Norcaradienes from the intramolecular cyclopropanation reactions of diazomethyl ketones. Valuable intermediates for the synthesis of polycyclic diterpenes

Article abstract of DOI:10.1055/s-1998-5932

The intramolecular cyclopropanation reactions of the aromatic ring in tetrahydronaphthyl diazomethyl ketones initiated by rhodium(II) and copper(II) derived transition metal catalysts afford stable norcaradiene products. Further elaboration has led to pentacyclic structures that have considerable potential for the expeditious synthesis of complex polycyclic diterpenes.

Full text of DOI:10.1055/s-1998-5932

SYNTHESIS
April 1998
455
Norcaradienes from the Intramolecular Cyclopropanation Reactions
of Diazomethyl Ketones. Valuable Intermediates for the Synthesis
of Polycyclic Diterpenes
Jonathan C. Morris,b Lewis N. Mander*a and David C. R. Hocklessa
a
Research School of Chemistry, Institute of Advanced Studies, Australian National University, Canberra, A.C.T. 0200, Australia
Fax: +61(2)62495995; E-mail: mander@rsc.anu.edu.au
Department of Chemistry, University of Canterbury, Christchurch, New Zealand
Fax +64(3)3642110; E-mail: j.morris@chem.canterbury.ac.nz
b
Received 5 September 1997
Dedicated to Professor Dieter Seebach on the occasion of his 60th birthday
Abstract: The intramolecular cyclopropanation reactions of the
aromatic ring in tetrahydronaphthyl diazomethyl ketones initiated
by rhodium(II) and copper(II) derived transition metal catalysts
afford stable norcaradiene products. Further elaboration has led to
pentacyclic structures that have considerable potential for the
expeditious synthesis of complex polycyclic diterpenes.
Key words: diazo ketones, aryl cyclopropanation, norcaradienes,
[4+2] cycloaddition
Benzenoid synthons have been used extensively in the assem-
bly of complex polycyclic natural products, their utility stem-
ming largely from their accessibility and stability, but also
from the latent functionality that is inherent in such units.1,2
The photo-initiated intramolecular 1,3-cycloadditions of alk-
enes to benzene derivatives developed by Wender, for exam-
ple, have been especially effective in allowing remarkably
short syntheses of complex target molecules,3 while in our
laboratories, the Birch reduction and the intramolecular ipso
alkylation of benzenoid moieties have been of inestimable
Scheme 2
value in the total synthesis of gibberellins.4
In order to test our basic hypothesis, diazomethyl ketone
1 (R = 6-OMe)11 was treated with rhodium(II) acetate,
thereby affording an excellent yield of the norcaradiene 2
(R = 6-OMe) (76% yield as estimated spectroscopically;
71% isolated) accompanied by the CH-insertion product,
cyclopentanone 7 (R = 6-OMe) (14% yield) (Scheme 3);
small amounts of the cyclobutanone 8 (R = 6-OMe) de-
rived from CH-insertion into the alternative benzylic po-
sition and of dihydronaphthalene 9 (R = 6-OMe) were
also obtained. Norcaradiene 2 (R = 6-OMe) was stable to
chromatography and could even be sublimed. Its structure
was readily apparent from its 13C NMR spectrum which,
inter alia, displayed resonances at δ 33.4, 42.7 and 47.1 for
the cyclopropyl resonances, and only four resonances that
could be attributed to alkene carbons. A doublet at δ 0.68
(J = 1.6 Hz) for the cyclopropyl CH resonance was ob-
served in the 1H NMR spectrum.
Scheme 1
In a continuing quest for further ways of utilising ben-
zenoid synthons in the construction of polycyclic natural
products, we have studied the intramolecular cyclopropa-
nation reactions of the aromatic ring in a series of tetrahy-
dronaphthyl diazomethyl ketones 1 initiated by transition
metal catalysts (Scheme 1). The norcaradiene products 2
were expected to be thermodynamically more stable than
the tautomeric cycloheptatrienes 3 because of the geomet-
ric constraints imposed by the bridging ring system.5,6 If
this prediction proved to be correct, and assuming that the
norcaradienes could be manipulated satisfactorily, we en-
visaged using them as precursors to a range of polycyclic
diterpenoids. We were especially attracted by the prospect
of good diastereofacial discrimination between the upper
and lower faces of such molecules. Our first targets were
the fern antheridiogens 4–6 based on the 20-norgibberel-
lane,7 9,15-cyclogibberellane8 and antheridane9 skele-
tons, respectively (Scheme 2)9 as well as possible
biosynthetic precursors to these compounds.10
A range of further tetrahydronaphthalene diazo ketones
were then examined so as to establish the scope and limi-
tations of this type of conversion. The results, summarised
in Table 1, proved to be extremely variable, the desired
norcaradiene products being formed in yields ranging
from 20–75%, depending on the substitution pattern of the
substrate 1. The norcaradienes were generally stable, ex-
cept for the 7-methoxy isomer of 2 which rearranged12 to
trienone 10 during chromatography on silica gel (Scheme
4). When lower yields of the cyclopropanated products 2

SYNTHESIS
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456
Table 1. Products from the Reactions of Tetrahydronaphthyl Diazo
Ketones with Rhodium Acetate
Substrate
Products
Entry
1a
2b
7b
8b
9
R=H
41 (39)
41 (34)
76 (71)
51 (46)c,d
24 (21)
46 (41)
45 (41)
16 (14)
49 (44)
57 (56)
33 (31)
32 (30)
7 (–)
6 (–)
1
2
3
4
5
6
7
R=5-OMe
R=6-OMe
R=7-OMe
R=8-OMe
7 (–) 11(–)
23 (20)
R=6,7-diOMe 66c
R=6,8-diOMe 39c
a
All reactions carried out with 2 mol% of catalyst in dichloro-
methane at reflux unless otherwise indicated.
Yields are based on NMR spectra of total reaction mixtures; yields
in parentheses are of isolated compounds.
Unstable to chromatography.
The indicated yield is that of 10.
b
Scheme 3
c
d
were obtained, these outcomes were mainly due to the for-
mation of greater amounts of CH-insertion products. This
was especially noticeable for the 7- and 8-methoxy deriv-
atives (entries 4 and 5). In the case of the 8-methoxy and
6,8-dimethoxy analogues, significant quantities of cy-
clobutanones 8 and dihydronaphthalenes 9 were also ob-
tained.
tion may not necessarily be concerted with hydride transfer,
especially where cyclobutanone formation would be in-
volved. Hydride transfer in advance of C–C bond
formation17 may then lead to fragmentation, with loss of
ketene as outlined in Scheme 5. In order to obtain evidence
for the formation of ketene, the solvent (CH2Cl2) from one
reaction mixture obtained from 1 [R = 6,8-(OMe)2] was
quickly distilled into a sample of p-toluidine, resulting in
the formation of the acetamide derivative.
Scheme 5
Nevertheless, these competing processes do not appear to
account fully for the low yield of cyclopropanation in the
case of the 8-methoxy derivative (entry 5), a result that
was especially discouraging, given that we regarded this
substitution pattern as being the most useful for further
synthetic development (vide infra). Although one might
invoke steric inhibition by the peri methoxy substituent,
this explanation is less than convincing. An examination
of models, however, reveals that in the transition state for
the cyclopropanation reaction, the methoxy substituent is
eclipsed with one of the neighbouring benzylic hydro-
gens, whereas these benzylic hydrogens and the methoxyl
are staggered in the competing CH-insertion process lead-
ing to 7 (R = 5-OMe).
