Model studies toward the synthesis of the bioactive diterpenoid, harringtonolide

Article abstract of DOI:10.1039/b707467k

In model studies towards the synthesis of harringtonolide, the construction of the tropone moiety via arene cyclopropanation was investigated. The installation of the lactone ring was accomplished by way of a Diels-Alder cycloaddition of various indenones

Full text of DOI:10.1039/b707467k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Model studies toward the synthesis of the bioactive diterpenoid,
harringtonolide†
Timothy P. O’Sullivan,*a Hongbin Zhangb and Lewis N. Manderc
Received 17th May 2007, Accepted 19th June 2007
First published as an Advance Article on the web 2nd July 2007
DOI: 10.1039/b707467k
In model studies towards the synthesis of harringtonolide, the construction of the tropone moiety via
arene cyclopropanation was investigated. The installation of the lactone ring was accomplished by way
of a Diels–Alder cycloaddition of various indenones and a-pyones. The incorporation of the key bridge
methyl group and subsequent control of its stereochemistry is also outlined.
While we have previously reported the successful synthesis of
Introduction
harringtonolide by way of an arene-cyclopropanation strategy,
the approach had some inherent drawbacks.5–7 In particular, the
relatively early formation of the reactive cycloheptatriene moiety
and the need to carry out extensive manipulations in its presence
had a deleterious impact on yields. It was clear from these
difficulties that an improved route to harringtonolide was required.
In this new scheme, the cyclopropanation–tautomerisation process
would be effected at a much later stage so that fewer subsequent
steps would be required. It was proposed that the lactone function
be installed by means of a Diels–Alder cycloaddition reaction,
while the ether ring would be established using cyclopropyl ring-
opening chemistry (Scheme 2). The bulk of the harringtonolide
skeleton would thus be in place prior to installation of the
cycloheptatriene motif. While the initial [4 + 2] cycloaddition
The diterpenoid tropone, harringtonolide (3), was first isolated
in North America from the seeds of Cephalotaxus harringtonia
(Taxaceae) and its structure established by X-ray crystallography
(Scheme 1).1 It was also isolated in China from C. hainanensis2,3
and found to have both anti-neoplastic and anti-viral properties,
being active against Lewis Lung carcinoma, Walker carcinoma,
Sarcoma-180, and L-1210, L-615 and P-388 leukaemias, as well
as showing in vitro activity against influenza type A, New-
castle disease, Japanese B encephalitis and vaccinia viruses.4
Harringtonolide is a structurally rigid and congested molecule,
consisting of seven adjacent stereocenters. Of particular interest is
the presence of the cycloheptatrienone, or tropone, substructure
since it is believed that this functionality is responsible for the
biological activity of the compound.
Scheme 1 Previous synthesis of harringtonolide.
aDepartment of Chemistry, University College Cork, Cork, Ireland. E-mail:
tim.osullivan@ucc.ie; Fax: +353 21 490 1656; Tel: +353 21 490 1655
bKey Laboratory of Medicinal Chemistry for Natural Resources, Yunnan
University, Kunming, P. R. C. E-mail: zhanghb@ynu.edu.cn; Fax: +86 871
5035538; Tel: +86 871 5031119
cResearch School of Chemistry, Australian National University, Canberra,
Australia. E-mail: mander@rsc.anu.edu.au; Fax: +61 2 6125 0750; Tel: +61
2 6125 3761
† Electronic supplementary information (ESI) available: Additional
experimental details. See DOI: 10.1039/b707467k
Scheme 2 Proposed route to harringtonolide.
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between the indenone and the pyrone was likely to be problematic,
the intramolecular cyclopropanation of the aromatic ring was
of greater concern. This crucial step was not expected to be
as favourable as the conversion of 1 to 2 in the previous total
synthesis, given the different ring sizes and the potential for
competing reactions, such as CH insertion at the benzylic position
and/or ylide formation with the lactone carbonyl group.
Results and discussion
In order to study this key synthetic step and other aspects of
the proposed route to harringtonolide, a series of model studies
was initiated. From a geometrical perspective, diazoketone 10 was
considered to be a good match for 7 (Fig. 1). This was supported
by some preliminary computational calculations in which both
molecules were overlaid for comparison purposes.
Fig. 1 Molecular geometry comparison.
5-Methoxyindanone (11),8 prepared in 2 steps from commer-
cially available m-methoxycinnamic acid, was treated with N-
bromosuccinimide and triethylamine to afford indenone 12 in
69% yield (Scheme 3). Birch reduction of p-methoxyphenylacetic
acid (13) followed by acidification and esterification afforded two
isomers 14a and 14b in a 1.5 : 1 ratio.
Scheme 4 Reagents and conditions: i, 19 Kbar, rt, DCM, 52%; ii, KOH,
rt, H2O, EtOH, 96%; iii, LiEt3BH, 0 ◦C, THF; iv, CH2N2, 0 ◦C, Et2O, 90%
overall; v, NIS, rt, THF, 75%; vi, AIBN, n-Bu3SnH, reflux, THF, 95%;
vii, KOH, rt, H2O, EtOH, 93%; viii, NaH, rt, THF; ix, (COCl)2, DMF,
0
◦C, THF; x, CH2N2, 0 ◦C, Et2O, 75% overall.
to reduction with lithium triethylborohydride, followed by re-
esterification with diazomethane. Following iodoetherification,
tetrahydrofuran 19 was obtained in 75% yield over 3 steps from
acid 16. The iodide was then subjected to reduction with tri-
n-butyltin hydride furnishing methyl ester 20. Hydrolysis of 20
produced carboxylic acid 21 which was subsequently converted to
diazoketone 10.
Having secured diazoketone 10, we reached the pivotal step for
this initial model study. Based on our previous synthesis, rhodium
mandelate was chosen as the catalyst for the initial test. Unfor-
tunately, in our model system, these conditions provided CH-
insertion compound 22 as the only isolable product (Scheme 5).
A variety of alternative rhodium catalysts, such as Rh2(OAc)4 and
Rh2(acam)4,10 were similarly unsuccessful. Copper(II) acetylaceto-
nate has proven to be an effective catalyst for the cyclopropanation
of aromatic rings,11 but it was unsuccessful in this instance. Finally,
the desired product was obtained on treatment of diazoketone 10
with bis(N-tert-butylsalicylaldiminato) copper(II).12
Having demonstrated that geometrical restraints still permitted
cyclopropanation to take place, we next turned our attention to the
installation of the lactone-ring framework of the harringtonolide
molecule by means of a [4 + 2] cycloaddition reaction with a
suitable pyrone (Scheme 6). A high pressure Diels–Alder reaction
Scheme 3 Reagents and conditions: i, NBS, reflux, CCl4 then Et3N, 85 ◦C,
CCl4, 69%; ii, Na, NH3, −33 ◦C, THF, EtOH; iii, CH2N2, 0 ◦C, Et2O, 67%
overall (40% 14a; 27% 14b).
