Stereoselective synthesis of (+)-11βH,13-dihydroestafiatin, (+)-11βH,13-dihydroludartin, (-)-compressanolide, and (-)-11βH,13-dihydromicheliolide from santonin

Article abstract of DOI:10.1021/np020109f

Starting from 2 and 3, obtained from santonin (1), we have synthesized natural guaianolides 4-7. Chemoselective epoxidation of 2 gave (+)-11βH,13-dihydroestafiatin (4), and epoxidation of 3 followed by regioselective elimination of the hydroxyl group afforded (+)-11βH,13-dihydroludartin (5). Sharpless' mild regioselective ring-opening of 4 and 5 followed by hydrogenolysis yielded (-)-compressanolide (6) and (-)-11βH,13-dihydromicheliolide (7), respectively.

Full text of DOI:10.1021/np020109f

J . Nat. Prod. 2002, 65, 1703-1706
1703
Ster eoselective Syn th esis of (+)-11âH,13-Dih yd r oesta fia tin ,
(+)-11âH,13-Dih yd r olu d a r tin , (-)-Com p r essa n olid e, a n d
(-)-11âH,13-Dih yd r om ich eliolid e fr om Sa n ton in
Victoria Bargues, Gonzalo Blay, 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
Received March 13, 2002
Starting from 2 and 3, obtained from santonin (1), we have synthesized natural guaianolides 4-7.
Chemoselective epoxidation of 2 gave (+)-11âH,13-dihydroestafiatin (4), and epoxidation of 3 followed
by regioselective elimination of the hydroxyl group afforded (+)-11âH,13-dihydroludartin (5). Sharpless’
mild regioselective ring-opening of 4 and 5 followed by hydrogenolysis yielded (-)-compressanolide (6)
and (-)-11âH,13-dihydromicheliolide (7), respectively.
The guaianolides represent one of the largest groups of
sesquiterpene lactones with over 500 known naturally
occurring compounds.1,2 On account of the wide spectrum
of their biological activities1,2 and their low availability from
natural sources, synthetic approaches to the guaianolides
have received much attention during the past years.3,4
However, the total synthesis of the hydroazulene frame-
work with the desired stereochemistry presents many
difficulties, and only a few successful total syntheses of
guaianolides have been reported in the literature.3-8
Several short biomimetic syntheses of guaianolides from
suitably functionalized natural germacranolides have also
been reported in the literature.1-3 However, this is not an
efficient synthetic approach, as either germacranolides are
not easily available in sufficient amounts or the reactions
afford frequently complex mixtures and poor yields.
Santonin (1), a commercially available natural eudes-
manolide that possesses a trans-6R,12-lactone moiety,
constitutes a good starting material for the syntheses of
guaianolides.3,4 In these syntheses the transformation of
eudesmane to guaiane skeleton has been carried out
through photochemical rearrangement of the cross-conju-
gated dienone system of santonin3,4,9 or solvolytic rear-
rangement of 1â-tosyloxy or 1â-mesyloxy trans-decalin
derivatives prepared from 1.3,4,10 As a continuation of our
research program on the synthesis of biologically active
sesquiterpenoids, we have carried out the synthesis of
several natural guaianolides from santonin (1) through
photochemical rearrangement.11-14 In a previous paper11
we reported a synthesis of guaianolide 2 (isocostus lactone)
and 3 from 1 that improved significantly on earlier
reports.15-17 With these compounds as intermediates, a
straightforward approach to the synthesis of other 6,12-
guaianolides was possible and we report herein the syn-
thesis of (+)-dihydroestafiatin (4), (+)-dihydroludartin (5),
(-)-compressanolide (6), and (-)-dihydromicheliolide (7).