Scheme 4
Although yields of the norcaradienes generally appear to
be enhanced by higher electron densities associated with
methoxy substitution, these same substituents could also
be expected to promote CH-insertion at benzylic posi-
tions, since a concerted 3-membered transition state is
postulated in which the C–C bond being formed is po-
larised towards the metallocarbene.13 Insertion could be
expected to become a more dominant pathway when such
electronic factors coincide with the formation of a 5-mem- Attempts to steer the reaction towards higher levels of cy-
bered ring,14 as in the case of the 7-methoxy isomer (entry clopropanation with different rhodium catalysts were ex-
4). The impact of benzylic activation is also apparent with amined next, but were not productive. Competitive
the formation of cyclobutanones from the 8-methoxy15 intramolecular experiments by Padwa, Doyle and co-
and 6,8-dimethoxy16 derivatives. The formation of signif- workers18 have shown that the use of rhodium perfluo-
icant amounts of alkenes 9 from these substrates, however, robutyrate [Rh2(pfb)4] favours aromatic cyclopropanation
indicates that with sufficient activation, C–C bond forma- over CH-insertion in diazo acetamides, but conversely,

SYNTHESIS
April 1998
457
only CH-insertion was observed with alkene substituted The problem of competing CH-insertion could be solved
diazo ketones. With amide based catalysts, however, com- by substituting a carbonyl function for the 4-methylene
plementary outcomes were obtained. For example, with group as outlined in Scheme 6, whereby the yields of cy-
rhodium(II) caprolactam dimer [Rh2(cap)4], CH-insertion clopropanation could be elevated above 60%, although in
was preferred over aromatic cyclopropanation in aryl di- these cases it was important to use rhodium mandelate,19
azo amides, but only cyclopropanation occurred with the rather than rhodium acetate. In order to obtain a more gen-
alkene substituted diazo ketones. Unfortunately, there eral solution, however, we turned to the use of copper cat-
was no direct precedent for our type of substrate. In the alysts, using diazo ketone 1 (R = 8-OMe) as the test
event, the use of both Rh2(cap)4 and Rh2(pfb)4 afforded substrate. Although treatment with copper bronze, cop-
lower yields of norcaradienes 2 in all cases (Table 2). The per(I) iodide, copper(I) chloride, trimethoxyphosphi-
ratio of cyclopropanation to CH-insertion for diazo ketone nocopper(I) chloride, bis(N-tert-butylsalicylaldiminato)
1 (R = 6-OMe) after substituting Rh2(pfb)4 for Rh2(OAc)4, copper(II) and copper(II) triflate afforded generally poor
for example, was essentially reversed. As might have yields (11–35%), Cu(II)(acac)2 gave an acceptable result
been expected, dirhodium(II) tetrakistriphenylacetate (66%). Moreover, the reaction was relatively insensitive
[Rh2(TPA)4]19 also favoured higher levels of CH-inser- to the substitution pattern of the diazo ketone 1, and simi-
tion (Table 3).
lar yields of the other cyclopropyl ketones 2 were also ob-
tained with this reagent (Table 4).
Table 2. Products from the Reactions of Tetrahydronaphthyl Diazo
Ketones with Rhodium Caprolactam [Rh2(cap)4] and Rhodium Per-
fluorobutyrate [Rh2(pfb)4]
Table 4. Products from the Reactions of Tetrahydronaphthyl Diazo
Ketones with Cu(acac)2
Substrate
Products
Substratea
Products [Rh2(cap)4]b
Products [Rh2(pfb)4]b
1a
2b
7b
6 (5)
12 (8)
10 (7)
5 (3)
1
2
7
2
7
R=H
56 (55)
56 (55)
65 (61)
65c
R=H
11
10
55
21
0
70
65
29
76
70
R=5-OMe
R=6-OMe
R=7-OMe
R=8-OMe
R=5-OMe
R=6-OMe
R=7-OMe
R=8-OMe
17
19
76
70
66 (65)
7 (6)
a
All reactions carried out with 2 mol % of catalyst in dichloroethane
at reflux unless otherwise indicated.
Yields are based on NMR spectra of total reaction mixtures; yields
in parentheses are of isolated compounds.
a
All reactions carried out with 2 mol% of catalyst in dichloromethane
at reflux unless otherwise indicated.
Yields are based on NMR spectra of total reaction mixtures.
b
c
b
Unstable to chromatography.
Table 3. Products from the Reactions of Tetrahydronaphthyl Diazo
Ketones with Rhodium Triphenylacetate [Rh2(TPA)4].
The norcaradienes all reacted when exposed to acid
(Scheme 7). Aqueous conditions led to high yields of oxo
dienones, whereas on exposure to Lewis acids under an-
hydrous conditions, the initial fragmentation of the 3-
membered ring was followed by rearrangement, as ob-
served earlier for the 7-methoxy analogue. The behaviour
of 2 (R = 7-OMe) is typical (Scheme 4). While 13 may be
obtained more directly by treatment of the original diazo
Substrate
Products
1a
2b
7b
8b
R=H
34 (31)
41 (32)
52 (51)
10c
48 (46)
50 (45)
45 (38)
89 (81)
73 (70)
trace
5 (4)
23 (17)
R=5-OMe
R=6-OMe
R=7-OMe
R=8-OMe
0
a
All reactions carried out with 2 mol% of catalyst in dichloromethane
at reflux unless otherwise indicated.
Yields are based on NMR spectra of total reaction mixtures; yields
in parenthesis are of isolated compounds.
b
c
Unstable to chromatography.
Scheme 7
Scheme 6

SYNTHESIS
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458
ketone 1 (R = 6-OMe) with trifluoroacetic acid,11 there ly as the use of Lewis acids as catalysts was almost cer-
could be advantages in the two step procedure with other tainly proscribed. It was therefore decided first to prepare
substrates. The similarity between 14 and the B-C-D ring 16 and examine its reaction with maleic anhydride
system of the scopadulcic acids20 may also offer useful (Scheme 9). The formyl substituted acid 18 is readily
synthetic utility with alternative skeletons. Nevertheless, available in only
3
steps from 1,6-dimethoxy-
to preserve the cyclopropyl ketone moiety in this type of naphthalene22 and was readily converted by means of the
intermediate through subsequent steps, it was clear that Wittig reaction into the vinyl derivative 19. Since the vi-
reaction conditions should be neutral or basic.
nyl group in 19 did not withstand the reagents required by
the more usual acyl chloride route, diazo ketone 15 was
first obtained by treatment of the mixed carbonate anhy-
dride with diazomethane. Unfortunately, this reaction was
somewhat sluggish and the extended reaction times led to
partial addition of the diazomethane to the styryl double
bond.23 We have subsequently developed a modified
route via the acid chloride that is more satisfactory, how-
ever (see Experimental Section).24 Treatment of 15 with
Cu(acac)2 afforded norcaradiene 16 in a crude yield of ca.
75%, but purification was accompanied by significant
losses, and so it became standard practice to carry out any
subsequent cycloadditions on the crude product in situ. In
this way, a yield of ca. 70% for the two steps was often ob-
tained with more reactive dienophiles. In the case of ma-
leic anhydride, a single, stereochemically homogeneous
adduct was obtained in high yield after a four hour reflux
in benzene.
Given the propensity of the norcaradienes to fragment un-
der acidic conditions, our plans to elaborate these com-
pounds further to the target diterpenes 4–6 tended to focus
on pericyclic processes. In particular, it appeared that the
[4+2] cycloaddition21 of an acrylate derivative (or syn-
thetic equivalent thereof) to a vinyl substituted derivative
such as 16 should allow the addition of the elements of the
A-ring, assuming that the more exposed vinylcyclohexene
moiety would function as the operational diene, rather
than the intra-annular diene. The choice of the 8-methoxy
analogue was made to allow subsequent manipulation of
the B-ring, and in the expectation that it would provide vi-
nylogous activation of the “diene”and favour an “ortho
adduct”. With the reasonable presumption that endo ad-
ducts would normally be kinetically preferred over the exo
isomers, and that the upper face of the triene would be ef-
fectively shielded by the hydrogen atom attached to the
cyclopropyl ring, it then appeared a reasonable expecta-
tion that transition state B‡ should be favoured over tran-
sition state A‡ (Scheme 8). In this way, the crucial syn
stereochemical relationship between the D-ring and H-6a
would be established.
Scheme 9
Spectroscopic analysis was consistent with structure 20.
