Diversity oriented synthesis of hispanane-like terpene derivatives from (R)-(+)-sclareolide

Article abstract of DOI:10.1002/chem.200401220

(R)-(+)-Sclareolide 1 has been used as a starting material to develop a diversity oriented methodology to access hispanane 28 a, and hispanane-like derivatives 27b-27e. This methodology is based on the intramolecular Friedel-Crafts acylation of the corres

Full text of DOI:10.1002/chem.200401220

FULL PAPER
Diversity Oriented Synthesis of Hispanane-like Terpene Derivatives from
(R)-(+)-Sclareolide
Marꢀa C. de la Torre,*[a] Isabel Garcꢀa,[b] and Miguel A. Sierra[c]
Dedicated to the memory of our friend Dr. Juan Carlos del Amo, who died as a victim of the terrorist attack in Madrid on
March 11th, 2004
Abstract: (R)-(+)-Sclareolide
1
has
cloheptane ring which is characteristic
of the hispananes. Acids 27 are ob-
tained from alcohols 20, available by
addition of the lithium or magnesium
reagents to amide 12 (followed by
Luche reduction), or to aldehyde 21.
This sequence has resulted in the prep-
aration of hispanane framework 27a.
The versatility of this methodology
therefore allows a structural diversity
oriented synthesis, since it allows the
access to a wide variety of hispanane-
like derivatives.
been used as a starting material to de-
velop a diversity oriented methodology
to access hispanane 28a, and hispa-
nane-like derivatives 27b–27e. This
methodology is based on the intramo-
lecular Friedel–Crafts acylation of the
corresponding 12-desoxylabdanoic-like
acids 27, for the construction of the cy-
Keywords: acylation · hispananes ·
natural products · terpenoids · total
synthesis
Introduction
regard, natural products are ideal templates for achieving an
increasing of structural complexity either by performing de-
signed modifications to incorporate new structural motifs[3]
or by joining different natural products in a single structure
producing natural product derivatives.[4] The increasing
awareness of the key role that small molecules play in the
protein–protein interactions[5] leading to the production of
drug-like molecules,[6] confers an added value to the new
structures.
The last years of the 20th century witnessed an enormous
grown of diversity oriented synthesis.[1] Contrary to modern
combinatorial chemistry,[2] which is able to produce impres-
sive amounts of new compounds but with the shortcoming
of the inability to yield new chemical identities, diversity ori-
ented organic synthesis is—according to Schreiber and
Burke[1]—a problem-solving technique for transforming a
collection of simple and similar starting materials into a col-
lection of more complex and diverse products. In this
In this context we reported recently[7] the suitability of
(R)-(+)-sclareolide 1 as a template to yield the diverse
tetra- 2 and pentacyclic 3 terpene derivatives by means of
the photochemical cyclization of easily available ketones 4
(Scheme 1). Clearly, by modifying the nature of the moieties
attached to the (R)-(+)-sclareolide template, the resulting
products are nicely set up to access to terpene-like products
containing the sclareolide scaffold. In fact, the stereochemis-
try of the bicyclic decaline of (R)-(+)-sclareolide framework
1 contributes the necessary stereocenters, and the lactone
ring of sclareolide may be manipulated to access to the key
intermediates to produce the final terpene-like products.
Natural hispananes are a scarce group of diterpenes that
include exclusively three compounds: hispanonic acid 5 and
hispaninic acid 6 isolated from Ballota hispanica[8] and
methyl verticoate 7 isolated from Sciadopitys verticillata
(Figure 1).[9] The isolation of these compounds in minute
amounts precluded the investigation of their biological prop-
[a] Dr. M. C. de la Torre
Instituto de Quꢀmica Orgꢁnica
Dpto. de Productos Naturales, CSIC, C/Juan de la Cierva 3
28006 Madrid (Spain)
Fax : (+34)915-644-853
E-mail: iqot310@iqog.csic.es
[b] Dr. I. Garcꢀa
Present address: Dpto. de Quꢀmica Orgꢁnica
Facultad de Ciencias, Mꢂdulo C-I/Despacho 408
Universidad Autꢂnoma de Madrid, 28049 Madrid (Spain)
[c] Prof. M. A. Sierra
Dpto. de Quꢀmica Orgꢁnica
Facultad de Quꢀmica, Universidad Complutense
28040 Madrid (Spain)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2005, 11, 3659 – 3667
DOI: 10.1002/chem.200401220
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hispanane skeleton and hispanane-like derivatives 9 starting
from (R)-(+)-sclareolide 1.
Scheme 1. Preparation of polycyclic terpene-like products from (R)-(+)-
sclareolide.
erties. To date no synthetic approaches to the hispanane
skeleton have been reported.
We devised a potentially versatile approach to the hispa-
nane skeleton and hispanane-like derivatives 8 based on a
Friedel–Crafts acylation to form the seven-membered ring,
Scheme 2. Approach to hispanane derivatives 9 from (R)-(+)-sclareolide.
Results and Discussion
To fine tune the sequence shown in Scheme 2, phenyllab-
dane ketone 13 was prepared by the reaction of Weinrebꢄs
amide 12 and phenylmagnesium bromide in 95% yield. The
ketone group of 13 was reduced by using Luche conditions
(NaBH4/CeCl3)[11] to yield the mixture of epimeric alcohols
14; the alcohols were then acetylated (Ac2O/py) to form
acetates 15, and treated with BH3·SMe2 followed by oxida-
tive (H2O2/NaOH) work-up. The primary alcohols 16 and
epi-16 were separated by column chromatography to yield
the pure epimers at C-12 (41 and 33% yield, respectively)
(Scheme 3).
Figure 1. Hispananes isolated from natural sources.
which is characteristic for these types of compounds
(Scheme 2). 17-Labdanoic-like acids 9, the substrates for
ring-closure, are prepared by oxidation of the corresponding
alcohols 10, derived from the D8,17 unsaturated labdanes 11;
the latter have been already prepared by our group by addi-
tion of the appropriate lithium or magnesium reagents to
Weinreb amide 12 derived from (R)-(+)-sclareolide 1.[10]
Herein we report a versatile and flexible approach to the
1
Alcohols 16 and epi-16 show identical H and 13C data for
the decaline moiety and differ only slightly in the side chain
at carbon C-9.[12] Therefore we can assume that 16 and epi-
16 posses the same stereochemistry at carbon C-8, while
they are epimers at carbon C-12. In fact, the presence of an
axial-b substituent at carbon C-8 is in accordance with the
strong shielding of carbon C-6 in both alcohols 16 (dC-6 18.5)
due to a g-gauche effect, with respect to ketone 13 (dC-6
23.9) having a D8(13) double bond. Equally, the C-20 Me-
group in a d-syn axial position with respect to C-8 b-axial
substituent appears low-field shifted (dC-20 15.8) with respect
to 13 (dC-20 14.8).[13] Regarding to the C-12 stereochemistry
of alcohols 16 and epi-16, the comparison of the H-12 cou-
pling constant values with those for the known compounds
(12R)- and (12S)-15,16-epoxy-12-hydroxylabda-7,13(16),14-
trienes evidences that for alcohol 16 (J=9.5 and 4.4 Hz) the
values are similar to the (12R) series (J=10.9 and 2.7 Hz),
while alcohol epi-16 shows values (J=8.1 and 6.5 Hz) relat-
ed to the (12S) series (J=8.8 and 6.6 Hz).[10a] Therefore, it is
reasonable to assign a (12R) absolute configuration to alco-
hol 16, while alcohol epi-16 has (12S) absolute configura-
tion.