Dihydroestafiatin (4) and dihydroludartin (5) are two
natural products isolated from Artemisia adamsii18 and A.
carruthii,19 respectively. Ando’s group has carried out the
synthesis of both compounds from santonin (1) through a
long sequence (14 steps) that afforded 4 and 5 in low yields
(1.5% and 0.5%, respectively).17 Compressanolide (6) was
first isolated from Michelia compressa,20 and a compound
with structure 7 (dihydromicheliolide) was assigned to a
natural product named 2,3-dihydrodesacetoxymatricarin
that was isolated from Achillea millefolium ssp. collina.21
Both 6 and 7 are well-known products of acid cyclization
of dihydroparthenolide.20,22 Compressanolide (6) has also
been obtained by cyclization of gallicin,23 and dihydromich-
* Corresponding author. Tel: +34-963864329. Fax: +34-963864328.
E-mail: jose.r.pedro@uv.es.
10.1021/np020109f CCC: $22.00
© 2002 American Chemical Society and American Society of Pharmacognosy
Published on Web 09/14/2002

1704 J ournal of Natural Products, 2002, Vol. 65, No. 11
Notes
Sch em e 1a
eliolide (7) has been obtained by solvolysis of a 4R-hydroxy-
1â-tosyl derivative of vulgarin.23
of hydroxy alkene 3. Thus, treatment of 3 with m-CPBA
in the previously mentioned conditions gave a mixture of
R- and â-epoxides in a ratio of 2.5:1 (84% yield). This ratio
was improved to about 4:1 with the use of magnesium
monoperoxyphthalate (MMPP),26 a bulkier reagent, and in
these conditions a mixture of R-epoxide 9 (74%) and
â-epoxide 10 (19%) was obtained. The stereochemistry of
the oxirane ring was assigned on the basis of the chemical
shifts of H-6, with reference to those of compound 311 in
In our approach to the synthesis of (-)-compressanolide
(6) and (-)-dihydromicheliolide (7), the 4R-OH group was
introduced by Sharpless’ mild regioselective opening of the
corresponding 3R,4R-epoxides 4 and 5, respectively. Iso-
costus lactone (2) was the starting material for the prepa-
ration of compounds 4 and 6. The simplest approach to 4
was the chemo- and stereoselective epoxidation of diene 2.
We have carried out this transformation by treatment of 2
with m-chloroperbenzoic acid (m-CPBA) at -10 °C, obtain-
ing 4 in 60% yield (6.8% overall yield from santonin). This
compound results from the approach of the epoxidizing
agent by the R-face of the molecule as a consequence of its
concave shape due to the cis-ring fusion and is in agree-
ment with our previous reports on the epoxidation of
related compounds.12,13 The spectral data for our synthetic
4 were coincident with those described for the natural18
and synthetic17 11âH,13-dihydroestafiatin. To obtain (-)-
compressanolide (6), we carried out the following two-step
sequence, which has proved useful in the synthesis of 4R-
OH guaianolides from the corresponding 3R,4R-epoxides.12,13
Mild regioselective cleavage of the oxirane ring by treat-
ment of 4 with PhSeNa/Ti(i-PrO)4/DMF24 gave hydroxy-
phenylselenide 8 in 92% yield, which by hydrogenolysis of
the C-Se bond with carefully deactivated Raney Ni25
afforded 6 in 65% yield. Starting material 8 was recovered
(18%), but attempts to improve the conversion were unsuc-
cessful, as the ∆10,14 double bond was too reactive and
mixtures of 6 and its 10,14-dihydroderivatives were iso-
lated in stronger conditions. The spectral data of our
synthetic compound were fully consistent with those re-
ported for the natural product isolated from Michelia
compressa20 and with those reported for the synthetic
compound obtained by cyclization of dihydropartheno-
lide20,22 or gallicin.23
1
their H NMR spectra.17,27 Proton H-6 (which appears at δ
4.09 in compound 3) shows a downfield shift to δ 4.31 in
compound 10 due to the deshielding effect of the oxirane
ring, whereas in compound 9 it appears at δ 3.96, a
highfield shift that can be due to steric compression of the
C4-Me with a â-orientation in the R-epoxide. These assign-
ments were confirmed by NOE experiments. Compound 9
shows a positive NOE among H6 and H3, H2′ and H15
,
whereas compound 10 shows a clear positive NOE only
among H6 and H14. The formation of the C1-C10 double
bond was achieved regioselectively by treatment of com-
pound 9 with triflic anhydride (Tf2O)/pyridine in CH2Cl2.11
The best results were obtained overnight at room temper-
ature and afforded the expected tetrasubstituted alkene 5
in 66% yield (8.6 overall yield from santonin). The NMR
spectra of 5 were consistent with its structure and were
identical to the reported data for the natural19 and
synthetic17b,27 11âH,13-dihydroludartin. Regioselective open-
ing of the C3-C4 oxirane ring with PhSeNa/Ti(i-PrO)4/DMF
followed by hydrogenolysis of the C-Se bond with deacti-
vated Raney Ni gave compound 7 (67% yield for the two
steps). The spectral and physical data for 7 were fully
coincident with those reported for the synthetic (-)-11âH,-
13-dihydromicheliolide,20,22,23 but clearly differ from those
for the natural product isolated from Achillea millefolia21
in the chemical shifts for H-5, H-6, H-11, H-14, and H-15.
