Synthesis of novel molecular probes inspired by harringtonolide

Article abstract of DOI:10.1039/c1ob05299c

A novel harringtonolide-inspired scaffold containing a cycloheptatriene ring and two fused cyclopentane rings has been synthesised from simple starting materials. The scaffold, containing a similar substitution pattern and relative stereochemistry to the

Full text of DOI:10.1039/c1ob05299c

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PAPER
Synthesis of novel molecular probes inspired by harringtonolide†
Vinayak Hegde, Marc Campitelli, Ronald J. Quinn and David Camp*
Received 24th February 2011, Accepted 31st March 2011
DOI: 10.1039/c1ob05299c
A novel harringtonolide-inspired scaffold containing a cycloheptatriene ring and two fused
cyclopentane rings has been synthesised from simple starting materials. The scaffold, containing a
similar substitution pattern and relative stereochemistry to the complex diterpenoid, has been
enumerated into a small library of derivatives. One of these library members has been converted into a
sub-library of substituted triazoles using copper-catalysed azide-alkyne cycloaddition (click) chemistry.
The scaffold may be useful in drug discovery or in the preparation of additional molecular probes for
chemical biology.
activity that spans plant and human health attributed to 1 suggests
that it may contain a privileged substructure.
Introduction
Small molecules are critical tools for understanding important
cellular events and biological pathways involved in health and
disease. The identification of new structural classes is one of the
many drivers en route to understanding biological systems and
developing innovative, safer therapeutics with novel modes of
action. This is a truly daunting task given there are in excess
of an estimated 1062 drug-like molecules with a molecular weight
below 500 Da comprised of the atoms that make up current small
molecule therapies.1 Indeed, it would be impossible to synthesize
even one molecule of each member from this set considering there
is estimated to be ‘only’ 1050 atoms on Earth.2 Various strategies
that attempt to address the relationship between chemistry and bi-
ology space have been developed in an effort to meet this challenge.
One popular approach, particularly within the pharmaceutical
industry, has been to exploit ‘privileged’ structures with known
drug-like properties.3 The term was originally introduced to
describe motifs that could be elaborated into libraries of drug-like
molecules (ligands) in which different members could selectively
and potently interact with a variety of unrelated biological
targets.4,5
Interestingly, homoharringtonine 2, which is currently in phase
II/III trials for chronic myeloid leukemia,9 is produced by the
R
same species while Taxolꢀ 3, an FDA approved drug for various
cancers,10 was originally isolated from another member of the
Taxaceae family, Taxus brevifolia (Fig. 1).11
Harringtonolide 1 was first isolated from the seeds of the
yew species Cephalotaxus harringtonia (Taxaceae) and shown
to inhibit plant growth in tobacco and beans.6 Soon after, 1
was independently discovered in the bark of the related Chinese
species, Cephalotaxus hainanensis, and found to be active against
Lewis lung carcinoma, Walker carcinoma, Sarcoma-180 and L-
1210, L-615 and P-388 leukemias.7 It has also exhibited in vitro
activity against influenza type A, Newcastle disease, Japanese
B encephalitis and vaccinia viruses.8 The breadth of biological
Fig. 1 Bioactive molecules isolated from the Taxaceae family.
Eskitis Institute, Griffith University, Nathan, QLD 4111, Australia.
E-mail: david.camp@griffith.edu.au; Fax: +61 7 3735 6001; Tel: +61 7
3735 6041
Results and discussion
Scaffolds 4 and 5 (Fig. 2) were initially selected for synthesis
(Scheme 1) because of the unusual 5-6-7 fused tricyclic sub-
structure embedded in harringtonolide. Scaffold 4 incorporates
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of all previously unreported compounds, i.e. 15, 16, 17, 20a–b,
21a–f, 23a–c. See DOI: 10.1039/c1ob05299c
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Fig. 2 Scaffolds 4 and 5 incorporating the 5-6-7 tricycle of harringtono-
lide and scaffolds 6 and 7 containing a 5-5-7 motif inspired by the natural
product.
the tropone moiety of 1 while 5 is the methoxycycloheptatriene
analogue. We also saw tactical value in preparing a second scaffold
inspired by the natural product that could afford a library of closely
related structural analogues. Ideally, such a motif would be novel,
derived from readily available starting materials and synthesized
via the same reaction sequence as that of 4 and 5.
The 5-5-7 fused tricyclic framework in 6 and 7 has not previously
been reported, which was somewhat surprising given that fused
seven-member ring systems are found in an increasing number of
natural products of interest to the biological and pharmaceutical
communities.12,13 For example, it has recently been proposed that
the 5-7-5 lactone ring system found in helenalin, parthenin and
chinensiolide B should be regarded as a privileged scaffold due to
the diverse biological activity exhibited by these compounds.14 We
therefore pursued the synthesis of the 5-5-7 tricycle on account of
the novel carbon skeleton containing a highly desirable 5-7 fused
ring system.
Fig. 3 Overlay of the natural product 5-6-7 substructure, 4, shown in
orange and the 5-5-7 series scaffold of 7 shown in green.
and Murko molecular framework representations were compared
using the Tanimoto coefficient (Tc).16 The calculated Tc of 0.74
between scaffolds 4 and 7 (R = H) indicates that the 5-6-7 and
5-5-7 scaffolds are within the commonly used heuristic (≥ 0.7) for
clustering similar chemical structures.17
Positioning of the methoxy group gamma to the carbonyl and
use of a 5-membered ring in the starting material (Scheme 2) was
also reasoned to provide sufficient variation in the key intermediate
and related downstream products so as to ameliorate any potential
stability issues that may be encountered with the series based on
the natural product.15
The methoxycycloheptatriene motif in 5 and 7 would clearly
have a different electron density to the tropone substructure of 4
and 6. Thus, libraries based on 5 and 7 would not be expected
to mimic binding of the tropone moiety in the natural product.
However, we considered the synthesis of 5 and 7 to nevertheless
be important from the perspective of being able to generate novel
probe libraries that may afford valuable SAR insights. In this sense,
our objective was not necessarily to produce scaffolds derived
directly from the natural product but rather explore the chemistry
of similarly substituted analogues based on, or inspired by, the
unusual carbon framework of 1.
Our synthetic strategy for the preparation of scaffolds 4–7 was
guided by model studies involving intramolecular cyclopropa-
nation of a benzenoid synthon described by Mander and co-
workers en route towards the first total synthesis of 1.18,19 Scheme
1 outlines the synthesis of intermediates 8–12 to construct the
5-6-7 framework found in the natural product while Scheme 2
summarises the synthesis of analogues 13–17 leading to the 5-5-7
tricycle.
Generally, more care or longer reaction times were necessary for
the 5-6-7 series but, overall, production of 12 and 17 proceeded
smoothly in fair to excellent yield (Table 1). Rhodium acetate
was also investigated in the critical reaction to install the cyclo-
heptatriene ring in an effort to improve yields. However, product
formation for both series was typically 10% lower than with the
copper catalyst in our hands.
Mander’s report15 that the tropone derived directly from the key
intermediate 12, i.e. 18, was unstable influenced the planning of the
next stage of our synthesis. Library enumeration would proceed
via the scaffolds 19 and 20a derived from reduction of the carbonyl
group on the key ketocycloheptatriene intermediates, 12 and 17
respectively, and not from reduction of the same group via the
tropones.
An overlay of the most dissimilar scaffolds, 4 and 7 (R =
CH3), as shown in Fig. 3 reveals that the 5-5-7 system inspired
by the natural product closely approximates the 5-6-7 assembly
in terms of placement of the oxygen atoms relative to each other.
R
Additionally, Scitegicꢀ EPFP4 fingerprints generated from Bennis
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Scheme 1 Synthesis of the key intermediate 12 for scaffolds based on the
5-6-7 ring system embedded in harringtonolide.
Scheme 2 Synthesis of the key intermediate 17 for scaffolds based on the
5-5-7 inspired by harringtonolide.
