Synthesis of plagiochiline N from santonin

Article abstract of DOI:10.1021/jo010567d

This article reports the transformation of O-acetylisophotosantonin, obtained by photochemical rearrangement of santonin, into plagiochiline N, an ent-2,3-secoaromadendrane isolated from Plagiochila ovalifolia. The synthesis was carried out in a sequence involving as the key steps (a) the substitution of the lactone moeity by a gem-dimethylcyclopropane ring through a synthetic intermediate having a C₆-C₇ double bond and (b) the ozonolysis of the C₂-C₃ bond followed by cyclization to the dihydropyran ring characteristic of plagiochiline N. Spectroscopic data of the synthetic product fully coincide with the reported data for the natural product.

Full text of DOI:10.1021/jo010567d

7700
J . Org. Chem. 2001, 66, 7700-7705
Syn th esis of P la gioch ilin e N fr om Sa n ton in
Gonzalo Blay, Luz Cardona, Begon˜a Garc´ıa, Luisa Lahoz, and J ose´ R. Pedro*
Departament de Quı´mica Orga`nica, Facultat de Qu´ımica, Universitat de Vale`ncia,
E-46100 Burjassot, Vale`ncia, Spain
jose.r.pedro@uv.es
Received J une 5, 2001
This article reports the transformation of O-acetylisophotosantonin, obtained by photochemical
rearrangement of santonin, into plagiochiline N, an ent-2,3-secoaromadendrane isolated from
Plagiochila ovalifolia. The synthesis was carried out in a sequence involving as the key steps (a)
the substitution of the lactone moiety by a gem-dimethylcyclopropane ring through a synthetic
intermediate having a C6-C7 double bond and (b) the ozonolysis of the C2-C3 bond followed by
cyclization to the dihydropyran ring characteristic of plagiochiline N. Spectroscopic data of the
synthetic product fully coincided with the reported data for the natural product.
In tr od u ction
current synthetic program toward sesquiterpenolides and
oxacyclic terpenoids,8 we report in this paper the first
synthesis of plagiochiline N (3), a product isolated from
Plagiochila ovalifolia,9 whose pyran ring bears a latent
unsaturated dialdehyde moiety masked as a cyclic enol
ether.
The genus Plagiochila is one of the largest liverwort
genera distributed worldwide.1 The genus includes more
than 3000 species, which are classified into two groups:
pungent and nonpungent species.2 The hot taste of the
former is due to the presence of unique ent-2,3-secoaro-
madendrane-type sesquiterpenes, while the nonpungent
species produce mainly aromatic compounds such as
bibenzyls or different types of sesqui- and diterpenes.
These compounds are important not only from the
taxonomic point of view but also because some of them
have interesting biological activities. Thus, some secoaro-
madendrane-type compounds have shown insect anti-
feedant,3 plant growth inhibitory4 or neurotrophic5 prop-
erties, as well as strong cytotoxic activity against P-388
murine leukemia.6 Furthermore, it has been suggested
that some relationship may exist between the pungency
and biological activity of these products and the occur-
rence of an actual or latent unsaturated dialdehyde
moiety in their molecules, in the same way as in other
hot-tasting bioactive compounds such as velleral (4) and
poligodial (5).7
Resu lts a n d Discu ssion
Aromadendrane sesquiterpenes are characterized by
a tricyclo[6,3,0,05,7]undecane skeleton. Although some
methods for the construction of such a system can be
found in the literature,10 they either start from materials
not easily available or do not give the proper stereochem-
istry and functionality for the synthesis of plagiochiline
N (3). For this reason we envisaged a synthesis of
plagiochiline N (3) starting from O-acetylisophotosanto-
nin (2), a compound with a bicyclo[5,3,0]decane skeleton
that can be easily obtained by photochemical rearrange-
ment of santonin (1) in a well-known procedure.8,11
Further transformation of compound 2 into plagiochiline
N (3) should involve the substitution of the lactone moiety
by a gem-dimethylcyclopropane ring between C6-C7 by
one hand, and transformation of the cyclopentane ring
into a dihydropyran by the other. For the first part, since
the stereochemistry of C7 in compound 2 was the opposite
of that of plagiochiline N (3), it became necessary to
The unique structures presented by the ent-2,3-
secoaromadendranes isolated from Plagiochila sp. as well
as the difficulties in obtaining sufficient amounts of plant
material from some species make the synthesis of these
compounds a worthwhile goal. As a continuation of our
(8) (a) Bargues, V.; Blay, G.; Cardona, L.; Garc´ıa, B.; Pedro, J . R.
Tetrahedron 1998, 54, 1845-1852. (b) Blay, G.; Bargues, V.; Cardona,
L.; Collado, A. M.; Garc´ıa, B.; Mun˜oz, M. C.; Pedro, J . R. J . Org. Chem.
2000, 65, 2138-2144. (c) Blay, G.; Cardona, L.; Garc´ıa, B.; Lahoz, L.;
Pedro, J . R. Eur. J . Org. Chem. 2000, 2145-2151. (d) Blay, G.;
Cardona, L.; Garc´ıa, B.; Lahoz, L.; Monje, B.; Pedro, J . R. Tetrahedron
2000, 56, 6331-6338. (e) Blay, G.; Bargues, V.; Cardona, L.; Garc´ıa,
B.; Pedro, J . R. J . Org. Chem. 2000, 65, 6703-6707.
* Corresponding author. Phone:
+34 963864328.
(1) Gradstein, S. R.; Reiner-Drehwald, M. E. Fragmenta Flora et
Geobotica 1995, 40, 31-32.
+34 963864329. Fax:
(2) (a) Asakawa, Y. In Progress in the Chemistry of Organic Natural
Products; Herz, W., Kirby, E. W., Moore, R. E., Steglich, W., Tamm,
C., Eds.; Springer: Wien, 1995; Vol. 65, p 1. (b) Asakawa, Y. In Progress
in the Chemistry of Organic Natural Products; Herz, W., Grisebach,
H., Kirby, E. W., Eds.; Springer: Wien, 1982; Vol. 42, p 1.
(3) Asakawa, Y.; Toyoto, M.; Takemoto, T; Kubo, I.; Nakanishi, K.
Phytochemistry 1980, 19, 2147-2154.
(9) Nagashima, F.; Tanaka, H.; Toyota, M.; Hashimoto, T.; Kan, Y.;
Takaoka, S.; Tori, M.; Asakawa, Y. Phytochemistry 1994, 36, 1425-
1430.
(10) (a) Pirrung, M. C.; Morehead, A. T.; Young, B. G. In The Total
Synthesis of Natural Products; Goldsmith, D., Ed.; J ohn Wiley &
Sons: New York, 2000; Vol. 11, pp 163-165. (b) Heathcock, C. H.;
Graham, S. C.; Pirrung, M. C.; Plavac, F.; White, C. T. In The Total
Synthesis of Natural Products; ApSimon, J . W., Ed.; J ohn Wiley &
Sons: New York, 1983; Vol. 5, pp 344-347. (c) Heathcock, C. H. In
The Total Synthesis of Natural Products; ApSimon, J . W., Ed.; J ohn
Wiley & Sons: Ney York, 1973; Vol. 2, pp 417-422.