In particular, infrared absorptions at 1850 and 1780 cm–1
confirmed the presence of the anhydride, while the car-
bonyl absorption at 1720 cm–1 was consistent with a cy-
clopropyl ketone. Interestingly, the base peak in the mass
spectrum was m/z 228, which may be presumed to occur
by the loss of maleic anhydride through a retro-Diels–Al-
der process. The 1H NMR spectrum showed a doublet at
δ 1.74 (J = 2.0 Hz) which was assigned to the cyclopropyl
proton H-4a. An alkenic proton at δ 6.18 (H10), and the
absence of resonances for the terminal vinyl group, con-
firmed that the Diels–Alder reaction had indeed occurred
with the more exposed terminal diene. A doublet at δ 4.58
(J = 4.6Hz) and a methoxy signal at δ 3.68 were consistent
with an intact enol ether moiety, which gave rise to char-
acteristic resonances at δ 89.1 ppm (C6) and 153.0 ppm
(C5) in the 13C NMR spectrum. This spectrum also re-
vealed the presence of the anhydride carbonyls (δ 170.2
Scheme 8
Given the expected lability of 16, one major concern for
the success of the Diels–Alder reaction was the relatively
low reactivity of acrylic esters in such processes, especial-

SYNTHESIS
April 1998
459
and δ 173.9 ppm) and the three high field cyclopropane Having established that the Diels–Alder reaction between
carbons (δ 34.3, 36.8, and 40.2 ppm). With the gross the norcaradiene 16 and maleic anhydride had gone as
structure of the adduct 20 established, it was important to planned, we turned our attention to the potentially more
determine the stereochemistry of the molecule, especially useful methyl acrylate as the dienophile. The reaction was
with regard to the relationship between the configuration complete after a 24 hour reflux in benzene, affording an
at C-6a and the cyclopropane ring. From a double-quan- inseparable and unstable mixture of diastereomers, hy-
1
tum filtered H–1H correlation spectroscopy experiment drolysis of which afforded a diastereomeric mixture of di-
(DQFCOSY),25 a doublet at δ 1.78 (J = 12Hz) could be as- ones in 62% yield for the three steps. Examination of the
1
signed to H-11α since it showed only one strong cross alkenic region of the H NMR spectrum of the reaction
peak to a multiplet at δ 2.76 that obviously arose from the product revealed four signals (δ 5.77, 5.80, 6.02, 6.08) in
geminal proton H-11β. This signal, in turn, had a cross- the ratio of 60:11:18:10, respectively. The major diaste-
peak to a multiplet at δ 2.24, which must therefore be reoisomer was obtained in high purity after two recrys-
H-3. Apart from the expected moderately strong cou- tallisations from diethyl ether/hexane. The 13C NMR
plings to both of the H-2 protons, H-3 had a small cross spectrum confirmed the presence of the cyclopropane ring
peak to the signal for the cyclopropyl proton (H-4a) at δ (δ 29.2, 45.2 and 48.0 ppm), the ester functionality (δ 51.8
1.74, thereby explaining the small coupling constant for and 173.5 ppm) and the two carbonyl groups (δ 203.7 and
H-4a observed in the 1D experiment. This small W-cou- 210.9 ppm), but overlapping signals in the 1H NMR spec-
pling has been observed in several 9,15-cyclogibberellin tra prevented a reliable structural analysis, even with
derivatives.26 The alkenic signal (H-10) at δ 6.18 was cou- DQFCOSY and psNOESY spectra at 500 MHz. However,
pled to H-9α and H-9β (δ 2.22 and δ 2.92, respectively) it appeared safe to assume that the major product would
which were coupled to one another and to a signal at δ result from endo addition of the dienophile anti to the cy-
3.44, assigned as H-8. A cross peak from H-8 to a multip- clopropane ring (as for the maleic anhydride reaction) and
let at δ 3.37 allowed this signal to be attributed to H-7, and would therefore have structure 21. To substantiate this
then a cross peak to the complex multiplet at δ 2.98 al- conclusion, 21 was treated with 0.2 M sodium methoxide
lowed this last resonance to be determined as H-6a, con- for 72 hours, affording a 95:5 mixture in which the minor
firmed by cross peaks to the enol ether proton (H-6) and compound was unchanged starting material and the new
to H-10 (allylic coupling). With most protons assigned, product corresponded to one of the minor diastereoiso-
our attention turned next to the determination of relative mers in the original mixture (Scheme 10).
stereochemistry.
In a psNOESY spectrum,25 a cross peak between H-4a and
H-6a confirmed that the dienophile had added anti to the
cyclopropyl ring system, thereby establishing the desired
relative stereochemistry between the A,B-ring fusion and
the D-ring. A reasonably strong NOE27 between H-6a and
H-7, together with a weaker one between H-6a and H-8,
provided strong evidence for the anti relationship of the an-
hydride moiety to H-6a, i.e. corresponding to an endo ad-
duct. These stereochemical assignments were finally
Scheme 10
confirmed by single crystal X-ray crystallographic analysis.
Interestingly, the cycloadduct crystallised as a conglomer-
ate.28 From the space group and inspection of the unit cell,
only one enantiomer, corresponding to the antipode of 20,
was present in the selected crystal (Figure 1).
This epimerisation was consistent with the expectation
that the kinetic endo isomer 21 was the major product and
that its isomerisation to the thermodynamically more sta-
ble exo product 22 had taken place. In the context of pos-
sible total syntheses, the configuration of the ester group
was not important, as there are good precedents to indicate
that C-methylation at C-7 should proceed with the desired
stereoselectivity to establish the correct configuration for
the kaurenoid diterpenes.29 However, we sought an alter-
native dienophile that might provide a more direct synthe-
sis of such compounds. Methyl methacrylate proved, not
surprisingly, to be totally unreactive; after 72 hours in
benzene at reflux, no trace of a Diels–Alder adduct was
detected. Regardless of the issue of low reactivity, without
catalysis, methyl methacrylate and its analogues often
give endo/exo-mixtures in which the exo isomers predom-
inate.30 We therefore turned our attention to the use of ci-
traconic anhydride as the dienophile in the hope that it
might serve as an acceptable surrogate for methacrylate
derivatives. We assumed that hyperconjugation from the
Figure 1

SYNTHESIS
Papers
460
methyl group would attenuate the activation from the less The synthetic strategy described in this paper has led in
substituted acyl group and that the regiochemistry of the only seven steps to advanced intermediates for the synthe-
cycloaddition would therefore be directed by the other sis of kaurenoid diterpenoids with excellent stereochemi-
carbonyl function to give the desired 7-methyl isomer.
cal control. Subsequent studies have furnished (±)-GA73
methyl ester (4) and (±)-GA103 (1-desoxy-5) in only 8 and
12 steps, respectively, from 23.24 The C-8 acyl group was
deleted in both cases, establishing, in the process, citra-
conic anhydride as an endo-selective synthetic equivalent
for 2-methylacrylic acid in [4+2] cycloadditions. The en-
hanced reactivity, high yields and stereochemical control
with this reactant more than compensate for the additional
steps required to delete the superfluous carboxy group.
For other synthetic targets, the 8-carboxy group could be
used to introduce A-ring substituents. Reliable methodol-
ogy for the stereocontrolled introduction of substituents at
C-10 (kaurene numbering, equivalent to C-10a in 23) has
been established on similar structures17a,31 and so targets
based on the full kaurenoid skeleton should also be avail-
able by application of the strategy described in this paper.
Minor variations in the substitution pattern of the initial
substrates could allow access to atisane, stemarane and
thyrsiflorane skeletons as well,32 and although the present
study has been conducted with racemates, good method-
ology for the enantioselective synthesis of tetralin carbox-
ylic acids is available.33
In the event, an overnight reaction of 16 with citraconic
anhydride at room temperature afforded a 76% yield (two
steps) of a single adduct, tentatively identified as 23.
Apart from the additional signal at δ 1.57 for the methyl
1
group, the H NMR spectrum was similar to that of the
maleic anhydride adduct, although there were significant
differences in the relative chemical shifts of H-6a and H-
8: δ 2.66 and δ 3.02, respectively, in the putative 23, com-
pared with δ 2.98 and δ 3.44 in 20. It was apparent from
NOEs to H-6a and H-8 that the methyl group was located
at C-7, and that an endo adduct had been obtained. The ab-
sence of an NOE interaction between H-4a and H-6a (as
had been observed in the spectrum of the maleic anhy-
dride adduct), however, raised the possibility that the di-
enophile might not have added anti to the cyclopropane
ring. The correct explanation emerged with the observa-
tion of a small NOE interaction between H-9β and H-6a,
as well as a moderate one between H-8 and H-9α. These
interactions would only be possible if the A-ring was in a
boat conformation, but in this case, H-4a and H-6a would
be well separated in space, so that an NOE interaction
would be unlikely. Such an interaction would only be pos-
sible in the alternative twist-chair conformation (Figure
2). Fortuitously, it was found that when the 1H NMR spec-
trum was recorded in d6-acetone, it was even more similar
to that of the maleic anhydride adduct, with H-6a and H-8
now at δ 2.78 and δ 3.30, respectively. Most importantly,
an NOE between H-4a and H-6a could now be discerned,
thus confirming the structure of the new cycloadduct as
the anti adduct 23. Thus, it appears that when 23 is dis-
solved in CDCl3, the A-ring adopts a boat conformation,
leading to significant spatial separation of H-4a and H-6,
whereas in d6-acetone, it is more favourable for the A-ring
to adopt a twist-chair conformation in which H-4a and
H-6 are sufficiently close as to lead to the observed NOE.