In our synthetic compound H5 appears at δ 2.62 and in
the natural product at δ 2.36, whereas H6, H11, H14, and
H15 appear at higher field (δ 3.80, 2.24, 1.66, and 1.28,
respectively) in comparison with those of the natural
product (δ 4.27, 2.69, 1.72, and 1.44, respectively).
For the synthesis of the ∆1,10 isomers 5 and 7 the starting
material was hydroxyalkene 3. As a tetrasubstituted double
bond would react faster toward electrophilic reagents than
the trisubstituted C3-C4, the first step was the epoxidation

Notes
In summary, an efficient procedure for the preparation
J ournal of Natural Products, 2002, Vol. 65, No. 11 1705
13.4 Hz, H-3), 2.85 (1H, br dt, J ) 10.3, 12.0 Hz, H-1), 2.63
(1H, dt, J ) 3.5, 13.0 Hz, H-9), 2.29 (1H, dd, J ) 10.6, 12.7
Hz, H-5), 2.18 (1H, dq, J ) 7.0, 11.6 Hz, H-11), 2.20-1.95 (3H,
m, 2H-2, H-8), 1.95-1.75 (2H, m, H-7, H-9′), 1.31 (3H, s, 3H-
15), 1.40-1.10 (1H, m, H-8′), 1.21 (3H, d, J ) 7.0 Hz, 3H-13);
13C NMR (50.3 MHz) δ 177.8, 147.2 (C, C-12, C-10), 134.0,
128.9 (CH, Ar), 128.9 (C, Ar), 127.1 (CH, Ar), 112.5 (CH2, C-14),
83.3 (CH, C-6), 80.4 (C, C-4), 54.7, 53.5, 51.4, 41.8, 41.3 (CH,
C-1, C-3, C-5, C-7, C-11), 39.6, 34.9, 32.8 (CH2, C-2, C-8, C-9),
21.1, 13.2 (CH3, C-13, C-15).
of compounds 4-7 from santonin (1) has been developed,
which clearly improves on earlier reports of the syntheses
of these compounds. Our method is based in the selective
transformation of 10R-hydroxy-∆3,4-guaianolides into 4R-
hydroxy-∆1,10-guaianolides or 4R-hydroxy-∆10,14-guaiano-
lides through mild regioselective opening of the correspond-
ing 3R,4R-epoxides. As a consequence of these syntheses,
the structures of natural products 4-6 have been con-
firmed, while the structure 7 appears to be inconsistent
with the data previously reported for the natural product
isolated from A. millefolia.21
(-)-4r-H yd r oxy-1,5,7rH ,6,11âH -gu a i-10(14)-e n -6,12-
olid e (6) [(-)-Com p r essa n olid e]. Hydroxy selenide 8 (30 mg,
0.74 mmol) in EtOH (0.7 mL) was treated with deactivated
ethanolic W-2 Raney Ni (0.9 mL, ca. 0.5 g) at room tempera-
ture. After 30 min the mixture was filtered through a short
plug of silica gel (EtOAc) and the solvent was evaporated at
reduced pressure. Chromatography of the residue (7:3 hex-
anes-EtOAc) afforded 5 mg (18%) of starting material and
12 mg (65%) of compound 6 with the following features:
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. All reactions involv-
ing air or moisture sensitive materials were carried out under