(4) Matsuo, A.; Nadaya, K.; Nakayama, M.; Hayashi, S. Nippon
Kagakukai Zasshi 1981, 665-770.
(5) Fukuyama, Y.; Asakawa, Y. Phytochemistry 1991, 30, 4061-
4065.
(6) Toyota, M.; Tanimura, K.; Asakawa, Y. Planta Med. 1998, 64,
462-464.
(7) Hashimoto, T.; Tanaka, H.; Asakawa, Y. Chem. Pharm. Bull.
1994, 42, 1452-1454.
(11) Barton, D. H. R.; de Mayo, P.; Shafiq, M. J . Chem. Soc. 1957,
929-935.
10.1021/jo010567d CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/24/2001

Synthesis of Plagiochiline N from Santonin
J . Org. Chem., Vol. 66, No. 23, 2001 7701
tected, we undertook the formation of the C7-C11 double
bond. A one-step procedure that uses LDA and dibromo-
ethane failed in our case.14 This problem was solved by
carrying out the oxidation of C11 in compound 9 upon
treatment of the sodium enolate of the lactone carbonyl
group with 2-phenylsulfonyl-3-phenyloxaziridine (Davis’
reagent).15 In this way the 11â-alcohol 10a was obtained
as the major product in 83% yield together with 6% of
the R-alcohol 10b. Mesylation of the alcohol 10a with
MsCl in the presence of triethylamine followed by heating
with DBU at a toluene reflux temperature afforded the
unsaturated lactone 11 with complete regioselectivity and
in 66% overall yield. However, the same treatment with
alcohol 10b gave rise to a complicated mixture and,
therefore, this minor alcohol was not used. Once the
double bond was introduced at the desired position, we
proceeded to cleave it by ozonolysis. This reaction took
place smoothly and with a very high yield (94%) when
the ozonide was reduced with dimethyl sulfide to give
compound 12.16 In contrast, the use of hydrides such as
NaBH4 or LiAlH4 that usually bring about reduction to
the alcohol only led to complex mixtures. The next step
was aimed at reducing both the C7 and C12 carbonyl
groups to give a vic-diol that should allow the regiose-
lective introduction of a double bond in a later step.
Reduction of compound 12 yielded the two alcohols 13a
and 13b in different ratios and yields depending on the
reagent. The highest selectivity was found with DIBAH,
which gave only compound 13b, although in a moderate
yield (46%); LiAlH4 and Red-Al reagent were less selec-
tive, although they gave better yields: 13a /13b in ratios
of 27%/40% and 25%/59%, respectively. Finally, LiBH4
inverted the selectivity giving 42% of 13a and 38% of 13b.
The stereochemistry of C7 in compounds 13a and 13b was
inferred from the study of the coupling constants in the
1H NMR spectra and from NOE experiments. Thus, a
NOE between H6 (δ 3.64) and the C14 methyl group (δ
1.25), both in the â-side of the molecule, was observed in
compound 13a . This NOE was only possible when the
cycloheptane ring adopted a boatlike conformation. In
this conformation, H5 and H6 were disposed almost anti-
coplanar. A decoupling experiment involving irradiation
on the OH signal at δ 3.39 collapsed the H6 signal into a
triplet (J 5,6 ∼ J 6,7 ∼ 7.0 Hz), indicating a similar disposi-
tion of H5 and H7 with regard to H6. Therefore, we
assigned H7 the R-disposition in this compound. On the
other hand, the coupling constant J 5,6 in compound 13b
had a value near zero, which indicated a dihedral angle
of ∼90° between the C5-H and C6-H bonds. This fact
indicated a change in the cycloheptane ring conformation
compared with compound 13a , which we assumed to be
caused by a hydrogen bond between the C7-OH group
and the C10-O atom, both in the R-side of the molecule.
Observation of Dreiding models for this conformation
showed an almost syn coplanar disposition of the C6-H
and C7-H bonds that would account for the observed J 6,7
) 10.7 Hz, according to the Karplus-Conroy equation.
F igu r e 1. Structures of compounds 1-5.
remove the C11-C13 carbon fragment and to introduce
the gem-dimethylcyclopropane ring later by cyclopropa-
nation of a synthetic intermediate having a C6-C7 double
bond.
With these ideas in mind, we undertook the synthesis
of plagiochiline N (3) from O-acetylisophotosantonin (2).
In the first instance (Scheme 1), compound 6b was
obtained in 65% yield by hydrogenation of compound 2
with 10% Pd/C followed by epimerization of C4 with KOH
and relactonization with HCl following a procedure
described in the literature.12 On the other hand, com-
pound 6b could also be obtained in an improved 86% yield
from 2 by a two-step procedure that involved reduction
of 2 with NaTeH8a to give compound 6a followed by basic
hydrolysis of the acetate group. It should be noted that
in both procedures, hydrogenation of the double bond is
completely stereoselective and gives the compound with
the same configuration at C5 as that in the target
compound. Treatment of compound 6b with NaBH4 in
MeOH gave the major alcohol 7 in 93% yield. The
stereochemistry of the resulting alcohol was proposed on
the assumption of a preferred attack of the hydride from
the less hindered R-side of the molecule.13
From compound 7, the preparation of 2,3-secoaroma-
dendranes required elimination of the C3-hydroxyl group
to give a C2-C3 double bond by one hand, and transfor-
mation of the lactone ring into a C6-C7 double bond by
the other. To avoid interference of the C2-C3 double bond,
elimination of the C3-hydroxyl group was left for a later
stage in the synthetic sequence after the introduction of
the cyclopropane ring at the C6-C7 position. So, the next
steps addressed the removal of the C11-C13 carbon
fragment of the lactone ring. For this purpose, we decided
to introduce a C7-C11 double bond that could be subse-
quently cleaved by ozonolysis. Prior to this, we needed
to protect the hydroxyl groups. Treatment of compound
7 with excess TMSCl protected both hydroxyl groups as
TMS ethers. However, the TMS protecting group at the
C3-hydroxyl group was too labile and caused many
experimental difficulties during purification of the prod-
ucts. The use of two different protecting groups was much
more convenient. Thus, the C3-hydroxyl group was
protected as a TBDMS ether and the C10-hydroxyl group
as a TMS ether. Once the hydroxyl groups were pro-
The reduction of vic-diols to alkenes is a procedure
often used for the regioselective formation of double
(14) Delair, P.; Kann, N.; Greene, A. E. J . Chem. Soc., Perkin Trans.
1 1994, 1651-1652.
(15) Lauridsen, A.; Cornett, C.; Vulpius, T.; Moldt, P.; Christensen,
S. B. Acta Chem. Scand. 1996, 50, 150-157.
(16) Lin, J .; Nikaido, M. M.; Clark, G. J . Org. Chem. 1987, 52, 3745-
3752.
(12) Barton, D. H. R.; Levisalles, J . E. D.; Pinhey, J . T. J . Chem.
Soc. 1962, 3472-3482.
(13) During the preparation of this paper, a paper dealing with the
stereochemistry of related alcohols appeared: Garcia-Marrero, B.
Tetrahedron 2001, 57, 1297-1300.

7702 J . Org. Chem., Vol. 66, No. 23, 2001
Blay et al.
