First synthesis of antitumoral dasyscyphin B

Article abstract of DOI:10.1039/c3ob41290c

The first synthesis of dasyscyphin B, an antitumoral metabolite obtained from the ascomycete Dasyscyphus niveus, has been achieved starting from commercial abietic acid. The key steps of the synthetic sequence are the diastereoselective α-methylation of a ketoaldehyde, followed by an intramolecular aldol condensation and the further Diels-Alder cycloaddition of a dienol ester. The procedure reported will allow the synthesis of related metabolites functionalized in the A ring. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob41290c

Organic &
Biomolecular Chemistry
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First synthesis of antitumoral dasyscyphin B†
a
b
a
b
Cite this: Org. Biomol. Chem., 2013, 11,
176
Ali Akhaouzan, Antonio Fernández, Ahmed I. Mansour, Esteban Alvarez,
6
b
c
b
Ali Haidöur, Ramón Alvarez-Manzaneda, Rachid Chahboun* and
Enrique Alvarez-Manzaneda*
b
The first synthesis of dasyscyphin B, an antitumoral metabolite obtained from the ascomycete
Dasyscyphus niveus, has been achieved starting from commercial abietic acid. The key steps of the
synthetic sequence are the diastereoselective α-methylation of a ketoaldehyde, followed by an intra-
molecular aldol condensation and the further Diels–Alder cycloaddition of a dienol ester. The procedure
reported will allow the synthesis of related metabolites functionalized in the A ring.
Received 21st June 2013,
Accepted 22nd July 2013
DOI: 10.1039/c3ob41290c
www.rsc.org/obc
Introduction
During the last few years, a new type of merosesquiterpene
a natural product of mixed biosynthetic origin) with a tetra-
(
cyclic structure, including a cyclopentane ring, has been iso-
lated from vegetable species, marine sponges and terrestrial
fungi. Examples of this are pelorol (1), first isolated from Dac-
1
tylospongia elegans, akaol A (2), found in a Micronesian
2
sponge of the genus Aka, and dasyscyphins A–E (3–7), meta-
3
,4
bolites from the ascomycete Dasyscyphus niveus (Fig. 1). Even
though the bioactivities of this family of compounds are yet to
be examined comprehensively, preliminary studies have
revealed that pelorol (1) is an activator of the inositol 5-phos- Fig. 1 Representative sesquiterpene quinols.
5
phatase SHIP, whereas dasyscyphin B (4) and C (5) show
3
a
potent cytotoxic activities in several human cell lines, and
dasyscyphin D (6) and E (7) exhibit antifungal properties.
Despite the significant biological activities and the interest-
ing tetracyclic structure of the above mentioned compounds,
only a few syntheses have been reported. A total synthesis of
dasyscyphin D (6) was recently described by She et al., includ-
4
ring; the success of the latter process required a sufficiently
activated aromatic moiety. The results reported by Andersen’s
group in their enantiospecific synthesis of pelorol (1), corrobo-
7
rated by our preliminary studies, revealed that the two-synthon
8
strategy followed by intramolecular Friedel–Crafts alkylation
led to the tetracyclic intermediate bearing a C8β methyl group
as the major diastereoisomer, but this is not applicable for
synthesizing sesquiterpene quinols such as compounds 2–7,
bearing a B/C cis fused system. Considering the above argu-
ments, we recently developed a new strategy to access this type
of compound, based on the Diels–Alder cycloaddition of a tri-
cyclic diene, having a cyclopentane C ring with a C8α methyl
group. Utilizing this, the first enantiospecific synthesis of
2
ing a PtCl -catalyzed pentannulation reaction and acid-cata-
6
lyzed Robinson annulations as key steps. Andersen et al.
previously reported the first synthesis of pelorol (1) starting
from (+)-sclareolide, after condensation of an aryllithium with
a drimane hydroxy aldehyde and a further difficult intramole-
cular Friedel–Crafts alkylation to create the cyclopentane C
9
akaol A (2) from commercial (−)-sclareol was achieved.
a
Laboratoire de Chimie Organique Appliquée, Département de Chimie, Faculté des
Sciences, Université Abdelmalek Essaâdi, Tetouan, Morocco
b
Departamento de Química Orgánica, Facultad de Ciencias, Instituto de
Biotecnología, Universidad de Granada, 18071 Granada, Spain.
Results and discussion
E-mail: rachid@ugr.es, eamr@ugr.es; Fax: +34 958 24 80 89; Tel: +34 958 24 80 89
c
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Almería,
Continuing our investigations of this new strategy to access
dasyscyphins and related compounds, we explored the use of
other terpenes, such as abietic acid (12), as the starting
0
†
4120 Almería, Spain
1
13
Electronic supplementary information (ESI) available: H and C NMR spectra
for compounds 4, 8–10 and 15–33. See DOI: 10.1039/c3ob41290c
6
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Scheme 1 Retrosynthesis of dasyscyphin B (4).
material. This, as well as being a very cheap commercial com-
pound, will make it possible to synthesize natural dasyscy-
phins bearing a function in the A ring, such as dasyscyphins A
(
3), D (6) or E (7), which could be difficult to prepare by
6
alternative methods. The synthesis starting from acid 12 will
also enable the preparation of unnatural analogues of these
compounds functionalized in the A ring, in order to investigate
the structure–activity relationship. Thus, we planned the
preparation of dasyscyphin B (4), which had not previously
been synthesized, starting from abietic acid (12).
Scheme 2 Synthesis of tricyclic intermediate 20.
Scheme 1 shows the retrosynthesis of metabolite 4. The
cyclopentane C ring of the target compound will be obtained
through the intramolecular aldol condensation of a ketoalde-
hyde. The aromatic D ring will be elaborated after the Diels–
Alder cycloaddition of dienol ester 9, obtained from the
α,β-enone resulting from the intramolecular aldol conden-
sation of ketoaldehyde derived from ketal 10. The C8α methyl
group of compound 4 will be introduced after the diastereo-
selective C-methylation of enol derived from the corresponding
ketal aldehyde. This will be prepared from ketoaldehyde 11,
after the chemoselective reduction of the enal group and the
3 2
subsequent oxidative degradation of the (CH ) CH–CO bond.
Compound 11 will be synthesized after the regioselective oxi-
dation of the C –C bond of abietic acid.
1
3
14
Scheme 2 shows the preparation of tricyclic intermediate
2
0, which contains the cyclopentane C ring and the methyl
group in the appropriate C8α arrangement. The regioselective
oxidative rupture of the C13–C14 double bond of acid 12, intermediate 27.
Scheme 3 Construction of the tetracyclic skeleton of dasyscyphins. Synthesis of
1
0
affording ketoaldehyde 13 in good yield, was achieved after
successive treatments with OsO and NaIO , without isolating
4
4
1
1
the intermediate diol. The α,β-unsaturated aldehyde 11 was compound 17 as ethylene ketal, the hydroxymethyl group was
chemoselectively reduced to ketoalcohol 14 by reaction with converted into the formyl group, thus obtaining the aldehyde
1
2
1
3
RANEY® Ni. The diol 15, obtained as a mixture of distereo- 19. The diastereoselective α-methylation of the latter was
isomers, was regioselectively dehydrated after treatment with efficiently achieved by treatment with MeI and t-BuOK in
I2 and PPh3 to give the corresponding tetrasubstituted benzene, affording compound 10. The ketal aldehyde 10 after
alkene 16, without iodination, which was transformed into the treatment with 1 M HCl in THF under reflux for 3 h underwent
hydroxy ketone 17 by ozonolysis. In an improved procedure, simultaneous ketone deprotection and intramolecular aldol
the diol 15 was directly converted into the hydroxy ketone 17 condensation, leading to tricyclic α,β-enone 20.
1
4
without isolating the intermediate alkene 16, after the treat-
The next step was to address the construction of the aro-
ment of a solution of diol 15 in dichloromethane with I
2
and matic D ring of the target compound (Scheme 3). Heating of
PPh3 and further bubbling of this solution with an O /O
dienol ester 9 with methyl propiolate in xylene in a sealed
3
2
mixture. After protecting the ketone carbonyl group of tube, and further oxidation with DDQ in dioxane at reflux,
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condensation, and the aromatic D ring was constructed via a
Diels–Alder cycloaddition involving dienol ester 9. The pro-
cedure reported here could also allow us to achieve the enantio-
specific synthesis of dasyscyphins functionalized at the A ring,
such as dasyscyphins A (3), D (6) or E (7).
Experimental section
General methods
Dichloromethane (DCM) was dried over calcium hydride.
Benzene and tetrahydrofuran were dried over sodium–benzo-
phenone. Chromatography separations were carried out by
flash column chromatography on silica gel 60 (230–400 mesh),
utilizing hexane–methyl tert-butyl ether (H–E) mixtures as an
eluent.
Instrumentation: Infrared (IR) spectra were obtained with
samples between sodium chloride plates. Data are presented
as the frequency of absorption (cm− ). Only selected absor-
bances (νmax) are reported. Proton and carbon-13 nuclear mag-
Scheme 4 Synthesis of dasyscyphin B (4).
1
yielded the tetracyclic acetoxy ester 21, together with its regio-
isomer (ratio 6 : 1). Compound 21 was obtained almost pure
after careful column chromatography. Treatment of diester
1
13
netic resonance ( H NMR or C NMR) spectra were recorded
1
13
at 400 or 500 MHz, for H, and at 100 or 125 MHz, for C, as
indicated in each case; chemical shifts are expressed in parts
per million (δ scale) downfield from tetramethylsilane. Data
are presented as follows: chemical shift, multiplicity (s =
singlet, br s = broad singlet, d = double, br d = broad double,
t = triplet, m = multiplet), J = coupling constant in hertz (Hz)
2
3 with LiAlH
lowed by Baeyer–Villiger rearrangement led to hydroxy formate
6. When this was reacted with I2 and PPh , iodide 27 was
4
gave diol 24, which after benzylic oxidation fol-
2
3
obtained.
After completing the reduction of the C4-ester group and
13
and the signals of the C NMR were assigned utilizing DEPT
performing an appropriate functionalization of the aromatic D
ring, dasyscyphin B (4) was obtained (Scheme 4). The succes-
sive treatment of iodo formate 27 with RANEY® Ni and
bromine gave the bromophenol 29, which was converted into
the dimethyl ether 8. Reaction of this with anh. DMF and
n-BuLi afforded aldehyde 30, whose formyl group was easily
transformed into the methoxymethyl group of compound 32.