As indenone 12 was prone to dimerisation at high temperatures
or in the presence of Lewis acids, high pressure activation was
instead employed for the [4 + 2] cycloaddition reaction.9 When
12 and 14a were subjected to 19 Kbar for 24 h, cycloadduct
15 was obtained as a single product in 52% yield (Scheme 4).
The endo stereochemistry was established by NOE differential
spectral analysis of the observed correlations between the protons
of the ethane bridge with the cyclopentanone ring protons. Methyl
ester 15 was hydrolysed to afford acid 16, which was submitted
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Scheme 8 Reagents and conditions: i, NaBH4, rt, MeOH, THF, 77%;
ii, CH2N2, Pd(OAc)2, 0 ◦C, Et2O, 95%.
Scheme 5 Reagents and conditions: i, Rh(mandelate)4, reflux, DCM, 47%
ii, bis(N-tert-butylsalicylaldiminato) copper(II), reflux, toluene, 30%.
reagents, most likely a result of the electron-withdrawing nature
of the adjacent lactone ring.14
In an effort to overcome this unexpected lack of reactivity,
we decided to incorporate a methyl group into the 4-position of
the pyrone, thereby obviating the need for the cyclopropyl ring-
opening step entirely and with the additional benefit of increasing
the electron density of the olefinic bond of the Diels–Alder adduct.
Treating 24 with ethereal diazomethane afforded 32 in 82% yield
(Scheme 9).15 When the newly prepared pyrone 32 and indenone
12 were subjected to high pressure, cycloadduct 33 was obtained.
Elaboration of 33 posed an interesting challenge. Attack of an
electrophilic reagent on the more exposed face of the olefinic
bond would position the methyl group over the aromatic ring
with the undesired endo stereochemistry. Accordingly, an indirect
strategy was employed. Reduction of 33 to benzylic alcohol 34
followed by hydroboration–oxidation afforded diol 35 with the
methyl substituent in the endo location. Oxidation of 35 with
the Dess–Martin periodinane furnished diketone 36.16 Treatment
of the diketone with a catalytic amount of DBU effected the
epimerisation of 36 to the thermodynamic product 37 with the
methyl group now adopting the requisite exo stereochemistry. The
transformation of 36 to 37 was manifestly apparent from the 1H-
NMR spectrum. The bridge methyl, which had appeared as a
doublet at d0.49 in 36, now had a chemical shift of d1.35 in 37. This
large downfield shift can be ascribed to the removal of the methyl
group from the shielding effect of the aromatic ring. Reduction
of diketone 37 afforded syn diol 38. Treatment of 38 with p-
toluenesulfonic acid led to formation of the benzylic cation and
trapping by the remaining hydroxyl to install the tetrahydrofuran
ring system (31).
Demethylation of 31 was accomplished by the method of Fujita
et al. using a combination of aluminium tribromide and tetrahy-
drothiophene (Scheme 10).17 Compound 39 was then converted to
the corresponding acid chloride which was immediately reduced to
primary alcohol 40. Following oxidation of the carbinol to 41, the
aldehyde was added to an excess of the methoxymethylene ylide
thereby producing (Z)-methylenol ether 42 in 58% yield. The enol
ether was hydrolysed to the homologated aldehyde 43 and then
oxidised to carboxylic acid 44. The acid chloride, generated by
addition of the Vilsmeier reagent to a benzene solution of 44, was
converted in situ to diazoketone 45 with ethereal diazomethane. A
strong band at 2106 cm−1 in the IR spectrum was characteristic of
Scheme 6 Reagents and conditions: i, 19 Kbar, rt, DCM, 72%.
between 12 and 24 furnished cycloadduct 25 as a single product in
72% yield with the desired endo stereochemistry being confirmed
by spectral analysis and X-ray crystallography.13
The next phase involved the construction of the internal frame-
work of the molecule. This entailed the formation of an ether bond
to introduce the tetrahydrofuran moiety and the incorporation of a
bridge methyl group with the correct stereochemistry. Based upon
previous work, the prospect of forming the tetrahydrofuran ring
in harringtonolide by a process equivalent to 26 → 28 appeared
to be feasible (Scheme 7).5
Scheme 7 Reagents and conditions: i, Hg(NO3)2; ii, KBr; iii, NaBH4, rt,
DME, 80% overall.
Accordingly, ketone 25 was reduced to benzylic alcohol 29
in 77% yield (Scheme 8). A combination of diazomethane and
a catalytic amount of palladium acetate afforded 30 in almost
quantitative yield. Unfortunately, subsequent mercury-mediated
ring-opening was wholly unsuccessful, despite recourse to a wide
range of reagents and conditions. Attempted iodoetherification of
intermediate 29 as per 18 → 19 merely resulted in oxidation of 29
to ketone precursor 25. Additional work would reveal the olefinic
bond in 29 to be quite unreactive towards an array of different
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Scheme 10 Reagents and conditions: i, tetrahydrothiophene, AlBr3, 0 ◦C,
DCM, 69%; ii (COCl)2, DMF, 0 ◦C, benzene then NaBH4, 0 ◦C, THF,
71%; iii, DMP, rt, tBuOH, THF, 92%; iv, [Ph3PCH2OMe]Cl, LiHMDS,
0 ◦C, THF, 58%; v, HCl, rt, H2O, THF, 83%; vi, NaClO2, H2O2, 0 ◦C, H2O,
ACN, 65%; vii, (COCl)2, DMF, 0 ◦C, benzene; viii, CH2N2, 0 ◦C, Et2O,
62% overall; ix, CH2N2, 0 ◦C, Et2O, 96%.
At this point, we opted to revise our synthetic approach.
First, we would incorporate the C8 methyl, which corresponds
to the tropone methyl substituent, into the indenone intermediate.
Secondly, we would seek to increase the reactivity of the olefinic
bond in the cycloadduct by reducing the carboxyl group at an
early stage in the synthetic plan. Finally, we would investigate the
feasibility of blocking unwanted ylide formation by reduction of
the lactone and subsequent protection of the resultant lactol.
Demethylation of 32 to carboxylic acid 47 by in situ generation
of trimethylsilyl iodide proceeded well (Scheme 11). Meanwhile,
bromination of indanone 48, a known compound,23 and subse-
quent elimination afforded indenone 4 in 63% yield. Once again, a
high pressure Diels–Alder reaction between 47 and 4 furnished
cycloadduct 49 with the required regio- and stereochemistry.
Compound 49 was converted to the corresponding acid chloride
and then reduced to carbinol 50. This alcohol was subse-
quently protected as the tert-butyldimethyl silyl ether 51 in good
yield.