Table 1 Reaction conditions and yields en route to the key intermediates
12 and 17
yield (%)
step
i
conditions
5-6-7 series
6420
5-5-7 series
7221
Triethyl phosphonoacetate, NaH,
toluene, reflux
ii
Pd/C, H2, ethanol, 50 ◦C, 5 h
9120
98
9821
98
iii
iv
v
vi
vii
1 M NaOH, aq. MeOH, 20◦◦
C
Unfortunately, in the case of the 5-6-7 series, any further
manipulation of 12 proved futile as the ensuing products were
unstable and either decomposed upon standing or further reaction
immediately following purification. Indeed, while 12 could be
obtained as a white powder following chromatography, it gradually
turned grey over 2–3 days despite being stored in the dark at 4 ◦C.
Attempted reduction of the ketone functionality with NaBH4
yielded the unstable alcohol 19 which decomposed completely
following reaction of freshly purified material with different benzyl
bromides.
In an effort to retrieve this series, we converted 12 to 18 despite
reservations about proceeding via the tropone. While the crude
tropone was produced in reasonable yield, it decomposed during
purification on silica or upon storage in the dark at 4 ◦C thus
obviating reduction of the ketone on the five-membered ring
to afford 4 (R = H) and effectively extinguishing this route for
subsequent enumeration.
Oxalyl chloride, DMF, -20 C, 2 ha
Diazomethane, ether, 0 ◦
C
90b
52b
85b
75b
Copper(II) ethylacetoacetate
DBU
a A temperature of -10 ◦C was used for the 5-5-7 series. b Overall yield
when combined with previous step.
mixture of syn and anti alcohols, 20a and 20b, in a diastereomeric
ratio of 95 : 5 respectively, and near quantitative yield using
NaBH4. Both alcohols are stable at room temperature, unlike the
corresponding analogues in the 5-6-7 series.
The relative stereochemistry of each isomer was established by
ROESY NMR spectroscopy. A through-space interaction was
observed between the C1 and C2a protons in CDCl3 of the
major product (Fig. 4) but not the minor adduct. Unfortunately,
the hydroxyl proton signal for both the syn and anti adducts
was not apparent in CDCl3 so that any additional correlations
supporting the relative stereochemistry of each isomer was not
possible. However, changing the solvent to acetone-D6 allowed
the hydroxyl proton signals for the syn and anti isomers to
It was therefore heartening to observe that the closely related
17 was not only obtained in improved yield following the crucial
cyclopropanation step but was also considerably more stable than
12. The ketocycloheptatriene 17 could readily be converted to a
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Table 3 Reaction conditions and yields of triazoles 23a–c
23
a
R
conditions
yield (%)
85a
CH2C6H5
(i) NaN3, DMF, 25 ◦C, 12 h
(ii) t-BuOH/H2O, CuSO4, sodium 60
ascorbate, 25 ◦C, 16 h
b
c
CH2CH2CH2CH3
(iii) t-BuOH/H2O, Cu/CuSO4,
52b
45b
microwave, 110 ◦C, 20 min
CH2CH2CH(CH3)2 (iii) t-BuOH/H2O, Cu/CuSO4,
Fig. 4 syn (20a) and anti (20b) Adducts obtained following reaction of
17 with NaBH4. ROESY correlations specific to each isomer are shown.
microwave, 110 ◦C, 20 min
a Two step procedure showing yield of individual reactions. b Overall yield
for the one pot cycloaddition-alkylation procedure performed in a sealed
microwave reactor.
be observed as doublets at dH 3.91 and 3.66 ppm respectively.
This facilitated detection of a through-space interaction between
the H atoms attached to the hydroxyl oxygen and C2a in
the case of the minor anti isomer 20b only. Importantly, the
ROESY NMR experiments established that the major product
had the same relative stereochemistry as harringtonolide’s fused
5-7 substructure.
The syn adduct is presumably favored because of steric approach
control. This occurs when delivery of hydride takes place from the
same face as the hydrogen atom on C2a. The syn isomers were
not resolved into their enantiomers as we considered the racemic
compound adequate for the purposes of a probe/lead generation
library.
1,4-disubstituted regioisomer in reasonable yield (Scheme 3, Table
3).23
Production of the tropones from the corresponding methyl
ethers remains elusive. Nucleophilic displacement reactions em-
ploying 21a as the model system and NaI or thiolate anions in
DMSO or TMSI in CH3CN did not afford the desired product.
Starting materialwas recoveredinallcases. Use of Lewis acids such
as BBr3 or Hg(NO3)2, not unexpectedly, cleaved both ethers of 21a
and afforded a complex mixture of products. Mass spectrometric
analysis of the crude reaction mixtures indicated that 4 (R = H)
Having successfully generated scaffold 20a, we next set about
converting it into a library of probe molecules. Thus, 20a was
reacted further with a selection of benzyl-, alkyl-, and propargyl
bromides to afford the corresponding ethers 21a–f in moderate to
good yields (Table 2).
The propargyl ether 21f was subsequently converted into a
sub-library of substituted triazoles using copper-catalysed azide-
alkyne cycloaddition (click) chemistry. Thus, reaction of benzy-
lazide 22, derived from the reaction of benzyl bromide with NaN3,
under standard click chemistry reaction conditions afforded the
triazole 23a in good yield with the expected regioselectivity22
(Scheme 3, Table 3). Preparation of the corresponding alkyl azides
from n-butyl and i-pentyl bromides was more problematic, most
likely due to their low boiling points which hampered isolation,
and necessitated use of a modified method to prepare the tria-
zoles. Employing a one-pot, three-component microwave-assisted
procedure directly afforded 23b–c with exclusive formation of the
Table 2 Reaction conditions and yields of ethers 21a–f
21
R
conditions
yield (%)
a
b
c
CH2C6H5
NaH, THF, 25 ◦C, 40 h
NaH, THF, 25 ◦C, 40 h
NaH, THF, 25 ◦C, 40 h
72
89
73
CH2(4-ClC6H4)
CH2(4-FC6H4)
CH2CH2CH2CH3
d
NaH, DMF, microwave, 110 ◦C, 55
45 min
e
f
CH2CH2CH(CH3)2 NaH, DMF, microwave, 115 ◦C, 52
45 min
CH2C CH
Scheme 3 Synthesis of triazoles 23a–c from benzyl-, n-butyl- and i-pentyl
bromide starting materials and 21f using two-step (23a) and one-pot
three-component procedure (23b–c).
NaH, THF, 60 ◦C, 48 h
55
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was present but all attempts to isolate the compound using silica
gel chromatography failed.
the residual CHCl3 peak at 7.26 ppm in CDCl3 or CH3COCH3
resonance at 2.09 ppm in acetone-D6. The 13C NMR chemical
shifts were referenced to the central peak of CDCl3 at 77.16 ppm.28
1H NMR and 13C NMR assignments were made with the aid of
COSY, ROESY, HMBC and HSQC experiments. Low resolution
ESI mass spectra (LRESIMS) were recorded on a Waters ZQ mass
spectrometer. High resolution ESI mass spectra (HRESIMS) were
measured on a Bruker Daltonics Apex III 4.7e Fourier transform
mass spectrometer, fitted with an Apollo API source. Melting
points (mp) were recorded on a Cole-Parmer hot stage and are
uncorrected. Schro¨dinger’s Macromodel 9.8 and Maestro 9.1 were
used to minimise and superimpose the 5-5-7 and 5-6-7 scaffolds
respectively. Accelrys’ Pipeline Pilot Student Edition 6.1.5 was
used to calculate Tanimoto similarity coefficients.
Conclusions
The work described here represents the first attempt to incorporate
structural elements of an unusual and highly complex diterpenoid,
harringtonolide, into a library of simpler probe molecules. The
novel 5-5-7 ring system inspired by the natural product was syn-
thesized from readily available, inexpensive starting materials. Key
intermediates were easily isolated, purified and stored to facilitate
production of the scaffold 20a and enumeration into libraries 21a–
f and 23a–c containing a fused cycloheptatriene moiety.
Although the final tropone substructure was not obtained,
the resulting library is nevertheless based on a scaffold that
incorporates a fused 5-7 ring with appropriate substitution and
stereochemistry at positions that closely resemble that of the
natural product.