Sch em e 1a
a
Key: (a) hν/AcOH; (b) (1) NaTeH, (2) KOH, (3) HCl; (c) NaBH4; (d) TBDMSCl-imidazole; (e) TMSCl-Et3N; (f) Na(Me3Si)2-Davis’
reagent; (g) (1) MsCl, (2) DBU; (h) (1) O3, (2) Me2S; (i) RedAl reagent; (j) (1) Ph2PCl-I2, (2) H2O-AcOH-THF; (k) HCBr3-Na tert-
amylate; (l) MeLi-MeI.
Sch em e 2a
bonds.17 However in our case, this transformation was
not straightforward and many procedures were tested.18
All these procedures failed due to different reasons, and
eventually, it was only possible to achieve the reduction
of diol 13b with chlorodiphenylphosphine and iodine.19
In this way, and after deprotection of the C10-TMS group
with H2O-AcOH-THF, compound 14 was obtained in
70% overall yield from 13b. In contrast, it was not
possible for us to transform compound 13a into 14 under
any of the attempted conditions, and hence the election
of Red-Al reagent as the reducing agent in the preceding
step is very important since it affords 13b with the
highest yield.
Once the C6-C7 double was obtained, the introduction
of the gem-dimethylcyclopropane ring was accomplished
in two steps.20 The first step was the introduction of a
gem-dibromocyclopropane ring by reaction with dibro-
mocarbene, prepared from bromoform and sodium tert-
a
Key: (m) HF/THF; (n) o-NO2C6H4SeCN-Bu3P; (o) H2O2; (p)
(1) O3, (2) Me2S, (3) TsOH.
amylate. The resulting product was then treated with
MeLi and MeI to give compound 16, which possesses a
basis of a favorable attack of the carbene from the less
hindered R-side of the molecule and was confirmed by
complete aromadendrane carbon skeleton. The cyclopro-
NOE experiments. Thus, irradiation at H6 (0.30 ppm)
panation reaction was completely stereoselective, and
gave NOE with H14 (1.47 ppm), H7 (0.55 ppm), and H12
only one of the two possible stereoisomers was obtained.
(1.03 ppm). Equally, H7 showed NOE with H6, H12, and
H14. These results indicated that H6 and H7 were on the
same side of the molecule as the C14 methyl group, which
The stereochemistry of compound 16 was assigned on the
(17) Block, E. In Organic Reactions; Dauben, W. G., Ed.; J ohn Wiley
is â-oriented, and therefore the cyclopropane ring must
& Sons: New York, 1984; Vol. 30.
be R-oriented.
(18) (a) Vedjes, E.; Wu, E. S. C. J . Org. Chem. 1974, 39, 3641-3648.
(b) Corey, E. J .; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 1979-1982.
(c) Barton, D. H. R.; Stick, R. V. J . Chem. Soc., Perkin Trans. 1 1975,
1773-1776. (d) Rao, A. V. R.; Mysorekar, S. V.; Gurjar, M. K.; Yadav,
J . S. Tetrahedron Lett. 1987, 19, 2183-2186. (e) Barrett, A. G. M.;
Barton, D. H. R.; Bielski, R. J . Chem. Soc., Perkin Trans. 1 1979, 2378-
2381. (f) Barua, N. C.; Sharma, R. P. Tetrahedron Lett. 1982, 23, 1365-
1366. (g) Bargues, V.; Blay, G.; Ferna´ndez, I.; Pedro, J . R. Synlett 1996,
655-656.
(19) Liu, Z.; Classon, B.; Samuelsson, B. J . Org. Chem. 1990, 55,
4273-4275.
(20) J enninskens, L. H. D.; Wijnberg, J . B. P. A.; de Groot, A. J .
Org. Chem. 1991, 56, 6585-6591.
With compound 16 available, we undertook the modi-
fication of the A-ring, which should involve cleavage of
the C2-C3 bond to give a 2,3-secoaromadendrane deriva-
tive (Scheme 2). First, the TBS protecting group was
removed by treatment with 45% aqueous HF in THF to
give diol 17 in 95% yield. The election of the reaction
solvent was critical in this reaction as it was found that
when the reaction was carried out in the usual solvent
acetonitrile, elimination of the tertiary alcohol took place.

Synthesis of Plagiochiline N from Santonin
J . Org. Chem., Vol. 66, No. 23, 2001 7703
mixture was stirred for 30 min. The mixture was extracted
with EtOAc (3 × 100 mL), washed with brine until neutrality
was reached, and dried with Na2SO4. Evaporation of the
solvent and chromatography (from 8:2 to 1:1 hexanes-EtOAc
mixtures) gave 302 mg (94%) of compound 6b: mp 137-138
Next, we considered the elimination of the hydroxyl group
at C3 to give the less substituted C2-C3 double bond. For
this purpose, alcohol 17 was treated with o-nitrophen-
ylselenocyanate and tri-n-butylphosphine to give selenide
18 with inversion of the configuration at C3, which upon
oxidation with H2O2 afforded only one alkene 19 with
total regioselectivity. Probably both the higher substitu-
tion21 at C4 and the impossibility of the selenoxide
undertaking a syn elimination toward C4 because of its
anti orientation with H4 account for the high regioselec-
tivity of this reaction.
The final transformations in the synthetic sequence
involved cleavage of the C2-C3 bond and the construction
of the pyran ring. Cleavage of the double bond was
brought about by ozonolysis followed by reduction of the
ozonide with Me2S. This reaction was expected to yield
a 2,3-dialdehyde. However, the resulting mixture showed
a complex TLC. 1H NMR analysis of the mixture showed
two signals of aldehyde protons together with other
signals of protons geminal to oxygen, which were at-
tributed to the presence of hemiacetal intermediates in
the cyclization to the divinyl ether. Consequently, we
decided to carry out the cyclization with the ozonolysis
mixture without isolation and purification of the alde-
hyde. Therefore, compound 19 was treated with ozone
and reduced with Me2S, and the resulting mixture was
heated at a benzene reflux temperature in the presence
of TsOH. From the reaction mixture was isolated pla-
giochiline N (3) in 23% yield as a volatile compound with
the same spectroscopic and optical rotation features as
those of the natural product isolated from P. ovalifolia.22
This synthesis gives chemical evidence of the structure
and absolute stereochemistry of plagiochiline N (3).
°C (hexanes-EtOAc) (lit.12 150-152 °C (EtOAc)); [R]24 +36
D
(c 1.2) (lit.12 [R]24 +39 (c 2.49)); MS (EI) m/z 266.1510 (M+,
D
77, C15H22O4 required 266.1518), 248 (17), 208 (20), 195 (48),
1
193 (67), 97 (100); IR (KBr) νmax 3460, 1760 cm-1; H NMR δ
4.11 (1H, t, J ) 9.6 Hz), 2.73 (1H, ddd, J ) 19.4, 5.2, 2.0 Hz),
2.59 (1H, ddd, J ) 9.0, 8.4, 5.2 Hz), 2.39 (1H, dd, J ) 19.4, 9.0
Hz), 2.37-2.20 (3H, m), 2.11-2.02 (2H, m), 1.98 (1H, td, J )
13.8, 4.8 Hz), 1.69 (1H, tdd, J ) 9.7, 5.2, 4.9 Hz), 1.45 (1H, br
q, J ) 9.7 Hz), 1.25 (3H, d, J ) 6.8 Hz), 1.21 (3H, d, J ) 6.8
Hz), 1.17 (3H, s); 13C NMR δ 220.1 (s), 178.5 (s), 86.5 (d), 73.8
(s), 50.0 (d), 48.4 (d), 48.3 (d), 45.5 (d), 42.1 (d), 42.1 (t), 39.8
(t), 26.5 (t), 25.5 (q), 15.3 (q), 12.9 (q).