Applying the previously established methodology, ketone51 was
reduced to the benzylic alcohol 52 and, following hydroboration-
oxidation of the olefinic bond, diol 53 was oxidised to diketone
54 (Scheme 12). Treatment of 54 with a catalytic amount of
DBU afforded epimer 55 in 98% yield. Interestingly, while the
epimerisation of 36 to 37 had provided a 1 : 3 ratio of endo :
exo products, conversion of 54 to 55 went to completion with no
starting material remaining. This unexpected result is presumably
due to the bulky TBDMS ether side chain, which favours the
thermodynamic product through steric interaction. Indeed, MM2
calculations suggest a 2.01 kcal mol−1 energy difference between
Scheme 9 Reagents and conditions: i, CH2N2, 0 ◦C, DCM, 82%,
ii, 19 Kbar, rt, DCM, 73%; iii NaBH4, rt, MeOH, THF, 85%; iv, BH3·DMS,
0 ◦C, THF then Et3NO, reflux, THF, 49%; v, DMP, rt, tBuOH, THF, 48%;
vi, DBU, rt, THF, 72%; vii, NaBH4, rt, MeOH, THF, 66%; viii, p-TsOH,
THF, 71%.
the asymmetric diazo stretch while a molecular ion of m/z 354 was
accompanied by a fragmentation pattern showing loss of nitrogen
to produce a peak at m/z 328.
Heating diazoketone 45 in the presence of bis(N–tert-
butylsalicylaldiminato) copper(II) resulted in a complex mixture
of products. Unfortunately, it was evident from the 1H-NMR
spectrum that no arene cyclopropanation had taken place. Neither
the use of Cu(acac)2 nor of Rh(OAc)2 was successful - both
catalysts merely produced a complex mixture of aromatic com-
pounds. The most likely explanation for the failure of the arene
cyclopropanation sequence involves carbonyl ylide formation with
the lactone ring.18,19 Masking of carbonyls as ortho acetals has
previously been used to circumvent ylide formation.20 Accordingly,
acid 44 was protected as the methyl ester 46 using diazomethane.
Regrettably, we were unable to transform 46 to the corresponding
ortho acetal derivative. Even powerful reagents such as the
Meerwein salt method21 or Noyori’s method22 failed to effect the
desired transformation.
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Finally, we proposed reducing the lactone to the corresponding
lactol, followed by masking of the resultant hydroxyl with a
bulkly protecting group, namely a TBDMS ether. The reason
for the introduction of this group was twofold - first, to block
any reaction between the carbenoid and the free hydroxyl and
secondly, to direct the carbenoid towards the aromatic ring.
Previous studies on gibberellin intermediates had demonstrated
that a DIBAL reduction could be conducted in the presence of a
dichloroacetate protecting group.24 With this information in mind,
we returned to substrate 56 and the TBDMS ether was cleaved with
tetrabutylammonium fluoride to afford the primary alcohol 57,
which was then reprotected as the dichloroacetate 58 (Scheme 13).
Reduction of 58 with DIBAL at −40 ◦C furnished the desired
hemi-acetal 59 in 57% yield. Protection of the hemi-acetal as the
TBDMS ether 60 proceeded readily while subsequent hydrolysis
of the acetate ester furnished advanced intermediate 61.
Scheme 11 Reagents and conditions: i, I2, (SiMe3)2, reflux, CHCl3, 75%;
i, NBS, reflux, CCl4 then Et3N, 85 ◦C, CCl4, 63%; iii, 19 Kbar, rt, DCM,
68%; iv, (COCl)2, DMF, 0 ◦C, THF then NaBH4, 0 ◦C, THF, 66%;
v, TBDMSOTf, N,N-diisopropylethylamine, 0 ◦C, DCM, 83%.
Scheme 13 Reagents and conditions: i, TBAF, rt, THF, 95%; ii, dichloro-
acetyl chloride, pyridine, rt, DCM, 96%; iii, DIBAL-H, −40 ◦C, toluene,
57%; iv, TBDMSOTf, N,N -diisopropylethylamine, rt, DCM, 72%; Et3N,
rt, H2O, MeOH, 90%.
Conclusions
These preliminary model studies have allowed us to investigate
the feasibility of a more concise route to the complex diterpenoid,
harringtonolide. While our initial studies demonstrated that the
geometry of the molecule is suitable for arene-cyclopropanation
purporse, we have also uncovered a number of unforeseen
obstacles. In particular, the low reactivity of the olefinic bond of the
Diels–Alder cycloadduct and the propensity of the a-diazoketone
intermediate to undergo unwanted ylide formation with the
lactone ring moiety were problematical. We have successfully
incorporated the bridge methyl substituent via the pyrone starting
material and have controlled its stereochemical orientation in
subsequent work.
Finally, we have modified the chemistry of the lactone ring
and incorporated a bulky protecting group in the expectation of
blocking ylide formation and directing cyclopropanation towards
the aromatic ring. We hope to report on our work on the remaining
steps (Scheme 14) and the completion of this synthesis in due
course.
Scheme 12 Reagents and conditions: i NaBH4, rt, MeOH, THF, 89%;
ii, BH3·DMS, 0 ◦C, THF then Et3NO, reflux, THF, 38%; iii, DMP, rt,
tBuOH, THF, 58%; iv, DBU, rt, THF, 98%; v, NaBH4, rt, MeOH, THF
then HCl work-up, 64%.
54 and 55 as compared to a gap of only 0.29 kcal mol−1 between
36 and 37. Reduction of 55, followed by acidic work-up, afforded
ether 56 in 64% yield.
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(2), 132 (10), 117 (18), 106 (12), 89 (87), 78 (5), 74 (28), 70 (68), 66
(10), 61 (100).
Methyl-2-(1ꢀ-methoxycyclohexa-1ꢀ,3ꢀ-dienyl)ethanoate (14a) and
methyl-2-(1ꢀ-methoxycyclohexa-1ꢀ,4ꢀ-dienyl)ethanoate (14b)
Liquid ammonia (150 ml) was added to a solution of 2-(4ꢀ-
methoxybenzene)ethanoic acid (13) (3.32 g, 20 mmol) in ethanol
(10 ml) and THF (20 ml). Sodium (metal, 3.2 g, 140 mmol, 7 eq.)
was added in small pieces over a period of approximately 1 h until
the blue colour persisted for 4 min. The ammonia was allowed
to evaporate overnight. Ice (200 g) was added to the residue. The
resulting mixture was acidified with 1 M HCl (pH = 5), and then
extracted with ethyl acetate (4 × 80 ml). The combined organic
phase was washed with water (2 × 40 ml), brine (40 ml) and
dried over sodium sulfate. After filtration, the solvent was removed
under reduced pressure and the residue was treated with ethereal
Scheme 14 Remaining steps in the synthesis of harringtonolide.