Notes on Nomenclature
The nomenclature system used in this paper conforms to
the indexing policies of the Chemical Abstracts Service
(CA Index Guide, Appendix IV), which are generally in
accordance with the rules published by the International
Union of Pure and Applied Chemistry (IUPAC). The par-
ent structures for the compounds named in the Experi-
mental Section are:
1H-3,4b-methanocycloprop[1,2:1,3]dibenzene
5,8-methano-1H-benzocycloheptene
Cyclobuta[a]naphthalene
4a,7-methano-4aH-benzocycloheptene
1H-3,4b-methanobenzo[1,3]cycloprop-
[1,2-a]napthalene
Figure 2

SYNTHESIS
April 1998
461
Melting points were recorded on a Reichert hot-stage and are uncor-
rected. Microanalyses were carried out by the Australian National
University Analytical Services Unit, Canberra. Low resolution EI
mass spectra (70 eV) and high resolution accurate mass measure-
ments were recorded on a VG Micromass 7070F double focussing
mass spectrometer. Infrared spectra were recorded on a Perkin-Elmer
683 infrared spectrophotometer in 0.25 mm NaCl solution cells with
corded. The ratio of products was determined by integration of select-
ed resonances. The oily product was chromatographed using MPLC
with EtOAc/hexane mixtures as eluents to afford the products.
(4aRS,7SR)-3-Methoxy-5,6-dihydro-4a,7-methano-4aH-benzocyclo-
hepten-8(7H)-one (10):
This material was isolated as a yellow gel.
CHCl3 as solvent unless otherwise stated. H and 13C NMR spectra
1H NMR (CDCl3, 300 MHz): δ = 1.50 (m, 1 H, H-10), 1.75–1.95 (m,
4 H, H-5 × 2 and H-6 × 2), 2.28 (m, 1 H, H-10), 3.08 (m, 1 H, H-7),
3.61 (s, 3 H, MeO), 4.87 (d, J = 1.7 Hz, 1 H, H-3), 5.82 (s, 1 H, H-9),
6.21 (dd, J = 1.7, 9.5 Hz, 1 H, H-2), 6.29 (d, J = 9.5 Hz, 1 H, H-1).
13C NMR (CDCl3, 75 MHz): δ = 23.2 (CH2), 38.5 (CH2), 48.1 (C-4a),
49.7 (C-10), 52.4 (C-7), 54.5 (MeO), 105.1 (C-4), 123.6 (C-9), 126.1
(C-2), 130.8 (C-1), 151.9 (C-9a), 164.3 (C-3), 203.0 (C-8).
MS (EI, 70eV): m/z (%) = 202 (M+, 6%), 188 (47), 160 (27), 147 (74),
132 (17), 117 (41), 91 (86), 77 (46), 65 (52), 51 (100).
IR (K Br): v = 2950, 1670, 1565 cm–1.
1
were recorded on the following instruments: Varian Gemini 300 at
300 MHz, Varian VXR300 at 300 MHz and Varian VXR500 at
500 MHz. Distortionless enhancement by polarisation transfer
(DEPT) and the attached proton test (APT) were used in the assign-
ment of carbon spectra.25 2D NMR experiments included homonucle-
ar (1H/1H) correlation spectroscopy (COSY), double quantum filtered
homonuclear (1H/1H) correlation spectroscopy (DQFCOSY), hetero-
nuclear (1H/13C) correlation spectroscopy (HETCOR) and phase sen-
sitive Nuclear Overhauser and exchange spectroscopy (PS-1H/1H-
NOESY).25 All organic extracts were dried with anhydrous Na2SO4.
Flash chromatography was conducted on Merck Kieselgel 60. Medi-
um pressure liquid chromatography (MPLC) was conducted using a
CfG Prominent Duramat pump, a Waters Associate Differential Re-
fractometer R40 diffractometer and Merck Lobar Fertigsäule Größe
LiChroprep Si60 (40–63 mm) columns.
HRMS (EI) calcd for C13H14O2: 202.0994, found 202.0994.
5,7-Dimethoxy-1,2-dihydronaphthalene [9, R = 5,7-(OMe)2]:
This compound, obtained from diazo ketone 1 [R = 6,8-(OMe)2], was
isolated as a clear oil.50
1H NMR (CDCl3, 300 MHz): δ= 2.26 (m, 1 H, H-2), 2.73 (t, J = 8.2
Hz, 1 H, H-1), 3.81 (s, 3 H, MeO), 5.90 (dt, J = 4.4, 9.6 Hz, 1 H, H-
3), 6.31 (s, 2 H, H-6 + H-8), 6.75 (dt, J = 1.8, 9.6 Hz, 1 H, H-4).
13C NMR (CDCl3, 75 MHz): δ = 22.8 (C-1), 28.5 (C-2), 55.3 (MeO),
55.5 (MeO), 96.3 (C-4), 104.8 (C-3), 121.2 (C-8 + C-6), 124.8 (C-8a),
138.1 (C-4a), 155.8 (C-5), 159.1 (C-7).
Rhodium(II) acetate [Rh2(OAc)4], copper(II) trifluoromethane-
sulfonate [Cu(OTf)2] and copper bronze were purchased from the Al-
drich Chemical Company and were used as supplied. Rhodium(II)
caprolactam [Rh2(cap)4]13b and rhodium(II) perfluorobutyrate
[Rh2(pfb)4]34 were kindly supplied by Professor Michael Doyle of
Trinity University. The following catalysts were prepared by litera-
ture procedures: copper(I) chloride,35 copper(I) iodide,36 copper(II)
(t-butylsalicylimidato)2 [Cu(TBS)2],37 rhodium(II) [S-(+)-mandelate]
[Rh2(mand)4],38 rhodium(II) triphenylacetate [Rh2(TPA)4],19 cop-
per(II) acetylacetonate [Cu(acac)2],39 and copper(I) chloride trimeth-
yl phosphite [CuCl.P(OMe)3].40
MS (EI, 70eV): m/z (%) = 190 (M+, 100%), 175 (40), 159 (20), 147
(15), 115 (28), 103 (10), 91 (9), 77 (46), 77 (8), 63 (3), 51 (3).
Rearrangement of Norcaradiene 2 [R = 6,7-(OMe)2]:
When the mixture from the reaction of diazo ketone 1 [R = 6,7-
(OMe)2] was chromatographed on silica gel, norcaradiene 2 [R = 6,7-
(OMe)2] rearranged to (4aRS,7SR)-2,3-dimethoxy-5,6-dihydro-4a,7-
methano-4aH-benzocyclohepten-8(7H)-one.
Preparation of Carboxylic Acids:
This material was isolated as a yellow gel and was identical to an au-
The following carboxylic acids were prepared by literature proce-
dures; 1,2,3,4-tetrahydro-2-naphthoic acid,41 5-methoxy-1,2,3,4-
tetrahydro-2-naphthoic acid,42 6-methoxy-1,2,3,4-tetrahydro-2-
thentic sample.49
1H NMR (CDCl3, 300 MHz): δ = 1.55 (m, 1 H, H-10), 1.70–1.95 (m,
4 H, H-5 × 2 and H-6 × 2), 2.23 (m, 1 H, H-10), 3.08 (m, 1 H, H-7),
3.68 (s, 3 H, MeO), 3.82 (s, 3 H, MeO), 5.02 (s, 1 H, H-1), 5.55 (s, 1
H, H-4), 5.82 (s, 1 H, H-9).
naphthoic
acid,43
7-methoxy-1,2,3,4-tetrahydro-2-naphthoic
acid,43,44 8-methoxy-1,2,3,4-tetrahydro-2-naphthoic acid,42 4-oxo-
1,2,3,4-tetrahydro-2-naphthoic acid,45 8-methoxy4-oxo-1,2,3,4-tet-
rahydro-2-naphthoic acid,46 6,7-dimethoxy-1,2,3,4-tetrahydro-2-
naphthoic acid,47 and 6,8-dimethoxy-1,2,3,4-tetrahydro-2-naphtho-
ic acid.16,48
Trapping of Ketene:
The apparatus was set up so that solvent could be distilled off
throughout the addition of the diazo ketone. The receiver flask of the
distillation apparatus contained p-toluidine (60 mg). Diazo ketone 1
[R = 6,8-(OMe)2] (75 mg, 0.289 mmol) in CH2Cl2 (4 mL) was added
via a syringe pump at a rate of 0.15 mL/min to a solution of
Rh2(OAc)4 (2 mg) in CH2Cl2 (2 mL) at reflux. Upon addition the dis-
tillation was continued for 5 min. The mixture was evaporated in vac-
uo to afford a green oil which was identical in composition to that of
the standard experiment. The distillate was diluted with CH2Cl2
(20 mL) and washed with 3M HCl solution (5 mL). The aqueous so-
lution was back-extracted (2 × 10 mL). The combined organic ex-
tracts were washed with H2O (5 mL) and brine (5 mL). Evaporation
of the solvent in vacuo gave p-methylacetanilide (6 mg, 70% of the
theoretical amount based on alkene) as a crystalline solid, mp 151–
153˚C which was identical to an authentic sample.
