An approach to furolabdanes and their photooxidation derivatives from R-(+)-sclareolide

Article abstract of DOI:10.1021/np010590u

A synthetic route to furolabdanes from commercially available R-(+)-sclareolide is reported, with the specific aim of preparing (12R and 12S,15ξ)-12,15-dihydroxylabda-7,13-dien-16,15-olides (3 and 5) and (12R and 12S, 16ξ)-12,16-dihydroxylabda-7,13-dien-15,16-olides (4 and 6). The key points of our approach are the use of Weinreb's amide 11 to join the furan ring to the terpenic unit. Photooxidation of the furan moiety of compounds 15 and 16, and of their acetates 19 and 20, has been used to built the hydroxybutenolide fragment. In this way the four possible isomers at the butenolide moiety, compounds 3-6, and their C-12 acetyl derivatives 21-24 have been obtained. On the basis of comparison of the spectral data (¹H NMR) of the synthetic peracetates 25-28 (derived from 21-24) with the reported data for the peracetate 2 (derived from the natural product 1), the relative configuration at carbon C-12 of the natural product has been corrected. Furthermore, the absolute configuration of the natural product 1, considered to belong to the enantio-series, has to be changed to the normal-series on the basis of the optical rotation obtained for the synthetic derivative.

Full text of DOI:10.1021/np010590u

J . Nat. Prod. 2002, 65, 661-668
661
An Ap p r oa ch to F u r ola bd a n es a n d Th eir P h otooxid a tion Der iva tives fr om
R-(+)-Scla r eolid e
Mar´ıa C. de la Torre,*,† Isabel Garc´ıa,† and Miguel A. Sierra‡
Instituto de Quı´mica Orga´nica, Consejo Superior de Investigaciones Cient´ıficas (CSIC), J uan de la Cierva 3, 28006-Madrid,
Spain, and Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad Complutense, 28040-Madrid, Spain
Received November 21, 2001
A synthetic route to furolabdanes from commercially available R-(+)-sclareolide is reported, with the
specific aim of preparing (12R and 12S,15ê)-12,15-dihydroxylabda-7,13-dien-16,15-olides (3 and 5) and
(12R and 12S,16ê)-12,16-dihydroxylabda-7,13-dien-15,16-olides (4 and 6). The key points of our approach
are the use of Weinreb’s amide 11 to join the furan ring to the terpenic unit. Photooxidation of the furan
moiety of compounds 15 and 16, and of their acetates 19 and 20, has been used to built the
hydroxybutenolide fragment. In this way the four possible isomers at the butenolide moiety, compounds
3-6, and their C-12 acetyl derivatives 21-24 have been obtained. On the basis of comparison of the
spectral data (1H NMR) of the synthetic peracetates 25-28 (derived from 21-24) with the reported data
for the peracetate 2 (derived from the natural product 1), the relative configuration at carbon C-12 of the
natural product has been corrected. Furthermore, the absolute configuration of the natural product 1,
considered to belong to the enantio-series, has to be changed to the normal-series on the basis of the
optical rotation obtained for the synthetic derivative.
Labdane diterpenoids are among the most common types
of diterpenes isolated from higher plants.1 The interest of
this class of compounds resides in their significant anti-
mutagenic,2 antibacterial, and antifungal activities.3 How-
ever, as in the case of many other natural products, they
can be isolated only in minute amounts. This fact inhibits
their unambiguous structural determination and often
precludes the study of biological and chemical reactivity.
Therefore, the hemisynthesis of minor components from
other abundant natural products is of longstanding inter-
est. As an example, (12S,16ê)-12,16-dihydroxy-ent-labda-
7,13-dien-15,16-olide, 1, has been recently isolated from
Alomira myriadenia (Asteraceae) only in a 0.011% yield
with respect to plant material. This compound shows sig-
nificant cytotoxic activity against human oral epidermoid
carcinoma and against colon cancer4 and is identical to one
of the products previously isolated by Bohlmann from
Acritopappus hagei,5 since both compounds yielded the
same diacetylated derivative 2. On the basis of biogenetic
grounds, Bohlmann suggested an enantio absolute config-
uration for these compounds, although neither the relative
stereochemistry at carbon C-12 nor the absolute configu-
ration of compound 2 has been rigorously established.
Continuing with our research directed toward the hemi-
synthesis of terpenoids,6 we have been interested in the
development of synthetic routes to furolabdane diterpe-
noids. With this in mind, (12R- and 12S)-12,15-dihydroxy-
labda-7,13-dien-16,15-olides 3 and 5, and their regioisomers
(12R- and 12S)-12,65-dihydroxylabda-7,13-dien-15,16-olides
4 and 6, were attractive targets, since their synthesis would
provide these labdanes in amounts sufficient for biological
assay. Additional reward would be the structural deter-
mination of 1. The study of compounds 3-6 shows that (+)-
sclareolide (7) may be a suitable starting material for their
synthesis. In fact (+)-sclareolide (7) bears the methyl
groups at carbons C-4, C-8, and C-10 of the decalin moiety,
placed in the appropriate positions. The butenolide frag-
ment present in the synthetic targets 3-6 may be derived
F igu r e 1.
from the oxidation of a furan ring in an intermediate like
8 (Scheme 1). The furan moiety required for this transfor-
Sch em e 1. Retrosynthetic Analysis of Compounds 3-6
* To whom correspondence should be addressed. Tel: 34-915622900.
Fax: 34-915644853. E-mail: iqot310@iqog.csic.es.
† Instituto de Qu´ımica Orga´nica.
‡ Departamento de Qu´ımica Orga´nica.
10.1021/np010590u CCC: $22.00
© 2002 American Chemical Society and American Society of Pharmacognosy
Published on Web 04/11/2002

662 J ournal of Natural Products, 2002, Vol. 65, No. 5
de la Torre et al.
Sch em e 2a
a
(i) 1 equiv of DIBAL-H, toluene, -78 °C (94%); (ii) Me3 Al-MeONHMe-HCl, CH2Cl2, 0°C to rt (88%); (iii) SOCl2, py, 0 °C; (iv) 3 equiv of 3-bromofuran,
3 equiv BuLi, THF, -78 °C, 1 h, then 1 equiv of 13, 2 h (72%); (v) 2 equiv of CeCl3 × 7H2O, 8 equiv of NaBH4, MeOH, 0 °C, 30 min (37% for 15, 33% for 16);
(vi) Ac2O/py (1:2) 24 h, rt (99% for 19, 98% for 20).
Ta ble 1. Chemical Shifts of H-14, H-15, H-16, and OMe for 17
mation would be incorporated into the (+)-sclareolide
a
and 18 and ∆δ Values (δ17-δ18
)
derivative 9, by reaction of 3-lithiofuran with the electro-
phillic function at carbon C-12. It should be noted that the
proposed synthesis would be effected in a compound having
a normal configuration instead of the enantio proposed for
1.
H
17
18
∆δ
14
15
16
OMe
6.43
7.47
7.37
3.43
6.27
7.42
7.36
3.51
+0.16
+0.05
+0.01
+0.08
a
At 300 MHz in CDCl3.