Abstract in Spanish: El (R)-(+)-esclareolido 1 se ha utiliza-
do como material de partida para desarrollar una metodolo-
gꢀa orientada a obtener diversidad estructural, que ha permiti-
do preparar el hispanano 28a, y los compuestos de tipo his-
panano 28b–28e. Esta metodologꢀa se basa en la acilaciꢁn
intramolecular de tipo Friedel–Crafts de los ꢂcidos 12-desoxi-
labdanoicos 27, para construir el anillo de cicloheptano, ca-
racterꢀstico de los hispananos. Los ꢂcidos 27 se obtienen a
partir de los alcoholes 20, accesibles por adiciꢁn del corres-
pondiente organolitio o magnesiano a la amida 12, seguido
de reducciꢁn en las condiciones de Luche, o al aldehido 21.
Esta secuencia de reacciones ha resultado en la preparaciꢁn,
por primera vez, del esqueleto de hispanano 27a. Con esta
sꢀntesis dirigida a obtener diversidad estructural es posible la
obtenciꢁn de una amplia variedad de derivados de tipo hispa-
nano tales como 28b–28e.
The oxidation of the C-17 hydroxyl groups of alcohols 16
and epi-16 to the C-12 labdanic acids 17 and epi-17 was ach-
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Terpene Synthesis
FULL PAPER
ieved by Swern oxidation[14] followed by air oxidation of the
obtained aldehydes. Friedel–Crafts cyclization of 17 was at-
tempted by using the Eaton reagent (P2O5/MeSO3H).[15]
These conditions led to a clean transformation of compound
17 to a new product 18 having the phenyl group unchanged.
A d lactone structure was assigned for compound 18 on the
spectroscopic results (Scheme 3). The configurations of C-8
and C-12 stereocenters were assigned from NOESY experi-
ments. A clear correlation between H-12 (d 6.19), H-8
(d 2.80) was observed, which is compatible with a structure
18 having hydrogens H-12 and H-8 placed in same side of
the plane defined by the lactone ring (Scheme 3).
oxygenation sequence. Reaction of the mixtures of alcohols
with 1,1-thiocarbonyldiimidazol yielded the mixture of thio-
esters which was reduced by using TBTH/AIBN to form 12-
desoxylabdane-like derivatives 22, as single isomers in fair
to excellent yields (Scheme 4).[17]
Scheme 3. Synthesis and Friedel–Crafts reaction of the 12-acetoxy-phe-
nyllabdanic acid 17.
Scheme 4. Synthesis of the 12-desoxylabdane-like derivatives 22 from
amide 12 via alcohols 20.
Clearly, a C-12 oxygenated group is not compatible with a
Friedel–Crafts ring closure on intermediates 9 (Scheme 2) to
construct the desired seven-membered ring of the hispa-
nane-like compounds 8. Therefore, a desoxygenation step
was introduced in the synthetic approach. More activated ar-
omatic rings were also considered to ensure the success of
the Friedel–Crafts reaction. Thus, ketones 19a–c were pre-
pared by addition of the corresponding lithium derivatives
to Weinrebꢄs amide 12. Epimeric alcohols 20a–c and epi-
20a–c were obtained by reduction of the carbonyl groups
under Luche conditions.[11] Additionally, alcohols 20d–e and
epi-20d–e, having a 1-naphthyl and 2-N-tosylindolyl sub-
stituents, respectively, were prepared by addition of the cor-
responding lithium reagents to aldehyde 21. Alcohols 20
were submitted to the two-step Barton–McCombie[16] des-
The oxidative hydroboration (B2H6·THF followed by
H2O2/NaOH work-up) of desoxylabdane derivatives 22a–e
resulted in the corresponding C-17 alcohols 24a–e as single
isomers.[18] The b-axial configuration of the hydroxymethyl
group at carbon C-8 was assigned on analogous as described
early for compounds 16 and epi-16,[10] and it is consistent
with the double-bond hydroboration by the less-hindered a
face of compounds 22.[12] One-step oxidation to the corre-
sponding 12-desoxylabdanic-like acids was achieved for
compounds 27b and d by using Jones reagent, while a two-
step sequence was used for alcohols 24a, c and e. Thus, alde-
hydes 26a, c and e were obtained by either Swern or Jones
oxidation and transformed to the 12-desoxylabdanic-like
acids by air (27c) or by buffered NaClO2 (27a, and 27e) ox-
idation (Scheme 5).[19]
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M. C. de la Torre et al.
eight steps in 40% overall yield. Furthermore, the prepara-
tion of compounds 28b–e demonstrates that our approach is
fully applicable to prepare novel indole–hispanane and aro-
matic–hispanane natural product derivatives (Scheme 6).
Particularly interesting is the hispanane–indol derivative
28e since indole diterpenes are also found in nature.[22]
The flexibility of this diversity oriented approach to
obtain hispanane-like derivatives is demonstrated by the
preparation of the C-8 epi-hispanane derivatives. Thus, com-
pound 28d was prepared according to the general methodol-
ogy depicted in Scheme 7, by simply introducing an addi-
tional epimerization step on intermediate aldehyde 26d.
This compound is available from alcohol 24d through con-
trolled Jones oxidation. Base epimerization produced com-
pound epi-26d (70%) which was further oxidized with Jones
reagent to yield acid epi-27d. The a-equatorial configuration
of carbon C-17 acid epi-27d is in accord with the coupling
constant values shown by H-8b axial (epi-27d d 2.46, J=12
and 4 Hz). Compound epi-27d was cyclized to pentacyclic
hispanane derivative epi-28d in 42% yield (Scheme 7). The
b-axial configuration of the ketone carbon C-17, with re-
spect to ring B, is based again on the coupling constant
values of H-8b axial (epi-27d d 3.05, J=11.9 and 3.8 Hz), as
well as on the shift to low-field of the signal attributable to
carbon C-6 with respect to hispanane 28d (Dd=+1.3, see
Scheme 5. Synthesis of 12-desoxylabdanic-like acids 27 by oxidation of al-
cohols 24.