Preparation of Diazo Ketones:
The carboxylic acid (1 mmol) in anhyd CH2Cl2 (10 mL) was added
dropwise to oxalyl chloride (2 mL) under an N2 atmosphere. One drop
of anhyd DMF was added (evolution of gas) and the yellow solution
was stirred for 14 h. The volatile components were removed in vacuo
and anhyd benzene was added. The benzene was removed in vacuo
and the procedure repeated twice more to yield the acid chloride
(100% recovery) as a yellow oil. After 1 h on high vacuum the acid
chloride was dissolved in CH2Cl2 (10 mL) and added to fresh ethereal
CH2N2 (0.4 M, 5 equivs) at –20˚C (MeOH/ice bath) under N2. The
bright yellow solution was stirred for 15 h and filtered through Celite
in a well-ventilated fumehood. The solvent was removed in vacuo to
afford a yellow oil which was purified on silica gel using EtOAc/hex-
ane mixtures as the eluent. The diazo ketones (70–85% yield) were
usually obtained as yellow crystalline solids.
1H NMR (CDCl3, 300 MHz): δ = 2.16 (s, 3 H), 2.31 (s, 3 H), 7.11 (d,
J = 8.4 Hz, 1 H, H-2), 7.37 (d, J = 8.4 Hz, 1 H, H-3).
Hydrolysis of Methoxynorcaradiene 2 (R = 7-OMe):
Cyclopropanations; General Procedure:
Enol ether 2 (R = 7-OMe) (50 mg, 0.248 mmol) was dissolved in ac-
etone (5 mL) and H2O (0.5 mL). Aqueous HCl solution (30%,
0.5 mL) was added to the solution, which turned yellow instantly. The
solution was stirred at r.t.for 5 min and diluted with H2O (10 mL). The
solution was extracted with EtOAc (3 × 5 mL) and washed with H2O
(5 mL) and brine (5 mL) respectively. Evaporation of the solvent in
vacuo gave a brown oil which was purified by chromatography on sil-
The diazo ketone (1 mmol), in anhyd CH2Cl2 [for Rh(II) reactions] or
CH2ClCH2Cl [for Cu(II) reactions], was added via a syringe pump at
a rate of 0.15 mL/min to a solution of the catalyst (2 mole %) in
CH2Cl2 or CH2ClCH2Cl at reflux. Upon addition, the solution was re-
fluxed for 5 min and the solvent removed in vacuo (no heating). The
1
residue was dissolved in CDCl3 and the H NMR spectrum was re-

SYNTHESIS
Papers
462
Table 5. Diazo Ketones
mp
1H NMR (CDCl3)
13C NMR (CDCl3)
MS
(¡C)
δ, J (Hz)
δ
m/z (rel int., %)
1
41–43 1.90 (m, 1 H, H-3), 2.15 (m, 1 H, H-3), 2.70
(m, 1 H, H-2), 2.80–3.10 (m, 4 H, H-4, H-1),
5.40 (br s, 1 H, COCHN2), 7.15 (m, 4 H, H-
5, H-6, H-7, H-8).
(R=H)11
1
62–64 1.80 (m, 1 H, H-3), 2.15 (m, 1 H, H-3),
2.50–2.70 (m, 2 H, H-1 and H-2), 2.85–3.10
(m, 3 H, H-1, H-4 × 2), 3.82 (s, 3 H, MeO),
5.39 (br s, 1 H, COCHN2), 6.68 (d, J = 8.1
1 H, H-6), 6.74 (d, J = 7.8, 1 H, H-
22.7 (C-3), 25.8 (C-1 or C-4),
31.7 (C-4 or C-1), 45.2 (C-2),
53.7 (COCHN2), 55.1 (MeO),
107.0 (C-6), 121.1 (C-7), 121.4
(C-4a), 126.1 (C-8), 136.2 (C-8a),
157.0 (C-5), 197.4 (COCHN2).
230 (M+, 1%), 202
(54), 174 (30), 159
(100), 146 (53), 134
(37), 128 (38), 115
(81), 104 (90), 91
(79), 77 (45), 65 (44).
(R=5-OMe)
8), 7.12 (dd, J = 7.8, 8.1, 1 H, H-7).
1
51–53 1.85 (m, 1 H, H-3), 2.08 (m, 1 H, H-3), 2.62
(m, 1 H, H-2), 2.70–3.00 (m, 4 H, H-4 × 2,
H-1 × 2), 3.78 (s, 3 H, MeO), 5.40 (br s, 1 H,
COCHN2), 6.62 (d, J = 2.6, 1 H, H-5),
6.71 (dd, J = 2.6, 8.7, 1 H, H-7), 7.00 (d,
J = 8.7, 1 H, H-8).
(R=6-OMe)11
1
35–37 1.83 (m, 1 H, H-3), 2.10 (m, 1 H, H-3), 2.65
(m, 1 H, H-2), 2.70–3.10 (m, 4 H, H-1 × 2
and H-4 × 2), 3.78 (s, 3 H, MeO), 5.37 (br s,
1 H, COCHN2), 6.64 (d, J = 2.6, 1 H, H-
8), 6.71 (dd, J = 2.6, 8.4, 1 H, H-6), 7.00
(d, J = 8.4, 1 H, H-5).
26.2 (C-3), 27.5 (C-1 or C-4),
31.6 (C-4 or C-1), 45.3 (C-2),
53.6 (COCHN2), 54.9 (MeO,
112.0, 113.2 (C-6, C-8), 127.4 (C-
4a), 129.4 (C-5), 135.7 (C-8a),
157.3 (C-7), 197.2 (COCHN2).
230 (M+, 1%), 202
(46), 174 (36), 159
(100), 146 (45), 134
(58), 115 (48), 104
(27), 91 (66), 77 (38),
65 (33), 51 (45).
(R=7-OMe)
1
73–74 1.90 (m, 1 H, H-3), 2.15 (m, 1 H, H-3), 2.70
(m, 1 H, H-2), 2.80–3.10 (m, 4 H, H-4 × 2,
H-1 × 2), 5.40 (br s, 1 H, COCHN2), 6.69 (d,
J = 7.8, 1 H, H-7), 6.72 (d, J = 7.8, 1
(R=8-OMe)12
H, H-5), 7.11 (t, J = 7.8, 1 H, H-6).
1
93–95 1.80 (m, 1 H, H-3), 2.08 (m, 1 H, H-3), 2.63
(m, 2 H, H-1, H-2), 2.75–3.00 (m, 3 H, H-1,
H-4 × 2), 3.84 (s, 6 H, MeO × 2), 5.36 (br s,
1 H, COCHN2), 6.58 (s, 2 H, H-5, H-8).
[R=
6,7-(OMe)2]50
1
83–85 1.80 (m, 1 H, H-3), 2.10 (m, 1 H, H-3), 2.60
(m, 2 H, H-1 and H-2), 2.70–3.00 (m, 3 H,
H-1, H-4 × 2), 3.78 (s, 3 H, MeO), 3.80 (s, 3
H, MeO), 5.38 (br s, 1 H, COCHN2), 6.25
(d, J = 1.6, 1 H, H-7), 6.30 (d, J = 1.6
1 H, H-5).
[R=6,8-
(OMe)2]16
11
88–89 2.80 (m, 2 H, H-3 ( 2), 3.00–3.30 (m, 3 H,
H-2 and H-1 × 2), 5.50 (br s, 1 H, COCHN2),
7.26 (d, J = 7.4, 1 H, H-8), 7.31 (t, J =
7.4, 1 H, H-6), 7.50 (t, J = 7.4, 1 H,
(R=H)45
H-7), 7.98 (d, J = 7.4, 1 H, H-5).
11
100–102 2.70–2.95 (m, 3 H, H-1 + H-3 × 2), 3.05 (m, 1
H, H-2), 3.27 (dd, J = 3.8, 17.0, 1 H, H-1),
3.86 (s, 3 H, MeO), 5.45 (br s, 1 H, COCHN2),
7.04 (d, J = 7.9, 1 H, H-7), 7.29 (t, J = 7.9,
1H, H-6), 7.63 (d, J = Hz, 1 H, H-5).
25.7 (C-1), 40.4 (C-3), 44.9 (C-2),
54.4 (COCHN2), 55.7 (MeO), 114.8 174 (100), 161 (67), 131
(C-7), 127.3 (C-5), 127.4 (C-8a),
156.7 (C-8), 194.2 (C-4), 196.5
(COCHN2).