This preliminary study suggests that use of 5-methoxyindanone
24 as the starting material may afford a library based on the 5-
5-7 scaffold 25 (Scheme 4) in which the positioning of the two
oxygen functionalities more closely resembles templates based on
the natural product, e.g. 19. The synthesis of 25 will shed light
on whether it is the replacement of the 6-membered ring by a
5-membered ring or the different substitution pattern between
oxygen functionalities in 20 that confers greater stability.
Cheminformatics
The 5-6-7 and 5-5-7 ring scaffolds 4 (R = H) and 20a, respectively,
were minimised using the MMFFs force-field with default settings
(H2O solvation, PRCG gradient optimization) on Macromodel
(MacroModel, version 9.8, Schro¨dinger, LLC, New York, NY,
2010). The minimised structures were overlaid by manual ma-
nipulation into the same plane followed by rigid superposition in
Maestro (Maestro, version 9.1, Schro¨dinger, LLC, New York, NY,
2010) by defining the corresponding oxygen atom pairs.
As described by Shelat and Guy,17 the MurkoAssemblies option
of Pipeline Pilot’s Generate Fragments component (Pipeline Pilot
Student Edition, version 6.1.5, Accelrys Software Inc., San Diego,
CA, 2007) was used to transform compounds 4 (R = H) and
20a into their respective scaffolds while retaining exocyclic double
bonds and excluding a attachment atoms. The Tanimoto similarity
coefficient (Tc) was calculated from the generated scaffolds using
R
SciTegicꢀ path-based fingerprints with Daylight-like atom types
and a 4-atom maximum depth (EPFP_4). Identical results were
R
obtained using SciTegicꢀ Extended Connectivity fingerprints
(ECFP4).
Scheme
5-methoxyindanone.
4
Production of
a
second 5-5-7 series based on
Ethyl 6¢-methoxy-1¢,2¢,3¢,4¢-tetrahydro-1¢-naphthylacetate (9)
Finally, while our motivation is defined by a continuing quest
to identify new privileged structures and scaffolds embedded
within natural products for drug discovery,24,25 screening the
cycloheptatriene probe library also has potential to provide
additional insights into the already rich biological activity of
harringtonolide itself. In this respect, our approach complements
the ongoing efforts of others26,27 to find accessible routes to the
synthesis of 1 and closely related analogues such as hainanolidol
for screening and drug discovery.
Triethyl phosphonoacetate (10.54 g, 47.0 mmol) was added
dropwise over 25 min to a stirred suspension of sodium hydride
(60% dispersion in mineral oil, 1.88 g, 47.0 mmol) in dry toluene
◦
(30 mL) at 0 C. The clear reaction mixture was stirred at room
temperature for a further 15 min and then cooled to 0 ◦C. A
solution of 6-methoxy-1-tetralone (4.0 g, 22.7 mmol) in toluene
(45 mL) was then added over 10 min after which time the reaction
mixture was heated to reflux for 14 h. The reaction mixture was
then cooled to room temperature and diluted with ethyl acetate
(50 mL) and washed with brine (2 ¥ 50 mL). The aqueous layer
was extracted with ethyl acetate (2 ¥ 30 mL) and the combined
organic extracts washed with brine (50 mL), dried over anhydrous
sodium sulfate, filtered and concentrated at reduced pressure. The
crude product was purified on silica (hexane : ethyl acetate, 98 : 2)
to afford 3.59 g (64.2%) of 8 as an oil containing a mixture of
endo- and (E, Z) exo-double bond isomers. The adducts were
dissolved in ethanol (35 mL) without further purification and
stirred in the presence of 10% Pd–C (110 mg) under a hydrogen
atmosphere at 50 ◦C for 5 h. After this time, the reaction mixture
Experimental
General
Starting materials and reagents used in reactions and purification
were obtained from commercial suppliers and used without further
purification unless otherwise stated. Silica chromatography was
conducted using Merck Kieselgel 60 silica as the adsorbant. IR
spectra were recorded on a Bruker Tensor 27 spectrometer. Proton
and carbon-13 nuclear magnetic resonance (1H NMR and 13C
NMR) spectra were recorded on a Varian Unity INOVA 500 MHz
R
1
spectrometer. The H NMR chemical shifts were referenced to
was filtered through Celiteꢀ and concentrated at reduced pressure.
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The crude product was purified on a silica column (hexane : ethyl
acetate, 98 : 2) to afford 3.31 g (91%, 58.5% overall yield) of the title
compound as a colourless oil with the same H NMR spectrum
and molecular ion as previously reported:20
dH (500 MHz, CDCl3)
7.07 (d, J = 8.5 Hz, 1H, H-8¢), 6.70 (dd, J = 2.5, 8.5 Hz, 1H,
H-7¢), 6.60 (d, J = 2.5 Hz, 1H, H-5¢), 4.17 (q, J = 7.1 Hz, 2H,
CO2CH2CH3), 3.76 (s, 3H, OCH3), 3.29 (m, 1H, H-1¢), 2.75 (m,
2H, CHCH2CO), 2.66 (dd, J = 5.0, 10.0 Hz, 1H, H-4¢), 2.48 (dd,
J = 10.0, 14.75 Hz, 1H, H¢-4¢), 1.92–1.65 (m, 4H, H-2¢, H¢-2¢, H-
3¢, H¢-3¢), 1.27 (t, J = 7.2 Hz, 3H, COCH2CH3); dC (125 MHz,
CDCl3) 173.02 (CO), 157.83 (C6¢), 138.48 (C4¢a), 131.69 (C8¢a),
129.36 (C8¢), 113.83 (C5¢), 112.31 (C7¢), 60.46 (CH2CH3), 55.34
(OCH3), 42.34 (CH2CO), 34.09 (C1¢), 30.04 (C4¢), 28.56 (C2¢),
19.72 (C3¢), 14.42 (CH2CH3); (+) LRESIMS m/z 271 [M + Na]+.
3.19 (m, 1H, H-8), 2.95–2.80 (m, 1H, H-2a), 2.73 (dd, J = 8.0,
18.2 Hz, 1H, H-2), 2.51–2.48 (m, 2H, H-5, H¢-5), 2.22–2.17 (m,
2H, H¢-8, H-3), 2.05 (dd, J = 9.0, 15.7 Hz, 1H, H¢-2), 2.03–1.97
(m, 1H, H-4), 1.76–1.67 (m, 1H, H¢-4), 1.28–1.20 (m, 1H, H¢-3);
dC (125 MHz, CDCl3) 206.00 (C1), 146.99 (C7), 139.09, 136.13,
134.57 (C5a, C9a, C9b), 115.44 (C9), 101.36 (C6), 56.29 (OCH3),
46.05 (C2a), 36.05, 32.76 (C2, C8), 31.00, 29.86 (C3, C5), 22.68
(C4); (+)-LRESIMS m/z 217 [M + H]+.
1
7-Methoxy-1,2,2a,3,4,5-hexahydro-(8H)-benz[cd]azulen-1-ol (19)
The title compound was prepared according to the method
reported by Mander et al.15 and obtained as an unstable white
solid that gradually turned grey: dH (500 MHz, CDCl3) 5.35 (t,
J = 6.5 Hz, H-9), 5.08 (s, 1H, H-6), 4.65 (m, 1H, H-1), 3.57 (s,
3H, OCH3), 2.92 (m, 1H, H-2), 2.52 (m, 2H, H-2a, H-5), 2.43 (dd,
J = 5.0, 14.0 Hz, 1H, H¢-2), 2.34 (m, 2H, H-8, H-8¢), 2.05 (m, 1H,
H-3), 1.87 (dt, J = 3.5, 13.0 Hz, 1H, H-4), 1.62–1.46 (m, 1H, H-4¢),
1.22–1.06 (m, 2H, H-5¢, H-3¢); dC (125 MHz, CDCl3) 149.01 (C7),
146.32 (C9a), 134.97, 132.18 (C5a, C9b), 110.70 (C9), 99.83 (C6),
73.29 (C1), 55.78 (OCH3), 44.60 (C5), 38.56 (C2a), 32.50 (C2),
31.60 (C8), 29.90 (C3), 22.85 (C4); (+)-LRESIMS m/z 219 [M +
H]+, 231 [M + Na]+.