Oxidation of the latter with AgO and nitric acid gave quinone
experiments and on the basis of heteronuclear correlations.
High resolution mass spectra (HRMS) were recorded using a
Q-TOF spectrometer, utilizing the APcI ionization technique.
(
1R,4aR,5R,8aR)-6-Formyl-1,4a-dimethyl-5-(4-methyl-3-oxopentyl)-
10
1
,2,3,4,4a,5,8,8a-octahydronaphthalene-1-carboxylic acid (13). .
To a solution of 12 (13 g, 43 mmol) in strictly deoxygenated
t-BuOH (150 mL) were added trimethylamine N-oxide dihy-
drate (6.2 g, 51.6 mmol) and pyridine (1 mL) under an argon
atmosphere. The solution was stirred for 10 min at room temp-
3
3, which was finally converted into dasyscyphin B (4) by treat-
ment with aq. Na S O in chloroform. The optical rotation
2
2 4
erature and 2% aq. OsO (20 mL, 0.2%, 1.5 mmol) was added
4
2
5
of synthetic dasyscyphin B (4) ([α]
was similar to that reported for the natural product ([α]
c 0.5, CHCl ); the spectroscopic properties were identical to
D
3
: −12; c 0.2, CHCl )
and the reaction mixture was further stirred under an argon
atmosphere at reflux for 5 days, at which time TLC indicated
2
5
D
: −19;
3
no remaining starting material. Then NaIO (12 g, 56.1 mmol)
4
3
a
those previously described.
was added, and the mixture was stirred for 1 h at room temp-
erature. After filtering and removing the solvent, the crude
product was directly purified by flash chromatography on
silica gel (20% ether–hexanes) to yield pure 13 (11.8 g, 82%) as
Conclusions
2
5
1
a colorless syrup. [α]
D 3 3
= +42.1 (c 1.1, CHCl ). H NMR (CDCl ,
In conclusion, the first synthesis of antitumoral dasyscyphin B 300 MHz) δ: 9.35 (s, 1H), 6.76 (t, J = 2.7 Hz, 1H), 3.10 (ddd, J =
4) starting from commercial abietic acid (12) is reported. The 17.2, 10.8, 4.7 Hz, 1H), 2.62 (h, J = 6.9 Hz, 1H), 2.43 (ddd, J =
(
optical rotation of the synthetic product, similar to that of 17.0, 10.8, 5.7 Hz, 1H), 2.35–2.07 (m, 2H), 2.05–1.81 (m, 4H),
the natural compound, confirms its absolute stereochemistry. 1.79–1.45 (m, 6H), 1.26 (s, 3H), 1.09 (d, J = 6.9 Hz, 6H), 0.82 (s,
1
3
3
The C ring of the starting material was efficiently transformed, 3H). C NMR (CDCl , 75 MHz) δ: 215.6 (C), 195.0 (CH), 184.4
utilizing conventional reactions realizable at a multigram scale, (C), 152.3 (CH), 144.4 (C), 50.0 (CH), 46.1 (C), 44.0 (CH), 42.6
providing the intermediate alcohol 17. The appropriate con- (CH ), 40.8 (CH), 37.8 (CH ), 37.1 (CH ), 36.4 (C), 26.8 (CH ),
2
2
2
2
figuration on C-8 was obtained after the diastereoselective 20.9 (CH
2
), 18.5 (CH
3
), 18.4 (CH
3
), 17.7 (CH
2
), 16.9 (CH
3
), 14.3
+
α-methylation of aldehyde 19. The cyclopentane C ring of (CH
3
). HRMS (APcI) m/z: calcd for C20
H
30
O
4
Na (M + Na )
the target compound was obtained after intramolecular aldol 357.2042, found: 357.2037.
6
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(1R,4aR,5R,8aR)-Methyl-6-formyl-1,4a-dimethyl-5-(4-methyl- (15 mL) was added slowly at 0 °C and the mixture was extracted
3
-oxopentyl)-1,2,3,4,4a,5,8,8a-octahydronaphthalene-1-carb- with ether (3 × 100 mL). The combined organic layers were
1
1
oxylate (11). Potassium carbonate (538 mg, 3.89 mmol) and washed with water and brine, and dried over anhydrous
methyl iodide were added to a stirred solution of 13 (1 g, Na SO and concentrated in vacuum. Purification by flash
.99 mmol) in acetone (30 mL) and the reaction mixture was column chromatography on silica gel (15% ether–hexanes)
stirred at reflux for 12 h, at which time TLC showed no starting gave 9.72 g of 15 (93%) (a 1 : 1 mixture of diastereomers) as a
2
4
2
1
3
material. The mixture was concentrated in vacuo to give a colourless oil. H NMR (CDCl , 400 MHz) δ: 3.74–3.66 (m, 2H),
crude product, which was diluted with ether–water (50–20 mL) 3.65 (s, 6H), 3.55–3.47 (m, 2H), 2.00–1.85 (m, 4H), 1.79–1.64
and the phases were shaken and separated. The organic phase (m, 8H), 1.61–1.39 (m, 12H), 1.36–1.22 (m, 8H), 1.14 (s, 6H),
was washed with water and brine and dried over anhydrous 1.07 (s, 6H), 0.99–0.92 (m, 4H), 0.91 (d, J = 6.7 Hz, 6H), 0.88 (d,
1
3
Na SO . Removal of the solvent under vacuum afforded a J = 6.7 Hz, 6H), 0.74 (s, 6H). C NMR (CDCl , 100 MHz) δ:
2
4
3
crude product which was purified by flash chromatography on 179.3 (2C), 77.2 (C), 74.9 (C), 61.7 (CH
silica gel (10% ether–hexanes) affording pure 11 (957 mg, 53.7 (CH), 51.8 (2CH
2
2
), 61.6 (CH ), 53.8 (CH),
3
), 50.8 (2CH), 47.7 (2C), 39.7 (2CH), 38.5
2
5
1
9
2%) as a colorless syrup. [α] = +9.0 (c = 12.5, CHCl3).
H
(CH ), 38.2 (CH ), 38.0 (CH ), 37.6 (2C), 37.0 (CH), 36.9 (CH ),
D
2
2
2
2
NMR (CDCl
3
, 500 MHz) δ: 0.83 (s, 3H), 0.88 (m, 1H), 1.09 (m, 36.1 (CH), 29.7 (CH
), 20.8 (CH
H), 1.47–1.77 (m, 5H), 1.88 (m, 1H), 1.93–2.10 (m, 3H), 2.29 (2CH ), 17.6 (2CH ), 16.9 (2CH ), 16.4 (2CH ), 16.1 (2CH ). IR
2
), 29.2 (2CH
2
), 29.0 (CH
2
), 23.2 (CH
3
), 22.7
1
3
H), 1.10 (d, J = 6.9 Hz, 3H), 1.10 (d, J = 6.9 Hz, 3H), 1.26 (s, (CH
3
2
), 20.7 (CH
2
), 18.4 (CH
2
), 18.3 (CH
2
), 17.8
2
3
3
3
3
(
6
6
m, 1H), 2.43 (ddd, J = 17.0, 10.6, 5.7 Hz, 1H), 2.62 (h, J = (film): 3370, 1726, 1457, 1386, 1250, 1195, 1145, 1018, 914,
.9 Hz, 1H), 3.11 (ddd, J = 17.1, 10.9, 4.7 Hz, 1H), 3.65 (s, 3H), 733 cm− . HRMS (APcI) m/z: calcd for C22
1
H O (M + H )
+
41 4
1
3
.75 (br s, 1H), 9.36 (s, 1H). C NMR (CDCl , 125 MHz) δ: 14.0 369.3005, found: 369.3012.
3
(CH
3
), 214.9 (C), 194.5 (CH), 178.2 (C), 152.0 (CH), 144.0 (C),
(1R,4aR,5S,6S,8aR)-Methyl 5-(3,4-dimethylpent-3-enyl)-
5
1.8 (CH ), 49.6 (CH), 45.9 (C), 43.9 (CH), 42.2 (CH ), 40.4 6-(hydroxymethyl)-1,4a-dimethyl-decahydronaphthalene-1-carb-
3
2
(
CH), 37.5 (CH ), 36.8 (CH ), 36.1 (C), 26.5 (CH ), 20.5 (CH ), oxylate (16). Iodine (9.35 g, 36.86 mmol) was slowly added to a
2
2
2
2
1
8.1 (CH
3
), 18.0 (CH
3
), 17.4 (CH
2
), 16.8 (CH
3
), 14.0 (CH
3
3
). IR solution of triphenylphosphine (PPh ) (9.67 g, 36.86 mmol) in
(
6
3
film): 1724, 1688, 1461, 1245, 1187, 1144, 1008, 727, CH
2
Cl
2
(80 mL) at 0 °C and the mixture was stirred at room
71 cm− . HRMS (APcI) m/z: calcd for C H O Na (M + Na ) temperature for 10 min. A solution of 15 (12.35 g, 33.51 mmol)
1
+
2
1
32 4
71.2198, found: 371.2206.