3â,10r-Dih ydr oxy-1,5,7rH,4,6,11âH-gu aian -6,12-olide (7).
A solution of ketolactone 6b (3.26 g, 12.2 mmol) in MeOH (50
mL) was treated with NaBH4 (355 mg, 9.3 mmol) at 0 °C. After
20 min, the reaction was quenched with saturated aqueous
NH4Cl (50 mL), MeOH was removed under reduced pressure,
and water (100 mL) was added; the mixture was then
extracted with EtOAc (3 × 100 mL). The organic layers were
washed with brine until neutrality was reached and dried with
Na2SO4, and the solvent was removed under reduced pressure.
Column chromatography, eluting with 1:9 hexanes-EtOAc,
gave 3.05 g (93%) of 7 as a white foam: [R]24 +3 (c 1.4); MS
D
(EI) m/z 268.1675 (M+, 3, C15H24O4 required 268.1675), 250
(19), 240 (5), 222 (5), 192 (43), 169 (100); IR (KBr) νmax 2530-
3275, 1757 cm-1; 1H NMR δ 4.17 (1H, t, J ) 9.6 Hz), 3.65 (1H,
q, J ) 7.4 Hz), 2.29 (2H, m), 2.20 (1H, dq, J ) 12.0, 6.8 Hz),
2.01-1.91 (2H, m), 1.88-1.75 (3H, m), 1.68-1.58 (2H, m), 1.36
(1H, m), 1.24 (3H, s), 1.21 (3H, d, J ) 6.8 Hz), 1.13 (3H, d, J
) 6.4 Hz); 13C NMR δ 178.8 (s), 85.5 (d), 74.7 (s), 77.7 (d), 50.2
(d), 49.9 (d), 47.5 (d), 46.8 (d), 42.0 (d), 41.7 (t), 36.0 (t), 26.1
(t), 25.5 (q), 17.4 (q), 12.9 (q).
3â-ter t-Bu tyldim eth ylsilyloxy-10r-h ydr oxy-1,5,7rH,4,6,-
11âH-gu a ia n -6,12-olid e (8). A solution of compound 7 (2.64
g, 9.85 mmol), imidazole (2.49 g, 36.6 mmol), and TBSCl (3.15
g, 20.3 mmol) in DMF (60 mL) was stirred at room tempera-
ture for 2 h. After this time, the reaction mixture was diluted
with EtOAc (300 mL), washed with water (200 mL) and brine
(200 mL), and dried with anhydrous Na2SO4. After filtration,
the solvent was removed under reduced pressure, and the
resulting residue was chromatographed on silica gel (1:1
hexane-EtOAc) to give 3.48 g (93%) of compound 8: mp 141-
Exp er im en ta l Section
Gen er a l P r oced u r es. All melting points are uncorrected.
Column chromatography was performed on silica gel (SDS,
silica gel 60, 0.035-0.070 mm particle size). Pyridine (10 drops/
100 mL) was added to the solvents for chromatography of
compounds containing the TMS protecting group. Commercial
reagents and solvents were analytical grade or purified by
standard procedures prior to use.23 All reactions involving air-
or moisture-sensitive materials were carried out under an
argon atmosphere. Specific rotations were measured in CHCl3.
IR spectra were recorded as liquid films in NaCl for oils and
as KBr disks for solids. NMR experiments were run in CDCl3
143 °C (hexanes-EtOAc); [R]24 +28 (c 0.8); MS (CI) m/z
D
383.2611 (M+ + 1, 8, C21H39O4Si required 383.2618), 365 (29),
307 (23), 263 (24), 233 (100); IR (KBr) νmax 1771 cm-1; 1H NMR
δ 4.15 (1H, t, J ) 9.8 Hz), 3.53 (1H, q, J ) 7.6 Hz), 2.27 (1H,
q, J ) 8.8 Hz), 2.19 (1H, dq, J ) 12.0, 7.2 Hz), 2.13 (1H, m),
2.00 (2H, m), 1.80-1.69 (3H, m), 1.66-1.57 (2H, m), 1.39 (1H,
m), 1.24 (3H, s), 1.21 (3H, d, J ) 7.2 Hz), 1.07, (3H, d, J ) 6.4
Hz), 0.89 (9H, s), 0.09 (3H, s), 0.05 (3H, s); 13C NMR δ 178.6
(s), 85.6 (d), 78.2 (d), 75.0 (s), 50.2 (d), 49.8 (d), 47.7 (d), 47.1
(d), 42.3 (t), 36.7 (t), 42.1 (d), 26.2 (t), 25.8 (q), 25.6 (q), 18.1
(s), 17.4 (q), 13.0 (q), -3.6 (q), -4.6 (q).
1
at 399.94 MHz for H NMR and at 50.3, 75.43, or 100.58 MHz
for 13C NMR and referenced to the solvent as the internal
standard. The carbon type was determined by DEPT experi-
ments. EIMS experiments were run at 70 eV. Methane was
used as an ionizing gas for CIMS experiments. FABMS
experiments were run at 30 kV in an MNBA matrix.
10r-H y d r o x y -3-o x o -1,5,7rH ,4,6,11âH -g u a ia n -6,12-
olid e (6b): P r oced u r e A. Compound 6b was obtained by
hydrogenation of O-acetylisophotosantonin (2)8,11 over 10%
palladium adsorbed onto carbon in EtOH, followed by basic
treatment as described in the literature.12
P r oced u r e B. A solution of compound 6a (370 mg, 1.21
mmol), obtained upon reduction of O-acetylisophotosantonin
(2) with NaTeH (92% yield),8a in EtOH (4.9 mL) was treated
with 5% aqueous KOH (66 mL) overnight. After this time, 18%
aqueous HCl was added until a pH of 2 was reached, and the
3â-ter t-Bu t yld im et h ylsilyloxy-10r-t r im et h ylsilyloxy-
1,5,7rH,4,6,11âH-gu a ia n -6,12-olid e (9). To a stirred solution
of compound 8 (2.49 g, 6.5 mmol), triethylamine (7.3 mL, 57.2
mmol), and 4-DMAP (157 mg, 1.29 mmol) was added TMSCl
(12.8 mL, 91.9 mmol) at room temperature. After 4 h, ad-
ditional triethylamine (7.6 mL, 55.2 mmol) and TMSCl (2.6
mL, 20.6 mmol) were added, and stirring was continued
overnight. The reaction mixture was concentrated under
reduced pressure and the residue chromatographed (9:1 hex-
ane-EtOAc) to give 3.41 g (100%) of compound 9: mp 60-63
°C (hexanes-EtOAc); [R]24D +13 (c 1.4); MS (CI) m/z 455.3020
(M+ + 1, 56, C24H47O4Si2 required 455.3013), 395 (10), 365
(100), 323 (9); IR (KBr) νmax 1776 cm-1; 1H NMR δ 4.20 (1H, t,
J ) 10.0 Hz), 3.60 (1H, q, J ) 6.8 Hz), 2.23 (1H, q, J ) 10.8
Hz), 2.17 (1H, dq, J ) 11.6, 7.2 Hz), 2.10-1.80 (5H, m), 1.66-
1.57 (2H, m), 1.51 (1H, ddd, J ) 13.2, 10.8, 6.8 Hz), 1.29 (1H,
m), 1.24 (3H, s), 1.19 (3H, d, J ) 7.2 Hz), 1.04, (3H, d, J ) 6.8
(21) (a) Blay, G.; Cardona, L.; Garcı´a, B.; Pedro, J . R. Can. J . Chem.