6¢-Methoxy-1¢,2¢,3¢,4¢-tetrahydro-1¢-naphthylacetic acid (10)
The ester 9 (2.73 g, 11.0 mmol) was dissolved in 1 M NaOH (90%
methanol in water, 60 mL) and stirred at room temperature for
3 h. The reaction mixture was concentrated, dissolved in water
(50 mL), acidified with 5 M HCl (12 mL) and extracted with ethyl
acetate (3 ¥ 40 mL). The organic extract was washed with brine
(2 ¥ 40 mL), dried over anhydrous sodium sulfate, filtered and
concentrated at reduced pressure to afford the crude product which
was purified on a silica column (hexane : ethyl acetate, 85 : 15) to
yield the title compound29 as a white solid (2.37 g, 97.8%): mp 80–
82 ◦C; dH (500 MHz, CDCl3) 7.10 (d, J = 8.5 Hz, 1H, H-8¢), 6.72
(dd, J = 2.5, 7.7 Hz, 1H, H-7¢), 6.62 (d, J = 2.0 Hz, 1H, H-5¢), 3.77
(s, 3H, OCH3), 3.32 (m, 1H, H-1¢), 2.81–2.70 (m, 3H, CH2CO,
H-4¢), 2.56 (dd, J = 10.0, 15.5 Hz, 1H, H¢-4¢), 1.98–1.92 (m, 1H,
H-2¢), 1.87–1.71 (m, 3H, H¢-2¢, H-3¢, H¢-3¢); dC (125 MHz, CDCl3)
178.82 (CO), 157.92 (C6¢), 138.53 (C4¢a), 131.30 (C8¢a), 129.30
(C8¢), 113.91 (C5¢), 112.43 (C7¢), 55.35 (OCH3), 41.93 (CH2CO),
33.89 (C1¢), 29.99 (C4¢), 28.43 (C2¢), 19.66 (C3¢); (+)-LRESIMS
m/z 243 [M + Na]+; (+)-HRESIMS m/z 243.0992, C13H16O3 [M
+ Na]+ requires 243.0992.
Ethyl 2-(6¢-methoxy-2¢,3¢-dihydro-1¢H-inden-1¢-yl)acetate (14)
Triethyl phosphonoacetate (4.15 g, 18.5 mmol) was added drop-
wise over 20 min to a stirred suspension of sodium hydride (60%
dispersion in mineral oil, 0.74 g, 18.5 mmol) in dry THF (40 mL)
at 0 ◦C under argon. Upon complete addition, the clear reaction
mixture was stirred at room temperature for 30 min and cooled
◦
to 0 C. A solution of 6-methoxy-1-indanone (2.5 g, 15.4 mmol)
in THF (10 mL) was then added over 5 min and the resulting
mixture stirred at room temperature for 1 h and heated to reflux
for a further 15 h. The reaction mixture was cooled to room
temperature and diluted with ethyl acetate (50 mL) and washed
with brine (2 ¥ 40 mL). The aqueous layer was extracted with
ethyl acetate (2 ¥ 30 mL) and the combined organic extracts
washed with brine (40 mL), dried over anhydrous sodium sulfate,
filtered and concentrated at reduced pressure. The crude product
was purified on silica (hexane : ethyl acetate, 98 : 2) to yield 2.59
g (72.3%) of 13 as a colourless oil containing a mixture of endo-
and (E, Z) exo-double bond isomers. The adducts were dissolved
in ethanol (45 mL) without further purification and stirred in the
presence of 10% Pd–C (200 mg) under a hydrogen atmosphere at
50 ◦C for 8 h. After this time, the reaction mixture was filtered
3-(6¢-Methoxy-1¢,2¢,3¢,4¢-tetrahydro-1¢-naphthyl)-1-diazo-propane-
2-one (11)
The title compound was prepared according to the ◦method
reported by Mander et al.15 as a yellow solid: mp 82–84 C (lit.15
84–86 ◦C); dH (500 MHz, CDCl3) 7.05 (d, J = 9.0 Hz, 1H, H-
8¢), 6.69 (dd, J = 2.5, 8.5 Hz, 1H, H-7¢), 6.60 (d, J = 2.0 Hz,
1H, H-5¢), 5.20 (br s, 1H, CH N), 3.76 (s, 3H, OCH3), 3.36 (m,
1H, H-1¢), 2.78–2.51 (m, 4H), 1.93–1.87 (m, 1H), 1.82–1.64 (m,
3H); dC (125 MHz, CDCl3) 194.25 (CO), 157.84 (C6¢), 138.48
(C4¢a), 131.76 (C8¢a), 129.41 (C8¢), 113.87 (C5¢), 112.33 (C7¢),
55.33 (OCH3), 55.25(CH N2), 48.69 (C1¢), 33.80 (CH2CO), 30.01
(C4¢), 28.53 (C2¢), 19.76 (C3¢); (+)-LRESIMS m/z 267 [M + Na]+;
(+)-HRESIMS m/z 267.1099, C14H16N2O2 [M + Na]+ requires
267.1104.
R
through Celiteꢀ and concentrated at reduced pressure. The crude
product was purified on a silica column (hexane : ethyl acetate,
98 : 2) to afford 2.56 g (98%, 70.9% overall yield) of the title
compound as a colourless oil with the same 1H NMR spectrum as
previously reported:21 dH (500 MHz, CDCl3) 7.11 (d, J = 8.0 Hz,
1H, H-4¢), 6.74–6.71 (m, 2H, H-7, H-5¢), 4.18 (q, J = 7.0 Hz, 2H,
CO2CH2CH3), 3.77 (s, 3H, OCH3), 3.55 (pent, J = 7.3 Hz, 1H, H-
1¢), 2.89–2.72 (m, 3H, CHCH2CO, H-3¢), 2.45-2.35 (m, 2H, H¢-3¢,
H-2¢), 1.76 (m, 1H, H¢-2¢), 1.28 (t, J = 7.0 Hz, 3H, COCH2CH3);
(+)-LRESIMS m/z 257 [M + Na]+.
7-Methoxy-1,2,2a,3,4,5-hexahydro-(8H)-benz[cd]azulen-1-one
(12)
The title compound was prepared according to the method
reported by Mander et al.15 and obtained as an unstable white
solid that gradually turned grey: dH (500 MHz, CDCl3) 5.99 (dd,
J = 6.0, 8.0 Hz, 1H, H-9), 5.28 (s, 1H, H-6), 3.60 (s, 3H, OCH3),
2-(6¢-Methoxy-2¢,3¢-dihydro-1¢H-inden-1¢-yl)acetic acid (15)
The ester 14 (2.55 g, 10.89 mmol) was dissolved in 1 M NaOH
(90% methanol in water, 60 mL) and stirred at room temperature
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for 3 h. The reaction mixture was concentrated, dissolved in water
(50 mL), acidified with 5 M HCl (13 mL) and extracted with ethyl
acetate (3 ¥ 40 mL). The ethyl acetate extract was washed with
brine (2 ¥ 40 mL), dried over anhydrous sodium sulfate, filtered
and concentrated at reduced pressure to afford the crude product
which was purified on silica gel (hexane : ethyl acetate, 85 : 15) to
yield the title compound as a white solid (2.37 g, 97.6%): mp 65–
followed by brine (2 ¥ 50 mL). The organic layer was decanted and
dried over anhydrous sodium sulfate. The solvent was removed at
reduced pressure to afford the reddish brown crude product which
was purified on silica gel (hexane : ethyl acetate, 98 : 2) to afford 165
mg of the title compound as a white solid (74.5%): mp 82–84 ◦C;
nmax (cm-1) 3010 (ArH), 1710 (C O), 1485 (CH2), 1250 (OCH3);
dH (500 MHz, CDCl3) 7.10 (d, J = 8.0 Hz, 1H, H-5), 6.69 (d, J =
8.0 Hz, 1H, H-6), 3.81 (s, 3H, OCH3), 3.60 (d, J = 22.0 Hz, 1H,
H-2), 3.36–3.26 (m, 2H, H-2a, H¢-2), 2.97–2.83 (m, 3H, H-8, H¢-8,
H-4), 2.49 (pent, J = 6.3 Hz, 1H, H-3), 2.21 (m, 1H, H¢-4), 1.72 (m,
1H, H¢-3); dC (125 MHz, CDCl3) 210.91 (C1), 155.58 (C7), 144.63
(C8b), 134.42 (C4a), 123.06 (C8a), 119.08 (C5), 109.16 (C6), 55.97
(OCH3), 47.00 (C4), 40.44 (2a), 37.27 (C2), 35.89 (C3), 31.81 (C8);
(+)-LRESIMS m/z 225 [M + Na]+; (+)-HRESIMS m/z 225.0888,
C13H14O2 [M + Na]+ requires 225.0886.