1R,4aR,5S,6S,8aR)-Methyl-6-(hydroxymethyl)-1,4a-dimethyl- was further stirred at room temperature for 2 h, at which time
-(4-methyl-3-oxopentyl)-decahydronaphthalene-1-carboxylate TLC showed no 15. Then the solvent was removed under
2 2
in CH Cl (40 mL) was then added and the resulting mixture
(
5
(
1
2
3
14). To a solution of 11 (1.00 g, 2.87 mmol) in THF (20 mL) vacuum and ether–5% NaHSO (120–30 mL) was added and
was added a 50% aqueous solution of RANEY® Nickel (4 mL), the phases were shaken and separated. The organic phase was
and the mixture was stirred at room temperature for 2 days, at washed with water and brine, and dried over anhydrous
which time TLC showed no 11. Then, the reaction mixture was Na
filtered through silica gel–Na SO (15 : 3 g), washed with crude product which was purified by flash chromatography on
acetone (20 mL) and concentrated to give pure 14 (0.98 g, 97%) silica gel (15% ether–hexanes) affording pure 16 (10.67 g, 91%)
2 4
SO . Removal of the solvent under vacuum afforded a
2
4
2
5
1
25
1
as a colorless syrup. [α]
CDCl , 500 MHz) δ: 0.73 (s, 3H), 0.93–1.05 (m, 2H), 1.08 (d, J = (CDCl
.9 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.13 (s, 3H), 1.29 (m, 1H), 10.3 Hz, 10.3 Hz, 1H), 3.65 (s, 3H), 2.10 (ddd, J = 12.4, 12.4,
.39–1.62 (m, 7H), 1.67–1.85 (m, 5H), 1.96 (m, 1H), 2.40 (ddd, 5.1 Hz, 1H), 2.02–1.83 (m, 3H), 1.79–1.66 (m, 2H), 1.64 (s, 3H),
D
= +33.8 (c = 71.5, CHCl
3
). H NMR as a colorless syrup. [α]
D 3
= +28.7 (c 4.0, CHCl ). H NMR
(
6
1
3
3
, 500 MHz) δ: 3.71 (d br, J = 9.3 Hz, 1H), 3.56 (dd, J =
J = 17.1, 9.1, 6.1 Hz, 1H), 2.53 (ddd, J = 15.2, 10.0, 6.1 Hz, 1H), 1.63 (s, 6H), 1.61–1.36 (m, 4H), 1.35–1.26 (m, 2H), 1.13 (s, 3H),
1
3
2
3
.59 (h, J = 6.9 Hz, 1H), 3.54 (dd, J = 10.1, 10.1 Hz, 1H), 3.64 (s, 1.07–0.93 (m, 3H), 0.79–0.72 (m, 2H), 0.71 (s, 3H). C NMR
1
3
H). C NMR (CDCl
3
, 125 MHz) δ: 215.1 (C), 179.3 (C), 61.3 (CDCl
3
, 125 MHz) δ: 179.5 (C), 128.1 (C), 124.1 (C), 61.6 (CH
2
),
(CH
2
), 52.7 (CH), 51.9 (CH
3
), 50.8 (CH), 47.7 (C), 41.0 (CH), 53.5 (CH), 52.0 (CH
3
), 51.0 (CH), 47.9 (C), 40.0 (CH), 38.3
3
9.7 (CH), 38.9 (CH ), 38.2 (CH ), 37.6 (C), 36.8 (CH ), 28.8 (CH ), 37.6 (C), 37.0 (CH ), 33.4 (CH ), 28.8 (CH ), 23.8 (CH ),
2
2
2
2
2
2
2
2
(
(
1
CH
CH
2
3
), 20.6 (CH
), 17.8 (CH
2
), 19.2 (CH
2
), 19.2 (CH
2
), 18.4 (CH
3
), 18.3 20.8 (CH
2
), 20.7 (CH
3
), 20.2 (CH
3
), 18.6 (CH
3
), 18.0 (CH
2
), 16.5
2
), 16.4 (CH
3
), 15.9 (CH
3
). IR (film): 3472, 1712, (CH
3
3
), 16.2 (CH ). IR (film): 3428, 1726, 1456, 1386, 1247,
−1
−1
459, 1386, 1248, 1141, 1023, 752 cm . HRMS (APcI) m/z: 1192, 1143, 1020, 773 cm . HRMS (APcI) m/z: calcd for
+
+
calcd for C21
H
36
O
4
Na (M + Na ) 375.2511, found: 375.2504.
C
22
H
39
O
3
(M + H ) 351.2899, found: 351.2907.
(1R,4aR,5S,6S,8aR)-Methyl 6-(hydroxymethyl)-1,4a-dimethyl-
hydroxymethyl)-1,4a-dimethyl-decahydronaphthalene-1-carb- 5-(3-oxobutyl)-decahydronaphthalene-1-carboxylate (17). A
oxylate (15). To a solution of 14 (10 g, 28.37 mmol) in anhydrous solution of 16 (2 g, 5.71 mmol) in CH Cl (30 mL) was cooled
THF (70 mL) was added dropwise a solution of methylmagne- to −78 °C and it was slowly bubbled with an O /O mixture;
sium bromide (50.7 mL of a 1.4 M solution in toluene–THF, the course of the reaction was monitored by TLC. When the
0.92 mmol) at 0 °C. The mixture was stirred under an argon starting material was consumed (1 h), the solution was flushed
(1R,4aR,5S,8aR)-Methyl 5-(3-hydroxy-3,4-dimethylpentyl)-6-
(
2
2
3
2
7
atmosphere at room temperature for 3 h, at which time TLC with argon, and triphenylphosphine (1.5 g, 5.72 mmol)
showed no starting material. Then, 5% aqueous NH Cl was added. The reaction mixture was then warmed to room
4
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temperature over 15 min and further stirred for 4 h. The
(1R,4aR,5S,6S,8aR)-Methyl
6-formyl-1,4a-dimethyl-5-(2-(2-
solvent was removed, and the crude product was purified by methyl-1,3-dioxolan-2-yl))-decahydronaphthalene-1-carboxylate
flash column chromatography on silica gel (20% ether– (19). Pyridinium dichromate (PDC; 5.33 g, 14.16 mmol) was
2
5
hexanes) to give 1.72 g of 17 (93%) as a colourless oil. [α]
D
=
added to a stirred solution of 18 (2.61 g, 7.08 mmol) in dry
1
+
3
2
2
2
1
24.3 (c 23.1, CHCl ). H NMR (CDCl , 500 MHz) δ: 3.64 (s, CH Cl (40 mL) and the mixture was stirred at room temp-
3
3
2
2
H), 3.63 (d, J = 10.1 Hz, 1H), 3.52 (dd, J = 10.1, 10.1 Hz, 1H), erature under an argon atmosphere for 10 h, at which time
.55 (dd, J = 10.7, 6.3 Hz, 1H), 2.51 (dd, J = 10.0, 5.6 Hz, 1H), TLC showed no remaining starting material. Then, the reaction
.38 (dd, J = 9.5, 6.0 Hz, 1H), 2.34 (dd, J = 10.3, 6.7 Hz, 1H), mixture was worked up by the addition of ether (40 mL), and
.13 (s, 3H), 1.95 (dd, J = 9.0, 3.2 Hz, 1H), 1.83–1.66 (m, 4H), the resulting mixture was filtered through a silica gel pad and
.58–1.38 (m, 4H), 1.31–1.22 (m, 2H), 1.12 (s, 3H), 1.01–0.93 washed with a mixture of ether (20 mL). The filtrate was
1
3
(
m, 2H), 0.72 (s, 3H). C NMR (CDCl , 125 MHz) δ: 209.45 (C), washed with a 1 N HCl solution (20 mL) and brine and dried
3
1
4
79.39 (C), 61.34 (CH
2
), 52.71 (CH), 52.01 (CH
3 2 4
), 50.87 (CH), over anhydrous Na SO . The solvent was evaporated to yield
2
5
7.83 (C), 42.45 (CH ), 39.76 (CH), 38.33 (CH
2
2
), 37.63 (C), 36.94 2.39 g of aldehyde 19 (92%) as a colourless syrup. [α] = +23.7
D
1
(CH ), 30.19 (CH ), 28.89 (CH ), 20.75 (CH ), 19.35 (CH ), (c 39.4, CHCl3). H NMR (CDCl , 500 MHz) δ: 9.97 (s, 1H),
2
3
2
2
2
3
1
1
7.93 (CH
2
), 16.50 (CH
3
3
), 16.05 (CH ). IR (film) 3437, 1720, 3.99–3.86 (m, 4H), 3.65 (s, 3H), 2.51 (t, J = 4.9 Hz, 1H), 2.31 (br
−
1
449, 1387, 1363, 1248, 1140, 1104, 1020 cm . HRMS (APcI) d, J = 14.6 Hz, 1H), 1.97–1.86 (m, 1H), 1.81–1.68 (m, 5H),
+
m/z: calcd for C H O (M + H ) 325.2379, found: 325.2371.
1.65–1.51 (m, 5H), 1.46 (ddd, J = 12.9, 12.9, 3.6 Hz, 1H), 1.34
1
9
33 4
(
1R,4aR,5S,6S,8aR)-Methyl 6-(hydroxymethyl)-1,4a-dimethyl- (s, 3H), 1.25 (d, J = 3.2 Hz, 1H), 1.18 (m, 1H), 1.12 (s, 3H), 1.05
1
3
5
3
-(3-oxobutyl)-decahydronaphthalene-1-carboxylate (17) from (m, 1H), 0.76 (s, 3H). C NMR (CDCl , 125 MHz) δ: 204.8
1
5. Iodine (2.10 g, 8.26 mmol) was added to a solution of tri- (CH), 179.3 (C), 110.2 (C), 64.8 (2CH ), 53.9 (CH), 52.1 (CH ),
2
3
phenylphosphine (2.17 g, 2.28 mmol) in CH
2
Cl
2
(15 mL) at 50.2 (CH), 47.7 (C), 47.6 (CH), 38.3 (C), 38.0 (2CH
2
), 37.1 (CH
2
),
0
1
2 3 2 2 2
°C and the mixture was stirred at room temperature for 26.0 (CH ), 23.9 (CH ), 21.8 (CH ), 19.3 (CH ), 18.0 (CH ), 16.5
0 min. A solution of 15 (3 g, 8.15 mmol) in CH Cl (20 mL) (CH ), 15.5 (CH ). IR (film): 1724, 1448, 1388, 1248, 1061,
2
2
3
3
was then added and the resulting mixture was further stirred 754 cm− . HRMS (APcI) m/z: calcd for C21
1
+
34 5
H O Na (M + Na )
at room temperature for 2 h, at which time TLC showed no 15. 389.2304, found: 389.2306.
Then, the mixture was cooled to −78 °C and it was slowly
bubbled with an O /O mixture; the course of the reaction was methyl-1,3-dioxolan-2-yl)ethyl)-decahydronaphthalene-1-carb-
monitored by TLC. When the starting material was consumed oxylate (10). Potassium tert-butoxide (252 mg, 2.249 mmol)
70 min), the solution was flushed with argon, and triphenyl- was added to a stirred solution of 19 (633 mg, 1.73 mmol) in
(1R,4aR,5R,6S,8aR)-Methyl 6-formyl-1,4a,6-trimethyl-5-(2-(2-
3
2
(
phosphine (2.2 g, 8.39 mmol) was added. Following the same dry benzene (30 mL) under an argon atmosphere. After 5 min
work-up used for 17 from 16, 2.35 g of 17 (89%) was obtained methyl iodide (0.4 mL, 5.19 mmol) was added and the reaction
as a colourless oil.