1992, 70, 817-822. (b) Reich, H. J .; Wollowitz, S.; Trend, J . E.; Chow,
F.; Wendelborn, D. F. J . Org. Chem. 1978, 43, 1697-1705.
(22) Copies of NMR spectra in CDCl3 of natural plagiochiline N were
available for comparison with our synthetic product.
(23) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.

7704 J . Org. Chem., Vol. 66, No. 23, 2001
Blay et al.
Hz), 0.87 (9H, s), 0.10 (9H, s), 0.05 (6H, s); 13C NMR δ 179.1
(s), 85.2 (d), 78.8 (d), 77.8 (s), 51.0 (d), 49.3 (d), 48.7 (d), 46.7
(d), 43.0 (d,), 37.8 (t, two signals), 28.6 (q), 26.2 (t), 25.8 (q),
18.3 (q), 18.0 (s), 13.1 (q), 2.5 (s), -4.7 (q), -4.6 (q).
temperature. After 2 h, additional dimethyl sulfide (2 mL) was
added and the mixture stirred at room temperature for 24 h.
The solvent was removed under reduced pressure and the
residue chromatographed (9:1 hexanes-EtOAc) to give 240 mg
(94%) of compound 12: colorless oil; [R]D23 +27 (c 1.8); MS (CI)
m/z 485.2762 (M+ + 1, 8, C24H45O6Si2 required 485.2755), 427
(13), 395 (49), 249 (32), 175 (100); IR (NaCl) νmax 1750-1730
cm-1; 1H NMR δ 5.35 (1H, d, J ) 12.5 Hz), 3.78 (1H, m), 2.55
(1H, ddd, J ) 17.0, 12.0, 6.5 Hz), 2.40-2.00 (5H, m), 1.95 (1H,
dd, J ) 12.0, 7.0 Hz), 1.69 (1H, dd, J ) 16.0, 6.0 Hz), 1.49
(1H, td, J ) 12.5, 5.0 Hz), 2.42 (3H, s), 1.29 (3H, s), 0.99 (3H,
d, J ) 7.5 Hz), 0.79 (9H, s), 0.05 (9H, s), 0.01 (3H, s), -0.05
(3H, s); 13C NMR δ 204.5 (s), 191.1 (s), 160.0 (s), 79.8 (d), 78.9
(d), 75.3 (s), 50.8 (d), 46.5 (d), 45.9 (d), 37.5 (t), 37.2 (t), 31.8
(q), 28.7 (t), 26.8 (s), 25.7, (q), 18.8 (q), 17.8 (s), 2.2 (q), -4.9
(q).
3â-t er t -Bu t yld im e t h ylsilyloxy-11â-h yd r oxy-10r-t r i-
m eth ylsilyloxy-1,5,7rH,4,6âH-gu a ia n -6,12-olid e (10a ) a n d
3â-ter t-Bu tyld im eth ylsilyloxy-11r-h yd r oxy-10r-tr im eth -
ylsilyloxy-1,5,7rH,4,6âH-gu a ia n -6,12-olid e (10b). To a so-
lution of compound 9 (1.98 g, 4.36 mmol) in 44 mL of THF at
-78 °C under argon was added dropwise a 1 M solution of
NaN(SiMe3)2 in THF (13.7 mL). The resulting solution was
stirred at this temperature for 30 min and then at room
temperature for 30 min and was cooled again to -78 °C. A
solution of Davis’ reagent24 (1.29 g, 4.94 mmol) in THF (40
mL) was injected into the reaction flask, and after 15 min,
the reaction was quenched with saturated aqueous NH4Cl (80
mL) and extracted with EtOAc (3 × 80 mL). The usual
treatment was followed by chromatography (from 8:2 to 1:1
hexane-EtOAc mixtures) that successively eluted 1.70 g (83%)
of compound 10a and 123 mg (6%) of compound 10b.
Diols 13a a n d 13b. To a solution of compound 12 (33 mg,
0.068 mmol) in THF (2 mL) under argon at 0 °C was added
via syringe 65% Red-Al reagent in toluene (0.16 mL, 0.53
mmol). After 15 min, the reaction mixture was diluted with
ether (50 mL) and washed with brine (15 mL). The major part
of the solvent was evaporated under reduced pressure, diluted
with EtOAc (50 mL), and washed again with brine (2 × 15
mL). The aqueous layers were extracted with EtOAc, and the
organic layers were dried with Na2SO4. Evaporation of the
solvents and chromatography (8:2 hexanes-EtOAc) afforded
7 mg (25%) of compound 13a and 16.5 mg (59%) of compound
13b.
Com p ou n d 10a : mp 175-176 °C (hexanes-EtOAc); [R]21
D
+39 (c 1.5); MS (CI) m/z 471.2945 (M+ + 1, 10, C24H47O5Si2
required 471.2962), 427 (9), 381 (100), 339 (17), 249 (44); IR
1
(KBr) νmax 3450, 1760 cm-1; H NMR δ 4.49 (1H, t, J ) 10.4
Hz), 3.61 (1H, q, J ) 6.7 Hz), 2.19 (1H, dt, J ) 11.6, 7.6 Hz),
2.10-1.90 (2H, m), 1.90-1.50 (6H, m), 1.49 (1H, ddd, J ) 13.0,
10.5, 6.8 Hz), 1.37 (3H, s), 1.23, (3H, s), 1.03 (3H, d, J ) 7.2
Hz), 0.86 (9H, s), 0.09 (9H, s), 0.03 (3H, s), 0.02 (3H, s); 13C
NMR δ 177.9 (s), 84.7 (d), 79.3 (d), 77.9 (s), 74.8 (s), 51.6 (d),
50.8 (d), 49.9 (d), 47.0 (d), 38.2 (t, two signals), 26.1 (q, two
signals), 22.4 (q), 18.9 (q), 18.3 (t), 18.3 (s), 2.8 (q), -4.3 (q),
-4.4 (q).