Resu lts a n d Discu ssion
The synthesis of the key furolabdanes, of general struc-
ture 8, was initially addressed by sequential reduction of
the (+)-sclareolide (7) to the lactol 10, followed by coupling
with 3-lithiofuran (Scheme 2). Lactol 10 was obtained
quantitatively by treatment of (+)-sclareolide with DIBAL-
H. In the next step, reaction of 3-lithiofuran with 10 must
be performed below 40 °C, to avoid isomerization of the
reagent to 2-lithiofuran.7 Unfortunately, lactol 10 was
unreactive at this temperature. A change of strategy was
required, and we devised Weinreb’s amides as suitable
candidates to react with 3-lithiofuran at the required
temperature. Weinreb’s amide 11 was prepared in 88%
yield by aminolysis of (+)-sclareolide (7) with the dimethyl-
aluminum amide derived from N-methoxy-N-methyl-
amine.8 To prevent waste of organometallic reagent as well
as undesired side-reactions, the tertiary alcohol at C-8 was
dehydrated prior to the furane addition. Treatment of
alcohol 11 with SOCl2 at 0 °C yielded the undesired ∆8(17)
unsaturated derivative 12, as the major reaction product
(60%), together with the desired ∆7-unsaturated isomer 13
(32% yield). However, the exo double bond of compound 12
quantitatively rearranged to the desired endo-isomer 13,
under acid treatment. Reaction of alkene 13 with 3-lithio-
furan at -78 °C yielded 12-ketolabdane 14 in excellent
yield. Reduction of the ketone at C-12 with NaBH4 and
excess CeCl3 × 7H2O9 yielded the epimeric 12-hydroxyfuro-
labdanes 15 and 16 in a 1:1 ratio. These alcohols were
separated by column chromatography, and their absolute
configuration at carbon C-12 was established by using
Mosher’s methodology.10
F igu r e 2. Ideal conformations for the Mosher’s esters 17 and 18.
(MTPA) yielded esters 17 and 18, respectively. The modi-
fied Mosher’s10 method is based on the diamagnetic effect
caused by the benzene ring of the MTPA moieties on the
â-protons of the alcohol. In the case of R-aromatic secondary
carbinols, an anisotropic effect due to the aromatic ring
produces negligible ∆δ values for these â-protons, which
may preclude the use of this method to establish absolute
configurations. In addition, the â-protons (H-11) on esters
17 and 18 overlapped with the decalin protons, preventing
their analysis. Nevertheless, Isobe11 has established that,
for secondary alcohols bearing an R-furyl substituent, the
analysis of the protons attached to the furan ring may be
applied to determine the absolute configuration. As shown
in Table 1, the furan protons H-14, H-15, and H-16 of ester
18 are shielded with respect to its epimer 17. This result
is fully consistent with the ideal conformation for ester 18
represented in Figure 2, in which the furan ring is eclipsed
with the benzene ring of the MTPA group. Therefore, ester
18 and subsequently alcohol 16 must have a C-12S
absolute configuration. In agreement with these results,
Accordingly, the reaction of the alcohols 15 and 16 with
(R)-(-)-R-methoxy-R-(trifluoromethyl)phenylacetic acid

Furolabdanes and Derivatives from R-(+)-Sclareolide
J ournal of Natural Products, 2002, Vol. 65, No. 5 663
Sch em e 3
the -OMe protons of the MTPA moiety in ester 17 are
shielded by the diamagnetic effect caused by the furan [∆δ-
(17-18) ) - 0.08], and therefore ester 17 and hence alcohol
15 must have a 12R absolute configuration.
With alcohols 15 and 16 in hand, we pursued the
oxidation of the furan ring to obtain the desired hydroxy-
butenolides. Among the number of methods that have been
developed for the synthesis of 5-hydroxy-2(5H)-furanones,12
1
the one involving oxidation of furan by O2 appears to be
the most efficient.13 In general, the photooxidation of
3-substituted furans is not regiospecific, yielding both the
2-alkyl-4-hydroxy- and the 3-alkyl-4-hydroxybutenolide
regioisomers.14 This fact may be advantageous for us, since
we were interested in obtaining both regioisomeric hy-
droxybutenolides to compare with the natural labdane
1.13,14 Irradiation of alcohol 15 in THF (220 W, tungsten
lamp, Pyrex well) in the presence of air and a catalytic
amount of Rose Bengal for 5 h yielded the regioisomeric
hydroxybutenolides 3 and 4. Both lactones were separated
by column chromatography as a mixture of epimers in a
16% and 11% yield, respectively. The 1H NMR spectrum
of 3, obtained in CDCl3, is consistent with an R-alkyl-
substituted-15-hydroxybutenolide. Specially relevant are
the signals at δ 7.04, which must be assigned to proton
H-14, placed at the â-position of an R,â-unsaturated
butenolide, and the signal at δ 6.12 attributable to H-15.15
With respect to the regioisomeric lactone derivative 4, the
although both free alcohols 15 and 16 and their acetates
19 and 20 are suitable substrates for the photooxidation
reaction, clearly the presence of the free alcohol group
considerably decreases the reaction yields.
1
most deshielded signal in the H NMR spectrum appeared
at δ 6.20, and therefore the structure of R,â-alkyl-
substituted-16-hydroxybutenolide has been asigned to this
compound.15 Therefore, we established the structure of
(12R)-12,15-dihydroxylabda-7,13-dien-16,15-olide for com-
pound 3 and the structure of (12R)-12,16-dyhydroxylabda-
7,13-dien-15,16-olide for compound 4. Alcohol 16, having
a 12S configuration, was submitted to analogous photo-
oxidation conditions, yielding compounds 5 and 6 in 20%
and 10% yields, respectively. The 1H NMR of product 5
showed signals at δ 7.08 and 7.04 attributable to H-14, and
at δ 6.14 for proton H-15. Compound 6 showed a signal at
δ 6.23 that could be assigned to proton H-16 in a 16-
hydroxy-15,16-butenolide. In addition, the olefinic proton
(H-14) of 6 appears at δ 6.07, 1 ppm shielded with respect
to its regioisomer 5. Consequently, we established a
structure of (12S)-12,15-dihydroxylabda-7,13-dien-16,15-
olide for compound 5 and (12S)-12,16-dihydroxylabda-7,-
13-dien-15,16-olide for compound 6.
Despite the reported data,4 12-hydroxybutenolides 3-6
were very unstable and their 1H NMR spectra could not
be obtained in py-d5. This instability thwarted the direct
comparison with the literature data for 1.4 Thus, the
diacetates 25-28 were prepared as mixtures of epimers
at the hemiacetalic carbon, by Ac2O-py treatment of
1
lactones 21-24, to compare their H NMR data with those
reported in the literature for 2.4 Comparison of the 1H NMR
spectra for the 15-acetoxy-16,15-butenolides 25 and 27
1
(C12R and C-12S, respectively) with the H NMR spectra
for the corresponding 15-hydroxy analogues 21 and 23
(Table 2) showed a strong downfield shift of the signal
attributed to H-15, confirming the acetylation of its geminal
1
hydroxyl group (∆δ = 0.9 ppm). Similarly, the H NMR of
the 16-acetoxy-15,16-butenolides 26 and 28 showed the
signals for H-16 deshielded (∆δ = 0.9 ppm), with respect
to the 16-hydroxy derivatives 22 and 24, while the signal
for the olefinic proton H-14 remained unchanged upon
acetylation. Thus, the structures of (12R and 12S)-12,15-
diacetoxylabda-7,13-dien-16,15-olide (25 and 27) and of
(12R and 12S)-12,16-diacetoxylabda-7,13-dien-15,16-olide
(26 and 28) have been unambiguously established.
In an attempt to increase the yield of the photooxidation
reaction, we checked the oxidation of the 12-acetylderiva-
tives 19 and 20, quantitatively obtained from alcohols 15
and 16, respectively, by treatment with Ac2O-Pyr. Acetate
19 yielded upon sun light irradiation, under the above
conditions, the regioisomeric hydroxybutenolides 21 and
22 (35% and 33% yield, respectively). Both compounds were
obtained as mixtures of epimers at carbons C-15 and C-16.