◦
68 C; nmax (cm-1) 3300–2500 (COOH), 3005 (ArH), 2835 (CH),
1710 (C O), 1240 (ArOCH3); dH (500 MHz, CDCl3) 7.13 (d,
J = 8.0 Hz, 1H, H-4¢), 6.77 (s, 1H, H-7¢), 6.74 (d, J = 8.0 Hz,
H-5¢), 3.79 (s, 3H, OCH3), 3.57 (5, J = 7.2 Hz, 1H, H-1¢), 2.91–
2.81 (m, 3H, COCH2, H-3¢), 2.52–2.40 (m, 2H, H¢-3¢, H-2¢), 1.79
(sext, J = 7.2 Hz, 1H, H¢-2¢); dC (125 MHz, CDCl3) 179.06 (CO),
159.15 (C6¢), 147.24 (C7¢a), 136.13 (C3¢a), 125.41 (C4¢), 112.97
(C5¢), 109.58 (C7¢), 55.82 (OCH3), 41.63 (CH2CO), 39.90 (C1¢),
33.25 (C3¢), 30.64 (C2¢); (+)-LRESIMS m/z 229 [M + Na]+; (+)-
HRESIMS m/z 229.0825, C12H14O3 [M + Na]+ requires 229.0835.
7-Methoxy-1,2,2a,3,4,8-hexahydrocyclopenta[cd]azulen-1-ol (20)
To a stirred and cooled (0 ◦C) solution of the cycloheptatriene 17
(140 mg, 0.69 mmol) in dry methanol (15 mL) was added sodium
borohydride (52 mg, 1.37 mmol). The resulting mixture was stirred
for 30 min at 0–5 ◦C. 0.1 M HCl in brine (25 mL) was slowly added
to the reaction mixture until evolution of hydrogen gas had ceased
at which time a voluminous white suspension was observed. The
product was extracted with ethyl acetate (4 ¥ 20 mL) and the
organic extract washed with brine (2 ¥ 25 mL). The organic layer
was dried over anhydrous sodium sulfate, filtered and evaporated
at reduced pressure to obtain the crude product (a 95 : 5 mixture of
syn and anti isomers 20a and 20b respectively). The crude products
were washed with hexane to obtain the pure cis adduct (96 mg).
After concentrating the hexane washes at reduced pressure, the
two isomers were separated on a silica gel column (hexane : ethyl
acetate, 92 : 8 → 90 : 10) to obtain a further 35 mg of 20a as a white
solid (131 mg overall, 92.7%) and 6 mg (4.2%) of 20b as a white
solid.
1-Diazo-3-(6¢-methoxy-2¢,3¢-dihydro-1¢H-inden-1¢-yl)propan-2-one
(16)
A solution of the acid 13 (1.29 g, 6.26 mmol) in DCM (20 mL) was
carefully added to a mixtur◦e of oxalyl chloride (1.6 g, 12.53 mmol)
and DMF (0.2 mL) at -5 C dropwise over 10 min all the while
ensuring the temperature did not rise above 0 ◦C. The reaction
mixture was then stirred at 0–5 ◦C for 1 h and ambient temperature
for an additional 1 h and the mixture was concentrated at reduced
pressure to afford a thick yellow oil. The residue was taken up
in toluene (10 mL) and added dropwise to a solution of freshly
prepared diazomethane in diethyl ether (25 mL) at 0 ◦C (CARE).
The reaction mixture stirred at 0–5 ◦C for 2 h and then overnight
at 25 ◦C. Excess diazomethane and diethyl ether was removed by
bubbling nitrogen gas into the reaction mixture. The crude yellow
product was purified on silica gel (hexane : ethyl acetate, 95 : 5 →
90 : 10) to yield 1.22 g (84.5%) of the title compound as a bright
yellow solid: mp 45–46 ◦C; nmax (cm-1) 3090 (ArH), 2940 (CH),
2102 (CHN2), 1640 (C O), 1490 (CH2), 1240 (ArOCH3); dH (500
MHz, CDCl3) d 7.11 (d, J = 7.5 Hz, 1H, H-4¢), 6.72 (m, 2H, H-7¢,
H-5¢), 5.24 (br s, 1H, CH N2), 3.78 (s, 3H, OCH3), 3.61 (pent,
1H, J = 7.1 Hz, H-1¢), 2.88–2.74 (m, 3H, COCH2, H-3¢), 2.44–2.34
(m, 2H, H¢-3¢, H-2¢), 1.74 (sext, J = 7.1 Hz, 1H, H¢-2¢); dC (125
MHz, CDCl3) 193.91 (CO), 158.90 (C6¢), 147.52 (C7¢a), 135.89
(C3¢a), 125.16 (C4¢), 112.64 (C5¢), 109.40 (C7¢), 55.60 (OCH3),
55.04 (CHN2), 46.49 (CH2CO), 41.73 (C1¢), 32.94 (C3¢), 30.47
(C2¢); (+)-LRESIMS m/z 253 [M + Na]+; (+)-HRESIMS m/z
253.0943, C13H14N2O2 [M + Na]+ requires 253.0947.
20a: mp 130–134 ◦C; nmax (cm-1) 3500 (OH); 3010 (ArH), 2935
(CH), 1485 (CH2), 1245 (OCH3), 1110 (C-OH); dH (500 MHz,
CDCl3) 7.01 (d, J = 8.0 Hz, 1H, H-5), 6.10 (d, J = 8.0 Hz, 1H,
H-6), 4.19 (m, 1H, H-1), 3.80 (s, 3H, OCH3), 3.22 (dd, J = 6.5,
17.0 Hz, 1H, H-2), 2.99 (hept, J = 5.7 Hz, 1H, H-2a), 2.88–2.81
(m, 1H, H-4), 2.73 (dd, J = 7.5, 14.7 Hz, 1H, H¢-4), 2.39 (dd,
J = 10.0, 17.0 Hz, H¢-2), 2.33–2.28 (m, 2H, H-8, H-3), 1.66–1.60
(m, 1H, H¢-3), 1.37 (q, J = 11.6 Hz, 1H, H¢-8); dC (125 MHz,
CDCl3) 155.79 (C7), 145.22 (C8b), 134.59 (C4a), 122.02 (C5),
120.71 (C8a), 108.18 (C6), 69.74 (C1), 55.69 (OCH3), 41.75 (C2a),
38.87 (C8), 35.31 (C3), 32.66 (C2), 31.71 (C4); (+)-LRESIMS m/z
227 [M + Na]+; (+)-HRESIMS m/z 227.1052, C13H16O2 [M + Na]+
requires 227.1043.
20b: nmax (cm-1) 3500 (OH); 3010 (ArH), 2920 (CH), 1485 (CH2),
1245 (OCH3), 1090 (C-OH); dH (500 MHz, CDCl3) 7.04 (d, J =
8.0 Hz, 1H, H-5), 6.62 (d, J = 8.0 Hz, 1H, H-6), 4.52 (br s, 1H,
H-1), 3.80 (s, 3H, OCH3), 3.20 (hept, J = 5.8 Hz, 1H, H-2a), 2.89–
2.81 (m, 3H, H-8, H-4, H¢-4), 2.77– 2.71 (m, 1H, H¢-8), 2.34 (m,
1H, H-2), 2.28 (m, 1H, H-3), 1.62 (m, 1H, H¢-2), 1.33 (m, 1H,
H¢-3); dC (125 MHz, CDCl3) 156.39 (C7), 145.50 (C8b), 135.23
(C4a), 121.97 (C5), 119.98 (C8a), 108.18 (C6), 66.67 (C1), 55.84
(OCH3), 35.77 (C2), 35.67 (C3), 35.34 (C2a), 31.48, 31.47 (C4, C8);
(+)-LRESIMS m/z 227 [M + Na]+; (+)-HRESIMS m/z 227.1045,
C13H16O2 [M + Na]+ requires 227.1043.