23
Com p ou n d 13a : colorless oil; [R]D +20 (c 0.6); MS (FAB)
m/z 439.2663 (M+ + Na, 13, C21H44O4NaSiO2 required 439.2676),
304 (25), 246 (32), 190 (34), 172 (100), 154 (45); IR (NaCl) νmax
1
3390 cm-1; H NMR δ 3.83 (1H, m), 3.64 (1H, q, J ) 7.0 Hz),
Com p ou n d 10b: mp 114-115 °C (hexanes-EtOAc); [R]21
3.47 (1H, q, J ) 7.1 Hz), 3.39 (1H, d, J ) 7.0 Hz, OH), 2.20
(3H, m), 2.00-1.80 (2H, m), 1.73 (1H, dt, J ) 8.0, 7.0 Hz),
1.60-1.40 (3H, m), 1.25 (3H, s), 1.03 (3H, d, J ) 6.7 Hz), 0.87
(9H, s), 0.12 (9H, s), 0.04 (3H, s), 0.03 (3H, s); 13C NMR δ 78.7
(s), 78.4 (d), 74.8 (d), 74.5 (d), 50.3 (d), 49.5 (d), 45.9 (d), 38.0
(d), 34.4 (d), 29.5 (q), 28.5 (t), 25.8 (q), 18.5 (q), 18.0 (s), 2.4
(q), -4.4 (q), -4.7 (q).
D
+84 (c 2.0); MS (CI) m/z 471.2953 (M+ + 1, 10, C24H47O5Si2
required 471.2962), 427 (12), 381 (100), 339 (32), 249 (48); IR
1
(KBr) νmax 3430, 1780 cm-1; H NMR δ 4.12 (1H, t, J ) 10.3
Hz), 3.51 (1H, q, J ) 7.0 Hz), 2.40-2.20 (2H, m), 2.00-1.50
(9H, m), 1.22 (3H, s), 1.15 (3H, s), 0.98 (3H, d, J ) 7.0 Hz),
0.83 (9H, s), 0.05 (9H, s), -0.01 (3H, s), -0.02 (3H, s); 13C NMR
δ 180.2 (s), 84.2 (d), 79.4 (s), 75.4 (s), 78.9 (d), 51.2 (d), 49.4
(d), 47.3 (d, four signals), 37.9 (t, two signals), 27.5 (q), 26.2
(q), 21.1 (t), 19.8 (q), 18.4 (s), 18.1 (q), 3.0 (q), -4.1 (q), -4.3
(q).
Com p ou n d 13b: mp 130-132 °C (hexanes-EtOAc); [R]22
D
+16 (c 0.9); MS (FAB) m/z 439.2667 (M+ + Na, 12, C21H44O4-
NaSiO2 required 439.2676), 309 (31), 269 (19), 177 (100); IR
1
(KBr) νmax 3420 cm-1; H NMR δ 4.68 (1H, d, J ) 11.2 Hz),
3â-ter t-Bu t yld im et h ylsilyloxy-10r-t r im et h ylsilyloxy-
1,5rH,4,6âH-gu a i-7(11)-en -6,12-olid e (11). A solution of
compound 10a (500 mg, 1.06 mmol) and triethylamine (0.75
mL, 5.4 mmol) in THF (14 mL) at 0 °C under argon was treated
with MsCl (0.16 mL, 2.1 mmol) for 2.5 h. After this time, the
reaction mixture was filtered through silica gel and eluted with
200 mL of ether. The solvent was removed under reduced
pressure, and the resulting residue was dissolved with toluene
(35 mL) under argon; DBU (1 mL) was then added, and the
mixture was heated under reflux for 20 min. The cold reaction
mixture was diluted with CH2Cl2 (120 mL), washed with water
(50 mL) and brine (50 mL), and dried with Na2SO4. Solvent
evaporation and chromatography (9:1 hexane-EtOAc) gave
320 mg (66%) of compound 11: mp 61-62 °C (hexanes-
EtOAc); [R]22D +29 (c 1.2); MS (CI) m/z 453.2853 (M+ + 1, 100,
3.76 (2H, br dd, J ) 11.2, 3.2 Hz), 3.44 (1H, td, J ) 9.4, 5.6
Hz), 2.29 (1H, td, J ) 12.0, 7.7 Hz), 2.17 (1H, br d, J ) 9.4 Hz,
OH), 1.97 (1H, td, J ) 12.0, 3.4 Hz), 1.49 (1H, m), 1.26 (3H,
s), 1.02 (3H, d, J ) 6.0 Hz), 0.88 (9H, s), 0.20 (9H, s), 0.05
(3H, s), 0.03 (3H, s); 13C NMR δ 79.7 (s), 77.5 (d), 77.1 (d),
71.4 (d), 48.9 (d), 48.4 (d), 45.4 (d), 39.0 (t), 31.9 (t), 31.4 (q),
27.4 (t), 25.8 (q), 18.1 (s), 16.7 (q), 2.2 (q), -4.4 (q), -4.7 (q).
Alk en e 14. A solution of diol 13b (25 mg, 0.06 mmol),
imidazole (17 mg, 0.25 mmol), chlorodiphenylphosphine (25
µL, 0.13 mmol), and 4-DMAP (1 mg, 0.008 mmol) in toluene
(1.5 mL) was heated at a reflux temperature under argon.
Iodine (35 mg, 0.14 mmol) was added in portions, and reflux
was continued for 30 additional min. After this time, the cold
reaction mixture was diluted with EtOAc (50 mL), washed
with aqueous 10% Na2S2O3 (10 mL) and brine (10 mL), and
dried with Na2SO4. After solvent removal, the resulting oil was
stirred in 0.8 mL of a 3:5:11 H2O-AcOH-THF mixture for 4
h. The reaction mixture was extracted with EtOAc. The usual
workup and chromatography (9:1 hexanes-EtOAc) gave 13
mg (70%) of compound 14: colorless oil; [R]D23 -58 (c 1.8); MS
(EI) m/z 310.2317 (M+, 1, C18H34O2Si required 310.2328), 253
(59), 235 (100); IR (NaCl) νmax 3412, 1462, 836 cm-1; 1H NMR
δ 5.65 (2 H, m), 3.51 (1H, td, J ) 9.2, 8.0 Hz), 2.40-2.20 (3H,
m), 2.18 (1H, br t, J ) 9.0 Hz), 1.99 (2H, m), 1.71 (1H, q, J )
7.2 Hz), 1.64 (1H, m), 1.54 (1H, ddd, J ) 12.4, 11.2, 8.0 Hz),
1.16 (3H, s), 0.99 (3H, d, J ) 6.4 Hz), 0.89 (9H, s), 0.06 (3H,
s), 0.05 (3H, s); 13C NMR δ 132.0 (d), 128.7 (d), 74.5 (s), 78.3
C
24H45O4Si2 required 453.2856), 438 (10), 396 (15); IR (KBr)
1
νmax 1758, 1675 cm-1; H NMR δ 5.08 (1H, dq, J ) 11.0, 1.2
Hz), 3.81 (1H, ddd, J ) 11.0, 7.0, 1.8 Hz), 2.87 (1H, ddd, J )
19.0, 12.0, 4.5 Hz), 2.43 (1H, q, J ) 7.2 Hz), 2.31 (1H, br d, J
) 19.0 Hz), 2.15 (2H, m), 1.96 (1H, ddd, J ) 12.5, 12.0, 4.5
Hz), 1.73 (3H, J ) 1.2 Hz), 1.60 (1H, dt, J ) 12.5, 4.5 Hz),
1.45 (2H, m), 1.26 (3H, s), 0.95 (3H, d, J ) 7.2 Hz), 0.84 (9H,
s), 0.05 (9H, s), 0.01 (6H, s); 13C NMR δ 175.0 (s), 165.0 (s),
121.1 (s), 83.2 (d), 79.2 (d), 75.4 (s), 52.1 (d), 50.8 (d), 46.5 (d),
38.0 (t), 31.9 (q), 31.4 (t), 25.8 (q), 22.6 (t), 17.9 (s), 19.2 (q),
8.2 (q), 2.5 (q), -4.7 (q), -4.9 (q).