Again the 15-hydroxy-16,15-butenolide isomer 21 showed
signals for protons H-14 and H-15 at δ 6.94 and 6.09,
respectively. On the contrary, the 1H NMR of derivative
22 showed a signal for δ H-14, at 5.97, shielded with respect
to 21, while H-16 appeared at δ 6.20 and 6.03. Thus,
compound 22 must be the 16-hydroxy-15,16-butenolide. In
turn, 12S-acetylderivative 20 yielded lactones 23 (42%) and
24 (23%) under analogous reaction conditions. As before,
lactone 23 showed signals at δ 7.02-7.01 for H-14 and at
6.13-6.10 for H-15, and therefore it was assigned the
structure of (12S)-12-acetoxy-15-hydroxylabda-7,13-dien-
16,15-olide, derivative 24 being the 16-hydroxy-15,16-
butenolide isomer. From these results it is clear that
F igu r e 3.

664 J ournal of Natural Products, 2002, Vol. 65, No. 5
de la Torre et al.
Ta ble 2. Chemical Shifts of H-14, H-15, H-16, and H-12 of Compounds 21-28 and 2
a
Taken from ref 4.
Comparison of the 1H NMR data reported for 24 with
the 1H NMR of diacetates 25-28 clearly shows that
derivatives 2 and 28 have identical 1H NMR spectra.
According to this, diacetate 2 and hence the natural product
1 have in fact a 15,16-butenolide moiety. Therefore, the
assignment of H-14 and H-16 protons given in the litera-
ture for the diacetate 2 must be changed, while the
stereochemistry at C-12 in 2 must be the reverse. Conse-
quently, overlooking the absolute stereochemistry, the
structure of the reported natural product should be amended
to 6.
Regarding the absolute configuration of compound 1
(isolated from A. myriadenia), the sign of the specific
rotation reported for its diacetate 2 is negative, like our
synthetic diacetate 28 obtained from 24. Assuming that
the ratio of anomeric acetates obtained from 1 and 24 are
the same, we conclude that 1 and 28 possess the same
absolute configuration. Therefore, diterpene 1 should be-
long to the normal labdane series.
solvents were HPLC grade and were used without purification.
Na2SO4 was used to remove water from the organic layer in
reaction workups. Silica gel 60 F254 plates were used for TLC.
Flash column chromatography was performed using silica gel
(Merck, no. 9385, 230-400 mesh) and mixtures of AcOEt-n-
hexane as eluents.
P r ep a r a tion of 10 fr om (+)-Scla r eolid e (7). To a solution
of (+)-sclareolide (7, 400 mg, 1.6 mmol) in 60 mL of toluene,
at -78 °C, was added DIBAL-H (1.7 mL, 1.7 mmol, 1.0 M in
toluene) dropwise. After 45 min of stirring 10 mL of H2SO4
aqueous solution (10%) was added, the reaction mixture was
allowed to reach room temperature, and it was stirred for an
additional 15 min. The mixture was extracted with CHCl3 (3
× 30 mL), and the combined organic phases were dried and
solvents removed under reduced pressure. The residue, chro-
matographed with hexanes-AcOEt (1:4), yielded 380 mg (94%)
of pure 10 as a syrup: IR (film) νmax 3314, 2925, 2854, 1460,
1
1379, 1333, 1205, 1153, 1131, 1074, 965, 888 cm-1; H NMR
(CDCl3, 300 MHz) δ 5.42 (1H, dd, J ) 6.1, 5.3 Hz, H-12), 2.02
(1H, ddd, J ) 18.5, 12.30, 6.3 Hz, HB-11), 1.93-1.88 (2H, m,
HA-11 and H-9), 1.75-1.65 (3H, m), 1.22 (3H, s,), 1.47-0.96
(8H, m), 0.85 (2 × 3H, s), 0.81 (3H, s); 13C NMR (CDCl3, 50.3
MHz) δ 101.8 (d, C-12), 81.2 (s, C-8), 60.2 (d, C-9), 57.0 (d,
C-5), 42.4 (t, C-3), 40.0 39.8 (t, C-1), 39.7 (t, C-7), 36.1 (s, C-10),
33.5 (q, C-18), 33.1 (s, C-4), 30.8 (t, C-11), 23.5 (q, C-17), 21.0
(q, C-19), 20.8 (t, C-6), 18.4 (t, C-2), 15.2 y 15.3 (q, C-20); EIMS
m/z 252 [M]+ (5), 237 [M - 15]+ (100), 219 (8), 201 (16), 177
(24), 137 (33), 125 (40), 109 (30), 95 (37), 81 (34), 69 (39), 43
(43); anal. C 76.05%, H 11.12%, calcd for C16H28O2, C 76.14%,
H 11.18%.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Melting points were
determined on a Kofler block. Optical rotations were measured
on a Perkin-Elmer 241 MC polarimeter. IR spectra were
1
obtained on a Perkin-Elmer 681 spectrophotometer. H NMR
spectra were recorded using a Bruker AM 200 apparatus at
200 MHz or a Varian INOVA-300 spectrometer at 300 MHz.
13C NMR spectra were recorded at 50.3 or 75 MHz. Chemical
1
shifts for H NMR are reported with respect to residual CHCl3
P r ep a r a tion of (1S,2S,4a S,8a S)-N-Meth oxy-N-m eth yl
1-(2-h yd r oxy-2,5,5,8a -tetr a m eth yld eca h yd r on a p h th a len -
yl)a ceta m id e (11) fr om (R)-(+)-Scla r eolid e (7). To a stirred
suspension of N,O-dimethylhydroxylamine hydrochloride (1.5
g, 15.4 mmol) in CH2Cl2 (40 mL) at 0 °C was added Me3Al (8
mL, 16.0 mmol, 2 M in toluene). The mixture was warmed to
room temperature and stirred for 2 h until a clear solution
was obtained. Sclareolide (7, 2.0 g, 8.0 mmol) was added in
CH2Cl2 (20 mL) and the mixture stirred for another 2 h. After
cooling to 0 °C, 15 mL of 10% aqueous H2SO4 was added slowly.
(δ 7.25) and with respect to CDCl3 (δ 77.00) for 13C NMR
spectra. MS were recorded in the positive EI mode on a
Hewlett-Packard HP 5989A instrument (70 eV). Elemental
analyses were made with a Carlo Erba EA 1108 apparatus.
R-(+)-Sclareolide was from Aldrich, and it was used as
received. All reagents were used as obtained from commercial
sources. Methylene chloride (CH2Cl2), toluene (C6H5-CH3),
and tetrahydrofuran (THF) were distilled under positive
pressure of argon from CaH2 or Na-benzophenone. Other

Furolabdanes and Derivatives from R-(+)-Sclareolide
J ournal of Natural Products, 2002, Vol. 65, No. 5 665
The reaction mixture was allowed to reach room temperature,
and the two layers were separated. The aqueous layer was
extracted with CH2Cl2 (3 × 30 mL), and the combined organic
extracts were dried and concentrated under reduced pressure.
The residue was purified over silica gel using hexanes-AcOEt
(2:3) as eluent to give 11 (2.2 g, 88%) as an amorphous solid:
Chromatography of the residue using hexanes-AcOEt (95:5)
yielded 223 mg (89%) of pure 13.