◦
diazomethane at 0 C. After removal of the solvent, the residue
Experimental
was purified by flash chromatography on silica gel (petroleum ether
40–60 ◦C: ethyl acetate = 100 : 1 → 20 : 1 → 10 : 1) to afford an
inseparable mixture of the methyl esters (14a : 14b = 1.5 : 1; 2.46 g,
67%) as a pale yellow oil.
General experimental
Starting materials and reagents used in reactions were obtained
commercially and were used without purification, unless otherwise
indicated. Flash chromatography was conducted with Merck
Kieselgel 60 silica gel as the adsorbent. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on a Varian Gemini
300 spectrometer at 300 MHz. Carbon-13 nuclear magnetic
resonance (13C NMR) were recorded on Varian Gemini 300
spectrometer at 75.5 MHz. Infrared (IR) spectra (mmax) were
recorded on a Perkin-Elmer 683 Infrared spectrophotometer in
0.25 mm NaCl solution cells or recorded on a Perkin-Elmer 1800
Fourier Transform Infrared spectrophotometer in KBr plates.
Low resolution EI mass (LRMS) spectra (70 eV) and high
resolution accurate mass measurements (HRMS) were recorded
on a VG Autospec double focussing mass spectrometer. Melting
points (mp) were recorded on a Reichert hot-stage and are
uncorrected. Microanalyses were conducted by the Australian
National University Analytical Services Unit, Canberra.
Methyl-2-(1ꢀ-methoxycyclohexa-1ꢀ,3ꢀ-dienyl)ethanoate
(14a).
=
dH (300 MHz, CDCl3) 5.69 (1H, d, J = 6.0 Hz, H–C C), 4.85
=
(1H, d, J = 6.1 Hz, H–C C–OCH3), 3.62 (3H, s, OCH3), 3.52
(3H, s, OCH3), 3.01 (2H, m), 2.72 (2H, m), 2.25 (2H, s, 2× H-2).
Methyl-2-(1ꢀ-methoxycyclohexa-1ꢀ,4ꢀ-dienyl)ethanoate
(14b).
=
dH (300 MHz, CDCl3) 5.50 (1H, m, H–C C), 4.55 (1H, m,
=
H–C C–OCH3), 3.62 (3H, s, OCH3), 3.49 (3H, s, OCH3), 2.96
(2H, m), 2.72 (1H, m), 2.25 (2H, s, 2× H-2), 1.95 (1H, m).
(1RS,4SR,4aRS,9aSR)-1,6-Dimethoxy-4-methoxycarbonyl-
methyl-9-oxo-4,4a,9,9a-tetrahydro-1,4-ethano-1H-fluorene (15)
The indenone 12 (160 mg, 1 mmol) and a mixture of dienes 14a
and 14b (364 mg, 2 mmol) were dissolved in dichloromethane
(1 ml) under nitrogen. The reaction mixture was then subjected
to high pressure (19 Kbar) for 2.5 h. The resulting mixture was
purified by flash chromatography on silica gel (petroleum ether
5-Methoxyindenone (12)
◦
N-Bromosuccinimide (356 mg, 2 mmol) was added to a solution of
the indanone 11 (324 mg, 2 mmol) in carbon tetrachloride (50 ml).
The resulting suspension was stirred at reflux with irradiation
from a tungsten lamp for 2 hours. Triethylamine (1 ml) was added,
then the reaction mixture was stirred at 85 ◦C (oil bath) for a
further 2 hours. The mixture was filtered through a short column
of silica gel and washed with petroleum ether 40–60 ◦C : ethyl
acetate = 1 : 1. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography on silica gel
(petroleum ether 40–60 ◦C : ethyl acetate = 10 : 1 → 2 : 1) to afford
5-methoxyindenone (12) (218 mg, 69%) as a yellow oil; mmax/cm−1
40–60 C : ethyl acetate = 10 : 1 → 5 : 1 → 1 : 1) to afford the
cycloadduct 15 (178 mg, 52%, based on indenone) as white needles;
mp 139–140 ◦C (from EtOAc); found: C, 70.18%; H, 6.35%. Calc.
for C20H22O5: C, 70.16%; H, 6.48%; mmax/cm−1 3030 (ArH), 2950
=
=
(CH), 1760 (C O), 1700 (C O), 1255 (ArOCH3), 1090 (C–O),
1030 (ArOCH3); dH (300 MHz, CDCl3) 7.63 (1H, d, J = 8.5 Hz,
H-8), 7.08 (1H, d, J = 2.1 Hz, H-5), 6.87 (1H, dd, J = 2.2, J =
8.6 Hz, H-7), 6.04 (1H, d, J = 8.7 Hz, H-2), 5.42 (1H, d, J =
8.7 Hz, H-3), 3.85 (3H, s, CH3O-C6), 3.74 (3H, s, COOCH3), 3.55
(1H, d, J = 7.1 Hz, H-4a), 3.52 (3H, s, CH3O-C1), 3.00 (1H, d,
J = 7.1 Hz, H9a), 2.95 (1H, d, J = 15.0 Hz, H-12A), 2.78 (1H, d,
J = 15.0 Hz, H-12B), 1.99–1.84 (2H, m, H-10a, H-11a), 1.62–1.42
(2H, m, H-10b, H-11b); dC (75 MHz, CDCl3) 202.20 (C9), 71.95
(COO), 164.55 (C6), 156.21 (C4b), 133.86 (C2), 132.91 (C8a),
131.76 (C3), 125.27 (C8), 114.98 (C7), 111.07 (C5), 79.28 (C1),
55.59 (CH3O-C6), 52.58 (C9a), 51.64 (COOCH3), 50.84 (CH3O-
C1), 46.62 (C4a), 40.41 (C4), 40.11 (C12), 31.01 (C10), 28.30 (C11);
m/z 342 (M+, 5%), 311 (12), 279 (3), 269 (15), 254 (6), 241 (30),
=
=
3005 (ArH), 1707 (C O), 1251 (ArOCH3), 1230 (CC OC), 1037
(ArOCH3); dH (300 MHz, CDCl3) 7.40 (1H, d, J = 5.8 Hz, H-3),
7.36 (1H, d, J = 7.7 Hz, H-7), 6.59 (1H, d, J = 2.2 Hz, H-4), 6.58
(1H, dd, J = 2.2, J = 7.7 Hz, H-6), 5.87 (1H, d, J = 5.8 Hz, H-2),
3.82 (3H, s, CH3O); dC (75 MHz, CDCl3) 196.88 (C1), 164.37 (C5),
147.52 (C3), 147.10 (C3a), 128.65 (C2), 124.28 (C7), 122.87 (C7a),
110.97 (C6), 110.36 (C4), 55.53 (CH3O); m/z 160 (M+, 40%), 145
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227 (4), 195 (4), 182 (100), 161 (8), 149 (27), 134 (7), 123 (69), 109
(20), 91 (17), 77 (13).