Table 1. 13C NMR data for compounds 28a, 28c, 28d, 28e and epi-28d.[a]
Friedel–Crafts cyclization of
compounds 27a–e was achieved
either by using the Eatonꢄs re-
agent[15] (compounds 27b–d) or
28a[b]
28c[c]
28d[b]
28e[d]
epi-28d[d]
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-11
C-12
C-17
C-18
C-19
C-20
C-13 (C-1’)
C-14 (C-2’)
C-15 (C-3’)
C-16 (C-4’)
C-5’
C-6’
C-7’
C-8’
C-9’
38.6 t
18.4 t
42.0 t
33.2 q
56.1 d
19.5 t
27.7 t
46.8 d
51.8 d
39.1 s
24.0 t
28.0 t
190.8 s
33.5 q
21.6 q
13.6 q
138.3 s
113.3 d
145.4 d
150.7 s
39.1 t
18.5 t
42.1 t
33.2 s
55.8 d
19.7 t
28.6 t
47.3 d
51.6 d
38.8 s
39.8 t
18.5 t
42.1 t
33.1 s
55.4 d
19.8 t
27.6 tꢅ2
47.8 d
51.7 d
38.6 s
39.0 t
18.4 t
42.0 t
33.1 s
55.8 d
19.5 t
27.8 t
48.2 d
51.0 d
38.8 s
38.8 t
18.7 t
41.9 t
33.2 s
50.7 d
21.1 t
29.6 t
51.6 d
54.7 d
38.4 s
trifluoracetic
anhydride
(TFAA)[20] (compounds 28a
and e) to produce hispanane
derivatives 28a–e in good to ex-
cellent yields and as single iso-
mers. The exception was the 2-
naphtyl-derivative 27b which
gave a mixture of the two re-
gioisomers 28b and 28b’ in low
yield (21%). The structure and
regiochemistry of the products
was unambiguously established
by 1D and 2D NMR spectros-
copic analyses. Table 1 shows
the 13C NMR spectra for the
tetra- and pentacyclic deriva-
tives 28a, 28c–e. It should be
noted that compound 28a has a
tetracyclic hispanane skeleton
with the correct natural stereo-
chemistry. Therefore, the syn-
thesis of compound 28a repre-
sents the first entry to the skel-
eton of this natural product
27.0 t
34.1 t
27.6 tꢅ2
28.4 t
28.0 t
24.8 t
28.4 t
26.0 t
202.7 s
33.6 q
21.7 q
13.9 q
162.2 s
148.0 s
131.9 d
130.9 s
115.3 d
111.6 d
205.6 s
33.7 q
21.9 q
14.0 q
144.6 s
136.1 s
134.8 s
132.3 s
128.7 d
127.4 d
126.4 d x2
125.2 d
124.8 d
200.0 s
33.6 q
21.6 q
13.8 q
151.6 s
136.1 s
127.5 s
125.2 d
124.8 d
122.6 s
122.3 d
114.4 d
210.5 s
33.6 q
21.8 q
14.7 q
139.1 s
133.6 s
134.5 s
131.5 s
128.7 d
127.0 d
126.7 d
126.6 d
124.7 d
124.2 d
C-10’
C-OMe
55.3 q
21.7 q
145.5 s ph
136.2 s ph
130.1 dꢅ2
126.4 dꢅ2
[a] Multiplicities were determined by DEPT experiments [b] Recorded at 125 MHz. [c] Recorded at 75 MHz.
from (R)-(+)-sclareolide 1 in [d] Recorded at 50 MHz.
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Terpene Synthesis
FULL PAPER
Scheme 7. Synthesis of the C-8 epi-hispanane derivative epi-28d from al-
dehyde epi-26d.
In conclusion, we have developed a versatile entry to nat-
ural product derivatives with a hispanane skeleton, including
the first building of the hispanane skeleton itself. The syn-
thesis uses (R)-(+)-sclareolide 1 as the basic building scaf-
fold and requires six or seven steps to produce the final
compounds. The capacity of this approach to produce struc-
turally diverse natural product derivatives is demonstrated
by its application to the synthesis of hispanane–indol and
hispanane–aromatic derivatives. By introducing an isomeri-
zation step on intermediate aldehyde 26, the C-8 epi-hispa-
nane series is also available. Application of this diversity ori-
ented approach to yield the 17-nor-hispanane–indol skeleton
has been demonstrated by using an oxidative decarboxyla-
tion step.
Scheme 6. Synthesis of hispanane 22a and hispanane derivatives 28b–e
by Friedel–Crafts reaction of acids 27a–e.
Table 1) Thus, the addition of an epimerization step, to the
general sequence results in an entry to epi-series of hispa-
nane derivatives.
Finally, the versatility of the Friedel–Crafts approach to
hispanane-like derivatives developed above was further im-
proved by the access of the 17-nor-hispanane–indol skeleton
(Scheme 8). This time, ketone 29 was prepared by oxidative
decarboxylation of aldehyde 26e (AgNO3/KOH/EtOH)[21]
and submitted to Eatonꢄs reagent to produce an inseparable
mixture of 17-nor-hispanane–indol derivatives 30 and 30’,
which are isomers around the newly formed double bond.
Formation of indolterpenes 30 and 30’ demonstrates that ke-
tones can also be used as initiators for the Friedel–Crafts ap-
proach to hispanane and nor-hispanane derivatives. The two
isomeric products 30 and 30’ should be formed by dehydra-
tion of the C-8 tertiary carbinol intermediate, which should
be the primary product of the cyclization reaction.
Scheme 8. Synthesis of the nor-hispanane derivative 30, 30’ from ketone
29.
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M. C. de la Torre et al.
(33% v/v) and NaOH (3m) were successively added. After the reaction
mixture was stirred for one additional hour, the solution was extracted
with AcOEt. The combined organic layers were dried and filtered. The
solvents were removed in vacuo and the residue was purified by flash
chromatography to yield pure alcohols 16 and epi-16 and 24a–e.
Experimental Section
General methods: All procedures with air-sensitive reagents were carried
out under dry argon atmosphere by using standard Schlenk techniques.
All reagents were used as obtained from commercial sources. THF, and
CH2Cl2 were distilled under positive pressure of argon from Na benzo-
quinone (THF) or CaH2 (CH2Cl2). Other 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 with silica gel
(Merk, no. 9385, 230–400 mesh) and mixtures of AcOEt/hexanes or hex-
anes/CH2Cl2 as eluents. Melting points were determined on a Koffler
Acids 27b and 27d by Jones oxidation of alcohols 24b and 24d: An
excess of Jones reagent (persistence of orange color) was added dropwise
to a solution of alcohol in acetone at 08C. The reaction mixture was stir-
red until the alcohol disappeared (TLC). The excess of the reagent was
quenched by addition of MeOH; the mixture was allowed to reach room
temperature and then diluted with H2O. The organic solvents were re-
moved under vacuum and the resulting residue was extracted with
AcOEt. The combined organic layers were dried and filtered; the residue
was purified by flash chromatography to yield the pure acid.
block. H NMR and 13C NMR spectra were recorded at 258C on a Varian
1
Inova-300, Inova-400, Unity-500 and Bruker AM-200 spectrometers as
1
Acids 17, epi-17 and 27c by oxidation of alcohols 16, epi-16 and 24e—
General procedure: A solution of Cl2(CO)2 in anhydrous CH2Cl2 was
slowly added under argon to a solution of DMSO in anhydrous CH2Cl2
at À788C. After 15 min of stirring at this temperature, the mixture was
added to a solution of the alcohol in CH2Cl2. After the reaction was com-
pleted (TLC), Et3N was added. The resulting reaction mixture was al-
lowed to reach room temperature; it was diluted with CH2Cl2 and
washed with H2O. The combined organic layers were dried and filtered.
The removal of the solvents produced a residue which was dissolved in
THF and air was bubbled through the solution. The solvents were re-
moved in vacuo. The residue was purified by flash chromatography to
afford the pure acid.
specified. Chemical shifts for H NMR are reported with respect to resid-
ual CHCl3 (d 7.25) and with respect to CDCl3 (d 77.0) for 13C NMR spec-
tra. MS were recorded in the positive EI mode (70 eV).
Synthesis of ketones 13 and 19a–c—General procedure: A solution of
the corresponding magnesium or lithium reagent in THF was added
under argon to a solution of amide 12 in THF at 08C. Lithium reagents
were generated by halogen–metal exchange from the corresponding
bromo-derivatives upon reaction with nBuLi at À788C. The mixtures
were stirred until amide 12 disappeared (checked by TLC). The reaction
was quenched by addition of aqueous NH4Cl (saturated solution) and al-
lowed to reach room temperature. The reaction mixture was diluted with
H2O and extracted with AcOEt. The combined organic layers were dried
and filtered, and solvents were removed under vacuum. Pure ketones
were obtained after flash chromatography of the residues.