P r ep a r a tion of 15,16-Ep oxy-12-oxola bd a -7,13(16),14-
tr ien e (14) fr om 13. 3-Bromofuran (0.23 mL, 2.5 mmol) was
added dropwise to a solution of n-butyllithium (1.2 M in
hexanes, 2.5 mL, 3.0 mmol) in dry THF (2.5 mL), at -78 °C
under argon. The mixture was stirred for 1 h and then
transferred via cannula into a solution of amide 13 (0.3 g, 1.0
mmol) in dry THF (40 mL) cooled at -78 °C. After 2 h the
substrate was consumed and the reaction was quenched by
adding 50 mL of NH4Cl (saturated solution). The aqueous
phase was extracted with AcOEt (3 × 50 mL), the combined
organic layers were dried, and the solvent was evaporated. The
residue was chromatographed using hexanes-CH2Cl2 (4:1) as
eluent. Thus, 220 mg of pure ketone 14 (72%) was obtained:
mp 107-109 °C; [R]20 +26.8°(c 0.112, CHCl3); IR (KBr) νmax
D
3439, 2934, 1643, 1645, 1387, 1167, 1107, 1010, 942 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 3.71 (3H, s), 3.18 (3H, s), 2.57 (1H,
dd, J ) 6.5, 16.6 Hz, HB-11), 1.93 (1H, dt, J ) 14.3, 2.9 Hz,
HA-11), 1.94 (1H, s, OH), 1.72-0.92 (10H, m), 1.15 (3H, s),
0.87 (s, 3H), 0.79 (s, 3H); 13C NMR (CDCl3, 50.3 MHz) δ 176.1
(s, C-12), 72.9 (s, C-8), 61.2 (q, OMe), 56.32 (d, C-9), 55.91 (d,
C-5), 44.57 (t, C-3), 41.78 (t, C-7), 39.20 (t, C-1), 38.72 (s, C10),
33.4 (q, NMe and C-18), 33.3 (s, C-4), 26.9 (t, C-11), 23.3 (q,
C-17), 21.4 (q, C-19), 20.6 (t, C-6), 18.5 (t,C-2), 15.8 (t, C-20);
EIMS m/z 311 [M]+ (1), 278 [M - Me - H2O]+ (2), 251 [M -
N(Me)OMe]+ (13), 191 (18), 137 (34), 116 (100), 109 (35), 95
(24), 61 (47), 55 (27), 43 (34), 41 (28); anal. C 69.22%, H 10.77%,
spontaneous white crystals mp 70-73 °C; [R]27 +42.9° (c
D
0.219, CHCl3); IR (KBr) νmax 2963, 2926, 2847, 1668, 1560,
1512, 1385, 1158, 873 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.04
(1H, d, J ) 0.9 Hz, H-16), 7.43 (1H, t, J ) 1.8 Hz, H-15), 6.78
(1H, dd, J ) 1.8, 0.9 Hz, H-14), 5.41 (1H, br s, H-7), 2.80 (1H,
m), 2.77 (1H, d J ) 16.5 Hz, HB-11), 2.67 (1H, dd, J ) 16.5,
14.3 Hz, HA-11), 2.04 (1H, m), 1.86 (1H, m), 1.64 (1H, br d, J
) 12.6 Hz), 1.45 (3H, br s, Me-17), 1.50-1.00 (7H, m), 0.88
(3H, s), 0.87 (3H, s), 0.81 (3H, s); 13C NMR (50.0 MHz, CDCl3)
δ 194.9 (s, C-12), 145.6 (d, C-15), 144.0 (d, C-16), 133.8 (s, C-8),
127.8 (s, C-13), 122.4 (d, C-7), 108.7 (d, C-14), 45.6 (d, C-5),
48.2 (d, C-9), 42.0 (t, C-3), 39.1 (t, C-1), 38.3 (t, C-11), 35.7 (s,
C-10), 33.0 (q, C-18), 32.8 (s, C-4), 23.6 (t, C-6), 21.9 (q, C-17)*,
21.7 (q, C-19)*, 18.7 (t, C-2), 14.3 (q, C-20), assignments
marked with an asterisk may be interchanged; EIMS m/z 300
[M]+ (12), 285 (2), 215 (2), 190 (100), 175 (39), 119 (35), 109
(61), 105 (30), 95 (99); anal. C 79.56%, H 9.52%, calcd for
N
4.41%, calcd for
C18H33NO3, C 69.41%, H 10.68%, N
4.50%.
P r ep a r a t ion of (1S,4a S,8a S)-N-Met h oxy-N-m et h yl 1-
(5,5,8a -tr im eth yl-2-m eth ylen ed eca h yd r on a p h th a len yl)-
a ceta m id e (12) a n d (1S,4a S,8a S)-N-m eth oxy-N-m eth yl
1-(2,5,5,8a -tetr a m eth yl-1,4,4a ,5,6,7,8-octa h yd r on a p h th a -
len yl)a ceta m id e (13) fr om 11. To a solution of 11 (0.5 g, 1.6
mmol) in pyridine (10.0 mL) at 0 °C was added dropwise 1.2
mL (16.0 mmol) of SOCl2 in pyridine (5 mL). The reaction
mixture was stirred for 30 min, poured into an ice-water
mixture (30 mL), and extracted with CH2Cl2 (3 × 40 mL). The
combined organic layers were dried and concentrated under
vacuum. The residue was chromatographed with hexanes-
AcOEt (95:5) as eluent, yielding 12 (280 mg, 60%) and 13 (150
mg, 32%).
C
20H28O2, C 79.96%, H 9.39%.
P r ep a r a tion of (12R)- a n d (12S)-15,16-Ep oxy-12-h y-
Com p ou n d 12: amorphous white solid, mp 90-93 °C;
d r oxyla bd a -7,13(16),14-tr ien e (15 a n d 16) fr om 14. To a
solution of ketone 14 (820 mg, 2.7 mmol) in MeOH (53 mL) at
room temperature was added 2.0 g of CeCl3 × 7H2O (5.5
mmol), and the mixture was stirred for 30 min. The resulting
slurry was cooled until 0 °C, and NaBH4 (625 mg, 16.4 mmol)
was added in portions. The mixture was allowed to reach room
temperature and stirred for 24 h. After this time, H2O (50 mL)
was added and the mixture stirred for an additional 1 h. The
resulting solution was concentrated under vacuum, and the
aqueous phase was extracted with AcOEt (3 × 50 mL). The
combined organic layers were dried and evaporated under
reduced pressure. Chromatography of the residue using hex-
anes-AcOEt (1:1) yielded in increasing order of polarity
unreacted ketone 14 (150 mg), alcohol 15 (250 mg, 37%), and
alcohol 16 (220 mg, 33%).