H-4a), 3.42 (3H, s, CH3O-C1), 2.99 (1H, dd, J = 8.4, J = 8.5 Hz,
H-9a), 2.92 (1H, d, J = 15.1 Hz, H-12A), 2.84 (1H, d, J = 15.1 Hz,
H-12B), 1.85 (1H, m, H-11b), 1.69 (2H, m, H-10 × 2), 1.40 (1H, m,
H-11a); dC (75 MHz, CDCl3) 171.99 (COO), 159.59 (C6), 143.23
(C4b), 137.54 (C8a), 133.53 (C2), 130.67 (C3), 125.67 (C8), 113.51
(C7), 110.57 (C5), 80.34 (C1), 75.70 (C9), 55.10 (CH3O-C6), 54.32
(C9a), 51.02 (COOCH3), 50.94 (C4a), 50.49 (CH3O-C1), 40.38
(C4), 40.02 (C12), 31.25 (C10), 27.97 (C11); m/z 344 (M+, 10%),
327 (6), 312 (24), 297 (6), 252 (7), 239 (15), 225 (8), 202 (14), 182
(84), 167 (32), 145 (90), 121 (100), 102 (28), 91 (23), 77 (14).
(1RS,4SR,4aRS,9aSR)-4-Carboxymethyl-1,6-dimethoxy-9-oxo-
4,4a,9,9a-tetrahydro-1,4-ethano-1H-fluorene (16)
The methyl ester 15 (410 mg, 1.2 mmol) and potassium hydroxide
(1.01 g, 18 mmol, 15 eq.) were dissolved in ethanol (25 ml) and
water (5 ml). The reaction mixture was stirred at room temperature
for 2 h. Ice (100 g) was added, then acidified with 1 M HCl (20 ml)
and extracted with chloroform (5 × 25 ml). The combined organic
phase was dried over sodium sulfate. After filtration, the solvent
was removed under reduced pressure and the residue was purified
by flash chromatography on silica gel (petroleum ether 40–60 ◦C :
ethyl acetate = 2 : 3 → 0 : 1 → DCM : MeOH = 10 : 1 → 5 : 1)
to afford the acid 16 (380 mg, 96.4%), after recrystallisation from
ethyl acetate, as colourless needles; mp 221–222 ◦C (from EtOAc);
found: C, 69.43%; H, 6.15%. Calc. for C19H20O5: C, 69.50%; H,
6.14%; mmax/cm−1 3500 (COOH), 3020 (ArH), 2940 (CH), 1700
(1SR,2SR,3SR,4RS,4aRS,9RS,9aRS)-1,6-Dimethoxy-2,9-
epoxy-3-iodo-4-methoxycarbonylmethyl-2,3,4,4a,9,9a-
hexahydro-1,4-ethano-1H-fluorene (19)
The alcohol 18 (275 mg, 0.8 mmol) and N-iodosuccinimide
(225 mg, 1 mmol) were dissolved in THF (25 ml). The resulting
solution was stirred at room temperature under darkness overnight
(14 hours), then diluted with ethyl acetate (100 ml) and washed
with 5% sodium thiosulfate (Na2S2O3) aqueous solution (2 ×
30 ml) and brine (30 ml). The aqueous phase was extracted with
ethyl acetate (20 ml). The combined organic phase was dried
over sodium sulfate. After filtration, the solvent was removed
under reduced pressure and the residue was purified by flash
chromatography on silica gel (petroleum ether 40–60 ◦C: ethyl
acetate = 5 : 1 → 2 : 1 → 1 : 1) to afford the product 19 (282 mg,
75.3%) as a colourless oil. Recrystallisation from ethyl acetate
=
(C O), 1260 (ArOCH3), 1090 (C–O); dH (300 MHz, CDCl3) 7.67
(1H, d, J = 8.5 Hz, H-8), 7.07 (1H, d, J = 2.1 Hz, H-5), 6.90 (1H,
dd, J = 2.1, J = 8.5 Hz, H-7), 6.08 (1H, d, J = 8.7 Hz, H-2), 5.45
(1H, d, J = 8.7 Hz, H-3), 3.87 (3H, s, CH3O-C6), 3.62 (1H, d, J =
7.0 Hz, H-4a), 3.54 (3H, s, CH3O-C1), 3.03 (1H, d, J = 7.0 Hz,
H-9a), 3.02 (1H, d, J = 14.8 Hz, H-12A), 2.86 (1H, d, J = 14.8 Hz,
H-12B), 2.05–1.95 (2H, m, H-10a, H-11a), 1.64–1.56 (2H, m, H-
10b, H-11b); dC (75 MHz, CDCl3) 203.37 (C9), 173.59 (COOH),
164.70 (C6), 156.73 (C4b), 132.85 (C2), 132.32 (C8a), 132.18 (C3),
124.94 (C8), 115.18 (C7), 110.81 (C5), 79.27 (C1), 55.35 (CH3O-
C6), 52.57 (C9a), 50.50 (CH3O-C1), 46.22 (C4a), 40.10 (C4), 39.74
(C12), 30.58 (C10), 28.01 (C11); m/z 328 (M+, 2%), 311 (0.7), 300
(1.2), 269 (5), 255 (4), 240 (35), 168 (100), 134 (7), 123 (65), 109
(18), 91 (12), 77 (9), 63 (6).
◦
solution afforded white crystals; mp 116–117 C (from EtOAc);
found: C, 51.13%; H, 4.87%; I, 26.92%. Calc. for C20H23O5I: C,
51.08%; H, 4.93%; I, 26.98%; mmax/cm−1 3040 (ArH), 2950 (CH),
=
1730 (C O), 1250 (ArOCH3), 1120 (C–O), 1090 (C–O), 1030
(ArOCH3); dH (300 MHz, CDCl3) 7.33 (1H, d, J = 8.2 Hz, H-8),
6.97 (1H, d, J = 2.3 Hz, H-5), 6.81 (1H, dd, J = 2.3, J = 8.3 Hz,
H-7), 5.26 (1H, d, J = 5.0 Hz, H-9), 4.74 (1H, d, J = 1.5 Hz, H-2),
3.93 (1H, d, J = 8.8 Hz, H-4a), 3.78 (3H, s, CH3O-C6), 3.75 (3H, s,
COOCH3), 3.62 (1H, s, H-3), 3.29 (3H, s, CH3O-C1), 3.08 (1H,
ddd, J = 1.5, J = 5.0, J = 8.8 Hz, H-9a), 2.58 (1H, d, J = 15.2 Hz,
H-12A), 2.40 (1H, d, J = 15.2 Hz, H-12B), 2.21–1.98 (4H, m,
H-11 × 2, H-10 × 2); dC (75 MHz, CDCl3) 171.76 (COO), 160.44
(C6), 144.49 (C4b), 136.47 (C8a), 125.98 (C8), 113,75 (C7), 112.14
(C5), 87.53 (C9), 84.73 (C2), 82.97 (C1), 55.31 (CH3O-C6), 51.59
(COOCH3), 50.59 (C4a), 50.29 (CH3O-C1), 46.63 (C9a), 44.50
(C3), 41.06 (C4), 38.30 (C12), 30.93 (C10), 18.62 (C11); m/z 470
(M+, 65%), 439 (8), 411 (3), 343 (37), 325 (50), 283 (12), 251 (10),
223 (13), 209 (25), 183 (6), 169 (27), 145 (100), 123 (13), 102 (11).
