) 2.8, 11.6), 2.81
(1H, br dt, J ) 7.6, 10.4), 2.68 (1H, quint, J ) 7.6), 2.30-2.25
(2H, m), 2.25 (1H, br t, J ) 11.6), 2.16 (1H, ddt, J ) 1.6, 7.6,
11.6), 1.68 (1H, dd, J ) 12.4, 12.6), 1.67 (1H, br d, J ) 13.6),
1.45 (3H, s), 1.13 (3H, d, J ) 7.6), 1.00 (1H, dt, J ) 11.6, 13.6).
4r-Hyd r oxy-1,5,7rH,8âH-gu a i-10(14),11(13)-d ien -8,12-
olid e (5). By the same procedure used in the synthesis of 3,
from phenylselenolactone 25 (11 mg, 0.027 mmol) was obtained
6.5 mg (95%) of 5: colorless oil; [R]24D -30.6 (c 0.62); IR (NaCl)
3614-3150, 3083, 1765 cm-1; MS m/e 249 (M+ + 1, 16), 248
Data for compound 22: oil; IR (NaCl) 1770, 1200 cm-1 1H
;
NMR (400 MHz) δ 5.13 (1H, s), 5.11 (1H, s), 3.99 (1H, td, J )
5.0, 11.2), 3.32 (1H, s), 2.99 (1H, dd, J ) 5.0, 11.2), 2.73 (1H,
br dd, J ) 9.6, 10.4), 2.66 (1H, quint, J ) 7.6), 2.32 (1H, ddd,
J ) 5.6, 9.6, 12.4), 2.25 (1H, d, J ) 15.6), 2.20-2.10 (2H, m),
2.01 (1H, t, J ) 11.2), 1.84 (1H, dd, J ) 5.6, 13.6), 1.36 (3H,
s), 1.30 (1H, ddd, J ) 9.6, 10.4, 13.6), 1.17 (3H, d, J ) 7.6).
3â-P h e n ylse le n yl-4r-h yd r oxy-1,5,7,11rH ,8âH -gu a i-
10(14)-en -8,12-olid e (23). NaBH4 (20 mg, 0.529 mmol) was
added in portions to a solution of PhSeSePh (149 mg, 0.477
mmol) in DMF (1.2 mL) under Ar at rt for 75 min. To the
resulting mixture were added via syringe AcOH (13 µL, 0.230
mmol), compound 21 (30 mg, 0.122 mmol) in DMF (2 mL), and
Ti(i-PrO)4 (80 µL, 0.308 mmol), and the mixture was stirred
for 32 h with addition of additional portions of Ti(i-PrO)4 (40
µL, 0.15 mmol) at 15, 22, and 29 h. Usual workup and
chromatography (8:2 to 5:5 hexane/EtOAc) yielded hydroxy
selenide 23 (33 mg, 66%): oil; IR (NaCl) 3570-3310, 3067,
(M+, 3), 231 (100), 213 (22), 203 (17); HRMS 249.1490,
1
C
15H21O3 required 249.1491; H NMR (400 MHz) δ 6.19 (1H,
d, J ) 3.2), 5.50 (1H, d, J ) 3.2), 5.07 (2H, br s), 3.82 (1H,
ddd, J ) 4.8, 10.4, 11.6), 3.15-3.05 (1H, m), 3.08 (1H, dd, J )
4.8, 12.0), 2.62 (1H, ddt, J ) 3.2, 10.0, 10.4), 2.28 (1H, dd, J )
11.6, 12.0), 2.17 (1H, ddd, J ) 5.2, 10.0, 13.2), 2.06 (1H, dd, J
) 5.2, 14.0), 1.94-1.66 (4H, m), 1.19 (3H, s), 1.10 (1H, ddd, J
) 10.0, 13.2, 14.0).
Ack n ow led gm en t. Financial support from the Eu-
ropean Commission (Grant FAIR CT96-1781) and from
the Direccio´n General de Investigacio´n Cient´ıfica y
Te´cnica (DGICYT; Grant PB 94-0985) is gratefully
acknowledged. V.B. and A.M.C. are especially thankful
to the Conselleria de Cultura, Educacio´ i Ciencia (Gen-
eralitat Valenciana), and European Commission, re-
spectively, for a grant.
1
1775 cm-1; H NMR (200 MHz) δ 7.65-7.50 (2H, m), 7.35-
7.20 (3H, m), 5.10 (1H, br s), 5.02 (1H, br s), 3.91 (1H, ddd, J
) 4.4, 10.8, 11.2), 3.46 (1H, dd, J ) 7.0, 13.2), 3.05 (1H, dd, J
) 4.4, 11.5), 2.82 (1H, br q, J ) 9.0), 2.61 (1H, quint, J ) 7.8),
2.30-1.90 (5H m), 1.81 (1H, dd, J ) 4.4, 13.5), 1.13 (3H, d, J
) 7.8), 1.07 (3H, s).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 3-25 and details of the X-ray data for
compound 9 with a labeled ORTEP diagram. This material is
available free of charge via the Internet at http://pubs.acs.org.
4r-H yd r oxy-1,5,7,11rH ,8âH -gu a i-10(14)-en -8,12-olid e
(24). From hydroxy selenide 23 (28 mg, 0.068 mmol) and
according to the procedure for the synthesis of 17 was obtained
J O991756N