1R,4aR,5S,8aR)-Methyl 6-(hydroxymethyl)-1,4a-dimethyl-5- TLC showed no starting material. The mixture was concen-
2-(2-methyl-1,3-dioxolan-2-yl)ethyl)-decahydronaphthalene-1- trated in vacuo to give a crude product, which was dissolved in
carboxylate (18). Ethylene glycol (2.7 mL, 49.01 mmol) fol- ether (40 mL) and washed with brine (2 × 10 mL). The organic
lowed by toluene p-toluenesulfonic acid (15 mg) was added to phase was dried over anhydrous Na SO and the solvent was
7 (10.6 g, 32.67 mmol) in benzene (40 mL) and the mixture evaporated to give a crude product, which was purified by
was heated under reflux for 16 h using a Dean Stark trap. After flash chromatography on silica gel (15% ether–hexanes),
mixture was stirred at room temperature for 2 h, at which time
(
(
2
4
1
2
5
cooling to room temperature and concentrating under reduced affording 545 mg of 10 (83%) as colourless syrups. [α]
pressure, ether (100 mL) was added and the solution was (c 16.1, CHCl ). H NMR (CDCl
3 3
D
= +2.7
, 500 MHz) δ: 9.80 (d, J =
washed with saturated aqueous NaHCO3 (3 × 30 mL). The 1.2 Hz, 1H), 4.01–3.89 (m, 4H), 3.64 (s, 3H), 2.16 (dt, J = 13.4,
organic phase was dried (MgSO ) and concentrated under 3.1 Hz, 1H), 1.85–1.65 (m, 5H), 1.62–1.37 (m, 5H), 1.32 (s, 3H),
reduced pressure to give the title compound 18 (11.80 g, 98%) 1.26–1.11 (m, 3H), 1.09 (s, 3H), 1.04 (m, 1H), 1.01 (s, 3H), 0.98
1
4
2
5
1
13
as a colourless oil. [α] = +16.8 (c 17.5, CHCl3). H NMR (d, J = 6.4 Hz, 1H), 0.74 (s, 3H). C NMR (CDCl , 125 MHz) δ:
D
3
(CDCl
3
, 500 MHz) δ: 3.97–3.87 (m, 4H), 3.67 (dd, J = 10.3, 10.3 206.3 (CH), 179.3 (C), 109.8 (C), 64.8 (2CH
2
), 60.9 (CH), 52.0
3 2
Hz, 1H), 3.64 (s, 3H), 3.52 (dd, J = 10.3, 10.3 Hz, 1H), 2.15 (d, (CH ), 50.3 (CH), 50.1 (C), 47.6 (C), 43.3 (CH ), 38.9 (C), 37.9
J = 9.5 Hz, 1H), 1.96 (d, J = 7.4 Hz, 1H), 1.87 (d, J = 9.4 Hz, 1H), (CH ), 37.1 (CH ), 35.1 (CH ), 24.2 (CH ), 23.8 (CH ), 22.1
2
2
2
3
3
1
.80–1.67 (m, 4H), 1.60–1.47 (m, 4H), 1.46–1.38 (m, 2H), 1.31 (CH
2
), 18.8 (CH
2
), 17.8 (CH
2
), 16.5 (CH
3
), 15.5 (CH
3
). IR (film):
−1
(
(
(
s, 3H), 1.30–1.22 (m, 2H), 1.13 (s, 3H), 1.03–0.93 (m, 2H), 0.73 1725, 1457, 1377, 1246, 1061, 857, 756 cm . HRMS (APcI) m/z:
s, 3H). C NMR (CDCl , 125 MHz) δ: 179.4 (C), 110.4 (C), 64.8 calcd for C H O Na (M + Na ) 403.2460, found: 403.2454.
2CH
1
3
+
3
22 36 5
2
), 61.5 (CH
2
), 53.3 (CH), 52.0 (CH
3
), 51.0 (CH), 47.9 (C),
(3aR,5aR,6R,9aR,9bS)-Methyl 2-acetyl-3a,6,9a-trimethyl-
3
9.9 (CH), 38.4 (CH
2
), 37.7 (CH
2
), 37.7 (C), 37.0 (CH
2
), 28.9 3a,4,5,5a,6,7,8,9,9a,9b-decahydro-1H-cyclopenta[a]naphthalene-
(
CH ), 27.1 (CH ), 23.9 (CH ), 20.8 (CH ), 19.5 (CH ), 18.0 6-carboxylate (20). HCl (4 mL, 1 M) was added to a stirred
2
3
3
2
2
(
1
CH
2
3 3
), 16.6 (CH ), 16.2 (CH ). IR (film): 3498, 1783, 1724, solution of 10 (300 mg, 0.79 mmol) in THF (25 mL). The reac-
−
1
580, 1451, 1389, 1247, 1187 cm . HRMS (APcI) m/z: calcd for tion mixture was heated under reflux for 3 h, at which time
+
C H O (M + H ) 369.2641, found: 369.2653.
TLC showed no 10. The reaction was allowed to cool to room
2
1
37 5
6
180 | Org. Biomol. Chem., 2013, 11, 6176–6185
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Paper
temperature and the solvent was evaporated in vacuo. Then, dicyano-1,4-benzoquinone (DDQ; 567 mg, 2.5 mmol), and the
the residue was dissolved in ether (30 mL) and washed with reaction mixture was stirred at 100 °C for 1 h. Then the solvent
water (2 × 10 mL) and brine (2 × 10 mL). The organic phase was evaporated in vacuo, and the residue was dissolved in
2 4
was dried over anhydrous Na SO and concentrated under ether (50 mL), washed with water (5 × 15 mL) and brine. The
vacuum. The crude product was purified by flash chromato- organic phase was dried over anhydrous Na SO and concen-
2
4
graphy (15% ether–hexanes) to give 213 mg (85%) of methyl trated to give a crude product which was chromatographed on
2
5
ketone 20 as a colourless syrup. [α]
D
= +7.7 (c 10.4, CHCl
3
). silica gel (10% ether–hexanes) to give 552 mg of a 6 : 1 mixture
1
H NMR (CDCl , 500 MHz) δ: 6.46 (d, J = 2.1 Hz, 1H), 3.66 (s, of compound 21 and its regioisomer (92%) as a colourless
3
3
H), 2.61 (ddd, J = 17.1, 7.8, 2.4 Hz, 1H), 2.46 (d, J = 16.9 Hz, syrup. A further chromatography of this mixture on silica gel
1
1
1
H), 2.28 (s, 3H), 1.88 (dt, J = 13.7, 6.0 Hz, 1H), 1.75 (dd, J = (5% ether–hexanes) provided 420 mg of the pure regioisomer
2
5
1
1.2, 4.7 Hz, 1H), 1.71–1.64 (m, 3H), 1.62–1.56 (m, 2H), 21 (70%). [α] = +21.0 (c 13.5, CHCl3). H NMR (CDCl3,
D
.55–1.44 (m, 2H), 1.39 (m, 1H), 1.26 (m, 1H), 1.18 (s, 3H), 1.08 500 MHz) δ: 7.35 (d, J = 8.3 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H),
1
3
(s, 3H), 0.97 (ddd, J = 12.9, 12.9, 4.3 Hz, 1H), 0.71 (s, 3H).
C
3.86 (s, 3H), 3.66 (s, 3H), 2.87 (dd, J = 16.7, 7.1 Hz, 1H), 2.57
NMR (CDCl , 125 MHz) δ: 197.3 (C), 179.3 (C), 154.7 (CH), (d, J = 16.6 Hz, 1H), 2.40 (dt, J = 14.9, 4.0 Hz, 1H), 2.31 (s, 3H),
3
1
43.1 (C), 59.8 (CH), 52.0 (CH
3
), 48.8 (C), 47.1 (C), 45.6 (CH), 1.82 (d, J = 7.1 Hz, 1H), 1.78 (dd, J = 11.7, 2.8 Hz, 1H),
), 31.2 (CH ), 30.5 1.75–1.66 (m, 3H), 1.66–1.51 (m, 3H), 1.48 (dt, J = 17.5, 6.5 Hz,
4
0.5 (CH ), 37.1 (CH ), 36.3 (C), 33.6 (CH
2
2
2
2
(
(
1
3
CH ), 26.7 (CH ), 21.4 (CH ), 17.7 (CH ), 17.0 (CH ), 16.0 1H), 1.34 (s, 3H), 1.24 (m, 1H), 1.08 (s, 3H), 1.00 (ddd, J = 12.5,
3
3
2
2
3
1
3
CH
3
3
). IR (film): 1726, 1667, 1457, 1366, 1245, 1175, 1137, 12.5, 4.9 Hz, 1H), 0.29 (s, 3H). C NMR (CDCl , 125 MHz) δ:
068, 603 cm− . HRMS (APcI) m/z: calcd for C20
1
+
31 3
H O (M + H ) 179.5 (C), 169.5 (C), 168.5 (C), 151.8 (C), 148.6 (C), 137.4 (C),
19.2273, found: 319.2271.