argon atmosphere. Commercial reagents and solvents were
analytical grade or were purified by standard procedures prior
to use. W-2 Raney Ni was prepared according to Mozingo’s
procedure28 and deactivated by heating the ethanolic suspen-
sion at 60 °C for 3-4 days. Column chromatography was
performed using silica gel (SDS, 40-60 µm). All melting points
are uncorrected. Optical rotations were measured in CHCl3
using a Perkin-Elmer 234 or a Polartronic D (Schmidt and
Haensch) polarimeter. IR spectra were recorded as liquid films
in NaCl for oils and as KBr disks for solids using a BIO-RAD
Digilab Division FTS-7 unit. NMR spectra were run in CDCl3,
and chemical shifts were reported in ppm units and referenced
colorless oil; [R]22 -3.6° (c 0.61); IR (NaCl) νmax 3540-3360,
D
1770, 1640, 1170, 892 cm-1; 1H NMR (400 MHz) δ 4.96 (1H, s,
H-14), 4.93 (1H, s, H-14′), 4.03 (1H, dd, J ) 9.6, 11.7 Hz, H-6),
2.96 (1H, dd, J ) 8.8, 12.4 Hz, H-1), 2.63 (1H, dt, J ) 4.0, 12.8
Hz, H-9), 2.24 (1H, dd, J ) 10.0, 12.0 Hz, H-5), 2.22 (1H, dq,
J ) 6.8, 12.0 Hz, H-11), 2.25-2.18 (1H, m, H-3), 2.10 (1H, dq,
J ) 3.6, 13.0 Hz, H-8), 1.90-1.70 (5H, m, 2H-2, H-3′, H-7,
H-9′), 1.28 (3H, s, 3H-15), 1.30-1.20 (1H, m, H-8′), 1.22 (3H,
d, J ) 6.8 Hz, 3H-13); 13C NMR (50.3 MHz) δ 178.1, 148.5 (C,
C-12, C-10), 112.0 (CH2, C-14), 83.9 (CH, C-6), 79.8 (C, C-4),
55.6, 51.6, 44.1, 41.4 (CH, C-1, C-5, C-7, C-11), 40.2, 39.5, 32.9,
26.3 (CH2, C-2, C-3, C-8, C-9), 24.1, 13.2 (CH3, C-13, C-15);
EIMS m/z 250 (M+, 5), 232 (12), 159 (14), 119 (47), 43 (100).
1
1
to the solvent as internal standard. H spectra including H-
1H decoupling experiments were recorded with a Bruker AC
200 or a Varian Unity 400 spectrometer. 13C NMR spectra
including DEPT experiments were recorded with a Brucker
AC 200 spectrometer at 50.3 MHz. Mass spectra were obtained
with a Fisons Instruments VG Autospec, GC 8000 series
spectrometer at 70 eV for electron impact or with methane as
ionizing gas for CI. Compounds 2 and 3 were prepared
according to our previously described procedure.11
(-)-3r,4r-E p oxy-10r-h yd r oxy-1,5,7rH ,6,11âH -gu a ia n -
6,12-olide (9) an d (+)-3â,4â-Epoxy-10r-h ydr oxy-1,5,7rH,6,-
11âH-gu a ia n -6,12-olid e (10). To a solution of compound 3
(436 mg, 1.74 mmol) in MeOH (11.2 mL) was added MMPP
(1.55 g, 3.49 mmol), and the mixture was stirred 5 h 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
(4:6 to 2:8 hexanes-EtOAc) afforded 343 mg (74%) of com-