Com pou n d 12. Ozone-enriched oxygen was bubbled through
a solution of compound 11 (240 mg, 0.53 mmol) in 9 mL of
CH2Cl2 at -78 °C until a blue color appeared in the solution.
The excess ozone was removed with an argon purge, and
dimethyl sulfide (2 mL) was added. The cooling bath was
removed, and the temperature was allowed to rise to room
(24) (a) Davis, F. A.; Vishwakarma, L. C.; Billmers, J . M.; Finn, J .
J . Org. Chem. 1984, 49, 3241-3243. (b) Davis, F. A.; Chattopadhyay,
S.; Towson, J . C.; Lal, S.; Reddy, T. J . Org. Chem. 1988, 53, 2087-
2089.

Synthesis of Plagiochiline N from Santonin
J . Org. Chem., Vol. 66, No. 23, 2001 7705
(d), 49.6 (d), 49.3 (d), 43.9 (d), 37.6 (t), 36.5 (t), 28.0 (t), 25.9
(q), 24.7 (q), 18.1 (s), 16.9 (q), -4.4 (q), -4.7 (q).
(84%) of compound 18: yellow oil; [R]24 -52 (c 2.0); IR νmax
D
(NaCl) 3300, 1508, 1337 cm-1; 1H NMR δ 8.21 (1H, d, J ) 8.0
Hz), 7.66 (1H, d, J ) 8.0 Hz), 7.47 (1H, t, J ) 8.0 Hz), 7.27
(1H, t, J ) 8.0 Hz), 3.97 (1H, t, J ) 5.5 Hz), 2.57 (1H, dt, J )
10.5, 7.6 Hz), 2.38 (1H, ddd, J ) 13.3, 10.5, 6.3 Hz), 2.11 (2H,
m), 1.92 (1H, td, J ) 13.3, 4.8 Hz), 1.80 (1H, t, J ) 8.4 Hz),
1.74 (1H, m), 1.61 (1H, br d, J ) 13.3 Hz), 1.42 (3H, s), 1.17
(1H, m), 1.11 (3H, d, J ) 6.8 Hz), 1.05 (3H, s), 1.00 (3H, s),
0.56 (1H, ddd, J ) 4.2, 8.8, 11.9 Hz), 0.24 (1H, t, J ) 8.8 Hz);
13C NMR δ 147.5 (s), 133.5 (d), 133.2 (s), 129.9 (d), 126.4 (d),
125.2 (d), 74.7 (s), 48.1 (d), 48.0 (d), 46.7 (d), 41.6 (d), 42.9 (t),
35.9 (t), 29.7 (d), 26.0 (d), 29.1 (q), 27.3 (q), 20.2 (s), 21.1 (t),
16.4 (q), 15.5 (q).
Dibr om id e 15. To a solution of alkene 14 (330 mg, 1.07
mmol) in dry toluene (9 mL) was added 3.5 M sodium tert-
amylate in toluene (3.15 mL, 11 mmol).24 To this mixture was
added a solution of HCBr3 (0.47 mL, 5.4 mmol) in toluene (2.3
mL) dropwise under vigorous stirring. When the reaction was
complete, the reaction mixture was allowed to stir for an
additional 10 min, and then 50 mL of brine was added. The
usual procedure and chromatography (9:1 hexanes-EtOAc)
gave 26 mg (8%) of starting material and 360 mg (70%) of
compound 15: mp 118-120 °C (hexanes-EtOAc); [R]21 +7
D
(c 2.0); IR (KBr) νmax 3420 cm-1; 1H NMR δ 3.60 (1H, ddd, J )
9.2, 7.8, 6.6 Hz), 2.25 (1H, ddd, J ) 11.6, 9.8, 7.8 Hz), 2.10-
2.00 (3H, m), 1.95 (1H, td, J ) 13.6, 4.8 Hz), 1.80-1.50 (5H,
m), 1.38 (3H, s), 1.27 (2H, m), 1.06 (3H, d, J ) 6.8 Hz), 0.89
(9H, s), 0.07 (3H, s), 0.06 (3H, s); 13C NMR δ 73.7 (s), 77.4 (d),
50.5 (d), 45.8 (d), 42.7 (d), 40.7 (t), 37.0 (t), 36.1 (d), 32.6 (d),
27.2 (q), 25.9 (q), 25.8 (s), 24.1 (t), 18.1 (s), 16.0 (q), -4.5 (q),
-4.7 (q).
10r-Hyd r oxy-1,5rH,4,6,7âH-2-a r om a d en d r en e (19). To
a solution containing compound 18 (114 mg, 0.26 mmol) in 7
mL of THF cooled to 0 °C was added 30% H2O2 (0.21 mL, 2.1
mmol). The mixture was stirred at room temperature for 1 h,
diluted with EtOAc (60 mL), and washed with 8% aqueous
Na2S2O3 (15 mL) and brine (50 mL). The usual procedure and
chromatography (9:1 hexanes-EtOAc) yielded 48 mg (84%) of
3â-t er t -Bu t yld im e t h ylsilyloxy-10r-h yd r oxy-1,5rH ,-
4,6,7âH-a r om a d en d r a n e (16). To a suspension of dry cop-
per(I) cyanide (727 mg, 8.12 mmol) in THF (7.7 mL) was added
1.6 M MeLi in ether (1.5 mL, 16.8 mmol) at -78 °C under
argon. The mixture was gradually warmed to 0 °C over 30 min
and was stirred at this temperature for an additional 30 min.
The mixture was then cooled to -78 °C, and dibromide 15 (268
mg, 0.56 mmol) in THF (11 mL) was added dropwise. The
resulting mixture was warmed to room temperature and
allowed to stir overnight. The reaction mixture was cooled to
0 °C, and MeI (0.42 mL, 6.75 mmol) was added. After 30 min,
the reaction was quenched with a mixture of 18 mL of
saturated aqueous NH4Cl and 2 mL of 34% NH4OH. The
mixture was extracted with ether (3 × 40 mL), washed with
NH4Cl-NH4OH (10 mL), saturated aqueous NaHCO3 (10 mL),
and brine (10 mL), and dried with Na2SO4. Chromatography
(9:1 hexanes-EtOAc) afforded 153 mg (80%) of compound 16:
compound 19: mp 68-69 °C (hexanes-EtOAc); [R]24 -260
D
(c 0.3); MS (EI) m/z 220.1829 (M+, 4, C15H24O required
220.1827), 202 (7), 177 (12), 140 (29), 119 (28), 107 (21), 80
(100); IR (KBr) νmax 3390 cm-1; 1H NMR (250 MHz) δ 5.78 (1H,
dt, J ) 6.0, 1.6 Hz), 5.74 (dt, J ) 6.0, 2.4 Hz), 2.94 (1H, br d,
J ) 9.6 Hz), 2.54 (1H, m), 1.93 (1H, td, J ) 13.2, 4.8 Hz), 1.79-
1.66 (3H, m), 1.35 (3H, s), 1.27 (1H, m), 1.05 (3H, s), 1.04 (3H,
d, J ) 6.0 Hz), 0.97 (3H, s), 0.56 (1H, ddd, J ) 12.2, 9.2, 4.2
Hz), 0.38 (1H, dd, J ) 9.2, 6.4 Hz); 13C NMR δ 138.1 (d), 130.6
(d), 75.5 (s), 56.1 (d), 50.5 (d), 42.9 (d), 42.7 (t), 29.3 (d), 26.2
(d), 29.0 (q), 27.3 (q), 21.2 (t), 19.6 (s), 19.7 (q), 15.6 (q).