[R]20D +45.7° (c 0.094, CHCl3); IR (KBr) νmax 2960, 2926, 1662,
1
1645, 1459, 1383, 1364, 1174, 1000, 904 cm-1; H NMR (300
MHz, CDCl3) δ 4.70 (1H, s, HB-17), 4.40 (1H, s, HA-17), 3.69
(3H, s, OMe), 3.13 (3H, s, NMe), 2.67 (1H, dd, J ) 15.8, 9.9
HB-11), 2.47 (1H, broad d, J ) 10.3 Hz, H-9R), 2.36 (1H, dd, J
) 15.7, 3.7 Hz, HA-11), 2.42-2.30 (2H, m), 2.11 (1H, td, J )
12.8, 5.5 Hz, H-7a), 1.76-1.08 (9H, m), 0.86 (3H, s), 0.79 (3H,
s), 0.71 (3H, s); 13C NMR (50.3 MHz, CDCl3) δ 174.7 (s, C-12),
149.7 (s, C-8), 105.8 (t, C-17), 61.3 (q, OMe), 55.1 (d, C-9), 51.7
(d, C-5), 42.1 (t, C-3), 39.0 (s, C-10), 38.9 (t, C-1), 37.63 (t, C-7),
33.6 (q, C-18), 33.5 (s, C-4), 32.6 (q, NMe), 27.3 (t, C-11), 24.1
(t, C-6), 21.8 (q, C-19), 19.4 (q, C-19), 19.3 (t, C-2), 14.7 (q,
C-20); EIMS m/z 293 [M]+ (22), 278 [M - 15]+ (43), 262 [M -
OMe]+ (13), 233 (25), 215 (18), 205 (18), 190 (20), 175 (28),
158 (56), 149 (330, 137 (46), 123 (45), 121 (59), 109 (79), 95
(66), 81 (69), 69 (91), 61 (100), 55 (58), 41 (71); anal. C 73.79%,
H 10.43%, N 4.52%, calcd for C18H31NO2, C 73.67%, H 10.65%,
N 4.77%.
Com p ou n d 15: oil; [R]21D +25.6° (c 0.340, CHCl3); IR (film)
ν
max 3400, 2922, 2847, 1502, 1455, 1387, 1159, 1024, 874 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.38 (2H, m, H-16 and H-15),
6.41 (H, dd, J ) 1.5, 0.8 Hz, H-14), 5.43 (1H, br s, H-7), 4.72
(1H, dd, J ) 8.4, 1.6 Hz, H-12), 2.20-0.90 (12 H, m), 1.66 (3H,
br s), 0.89 (3H, s), 0.87 (3H, s), 0.76 (3H, s); 13C NMR (50.3
MHz, CDCl3) δ 143.3 (d, C-15), 138.5 (d, C-16), 134.6 (s, C-8),
130.1 (s, C-13), 123.0 (d, C-7), 108.5 (d, C-14), 67.6 (d, C-12),
50.5 (d,C-9)*, 50.4 (d, C-5)*, 42.3 (t, C-3), 39.4 (t, C-1), 36.3 (t,
C-11), 36.3 (s, C-10)*, 33.1 (q, C-18), 33.0 (s, C-4)*, 23.9 (t, C-6),
22.3 (q, C-17)*, 21.8 (q, C-19)*, 18.8 (t, C-2), 13.6 (q, C-20),
assignments marked with an asterisk may be interchanged;
EIMS m/z 302 [M]+ (absent), 284 [M - 18]+ (11), 205 (32), 190
(40), 175 (29), 160 (82), 119 (31), 109 (72), 97 (100), 82 (54), 69
(48), 41 (54); anal. C 79.60%, H 9.59%, calcd for C20H30O2, C
79.42%, H 10.00%.
Com p ou n d 13: syrup, [R]24 +15.2° (c 0.250, CHCl3); IR
D
(KBr) νmax 2924, 2847, 2862, 1776, 1668, 1444, 1383, 1173,
1100, 1007 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.41 (1H, br s,
H-7), 3.70 (3H, s), 3.19 (3H, s), 2.80-1.00 (11H, m), 1.53 (3H,
br s), 0.89 (3H, s), 0.87 (3H, s), 0.80 (3H, s); 13C NMR (75.0
MHz, CDCl3) δ 175.4 (s, C-12), 134. 1 (s, C-8), 122.1 (d, C-7),
61.1 (q, OMe), 49.7 (d, C-9), 48.9 (d, C-5), 42.0 (t, C-3), 38.8 (t,
C-1), 35.8 (s, C-10), 33.0 (q, C-18), 32.8 (s, C-4), 32.7 (q, NMe),
29.1 (t, C-11), 23.6 (t, C-6), 21.7 (q, C-17), 21.3 (q, C-19), 18.7
(t, C-2), 14.2 (q, C-20); EIMS m/z 293 [M]+ (56), 278 (25), 262
(15), 233 (20), 215 (38), 190 (53), 175 (27), 137 (33), 119 (88),
109 (94), 103 (100), 95 (47), 81 (55), 69 (44), 61 (53), 41 (30);
anal. C 73.89%, H 10.56%, N 4.89%, calcd for C18H31NO2, C
73.67%, H 10.65%, N 4.77%.
Com p ou n d 16: oil; [R]21D -18.6° (c 0.200, CHCl3); IR (film)
νmax 3367, 2922, 2847, 1503, 1456, 1387, 1155, 1022, 874, 790
1
P r ep a r a t ion of (1S,4a S,8a S)-N-Met h oxy-N-m et h yl 1-
(2,5,5,8a -tetr a m eth yl-1,4,4a ,5,6,7,8-octa h yd r on a p h th a le-
n yl)a ceta m id e (13) fr om 12. A mixture of 12 (250 mg, 0.85
mmol) and p-TsOH (25 mg) in toluene (25 mL) was heated at
50 °C for 2 h. The reaction mixture was cooled at room
temperature and diluted with AcOEt (30 mL). The mixture
was washed with NaHCO3 (saturated solution, 3 × 50 mL).
The organic layer was dried, and the solvents were evaporated.
cm-1; H NMR (300 MHz, CDCl3) δ 7.38 (1H, m, H-16), 7.36
(1H, m, H-15), 6.44 (1H, dd, J ) 1.6, 1.0 Hz, H-14), 5.42 (1H,
br s, H-7), 4.75 (1H, dd, J ) 9.4, 5.4 Hz, H-12), 2.20-0.40 (12H,
m), 1.76 (3H, br s, Me-17), 0.84 (3H, s), 0.81 (3H, s), 0.74 (3H,
s); 13C NMR (50.3 MHz, CDCl3) δ 143.4 (d, C-15), 139.7 (d,
C-16), 134.6 (s, C-8), 128.5 (s, C-13), 122.9 (d, C-7), 108.7 (d,
C-14), 68.0 (d, C-12), 50.4 (d, C-5)*, 50.0 (d, C-9)*, 42.2 (t, C-3),
39.1 (t, C-1), 36.7 (s, C-10), 35.5 (t, C-11), 33.1 (q, C-18), 32.9

666 J ournal of Natural Products, 2002, Vol. 65, No. 5
de la Torre et al.
(s, C-4), 23.9 (t, C-6), 22.7 (q, C-17), 21.8 (q, C-19), 18.7 (t, C-2),
13.6 (q, C-20), assignments marked with an asterisk may be
interchanged; EIMS m/z 302 [M]+ (absent), 284 [M - 18]+ (9),
205 (28), 190 (25), 160 (78), 119 (24), 109 (61), 97 (100), 82
(47), 69 (44), 41 (52); anal. C 79.67%, H 9.68%, calcd for
Com p ou n d 6: IR (KBr) νmax 3435, 2920, 1754, 1631, 112
1
cm-1; H NMR (300 MHz, CDCl3) δ 6.23 (1H, m, H-16), 6.07
(1H, m, H-14), 5.46 (1H, br s, H-7), 4.68 (1H, t, J ) 6.2 Hz,
H-12), 1.73 (3H, br s, Me-17), 2.05-1.11 (12H, m), 0.88 (3H, s,
Me-18), 0.86 (3H, s, H-19), 0.79 (3H, s, Me-20); EIMS m/z 334
[M]+ (absent), 205 (10), 190 (80), 175 (7), 124 (40), 109 (100),
91 (18), 81 (46), 69 (20), 55 (27), 41 (21).
C
20H30O2, C 79.42%, H 10.00%.
P r ep a r a tion of Mosh er ’s Ester 17 fr om Alcoh ol 15.