pound 9 and 88 mg (19%) of compound 10. Data for 9: white
(+)-3r,4r-E p oxy-1,5,7rH ,6,11âH -gu a i-1(14)-e n -6,12-
olid e (4) [(+)-11âH,13-Dih yd r oesta fia tin ]. To a precooled
(-10 °C) solution of compound 2 (70 mg, 0.30 mmol) in CHCl3
(3.6 mL) was added 86% m-CPBA (73 mg, 0.96 mmol), and
the mixture was stirred at this temperature 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. The combined extract
was dried (Na2SO4), filtered, and concentrated under reduced
pressure to leave an oil, which after chromatography (9:1 to
7:3 hexanes-EtOAc) afforded 5 mg (7%) of starting diene 2
and 45 mg (60%) of R-epoxide 4: white crystals, mp 92-93 °C
crystals, mp 118-120 °C (hexanes-EtOAc); [R]20 -13.3° (c
D
1.50); IR (KBr) νmax 3540-3370, 1762, 1174, 989 cm-1; 1H NMR
(400 MHz) δ 3.96 (1H, t, J ) 10.6 Hz, H-6), 3.26 (1H, br s,
H-3), 2.55 (1H, dtd, J ) 6.4, 10.6, 11.2 Hz, H-7), 2.31 (1H, dd,
J ) 7.6, 10.6 Hz, H-5), 2.25-2.03 (3H, m, H-1, H-8, H-11), 2.00
(1H, dd, J ) 6.8, 13.6 Hz, H-2), 1.80-1.60 (3H, m, H-9, H-9′,
-OH), 1.54 (3H, s, 3H-15), 1.49 (1H, t, J ) 12.4 Hz, H-2′),
1.40-1.25 (1H, m, H-8′), 1.19 (3H, s, 3H-14), 1.17 (3H, d, J )
7.2 Hz, 3H-13); 13C NMR (50.3 MHz) δ 178.6 (C, C-12), 80.8
(CH, C-6), 73.4, 65.8 (C, C-10, C-4), 61.6, 48.9, 48.3, 46.4, 43.1
(CH, C-1, C-3, C-5, C-7, C-11), 33.5 (CH3, C-14), 31.2, 30.6,
25.3 (CH2, C-2, C-8, C-9), 19.1, 13.1 (CH3, C-13, C-15); CIMS
m/z 267 (M+ + 1, 22), 266 (M+, 5), 251 (27), 249 (100), 231
(50), 203 (52); CIHRMS 267.1605 (M+ + 1) (calcd for C15H23O4,
267.1596). Data for 10: white crystals, mp 116-119 °C
(hexanes-EtOAc); [R]22 +2.7° (c 1.46); IR (KBr) νmax 1760,
D
1640, 1170 cm-1
;
1H NMR (400 MHz), see ref 17; 13C NMR
(50.3 MHz) δ 178.3, 147.3 (C, C-12, C-10), 114.1 (CH2, C-14),
80.7 (CH, C-6), 66.0 (C, C-4), 63.1, 50.4, 49.9, 44.2, 41.9 (CH,
C-1, C-3, C-5, C-7, C-11), 33.6, 30.9, 30.9 (CH2, C-2, C-8, C-9),
18.7, 13.2 (CH3, C-13, C-15); EIMS m/z 248 (M+, 30), 233 (77),
205 (20), 175 (40), 131 (51), 97 (100).
(hexanes-EtOAc); [R]21 +15.3° (c 1.44); IR (KBr) νmax 3560-
D
3â-P h en ylselen yl-4r-h yd r oxy-1,5,7rH,6,11âH-gu a i-10-
(14)-en -6,12-olid e (8). To a mixture of NaBH4 (18 mg, 0.47
mmol) and PhSeSePh (133 mg, 0.40 mmol) under Ar was
added DMF (1 mL), and the suspension was stirred at room
temperature for 2 h. To the resulting solution were added via
syringe AcOH (11 µL, 0.19 mmol), compound 4 (35 mg, 0.14
mmol) in DMF (1.7 mL), and Ti(i-PrO)4 (54 µL, 0.18 mmol),
and the mixture was stirred at room temperature for 23 h.
