Enantioselective synthesis of the hydroazulene core of 3α-hydroxy-15- rippertene

Article abstract of DOI:10.1002/ejoc.200700904

As part of a project directed toward the total synthesis of the tetracyclic diterpene 3α-hydroxy-15-rippertene, a constituent of the defense secretion of higher termites, a fast access to two advanced hydroazulene key intermediates has been achieved by st

Full text of DOI:10.1002/ejoc.200700904

FULL PAPER
DOI: 10.1002/ejoc.200700904
Enantioselective Synthesis of the Hydroazulene Core of
3α-Hydroxy-15-rippertene
Thomas Kreuzer[a] and Peter Metz*[a]
Dedicated to Professor Hans J. Schäfer on the occasion of his 70th birthday
Keywords: Hydroazulenes / Hydroboration / Ring expansion / Organocopper compounds / Aldol reactions
As part of a project directed toward the total synthesis of the
tetracyclic diterpene 3α-hydroxy-15-rippertene, a constituent
of the defense secretion of higher termites, a fast access to
two advanced hydroazulene key intermediates has been
achieved by starting from (–)-isopulegol. A regio- and dia-
of the seven-membered ring. Completion of the bicyclic title
compounds was then achieved by cyclopentene annulation
through diastereoselective conjugate addition of organo-
cuprates and subsequent intramolecular aldol condensations.
stereoselective formal hydromethallylation and a regioselec- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tive ring expansion served as the key steps in the formation
Germany, 2008)
system, and the hydroazulenes 4a and 4b represent suitable
precursors for this intermediate; 4a and 4b, in turn, should
be available from the cycloheptenone 5 by cyclopentene an-
nulation, while 5 can be retrosynthetically traced back to
(–)-isopulegol (6) by a sequence of chain elongation, oxi-
dation and ring expansion.
Introduction
The defense secretion of the nasute termite soldiers con-
tains structurally unique bi- to tetracyclic diterpenes de-
rived from cembrene A dissolved in monoterpene hydro-
carbons.[1] The biological effects of these diterpenes are cur-
rently only poorly investigated due to the low quantities
isolated. However, several tricyclic trinervitane diterpenes
showed interesting antimicrobial activities in recent stud-
ies.[2] Due to their complex architecture, the tetracyclic ter-
mite diterpenes are attractive synthetic targets. So far, the
total synthesis of a single naturally occurring kempane,
kempene-2,[3] has been achieved in racemic form, and many
advanced synthetic investigations directed to this class of
natural products have been reported.[4,5]
We recently reinitiated our studies toward the enantiose-
lective total synthesis of the diterpene 3α-hydroxy-15-rip-
pertene (1) that has been isolated from the defense secretion
of the higher termites Nasutitermes rippertii and Nasuti-
termes ephratae by Prestwich[6] (Figure 1). Several years
ago, we accomplished the first enantioselective construction
of the tetracyclic skeleton of 1 starting from the sesquiter-
pene lactone (–)-α-santonin.[5] Herein we disclose a concise
synthetic sequence to two advanced key intermediates 4a
and 4b containing the complete hydroazulene moiety of 1
by commencing with (–)-isopulegol (6) as the chiral source.
As outlined in Figure 1, a domino Heck cyclization[7] of
enol triflate 3 is envisioned to generate the tetracyclic ring
Figure 1. Retrosynthetic analysis.
Results and Discussion
Preparation of 5 from 6 started with a high-yielding syn-
thesis of the alcohol 8 according to a methodology devel-
oped by Knochel (Scheme 1).[8] To this end, a completely
diastereoselective hydroboration of the silyl-protected[9] (–)-
[a] Department of Chemistry, Technische Universität Dresden,
Bergstr. 66, 01069 Dresden, Germany
Fax: +49-351-463-33162
E-mail: peter.metz@chemie.tu-dresden.de
572
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 572–579

Hydroazulene Core of 3α-Hydroxy-15-rippertene
Scheme 1. Synthesis of cycloheptenone 5.
isopulegol derivative 7 was effected with diethylborane fol- Table 1. Ring expansion with various Lewis acids.
lowed by a boron/zinc exchange reaction with diethylzinc
to generate a diorganozinc species. Hydroboration of 7 fol-
lows the stereochemical course already observed with 6[10]
through minimization of allylic strain.[11] After copper-in-
duced allylic substitution with methallyl bromide and de-
protection of the intermediate silyl ether with aqueous
HCl,[12] the enantiomerically pure alcohol 8 was isolated in
excellent yield with Ͼ98% de (GC). PCC oxidation[13] of 8
to give the ketone 9 and a Lewis acid catalyzed ring expan-
Entry[a] Lewis acid
Conditions
Yield Ratio 10/10a[a]
sion of 9 with (trimethylsilyl)diazomethane[14] afforded the
cycloheptanone 10 after hydrolysis of the trimethylsilyl enol
ether intermediate. Subsequent reconversion of 10 into the
TMS enol ether[15] and oxidation of this compound accord-
ing to the Saegusa–Ito method[16] in DMSO with oxygen
as the stoichiometric oxidant then smoothly furnished the
cycloheptenone 5. An attempt at a one-pot conversion of
ketone 9 to give 5 was less efficient due to partial hydrolysis
of the silyl enol ether in the course of the trifluoroborane-
triggered ring enlargement.
1
2
3
4
Me3Al
Me2AlCl
EtAlCl2
BF3·OEt2
–78 °C to room temp., 16 h 66%
1:1
6:1
1:1
5:1
–78 °C, 1 h
–78 °C, 1 h
–78 °C, 1 h
78 %
57 %
90 %
[a] Ratio of isolated isomers.
During optimization of the ring expansion with (trimeth-
ylsilyl)diazomethane, we found that the ratio of cyclohep-
tanones 10/10a showed a marked dependence on the nature
of the Lewis acid applied (Table 1).[17] Gratifyingly, the de-
sired regioisomer 10 could be isolated in 75% yield with the
aid of trifluoroborane–diethyl ether followed by hydrolysis.
For construction of the hydroazulenes 4a,b from 5 we
used a conjugate addition followed by either an acetal cleav-
age/aldol or an oxidation/aldol sequence. The first route
commenced with a diastereoselective copper-catalyzed 1,4-
addition[18] of the acetal-protected Grignard species 11 or
13, respectively, to cycloheptenone 5 (Scheme 2).[19] A con-
jugate addition trans to the allylic methyl group in 5 to give
12 and 14, respectively, was proven by NOESY experiments.
Scheme 2. Copper-catalyzed 1,4-addition.