244 (M+, 3%), 216 (50),
(R=8-OMe)
(28), 115 (20), 90 (70).
ica gel, using 50% EtOAc/hexane as the eluent, to give the dienedione
13 as a colourless solid (19 mg, 91%). This material was identical to
an authentic sample.11
1H NMR (CDCl3, 300 MHz): δ = 1.55 (m, 1 H, H-10), 1.70–1.83 (m, 2
H, H-5), 1.85–1.95 (m, 2 H, H-6), 2.22 (m, 1 H, H-10), 3.05 (m, 1 H,
H-7), 3.76 (s, 3 H, MeO), 5.49 (d, J = 2.0 Hz, 1 H, H-1), 5.67 (s, 1 H,
H-9), 5.75 (dd, J = 1.0, 8.7 Hz, 1 H, H-3), 6.00 (d, J = 8.7 Hz, 1 H, H-4).
13C NMR (CDCl3, 75 MHz): δ = 23.9 (CH2), 37.5 (CH2), 48.1 (CH2),
48.6 (C-4a), 52.4 (C-7), 55.4 (MeO), 96.1 (C-1), 118.5 (C-3 or C-4),
121.9 (C-4 or C-3), 142.4 (C-9), 161.2 (C-9a), 167.7 (C-2), 201.9 (C-8).
MS (EI, 70 eV): m/z (%) = 202 (M+, 57%), 174 (17), 161 (96), 146
(45), 133 (100), 115 (36), 103 (44), 91 (28), 77 (60), 76 (40), 51 (55).
IR (KBr): v = 2970, 1730, 1640, 1575 cm–1.
Rearrangement of Methoxynorcaradiene 2 (R = 7-OMe):
The norcaradiene 2 (R = 7-OMe) (12 mg, 0.474 mmol) was dissolved
in 5 M LiClO4 in Et2O (1 mL) under N2. The clear solution was stirred
at r.t.for 1 h, in which time the solution became red. The solution was
diluted with Et2O (25 mL) and washed with H2O (5 mL) and brine
(5 mL). The solvent was removed in vacuo to afford an orange oil.
Chromatography on silica gel using 50% EtOAc/hexane as eluent
gave 2-methoxy-5,6-dihydro-4a,7-methano-4aH-benzocyclohepten-
8(7H)-one 14, as an orange gel (11 mg, 95%).
Anal. Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C, 77.48; H,
7.08.
HRMS (EI) calcd for C13H14O2: 202.0994, found 202.0994.

SYNTHESIS
April 1998
463
(2RS)-8-Methoxy-5-vinyl-1,2,3,4-tetrahydro-2-naphthoic Acid (19):
A solution of methylenetriphenylphosphorane in THF (0.54 M, pre-
pared from methyl triphenylphosphonium bromide and NaH in THF)
was cannulated into a solution of the aldehyde 1822,51 (2.0 g,
8.62 mmol) in THF (100 mL) until a yellow colour persisted and TLC
analysis indicated that no starting material remained. The mixture
was quenched with H2O and acidified to pH 1 with conc. HCl to give
a white precipitate. The aqueous layer was extracted with EtOAc
(3 × 20 mL). The organic extracts were washed with H2O (10 mL)
and brine (10 mL). Evaporation of the solvent in vacuo gave an or-
ange oil which was purified by chromatography on silica gel using 50%
EtOAc/hexane as eluent to afford the vinyl acid 19 as white crystals
(1.6 g, 81%). A small sample was recrystallised from Et2O to give
small white prisms; mp 179–181˚C.
1H NMR (CDCl3, 300 MHz): δ = 1.82 (m, 1 H, H-3), 2.25 (m, 1 H,
H-3), 2.65–2.80 (m, 3 H, H-2, H-1 and H-4), 2.96 (dt, J = 4.6, 15.9
Hz, 1 H, H-4), 3.14 (m, 1 H, H-1), 3.83 (s, 3 H, OMe), 5.19 (dd, J =
1.5, 10.9 Hz, 1 H, CH=CH2), 5.51 (dd, J = 1.5, 17.4 Hz, 1 H,
CH=CH2), 6.71 (d, J = 8.5 Hz, 1 H, H-7), 6.86 (dd, J = 10.9, 17.4 Hz,
1 H, CH=CH2), 7.54 (d, J = 8.5 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): δ = 25.1 (CH2), 25.7 (CH2), 26.1 (CH2),
38.9 (C-2), 55.3 (OMe), 107.2 (C-7), 113.9 (CH=CH2), 123.5 (C-8a),
Table 6. Norcaradienes
Compound mp
(¡C)
1H NMR (CDCl3)
δ, J (Hz)
13C NMR (CDCl3)
δ
MS
m/z (rel int., %)
2
73–75 0.59 (s, 1 H, H-4a), 1.86 (m, 2 H, H-2 × 2),
1.96 (d, J = 11.9, 1 H, H-9α), 2.08 (m, 1
H, H-1α), 2.20Ð2.40 (m, 2 H, H-3, H-1β),
2.52 (m, 1 H, H-9β), 6.02 (m, 3 H, H-5, H-6,
and H-7), 6.23 (m, 1 H, H-8).
22.6 (C-1), 27.5 (C-2), 30.9 (C-9),
32.6 (C-4a), 42-1 (C-3), 45.0 (C-4b
or C-8a), 48.1 (C-8a or C-4b), 122.3
(CH), 122.6 (CH), 129.6 (CH),
131.0 (CH), 216.9 (C-4).
172 (M+, 24%), 144 (19),
129 (100), 116 (97), 103
(60), 91 (14), 77 (39), 63
(33), 51 (44).
(R=H)
2
45–47 0.84 (d, J = 1.6, 1 H, H-4a), 1.80 (m, 2
H, 2 × H-2), 1.95 (d, J = 11.8, 1 H, H-
9α), 2.00 (m, 1 H, H-1α), 2.24 (m, 1 H, H-
3), 2.47 (m, 1 H, H-9β), 2.57 (m, 1 H, H-1β),
3.60 (s, 3 H, MeO), 5.10 (d, J = 6.8, 1 H,
H-7), 5.78 (d, J = 9.1, 1 H, H-6), 5.96
(dd, J = 6.8, 9.1, 1 H, H-5).
17.6 (C-1), 27.1 (C-2), 30.5 (C-9),
32.6 (C-4a), 41.6 (C-3), 45.3 (C-4b)
or C-8a), 46.4 (C-8a or C-4b), 55.2
(MeO), 93.1 (C-7), 120.8 (C-6),
122.9 (C-5), 160.1 (C-8), 216.4
(C-4).
202 (M+, 98%), 174 (26),
159 (100), 146 (86), 131
(38), 115 (68), 103 (69).
91 (43), 77 (67), 63 (50),
51 (77).
(R=8-OMe)
2
69–71 0.68 (d, J = 1.6, 1 H, H-4a), 1.80 (m, 2 H,
H-2), 1.90 (d, J = 11.8, 1 H, H-9α), 2.10
(m, 1 H, H-1α), 2.20Ð2.40 (m, 2 H, H-3,
H-1β), 2.44 (m, 1 H, H-9β), 3.52 (s, 3 H,
MeO), 4.95 (d, J = 1.8, 1 H, H-8), 5.78
(dd, J = 1.8, 9.7, 1 H, H-6), 5.96 (d, J =
9.7, 1 H, H-5).
23.7 (C-1), 27.1 (C-2), 32.4 (C-9),
33.4 (C-4a), 42.2 (C-3), 42.7 (C-4b
or C-8a), 47.1 (C-8a or C-4b), 54.5
(MeO), 100.0 (C-8), 122.0 (C-6),
131.9 (C-5), 153.6 (C-7), 216.0
(C-4).
202 (M+, 60%), 187 (6),
174 (29), 159 (71), 146
(57), 133 (100), 115 (39),
103 (31), 91 (35), 77
(R=7-OMe)
(50), 63 (38), 51 (68).
2
–
0.66 (s, 1 H, H-4a), 1.84 (m, 2 H, H-2), 1.97
(d, J = 11.7, 1 H, H-9β), 2.05 (m, 1 H, H-
1α), 2.25Ð2.42 (m, 2 H, H-3, H-1β), 2.45
(m, 1 H, H-9α, 3.57 (s, 3 H, MeO), 5.13 (d, J
= 2.1, 1 H, H-5), 5.85 (dd, J = 2.1, 9.9
1 H, H-7), 6.04 (d, J = 9.9, 1 H, H-8).
23.7 (C-1), 27.1 (C-2), 32.4 (C-9),
33.4 (C-4a), 42.2 (C-3), 42.7 (C-4b
or C-8a), 47.1 (C-8a or C-4b), 54.5
(MeO), 100.0 (C-8), 122.0 (C-6),
131.9 (C-5), 153.6 (C-7), 216.0
(C-4).