(1RS,4SR,4aRS,9RS,9aRS)-1,6-Dimethoxy-9-hydroxy-4-
methoxy-carbonylmethyl-4,4a,9,9a-tetrahydro-1,4-ethano-
1H-fluorene (18)
A solution of the ketone 16 (295 mg, 0.9 mmol) in anhydrous THF
(50 ml) was cooled to 0 ◦C. Lithium triethylborohydride (1 M
in THF, 2.7 ml, 2.7 mmol, 3.0 eq.) was added dropwise. After
addition, the reaction mixture was stirred at room temperature
for 2 h. Water (5 ml) was then added to decompose the excess
of super-hydride. The resulting mixture was diluted with ethyl
acetate (150 ml) and washed with water (50 ml, containing 1 M
HCl 4 ml) and brine (30 ml). The aqueous phase was extracted
with chloroform (2 × 25 ml). The combined organic phase
was dried over sodium sulfate. After filtration, the solvent was
removed and the residue was esterified with an ethereal solution
of diazomethane. After removal of the solvent, the residue was
purified by flash chromatography on silica gel (petroleum ether 40–
60 ◦C : ethyl acetate = 4 : 1 → 2 : 1 → 1 : 1) to afford the methyl ester
18 (278 mg, 90%) as a colourless oil; mmax/cm−1 3640 (OH), 3030
Methyl (1ꢀSR,2ꢀRS,4ꢀRS,4aꢀRS,9ꢀRS,9aꢀRS)-1ꢀ,6ꢀ-dimethoxy-
2ꢀ,9ꢀ-epoxy-2ꢀ,3ꢀ,4ꢀ,4aꢀ,9ꢀ,9aꢀ-hexahydro-1ꢀ,4ꢀ-ethano-1ꢀH-
fluoren-4ꢀ-yl-ethanoate (20)
The iodide 19 (262.3 mg, 0.56 mmol) and azobisisobutyronitrile
(AIBN) (5 mg) were dissolved in anhydrous THF (30 ml) under
a flow of nitrogen. The solution was degassed with nitrogen for
5 minutes then treated with n-Bu3SnH (0.3 ml, 1.1 mmol, 2 eq.).
The resulting solution was stirred at reflux with irradiation from a
tungsten lamp for 60 min. After removal of the solvent, the residue
was purified by flash chromatography on silica gel (petroleum
ether 40–60 ◦C : ethyl acetate = 2 : 1 → 1 : 1) to afford the
product 20 (183 mg, 94.8%) as a colourless oil. Recrystallisation
=
=
(ArH), 2950 (CH), 1730 (C O), 1240 (ArOCH3), 1210 (CC OC),
1130 (C–OH), 1095 (C–O), 1000 (ArOCH3); dH (300 MHz, CDCl3)
7.25 (1H, d, J = 8.4 Hz, H-8), 6.83 (1H, d, J = 2.4 Hz, H-5), 6.78
(1H, dd, J = 2.4, J = 8.4 Hz, H-7), 6.28 (1H, d, J = 8.8 Hz, H-2),
5.53 (1H, d, J = 8.8 Hz, H-3), 5.24 (1H, d, J = 8.4 Hz, H-9), 3.73
(3H, s, CH3O-C6), 3.68 (3H, s, COOCH3), 3.44 (1H, d, J = 8.4 Hz,
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from ethyl acetate afforded colourless crystals; mp 98–99 ◦C (from
EtOAc); found: C, 69.37%; H, 6.98%. Calc. for C20H24O5: C,
0.33 mmol) in THF (8 ml) was then added via a cannula and
washed with THF (6 ml). The resulting suspension was stirred at
ambient temperature for 20 min. DMF (160 ll, 2 mmol, 6 eq.)
was added, followed by oxalyl chloride (180 ll, 2.1 mmol, 6 eq.)
at 0 ◦C. The reaction mixture was stirred at room temperature
under nitrogen for 20 h, then carefully filtered into an ethereal
diazomethane solution at 0 ◦C. The reaction was allowed to
proceed at room temperature for 30 min. The resulting mixture
was filtered through a short column of silica gel and washed with
ethyl acetate. After removal of the solvent, the residue was purified
by flash chromatography on silica gel (petroleum ether 40–60 ◦C :
ethyl acetate = 2 : 1 → 1 : 1 → 1 : 2 → 0 : 1) to yield the diazo
ketone 10 (88 mg, 74.6%) as a yellow oil; mmax/cm−1 3000 (ArH),
69.75%; H, 7.02%; mmax/cm−1 3005 (ArH), 2950 (CH), 1730 (C O),
=
1260 (ArOCH3), 1150 (C–O), 1085 (C–O), 1030 (ArOCH3); dH
(300 MHz, CDCl3) 7.29 (1H, d, J = 8.2 Hz, H-8), 6.88 (1H,
d, J = 2.2 Hz, H-5), 6.75 (1H, dd, J = 2.2, J = 8.3 Hz, H-7),
5.20 (1H, d, J = 5.0 Hz, H-9), 4.09 (1H, d, J = 7.2 Hz, H-2),
3.73 (3H, s, CH3O-C6), 3.65 (3H, s, COOCH3), 3.36 (1H, d, J =
8.8 Hz, H-4a), 3.24 (3H, s, CH3O-C1), 2.98 (1H, dd, J = 5.0, J =
8.7 Hz, H-9a), 2.38 (1H, d, J = 14.4 Hz, H-12A), 2.05 (1H, d,
J = 14.4 Hz, H-12B), 1.94 (2H, m), 1.80 (1H, m), 1.61 (1H, m),
1.59 (1H, dd, J = 7.2, J = 14.7 Hz, H-3a), 1.20 (1H, dd, J = 2.0,
J = 14.7 Hz, H-3b); dC (75 MHz, CDCl3) 171.90 (COO), 159.83
(C6), 145.75 (C4b), 136.80 (C8a), 125.78 (C8), 113.02 (C7), 111.85
(C5), 83.89 (C9), 82.99 (C1), 77.35 (C2), 55.12 (CH3O-C6), 51.31
(C4a), 51.19 (COOCH3), 51.00 (CH3O-C1), 49.86 (C9a), 41.27
(C3), 40.43 (C4), 34.01 (C12), 32.18 (C10), 18.90 (C11); m/z 344
(M+, 100%), 326 (2), 313 (35), 300 (75), 284 (10), 269 (65), 252
(15), 241 (82), 227 (26), 202 (70), 171 (40), 159 (30), 145 (54), 128
(30), 115 (26), 102 (30), 91 (11).