P r ep a r a t ion of (12R)-12-Acet oxy-15,16-ep oxyla b d a -
7,13(16),14-tr ien e (19) fr om 15. Alcohol 15 (50 mg), was
treated with Ac2O-Pyr (12.0 mL, 1:2) for 24 h. Solvents were
removed under reduced pressure, and the residue was filtered
through a short pad of silica gel using AcOEt as solvent,
yielding 55 mg (99%) of pure 19: amorphous solid; mp 64-67
Alcohol 15 (8 mg, 0.025 mmol) in CH2Cl2 (1.0 mL) and a
catalytic amount of 4-(dimethylamino)pyridine were added to
a solution of (R)-(+)-R-methoxy-R-(trifluoromethyl)phenylacetic
acid (16.0 mg, 0.07 mmol) and 1,3-dicyclohexylcarbodiimide
(14.0 mg, 0.07 mmol) in CH2Cl2 (0.5 mL) at room temperature.
The mixture was stirred for 2 h until complete consumption
of alcohol. Then, the reaction mixture was filtered through a
pad of Celite and evaporated under vacuum. Chromatography
of the residue with hexanes-AcOEt (99:1) yielded 11 mg of
°C; [R]21 + 15.7° (c 0.070, CHCl3); IR (KBr) νmax 2923, 2847,
D
1725, 1361, 1240, 1020 cm-1
;
1H NMR (300 MHz, CDCl3) δ
7.40 (1H, d, J ) 0.6 Hz, H-16), 7.36 (1H, t, J ) 1.8 Hz, H-15),
6.38 (1H, dd, J ) 1.8, 0.6 Hz, H-14), 5.93 (1H, dd, J ) 10.9,
2.7 Hz, H-12), 5.41 (1H, br s, H-7), 2.06 (3H, s, OAc), 1.70 (3H,
br s, Me-17), 0.88 (3H, Me-18), 0.86 (3H, s, Me-19), 0.76 (3H,
s, Me-20); 13C NMR (50.3 MHz, CDCl3) δ 170.7 (s, OAc), 143.2
(d, C15), 139.8 (d, C-16), 134.2 (s, C-8), 125.7 (s, C-13), 123.1
(d, C-7), 108.8 (d, C-14), 69.0 (d, C-12), 50.4 (d, C-5)*, 49.9 (d,
C-9)*, 42.3 (t, C-3), 39.3 (t, C-1), 36.3 (s, C-10), 33.2 (q, C-18),
33.1 (t, C-11), 33.0 (s, C-4), 23.2 (q, C-17)*, 21.9 (q, C-19)*,
21.3 (q, OAc)*, 18.8 (t, C-2), 13.6 (q, C-20); EIMS m/z 344 [M]+
(absent), 284 [M - 60]+ (11), 190 (38), 175 (16), 160 (100), 145
(14), 119 (40), 109 (39), 97 (36), 81 (31), 43 (56); anal. C 76.53%,
H 9.52%, calcd for C22H32O3, C 76.70%, H 9.36%.
1
pure 17 (89%): H NMR (300 MHz, CDCl3) δ 7.50-7.31 (7H,
m, Ph, H-15, H-16), 6.44 (1H, m, H-14), 6.11 (1H, dd J ) 11.3,
1.7 Hz, H-12), 5.39 (1H, br s, H-7), 3.44 (3H, br s, OMe), 3.19
(1H, m), 2.07 (1H, dd J ) 13.9, 11.5 Hz, HB-11), 1.70 (3H, br
s, Me-17), 2.11-1.13 (11 H, m, decalin protons), 0.81 (3H, s),
0.80 (3H, s), 0.64 (3H, s).
P r ep a r a tion of Mosh er ’s Ester 18 fr om Alcoh ol 16.
Alcohol 16 (13 mg, 0.043 mmol) in CH2Cl2 (2.0 mL) and a
catalytic amount of 4-(dimethylamino)pyridine were added to
a solution of (R)-(+)-R-methoxy-R-(trifluoromethy)phenylacetic
acid (26.0 mg, 0.13 mmol) and 1,3-dicyclohexylcarbodiimide
(22.0 mg, 0.13 mmol), in CH2Cl2 (1 mL) at room temperature.
Working as above, 21 mg (93%) of pure 18 was obtained: 1H
NMR (300 MHz, CDCl3) δ 7.63-7.27 (7H, m, Ph, H-15, H-16),
6.28 (1H, m, H-14), 6.06 (1H, dd J ) 10.0, 5.7 Hz, H-12), 5.44
(1H, m, H-7), 3.52 (3H, br s, OMe), 2.03-1.05 (12H, m,), 1.77
(3H, br s, Me-17), 0.85 (3H, s), 0.82 (3H, s), 0.74 (3H, s).
Gen er a l P r oced u r e for Ir r a d ia tion of 15 a n d 16. A
solution of alcohol (100 mg) in THF (10 mL), containing ca. 1
mg of Rose Bengal, was irradiated with a 220 W tungsten lamp
for 5 h. The solvent was removed under reduced pressure, and
the residue was submitted to column chromatography, yielding
pure compounds.
P r ep a r a t ion of (12R,15ú)-12,15-d ih yd r oxyla b d a -7,14-
d ien -16,15-olid e (3) a n d (12R,16ú)-12,16-d ih yd r oxyla bd a -
7,14-d ien -15,16-olid e (4). P h otooxid a tion of 15. Irradiation
of alcohol 15 yielded, after chromatographic separation with
hexanes-AcOEt (3:1), 18 mg (16%) of lactone 3 and 12 mg
(11%) of lactone 4. Compounds 3 and 4 were unstable, and
correct analytical data could not be obtained.
P r ep a r a t ion of (12S)-12-Acet oxy-15,16-ep oxyla b d a -
7,13(16),14-tr ien e (20) fr om 16. Alcohol 16 (150 mg) was
treated with Ac2O-Pyr (18.0 mL, 1:2) for 24 h at room
temperature. Solvents were removed under reduced pressure.
The residue, filtered through a short pad of silica gel using
AcOEt solvent, yielded 160 mg (98%) of pure 20 as a syrup:
[R]22D -32.8° (c 0.090, CHCl3); IR (film) νmax 2925, 1739, 1369,
1
1239, 1022 cm-1; H NMR (200 MHz, CDCl3) δ 7.42 (1H, m,
H-16), 7.39 (1H, t, J ) 1.5 Hz, H-15), 6.41 (1H, dd, J ) 1.7,
0.7 Hz, H-14), 5.87 (1H, dd, J ) 8.8, 6.59 Hz, H-12), 5.42 (1H,
br s, H-7), 2.02 (3H, OAc), 1.90-1.40 (12H, m), 1.80 (3H, s,
Me-17), 0.84 (3H, Me-18), 0.80 (3H, s, Me-19), 0.73 (3H, s, Me-
20); 13C NMR (50.3 MHz, CDCl3) δ 170.3 (s, OAc), 143.2 (d,
C-15), 140.9 (d, C-16), 134.3 (s, C-8), 124.5 (s, C-13), 123.0 (d,
C-7), 109.2 (d, C-14), 69.9 (d, C-12), 50.2 (d, C-5), 49.9 (d, C-9),
42.1 (t, C-3), 39.2 (t, C-1), 36.8 (s, C-10), 33.0 (q, C-18), 33.0
(s, C-4), 32.3 (t, C-11), 23.8 (t, C-6), 22.7 (q, C-17), 21.8 (q,
C-19), 21.3 (q, OAc), 18.7 (t, C-2), 13.6 (q, C-20); EIMS m/z
344 [M]+ (absent), 284 [M - 60]+ (11), 269 (3), 190 (26), 160
(100), 140 (25), 119 (36), 109 (48), 105 (23), 97 (50), 81 (38), 43
(74); anal. C 76.48%, H 9.60%, calcd for C22H32O3, C 76.70%,
H 9.36%.