7-Methoxy-2,2a,3,4-tetrahydro-(8H)-cyclopenta[cd]azulen-1-one
(17)
A solution of the diazoketone 16 (252 mg, 1.1 mmol) in dry
DCE (25 mL) was added slowly (25 mL min-1) via a syringe
R
pump fitted with fine Teflonꢀ tubing into a solution of copper(II)
ethylacetoacetate (22 mg, 6 mol%) in dry DCE (25 mL) at mild
reflux under an inert argon atmosphere. The reaction mixture
was heated to reflux for 15 min and cooled to room temperature.
DBU (0.25 mL) was added dropwise under argon and the mixture
stirred for a further 10 min. After this time, the reaction mixture
was diluted with DCM (50 mL) and washed with 1 M HCl (40 mL)
4576 | Org. Biomol. Chem., 2011, 9, 4570–4579
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General procedure for the synthesis of compounds 21a–c
CDCl3) 7.38 (m, 2H, PhH), 7.03 (m, 3H, PhH, H-5), 6.63 (d, J =
8.0 Hz, H-6), 4.66 (q, J = 12.5 Hz, 2H, OCH2), 3.92 (m, 1H, H-1),
3.82 (s, 3H, OCH3), 3.29 (dd, J = 6.5, 17.0 Hz, 1H, H-2), 2.94
(m, 1H, H-2a), 2.85 (m, 1H, H-8), 2.74 (dd, J = 8.0 Hz, 15.0 Hz,
H¢-8), 2.51 (dd, J = 9.5, 17.0 Hz, H¢-2), 2.43 (dt, J = 4.0, 11.5 Hz,
H-4), 2.31 (pent, J = 6.1 Hz, 1H, H¢-4), 1.63 (m, 1H, H-3), 1.39
(q, J = 11.6 Hz, 1H, H¢-3); dC (125 MHz, CDCl3) 163.51 and
161.56 (C4¢), 155.96 (C7), 145.57 (C8b), 134.90 (C4a), 134.93 and
134.68 (C1¢), 129.58 and 129.52 (C2¢), 122.07 (C5), 120.83 (C8a),
115.53 and 115.36 (C3¢), 108.25 (C6), 76.52 (C1), 69.93 (OCH2),
55.70 (OCH3), 41.69 (C2a), 35.62 (C4), 35.29 (C3), 31.76 (C8),
29.79 (C2); (+)-LRESIMS m/z 335 [M + Na]+; (+)-HRESIMS
m/z 335.1408, C20H21FO2 [M + Na]+ requires 335.1418.
Alcohol 20a (24 mg, 0.12 mmol) in dry THF (0.6 mL) was slowly
added to a stirred and cooled suspension of sodium hydride (60%
dispersion in mineral oil, 14 mg, 0.35 mmol) in dry THF (1.0 mL).
Following complete addition, the reaction mixture was stirred at
ambient temperature for 1 h under argon. The appropriate benzyl
bromide (0.176 mmol) was then added and the mixture stirred
for an additional 40 h under argon. The reaction mixture was
quenched with brine (3 mL) and extracted with ethyl acetate (4
¥ 2 mL). The organic extract was washed with brine (3 mL),
dried over anhydrous sodium sulfate, filtered and concentrated
at reduced pressure. The crude oil was purified on silica gel
(hexane : ethyl acetate, 98 : 2) to obtain the desired compounds
in yields ranging from 72–89%.
General procedure for the synthesis of compounds 21d–e
A solution of 20a (25 mg, 0.12 mmol) in dry DMF (0.5 mL) was
added slowly to a 2 mL microwave process vial equipped with a
stirrer bar and containing a cooled suspension of sodium hydride
(60% dispersion in oil, 15 mg, 0.36 mmol) in dry DMF (1.0 mL).
Following complete addition, the reaction mixture was stirred
at ambient temperature for 1 h under argon prior to addition
of alkyl bromide (0.25 mmol). The mixture was subsequently
heated in a microwave reactor at 110–115 ◦C for 45 min. The
reaction mixture was quenched with brine (3 mL) and extracted
with ethyl acetate (4 ¥ 2 mL). The organic extracts were washed
with brine (3 mL), dried over anhydrous sodium sulfate, filtered
and concentrated at reduced pressure. The crude oil was purified
on silica gel (hexane : ethyl acetate, 98 : 2 → 99 : 1) to obtain the
desired ethers as colourless oils in yields ranging from 52–55%.
1-(Benzyloxy)-7-methoxy-1,2,2a,3,4,8-hexahydrocyclopenta[cd]-
azulene (21a)
Colourless oil; 24.9 mg (72.0%); nmax (cm-1) 3010 (ArH), 2835
(CH2), 1485 (CH2), 1245 (OCH3); dH (500 MHz, CDCl3) 7.41 (d,
J = 7.5 Hz, 2H, PhH), 7.35 (t, J = 7.5 Hz, 2H, PhH), 7.29 (d,
J = 7.0 Hz, 1H, PhH), 7.01 (d, J = 8.0 Hz, 1H, H-5), 6.61 (d,
J = 8.0 Hz, 1H, H-6), 4.70 (q, J = 12.3 Hz, 2H, OCH2), 3.92
(m, 1H, H-1) 3.81 (s, 3H, OCH3), 3.29 (dd, J = 6.5, 8.5 Hz, 1H,
H-2), 2.93 (m, 1H, H-2a), 2.84 (m, 1H, H-8), 2.72 (dd, J = 8.0,
15.0 Hz, H¢-8), 2.51 (dd, J = 9.5 Hz, 16.7 Hz, 1H, H¢-2), 2.45 (dt,
J = 3.7, 11.5 Hz, 1H, H-4), 2.30 (pent, J = 6.0 Hz, 1H, H¢-4),
1.62 (m, 1H, H-3), 1.38 (q, J = 11.6 Hz, 1H, H¢-3); dC (125 MHz,
CDCl3) 156.08 (C7), 145.74 (C8b), 139.28 (C4a), 134.79 (C1¢),
128.72 (C3¢), 127.98 (C4¢), 127.81 (C2¢), 122.12 (C5), 121.08 (C8a),
108.35 (C6), 76.50 (C1), 70.71 (OCH2), 55.91 (OCH3), 41.82 (C2a),
35.72 (C4), 35.57 (C3), 31.87 (C8), 29.90 (C2); (+)-LRESIMS m/z
317 [M + Na]+; (+)-HRESIMS m/z 317.1511, C20H22O2 [M + Na]+
requires 317.1512.
1-Butoxy-7-methoxy-1,2,2a,3,4,8-hexahydrocyclopenta[cd]azulene
(21d)
Colourless oil; 17.6 mg (55%); nmax (cm-1) 3010 (ArH), 2940 (CH),
1620 (C C), 1485 (CH2), 1245 (OCH3); dH (500 MHz, CDCl3)
7.01 (d, J = 8.0 Hz, 1H, H-5), 6.61 (d, J = 8.0 Hz, 1H, H-6), 3.81–
3.75 (m, 4H, OCH3, H-1), 3.61 (m, 2H, OCH2), 3.23 (dd, J = 6.5,
19.0 Hz, 1H, H-2), 2.94 (m, 1H, H-2a), 2.84 (m, 1H, H-8), 2.72
(dd, J = 7.5, 14.7 Hz, H¢-8), 2.39 (m, 2H, H-4, H¢-2), 2.30 (pent,
J = 6.1 Hz, 1H, H¢-4), 1.61 (m, 3H, OCH2CH2, H-3), 1.42 (m, 2H,
CH2CH3), 1.30 (q, J = 11.6 Hz, 1H, H¢-3), 0.95 (t, J = 7.2 Hz,
3H, CH2CH3); dC (125 MHz, CDCl3) 155.90 (C7), 145.60 (C8b),
134.58 (C4a), 121.83 (C5), 121.06 (C8a), 108.31 (C6), 76.86 (C1),
68.55 (OCH2), 55.70 (OCH3), 41.70 (C2a), 35.66 (C4), 35.37 (C3),
32.45 (OCH2CH2), 31.66 (C8), 29.73 (C2), 19.60 (CH2CH3), 14.10
(CH2CH3); (+)-LRESIMS m/z 283 [M + Na]+; (+)-HRESIMS
m/z 283.1663, C17H24O2 [M + Na]+ requires 283.1668.