=
2950 (CH), 2110 (CHN2), 1670 (C O); dH (300 MHz, CDCl3) 7.34
(1H, d, J = 8.2 Hz, H-8), 6.92 (1H, d, J = 2.4 Hz, H-5), 6.78 (1H,
dd, J = 2.4, J = 8.2 Hz, H-7), 5.24 (1H, d, J = 5.1 Hz, H-9),
5.20 (1H, br s, CHN2), 4.12 (1H, d, J = 7.2 Hz, H-2), 3.77 (3H, s,
CH3O-C6), 3.47 (1H, d, J = 8.8 Hz, H-4a), 3.28 (3H, s, CH3O-
C1), 3.01 (1H, ddd, J = 1.5, J = 5.1, J = 8.8 Hz, H-9a), 2.38
(1H, d, J = 14.4 Hz, H-12A), 2.04 (1H, d, J = 14.4 Hz, H-12B),
1.96 (3H, m), 1.64 (2H, m), 1.20 (1H, dd, J = 2.5, J = 14.7 Hz,
H-3b); dC (75 MHz, CDCl3) 193.45 (CO), 159.94 (C6), 146.12
(C4b), 136.98 (C8a), 125.95 (C8), 113.14 (C7), 112.24 (C5), 84.04
(C9), 83.14 (C1), 77.64 (C2), 55.41 (CH3O-C6), 55.37 (CHN2),
51.83 (CH3O-C1), 51.18 (C4a), 50.02 (C9a), 44.48 (C12), 41.57
(C3), 35.12 (C10), 32.28 (C4), 19.08 (C11); m/z 354 (M+, 4%), 326
(100), 298 (51), 283 (20), 270 (17), 251 (35), 241 (80), 223 (44),
202 (58), 171 (37), 158 (52), 146 (76), 128 (33), 102 (34), 91 (20),
71 (27).
(1ꢀSR,2ꢀRS,4ꢀRS,4aꢀRS,9ꢀRS,9aꢀRS)-1ꢀ,6ꢀ-Dimethoxy-2ꢀ,9ꢀ-
epoxy-2ꢀ,3ꢀ,4ꢀ,4aꢀ,9ꢀ,9aꢀ-hexahydro-1ꢀ,4ꢀ-ethano-1ꢀH-
fluoren-4ꢀ-yl-ethanoic acid (21)
The methyl ester 20 (172 mg, 0.5 mmol) and potassium hydroxide
(560 mg, 10 mmol, 20 eq.) were dissolved in ethanol (12 ml) and
water (3 ml). The reaction mixture was stirred at room temperature
for 6 h. Ice (80 g) was then added and the mixture was acidified
with 1 M HCl (15 ml) and extracted with chloroform (5 × 20 ml).
The organic phase was dried over sodium sulfate. After filtration,
the solvent was removed under reduced pressure and the residue
was purified by flash chromatography on silica gel (ethyl acetate)
to afford the acid 21 (153 mg, 92.7%), after recrystallisation from
ethyl acetate, as colourless needles; mp 189–190 ◦C (from EtOAc);
found: C, 68.65%; H, 6.67%. Calc. for C19H22O5: C, 69.07%; H,
(3aSR,5SR,5aRS,6RS,10bRS,10cRS,10eRS)-5,9-Dimethoxy-
6,11-epoxy-2-oxo-2,3,3a,4,5,5a,6,10b-octahydro-5,10c-ethano-
1H-cyclopenta[c]-fluorene (22)
A
solution of diazoketone 10 (3 mg, 0.0085 mmol) in
dichloromethane (2 ml) was added to a suspension of Rh2
(mandelate)4 (0.2 mg) in dichloromethane (2 ml) at reflux. After
the addition, the resulting mixture was stirred at reflux for a further
10 min. One drop of DBU was added and stirring was continued
for another 2 min. After removal of the solvent, the residue was
purified by flash chromatography on silica gel (ethyl acetate) to
afford an inseparable mixture of C–H insertion products (3aa :
3ab = 2 : 1; 1.3 mg, 46.9%) as a colourless oil.
6.71%; mmax/cm−1 3500 (OH), 3000 (ArH), 2950 (CH), 1705 (C O),
=
1248 (ArOCH3), 1200 (C–O), 1085 (ArOCH3), 1030 (ArOCH3);
dH (300 MHz, CDCl3) 7.35 (1H, d, J = 8.2 Hz, H-8), 6.92 (1H,
d, J = 2.2 Hz, H-5), 6.79 (1H, dd, J = 2.2, J = 8.2 Hz, H-7),
5.27 (1H, d, J = 5.1 Hz, H-9), 4.17 (1H, d, J = 7.2 Hz, H-2),
3.77 (3H, s, CH3O-C6), 3.65 (3H, s, COOCH3), 3.44 (1H, d, J =
8.8 Hz, H-4a), 3.28 (3H, s, CH3O-C1), 3.03 (1H, dd, J = 5.0, J =
8.8 Hz, H-9a), 2.47 (1H, d, J = 14.5 Hz, H-12A), 2.12 (1H, d,
J = 14.5 Hz, H-12B), 1.98 (3H, m), 1.70 (1H, m), 1.67 (1H, dd,
J = 7.2, J = 15.2 Hz, H-3a), 1.25 (1H, dd, J = 2.5, J = 15.2 Hz,
H-3b); dC (75 MHz, CDCl3) 174.15 (COO), 159.94 (C6), 145.88
(C4b), 136.41 (C8a), 125.83 (C8), 113.17 (C7), 111.96 (C5), 84.06
(C9), 83.23 (C1), 77.51 (C2), 55.14 (CH3O-C6), 51.25 (C4a), 50.95
(CH3O-C1), 49.80 (C9a), 41.13 (C3), 40.46 (C4), 33.77 (C12), 31.98
(C10), 18.86 (C11); m/z 330 (M+, 100%), 312 (2), 298 (4), 286 (60),
270 (14), 255 (50), 241 (60), 227 (12), 211 (16), 202 (74), 171 (18),
158 (34), 145 (24), 128 (10), 102 (11), 79 (5).