128.7 (CH), 125.9 (C), 119.5 (CH), 63.1 (CH), 52.2 (CH ), 52.0
3
(
3aR,5aR,6R,9aR,9bS)-Methyl 2-(1-acetoxyvinyl)-3a,6,9a-trimethyl- (CH
a,4,5,5a,6,7,8,9,9a,9b-decahydro-1H-cyclopenta[a]naphthalene- (C), 33.7 (CH
-carboxylate (9). p-Toluenesulfonic acid (15 mg) was added to 17.7 (CH ), 17.1 (CH ), 15.6 (CH ). IR (film): 1768, 1725, 1448,
3
), 49.5 (C), 48.0 (CH), 47.3 (C), 39.7 (CH
2
), 37.0 (CH
2
), 36.8
3
6
2
), 31.8 (CH ), 28.4 (CH ), 22.1 (CH
3
2
2
), 21.0 (CH
3
),
2
3
3
−
1
a stirred solution of 20 (450 mg, 1.41 mmol) in isopropenyl 1252, 1207, 1162, 986, 755 cm . HRMS (APcI) m/z: calcd for
acetate (15 mL). The reaction mixture was heated under reflux
+
C
26
H
34
O
6
Na (M + Na ) 465.2253, found: 465.2246.
for 3 h, at which time TLC showed no 20. The reaction was
(4R,4aR,6aS,11aR,11bR)-Dimethyl 10-hydroxy-4,6a,11b-tri-
allowed to cool to room temperature and ether (30 mL) was methyl-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]fluor-
added. Then, the solution was washed with saturated aqueous ene-4,7-dicarboxylate (22). Conc. hydrochloric acid (1 mL) was
NaHCO (3 × 10 mL). The organic phase was dried over anhy- added to a stirred solution of 21 (440 mg, 0.99 mmol) in
3
2 4
drous Na SO and the solvent was evaporated to give a crude MeOH (10 mL) and the reaction mixture was refluxed for
product, which was purified by flash chromatography on silica 30 min, at which time TLC showed no starting material
gel (5% ether–hexanes), affording 494 mg of 9 (97%) as a remaining. Then, the solvent was removed under vacuum and
2
5
1
colourless syrup. [α]
D
= +25.7 (c 16.1, CHCl
3
). H NMR (CDCl
3
,
ether–water (30 : 10 mL) was added. The phases were shaken
5
4
2
1
3
00 MHz) δ: 5.52 (d, J = 1.7 Hz, 1H), 4.90 (d, J = 1.3 Hz, 1H), and separated. The organic phase was washed with water and
.79 (d, J = 1.5 Hz, 1H), 3.65 (s, 3H), 2.64 (ddd, J = 16.1, 7.9, brine, and dried over anhydrous Na SO . Removal of the
2
4
.3 Hz, 1H), 2.26 (d, J = 16.0 Hz, 1H), 2.19 (s, 3H), 1.79 (dd, J = solvent under vacuum afforded a crude product which was
3.4, 6.0 Hz, 1H), 1.74 (dd, 10.9, 4.8 Hz, 1H), 1.71–1.63 (m, directly purified by flash chromatography (35% ether–hexanes)
2
5
H), 1.61–1.52 (m, 2H), 1.51–1.34 (m, 3H), 1.22 (m, 1H), 1.18 to yield 386 mg of 22 (97%) as a colourless syrup. [α] = +17.8
D
1
(
(
s, 3H), 1.02 (s, 3H), 0.98 (ddd, J = 12.9, 12.9, 3.9 Hz, 1H), 0.78 (c 11.5, CHCl
s, 3H). C NMR (CDCl
3
). H NMR (CDCl
3
, 500 MHz) δ: 7.35 (d, J =
1
3
3
, 125 MHz) δ: 179.4 (C), 169.0 (C), 8.3 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 5.31 (s, 1H), 3.84 (s, 3H),
1
50.8 (C), 140.2 (CH), 134.8 (C), 102.4 (CH ), 60.3 (CH), 52.0 3.66 (s, 3H), 2.87 (dd, J = 16.1, 7.1 Hz, 1H), 2.67 (d, J = 16.1 Hz,
2
(
(
CH
C), 33.9 (CH
3
), 47.9 (C), 47.1 (C), 45.7 (CH), 40.8 (CH
2
), 37.1 (CH
2
), 36.3 1H), 2.45 (dt, J = 14.8, 4.3 Hz, 1H), 1.84 (d, J = 7.1 Hz, 1H), 1.79
), (dd, J = 11.5, 3.1 Hz, 1H), 1.77–1.69 (m, 3H), 1.68–1.60 (m, 2H),
2
), 32.8 (CH
2
), 31.0 (CH
3
), 21.4 (CH
2
), 21.1 (CH
3
1
1
C
7.8 (CH ), 17.0 (CH ), 15.8 (CH ). IR (film): 1765, 1725, 1447, 1.55 (m, 1H), 1.49 (dt, J = 10.1, 3.1 Hz, 1H), 1.37 (s, 3H), 1.24
370, 1204, 1069, 1020, 858 cm . HRMS (APcI) m/z: calcd for (m, 1H), 1.08 (s, 3H), 1.02 (ddd, J = 12.7, 12.7, 5.2 Hz, 1H), 0.31
2
3
3
−
1
+
13
22
H
32
O
4
Na (M + Na ) 383.2198, found: 383.2206.
4R,4aR,6aS,11aR,11bR)-Dimethyl 10-acetoxy-4,6a,11b-tri- 153.9 (C), 152.6 (C), 130.4 (C), 130.1 (CH), 120.8 (C), 112.9
methyl-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]fluor- (CH), 63.5 (CH), 52.1 (CH ), 51.9 (CH ), 49.6 (C), 48.0 (CH),
ene-4,7-dicarboxylate (21). Methyl propiolate (262 mg, 47.3 (C), 39.9 (CH ), 37.0 (CH ), 36.9 (C), 33.4 (CH ), 31.5
3
(s, 3H). C NMR (CDCl , 125 MHz) δ: 179.6 (C), 169.6 (C),
(
3
3
2
2
2
3
1
1
.12 mmol) was added to a solution of diene 9 (450 mg, (CH ), 27.4 (CH ), 22.2 (CH ), 17.8 (CH ), 17.1 (CH ), 15.7
3
2
2
2
3
.25 mmol) in xylene (5 mL), and the mixture was heated at (CH
3
). IR (film): 3413, 1721, 1700, 1583, 1434, 1258, 1134,
70 °C for 36 h in a sealed tube. At this time, TLC showed no 757 cm− . HRMS (APcI) m/z: calcd for C24
1
+
33 5
H O (M + H )
remaining starting material. The reaction was allowed to cool 401.2328, found: 401.2331.
to room temperature and then concentrated in vacuo to give an (4R,4aR,6aS,11aR,11bR)-Dimethyl 10-methoxy-4,6a,11b-tri-
unresolvable mixture of adducts. To a solution of this crude methyl-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]fluor-
product in 1,4-dioxane (15 mL) was added 2,3-dichloro-5,6- ene-4,7-dicarboxylate (23). Methyl iodide (160 mg, 1.13 mmol)
This journal is © The Royal Society of Chemistry 2013
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2
5
1
was added to a stirred suspension of 22 (350 mg, 0.87 mmol) colourless syrup. [α]
D
= −23.8 (c 6.3, CHCl
3
). H NMR (CDCl
3
,
and K CO (180 mg, 1.30 mmol) in acetone (10 mL) under an 500 MHz) δ: 10.33 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 6.76 (d, J =
2
3
argon atmosphere. The mixture was heated under reflux over- 8.5 Hz, 1H), 3.90 (s, 3H), 3.40 (d, J = 10.7 Hz, 1H), 3.15 (d, J =
night. Then, the solvent was evaporated in vacuo, ether (40 mL) 10.6 Hz, 1H), 2.91 (dd, J = 17.3, 8.7 Hz, 1H), 2.79 (d, J =
was added and the mixture was washed with water (2 × 10 mL) 17.3 Hz, 1H), 2.37 (dd, J = 14.3, 6.3 Hz, 1H), 2.06 (dd, J = 14.1,
and brine (1 × 10 mL). The organic phase was dried over anhy- 6.8 Hz, 1H), 1.81 (d, J = 8.7 Hz, 1H), 1.72 (d, J = 13.1 Hz, 1H),
2 4
drous Na SO and concentrated to give a crude product which 1.65 (m, 1H), 1.60–1.45 (m, 2H), 1.42 (s, 3H), 1.41–1.25 (m,
was purified by flash chromatography (10% ether–hexanes) to 4H), 0.95 (ddd, J = 13.0, 13.0, 3.4 Hz, 1H), 0.78 (s, 3H), 0.56 (s,
2
5
13
give 355 mg (98%) of 23 as a colourless syrup. [α]
D
= +21.1 3H). C NMR (CDCl
, 400 MHz) δ: 7.45 (d, J = (C), 132.1 (C), 132.0 (CH), 126.4 (C), 108.2 (CH), 71.9 (CH
.5 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 62.3 (CH), 55.6 (CH ), 50.1 (C), 44.3 (CH), 41.1 (CH ), 38.0 (C),
3
, 125 MHz) δ: 190.4 (CH), 160.1 (C), 156.5
1
(
c 13.1, CHCl
3
). H NMR (CDCl
3
2
),
8
3
1
3
2
.66 (s, 3H), 2.84 (dd, J = 17.0, 6.8 Hz, 1H), 2.72 (d, J = 16.7 Hz, 37.1 (C), 35.5 (CH
H), 2.43 (dt, J = 14.8, 4.4 Hz, 1H), 1.83–1.76 (m, 2H), 1.68 (CH ), 17.9 (CH ), 17.4 (CH
ddd, J = 14.0, 13.5, 8.2 Hz, 2H), 1.57–1.44 (m, 3H), 1.37 (s, 1593, 1462, 1273, 1251, 1050, 757 cm . HRMS (APcI) m/z:
2
), 34.6 (CH
2
), 32.5 (CH
3
2
), 28.8 (CH ), 19.1
2
2
3
), 16.3 (CH
3
). IR (film): 3481, 1675,
−1
(
+
3
1
1
1
H), 1.30–1.21 (m, 2H), 1.12 (m, 1H), 1.08 (s, 3H), 1.02 (m, calcd for C23
H
33
O
3
(M + H ) 357.2430, found: 357.2422.
(4R,4aR,6aS,11aR,11bR)-4-(Hydroxymethyl)-10-methoxy-
69.6 (C), 157.6 (C), 151.9 (C), 132.8 (C), 130.1 (CH), 120.6 (C), 4,6a,11b-trimethyl-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-
1
3
3
H), 0.29 (s, 3H). C NMR (CDCl , 100 MHz) δ: 179.6 (C),
07.7 (CH), 63.4 (CH), 55.4 (CH
3
), 52.0 (CH
3
), 51.9 (CH
3
), 49.6 benzo[a]fluoren-7-yl formate (26). m-Chloroperoxybenzoic acid
(
(
(
C), 47.9 (CH), 47.3 (C), 39.8 (CH
2
), 37.0 (C), 36.9 (CH
2
), 33.3 (MCPBA, 75%; 106 mg, 0.46 mmol) was added at 0 °C to a
CH ), 31.4 (CH ), 28.0 (CH ), 22.1 (CH ), 17.8 (CH ), 17.1 stirred solution of 25 (147 mg, 0.38 mmol) in CH Cl (10 mL)
2
3
2
2
2
2
2
CH
3
), 15.7 (CH
3
). IR (film): 1727, 1457, 1434, 1259, 1188, and the reaction was stirred for 3 h, at which time TLC indi-
−
1
1
138, 755 cm . HRMS (APcI) m/z: calcd for C25
H
34
O
5
Na (M + cated no starting material remaining. The reaction was
quenched with sat. aq. Na SO (0.5 mL) and stirred for an
+
Na ) 437.2304, found: 437.2297.