Finally, the hydroazulenes 4a and 4b could be generated into hydroazulene enones with aqueous HCl in a one-pot
by palladium-catalyzed acetal cleavage[20] and subsequent procedure,[19,24] all attempts to use this methodology for the
aldol condensations under basic
conditions[21,22] preparation of hydroazulene 4a by varying the acid concen-
(Scheme 3). For 4b, an alternative combination of PPTS- tration, temperature and solvent met with failure in our
induced deblocking[23] of 14 and aldol condensation with- hands. In addition, an acid-catalyzed shift of the terminal
out purification of diketone 16 turned out to be more pro- double bond took place at higher temperature, e.g. in re-
ductive. Whereas acetals similar to 12 have been converted fluxing THF. Only the palladium-catalyzed transacetaliza-
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T. Kreuzer, P. Metz
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Scheme 3. Acetal cleavage and aldol condensation.
tion reaction[20] gave rise to aldehyde 15 in good yield. Due per-catalyzed conjugate addition[18,19] of the TBS-protected
to 1,4-addition of the solvent methanol, the conditions ap- Grignard species 17[25] to cycloheptenone 5, which suc-
plied for cyclization of ketone 16 could not be transferred ceeded with high stereochemical control (93% de) in 86%
to the production of enone 4a from aldehyde 15. Eventually, yield. Desilylation of 18 with TBAF[26] had to be monitored
the desired aldol condensation of 15 was attained by using very carefully by TLC, because longer reaction times led to
KOH in the presence of the phase-transfer catalyst 18- an epimerization α to the carbonyl group. After oxi-
crown-6 in benzene with the aid of a Dean–Stark trap.[22] dation[27] of alcohol 19 with the Dess–Martin periodinane
Unfortunately, the strongly basic conditions required for cy- (DMP), aldehyde 15 was isolated in an overall yield of 70%
clization caused a significant epimerization α to the ketone over 3 steps in a total reaction time of 8 h. Compared to
function for both 4a and 4b. Gratifyingly, however, the two the acetal cleavage sequence, which produces 15 in an over-
resultant epimeric mixtures could be readily separated by all yield of 68% (2 steps) from 5 in 3 d, this oxidation route
flash chromatography, which allowed a high-yielding equili- is now our preferred pathway, since it also delivers the alde-
bration of the undesired isomers 4c and 4d under condi- hyde 15 with an improved purity of Ͼ99% (GC).
tions analogous to those used during their formation from
15 and 16.
The relative configuration of isomers 4a–d was estab-
lished by 2D NMR measurements through the NOESY re-
sults summarized in Figure 2.
Scheme 4. Alternative route to aldehyde 15.
Conclusions
The synthetic sequence reported herein permits a fast ac-
Figure 2. Results of NOESY experiments.
cess to the hydroazulenes 4a and 4b, two advanced interme-
In order to reduce the time needed for the preparation diates for the enantioselective total synthesis of 3α-hydroxy-
of aldehyde 15 from 5 and to facilitate its purification, we 15-rippertene (1). Studies toward completion of the synthe-
additionally developed the alternative route to 15 depicted sis according to the strategy illustrated in Figure 1 are cur-
in Scheme 4. This sequence commenced again with a cop- rently in progress.
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Eur. J. Org. Chem. 2008, 572–579

Hydroazulene Core of 3α-Hydroxy-15-rippertene
34.36 (t), 31.68 (d), 30.46 (t), 22.24 (q), 21.17 (q), 0.45 (q) ppm.
GC-MS (EI): m/z (%) = 226 (3) [M+], 143 (100). C13H26OSi
(226.43): calcd. C 68.96, H 11.57; found C 68.72, H 11.79.
Experimental Section
General Remarks: NMR spectra were recorded with Bruker ASP-
500 (1H: 500.13 MHz; 13C: 125.77 MHz). The chemical shifts are
reported in ppm and refer to the applied NMR solvent (for CDCl3:
1H: δ = 7.26 ppm; 13C: δ = 77.0 ppm). The assignment of the signals
resulted from two-dimensional NMR methods (COSY, HSQC,
HMBC, NOESY). The coupling constants (J) are given in Hertz
(Hz). Resonance patterns are reported with the following notations:
br. (broad), s (singlet), d (doublet), t (triplet), q (quartet) and m
(multiplet). The multiplicities of the 13C NMR signals were deter-
mined by DEPT spectra. FT-IR spectra were recorded with Nicolet
205 FT-IR and Nicolet Avatar 360 FT-IR instruments, and only
the most significant absorption bands are given in cm–1. Mass spec-
tra were recorded by GC/MS coupling with Hewlett Packard
5890 II and Agilent 6890N instruments by using the mass-selective
detectors Hewlett Packard 5972 and Agilent 5973N (EI, 70 eV).
Specific rotations were determined at 589 nm with Perkin–Elmer
241 and 341 LC instruments and refer to the given temperature.
Thin-layer chromatography (TLC) was carried out by using TLC
aluminum sheets with silica gel 60 F254 purchased from Merck.
Flash column chromatography[28] was performed by using silica gel
60 (40–60 mesh) as the stationary phase purchased from Merck.
All eluant mixtures are given in vol.-%. All solvents used for flash
chromatography were distilled prior to use (ethyl acetate from tar-
taric acid, diethyl ether from KOH). Unless otherwise noted, sol-
vents and reagents were of reagent grade, purchased from ABCR,
Acros, Aldrich, Fluka, Merck, Lancaster, and used without further
purification. Tetrahydrofuran and diethyl ether were first distilled
from CaH2 and finally dried with sodium/potassium alloy. Dichlo-
romethane was first distilled and then finally dried with aluminum
oxide (basic) using a cartridge device.[29] Triethylamine and chloro-
trimethylsilane were distilled from calcium hydride. Methanol was
dried with magnesium turnings. Copper cyanide was dried at
0.05 mbar and 160 °C for 3 d, and lithium bromide was dried at
0.1 mbar and 120 °C for 2 h. All reactions were carried out in heat
gun dried flasks under argon unless otherwise stated. Diethylzinc
and triethylborane were transferred to the Schlenk flask by using
heat gun dried glass syringes, which were cooled down under argon.
The excess of diethylzinc and triethylborane was removed from the
reaction mixture under reduced pressure and condensed in a safety
flask cooled down to –78 °C. After complete removal of the pyro-
phoric liquids from the reaction mixture, the safety flask was
flushed with argon, and the residue was diluted with THF and
carefully hydrolyzed with ethanol at –78 °C and finally treated with
water.