Major isomer. dH (300 MHz, CDCl3) 7.38 (1H, d, J = 8.3 Hz,
H-7), 6.82 (1H, dd, J = 2.3, J = 8.3 Hz, H-8), 6.62 (1H, d, J =
2.3 Hz, H-10), 5.27 (1H, d, J = 5.4 Hz, H-6), 4.34 (1H, d, J =
8.5 Hz, H-11a), 3.79 (3H, s, CH3O-C9), 3.33 (3H, s, CH3O-C5),
3.11 (1H, dd, J = 1.8, J = 8.7 Hz, H-10b), 3.02 (1H, ddd, J = 1.7,
J = 5.4, J = 8.7 Hz, H-5a), 2.70–2.55 (2H, m), 2.45–2.30 (2H, m),
2.25 (1H, m), 1.93–1.60 (3H, m), 1.54 (1H, ddd, J = 2.0, J = 8.5,
J = 13.9 Hz, H-12a).
Minor isomer. dH (300 MHz, CDCl3) 7.38 (1H, d, J = 8.3 Hz,
H-7), 6.82 (1H, dd, J = 2.3, J = 8.3 Hz, H-8), 6.62 (1H, d, J =
2.3 Hz, H-10), 5.36 (1H, d, J = 5.4 Hz, H-6), 4.13 (1H, dd, J = 1.7,
J = 8.5 Hz, H-11a), 3.79 (3H, s, CH3O-C9), 3.32 (3H, s, CH3O-
C5), 3.22 (1H, dd, J = 1.8, J = 8.7 Hz, H-8), 3.16 (1H, ddd, J =
1.7, J = 5.4, J = 8.7 Hz, H-5a), 2.90–1.50 (9H, m).
(1SR,2RS,4RS,4aRS,9RS,9aRS)-4-(3ꢀ-Diazo-2ꢀ-oxopropyl)-
1,6-dimethoxy-2,9-epoxy-2,3,4,4a,9,9a-hexahydro-1,
4-ethano-1H-fluorene (10)
Sodium hydride (60% in mineral oil, 80 mg, 2 mmol, 6 eq.) was
washed with anhydrous THF (3 times). The acid 21 (110 mg,
2634 | Org. Biomol. Chem., 2007, 5, 2627–2635
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©

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(2RS,3RS,3aRS,10aRS,10bRS)-3,7-Dimethoxy-2,4-epoxy-
1,2,3,3a,4,5-hexahydro-10H,10bH-3,10a-ethanocyclohept[bc]-
acenaphthylen-9-one (23)
2 N. Sun, Z. Xue, X. Liang and L. Huang, Acta. Pharm. Sin., 1979, 14,
39.
3 J. Du, C. M.-H and R.-L. Nie, J. Nat. Prod., 1999, 62, 1664.
4 S. Kang, S. Cai and L. Teng, Acta. Pharm. Sin., 1981, 16, 867.
5 B. Frey, L. N. Mander and D. C. R. Hockless, J. Chem. Soc., Perkin
Trans. 1, 1998, 1555.
6 D. H. Rogers, B. Frey, F. S. Roden, F.-W. Russkamp, A. C. Willis and
L. N. Mander, Aust. J. Chem., 1999, 52, 1093.
7 B. Frey, A. P. Wells, F. S. Roden, T. D. Au, D. C. R. Hockless, A. C.
Willis and L. N. Mander, Aust. J. Chem., 2000, 53, 819.
8 J. Koo, J. Am. Chem. Soc., 1953, 75, 1891.
9 G. H. Posner, A. Haces, W. Harrison and C. M. Kitner, J. Org. Chem.,
1987, 52, 4836.
10 M. P. Doyle, V. Bagheri, T. J. Wandless, N. K. Harn, D. A. Brinker,
C. T. Eagle and K.-L. Loh, J. Am. Chem. Soc., 1990, 112, 1906.
11 J. C. Morris, L. N. Mander and D. C. R. Hockless, Synthesis, 1998,
455.
A solution of the diazoketone 10 (21 mg, 0.06 mmol) in toluene
(5 ml) was added dropwise to a solution of copper(II) bis(N-tert-
butylsalicylaldiminato) (3 mg) in toluene (3 ml) at reflux. After the
addition, the resulting mixture was stirred at reflux for a further
15 min. The reaction mixture was cooled to room temperature a◦nd
one drop of DBU was added. After stirring for 30 min at 40 C
(oil bath), the solvent was removed and the residue was purified
by flash chromatography on silica gel (petroleum ether 40–60 ◦C :
ethyl acetate = 1 : 1 → 1 : 5 → 0 : 1) to afford the product 23
(5.8 mg, 30%) as a yellow oil; mmax/cm−1 2924 (CH), 1730 (C O),
=
12 E. J. Corey and A. G. Myers, J. Am. Chem. Soc., 1985, 107,
=
=
1660 (C O), 1245 (CC OC); dH (300 MHz, CDCl3) 5.91 (1H, s,
H-8), 5.44 (1H, dd, J = 2.6, J = 5.6 Hz, H-6), 4.89 (1H, d, J =
3.7 Hz, H-4), 4.07 (1H, d, J = 5.0 Hz, H-2a), 3.50 (3H, s, CH3O-
C7), 3.30 (3H, s, CH3O-C3), 3.11 (1H, d, J = 10.2 Hz, H-10b), 3.01
(1H, m, H-5a), 2.87 (1H, dd, J = 3.8, J = 9.9 Hz, H-3a), 2.10–1.85
(3H, m), 1.70–1.45 (6H, m); dC (75 MHz, CDCl3) 197.37 (C9,CO),
155.47 (C7), 148.49 (C4a), 143.76 (C10c), 130.04 (C8a), 120.77
(C8), 94.75 (C6), 84.55 (C4), 83.67 (C3), 78.32 (C2), 55.82 (CH3O-
C7), 50.29 (C10b), 49.39 (CH3O-C3), 47.43 (C10a), 45.57 (C3a),
38.69 (C12), 34.16 (C11), 33.99 (C10), 32.00 (C5), 19.18 (C1); m/z
326 (M+, 94%), 325 (100), 310 (7), 295 (8), 281 (14), 265 (20),
249 (44), 237 (20), 224 (65), 211 (24), 178 (10), 167 (7), 158 (23),
139 (9), 128 (11), 115 (18), 91 (5), 71 (10).
5574.
13 H. Zhang, D. C. Appels, D. C. R. Hockless and L. N. Mander,
Tetrahedron Lett., 1998, 39, 6577.
14 L. N. Mander and T. P. O’Sullivan, Synlett, 2003, 9, 1367.
15 J. Fried and R. C. Elderfield, J. Org. Chem., 1941, 6, 577.
16 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
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