Com p ou n d 3: 1H NMR (300 MHz, CDCl3) δ 7.04 (1H, m,
H-14), 6.12 (1H, m, H-15), 5.42 (1H, m, H-7), 4.56 (1H, m,
H-12), 1.73 (3H, s, Me-17), 0.87 (3H, s), 0.86 (3H, s), 0.73 (3H,
s). Due to the instability of 3 IR and MS data could not be
obtained.
Gen er a l P r oced u r e for Ir r a d ia tion of 19 a n d 20. A THF
solution of the corresponding acetate, containing a catalytic
amount of Rose Bengal, was irradiated under direct sunlight
until TLC analysis showed complete transformation of the
starting material. The solvent was removed under reduced
pressure, and the residue was submitted to column chroma-
tography to yield analytically pure compounds.
Com p ou n d 4: IR (KBr) νmax 3434, 2925, 1752, 1631, 1009
cm-1 1H NMR (300 MHz, CDCl3) δ 6.24 (1H, s, H-16), 6.12
;
(1H, br s, H-14), 5.44 (1H, br s, H-7), 4.67 and 4.55 (1H, m,
H-12), 1.73 and 1.69 (3H, br s, Me-17), 2.08-1.01 (12H, m),
0.87 (3H, s Me-18), 0.86 (3H, s, Me-19), 0.74 and 0.73 (3H, s,
Me-20); EIMS m/z 334 [M]+ (absent), 205 (14), 189 (10), 175
(7), 124 (36), 109 (100), 91 (22), 81 (50), 69 (26), 55 (32), 41
(27).
P r ep a r a t ion of (12R)-12-Acet oxy-15-h yd r oxyla b d a -
7,14-d ien -16,15-olid e (21) a n d (12R)-12-Acetoxy-16-h y-
d r oxyla bd a -7,14-d ien -15,16-olid e (22) fr om 19. Irradiation
of 19 (75 mg) in THF (15 mL) yielded, after chromatographic
separation with hexanes-AcOEt (4:1), 29 mg of the hydroxy-
butenolide 21 (35%) and 23 mg (33%) of its isomer 22.
Com p ou n d 21: syrup; IR (film) νmax 3429, 2925, 2847, 1747,
1456, 1373, 1230, 1131, 1042 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.94 (1H, m, H-14), 6.09 (1H, m, H-15), 5.70 (1H, dd, J )
6.7, 3.8 Hz, H-12), 5.42 (1H, br s, H-7), 2.13 (3H, s, OAc), 1.75
(3H, br s, Me-17), 2.00-1.15 (12H, m), 0.87 (3H, s, Me-19),
0.72 (3H, s, Me-20); EIMS m/z 376 [M]+ (absent), 316 [M -
60]+ (23), 301 (5), 205 (9), 190 (30), 147 (28), 119 (54), 109 (100),
105 (26), 91 (28), 81 (36), 69 (27), 55 (27), 43 (52); anal C
69.84%, H 8.35%, calcd for C22H32O5 C 70.18%, H 8.57%.
Com p ou n d 22: syrup; IR (film) νmax 3430, 2924, 2827, 1749,
1373, 1235, 1011 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.20 6.03
(1H, m, H-16), 5.97 (1H, m, H-14), 5.56 (1H, br d, J ) 10.6
P r ep a r a tion of (12S,15ú)-12,15-d ih yd r oxyla bd a -7,14-
d ien -16,15-olid e (5) a n d (12S,16ú)-12,16-Dih yd r oxyla bd a -
7,14-d ien -15,16-olid e (6). P h otooxid a tion of 16. Irradiation
of alcohol 15 yielded, after chromatography with hexanes-
AcOEt (3:1), 22 mg (20%) of lactone 5 and 15 mg (10%) of
lactone 6. Compounds 5 and 6 were unstable, and correct
analytical data could not be obtained.
Com p ou n d 5: IR (KBr) νmax 3455, 2924, 2847, 1749, 1634,
1129 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.08 and 7.05 (1H, s,
H-14), 6.15 (1H, br s, H-15), 5.45 (1H, br s, H-7), 4.55 (1H, t,
J ) 6.7 Hz, H-12), 1.95-1.12 (12H, m), 1.70 (3H, br s, Me-17),
0.87 (3H, s, Me-18), 0.84 (3H, s, H-19), 0.76 (3H, s, Me-20);
EIMS m/z 334 [M]+ (absent), 316 [M - 18]+ (1), 298 [M - 36]+
(1), 205 (50), 149 (17), 124 (25), 109 (100), 81 (59), 55 (27), 41
(21).

Furolabdanes and Derivatives from R-(+)-Sclareolide
J ournal of Natural Products, 2002, Vol. 65, No. 5 667
Hz, H-12), 5.46 (1H, br s, H-7), 2.14 (3H, s, OAc), 1.71 (3H, br
s, Me-17), 2.00-1.20 (12H, m), 0.88 (3H, s, Me-18), 0.86 (3H,
s, Me-19), 0.75 (3H, s H-20); EIMS m/z 376 [M]+ (absent), 298
[M - 60 - 18]+ (1), 205 (5), 190 (43), 175 (14), 124 (39), 119
(28), 109 (100), 81 (27), 69 (21), 43 (36); anal C 69.93%, H
8.38%, calcd for C22H32O5 C 70.18%, H 8.57%.
P r epar ation of (12S)-12-Acetoxy-15-h ydr oxylabda-7,14-
d ien -16,15-olid e (23) a n d (12S)-12-Acetoxy-16-h yd r oxyl-
a bd a -7,14-d ien -15,16-olid e (24) fr om 20. Irradiation of 20
(120 mg), in THF (25 mL), yielded, upon chromatography with
hexanes-AcOEt (4:1), 55 mg of pure hydroxybutenolide 23
(42%) and 30 mg (23%) of its isomer 24.
Com p ou n d 23: syrup; IR (film) νmax 3434, 2926, 2847,
1768, 1749, 1635, 1458, 1370, 1236, 1014 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.01, 7.00 (1H, br s, H-14), 6.12, 6.09 (1H, br
s, H-15), 5.57 (1H, t, J ) 6.5 Hz, H-12), 5.43 (1H, br s, H-7),
2.10, 2.01 (3H, s, OAc), 1.73 (3H, br s, Me-17), 2.06-0.89 (12H,
m), 0.85 (3H, s, Me-18), 0.82 (3H, s, Me-19), 0.75 (3H, s, Me-
20); EIMS m/z 376 [M]+ (absent), 316 [M - 60]+ (25), 301 (6),
215 (5), 190 (27), 133 (14), 119 (48), 109 (100), 105 (26), 91
(29), 81 (36), 69 (26), 55 (27), 43 (57); anal C 69.90%, H 8.46%,
calcd for C22H32O5 C 70.18%, H 8.57%.
Com p ou n d 24: syrup; IR (film) νmax 3430, 2926, 2862, 2847,
1747, 1638, 1458, 1367, 1232 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.24, 6.05 (1H, br s, H-16), 6.02 (1H, br s, H-14), 5.47 (1H,
br s, H-7), 5.36 (1H, t, J ) 7.7 H-12), 2.12, 2.09 (3H, s, OAc),
2.00-2.70 (12H, m), 1.71 (3H, s, Me-17), 0.86 (3H, s, Me-17),
0.84 (3H, s, Me-19), 0.76 (3H, s, Me-20); anal C 70.25%, H
8.50%, calcd for C22H32O5 C 70.18%, H 8.57%.