Alcohol 8: Preparation of diethylborane (solution in diethyl ether):
To a solution of borane–dimethyl sulfide complex (4.75 mL,
50.0 mmol, 1.0 equiv.) in diethyl ether (21 mL) at 0 °C was added
triethylborane (14.5 mL, 0.1 mol, 2.0 equiv.). After 30 min at 0 °C,
the diethylborane solution is ready for use. Alkene 7 (6.50 g,
28.7 mmol, 1.0 equiv.) was placed in a Schlenk flask and treated
through cannula dropwise with the diethylborane solution
(14.4 mL, 57.4 mmol, 2.0 equiv.) at 0 °C. After the reaction mixture
was stirred at room temperature for 2 d, the solvent was removed
in vacuo (0 °C, 0.1 mbar) for 30 min. Diethylzinc (5.74 mL,
57.4 mmol, 2.0 equiv.) was added with a heat gun dried glass sy-
ringe (cooled down under argon) at 0 °C, and the mixture was
stirred at this temperature for 2 h. The excess diethylzinc and
formed triethylborane was distilled off under reduced pressure
(0 °C, 0.1 mbar) for 4 h. The residue was dissolved in THF
(20 mL), cooled down to –78 °C and treated with a solution of
copper cyanide (2.57 g, 28.7 mmol, 1.0 equiv.) and lithium bromide
(4.99 g, 57.4 mmol, 2.0 equiv.) in THF (30 mL). The reaction mix-
ture was allowed to warm to 0 °C for 30 min and, after a color
change from olive-green to black, immediately cooled back to
–78 °C and treated with methallyl bromide (11.6 g, 86.1 mmol,
3.0 equiv.). The reaction mixture was allowed to warm to room
temperature overnight and poured into an aqueous saturated solu-
tion of NH4Cl (500 mL). The aqueous layer was extracted with
diethyl ether (3ϫ500 mL). The combined organic phases were
washed with brine (80 mL), dried with MgSO4, filtered and concen-
trated under reduced pressure. The crude silyl ether was dissolved
in THF (200 mL) and treated at room temperature with aqueous
HCl (1 ) (50 mL). After 1 h, the reaction mixture was neutralized
with an aqueous saturated solution of NaHCO3 (50 mL), and the
aqueous layer was extracted with diethyl ether (5ϫ100 mL). The
combined organic phases were washed with brine (80 mL), dried
with MgSO4, filtered, and concentrated in vacuo. Purification of
the residue by flash column chromatography on silica gel (dichloro-
methane) gave 8 (4.75 g, 79%) as a colorless oil. Rf = 0.36 (dichlo-
romethane). [α]2D5 = –51.3 (c = 1.01, in CHCl ). IR (KBr): ν = 3363,
˜
3
2952, 2927, 2921, 884 cm–1. H NMR (CDCl3): δ = 4.69 (s, 1 H),
1
4.67 (s, 1 H), 3.46 (ddd, J = 10.4, 10.4, 4.3 Hz, 1 H), 2.13–2.07 (m,
1 H), 1.97–1.87 (m, 3 H), 1.71 (s, 3 H), 1.66–1.60 (m, 2 H), 1.58–
1.51 (m, 1 H), 1.44–1.38 (m, 1 H), 1.31 (br. s, OH), 1.16–1.06 (m,
2 H), 1.03–0.97 (m, 1 H), 0.92 (d, J = 7.0 Hz, 3 H), 0.90 (d, J =
6.5 Hz, 3 H), 0.95–0.89 (m, 1 H), 0.87–0.78 (m, 1 H) ppm. 13C
NMR (CDCl3): δ = 147.61 (s), 109.62 (t), 71.05 (d), 50.75 (d), 45.08
(t), 36.30 (t), 34.68 (t), 31.60 (d), 31.20 (d), 29.27 (t), 24.53 (t), 22.50
(q), 22.18 (q), 17.78 (q) ppm. GC-MS (EI): m/z (%) = 210 (2) [M+],
81 (100). C14H26O (210.36): calcd. C 79.94, H 12.46; found C 79.65,
H 12.73.
Silyl Ether 7: (–)-Isopulegol (6) (15.0 g, 97.2 mmol, 1.0 equiv.) was
dissolved in DMF (200 mL) and subsequently treated with imid-
azole (13.2 g, 0.195 mol, 2.0 equiv.), 4-(dimethylamino)pyridine
(200 mg, 1.64 mmol, 0.02 equiv.) and chlorotrimethylsilane
(18.5 mL, 15.9 g, 0.146 mol, 1.5 equiv.) at room temperature. After Cyclohexanone 9: Pyridinium chlorochromate (5.33 g, 24.7 mmol,
16 h, the reaction mixture was poured into diethyl ether/pentane/ 2.0 equiv.) was suspended in dichloromethane (60 mL) and treated
H2O (1:1:1) (1500 mL). The organic layer was washed with water with a solution of alcohol 8 (2.60 g, 12.4 mmol, 1.0 equiv.) in
(3ϫ300 mL), dried with MgSO4, filtered, and concentrated in
vacuo. Purification of the residue by distillation under reduced
pressure afforded 7 (21.9 g, 99%) as a colorless liquid. B.p. 86 °C
dichloromethane (20 mL) at room temperature. After 16 h, the re-
action mixture was diluted with diethyl ether (20 mL) and passed
through a pad of silica gel by using diethyl ether as eluant. Evapo-
ration of the solvent afforded 9 (2.55 g, 99%) as a colorless and
(13 mbar). [α]2D5 = –37.3 (c = 1.12, in CHCl ). IR (KBr): ν = 2955,
˜
3
1
2924, 1250, 1009, 885 cm–1. H NMR (CDCl3): δ = 4.75 (s, 1 H),
analytically pure oil. Rf = 0.46 (diethyl ether/pentane, 1:5). [α]D25
=
4.72 (s, 1 H), 3.45 (ddd, J = 10.3, 10.3, 4.4 Hz, 1 H), 1.91–1.86 (m, –38.7 (c = 1.04, in CHCl ). IR (KBr): ν = 2955, 2929, 2871, 1712,
˜
3
1 H), 1.86–1.82 (m, 1 H), 1.68 (s, 3 H), 1.63–1.58 (m, 2 H), 1.45– 884 cm–1. 1H NMR (CDCl3): δ = 4.66 (s, 1 H), 4.65 (s, 1 H), 2.35–
1.40 (m, 1 H), 1.34–1.26 (m, 1 H), 1.06–0.99 (m, 1 H), 0.90 (d, J 2.31 (m, 1 H), 2.13–2.00 (m, 3 H), 1.98–1.81 (m, 5 H), 1.71 (s, 3
= 6.5 Hz, 3 H), 0.87–0.85 (m, 1 H), 0.06 (s, 9 H) ppm. 13C NMR
(CDCl3): δ = 147.94 (s), 110.78 (t), 73.69 (d), 53.09 (d), 45.16 (t),
H), 1.54–1.48 (m, 1 H), 1.46–1.38 (m, 1 H), 1.36–1.30 (m, 1 H),
1.18–1.10 (m, 1 H), 0.98 (d, J = 6.4 Hz, 3 H), 0.89 (d, J = 6.9 Hz,
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T. Kreuzer, P. Metz
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3 H) ppm. 13C NMR (CDCl3): δ = 212.02 (s), 146.35 (s), 109.55 (t), 24.10 (q), 22.39 (q), 15.04 (q) ppm. GC-MS (EI): m/z (%) =
(t), 55.26 (d), 50.84 (t), 35.66 (t), 35.18 (d), 33.98 (t), 30.92 (t), 30.76
(d), 27.91 (t), 22.41 (q), 22.25 (q), 17.36 (q) ppm. GC-MS (EI): m/z
(%) = 208 (5) [M+], 96 (100). C14H24O (208.34): calcd. C 80.71, H
11.61; found C 80.77, H 11.66.