1-(4¢-Chlorobenzyloxy)-7-methoxy-1,2,2a,3,4,8-hexahydrocyclo-
penta[cd]azulene (21b)
White solid; 34.4 mg (89.1%); mp 78–80 ◦C; nmax (cm-1) 3010
(ArH), 2835 (CH2), 1485 (CH2), 1245 (OCH3); dH (500 MHz,
CDCl3) 7.35 (m, 4H, PhH), 7.02 (d, J = 8.0 Hz, 1H, H-5), 6.62
(d, J = 8.0 Hz, 1H, H-5), 4.66 (q, J = 12.5 Hz, 2H, OCH2), 3.91
(m, 1H, H-1), 3.82 (s, 3H, OCH3), 3.27 (dd, J = 6.0, 17.0 Hz, 1H,
H-2), 2.94 (m, 1H, H-2a), 2.84 (m, 1H, H-8), 2.73 (dd, J = 8.5,
15.2 Hz, 1H, H¢-8), 2.49 (dd, J = 9.5, 17.5 Hz, 1H, H¢-2), 2.44
(dt, J = 3.7, 11.0 Hz, 1H, H-4), 2.31 (pent, J = 6.0 Hz, 1H, H¢-4),
1.64 (m, 1H, H-3), 1.38 (q, J = 7.6 Hz, 1H, H¢-3); dC (125 MHz,
CDCl3) 156.06 (C7), 145.66 (C8b), 137.83 (C4a), 134.79 (C1¢),
133.54 (C4¢), 129.23 (C2¢), 128.87 (C3¢), 122.18 (C5), 120.88 (C8a),
108.37 (C6), 76.55 (C1), 69.95 (OCH2), 55.90 (OCH3), 41.77 (C2a),
35.71 (C4), 35.56 (C3), 31.87 (C8), 29.88 (C2); (+)-LRESIMS m/z
351 [M + Na]+; (+)-HRESIMS m/z 351.1110, C20H21ClO2 [M +
Na]+ requires 351.1123.
1 - (Isopentyloxy) - 7 - methoxy - 1 ,2 ,2a ,3 ,4 ,8 - hexahydrocyclo-
penta[cd]azulene (21e)
Colourless oil; 17.5 mg (52.2%); nmax (cm-1) 3010 (ArH), 2950
(CH), 1620 (C C), 1485 (CH2), 1245 (OCH3); dH (500 MHz,
CDCl3) 7.01 (d, J = 8.0 Hz, 1H, H-5), 6.60 (d, J = 8.0 Hz, 1H,
H-6), 3.81 (m, 4H, OCH3, H-1), 3.61 (m, 2H, OCH2), 3.23 (dd,
J = 6.5, 17.0 Hz, H-2), 2.94 (m, 1H, H-2a), 2.84 (m, 1H, H-8), 2.72
(dd, J = 7.5, 15.0 Hz, H¢-8), 2.38 (m, 2H, H-4, H¢-2), 2.30 (pent,
J = 6.0 Hz, 1H, H¢-4), 1.75 (m, 1H, CH(CH3)2), 1.63 (m, 1H, H-3),
1.52 (q, J = 6.8 Hz, 2H, OCH2CH2), 1.30 (q, J = 11.6 Hz, 1H, H¢-3),
1-(4¢-Fluorobenzyloxy)-7-methoxy-1,2,2a,3,4,8-hexahydrocyclo-
penta[cd]azulene (21c)
White solid, 26.9 mg (73.2%); mp 47–50 ◦C; nmax (cm-1) 3010
(ArH), 2835 (CH2), 1485 (CH2), 1245 (OCH3); dH (500 MHz,
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0.93 (d, J = 6.5 Hz, 6H, CH(CH3)2); dC (125 MHz, CDCl3) 155.90
(C7), 145 (C8b), 134.58 (4a), 121.84 (C5), 121.07 (C8a), 108.13
(C6), 76.89 (C1), 67.17 (OCH2), 55.70 (OCH3), 41.70 (C2a), 39.19
(OCH2CH2), 35.65 (C4), 35.37 (C3), 31.67 (C8), 29.74 (C2), 25.33
(CH), 22.85 (CH(CH3)2); (+)-LRESIMS m/z 297 [M + Na]+; (+)-
HRESIMS m/z 297.1824, C18H26O2 [M + Na]+ requires 297.1825.
13.5 Hz, 1H, H¢-3); dC (125 MHz, CDCl3) 155.82 (C7), 145.41
(C8b), 134.78 (C4a), 134.54 (C1¢¢), 129.25 (C4¢¢), 128.88 (C3¢¢),
128.29 (C2¢¢), 122.35 (C5¢), 121.94 (C5), 120.63 (C8a), 108.14 (C6),
77.41 (C4¢), 76.86 (C1), 62.40 (OCH2), 55.67 (OCH3), 54.34 (N-
CH2), 41.48 (C2a), 35.31 (C4), 35.31 (C3), 31.64 (C8), 29.66 (C2);
(+)-LRESIMS m/z 398 [M + Na]+; (+)-HRESIMS m/z 398.1825,
C23H25N3O2 [M + Na]+ requires 398.1838.
1-(Prop-2¢-ynyloxy)-7-methoxy-1,2,2a,3,4,8-hexahydrocyclo-
penta[cd]azulene (21f)
General procedure for the synthesis of compounds 23b–c
Copper sulfate solution (1 M, 0.5 mL) was added to a 2 mL
microwave process vial equipped with stirrer bar and containing
21f (35.0 mg, 0.14 mmol), alkyl bromide, sodium azide (10.4 mg,
0.16 mmol) and copper powder (8 mg) in t-butanol (0.8 mL).
The reaction vessel was sealed and the mixture was heated in a
microwave reactor at 110 ◦C for 20 min. The reaction mixture
was quenched with brine (3 mL) and extracted with ethyl acetate
(4 ¥ 3 mL). The organic solvent was washed with brine (4 mL),
dried over anhydrous sodium sulfate, filtered and concentrated at
reduced pressure to afford an oil. The crude product was purified
on silica gel (hexane : ethyl acetate, 85 : 15 → 80 : 20) to obtain the
title compounds as white solids in 42–45% yield.
A solution of 20a (100 mg, 0.12 mmol) in dry THF (1.0 mL)
was added slowly to a stirred and cooled suspension sodium
hydride (60% dispersion in oil, 79 mg, 1.96 mmol) in dry THF
(1.2 mL). Upon complete addition, the reaction mixture was
stirred at ambient temperature for 1 h under argon. Propargyl
bromide (233 mg, 1.96 mmol) was then added and the mixture
stirred for an additional 40 h at 55 ◦C under argon. The reaction
mixture was quenched with brine (3 mL) and extracted with
ethyl acetate (4 ¥ 2 mL). The organic extract was washed with
brine (3 mL), dried over anhydrous sodium sulfate, filtered and
concentrated at reduced pressure. The crude oil was purified on
silica gel (hexane : ethyl acetate, 98 : 2) to obtain the title compound
as a yellow oil (62 mg, 65% after recovery of 20 mg of unreacted
starting material): nmax (cm-1) 3285 (CC-H), 3010 (ArH), 2940
(CH), 1620 (C C), 1485 (CH2), 1245 (OCH3), 670 (CC-H); dH
(500 MHz, CDCl3) 7.02 (d, J = 8.0 Hz, 1H, H-5), 6.61 (d, J =
8.0 Hz, 1H, H-6), 4.37–4.30 (m, 2H, OCH2), 4.06 (m, 1H, H-1),
3.80 (s, 3H, OCH3), 3.26 (dd, J = 6.5, 17.0 Hz, 1H, H-2), 2.97 (hept,
J = 5.6 Hz, 1H, H-2a), 2.85 (m, 1H, H-8), 2.73 (dd, J = 7.5, 15.2 Hz,
1H, H¢-8), 2.45–2.39 (m, 3H, CH2CCH, H¢-2, H-4), 2.32 (pent, J =
6.1 Hz, H¢-4), 1.63 (m, 1H, H-3), 1.33 (q, J = 8.7 Hz, 1H, H¢-3); dC
(125 MHz, CDCl3) 155.85 (C7), 145.37 (C8b), 134.54 (4a), 121.99
(C5), 120 (C8a), 108.17 (C6), 80.40 (CH2CCH), 75.94 (C1), 74.11
(CH2CCH), 55.77 (OCH2), 55.69 (OCH3), 41.49 (C2a), 35.34 (C4),
35.21 (C3), 31.66 (C8), 29.31 (C2); (+)-LRESIMS m/z 265 [M +
Na]+; (+)-HRESIMS m/z 265.1195, C16H18O2 [M + Na]+ requires
265.1199.