Acids 27a and 27e by NaClO2 oxidation of aldehydes 26a and 26e—
General procedure: An aqueous NaClO2 solution (1.1m) was added at
08C to a solution of the aldehyde in THF/tBuOH/2-methy-2-butene
(1:2:1) in the presence of a Na2HPO4·H2O buffer (6.9ꢅ10À1 m), and the
mixture was allowed to reach room temperature slowly. Then, HCl (10%
v/v) was added, organic solvents were removed under vacuum and the
residue was extracted with AcOEt. The combined organic layers were
dried and filtered. The solvents were removed and the residie was puri-
fied by flash chromatography to yield the pure acids.
Alcohols 14 and, 20a–c and epi-20a–c—General procedure: In a typical
experiment, CeCl3·7H2O (2 equiv) was added to a solution of ketone in
MeOH at room temperature. The mixture was stirred until the cerium
salt was dissolved, and then cooled at 08C. At this temperature NaBH4
was added portionwise. When the starting material disappeared (by
TLC), the excess of reagent was quenched by addition of H2O and the
mixtures were allowed to reach room temperature. MeOH was removed
under vacuum and the residue was extracted with AcOEt. The combined
organic layers were dried and filtered yielding a residue, which was puri-
fied by flash chromatography to yield the pure alcohols.
General procedures for Friedel–Crafts acylations—Method A: The re-
spective acid 27 in methanesulfonic acid or CH2Cl2 was added to a so-
lution of P2O5 (10%) in methanesulfonic acid at room temperature. The
mixture was stirred until the starting material was consumed (TLC). The
reaction mixture was poured into a solution of saturated NaHCO3 and
the aqueous layer was separated and extracted with AcOEt. Reaction
product was purified by column chromatography.
Alcohols 20d, epi-20d and 20e, epi-20e—General procedure: The so-
lution of the respective lithium reagent in THF was added under argon
to a solution of aldehyde 21 in THF at À788C. The lithium reagents were
generated either by halogen–metal exchange from the corresponding
bromo-derivatives or by hydrogen–metal exchange upon reaction with
nBuLi at À788C. The mixture was stirred until aldehyde 21 disappeared
(TLC). The reaction was quenched by addition of aqueous NH4Cl satu-
rated solution and allowed to reach room temperature. The reaction mix-
ture was diluted with H2O and extracted with AcOEt. The combined or-
ganic layers were dried and filtered, and solvents removed under
vacuum. Pure alcohols were obtained after flash chromatography of the
residues.
Method B: A solution of trifluoracetic anhydride in CH2Cl2 was slowly
added to solution of respective acid 27 in CH2Cl2 at 08C. The mixture
was stirred until the acid was consumed, then the reaction mixture was
poured into NaHCO3 saturated solution and the aqueous layer was ex-
tracted with AcOEt. The residues were purified by column chromatogra-
phy to yield the pure reaction products as described above.
Compound 28a by Friedel–Crafts reaction of acid 27a (method B): A so-
lution of acid 27a (15.0 mg, 0.05 mmol) in CH2Cl2 at 08C was treated
with a solution of trifluoroacetic acid in CH2Cl2 (50 mL, 1.4ꢅ10À3 m).
After 10 min of stirring, acid 27a had been consumed and the reaction
mixture was worked-up according to the general procedure. Chromatog-
raphy of the residue by using hexanes/AcOEt 95:5 yielded pure 28a
Compounds 22a–e by desoxygenation of alcohols 20a–e, and epi-20a–e—
General procedure: 1,1’-Thiocarbonyldiimidazole (3.5 equiv) was added
to a solution of alcohols 20 in CH2Cl2. After the reagent was dissolved,
most of the solvent was removed under vacuum and the reaction mixture
was cooled to À208C. The crude reaction mixture was submitted to flash
chromatography without any further treatment. The mixture of pure thio-
esters was immediately dissolved in degassed toluene under argon, fol-
lowed by addition of HSnBu3 (3 equiv) and a catalytic amount of AIBN.
The mixture was heated under reflux until the esters disappeared (TLC).
Then, the organic solvents were removed under vacuum and the residue
was submitted to flash chromatography to give pure C-12 desoxygenated
derivatives 22.
(9.6 mg, 68%) as a white crystalline solid. M.p. 184–1868C; [a]D20
= +
45.5 (c=0.07 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.47 (d, 3J=
1.7 Hz, 1H; H-15), 6.35 (d, 3J=1.7 Hz, 1H; H-14), 2.81 (ddd, 2J=15.8,
3J=5.8, 3J=1.7 Hz, 1H; HB-12), 2.75 (brt, 3J=5.5 Hz, 1H; H-8a), 2.50
(m, 2H; HA-12), 2.17 (dddd, J=15, J=8.9, J=5.9, J=1.7 Hz, 1H; H-11),
1.96 (td, J=9.5, J=6.4 Hz, 1H; H-9a), 1.76 (qd, J=13.4, J=3.8 Hz, 1H;
H-7a), 1.65 (m, 1H), 1.48–1.20 (m, 8H), 1.114 (td, J=12.8, J=4.7 Hz,
1H; H-3a), 0.95 (dd, J=5.8, J=2.8 Hz, 1H; H-5a), 0.92–0.87 (m, 2H),
0.87 (s, 3H; CH3-18), 0.79 (s, 3H; CH3-19), 0.62 (s, 3H; CH3-20);
13C NMR (125 MHz, CDCl3): d = 190.8 (s, C-17), 150.7 (s, C-16), 145.4
(d, C-15), 138.3 (s, C-13), 113.3 (d, C-14), 56.1 (d, C-5), 51.8 (d, C-9), 46.8
(d, C-8), 42.0 (t, C-3), 39.1 (s, C-10), 38.6 (t, C-1), 33.5 (q, C-18), 33.2 (s,
C-4), 28.0 (t, C-12), 27.7 (t, C-7), 24.0 (t, C-11), 21.6 (q, C-19), 19.5 (t, C-
6), 18.4 (t, C-2), 13.6 (q, C-20); IR (nujol): n˜ =2924, 2854, 1654, 1582,
Alcohols 16, epi-16 and 24 by hydroboration–oxidation of alkenes 1, epi-
15 and 22a–e—General procedure: The respective alkene in THF was
slowly added to a solution of B2H6·SMe2 or B2H6·THF in THF at 08C.
The mixture was stirred at room temperature until the starting material
disappeared (TLC). Then, the mixture was cooled at 08C and H2O2
3664
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 3659 – 3667

Terpene Synthesis
FULL PAPER
1480, 1458, 1428, 1384, 1265, 1241, 886, 792 cmÀ1; MS (70 eV, EI): m/z
(%): 300 (13) [M]+, 285 (1), 176 (5), 163 (32), 149 (47), 136 (9), 91 (9), 58
(35), 43 (100); elemental analysis calcd (%) for C20H28O2: C 79.96, H
9.39; found: C 79.87, H 9.24.