222 (7) [M+], 55 (100). C15H26O (222.37): calcd. C 81.02, H 11.79;
found C 81.06, H 11.98.
Cycloheptenone 5: To a solution of diisopropylamine (1.67 mL,
1.21 g, 11.9 mmol, 1.5 equiv.) was added dropwise BuLi (6.21 mL,
1.6  in hexane, 9.93 mmol, 1.25 equiv.) at 0 °C. After 30 min, the
reaction mixture was cooled down to –78 °C and treated slowly
with a solution of ketone 9 (1.77 g, 7.95 mmol, 1.0 equiv.) in THF
(16 mL). After 90 min, chlorotrimethylsilane (1.51 mL, 1.29 g,
11.9 mmol, 1.5 equiv.) was added, and the reaction mixture was
stirred for another 90 min. For workup, the solution was passed
through a pad of basic aluminum oxide by using diethyl ether as
eluant. Evaporation of the solvent afforded the crude silyl enol
ether (2.34 g, 100%), which was used without further purification
in the next step. To a solution of the crude silyl enol ether (2.34 g,
7.94 mmol, 1.0 equiv.) in DMSO (160 mL) was added Pd(OAc)2
(178 mg, 0.793 mmol, 0.1 equiv.) at room temperature, and a slow
stream of oxygen was passed through the reaction mixture. After
16 h, the solution was poured into a cold solution (0 °C) of diethyl
ether/H2O (1:1) (400 mL), and the aqueous layer was extracted with
diethyl ether (4ϫ150 mL). The combined organic phases were sub-
sequently washed with H2O and brine (150 mL each), dried with
MgSO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash column chromatography on
silica gel (diethyl ether/pentane, 1:10) to furnish 5 (1.50 g, 86%) as
a colorless oil. Rf = 0.43 (diethyl ether/pentane, 1:10). [α]2D5 = –25.0
General Procedure for the Ring Expansion of Ketone 9: To a solu-
tion of the Lewis acid (aluminum Lewis acids were used as solu-
tions in hexanes) in dichloromethane (0.13 , 1.5 equiv.) cooled
down to –78 °C was added dropwise a solution of ketone 9 in
dichloromethane (0.31 , 1.0 equiv.), followed by a solution of (tri-
methylsilyl)diazomethane (2  in hexane, 1.5 equiv.). After the
given reaction time, an aqueous saturated solution of NaHCO3 was
added, and the aqueous layer was extracted with dichloromethane.
The combined organic phases were washed with brine, dried with
MgSO4, filtered, and concentrated in vacuo. The crude silyl enol
ether was dissolved in THF (0.12 ) and treated at room tempera-
ture with aqueous HCl (1 ) (0.25 mL per mL THF). After 1 h, the
reaction mixture was neutralized with an aqueous saturated solu-
tion of NaHCO3, and the aqueous layer was extracted with diethyl
ether. The combined organic phases were washed with brine, dried
with MgSO4, filtered and concentrated under reduced pressure. Pu-
rification of the residue by flash column chromatography on silica
gel (diethyl ether/pentane, 1:10) gave 10 and 10a as colorless oils
as listed in Table 1.
Cycloheptanones 10 and 10a: To a solution of boron trifluoride–
diethyl ether (1.32 g, 9.30 mmol, 1.18 mL, 1.5 equiv.) in dichloro-
methane (70 mL) cooled down to –78 °C was added dropwise a
solution of ketone 9 (1.29 g, 6.19 mmol, 1.0 equiv.) in dichloro-
methane (20 mL), followed by a solution of (trimethylsilyl)diazo-
methane (4.65 mL, 2  in hexane, 9.30 mmol, 1.5 equiv.). After 1 h,
an aqueous saturated solution of NaHCO3 (6 mL) was added, and
the aqueous layer was extracted with dichloromethane (4ϫ50 mL).
The combined organic phases were washed with brine (50 mL),
dried with MgSO4, filtered, and concentrated in vacuo. The crude
silyl enol ether was dissolved in THF (50 mL) and treated at room
temperature with aqueous HCl (1 ) (12.5 mL). After 1 h, the reac-
tion mixture was neutralized with an aqueous saturated solution of
NaHCO3 (12.5 mL), and the aqueous layer was extracted with di-
ethyl ether (3ϫ30 mL). The combined organic phases were washed
with brine (30 mL), dried with MgSO4, filtered and concentrated
under reduced pressure. Purification of the residue by flash column
chromatography on silica gel (diethyl ether/pentane, 1:10) gave 10
(1.03 g, 75%) and 10a (205 mg, 15%) as colorless oils (10/10a =
(c = 1.14, in CHCl ). IR (ATR): ν = 2960, 2930, 2872, 1651,
˜
3
882 cm–1. H NMR (CDCl3): δ = 6.12 (ddd, J = 12.6, 3.5, 1.5 Hz,
1
1 H), 5.81 (dd, J = 12.6, 2.6 Hz, 1 H), 4.66 (s, 1 H), 4.63 (s, 1 H),
2.48–2.41 (m, 2 H), 2.04–1.97 (m, 2 H), 1.94–1.85 (m, 3 H), 1.67
(s, 3 H), 1.53–1.42 (m, 2 H), 1.31–1.19 (m, 2 H), 1.05 (d, J = 7.2 Hz,
3 H), 0.88 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 208.39
(s), 147.66 (d), 145.97 (s), 129.32 (d), 109.79 (t), 59.82 (d), 39.14
(d), 36.15 (d), 35.55 (t), 32.96 (t), 31.06 (t), 24.17 (t), 22.33 (q),
21.49 (q), 17.37 (q) ppm. GC-MS (EI): m/z (%) = 220 (7) [M+], 124
(100). C15H24O (220.35): calcd. C 81.76, H 10.98; found C 81.82,
H 11.14.