(R=6-OMe)
2
95Ð97 0.80 (d, J = 1.6, 1 H, H-4α), 1.83 (d, J =
22.3, 1 H, H-9α ), 1.90 (m, 2 H, H-2 × 2),
2.11 (m, 1 H, H-1a), 2.28 (m, 1 H, H-1β),
2.30 (m, 1 H, H-3), 2.81 (m, 1 H, H-9β), 3.68
(s, 3 H, MeO), 5.11 (d, J = 7.0, 1 H, H-6),
5.62 (d, J = 9.4, 1 H, H-8), 5.92 (dd, J =
7.0, 9.9, 1 H, H-7).
22.3 (C-1), 27.4 (C-2), 28.0 (C-9),
30.9 (C-4a), 41.6 (C-3), 43.6 (C-4b
or C-8a), 48.4 (C-8a or C-4b), 55.5
(MeO), 91.9 (C-6), 122.0 (C-7 or C-
8), 122.6 (C-8 or C-7), 158.5 (C-5),
217.0 (C-4).
202 (M+, 82%), 187 (7),
174 (25), 159 (100), 146
(91), 133 (83), 115 (79),
103 (77), 91 (47), 77
(R=5-OMe)
(70), 63 (50), 51 (70).
2
[R=
5,7-(OMe)2]
–
0.90 (s, 1 H, H-4a), 1.70–2.30 (m, 7 H), 3.53
(s, 3 H, MeO), 3.65 (s, 3 H, MeO), 4.65 (s, 1
H, H-6), 4.95 (s, 1 H, H-8).
2
[R=
6,7-(OMe)2]
–
0.72 (s, 1 H, H-4a), 1.75–1.85 (m, 2 H, H-2),
1.92 (d, J = 11.8, 1 H, H-9α), 2.00Ð2.40
(m, 4 H), 3.58 (s, 3 H, MeO), 3.63 (s, 3 H,
MeO), 5.05 (s, 1 H, H-5), 5.20 (s, 1 H, H-8).
12
(R=H)
–
–
1.04 (s, 1 H, H-4a), 2.14 (d, J = 12.5, 1 H,
H-9α), 2.45 (dd, J = 1.1, 15.7, 1 H, H-
9β), 2.60 (m, 2 H, H-2 × 2), 2.82 (m, 1 H, H-
-3), 6.20–6.30 (m, 3 H, H-5, H-6, H-7),
6.70 (m, 1 H, H-8).
31.1 (C-4a), 33.1 (C-9), 39.0 (C-3),
41.4 (C-2), 45.1 (C-4b), 55.6 (C-8a),
122.5 (CH), 123.4 (CH), 124.2
(CH), 126.2 (CH), 200.0 (C-1),
211.3 (C-4).
186 (M+, 85%), 168 (9),
157 (17), 141 (38), 129
(80), 115 (100), 104 (24),
89 (32), 77 (35), 63 (52),
51 (64).
216 (M+, 39%), 187 (18).
171 (10), 159 (29), 145 (41),
129 (31), 115 (79), 103 (38),
12
1.18 (s, 1 H, H-4a), 1.98 (d, J = 12.7, 1 H,
H-9α), 2.42 (m, 1 H, H-9β), 2.58 (m, 2 H, H-2 41.4 (C-2), 44.2 (C-4b), 55.9 (MeO),
× 2), 3.06 (m, 1 H, H-3), 3.71 (s, 3 H, MeO),
5.25 (d, J = 6.6, 1 H, H-6), 6.12 (d, J = 9.4,
1 H, H-8), 6.18 (dd, J = 6.6, 9.4, 1 H,
H-7).
29.2 (C-4a), 31.3 (C-9), 38.8 (C-3),
(R=5-OMe)
56.3 (C-8a), 93.5 (C-6), 113.7 (C-7),
123.9 (C-8), 155.5 (C-5), 200.4 (C-1), 91 (55), 77 (67), 63 (77), 51
211.6 (C-4). (100).

SYNTHESIS
Papers
464
123.7 (CH=CH2), 129.4 (C-4a), 134.2 (C-5), 134.3 (C-6), 156.9 (C-
8), 181.7 (CO2H).
flash chromatography (20% EtOAc/petroleum ether) and the product
was further purified by recrystallisation from CH2Cl2/petroleum
ether. Diazo ketone 15 (1.6 g, 73% yield; 86% net) was obtained as
yellow needles, mp 106–107˚C. Also separated from the crude mix-
ture was the methyl ester of 19 (0.31 g, 15%), which could be readily
hydrolysed to the parent acid.
MS (EI, 70 eV) m/z (%) = 232 (M+, 100%), 217 (13), 187 (75), 171
(46), 155 (43), 128 (39), 115 (49), 91 (23), 77 (24), 63 (21), 51 (27).
Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.48; H,
7.25.
(2RS)-Diazomethyl 8-Methoxy-5-vinyl-1,2,3,4-tetrahydronaph-
thalen-2-yl Ketone (15):
(2RS,5′RS)-Diazomethyl
nyl-1,2,3,4-tetrahydronaphthalen-2-yl Ketone:
8-Methoxy-5-(3′-1′-pyrazolinyl)-5-vi-
Method A. A solution of the vinyl acid 19 (70 mg, 0.30 mmol) in an-
hyd Et2O (20 mL) was added slowly to an ice-cold solution of ethyl
chloroformate (50 µL, 2 equiv) and Et3N (225 µL, 5 equiv) in anhyd
Et2O (10 mL). The solution was stirred for 2 h at 0˚C, diluted with
Et2O (20 mL) and washed with H2O (10 mL) and brine. Removal of
the solvent in vacuo gave (2RS)-ethoxycarbonyl 8-methoxy-5-vinyl-
1,2,3,4-tetrahydro-2-naphthoate as a clear oil.
The reaction to form diazo ketone 15 was repeated, except that the
mixture was allowed to stir for 18 h at r.t. The solvent was removed
and the residue chromatographed, using 25% EtOAc/hexane to re-
move the diazo ketone 15 (35%), and 50% EtOAc/hexane to ob-
tain (2RS,5'RS)-diazomethyl 8-methoxy-5-(3′-1′-pyrazolinyl)-5-vinyl-
1,2,3,4-tetrahydronaphthalen-2-yl ketone as yellow crystals (17 mg,
21%). From the NMR data it was evident that a mixture of diaste-
reomers had been obtained.
1H NMR (300 MHz, CDCl3): δ = 1.40 (t, J = 7.1 Hz, 3 H, CH2CH3),
1.83 (m, 1 H, H-3), 2.30 (m, 1 H, H-3), 2.65–2.82 (m, 3 H, H-2, H-1
and H-4), 2.94 (m, 1 H, H-4), 3.18 (dd, J = 4.0, 16.5 Hz, 1 H, H-1),
3.82 (s, 3 H, OMe), 4.34 (q, J = 7.1 Hz, 2 H, CH2CH3), 5.18 (dd, J =
1.5, 10.9 Hz, 1 H, CH=CH2), 5.51 (dd, J = 1.5, 17.4 Hz, 1 H,
CH=CH2), 6.70 (d, J = 8.7 Hz, 1 H, H-7), 6.83 (dd, J = 10.9, 17.4 Hz,
1 H, CH=CH2), 7.32 (d, J = 8.7 Hz, 1 H, H-6).
1H NMR (300 MHz, CDCl3): δ = 1.35 (m, 1 H, H-4′), 1.85 (m, 1 H,
H-3), 2.10–2.30 (m, 2H, H-3 and H-4′), 2.55 (m, 1 H, H-2), 2.50–2.80
(m, 3 H, H-1, H-2 and H-3), 2.90–3.10 (m, 2 H, H-4), 3.15 (m, 1 H,
H-1′), 3.83 (s, 3 H, OMe), 4.36 (m, 1 H, H-3′), 4.76 (m, 1 H, H-5′),
5.42 (br s, 1 H, COCHN2), 5.50 (m, 1 H, H-5′), 6.58–6.75 (m, 2 H, H-
6 and H-7).
13C NMR (75 MHz, CDCl3): δ = 13.9 (CH3), 24.9 (CH2), 25.5 (CH2),
26.0 (CH2), 39.4 (C-2), 55.3 (OMe), 55.9 (OMe), 65.7 (OCH2), 107.4
(C-7), 114.0 (CH=CH2), 122.8 (C-8a), 124.1 (CH=CH2), 129.4 (C-
4a), 133.9 (C-5), 134.1 (C-6), 149.3 (CO2CO2Et), 156.9 (C-8), 170.0
(CO2CO2Et).