2
3
(
(4R,4aR,6aS,11aR,11bR)-10-Methoxy-4,6a,11b-trimethyl- additional 10 min. Then, it was poured into ether–water
,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]fluorene-4,7- (20 : 7 mL), and the organic phase was washed with sat. aq.
diyl)dimethanol (24). LiAlH (40 mg, 1.05 mmol) was added NaHCO (5 × 8 mL) and brine, dried over Na SO and concen-
2
4
3
2
4
2
5
to a stirred solution of 23 (175 mg, 0.42 mmol) in dry THF trated to give 26 (148 mg, 97%) as a colourless oil. [α]
10 mL) cooled to 0 °C and the reaction mixture was stirred (c 9.6, CHCl ). H NMR (CDCl , 500 MHz) δ: 8.30 (s, 1H), 6.78
D
= −4.3
1
(
3 3
under an argon atmosphere for 2 h, at which time TLC showed (d, J = 8.7 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H), 3.82 (s, 3H), 3.39 (d,
no remaining starting material. Then 2 N HCl (0.5 mL) was J = 10.8 Hz, 1H), 3.12 (d, J = 10.8 Hz, 1H), 2.87 (dd, J = 17.2,
added slowly at 0 °C, and the mixture was extracted with ether 7.8 Hz, 1H), 2.76 (d, J = 16.3 Hz, 1H), 2.43 (dt, J = 16.3, 5.1 Hz,
(
2 × 20 mL). The organic phase was washed with brine, dried 1H), 1.74 (d, J = 6.3 Hz, 1H), 1.67 (m, 1H), 1.57 (m, 1H),
over anhydrous Na SO , and the solvent was evaporated to give 1.55–1.41 (m, 2H), 1.38 (dd, J = 13.2, 4.0 Hz, 1H), 1.33–1.24 (m,
53 mg of pure 24 (94%) as a colourless syrup. [α]
2
4
2
5
1
(
D
= +4.2 4H), 1.20 (s, 3H), 0.92 (ddd, J = 12.9, 12.9, 3.5 Hz, 1H), 0.74 (s,
1
13
c 8.5, CHCl ). H NMR (CDCl , 400 MHz) δ: 7.10 (d, J = 8.1 Hz, 3H), 0.50 (s, 3H). C NMR (CDCl , 125 MHz) δ: 160.5 (CH),
3 3 3
1
H), 6.64 (d, J = 8.3 Hz, 1H), 4.71 (s, 2H), 3.82 (s, 3H), 3.41 (d, 153.7 (C), 143.4 (C), 139.6 (C), 133.5 (C), 121.1 (CH), 109.0
), 62.1 (CH), 55.6 (CH ), 48.6 (C), 45.2 (CH),
J = 10.3 Hz, 1H), 3.13 (d, J = 10.6 Hz, 1H), 2.85 (dd, J = 16.9, (CH), 72.1 (CH
2
3
7
1
.5 Hz, 1H), 2.73 (d, J = 17.0 Hz, 1H), 2.59 (d, J = 14.5 Hz, 1H), 40.8 (CH ), 37.8 (C), 37.1 (C), 35.5 (CH ), 33.5 (CH ), 31.5
2
2
2
.81–1.67 (m, 3H), 1.66–1.35 (m, 5H), 1.25 (s, 3H), 1.03–0.80 (CH
3
3
), 29.0 (CH
2
), 19.2 (CH
2
), 17.8 (CH
2
), 17.8 (CH
3
), 16.2
1
3
(m, 3H), 0.73 (s, 3H), 0.43 (s, 3H). C NMR (CDCl
3
, 100 MHz) (CH
). IR (film): 3455, 1740, 1591, 1485, 1465, 1221, 1129,
−
1
+
δ: 155.4 (C), 151.0 (C), 132.0 (C), 129.3 (CH), 127.9 (C), 108.0 1056, 757 cm . HRMS (APcI) m/z: calcd for C H O (M + H )
2
3
33 4
(
4
3
CH), 72.2 (CH
2
), 63.1 (CH
6.1 (CH), 40.4 (CH ), 37.7 (C), 37.2 (C), 35.5 (CH
2.6 (CH ), 28.3 (CH ), 19.7 (CH ), 17.9 (CH ), 17.9 (CH ), 16.1 trimethyl-2,3,4,4a,5,6,6a,7,10,11,11a,11b-dodecahydro-1H-
2
), 62.4 (CH), 55.3 (CH
3
), 49.6 (C), 373.2379, found: 373.2386.
2
2
), 34.8 (CH
2
), (4R,4aR,6aS,11aR,11bR)-4-(Iodomethyl)-10-methoxy-4,6a,11b-
3
2
2
2
3
(
6
3
3
CH ). IR (film): 3357, 1605, 1493, 1462, 1385, 1249, 1056, 757, benzo[a]fluoren-7-yl formate (27). To a solution of triphenyl-
68 cm− . HRMS (APcI) m/z: calcd for C23
1
H
O
(M + H ) phosphine (487 mg, 1.86 mmol) in dry CH
added successively iodine (503 mg, 1.98 mmol) and imidazole
+
35
3
2 2
Cl (10 mL) was
59.2586, found: 359.2588.
(4R,4aR,6aS,11aR,11bR)-4-(Hydroxymethyl)-10-methoxy-4,6a,- (253 mg, 3.72 mmol). The mixture was stirred at room temp-
11b-trimethyl-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]- erature for 5 min and a solution of alcohol 26 (230 mg,
fluorene-7-carbaldehyde (25). To a solution of 24 (275 mg, 0.62 mmol) in dry benzene (40 mL) was added. The resulting
.71 mmol) in chloroform (15 mL) was added manganese(IV) mixture was stirred at reflux for 16 h; at this time TLC showed
oxide (371 mg, 4.26 mmol) and the reaction mixture was no 26. Then, aq. 5% NaHSO (5 mL) was added and the
stirred at room temperature for 4 h. The inorganic solid was mixture was stirred for 5 min. The solvent was removed under
removed by filtration of the mixture through a silica gel pad vacuum and the crude product was diluted with Et O–water
10 g) and washed with ether (10 mL). The combined filtrates (50–15 mL) and the phases were shaken and separated. The
were evaporated to yield 246 mg (91%) of compound 25 as a organic phase was washed with water and brine, and dried
0
3
2
(
6
182 | Org. Biomol. Chem., 2013, 11, 6176–6185
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over anhydrous Na SO . Removal of the solvent under vacuum 5.09 (s, 1H), 3.75 (s, 3H), 2.80 (dd, J = 17.2, 8.0 Hz, 1H), 2.69
2
4
afforded a crude product which was directly purified by flash (dd, J = 17.5, 2.3 Hz, 1H), 2.65 (dt, J = 12.0, 5.6 Hz, 1H), 2.64
chromatography on silica gel (5% ether–hexanes) to give 27 (dd, J = 10.0, 4.0 Hz, 1H), 1.75 (dd, J = 8.6, 6.2 Hz, 1H), 1.72
2
5
(
229 mg, 77%) as a colourless oil. [α]
D
= −32.8 (c 11.9, CHCl
3
). (dd, J = 5.4, 3.1 Hz, 1H), 1.70–1.59 (m, 2H), 1.50 (m, 1H),
1
H NMR (CDCl , 500 MHz) δ: 8.30 (s, 1H), 6.79 (d, J = 8.6 Hz, 1.44–1.25 (m, 2H), 1.23 (s, 3H), 1.15 (m, 1H), 0.98 (dd, J = 11.2,
3
1
1
2
1
3
1
0
H), 6.65 (d, J = 8.7 Hz, 1H), 3.82 (s, 3H), 3.28 (d, J = 9.9 Hz, 4.8 Hz, 1H), 0.91 (dd, J = 13.0, 3.5 Hz, 1H), 0.88 (s, 3H), 0.81 (s,
1
3
H), 3.15 (d, J = 9.9 Hz, 1H), 2.91 (dd, J = 17.4, 8.2 Hz, 1H), 3H), 0.50 (s, 3H). C NMR (CDCl
.76 (dd, J = 17.3, 2.0 Hz, 1H), 2.32 (dt, J = 14.4, 6.2 Hz, 1H), 142.7 (C), 139.1 (C), 133.1 (C), 111.7 (CH), 107.8 (C), 62.0 (CH),
.78 (dd, J = 8.3, 1.9 Hz, 1H), 1.75 (m, 1H), 1.70 (dt, J = 12.9, 56.0 (CH ), 51.8 (CH), 49.2 (C), 42.3 (CH ), 41.5 (CH ), 37.3 (C),
.0 Hz, 1H), 1.54–1.42 (m, 2H), 1.37–1.30 (m, 3H), 1.24 (s, 3H), 33.4 (CH ), 33.4(C), 32.9 (CH ), 30.5 (CH ), 29.1 (CH ), 21.9
.18 (d, J = 4.9 Hz, 1H), 1.11 (d, J = 12.3 Hz, 1H), 0.97 (s, 3H), (CH ), 19.6 (CH ), 18.6 (CH ), 15.7 (CH ). IR (film): 3525, 1474,
3
, 125 MHz) δ: 149.5 (C),
3
2
2
3
2
3
2
3
2
2
3
1
3
−1
3
.93 (m, 1H), 0.53 (s, 3H). C NMR (CDCl , 125 MHz) δ: 160.4 1451, 1268, 1224, 1175, 1061, 1013, 771, 669 cm . HRMS
+
(CH), 153.7 (C), 143.5 (C), 139.6 (C), 133.1 (C), 121.1 (CH), (APcI) m/z: calcd for C22
2
H32BrO (M + H ) 407.1586, found:
1
08.9 (CH), 62.1 (CH), 55.6 (CH ), 48.6 (C), 48.1 (CH), 40.9 407.1586.