General Procedure for the Conjugate Addition of Alkyl Bromides to
Cycloheptenone 5: Magnesium (2.5 equiv.) was suspended in THF
(0.23 mL per mmol), and some crystals of iodine and 3 drops of
alkyl bromide (1.35 equiv.) were added at room temperature. The
reaction mixture was stirred and eventually heated (max. 60 °C)
until the color disappeared and the solution turned cloudy. Sub-
sequently, the mixture was diluted with THF (1.13 mL per mmol
Mg) and the remaining alkyl bromide was added within 1 h by
using a syringe pump. After 15 min at room temperature, the mix-
ture was cooled down to 0 °C, stirred for 20 min, cooled down to
–20 °C and treated with copper(I) iodide (0.13 equiv.). After 5 min
at –20 °C, a solution of cycloheptenone 5 in THF (1.33 mL per
mmol, 1.0 equiv.) was added within 90 min by using a syringe
pump. After the addition, the mixture was stirred at –20 °C for
15 min, warmed to 0 °C and stirred for 15 min before warming to
room temperature. After 30 min, the solution was poured into a
rapidly stirred 4:1 mixture of saturated aqueous ammonium chlo-
ride solution and aqueous ammonium hydroxide (25%) (13 mL per
mmol 5) and diethyl ether (17 mL per mmol 5) until a clear phase
separation appeared. The organic phase was separated, washed
twice with ammonia buffer (13 mL per mmol 5), once with brine
(13 mL per mmol 5), dried with MgSO4, filtered and concentrated
under reduced pressure.
5:1). Data for 10: Rf = 0.50 (diethyl ether/pentane, 1:10). [α]D25
=
–115.0 (c = 1.05, in CHCl ). IR (KBr): ν = 2954, 2929, 2871, 1699,
˜
3
885 cm–1. H NMR (CDCl3): δ = 4.67 (s, 1 H), 4.64 (s, 1 H), 2.58
1
(ddd, J = 12.8, 12.8, 2.9 Hz, 1 H), 2.30 (ddd, J = 12.7, 6.3, 2.4 Hz,
1 H), 2.24–2.20 (m, 1 H), 2.05–2.00 (m, 1 H), 1.95–1.70 (m, 5 H),
1.69 (s, 3 H), 1.57–1.50 (m, 2 H), 1.48–1.41 (m, 1 H), 1.26–1.17 (m,
2 H), 1.00–0.94 (m, 1 H), 0.91 (d, J = 6.7 Hz, 3 H), 0.86 (d, J =
6.8 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 217.03 (s), 145.95 (s),
109.82 (t), 58.53 (d), 42.08 (t), 36.99 (t), 36.91 (d), 35.52 (d), 35.14
(t), 33.83 (t), 31.26 (t), 27.38 (t), 23.46 (q), 22.37 (q), 17.26 (q) ppm.
GC-MS (EI): m/z (%) = 222 (2) [M+], 96 (100). C15H26O (222.37):
calcd. C 81.02, H 11.79; found C 80.97, H 11.97. Data for 10a: Rf
= 0.36 (diethyl ether/pentane, 1:10). [α]2D5 = +54.4 (c = 1.01, in
CHCl ). IR (KBr): ν = 2958, 2919, 2873, 1701, 885 cm–1. 1H NMR
˜
3
(CDCl3): δ = 4.67 (s, 1 H), 4.64 (s, 1 H), 2.38–2.28 (m, 4 H), 2.06–
2.00 (m, 1 H), 1.96–1.90 (m, 1 H), 1.86–1.77 (m, 2 H), 1.71–1.66
(m, 2 H), 1.69 (s, 3 H), 1.47–1.28 (m, 3 H), 1.27–1.16 (m, 2 H),
0.97 (d, J = 6.7 Hz, 3 H), 0.81 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(CDCl3): δ = 214.36 (s), 145.90 (s), 109.87 (t), 51.80 (t), 45.93 (t),
40.52 (d), 38.73 (t), 38.55 (d), 35.70 (t), 33.84 (t), 32.17 (d), 31.75
1,4-Adduct 12: According to the general procedure for conjugate
addition, 12 (531 mg, 91%, 86% de) was obtained from cyclohep-
576
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 572–579

Hydroazulene Core of 3α-Hydroxy-15-rippertene
tenone 5 (400 mg, 1.82 mmol) after purification of the crude prod-
uct by flash column chromatography on silica gel (diethyl ether/
1 H), 4.64 (s, 1 H), 2.56–2.88 (m, 2 H), 2.44–2.38 (m, 1 H), 2.16–
2.09 (m, 2 H), 2.06–1.90 (m, 4 H), 1.84–1.77 (m, 1 H), 1.69 (s, 3
pentane, 1:1) as a colorless oil. Rf = 0.58 (diethyl ether/pentane, H), 1.65–1.54 (m, 2 H), 1.52–1.36 (m, 2 H), 1.35–1.17 (m, 3 H),
1:1). [α]2D5 = –94.1 (c = 1.05, in CHCl ). IR (ATR): ν = 2955, 2928,
1.05–0.97 (m, 1 H), 0.94 (d, J = 6.3 Hz, 3 H), 0.83 (d, J = 6.2 Hz,
˜
3
2874, 1698, 885 cm–1. H NMR (CDCl3): δ = 4.82–4.80 (m, 1 H),
3 H) ppm. 13C NMR (CDCl3): δ = 216.85 (s), 201.91 (d), 145.76
1
4.67 (s, 1 H), 4.64 (s, 1 H), 3.95–3.91 (m, 2 H), 3.90–3.71 (m, 2 H), (s), 109.95 (t), 58.94 (d), 45.17 (t), 43.74 (d), 40.86 (t), 40.54 (d),
2.52 (dd, J = 11.1 Hz, 1 H), 2.18–2.10 (m, 2 H), 2.06–1.89 (m, 3 35.74 (d), 35.31 (t), 34.74 (t), 31.29 (t), 27.09 (t), 26.50 (t), 22.38
H), 1.82–1.77 (m, 1 H), 1.68 (s, 3 H), 1.74–1.54 (m, 5 H), 1.48–1.16
(m, 5 H), 1.03–0.93 (m, 1 H), 0.91 (d, J = 6.1 Hz, 3 H), 0.82 (d, J
(q), 21.26 (q), 17.33 (q) ppm. GC-MS (EI): m/z (%) = 278 (1) [M+],
96 (100). C18H30O2 (278.43): calcd. C 77.65, H 10.86; found C
= 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 216.49 (s), 145.79 (s), 77.68, H 10.98.
109.92 (t), 104.50 (d), 64.87 (t), 64.84 (t), 58.93 (d), 45.56 (t), 43.87
Hydroxy Ketone 19: To a solution of the silyl ether 18 (780 mg,
(d), 40.34 (d), 35.80 (d), 35.44 (t), 34.78 (t), 31.29 (t), 30.13 (t),
28.69 (t), 27.15 (t), 22.36 (q), 21.24 (q), 17.32 (q) ppm. GC-MS
(EI): m/z (%) = 322 (3) [M+], 73 (100). C20H34O3 (322.48): calcd.