Compound 28e by Friedel–Crafts reaction of acid 27e (method B): Tri-
fluoroacetic anhydride (60 mL, 0.7ꢅ10À3 m) in CH2Cl2 was added at 08C
to a solution of acid 27e (19 mg, 0.04 mmol) in CH2Cl2 (0.5 mL). The
starting material was consumed after 3 h of stirring. Workup as described
above, yielded a residue which was purified by chromatography by using
hexanes/AcOEt 95:5; the pure compound 28e (15 mg, 82%) was ob-
tained as a white crystalline solid. M.p. 169–1718C; [a]2D0 = À11.2 (c=
0.12 in CHCl3); 1H NMR (400 MHz, CDCl3): d=8.43 (m, 1H; H-Ar),
Compounds 28b, 28b’ by Friedel–Crafts reaction of acid 27b (method
A): Acid 27b (20.0 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was added to a
solution of P2O5 (15 mg) in methanesulfonic acid (1.0 mL). The reaction
was stirred at room temperature for 1 h and it was heated under reflux
for another 30 min until the starting material was consumed. After
workup as above, a mixture of pure 28b and 28b’ (4.0 mg, 21%) was ob-
tained as a colourless oil. 1H NMR (500 MHz, CDCl3): d=8.01 (s, 1H;
3
8.21 (m, 1H; H-Ar), 7.65 (d, J=8.4 Hz, 2H; H-Ar), 7.32 (m, 2H; H-Ar),
7.23 (d, J=8.1 Hz, 2H; H-Ar), 4.09 (dd, 2J=16.4, 3J=5.4 Hz, 1H; HB-
3
2
3
12), 2.87 (t, J=6 Hz, 1H; H-8), 2.71 (dd, J=16.5, J=12.3 Hz, 1H; HA-
12), 2.42 (brd, J=13.5 Hz, 1H; H-3a), 2.36 (s, 3H; CH3-Ar), 2.23 (quin,
J=7 Hz, 1H; HB-11), 1.89 (ddd, J=15.6, J=11.9, J=7.9 Hz, 1H; H-9),
1.78 (td, J=13.3, J=3.9 Hz, 1H; H-7a), 1.62 (m, 1H), 1.49–1.30 (m, 7H),
1.15 (td, J=12.5, J=3.7 Hz; 1H), 0.94 (dd, J=12.5, J=2.4 Hz, 1H; H-
5a), 0.88 (s, 3H; CH3-18), 0.81 (s, 3H; CH3-19), 0.63 (s, 3H; CH3-20);
13C NMR (50.3 MHz, CDCl3): d = 200.0 (s, C-17), 151.6 (s, C-Ar), 145.5
(s, C-Ar), 136.2 (s, C-Ar), 136.1 (s, C-Ar), 130.1 (d, 2C-Ar), 127.5 (s, C-
Ar), 126.4 (d, 2C-Ar), 125.2 (d, C-Ar), 124.8 (d, C-Ar), 122.6 (s, C-Ar),
122.3 (d, C-Ar), 114.4 (d, C-Ar), 55.8 (d, C-5), 51.0 (d, C-9), 48.2 (d, C-
8), 42.0 (t, C-3), 39.0 (t, C-1), 38.8 (s, C-10), 33.6 (q, C-18), 33.1 (s, C-4),
28.0 (t, C-11), 27.8 (t, C-7), 24.8 (t, C-12), 21.7 (q, Me-Ar), 21.6 (q, C-19),
19.5 (t, C-6), 18.4 (t, C-2), 13.8 (q, C-20); IR (nujol): n˜ =2924, 2854,
1668, 1460, 1371, 1165, 1055, 990, 760 cmÀ1; MS (70 eV, EI): m/z (%): 503
(11) [M]+, 366 (6), 352 (23), 320 (4), 220 (8), 196 (16), 180 (15), 167 (23),
155 (27), 130 (26), 91 (100), 81 (19), 69 (38), 55 (33), 41 (34); elemental
analysis calcd (%) for C31H37NO3S: C 73.92, H 7.40; found: C 73.79, H
7.27.
3
H-Ar), 7.86 (d, J=7 Hz, 1H, H-Ar), 7.83–7.75 (m, 4H; H-Ar), 7.52–7.32
(m, 5H; H-Ar), 3.21–2.7 (m, 6H), 2.01–1.01 (m, 28H), 0.97(s, 3H; CH3-
18-isomer A), 0.88 (s, 3H; CH3-18-isomer B), 0.84 (s, 3H; CH3-19-isomer
A), 0.82 (s, 3H; CH3-20-isomer A), 0.80 (s, 3H; CH3-19-isomer B), 0.77
(s, 3H; CH3-20-isomer B); MS (70 eV, EI): m/z (%): 360 (100) [M]+, 345
(6), 332 (27), 236 (7), 223 (47), 209 (54), 196 (37), 181 (25), 168 (29), 152
(13), 140 (33), 123 (7),109 (8), 95 (12), 81 (10), 69 (14), 55 (14), 41 (14).
Compound 28c by Friedel–Crafts reaction of acid 27c (method A): Acid
27c (8 mg, 0.02 mmol) in methanesulfonic acid (0.5 mL) was added to a
solution containing P2O5 (10 mg) in methanesulfonic acid (1 mL). The re-
action was completed after 10 min of stirring. After workup as described
above, a residue was purified by chromatography with hexanes/AcOEt
95:5 to yield pure 28c (4.6 mg, 61%) as white solid. M.p. 174–1778C;
[a]2D3 = +16.4 (c=0.07 in CHCl3); 1H NMR (300 MHz, CDCl3): d=8.09
3
3
4
(d, J=8.8 Hz, 1H; H-Ar), 6.70 (dd, J=8.8, J=2.7 Hz, 1H; H-Ar), 6.72
(d, 4J=2.4 Hz, 1H; H-Ar), 3.83 (s, 3H; MeO-Ar), 3.07 (d, 2J=15.6 Hz,
1H; HB-12), 3.03 (brt, 3J=6.1 Hz, 1H; H-8), 2.90 (dd, 2J=15.4, 3J=
6.6 Hz, 1H; HA-12), 2.36 (brd, 2J=13.2 Hz, 1H; H-7b), 2.20 (quin, J=
6.8 Hz, 1H; HB-11), 1.86 (m, overlapped 2H; H-9+ H-7a), 1.62 (ddq,
2J=13.4, 3J=2.7, 3J=2.3 Hz, 1H; H-2a), 1.55–1.10 (overlapped m, 7H),
0.90 (overlapped m, 2H), 0.88 (s, 3H; CH3-18), 0.82 s, 3H; CH3-19), 0.66
(s, 3H; CH3-20); 13C NMR (75.1 MHz, CDCl3): d = 202.7 (s, C-17), 162.2
(s, C-Ar), 148.0 (s, C-Ar), 131.9 (d, C-Ar), 130.9 (s, C-Ar), 115.3 (d, C-
Ar), 111.6 (d, C-Ar), 55.8 (d, C-5), 55.3 (q, MeO-Ar), 51.6 (d, C-9), 47.3
(d, C-8), 42.1 (t, C-3), 39.1 (t, C-1), 38.8(s, C-10), 34.1 (t, C-12), 33.6 (q,
C-18), 33.2 (s, C-4), 28.6 (t, C-7), 27.0 (t, C-11), 21.7 (q, C-19), 19.7 (t, C-
6), 18.5 (t, C-2), 13.9 (q, C-20); IR (nujol): n˜ =2924, 2854, 1663, 1601,
1461, 1265, 1226, 1106, 1034, 967, 815 cmÀ1; MS (70 eV, EI): m/z (%): 340
(25) [M]+, 325 (2), 215 (7), 203 (51), 189 (100), 176 (28), 161 (18), 148
(28), 91 (21), 81 (14), 69 (23), 55 (27), 41 (31); elemental analysis calcd
(%) for C23H32O2: C 81.13, H 9.47; found: C 80.94, H 9.32.