After this time, the reaction was quenched with water and
extracted with EtOAc. Usual workup and chromatography (5:5
hexanes-EtOAc) afforded 53 mg (92%) of hydroxy selenide 8:
yellow oil; IR (NaCl) νmax 3530-3340, 1760, 1640, 1170, 890
cm-1; 1H NMR (200 MHz) δ 7.70-7.60 (2H, m, 2Ar-H), 7.25-
7.20 (3H, m, 3Ar-H), 4.97 (1H, s, H-14), 4.92 (1H, s, H-14′),
4.06 (1H, dd, J ) 9.7, 10.6 Hz, H-6), 3.57 (1H, dd, J ) 7.0,
3340, 1763, 1174, 980 cm-1; 1H NMR (400 MHz) δ 4.31 (1H, t,
J ) 10.2 Hz, H-6), 3.20 (1H, d, J ) 1.4 Hz, H-3), 2.46 (1H, td,
J ) 2.4, 10.4 Hz, H-1), 2.39 (1H, t, J ) 10.4 Hz, H-5), 2.29
(1H, dd, J ) 2.4, 16.0 Hz, H-2), 2.20 (1H, dq, J ) 6.8, 12.0 Hz,
H-11), 2.00 (1H, br dd, J ) 10.4, 16.0 Hz, H-2′), 1.86 (2H, br
d, J ) 16.0 Hz, 2H-9), 1.66 (1H, br q, J ) 10.4 Hz, H-7), 1.55-
1.40 (1H, m, H-8), 1.49 (3H, s, 3H-15), 1.40-1.16 (1H, m, H-8′),
1.20 (3H, d, J ) 6.8 Hz, 3H-13), 1.14 (3H, s, 3H-14); 13C NMR
(50.3 MHz) δ 178.3 (C, C-12), 82.6 (CH, C-6), 74.9, 67.2 (C,
C-4, C-10), 65.1, 50.8, 50.4, 49.7 (CH, C-1, C-3, C-5, C-7), 45.1
(CH2, C-2), 41.4 (CH, C-11), 29.5, 26.3 (CH2, C-8, C-9), 24.3,
18.0, 12.7 (CH3, C-13, C-14, C-15) CIMS m/z 267 (M+ + 1, 15),
251 (31), 249 (100), 231 (92), 203 (60); CIHRMS 267.1593 (M+
+ 1) (calcd for C15H23O4, 267.1596).

1706 J ournal of Natural Products, 2002, Vol. 65, No. 11
Notes
(+)-3r,4r-E p o x y -5,7rH ,6,11âH -g u a i-(1,10)-e n -6,12-
olid e (5) [(+)-11âH,13-Dih yd r olu d a r tin ]. To a solution of
compound 9 (102 mg, 0.38 mmol) and pyridine (0.48 mL, 5.74
mmol) in CH2Cl2 (8.7 mL) at 0 °C and under argon was added
dropwise via syringe triflic anhydride (0.4 mL, 2.37 mmol),
and the mixture was stirred overnight at room temperature.
The reaction was quenched with aqueous saturated NaHCO3
and after usual workup (CH2Cl2) and chromatography (4:6 to
2:8 hexanes-EtOAc) afforded 10 mg (10%) of starting material
Ack n ow led gm en t. Financial support from the European
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 especially
thankful to Conselleria de Cultura, Educacio´ i Ciencia (Gen-
eralitat Valenciana) for a grant.
Refer en ces a n d Notes
and 62 mg (66%) of compound 5: colorless oil; [R]22 +8.5° (c
(1) Connolly, J . D.; Hill, R. A., Dictionary of Terpenoids Vol 1, Mono-
and Sesquiterpenoids; Chapman & Hall: London, 1991; pp 476-523.
(2) (a) Roberts, J . S.; Bryson, I. Nat. Prod. Rep. 1984, 1, 105-169. (b)
Fraga, B. M. Nat. Prod. Rep. 1985, 2, 147-161; 1986, 3, 273-296;
1987, 4, 473-498; 1988, 5, 497-521; 1990, 7, 61-84; 1990, 7, 515-
537; 1993, 9, 217-241; 1992, 9, 557-580; 1993, 10, 397-419; 1994,
11, 533-554; 1995, 12, 303-320; 1996, 13, 307-326; 1997, 14, 145-
162; 1998, 15, 73-92; 1999, 16, 21-38; 1999, 16, 711-730; 2000,
17, 483-504; 2001, 18, 650-673.