C 74.49, H 10.63; found C 74.35, H 10.75.
1.89 mmol, 1.0 equiv.) in THF (33 mL) was added TBAF (3.03 mL,
1  in THF, 3.03 mmol, 1.6 equiv.) at room temperature. After
90 min, the reaction mixture was poured into diethyl ether/H2O
(1:1) (50 mL), and the aqueous layer was extracted with diethyl
ether (4ϫ50 mL). The combined organic phases were washed with
brine (100 mL), dried with MgSO4, filtered, and concentrated in
vacuo. Purification of the residue by flash column chromatography
on silica gel (diethyl ether/pentane, 2:1) afforded 19 (524 mg, 95%)
1,4-Adduct 14: According to the general procedure for conjugate
addition, 14 (785 mg, 92%, 85% de) was obtained from cyclohep-
tenone 5 (497 mg, 2.26 mmol) after purification of the crude prod-
uct by flash column chromatography on silica gel (diethyl ether/
pentane, 1:3) as a colorless oil. Rf = 0.48 (diethyl ether/pentane, as a colorless oil. Rf = 0.30 (diethyl ether/pentane, 2:1). [α]D25
=
1:3). [α]2D5 = –77.5 (c = 1.02, in CHCl ). IR (ATR): ν = 2955, 2928,
–94.1 (c = 1.02, in CHCl ). IR (ATR): ν = 3395, 2933, 2873, 1693,
˜
3
˜
3
2866, 1698, 884 cm–1. 1H NMR (CDCl3): δ = 4.67 (s, 1 H), 4.63 (s,
1 H), 3.37–3.55 (m, 4 H), 2.53 (dd, J = 11.3, 11.3 Hz, 1 H), 2.17–
2.09 (m, 2 H), 2.02–1.91 (m, 3 H), 1.82–1.77 (m, 1 H), 1.68 (s, 3
885 cm–1. 1H NMR (CDCl3): δ = 4.68 (s, 1 H), 4.64 (s, 1 H), 3.65–
3.58 (m, 2 H), 2.53 (dd, J = 11.0, 11.0 Hz, 1 H), 2.19–2.10 (m, 2
H), 2.06–1.89 (m, 3 H), 1.83–1.72 (m, 1 H), 1.69 (s, 3 H), 1.67–1.52
H), 1.73–1.65 (m, 2 H), 1.62–1.55 (m, 3 H), 1.42–1.34 (m, 3 H), (m, 4 H), 1.51–1.38 (m, 2 H), 1.35–1.17 (m, 4 H), 1.04–0.93 (m, 1
1.32 (s, 3 H), 1.25–1.16 (m, 2 H), 0.98 (s, 3 H), 1.02–0.96 (m, 1 H), H), 0.91 (d, J = 6.4 Hz, 3 H), 0.83 (d, J = 6.7 Hz, 3 H) ppm. 13C
0.91 (d, J = 6.4 Hz, 3 H), 0.86 (s, 3 H), 0.82 (d, J = 6.7 Hz, 3 H)
ppm. 13C NMR (CDCl3): δ = 216.71 (s), 145.76 (s), 109.91 (t),
98.85 (s), 70.29 (t), 58.93 (d), 45.70 (t), 44.20 (d), 40.32 (d), 35.78
NMR (CDCl3): δ = 216.85 (s), 145.80 (s), 109.91 (t), 62.98 (t), 58.97
(d), 45.56 (t), 44.05 (d), 40.50 (d), 35.79 (d), 35.45 (t), 34.76 (t),
31.29 (t), 30.77 (t), 29.05 (t), 27.13 (t), 22.37 (q), 21.28 (q), 17.33
(d), 35.50 (t), 34.76 (t), 34.13 (t), 31.26 (t), 29.88 (s), 27.99 (t), 27.11 (q) ppm. GC-MS (EI): m/z (%) = 280 (2) [M+], 96 (100). C18H32O2
(t), 22.74 (q), 22.45 (q), 22.35 (q), 21.29 (q), 20.42 (q), 17.32 (q)
ppm. GC-MS (EI): m/z (%) = 378 (0.3) [M+], 129 (100). C24H42O3
(378.59): calcd. C 76.14, H 11.18; found C 76.23, H 11.24.
(280.45): calcd. C 77.09, H 11.50; found C 76.92, H 11.37.
Oxidation of Alcohol 19: To a solution of alcohol 19 (500 mg,
1.78 mmol, 1.0 equiv.) in dichloromethane (20 mL) was added
Dess–Martin periodinane (1.51 g, 3.56 mmol, 2.0 equiv.) at room
temperature. After 90 min, the reaction mixture was diluted with
diethyl ether (20 mL) and filtered through a short pad of silica gel
by using diethyl ether as eluant. The organic layer was subsequently
1,4-Adduct 18: According to the general procedure for conjugate
addition, 18 (893 mg, 86%, 93% de) was obtained from cyclohep-
tenone 5 (577 mg, 2.62 mmol) after purification of the crude prod-
uct by flash column chromatography on silica gel (diethyl ether/
pentane, 1:15) as a colorless oil. Rf = 0.26 (diethyl ether/pentane, washed with an aqueous saturated solution of Na2CO3 and brine
1:15). [α]2D5 = –81.5 (c = 1.10, in CHCl ). IR (ATR): ν = 2952, 2928,
(25 mL each), dried with MgSO4, filtered and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography on silica gel (diethyl ether/pentane, 1:1) furnished
15 (425 mg, 86%) as a colorless oil.
˜
3
2857, 1699, 1254, 885 cm–1. H NMR (CDCl3): δ = 4.68 (s, 1 H),
1
4.65 (s, 1 H), 3.58–3.56 (m, 2 H), 2.53 (dd, J = 11.0, 11.0 Hz, 1 H),
2.18–2.10 (m, 2 H), 2.05–1.90 (m, 3 H), 1.83–1.78 (m, 1 H), 1.69
(s, 3 H), 1.68–1.55 (m, 4 H), 1.46–1.38 (m, 2 H), 1.34–1.18 (m, 4
H), 1.04–0.97 (m, 1 H), 0.90 (d, J = 6.4 Hz, 3 H), 0.87 (s, 9 H),
0.84 (d, J = 6.7 Hz, 3 H), 0.02 (s, 6 H) ppm. 13C NMR (CDCl3):
δ = 216.87 (s), 145.86 (s), 109.91 (t), 63.16 (t), 58.96 (d), 45.70 (t),
44.04 (d), 40.34 (d), 35.84 (d), 35.55 (t), 34.81 (t), 31.33 (t), 30.81
(t), 29.00 (t), 27.16 (t), 25.92 (q), 22.40 (q), 21.26 (q), 18.29 (s),
17.35 (q), –5.31 (q) ppm. GC-MS (EI): m/z (%) = 394 (1) [M+], 75
(100). C24H46O2Si (394.71): calcd. C 73.03, H 11.75; found C 73.37,
H 11.98.