Aldehyde 26d by oxidation of alcohol 24d: Alcohol 24d (248 mg,
0.68 mmol) in acetone (30 mL) was treated with Jones reagent for 2 h.
Workup as described yielded a residue which was purified by flash chro-
matography with hexanes/CH2Cl2 (4:1) to produce pure aldehyde 26d
(230 mg, 94%) as a white amorphous solid. M.p. 106–1088C; [a]2D1 = +
4.13 (c=0.41 in CHCl3); 1H NMR (200 MHz, CDCl3): d=10.11 (s, 1H;
H-17), 8.03 (d, 3J=8.1 Hz, 1H; H-Ar), 7.86 (d, 3J=7.8 Hz, 1H; H-Ar),
7.72 (d, 3J=8.1 Hz, 1H; H-Ar), 7.58–7.30 (overlapped m, 4H; H-Ar),
2
3
3
2
3.34 (ddd, J=13.4, J=10.2, J=6.8 Hz, 1H; HA-12), 2.99 (ddd, J=13.4,
3J=9.5, 3J=6.3 Hz, 1H; HB-12), 2.70 (t, 3J=4.6 Hz, 1H; H-8), 2.40
(brdd, J=7.6 Hz, J=4.6 Hz, 1H; H-7a), 2.05 (dd, J=6.4, J=3.7 Hz, 1H;
H-9), 2.02 (dd, J=8.5, J=6.8 Hz, 1H; H-11), 1.70–1.10 (overlapped m,
10H), 0.94 (dd, J=11.5, J=2.6 Hz, 1H; H-5), 0.86 (s, 3H; CH3), 0.77 (s,
3H; CH3), 0.68 (s, 3H; CH3); 13C NMR (75.3 MHz, CDCl3): d = 205.2
(d, C-17), 138.7 (s, C-Ar), 133.9 (s, C-Ar), 131.7 (s, C-Ar), 128.8 (d, C-
Ar), 126.7 (d, C-Ar), 126.0 (d, C-Ar), 125.9 (d, C-Ar), 125.6 (d, C-Ar),
125.5 (d, C-Ar), 123.6 (d, C-Ar), 55.7 (d, C-5), 54.5 (d, C-9), 47.5 (d, C-
8), 41.9 (t, C-1), 38.6 (t+s, C-3+C-10), 33.5 (q, C-18), 33.3 (s, C-4), 32.3
(t, C-12), 26.9 (t, C-7), 26.6 (t, C-11), 21.5 (q, C-19), 18.8 (t, C-6), 18.6 (t,
C-2), 15.4 (q, C-20); MS (70 eV, EI): m/z (%): 362 (66) [M]+, 344 (3),
331 (4), 170 (15), 167 (16), 154 (32), 141 (100), 123 (13), 115 (17), 107 (4),
95 (10), 81 (10), 69 (15), 55 (10), 41 (9); elemental analysis calcd (%) for
C26H34O: C 86.13, H 9.45; found: C 85.94, H 9.38.
Compound 28d by Friedel–Crafts reaction of acid 27d (method A): Acid
27d (20 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was added to a solution of
P2O5 (15 mg) in methanesulfonic acid (1 mL) at room temperature. The
reaction was completed after 5 h of stirring (TLC). The residue was puri-
fied by chromatography with hexanes/CH2Cl2 9:1 to yield pure 28d
(4.0 mg, 42%) as a white crystalline solid. M.p. 159–1618C; [a]D21
=
À12.5 (c=0.12 in CHCl3); 1H NMR (500 MHz, CDCl3): d=8.27 (dd, J=
3
6.2, J=3.6 Hz, 1H; H-Ar), 8.09 (d, 3J=8.7 Hz, 1H; H-Ar), 7.83 (dd, J=
Aldehyde epi-26d by epimerization of aldehyde 26d: A solution of alde-
hyde 26d (50 mg, 0.14 mmol) in EtOH (3.5 mL) at room temperature
was treated with an aqueous solution of KOH (2.0 mL, 6ꢅ10À2 m). After
24 h of stirring the reaction mixture was filtered through a pad of Celite,
diluted with water (10 mL) and extracted with AcOEt (3ꢅ20 mL).
Workup as described yielded a residue which after chromatography with
hexanes/AcOEt 95:5 produced pure epi-26d (30 mg, 70%) as a colorless
4
6.2, J=3.6 Hz, 1H; H-Ar), 7.72 (d, 1H, J=8.7 Hz, H-Ar), 7.55 (dd, 1H,
J=9.6, J=3.2 Hz, H-Ar), 7.54 (dd, J=9.8, J=3.6 Hz, 2H; H-Ar), 4.00
(dd, 2J=17, 3J=7 Hz, 1H; HB-12), 3.28 (t, 3J=6.8 Hz, 1H; H-8), 3.05
(dd, 2J=17, 3J=11.7 Hz, 1H; HA-12), 2.38 (q, 2J=3J=7.2 Hz, 1H; HB-
11), 2.30 (brd, 2J=13.4 Hz, 1H), 1.93 (dd, 3J=8.7, 3J=3.8 Hz, 1H; H-9),
1.90 (overlapped m, 2H), 1.89–0.93 (m, 9H), 0.91 (s, 3H; CH3-18), 0.87
(s, 3H; CH3-19), 0.80 (s, 3H; CH3-20); 13C NMR (125 MHz, CDCl3): d =
205.6 (s, C-17), 144.6 (s, C-Ar), 136.1 (s, C-Ar), 134.8 (s, C-Ar), 132.3 (s,
C-Ar), 128.7 (d, C-Ar), 127.4 (d, C-Ar), 126.4 (d, 2C-Ar), 125.2 (d, C-
Ar), 124.8 (d, C-Ar), 55.4 (d, C-5), 51.7 (d, C-9), 47.8 (d, C-8), 42.1 (t, C-
3), 39.8 (t, C-1), 38.6 (s, C-10), 33.7 (q, C-18), 33.1 (s, C-4), 28.4 (t, C-12),
27.6 (2t, C-7, C-11), 21.9 (q, C-19), 19.8 (t, C-6), 18.5 (t, C-2), 14.0 (q, C-
20); IR (nujol): n˜ = 2925, 2854, 1668, 1462, 1377, 1217, 1102, 1032, 813,
765, 747 cmÀ1; MS (70 eV, EI): m/z (%): 360 (88) [M]+, 345 (5), 332 (5),
223 (52), 209 (100), 196 (33), 181 (20), 168 (29), 152 (16), 140 (34), 123
(7), 109 (7), 95 (12), 81 (11), 69 (16), 55 (18), 41 (18); elemental analysis
calcd (%) for C26H32O: C 86.62, H 8.95; found: C 86.28, H 8.70.