(3) (a) Heathcock, C. H. In The Total Synthesis of Natural Products Vol
2; Apsimon, J . Ed.; Wiley-Interscience: New York, 1973; pp 197-
558. (b) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. In The Total Synthesis of Natural Products Vol 5;
Apsimon, J ., Ed.; Wiley-Interscience: New York, 1983. (c) Pirrung,
M. C. In The Total Synthesis of Natural Products Vol 11; Goldsmith,
D., Ed.; Wiley-Interscience: New York, 2000. (d) Roberts, J . S. Nat.
Prod. Rep. 1985, 2, 97-145.
D
0.46); IR (NaCl) νmax 1774, 999 cm-1
;
1H NMR (200 MHz) δ
3.63 (1H, dd, J ) 8.8, 10.2 Hz, H-6), 3.36 (1H, br s, H-3), 2.97
(1H, br d, J ) 10.0 Hz, H-5), 2.69 (1H, br d, J ) 17.8 Hz, H-2),
2.41 (1H, d quint., J ) 1.5, 17.8 Hz, H-2′), 2.19 (1H, dq, J )
7.0, 12.3 Hz, H-11), 2.20-2.00 (2H, m, 2H-9), 1.90-1.70 (2H,
m, H-8, H-7), 1.66 (3H, d, J ) 1.1 Hz, 3H-14), 1.60 (3H, s, 3H-
15), 1.40-1.25 (1H, m, H-8′), 1.20 (3H, d, J ) 7.0 Hz, 3H-13);
13C NMR (50.3 MHz) δ 178.1, 135.3, 133.4 (C, C-12, C-1, C-10),
80.4 (CH, C-6), 67.2 (C, C-4), 63.8, 57.6, 51.9, 41.3 (CH, C-3,
C-5, C-7, C-11), 34.4, 33.5, 27.4 (CH2, C-2, C-8, C-9), 22.5, 19.1,
12.2 (CH3, C-13, C-14, C-15); EIMS m/z 248 (M+, 5), 233 (11),
205 (5), 152 (8), 95 (100).
3â-P h en ylselen yl-4r-h yd r oxy-5,7rH,6,11âH-gu a i-1(10)-
en -6,12-olid e (11). The reagent was prepared as reported with
NaBH4 (12 mg, 0.31 mmol), PhSeSePh (87 mg, 0.26 mmol),
and DMF (0.6 mL).To the resulting solution were added via
syringe AcOH (8 µL, 0.14 mmol), R-epoxide 5 (20 mg, 0.08
mmol) in DMF (1 mL), and Ti(i-PrO)4 (31 µL, 0.10 mmol), and
the mixture was stirred at room temperature for 18 h. After
this time, the reaction was quenched with water and extracted
with EtOAc. Usual workup and chromatography (8:2 to 6:4
hexanes-EtOAc) afforded 2 mg (10%) of starting material 5
and 24 mg (74%) of compound 11: yellow crystals, mp 152-
154 °C (hexanes-EtOAc); IR (KBr) νmax 3524-3400, 1774,
1180, 985 cm-1; 1H NMR (200 MHz) δ 7.70-7.60 (2H, m, 2Ar-
H), 7.25-7.20 (3H, m, 3Ar-H), 3.81 (1H, t, J ) 10.1 Hz, H-6),
3.52 (1H, dd, J ) 8.1, 13.0 Hz, H-3), 2.81 (1H, br dd, J ) 8.1,
16.5 Hz, H-2), 2.69 (1H, br d, J ) 10.0 Hz, H-5), 2.50-2.10
(4H, m, H-2′, H-8, H-9, H-11), 1.95-1.65 (2H, m, H-7, H-9′),
1.64 (3H, d, J ) 1.3 Hz, 3H-14), 1.35 (3H, s, 3H-15), 1.35-
1.20 (1H, m, H-8′), 1.22 (3H, d, J ) 7.0 Hz, 3H-13); 13C NMR
(50.3 MHz) δ 177.8 (C, C-12), 133.8 (CH, Ar), 132.0, 129.9 (C,
C-1, C-10), 128.9 (CH, Ar), 128.8 (C, Ar), 127.1, 83.5 (CH, Ar,
C-6), 81.1 (C, C-4), 57.9, 52.2, 53.5, 41.0 (CH, C-3, C-5, C-7,
C-11), 39.1, 35.2, 26.8 (CH2, C-2, C-8, C-9), 23.8, 20.0, 12.3
(CH3, C-13, C-14, C-15).