Hydroazulenes 4a and 4c: To a stirred suspension of potassium hy-
droxide powder (1.21 g, 21.6 mmol, 10.0 equiv.) in benzene
(400 mL) in a Dean–Stark apparatus was added 18-crown-6
(285 mg, 1.08 mmol, 0.5 equiv.) and oxo aldehyde 15 (600 mg,
2.16 mmol, 1.0 equiv.), and the mixture was stirred at 80 °C for
2 h. The reaction mixture was poured into H2O (150 mL), and the
aqueous layer was extracted with diethyl ether (4ϫ100 mL). The
combined organic phases were washed with aqueous HCl (1 ) and
brine (100 mL each), dried with MgSO4, filtered and concentrated
under reduced pressure. Purification of the residue by flash column
chromatography on silica gel (diethyl ether/pentane, 1:10) furnished
4a (194 mg, 35%) and 4c (112 mg, 20%) as light yellow oils (4a/4c
= 1.7:1). Data for 4a: Rf = 0.50 (diethyl ether/pentane, 1:10). [α]D25
Oxo Aldehyde 15: To
a solution of dioxolane 12 (531 mg,
1.65 mmol, 1.0 equiv.) in acetone (165 mL) was added bis(aceto-
nitrile)dichloridopalladium(II) (21 mg, 80.9 µmol, 0.05 equiv.) at
room temperature. After 2 d, the solvent was removed under re-
duced pressure, and the residue was filtered through a short pad of
silica gel by using diethyl ether as eluant. Evaporation of the sol-
vent and purification of the crude product by flash column
chromatography on silica gel (diethyl ether/pentane, 1:3) yielded 15
(342 mg, 75%) as a colorless oil. Rf = 0.48 (diethyl ether/pentane,
= –18.9 (c = 1.05, in CHCl ). IR (ATR): ν = 2954, 2918, 2859,
˜
3
1677, 882 cm–1. 1H NMR (CDCl3): δ = 6.72–6.70 (m, 1 H), 4.64
(s, 2 H), 2.57–2.51 (m, 1 H), 2.38–2.12 (m, 4 H), 2.07–2.03 (m, 1
H), 2.01–1.92 (m, 2 H), 1.91–1.73 (m, 2 H), 1.71 (s, 3 H), 1.69–1.53
(m, 2 H), 1.38–1.24 (m, 3 H), 1.24–1.13 (m, 1 H), 0.94 (d, J =
5.9 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3):
δ = 202.33 (s), 148.99 (s), 146.46 (s), 142.00 (d), 109.54 (t), 56.82
1:1). [α]2D5 = –86.1 (c = 1.05, in CHCl ). IR (ATR): ν = 2930, 2870,
˜
3
1724, 1697, 883 cm–1. 1H NMR (CDCl3): δ = 9.77 (s, 1 H), 4.68 (s,
Eur. J. Org. Chem. 2008, 572–579
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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577

T. Kreuzer, P. Metz
(d), 50.55 (d), 40.26 (t), 40.20 (d), 35.67 (t), 32.93 (d), 31.02 (t), 1.98 (s, 3 H), 2.06–1.83 (m, 6 H), 1.71 (s, 3 H), 1.68–1.61 (m, 1 H),
FULL PAPER
30.76 (t), 30.66 (t), 27.10 (t), 22.42 (q), 21.28 (q), 17.15 (q) ppm.
GC-MS (EI): m/z (%) = 260 (5) [M+], 164 (100). C18H28O (260.41):
calcd. C 83.02, H 10.84; found C 83.15, H 10.68. Data for 4c: Rf
= 0.28 (diethyl ether/pentane, 1:10). [α]2D5 = +73.8 (c = 1.03, in
1.48–1.34 (m, 1 H), 1.33–1.17 (m, 4 H), 0.92–0.90 (m, 6 H) ppm.
13C NMR (CDCl3): δ = 205.37 (s), 153.03 (s), 146.51 (s), 141.13
(s), 109.50 (t), 56.94 (d), 52.22 (d), 39.80 (t), 39.42 (d), 37.95 (t),
35.40 (t), 33.14 (d), 31.15 (t), 29.09 (t), 27.72 (t), 22.49 (q), 21.11
CHCl ). IR (ATR): ν = 2957, 2919, 2856, 1669, 882 cm–1. 1H NMR (q), 17.58 (q), 16.72 (q) ppm. GC-MS (EI): m/z (%) = 274 (8) [M+],
˜
3
(CDCl3): δ = 6.84–6.83 (m, 1 H), 4.66 (s, 1 H), 4.61 (s, 1 H), 2.65–
2.58 (m, 1 H), 2.37–2.15 (m, 4 H), 2.09–2.03 (m, 1 H), 1.99–1.90
178 (100). C19H30O (274.44): calcd. C 83.15, H 11.02; found C
82.81, H 11.12. Data for 4d: Rf = 0.41 (diethyl ether/pentane, 1:10).
(m, 3 H), 1.61 (s, 3 H), 1.69–1.44 (m, 4 H), 1.41–1.26 (m, 2 H), [α]2D5 = +150.8 (c = 1.00, in CHCl ). IR (ATR): ν = 2958, 2917,
˜
3
1.22–1.11 (m, 1 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.88 (d, J = 6.5 Hz, 2859, 1664, 880 cm–1. 1H NMR (CDCl3): δ = 4.65 (s, 1 H), 4.58 (s,
3 H) ppm. 13C NMR (CDCl3): δ = 204.34 (s), 148.35 (s), 145.63 1 H), 2.68–2.63 (m, 1 H), 2.29–2.21 (m, 3 H), 1.97 (s, 3 H), 2.07–
(s), 144.82 (d), 110.05 (t), 58.80 (d), 50.22 (d), 39.76 (d), 34.60 (t), 1.71 (m, 5 H), 1.59 (s, 3 H), 1.62–1.53 (m, 2 H), 1.46–1.38 (m, 1
33.06 (t), 32.69 (t), 32.13 (t), 30.68 (t), 29.35 (d), 25.77 (t), 22.05
(q), 21.27 (q), 15.70 (q) ppm. GC-MS (EI): m/z (%) = 260 (6) [M+],
164 (100). C18H28O (260.41): calcd. C 83.02, H 10.84; found C
83.02, H 10.67.