1¢ - Butyl - 4¢ - (( - 7 - methoxy - 1 ,2 ,2a ,3 ,4 ,8 - hexahydrocyclo-
penta[cd]azulen-1-yloxy)methyl)-1H-1¢,2¢,3¢-triazole (23b)
◦
White solid; 20.9 mg (44.8%); 90–92 C; nmax (cm-1) 2940 (CH),
1615 (N N), 1485 (CH2), 1245 (OCH3); dH (500 MHz, CDCl3)
7.5 (s, 1H, H-5¢); 7.01 (d, J = 8.0 Hz, 1H, H-5), 6.60 (d, J = 8.0 Hz,
1H, H-6), 4.81 (q, J = 10.0 Hz, 2H, N-CH2), 4.35 (t, J = 7.2 Hz,
2H, OCH2), 3.95 (m, 1H, H-1), 3.80 (s, 3H, OCH3), 3.26 (dd, J =
6.0, 17.0 Hz, 1H, H-2), 2.94 (m, 1H, H-2a), 2.84 (m, 1H, H-8), 2.72
(dd, J = 8.0, 14.7 Hz, 1H, H¢-8), 2.45 (m, 2H, H¢-2, H-4), 2.30 (5,
J = 6.2 Hz, 1H, H¢-4), 1.90 (m, 2H, NCH2CH2), 1.61 (m, 1H, H-3),
1.36 (m, 3H, CH2CH3, H¢-3), 0.96 (t, J = 7.2 Hz, 3H, CH2CH3); dC
(125 MHz, CDCl3) 155.86 (C7), 146.10 (C4¢), 145.47 (C8b), 134.59
(C4a), 122.20 (C5¢), 121.97 (C5), 120.70 (C8a), 108.17 (C6), 76.79
(C1), 62.49 (OCH2), 55.71 (OCH3), 50.21 (NCH2), 41.53 (C2a),
35.37 (C4), 35.32 (C3), 32.43 (NCH2CH2), 31.68 (C8), 29.73 (C2),
19.90 (CH2CH3), 13.60 (CH2CH3); (+)-LRESIMS m/z 364 [M
+ Na]+; (+)-HRESIMS m/z 364.1997, C20H27N3O2 [M + Na]+
requires 364.1995.
1¢ - Benzyl - 4¢ - (( - 7 - methoxy - 1 ,2 ,2a ,3 ,4 ,8 - hexahydrocyclo-
penta[cd]azulen-1-yloxy)methyl)-1H-1¢,2¢,3¢-triazole (23a)
To a stirred suspension of 21f (40 mg, 0.17 mmol), benzyl azide
(26.4 mg, 0.2 mmol) and sodium ascorbate (20 mol%) in a solution
of t-butanol (0.5 mL), water (0.5 mL) and ethanol (0.5 mL) was
added copper sulfate pentahydrate (5 mol%). The reaction mixture
was stirred at room temperature for 16 h then diluted with brine
(3 mL) and extracted with ethyl acetate (4 ¥ 3 mL). The organic
extracts were dried over anhydrous sodium sulfate, filtered and
concentrated at reduced pressure to afford the crude product.
Silica gel chromatography (hexane : ethyl acetate, 85 : 15 → 80 : 20)
afforded the title compound as a white solid (37 mg, 60%): mp 78–
82 ◦C; nmax (cm-1) 2940 (CH), 1615 (N N), 1485 (CH2), 1245
(OCH3); dH (500 MHz, CDCl3) 7.48 (s, 1H, H-5¢), 7.40–7.34 (m,
3H, PhH), 7.28 (d, J = 7.0 Hz, 2H, PhH), 7.00 (d, J = 8.0 Hz, 1H,
H5), 6.59 (d, J = 8.0 Hz, 1H, H6), 5.52 (s, 2H, N-CH2), 4.82–4.76
(m, 2H, OCH2), 3.95 (m, 1H, H-1), 3.79 (s, 3H, OCH3), 3.24 (dd,
J = 6.0, 17.2 Hz, H-2), 2.92 (m, 1H, H-2a), 2.82 (m, 1H, H-8),
2.71 (dd, J = 8.0, 15.0 Hz, 1H, H¢-8), 2.46 (m, 2H, H¢-2, H-4),
2.29 (5, J = 6.1 Hz, 1H, H¢-4), 1.60 (m, 1H, H-3), 1.30 (q, J =
1¢ - Isopentyl - 4¢ - (( - 7 - methoxy - 1 ,2 ,2a ,3 ,4 ,8 - hexahydrocyclo-
penta[cd]azulen-1-yloxy)methyl)-1H-1¢,2¢,3¢-triazole (23c)
White solid: 23.1 mg (42.4%); mp 88–90 ◦C; nmax (cm-1) 2950 (CH),
1615 (N N), 1485 (CH2), 1245 (OCH3); dH (500 MHz, CDCl3)
7.55 (s, 1H, H-5¢), 7.01–6.99 (d, J = 8.0 Hz, 1H, H-5), 6.61 (d, J =
8.0 Hz, 1H, H-6), 4.42 (q, J = 10.0 Hz, 2H, N-CH2), 4.37 (t, J =
7.7 Hz, 2H, OCH2), 3.96 (m, 1H, H-1), 3.80 (s, 3H, OCH3), 3.26
(dd, J = 6.0, 17.0 Hz, 1H, H-2), 2.94 (m, 1H, H-2a), 2.83 (m, 1H,
H-8), 2.72 (dd, J = 8.0, 15.0 Hz, 1H, H¢-8), 2.44 (m, 2H, H¢-2,
H-4), 2.30 (5, J = 6.1 Hz, 1H, H¢-4), 1.81 (m, 2H, CH2CH2CH),
1.62 (m, 2H, CH2CH, H-3), 1.33 (q, J = 11.6 Hz, 1H, H¢-3); dC
(125 MHz, CDCl3) 155.84 (C7), 146.11 (C4¢), 145.45 (C8b), 134.57
(C4a), 122.11 (C5¢), 121.95 (C5), 120.68 (C8a), 108.15 (C6), 76.76
(C1), 62.46 (OCH2), 55.69 (OCH3), 48.81 (N-CH2), 41.51 (C2a),
39.21 (CH2CH), 35.34 (C4), 35.32 (C3), 31.66 (C8), 29.71 (C2),
25.69 (CH2CH), 22.34 (CH3)2; (+)-LRESIMS m/z 378 [M + Na]+,
4578 | Org. Biomol. Chem., 2011, 9, 4570–4579
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356 [M + H]+; (+)-HRESIMS m/z 378.2136, C21H29N3O2 [M +
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Acknowledgements
The authors acknowledge financial support of this work by
Griffith University and the Eskitis Institute. We thank Hoan Vu
from Griffith University for acquiring the HRESIMS data and
the Australian Research Council for LIEF grants that enabled
purchase of the NMR spectrometer (LE0668477) and FTMS
(LE0237908) used in this work.
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