3
(CH
2
), 39.3 (CH
2
), 37.2 (C), 35.8 (C), 32.8 (CH
2
), 31.2 (CH
3
),
(4aS,6aS,11aR,11bS)-8-Bromo-7,10-dimethoxy-4,4,6a,11b-
2
9.2 (CH ), 28.7 (CH
2
2
), 18.7 (CH ), 18.6 (CH ), 18.2 (CH
2
3
2
), 15.6 tetramethyl-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]-
−
1
(CH ). IR (film): 1740, 1485, 1220, 1126, 1054, 756 cm
.
fluorene (8). Methyl iodide (139 mg, 0.98 mmol) was added to
INa (M + Na ) 505.1216, a stirred suspension of 29 (305 mg, 0.75 mmol) and K CO
(155 mg, 1.13 mmol) in acetone (25 mL) under an argon
3
+
HRMS (APcI) m/z: calcd for C23
found: 505.1208.
H
31
O
3
2
3
(
4aS,6aS,11aR,11bS)-10-Methoxy-4,4,6a,11b-tetramethyl- atmosphere. The mixture was heated under reflux overnight.
,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]fluoren-7-ol Then, the solvent was evaporated in vacuo, ether (40 mL) was
28). To a solution of 27 (250 mg, 0.52 mmol) in THF (10 mL) added and the mixture was washed with water (2 × 10 mL) and
was added 50% aqueous solution of RANEY® Nickel (5 mL) brine (1 × 10 mL). The organic phase was dried over anhydrous
and the mixture was stirred at room temperature for 10 h; at Na SO and concentrated to give a crude product which was
this time TLC showed no 27. Then, the reaction mixture was purified by flash chromatography (5% ether–hexanes) to give
2
(
2
4
2
5
filtered through a silica gel–Na SO pad (20 : 5 g), washed with 306 mg (97%) of 8 as a colorless syrup. [α] = +0.2 (c 8.7,
2
4
D
1
acetone (20 mL) and concentrated to give pure 28 (150 mg, CHCl
3
). H NMR (CDCl
3
, 500 MHz) δ: 6.82 (s, 1H), 3.82 (s, 3H),
3.77 (s, 3H), 2.76 (ddd, J = 10.4, 8.3, 4.2 Hz, 1H), 2.65 (d, J =
2
5
1
9
1%) as a colourless syrup. [α]
D
= −7.5 (c 13.7, CHCl
3
).
H
NMR (CDCl , 500 MHz) δ: 6.50 (d, J = 8.5 Hz, 1H), 6.46 (d, J = 16.8 Hz, 1H), 1.71 (br d, J = 11.3 Hz, 1H), 1.67–1.57 (m, 3H),
3
8
1
1
1
3
.5 Hz, 1H), 4.31 (s, 1H), 3.77 (s, 3H), 2.86 (dd, J = 17.1, 8.1 Hz, 1.48 (m, 1H), 1.43–1.24 (m, 5H), 1.15 (ddd, J = 13.1, 13.1,
H), 2.73 (dd, J = 17.1, 2.0 Hz, 1H), 2.60 (dt, J = 13.8, 6.2 Hz, 4.0 Hz, 1H), 0.95 (dd, J = 11.5, 3.3 Hz, 1H), 1.22 (s, 3H), 0.88 (s,
1
3
H), 1.78 (d, J = 14.5 Hz, 1H), 1.77 (dd, J = 14.0, 1.9 Hz, 1H), 3H), 0.78 (s, 3H), 0.41 (s, 3H). C NMR (CDCl , 125 MHz) δ:
3
.75–1.70 (m, 2H), 1.50 (m, 1H), 1.44–1.29 (m, 4H), 1.26 (s, 152.0 (C), 147.4 (C), 145.7 (C), 132.6 (C), 114.9 (C), 113.6 (CH),
3 3
H), 1.16 (ddd, J = 13.8, 13.8, 4.3 Hz, 1H), 1.01 (dd, J = 11.2, 5.0 62.3 (CH), 61.6 (CH), 55.8 (CH ), 52.8 (CH ), 49.4 (C), 42.2
13
Hz, 1H), 0.88 (s, 3H), 0.81 (s, 3H), 0.52 (s, 3H). C NMR (CH ), 41.0 (CH ), 37.4 (C), 34.2 (CH ), 33.6 (CH ), 33.3 (C),
2
2
2
3
(CDCl
3
, 125 MHz) δ: 149.9 (C), 146.0 (C), 138.7 (C), 133.0 (C), 32.7 (CH
3
), 28.6 (CH
2
), 22.1 (CH
3
), 20.0 (CH
2
2
), 18.6 (CH ), 15.5
1
3 3
14.3 (CH), 109.0 (CH), 62.1 (CH), 55.8 (CH ), 51.7 (CH), 48.3 (CH ). IR (film): 1595, 1472, 1427, 1224, 1052, 966, 828,
C), 42.4 (CH ), 41.6 (CH ), 37.3 (C), 33.5 (C), 33.4 (CH ), 33.4 770 cm− . HRMS (APcI) m/z: calcd for C H BrO Na (M + Na )
1
+
(
(
(
2
2
2
23 33
2
CH
CH
3
), 30.8 (CH
3
), 29.2 (CH
2
), 21.9 (CH
3
), 19.6 (CH
2
), 18.6 443.1562, found: 443.1557.
2
), 15.7 (CH
3
). IR (film): 3419, 1493, 1452, 1264, 1247, (4aS,6aS,11aR,11bS)-7,10-Dimethoxy-4,4,6a,11b-tetramethyl-
060, 795 cm− . HRMS (APcI) m/z: calcd for C H O (M + H ) 2,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]fluorene-8-
1
+
1
3
2
2
33 2
29.2481, found: 329.2484.
4aS,6aS,11aR,11bS)-8-Bromo-10-methoxy-4,4,6a,11b-tetra- THF (20 mL) was added n-butyllithium (2.4 M, 0.9 mL,
methyl-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]fluoren- 2.19 mmol) at −78 °C under an argon atmosphere, and the
-ol (29). A solution of bromine (0.09 mL, 1.72 mmol) in reaction mixture was stirred at this temperature for 45 min.
CH Cl (3 mL) was added to a solution of 28 (283 mg, Freshly distilled DMF (0.17 mL, 2.19 mmol) was then added
.86 mmol) in CH Cl (10 mL) at 0 °C, and the reaction and the mixture was stirred for a further 2 h, at which time
carbaldehyde (30). To a solution of 8 (310 mg, 0.73 mmol) in
(
7
2
2
0
2
2
3
mixture was stirred for 10 min. A 5% NaHSO solution (1 mL) TLC showed no starting material. Then the mixture was
was added to quench the reaction and the mixture was stirred quenched with water (0.3 mL) and the solvent was removed,
for an additional 5 min. Then ether (25 mL) was added and and ether–water (40–10 mL) were added to the crude product.
the organic phase was washed with water (6 × 10 mL) and The phases were shaken and separated, and the organic phase
2 4 2 4
brine and dried over anhydrous Na SO . The solvent was was washed with brine and dried over anhydrous Na SO .
removed under vacuum and the crude product was purified by Removal of the solvent under vacuum afforded a crude
flash column chromatography on silica gel (15% ether– product that was directly purified by flash chromatography
2
5
hexanes) to give 312 mg of 29 (89%) as a yellow syrup. [α]
D
=
(7% ether–hexanes) to give 229 mg of aldehyde 30 (84%) as a
1
25
1
+
4.6 (c 8.3, CHCl ). H NMR (CDCl , 500 MHz) δ: 6.72 (s, 1H), colorless syrup. [α]D = −29.5 (c 14.5, CHCl ). H NMR (CDCl ,
3
3
3
3
This journal is © The Royal Society of Chemistry 2013
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Paper
Organic & Biomolecular Chemistry
5
3
1
1
1
00 MHz) δ: 10.29 (s, 1H), 7.13 (s, 1H), 3.89 (s, 3H), 3.83 (s, 1H), 1.42–1.32 (m, 3H), 1.32–1.24 (m, 2H), 1.22 (s, 3H), 1.15
H), 2.83 (ddd, J = 15.7, 14.5, 6.9 Hz, 1H), 2.76 (d, J = 17.8 Hz, (ddd, J = 13.2, 13.2, 4.0 Hz, 1H), 0.95 (dd, J = 11.4, 3.1 Hz, 1H),
1
3
H), 1.76–1.59 (m, 4H), 1.54–1.43 (m, 2H), 1.43–1.28 (m, 4H), 0.88 (s, 3H), 0.77 (s, 3H), 0.39 (s, 3H). C NMR (CDCl
3
,
.26 (s, 3H), 1.16 (dd, J = 13.2, 13.2, 4.2 Hz, 1H), 0.97 (dd, J = 125 MHz) δ: 151.8 (C), 148.9 (C), 144.3 (C), 132.8 (C), 130.4 (C),
1
3
1.5, 3.2 Hz, 1H), 0.89 (s, 3H), 0.78 (s, 3H), 0.39 (s, 3H).
, 125 MHz) δ: 189.7 (CH), 154.9 (C), 152.3 (C), (CH
45.4 (C), 142.1 (C), 129.0 (C), 107.6 (CH), 65.8 (CH), 62.4 (CH), 34.4 (CH
C
110.1 (CH), 69.9 (CH ), 62.9 (CH), 62.6 (CH), 58.5 (CH ), 55.6
2
3
NMR (CDCl
3
3
), 52.9 (CH
3
), 48.9 (C), 42.3 (CH
2
), 41.1 (CH
2
), 37.4 (C),
1
5
2
), 33.7 (CH
3
), 33.3 (C), 32.8 (CH
3
), 28.6 (CH
2
), 22.1
5.7 (CH ), 52.7 (CH ), 48.8 (C), 42.2 (CH ), 40.9 (CH ), 37.4 (CH ), 20.2 (CH ), 18.6 (CH ), 15.5 (CH ). IR (film): 1595, 1464,
3
3
2
2
3
2
2
3
−
1
(C), 34.2 (CH
2
), 33.6 (CH
3
), 33.3 (C), 32.6 (CH
3
2
), 29.4 (CH ), 1378, 1319, 1218, 1191, 1117, 1054, 990 cm . HRMS (APcI)
). IR (film): 1683, m/z: calcd for C25
+
2
2.1 (CH
3
), 20.0 (CH
2
), 18.5 (CH
2
), 15.5 (CH
3
H O
38 3
Na (M + Na ) 409.2719, found: 409.2726.