P la gioch ilin e N (3). A solution of alkene 19 (30 mg, 0.14
mmol) in 5 mL of dry dichloromethane was treated with ozone
as described in the synthesis of compound 12. The resulting
solution was treated with dimethyl sulfide (0.85 mL) and
stirred for 36 h at room temperature, and the solvent was
removed under reduced pressure. The resulting oil was dis-
solved in benzene (5.7 mL), and TsOH was added (18 mg, 2.1
mmol); the mixture was heated at a reflux temperature for 1
h. The mixture was diluted with EtOAc (50 mL), washed with
saturated aqueous NaHCO3 (10 mL), dried, and concentrated.
Column chromatography (pentane) afforded 7 mg (23%) of
oil; [R]D +5 (c 2.0); MS (EI) m/z 352.2809 (M+, 1, C21H40O2Si
23
required 352.2798), 334 (6), 295 (14), 277 (34), 203 (100); IR
1
(NaCl) νmax 3411 cm-1; H NMR δ 3.51 (1H, dt, J ) 9.9, 6.1
Hz), 2.21 (1H, dt, J ) 11.4, 8.2 Hz), 1.99 (1H, ddd, J ) 11.7,
7.6, 6.1 Hz), 1.93 (1H, td, J ) 12.6, 5.3 Hz), 1.47 (3H, s), 1.03
(3H, s), 0.94 (3H, s), 0.92 (3H, d, J ) 6.4 Hz), 0.89 (9H, s),
0.55 (1H, ddd, J ) 12.0, 8.2, 4.0 Hz), 0.30 (1H, t, J ) 8.2 Hz),
0.06 (3H, s), 0.05 (3H, s); 13C NMR δ 77.8 (d), 74.9 (s), 50.7
(d), 45.2 (d), 39.2 (d), 43.0 (t), 36.8 (t), 29.6 (d), 25.9 (d), 29.0
(q), 27.2 (q), 25.9 (q), 20.1 (s), 21.3 (t), 18.2 (s), 15.9 (q), 15.5
(q), -4.9 (q).
plagiochiline N (3): oil; [R]20 +43 (c 0.2) (lit.9 +46.1 (c 2.08));
D
MS (EI) m/z 216.1522 (M+, 100, C15H20O required 216.1514),
3â,10r-Dih yd r oxy-1,5rH,4,6,7âH-a r om a d en d r a n e (17).
To a solution of compound 16 (370 mg, 1.05 mmol) in THF (60
mL) was added 45% aqueous HF (4 mL), and the resulting
mixture was stirred for 2 h. The reaction mixture was diluted
with EtOAc (75 mL), washed with saturated aqueous NaHCO3
(30 mL) and brine (30 mL), dried, and concentrated under
reduced pressure. Chromatography of the residue with 2:8
hexanes-EtOAc gave 237 mg (95%) of compound 17: mp 234-
201 (21), 173 (62); IR (NaCl) νmax 2930, 1695, 1631, 1200 cm-1
;
1H NMR δ 6.44 (1H, s), 6.08 (1H, br s), 5.51 (1H, br dd, J )
8.9, 2.5 Hz), 2.97 (1H, d, J ) 10.2 Hz), 2.25 (1H, m), 2.15 (1H,
m), 1.75 (3H, s), 1.55 (3H, s), 1.19 (1H, m), 1.10 (3H, s), 0.97
(3H, s), 0.70 (1H, dd, J ) 10.6, 9.4 Hz); 13C NMR δ 138.4 (d),
133.8 (d), 132.0 (s), 127.2 (d), 117.7 (s), 111.9 (s), 34.8 (d), 34.4
(d), 30.5 (d), 28.3 (q), 24.1 (t), 22.7 (q), 20.2 (s), 16.5 (q, two
signals).
236 °C (hexanes-EtOAc); [R]24 -25 (c 0.8); MS (EI) m/z
D
238.1935 (M+, 3, C15H26O2 required 238.1933), 220 (27), 205
(17), 202 (21), 177 (26), 147 (83), 122 (100); IR (KBr) νmax 3290
1
cm-1; H NMR δ 3.60 (1H, m), 2.22 (1H, br q, J ) 12.1 Hz),
Ack n ow led gm en t. Financial support from Direc-
cio´n General de Investigacio´n Cient´ıfica y Te´cnica (PB
94-0985) is gratefully acknowledged. L.L. is especially
thankful to Conselleria de Cultura, Educacio´ i Cie`ncia
(Generalitat Valenciana) for a grant. We thank Profes-
sor Y. Asakawa and Dr. F. Nagashima from Tokushima
Bunri University for providing us with copies of NMR
spectra of natural plagiochiline N.
2.12 (1H, m), 1.94 (1H, td, J ) 12.7, 4.8 Hz), 1.80-1.50 (4H,
m), 1.47 (3H, s), 1.12 (1H, m), 1.04 (3H, s), 0.99 (3H, d, J )
6.0 Hz), 0.95 (3H, s), 0.57 (1H, ddd, J ) 12.2, 8.2, 4.1 Hz),
0.31 (1H, t, J ) 8.2 Hz); 13C NMR δ 77.5 (d), 74.8 (s), 50.7 (d),
45.3 (d), 42.8 (d), 39.9 (d), 36.6 (t), 29.6 (d), 26.0 (d), 29.0 (q),
27.1 (q), 21.2 (t), 20.1 (s), 15.8 (q), 15.5 (q).
10r-Hydr oxy-3r-(o-n itr oph en ylselen en yl)-1,5rH,4,6,7âH-
a r om a d en d r a n e (18). To a solution of diol 17 (80 mg, 0.34
mmol) and o-nitrophenylselenocyanate (540 mg, 2.38 mmol)
in pyridine (0.45 mL) was added via syringe n-Bu3P (0.77 mL,
3.09 mmol) under argon. After 24 h, the reaction mixture was
diluted with ether (50 mL), washed with 2 M HCl (2 × 10 mL)
and brine (15 mL), and dried with Na2SO4. After filtration and
evaporation of the solvent under reduced pressure, the residue
was chromatographed (8:2 hexanes-EtOAc) to give 124 mg
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of 3 and 7-19. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O010567D