(4) Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R. In Studies in Natural
Products Chemistry Vol 24; Atta-ur-Rahman, Ed.; Elsevier Science:
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7438-7435.
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4527-4540. (b) Arigoni, D.; Bosshard, H.; Bruderer, H.; Bu¨chi, G.;
J eger, O.; Krebaum, L. J . Helv. Chim. Acta 1957, 11, 1732-1748.
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Chem. 2000, 2145-2151.
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159-160. (b) Delair, P.; Kann, N.; Greene, A. E. J . Chem. Soc., Perkin
Trans. 1 1994, 1651-1652.
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445.
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17, 957-961.
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1266.
(-)-4r-H y d r o x y -5,7rH ,6,11âH -g u a i-1(10)-e n -6,12-
olid e (7) [(-)-11âH,13-Dih yd r om ich eliolid e]. Hydroxy se-
lenide 11 (16 mg, 0.039 mmol) in EtOH (0.3 mL) was treated
with deactivated ethanolic W-2 Raney Ni (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 7
(9 mg, 90%): white crystals, mp 124-126 °C (hexanes-EtOAc)
[lit.22a 124-127 °C (CHCl3)]; [R]22D -4.7° (c 0.68) [lit.23 [R]D -8°
1
(c 0.25)]; IR (KBr) νmax 3600-3400, 1775, 1181, 987 cm-1; H
NMR (400 MHz) δ 3.80 (1H, t, J ) 10.5 Hz, H-6), 2.62 (1H, br
d, J ) 10.5 Hz, H-5), 2.59 (1H, br s, OH), 2.38 (1H, br dd, J )
8.0, 17.4 Hz, H-2), 2.24 (1H, dq, J ) 6.8, 12.0 Hz, H-11), 2.20-
2.10 (3H, m, H-3, 2H-9), 1.90-1.84 (1H, m, H-8), 1.84-1.70
(3H, m, H-2′, H-3′, H-7), 1.66 (3H, d, J ) 1.6 Hz, 3H-14), 1.28
(3H, s, 3H-15), 1.26-1.20 (1H, m, H-8′), 1.22 (3H, d, J ) 6.8
Hz, 3H-13); 13C NMR (50.3 MHz) δ 178.2 (C, C-12), 131.9 (CH,
C-1), 131.1 (C, C-10), 84.1 (CH, C-6), 80.2 (C, C-4), 58.2, 53.5,
41.1 (CH, C-5, C-7, C-11), 35.2, 30.0, 27.0 (CH2, C-2, C-8, C-9),
23.7, 22.8, 12.3 (CH3, C-13, C-14, C-15); CIMS m/z 250 (M+,7),
234 (31), 233 (100), 232 (41), 159 (57); CIHRMS 250.2589 (M+)
(calcd for C15H22O3 250.1568).
(23) Gonza´lez, A. G.; Galindo, A.; Mansilla, H. Tetrahedron 1980, 36,
2015-2017.
(24) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557-1560.
(25) Sevrin, M.; Van Ende, D.; Krief, A. Tetrahedron Lett. 1976, 2643-
2646.
(26) Broghman, P.; Cooper, M. S.; Cunmerson, D. A.; Heaney, H.;
Thompson, N. Synthesis 1987, 1015-1017.
(27) Sosa, V. E.; Oberti, J . C.; Gil, R. R.; Ru´veda, E. A.; Goedken, V. L.;
Gutie´rrez, A. B.; Herz, W. Phytochemistry 1989, 28, 1925-1929.
(28) (a) Mozingo, R. Organic Syntheses; Wiley & Sons: New York, 1955;
Collect. Vol. III, pp 181-183. (b) W-2 Raney Ni was deactivated by
heating the ethanolic suspension at 60 °C for 3-4 days.
NP020109F