syrup. [a]2D3
=
+28.6 (c=0.28 in CHCl3); 1H NMR (200 MHz, CDCl3):
d=9.61 (d, 3J=4.6 Hz, 1H; H-17), 7.93 (d, 3J=8.2 Hz, 1H; H-Ar), 7.81
(dd, J=7.5, J=1.8 Hz, 1H; H-Ar), 7.68 (d, J=7.9 Hz, 1H; H-Ar), 7.56
(overlapped m, 4H; H-Ar), 3.16–2.84 (m, 3H), 2.44–2.31 (m, 1H), 1.9–
0.93 (m, 13H), 0.89 (s, 3H; CH3-18), 0.83 (s, 3H; CH3-19), 0.80 (s, 3H;
CH3-20); 13C NMR (75.3 MHz, CDCl3): d =205.3 (d, C-17), 138.7 (s, C-
Ar), 133.8 (s, C-Ar), 131.6 (s, C-Ar), 128.7 (d, C-Ar), 126.6 (d, C-Ar),
126.0 (d, C-Ar), 125.9 (d, C-Ar), 125.6 (d, C-Ar), 125.4 (d, C-Ar), 123.7
(d, C-Ar), 54.6 (d, C-5), 54.2 (d, C-9), 51.0 (d, C-8), 42.0 (t, C-1), 38.5 (t,
C-3), 37.9 (s, C-10), 34.4 (t, C-12), 33.4 (q, C-18), 33.2 (s, C-4), 30.9 (t, C-
7), 26.7 (t, C-11), 21.7 (q, C-19), 20.1 (t, C-6), 18.6 (t, C-2), 14.1 (q, C-20);
Chem. Eur. J. 2005, 11, 3659 – 3667
www.chemeurj.org
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3665

M. C. de la Torre et al.
IR (nujol): n˜ =2924, 2853, 2715, 1724, 1596, 1462, 1376, 798 cmÀ1; MS
(70 eV, EI): m/z (%): 362 (14) [M]+, 348 (3), 332 (2), 179 (7), 170 (7),
154 (34), 141 (100), 115 (16), 95 (11), 81 (12), 69 (26), 55 (20), 41 (20); el-
emental analysis calcd (%) for C26H34O: C 86.13, H 9.45; found: C 86.09,
H 9.40.
4.9, 3J=2.1 Hz, 1H; H-7b), 2.30 (overlapped m, 1H; H-6a), 2.31 (s, 3H,
CH3-Ar), 2.16 (d, J=9.8 Hz, 1H; H-9), 2.04 (m, 2H), 1.77 (overlapped
m), 1.66 (qd, J=13.4 Hz, J=5.1 Hz, 1H; H-6b), 1.5–1.3 (m, 4H), 1.25–
1.03 (m, 3H), 0.95 (s, 3H; CH3), 0.84 (s, 3H; CH3), 0.73 (s, 3H; CH3);
13C NMR (75.3 MHz, CDCl3): d=212.3 (s, C-8), 144.6 (s, C-Ar), 142.4 (s,
C-Ar), 137.2 (s, C-Ar), 136.1 (s, C-Ar), 129.9 (s, C-Ar), 129.8 (d, 2C-Ar),
126.3 (d, 2C-Ar), 123.8 (d, C-Ar), 123.5 (d, C-Ar), 120.1 (d, C-Ar), 114.9
(d, C-Ar), 109.2 (d, C-Ar), 63.4 (d, C-9), 54.1 (d, C-5), 42.7 (s, C-10), 42.6
(t, C-7), 41.8 (t, C-3), 39.1 (t, C-1), 33.7 (s- C-4), 33.5 (q, C-18), 28.2 (t, C-
12), 24.0 (t, C-11), 21.7 (q, Me-Ar), 21.6 (q, C-19), 21.5 (t, C-6), 19.0 (t,
C-2), 14.8 (q, C-20); IR (KBr): n˜ =2925, 2850, 1707, 1597, 1452, 1368,
1175, 1145, 1091, 1053, 811, 748 cmÀ1; MS (70 eV, EI): m/z (%): 491 [M]+
(2), 366 (3), 350 (4), 336 (100), 318 (7), 297 (14), 285 (24), 233(10), 220
(21), 198 (10), 180 (9), 168 (6), 156 (14), 143 (19), 130 (58), 109 (6), 91
(40), 69 (17), 55 (16), 41 (12); elemental analysis calcd (%) for
C30H37NO3S: C 73.28, H 7.58; found: C 72.97, H 7.61.
Acid epi-27d by Jones oxidation of aldehyde epi-26d: Aldehyde epi-26d
(25 mg, 0.07 mmol) in acetone (2.0 mL) was treated with the Jones re-
agent for 1 h. Workup as described yielded a residue which after flash
chromatography with hexanes/AcOEt 9:1 produced pure epi-27d (17 mg,
65%) as colorless syrup. [a]D22
=
+14.1 (c=1.49 in CHCl3); 1H NMR
(200 MHz, CDCl3): d=7.96 (dd, 3J=9.2, 4J=1.5 Hz, 1H; H-Ar), 7.78
3
4
3
4
(dd, J=7.5, J=2.0 Hz, 1H; H-Ar), 7.61 (dd, J=7.7, J=1.5 Hz 1H; H-
Ar), 7.40 (m, 2H; H-Ar), 7.24 (m, 2H; H-Ar), 3.19 (td, 3J=13, 3J=
4.9 Hz, 1H; HA-12), 2.93 (td, 2J=3J=13, 3J=5.7 Hz, 1H; HB-12), 2.46
(td, 3J=12, 3J=4 Hz, 1H; H-8), 2.06 (m, 1H), 1.99–0.90 (m, 13H), 0.87
(s, 3H; CH3), 0.81 (s, 3H; CH3), 0.79 (s, 3H; CH3); 13C NMR (50.3 MHz,
CDCl3): d =183.2 (s, C-17), 139.1 (s, C-Ar), 133.8 (s, C-Ar), 131.7 (s, C-
Ar), 128.6 (d, C-Ar), 126.4 (d, C-Ar), 125.8 (d, C-Ar), 125.7 (d, C-Ar),
125.5 (d, C-Ar), 125.3 (d, C-Ar), 123.8 (d, C-Ar), 54.6 (d, C-5), 52.6 (d,
C-9), 47.2 (d, C-8), 42.0 (t, C-3), 38.4 (t, C-1), 38.1 (s, C-10), 34.8 (t, C-
12), 33.4 (q, C-18), 33.2 (s, C-4), 31.7 (t, C-7), 30.9 (t, C-11), 21.7 (q, C-
19), 20.7 (t, C-6), 18.6 (t, C-2), 14.0 (q, C-20); IR (film): n˜ =2923
(broad), 1694, 1596, 1511, 1455, 1398, 1215, 796 cmÀ1; MS (70 eV, EI):
m/z (%): 378 (78) [M]+, 363 (6), 167 (11), 154 (19), 141 (100), 123 (15),
109 (7), 95 (9), 81 (9), 69 (18), 55 (14), 41 (14); elemental analysis calcd
(%) for C26H34O2: C 82.49, H 9.05; found: C 82.33, H 8.87.