−
1
1
590, 1474, 1389, 1303, 1217, 1114, 1052 cm . HRMS (APcI)
(4aS,6aS,11aR,11bS)-8-(Methoxymethyl)-4,4,6a,11b-tetra-
+
m/z: calcd for C24
H
34
O
3
Na (M + Na ) 393.2406, found: methyl-1,2,3,4,4a,5,6,6a,11,11a-decahydro-11bH-benzo[a]fluorene-
7,10-dione (33). AgO (124 mg, 1.00 mmol) was added to a
3
93.2409.
((4aS,6aS,11aR,11bS)-7,10-Dimethoxy-4,4,6a,11b-tetramethyl- stirred solution of 32 (110 mg, 0.20 mmol) in 1,4-dioxane
2
,3,4,4a,5,6,6a,11,11a,11b-decahydro-1H-benzo[a]fluoren-8-yl)- (6 mL) at 4 °C. After 5 min, HNO (4 N, 0.1 mL) was added
3
methanol (31). Sodium borohydride (31 mg, 0.82 mmol) was dropwise and the mixture was stirred for a further 15 min, at
added to a stirred solution of 30 (190 mg, 0.51 mmol) in EtOH which time TLC showed no starting material. Then, the reac-
(
8 mL), and the reaction mixture was stirred at room temp- tion mixture was poured into H
erature for 10 min at which time TLC showed no 30. The CH Cl (3 × 50 mL). The combined organic layers were dried
reaction mixture was quenched at 0 °C with water (1 mL), the over anhydrous Na SO and the solvent was evaporated to give
2
O (60 mL) and extracted with
2
2
2
4
solvent was evaporated, and the crude product was diluted a crude product which was purified by flash chromatography
with ether (20 mL) and washed with water and brine. The on silica gel (10% ether–hexanes) affording 90 mg of pure 33
2
5
1
organic phase was dried over anhydrous Na SO and con- (89%) as a yellow syrup. [α] = +1.5 (c 3.3, CHCl ). H NMR
2
4
D
3
centrated to give 187 mg of 31 (98%) as a colorless syrup. (CDCl
3
, 600 MHz) δ: 6.63 (s, 1H), 4.28 (d, J = 2.2 Hz, 1H), 4.27
2
5
1
[
(
(
α]
D
= −4.4 (c 7.7, CHCl ). H NMR (CDCl , 500 MHz) δ: 6.68 (d, J = 2.2 Hz, 1H), 3.45 (s, 3H), 2.73 (dd, J = 19.6, 8.9 Hz, 1H),
3 3
s, 1H), 4.73 (d, J = 12.4 Hz, 1H), 4.69 (d, J = 12.4 Hz, 1H), 3.80 2.61 (dd, J = 19.6, 2.8 Hz, 1H), 2.17 (dt, J = 14.3, 7.4 Hz, 1H),
s, 3H), 3.78 (s, 3H), 2.82 (dd, J = 10.7, 6.3 Hz, 1H), 2.79 (m, 1.80 (dt, J = 14.5, 7.6 Hz, 1H), 1.73–1.63 (m, 2H), 1.60 (br d, J =
1
1
H), 2.69 (d, J = 16.8 Hz, 1H), 2.03 (br s, 1H), 1.73 (br d, J = 13.1 Hz, 1H), 1.46–1.30 (m, 3H), 1.25 (s, 3H), 1.15 (ddd, J =
2.7 Hz, 1H), 1.66–1.54 (m, 5H), 1.54–1.44 (m, 2H), 1.42–1.24 13.2, 13.2, 3.3 Hz, 1H), 1.01 (dd, J = 10.9, 6.4 Hz, 1H),
1
3
(m, 4H), 1.23 (s, 3H), 1.15 (ddd, J = 14.1, 14.1, 4.6 Hz, 1H), 0.95 0.97–0.87 (m, 2H), 0.86 (s, 3H), 0.85 (s, 3H), 0.71 (s, 3H).
C
13
3
(dd, J = 11.5, 3.2 Hz, 1H), 0.88 (s, 3H), 0.77 (s, 3H). C NMR NMR (CDCl , 150 MHz) δ: 187.3 (C), 186.1 (C), 153.6 (C), 147.5
(
CDCl , 125 MHz) δ: 151.9 (C), 148.5 (C), 144.6 (C), 133.2 (C), (C), 146.2 (C), 131.0 (CH), 68.1 (CH ), 59.9 (CH ), 59.3 (CH),
3
2
3
1
32.9 (C), 109.5 (CH), 62.7 (CH), 62.5 (CH), 61.6 (CH
2
), 55.6 49.9 (CH), 49.6 (C), 42.3 (CH
2
), 41.8 (CH
2
), 36.9 (C), 33.5 (C),
(CH
3
), 53.0 (CH
3
), 48.9 (C), 42.3 (CH
2
), 41.0 (CH
2
), 37.4 (C), 33.0 (CH
3
), 30.8 (CH ), 29.8 (CH ), 29.5 (CH ), 21.6 (CH ), 19.0
2 3 2 3
3
4.4 (CH ), 33.7 (CH ), 33.3 (C), 32.9 (CH ), 28.5 (CH ), 22.1 (CH ), 18.5 (CH ), 16.0 (CH ). IR (film): 1732, 1651, 1456,
2
3
3
2
2
2
3
−
1
(CH
3
), 20.2 (CH
2
), 18.6 (CH
2
), 15.5 (CH
3
). IR (film): 3407, 1595, 1107, 772, 669 cm . HRMS (APcI) m/z: calcd for C23
H
32
O
3
Na
−1
+
1
464, 1218, 1110, 1053 cm . HRMS (APcI) m/z: calcd for (M + Na ) 379.2249, found: 379.2244.
+
C H O (M + H ) 373.2743, found: 373.2738.
Dasyscyphin B (4). Na S O (157 mg, 0.90 mmol) was added
2
4
37
3
2 2 4
(
4aS,6aS,11aR,11bS)-7,10-Dimethoxy-8-(methoxymethyl)- to a suspension of quinone 33 (35 mg, 0.098 mmol) in 8 mL of
,4,6a,11b-tetramethyl-2,3,4,4a,5,6,6a,11,11a,11b-decahydro- CHCl –H O (1 : 1) and the mixture was stirred at room temp-
H-benzo[a]fluorene (32). Sodium hydride 60% dispersion in erature for 4 h, at which time TLC showed no starting material.
was removed under vacuum, and the mixture was
4
1
3
2
mineral oil (100 mg, 2.5 mmol) was added to a stirred solution Then, CHCl
3
of 31 (142 mg, 0.38 mmol) in dry THF (12 mL) cooled to 0 °C diluted with ether (25 mL) and the phases were shaken and
under an argon atmosphere. After 5 min, methyl iodide separated. The organic layer was washed with water and brine,
2 4
(0.2 mL, 3.21 mmol) was added and the reaction mixture was and dried over Na SO . The solvent was evaporated to give a
stirred at room temperature for 2 h. The reaction was poured crude product which was purified by flash chromatography on
over ice (4 g) and concentrated in vacuo to give a crude silica gel (30% ether–hexanes) affording 22 mg of pure 4 (63%)
2
5
1
product, which was dissolved in ether (40 mL) and washed as a colorless syrup. [α]
D
3 3
= −12 (c 0.2, CHCl ). H NMR (CDCl ,
with brine. The organic phase was dried over anhydrous 600 MHz) δ: 6.31 (s, 1H), 4.59 (d, J = 11.8 Hz, 1H), 4.51 (d, J =
Na SO and the solvent was evaporated to give a crude product 11.8 Hz, 1H), 3.42 (s, 3H), 2.70 (m, 1H), 2.62 (d, J = 16.4, 1H),
2
4
which was purified by flash chromatography on silica gel (5% 1.75–1.67 (m, 3H), 1.64–1.52 (m, 3H), 1.42–1.25 (m, 3H), 1.24
ether–hexanes) affording 143 mg of pure 32 (97%) as a color- (s, 3H), 1.20–0.90 (m, 3H), 0.88 (s, 3H), 0.80 (s, 3H), 0.51 (s,
2
5
1
13
less syrup. [α] = −5.9 (c 7.9, CHCl3). H NMR (CDCl3, 3H). C NMR (CDCl , 150 MHz) δ: 146.6 (C), 144.1 (C), 139.2
D
3
5
3
1
00 MHz) δ: 6.70 (s, 1H), 4.46 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), (C), 130.3 (C), 121.4 (C), 113.0 (CH), 74.4 (CH
.44 (s, 3H), 2.81 (dd, J = 16.5, 7.1 Hz, 1H), 2.68 (d, J = 16.8 Hz, (CH ), 52.0 (CH), 48.5 (C), 42.2 (CH ), 41.5 (CH
H), 1.72 (br d, J = 12.4 Hz, 1H), 1.66–1.54 (m, 3H), 1.48 (m, (CH ), 33.4 (C), 33.3 (CH ), 30.8 (CH ), 28.3 (CH ), 22.0 (CH ),
2
), 62.2 (CH), 58.2
3
2
2
), 37.3 (C), 33.5
3
2
3
2
3
6
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1
9.7 (CH
2
), 18.6 (CH
2
), 15.6 (CH
3
). HRMS (APcI) m/z: calcd for
8 The two-synthon strategy, involving the reaction of an aryl-
lithium derived from a suitably protected polyphenol with
a bicyclic sesquiterpene (drimane derivative) electrophile,
has been widely utilized for synthesizing merosesquiter-
penes. For recent examples, see: (a) A. F. Barrero,
E. J. Alvarez-Manzaneda and R. Chahboun, Tetrahedron
Lett., 1997, 38, 2325–2328; A. F. Barrero, E. J. Alvarez-
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7252; (c) K.-I. Takao, T. Sasaki, T. Kozaki, Y. Yaganisawa,
K.-I. Tadano, A. Kawashima and H. Shinonaga, Org. Lett.,
+
C H O (M + H ) 359.2586, found: 359.2590.
2
3
35 3
Acknowledgements
The authors thank the Spanish Ministry of Science and Inno-
vation (project CTQ2009-09932) and the Regional Government
of Andalucia (project P11-CTS-7651 and assistance to the
FQM-348 group) for financial support. A.F. thanks the Spanish
Ministry of Science and Innovation for the predoctoral grant
provided.
2
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This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 6176–6185 | 6185