H), 1.34–1.23 (m, 3 H), 1.15–1.08 (m, 1 H), 0.90 (d, J = 6.6 Hz, 3
H), 0.85 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3): δ = 207.10
(s), 155.97 (s), 145.53 (s), 140.55 (s), 109.97 (t), 60.27 (d), 52.19 (d),
39.15 (d), 37.89 (t), 34.60 (t), 33.40 (t), 33.10 (t), 30.20 (t), 29.60
(d), 26.39 (t), 21.88 (q), 21.20 (q), 17.04 (q), 15.68 (q) ppm. GC-
MS (EI): m/z (%) = 274 (11) [M+], 178 (100). C19H30O (274.44):
calcd. C 83.15, H 11.02; found C 82.93, H 11.14.
Basic Equilibration of 4c: To a stirred suspension of potassium hy-
droxide powder (76 mg, 1.35 mmol, 10 equiv.) in benzene (15 mL)
was added 18-crown-6 (18 mg, 67.5 µmol, 0.5 equiv.) and hy-
droazulene 4c (35 mg, 134.6 µmol, 1.0 equiv.), and the mixture was
stirred at 80 °C for 4 h. The reaction mixture was poured into brine
(10 mL), and the aqueous layer was extracted with diethyl ether
(4ϫ15 mL). The combined organic phases were washed with aque-
ous HCl (1 ) and brine (15 mL each), dried with MgSO4, filtered
and concentrated under reduced pressure. Purification of the resi-
due by flash column chromatography on silica gel (diethyl ether/
pentane, 1:10) furnished 4a (16 mg, 46%) and 4c (12 mg, 34%) as
light yellow oils (4a/4c = 1.3:1).
Synthesis of the Hydroazulenes 4b and 4d by PPTS-Induced Acetal
Cleavage and Aldol Condensation: To a solution of dioxane 14
(590 mg, 1.56 mmol, 1.0 equiv.) in acetone (60 mL) and H2O
(1.2 mL) was added PPTS (392 mg, 1.56 mmol, 1.0 equiv.) at room
temperature. After 24 h, the solvent was removed in vacuo, and the
residue was taken up in diethyl ether (50 mL). The organic layer
was subsequently washed with an aqueous saturated solution of
NaHCO3 (25 mL) and brine (25 mL), dried with MgSO4, filtered
and concentrated under reduced pressure. To a solution of potas-
sium hydroxide (3.58 g, 63.8 mmol, 40.9 equiv.) in methanol
(136 mL) was added the crude diketone 16 (1.0 equiv.), and the
mixture was stirred at 65 °C for 48 h. The reaction mixture was
poured into H2O (110 mL), and the aqueous layer was extracted
with diethyl ether (4ϫ100 mL). The combined organic phases were
washed with brine (100 mL), dried with MgSO4, filtered and con-
centrated under reduced pressure. Purification of the residue by
flash column chromatography on silica gel (diethyl ether/pentane,
1:10) gave 4b (197 mg, 46%) and 4d (163 mg, 38%) as colorless oils
(4b/4d = 1.2:1).
Diketone 16: To a solution of dioxane 14 (190 mg, 0.502 mmol,
1.0 equiv.) in acetone (5 mL) was added bis(benzonitrile)dichlorid-
opalladium(II) (2 mg, 5.02 µmol, 0.01 equiv.) at room temperature.
After 24 h, the solvent was removed under reduced pressure, and
the residue was filtered through a short pad of silica gel using di-
ethyl ether as eluant. Evaporation of the solvent and purification
of the crude product by flash column chromatography on silica gel
(diethyl ether/pentane, 1:2) yielded 16 (107 mg, 73%) as a colorless
oil. Rf = 0.25 (diethyl ether/pentane, 1:2). [α]2D5 = –114.9 (c = 1.01,
in CHCl ). IR (ATR): ν = 2954, 2929, 2872, 1715, 1698, 885 cm–1.
˜
3
1H NMR (CDCl3): δ = 4.67 (s, 1 H), 4.64 (s, 1 H), 2.52–2.46 (m,
2 H), 2.42–2.35 (m, 1 H), 2.13 (s, 3 H), 2.14–2.07 (m, 2 H), 2.06–
1.85 (m, 4 H), 1.83–1.78 (m, 1 H), 1.68 (s, 3 H), 1.66–1.54 (m, 2
H), 1.45–1.36 (m, 2 H), 1.34–1.15 (m, 3 H), 1.03–0.95 (m, 1 H),
0.92 (d, J = 6.5 Hz, 3 H), 0.82 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR
(CDCl3): δ = 216.59 (s), 208.55 (s), 145.79 (s), 109.96 (t), 58.98 (d),
45.27 (t), 43.96 (d), 40.71 (d), 40.63 (t), 35.78 (d), 35.41 (t), 34.78
(t), 31.32 (t), 30.05 (q), 28.23 (t), 27.11 (t), 22.39 (q), 21.30 (q),
17.34 (q) ppm. GC-MS (EI): m/z (%) = 292 (0.3) [M+], 43 (100).
C19H32O2 (292.46): calcd. C 78.03, H 11.03; found C 78.05, H
11.08.
Basic Equilibration of 4d: To a solution of potassium hydroxide
(1.33 g, 23.7 mmol, 35.1 equiv.) in methanol (50 mL) was added hy-
droazulene 4d (180 mg, 0.656 mmol, 1.0 equiv.), and the mixture
was stirred at 65 °C for 24 h. The reaction mixture was poured into
H2O (40 mL), and the aqueous layer was extracted with diethyl
ether (4ϫ40 mL). The combined organic phases were washed with
brine (40 mL), dried with MgSO4, filtered and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography on silica gel (diethyl ether/pentane, 1:10) gave 4b
(90 mg, 50%) and 4d (74 mg, 41%) as colorless oils (4b/4d = 1.2:1).
Acknowledgments
Hydroazulenes 4b and 4d: To a solution of potassium hydroxide
(2.50 g, 44.6 mmol, 40.9 equiv.) in methanol (95 mL) was added di-
ketone 16 (318 mg, 1.09 mmol), and the mixture was stirred at
65 °C for 48 h. The reaction mixture was poured into H2O (80 mL),
and the aqueous layer was extracted with diethyl ether (4ϫ80 mL).
The combined organic phases were washed with brine (80 mL),
dried with MgSO4, filtered and concentrated under reduced pres-
sure. Purification of the residue by flash column chromatography
on silica gel (diethyl ether/pentane, 1:10) gave 4b (156 mg, 52%)
and 4d (126 mg, 42%) as colorless oils (4b/4d = 1.2:1). Data for 4b:
Rf = 0.66 (diethyl ether/pentane, 1:10). [α]2D5 = +165.9 (c = 1.03, in
Financial support of this work by the Studienstiftung des Deut-
schen Volkes and the Fonds der Chemischen Industrie is gratefully
acknowledged. We thank Takasago Inc. for a generous donation
of (–)-isopulegol (6). Special thanks are due to Rabea Hennig, TU
Dresden, for her valuable experimental help.
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Published Online: November 20, 2007
Eur. J. Org. Chem. 2008, 572–579
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
579