Compounds 30, 30’ by Friedel–Crafts reaction of ketone 29 (method A):
Ketone 29 (8.0 mg, 0.02 mmol) in methanesulfonic acid (0.5 mL) was
added to a solution of P2O5 (5.0 mg) in methanesulfonic acid (0.5 mL) at
room temperature. The reaction mixture was stirred for 10 min. The resi-
due obtained after the usual workup was purified by chromatography
with hexanes/AcOEt 97:3 to yield a pure mixture of 30 and 30’ (5.0 mg,
65%) as a colorless oil. 1H NMR (300 MHz, CDCl3): d=8.36 (d, 3J=
8.4 Hz, 1H), 8.21 (dd, 3J=7, 4J=1.9 Hz, 1H), 8.14 (d, 3J=8.8 Hz, 1H),
8.03 (d, J=7.6 Hz, 1H), 7.83 (dd, J=7.1 Hz, J=1.8 Hz, 1H), 7.70 (d, J=
8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.42 (dd, J=7.3 Hz, J=1.9 Hz,
1H), 7.25 (m, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 6.44
(t, J=2.6 Hz, 1H), 3.41 (m, 2H), 3.19 (ddd, J=19.0 Hz, J=11.4 Hz, J=
7.6 Hz, 1H), 2.81 (ddd, J=19.0 Hz, J=12.0 Hz, J=6.6 Hz, 1H), 2.37
(broad d, J=13.3 Hz, 1H), 2.32 (s, 3H; CH3-Ar), 2.26 (s, 3H; CH3-Ar),
0.97 (s, 3H; CH3), 0.95 (s, 3H; CH3), 0.94 (s, 3H; CH3), 0.89 (s, 6H;
2CH3), 0.85 (s, 3H; CH3); IR (KBr): n˜ =2924, 2854, 1598, 1460, 1376,
1175, 1153, 1091, 1003, 811, 743, 659 cmÀ1; MS (70 eV, EI): m/z (%): 473
[M]+ (100), 456 (61), 360 (25), 318 (68), 300 (1), 232 (29), 217 (27), 206
(20), 194 (48), 91 (31), 69 (9), 55 (7), 41 (5).
Compound epi-28d by Friedel–Crafts reaction of acid epi-27d: Acid epi-
27d (20 mg, 0.05 mmol) in methanesulfonic acid (0.5 mL) was treated
with a solution of P2O5 (15 mg) in methanesulfonic acid (1.0 mL) at room
temperature. The mixture was stirred for 5 h. The residue which was ob-
tained following the general procedure was purified by chromatography
with hexanes/CH2Cl2 4:1 to yield unreacted acid (10 mg) and pure ketone
epi-28d (4 mg, 42% based on recovered acid) as a colorless syrup.
[a]2D2 = +28.7 (c=0.60 in CHCl3); 1H NMR (200 MHz, CDCl3): d=8.14
(dd, 3J=8.9, 4J=1.7 Hz, 1H; H-Ar), 7.84 (dd, 3J=9.2, 4J=2.3 Hz, 1H;
H-Ar), 7.71 (d, 3J=8.5 Hz, 1H; H-Ar), 7.57 (d, 3J=8.5 Hz, 1H; H-Ar),
7.53 (overlapped m, 2H; H-Ar), 3.61 (ddd, 2J=17.4, 3J=7.4, 3J=3.4 Hz,
2
3
3
1H; HB-12), 3.21 (ddd, J=17, J=10, J=3 Hz 1H; HA-12), 3.05 (td, J=
11.9 Hz, J=3.8 Hz, 1H; H-8), 2.10–1.20 (m, 9H), 1.12 (td, J=13.2 Hz,
J=3.8 Hz, 1H), 1.00 (s, 3H; CH3-18), 0.90 (overlapped m, 3H), 0.83 (s,
3H; CH3-19), 0.82 (s, 3H; CH3-20); 13C NMR (50.3 MHz, CDCl3): d =
210.5 (s, C-17), 139.1 (s, C-Ar), 133.6 (s, C-Ar), 134.5 (s, C-Ar), 131.5 (s,
C-Ar), 128.7 (d, C-Ar), 127.0 (d, C-Ar), 126.7 (d, C-Ar), 126.6 (d, C-Ar),
124.7 (d, C-Ar), 124.2 (d, C-Ar), 54.7 (d, C-5), 51.6 (d, C-8), 50.7 (d, C-
9), 41.9 (t, C-3), 38.8 (t, C-1), 38.4 (s, C-10), 33.6 (q, C-18), 33.2 (s, C-4),
29.6 (t, C-7), 28.4 (t, C-11), 26.0 (t, C-12), 21.8 (q, C-19), 21.1 (t, C-6),
18.7 (t, C-2), 14.7 (q, C-20); IR (KBr): n˜ =2922, 2847, 1664, 1459, 1386,
1260, 1219, 1158, 1087, 1036, 818, 801, 759, 741 cmÀ1; MS (70 eV, EI): m/z
(%): 360 (35) [M]+, 332 (7), 223 (31), 209 (39), 196 (39), 178 (39), 168
(62), 152 (41), 140 (100), 95 (33), 81 (31), 69 (58), 55 (68), 41 (77); ele-
mental analysis calcd (%) for C26H32O: C 86.62, H 8.95; found: C 86.49,
H 8.83.
Acknowledgements
Financial support by the Spanish Ministerio de Ciencia y Tecnologꢀa
(Grants No. BQU2001-1283, CTQ2004-06250-C02-02/BQU (M.C.T.) and
CTQ2004-06250-C02-01/BQU (M.A.S.)) and by the Consejerꢀa de Educa-
ciꢂn (Comunidad de Madrid, Grants No. 07M/0044/2002 to M.C.T. and
07m/0043/2002 to M.A.S.) is gratefully acknowledged. I. Garcꢀa thanks
the MCyT (Spain) for a FPI-predoctoral fellowship.
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Ketone 29 by oxidation of alcohol 24e: Alcohol 24e (40 mg, 0.08 mmol)
in acetone (2 mL) was treated with Jones reagent for 15 min. Working in
the usual way a residue was obtained which, without any further purifica-
tion, was dissolved in dry ethanol (2 mL) and cooled to 08C. The mixture
was treated consecutively with AgNO3 aqueous solution (1.0 mL, 6ꢅ
10À3 m) and aqueous KOH (1.0 mL, 7ꢅ10À3 m). After 15 min of stirring,
the mixture was filtered through a pad of Celite. Aqueous HCl was
added until pH 1 and the mixture was extracted with CHCl3 (3ꢅ20 mL).
The residue obtained in the usual way was purified by chromatography
with hexanes/AcOEt 95:5 to yield pure ketone 29 (15 mg, 39%) as color-
less syrup. [a]2D3
=
+42.5 (c=0.35 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=8.14 (d, 3J=8.3 Hz, 1H; H-Ar), 7.58 (d, 3J=8.3 Hz, 2H; H-
3
3
4
Ar), 7.38 (d, J=7.9 Hz, 1H; H-Ar), 7.22 (td, J=8.3, J=1.5 Hz, 1H; H-
3
Ar), 7.18 (t, J=8.3 Hz, 1H; H-Ar), 7.15 (d, 3J=8.1 Hz, 2H; H-Ar), 6.40
(s, 1H; H-Ar), 3.05 (ddd, 2J=14.9, 3J=9.7, 3J=5.1 Hz, 1H; HB-12), 2.80
(ddd, 2J=14.9, 3J=8.7, 3J=6.6 Hz, 1H; HA-12), 2.43 (ddd, 2J=13.2, 3J=
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3666
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 3659 – 3667

Terpene Synthesis
FULL PAPER
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Received: November 29, 2004
Published online: April 5, 2005
Chem. Eur. J. 2005, 11, 3659 – 3667
www.chemeurj.org
ꢃ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3667