5.64 (1H, t J ) 7.1 Hz, H-12 major), 5.62 (1H, t, J ) 7.3 Hz,
H-12 minor), 5.43 (1H, br s, H-7), 2.15, 2.14, 2.11 and 2.10
(3H each, s, OAc), 1.74 (3H, br s, Me-17), 2.03-1.13 (12H, m),
0.85 (3h, s, Me), 0.83 (3H, s, Me), 0.75 (3H, s, Me); EIMS m/z
358 [M+ - 60] (25), 316 (8), 298 (10), 205 (13), 190 (40), 174
(48), 119 (49), 109 (90), 91 (27), 81 (34), 69 (27), 55 (23), 43
(100); anal. C 68.63%, H 8.22%, calcd for C24H34O6, C 68.87%,
H 8.19%.
Com p ou n d 28. Following the general procedure, 25 mg
(0.06 mmol) of 24 yielded 20 mg (80%) of an epimeric mixture
of 28 as a syrup: [R]24 -5.8° (c 2.170, CHCl3); IR (film) νmax
D
2962, 2920, 2850, 1797, 1744, 1455, 1372, 1260, 1024, 865, 799
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.04 (1H, m, H-16 minor),
6.97 (1H, d, J ) 1.0 Hz, H-16 major), 6.16 and 6.07 (1H each,
t, J ) 1.1 Hz, H-14), 5.68 (1H, td, J ) 8.1, 1.20 Hz, H-12 major),
5.46 (2H, br s, and td H-7 and H12 minor), 2.18 and 2.12 (3H
each, s, 2 × OAc, major), 2.15 and 2.07 (3H, each, s 2 × OAc
minor), 2.02 (12H, m), 1.69 (3H, me-17), 0.86 (3H, s, Me), 0.84
(3H, s, Me), 0.77 and 0.75 (3H, s, Me-20); IEMS m/z 358 [M+
- 60] (1), 343 (1), 298 (7), 283 (5), 189 (43), 175 (17), 124 (34),
119 (34), 109 (100), 91 (17), 81 (26), 69 (19), 55 (17), 43 (53);
anal. C 69.12%, H 7.84%, calcd for C24H34O6, C 68.87%, H
8.19%.
Ack n ow led gm en t. Financial support by the Spanish
Comision Interministerial de Ciencia y Tecnolog´ıa (M.C.T.,
CICYT, Grant No. AGF98-0805), the Direccio´n General de
Ensen˜anza Superior e Investigacio´n Cient´ıfica y Te´cnica
(MEC-Spain), and the European Commision (M. A. Sierra,
grants PB97-0323 and 2FD97-0314-CO2-02) is acknowledged.
I.G. thanks the MEC (Spain) for a predoctoral fellowship. We
wish to thank Prof. Mar Go´mez-Gallego (UCM) for her careful
editing of the manuscript and her valuable suggestions.
P r ep a r a tion of (12R)-12,15-Dia cetoxyla bd a -7,14-d ien -
16,15-olid e (25), (12R)-12,16-Dia cetoxyla bd a -7,14-d ien -
15,16-olid e (26), (12S)-12,15-Dia cetoxyla bd a -7,14-d ien -
16,15-olid e (27), a n d (12S)-12,16-Dia cetoxyla bd a -7,14-
d ien -15,16-olid e (28) fr om 21 to 24. Compounds 21-24 were
treated with the mixture Ac2O-Pyr (2 mL, 1:2) for 24 h at
room temperature. Solvents were removed under reduced
pressure, and the residues were purified by chromatography,
using hexanes-AcOEt (9:1).
Refer en ces a n d Notes
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Com p ou n d 25. Following the general procedure, 24 mg
(0.064 mml) of 21 yielded 23 mg (86%) of an epimeric mixture
of 25 as a syrup: [R]23 +30.9°(c 0.330 CHCl3); IR (film) νmax
D
2925, 2862, 1780, 1743, 1456, 1373, 1226, 1022, 757 cm-1; 1H
NMR (300 MHz, CDCl3) δ 6.89 (1H, m, H-15 minor), 6.87 (1H,
t, J ) 1.6 Hz, H-14 minor), 6.97 (2H, m, H-14 and H-15 major),
5.76 (1H, tdd, J ) 7.8, 1.6 Hz, H-12 minor and major), 5.42
(1H, br s, H-7), 2.14 (6H, 2 × OAc major), 2.13 (3H, s, OAc,
minor), 2.15 (3H, s, OAc, minor), 1.80 (3H, s, Me-17), 0.86 (6H,
2 × Me, minor), 0.85 (6H, 2 × Me, major), 0.73 (3H, Me-20,
major), 0.72 (3H, Me-20 minor); EIMS m/z 418 [M+] (1), 358
[M+ - 60] (19), 298 (8), 205 (10), 190 (36), 174 (43), 119 (53),
109 (88), 105 (24), 91 (26), 81 (36), 69 (31), 43 (100); anal. C
68.59%, H 7.95%, calcd for C24H34O6, C 68.87%, H 8.19%.
Com p ou n d 26. Following the general procedure, 19 mg
(0.051 mml) of 22 yielded 18 mg (84%) of an epimeric mixture
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1199-1210.
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of 26 as a syrup: [R]24 +14.7° (c 0.660, CHCl3); IR (film) νmax
D
2962, 2920, 2847, 1800, 1747, 1653, 1455, 1373, 1261, 1226,
1026, 866 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.02 (1H, d, J )
1.0 Hz, H-16 minor), 6.94 (1H, d, J ) 0.9 Hz, H-16 major),
6.12 (1H, dd, J ) 1.6, 1.1 Hz, H-14 minor), 6.04 (1H, t, J ) 1.1
Hz, H-14 major), 5.81 (1H, dt, J ) 11.7, 1.7 Hz, H-12 major),
5.62 (1H, br d, J ) 13.5 Hz, H-12 minor), 5.45 (1H, br s, H-7),
2.17 and 2.16 (3H each, s, 2 × OAc major), 2.14 and 2.10 (3H
each, s, 2 × OAc minor), 1.55 (3H, s, Me-17), 2.03-1.10 (12H,
m), 0.87 (3H, s, Me minor), 0.85 (3H, s, Me major), 0.85 (3H,
s, Me), 0.75 (3H, s, Me minor), 0.73 (3H, s, Me major); EIMS
m/z 298 [M+ - 60 - 60] (3), 283 (2), 255 (1), 189 (24), 175 (12),
124 (30), 119 (35), 109 (100), 81 (30), 69 (26), 55 (25), 43 (79);
anal. C 69.03%, H 7.88%, calcd for C24H34O6, C 68.87%, H
8.19%.
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Com p ou n d 27. Following the general procedure, 50 mg
(0.133 mmol) of 23 yielded 51 mg (92%) of an epimeric mixture
of 27 as a syrup: [R]23 -29.1° (c 0.500, CHCl3); IR (film) νmax
D
2925, 2847, 2862, 1780, 1746, 1458, 1372, 1335, 1227, 1022,
966, 797, 757 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.05 (1H, m,
H-15 or H-14), 6.92 and 6.89 (1H, d, J ) 1.1 Hz, H-14 or H-15),

668 J ournal of Natural Products, 2002, Vol. 65, No. 5
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NP010590U