13C NMR (75 MHz, CDCl3): δ = 25.40 (CH2), 25.45 (CH2), 25.52
(CH2), 25.64 (CH2), 25.80 (CH2), 26.19 (CH2), 26.30 (CH2), 26.40
(CH2), 44.6/44.8 (C2), 53.8/53.9 (COCHN2), 55.3 (OMe), 76.4/76.5
(CH), 86.6/86.8 (CH), 107.2/107.3 (C-7), 123.8/124.5 (C-8a), 129.4/
129.6 (C-4a), 134.5 (C-6), 156.7 (C-8), 197.4 (COCHN2).
MS (EI, 70 eV) m/z (%) = 304 (M+, 57%), 260 (13), 231 (14), 215
(24), 186 (100), 171 (65), 155 (28), 128 (27), 115 (22).
(3RS,4aSR,4bRS,10bRS)-5-Methoxy-8-vinyl-2,3-dihydro-1H-
3,4b-methanocyclopropa[1,2:1,3]dibenzen-4(4aH)-one (16):
The diazo ketone 15 (276 mg, 1.08 mmol) in anhyd CH2ClCH2Cl
(20 mL) was added to a solution of Cu(acac)2 (6 mg, 2 mol %) in
CH2ClCH2Cl at reflux, at a rate of 0.35 mL/min using a syringe pump.
Upon addition the solution was refluxed for 5 min. To remove the
copper residues the solution was filtered through a small plug of silica
gel using 50% EtOAc/hexane as the eluent to afford the impure nor-
caradiene as a yellow oil. The oil was purified using MPLC with 25%
EtOAc/hexane as eluent to give the vinyl norcaradiene 16 as a clear
oil (131 mg, 53%).
IR (CHCl3): ν = 2985, 1825, 1760, 1600, 1480 cm–1.
HRMS (EI) m/z calcd for C17H20O5: 304.1309, found 304.1311.
After 30 min on high vacuum, the crude anhydride was dissolved in
CH2Cl2 (20 mL) and added dropwise to fresh ethereal CH2N2 (0.4 M,
10 equiv) at 0˚C. The yellow solution was stirred at 0˚C for 30 min
and 4.5 h at r.t. The solvent was removed in vacuo to afford the crude
diazo ketone as an orange oil. Chromatography on silica gel, using
25% EtOAc/hexane, gave the diazo ketone 15 as a yellow solid
(39 mg, 51%; net yield 68% based on recovered starting material) fol-
lowed by the starting acid 19 (18 mg).
A small sample of 15 was recrystallised from Et2O to give fine yellow
needles; mp 106–107˚C.
1H NMR (300 MHz, CDCl3): δ = 0.91 (d, J = 1.6 Hz, 1 H, H-4a),
1.70–1.90 (m, 2 H, H-2 x 2), 1.82 (d, J= 12.3 Hz, 1 H, H-9α), 1.98 (m,
1 H, H-1α), 2.29 (m, 1 H, H-3), 2.77 (m, 1 H, H-1β), 3.49 (m, 1H, H-
9β), 3.66 (s, 3 H, OMe), 5.01 (dd, J = 1.5, 11.8 Hz, 1 H, CH=CH2),
5.09 (d, J = 7.2 Hz, 1 H, H-6), 5.34 (dd, J = 1.5, 17.3 Hz, 1 H,
CH=CH2), 6.06 (dd, J = 1, 7.2 Hz, 1 H, H-7), 6.42 (ddd, J = 1.0, 11.8,
17.3 Hz, 1 H, CH=CH2).
1H NMR (300 MHz, CDCl3): δ = 1.80 (m, 1 H, H-3), 2.12 (m, 1 H,
H-3), 2.55 (m, 1 H, H-2), 2.55–2.72 (m, 2 H, H-1 and H-4), 2.95 (dd,
J = 3.4, 5.0 Hz, 1 H, H-4), 3.02 (dd, J = 3.8, 17.6 Hz, 1 H, H-1), 3.83
(s, 3 H, OMe), 5.20 (dd, J = 1.6, 11.0 Hz, 1 H, CH=CH2), 5.41 (br s,
1 H, COCHN2), 5.52 (dd, J = 1.6, 17.2 Hz, 1 H, CH=CH2), 6.70 (d, J
= 8.6 Hz, 1 H, H-7), 6.86 (dd, J = 11.0, 17.2 Hz, 1 H, CH=CH2), 7.34
(d, J = 8.6 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): δ = 19.7 (C-1), 27.6 (C-2), 27.7 (C-9),
30.5 (C-4a), 41.1 (C-3), 42.7 (C-4b), 46.5 (C-8a), 55.5 (OMe), 92.3
(C-6), 113.0 (CH=CH2), 120.5 (CH=CH2), 131.1 (C-8), 134.8 (C-7),
158.5 (C-5), 216.5 (C-4).
13C NMR (75 MHz, CDCl3): δ = 25.4 (CH2), 26.1 (CH2), 26.3 (CH2),
44.7 (C-2), 53.7 (COCHN2), 55.3 (OMe), 107.2 (C-7), 113.7
(CH=CH2), 123.6 (C-8a), 123.8 (CH=CH2), 129.3 (C-4a), 134.1 (C-
6), 134.3 (C-5), 156.8 (C-8), 197.6 (COCHN2).
MS (EI) m/z (%) = 228 (M+, 8%), 200 (2), 172 (4), 159 (9), 141 (4),
115 (10), 84 (100), 77 (14), 57 (32), 51 (73).
Anal. Calcd for C15H16O2: C, 78.92; H, 7.06. Found: C, 78.80; H,
7.44.
MS (EI) m/z (%) = 256 (M+, 9%), 228 (37), 197 (36), 185 (45), 171
(40), 141 (36), 129(65), 115 (100), 91 (41), 77 (34), 63 (32), 51 (45).
IR (CHCl3) 2950, 2115, 1645, 1600 cm–1.
Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C,
70.34; H, 6.41; N, 10.82.
HRMS (EI) m/z calcd for C15H16N2O2: 256.1212, found 256.1211.
(3RS,4aSR,4bRS,6aSR,7RS,8RS,10bRS)-5-Methoxy-2,3,6a,7,8,9-
hexahydro-1H-3,4b-methanobenzo[1,3]-cyclopropa[1,2-a]naph-
thalen-4(4aH)-one-7,8-dicarboxylic Anhydride (20):
The norcaradiene 16 (15 mg, 0.658 mmol) and freshly sublimed ma-
leic anhydride (13 mg, 2 equiv) in anhyd benzene (4 mL) were heated
at 80˚C for 4 h. The solvent was removed in vacuo. Only one diaster-
eoisomer could be detected by 1H NMR spectroscopy. The white sol-
id was purified by MPLC, using 50% EtOAc/hexane as the eluent, to
afford the adduct 20 as a white solid (17 mg, 79%). A sample was re-
crystallised from Et2O to give white needles; mp 220–222˚C.
1H NMR (500 MHz, CDCl3): δ = 1.74 (d, J = 2.0 Hz, 1 H, H-4a), 1.78
(d, J = 12.0 Hz, 1 H, H-11α), 1.84–2.00 (m, 3 H, H-1α and H-2 x 2),
2.22 (m, 1 H, H-9β), 2.24 (m, 1 H, H-3), 2.42 (m, 1 H, H-1β), 2.76
(m, 1 H, H-11β), 2.92 (m, 1 H, H-9α), 2.98 (m, 1 H, H-6a), 3.37 (m,
Method B. A solution of the vinyl acid (2.0 g, 8.62 mmol) in THF
(70 mL) was treated with NaH (60% disp, 410 mg, 10.3 mmol) and
the resultant mixture was stirred at r.t.for 3 h. A solution of oxalyl
chloride (1.5 mL, 17.2 mmol) in benzene (70 mL) was treated with
DMF (1.4 mL, 18.1 mmol) at r.t. The resultant slurry was poured onto
the sodium carboxylate slurry at r.t.and this mixture was stirred at this
temperature overnight. The mixture was then cautiously filtered into
an ethereal solution of diazomethane (ca 0.4M, 500 mL) and this mix-
ture was stirred at r.t. for 3 h, before the residual diazomethane was
dispersed under a stream of N2. The crude product was purified by

SYNTHESIS
April 1998
465
Table 7. CH-Insertion Products
mp
1H NMR (CDCl3)
13C NMR (CDCl3)
MS
(¡C)
δ, J (Hz)
δ
m/z (rel int., %)
7
–
2.16 (ddd, J = 1.0, 2.9, 11.4, 1 H, H-10), 2.33
(dd, J = 3.3, 17.6, 1 H, H-6), 2.34 (m, 1 H,
H-10), 2.54 (dd, J = 6.7, 17.6, 1 H, H-6), 2.77
(m, 1 H, H-8), 2.96 (d, J = 17.0, H-9α), 3.15
(dd, J = 5.7, 17.0, 1 H, H-9β), 3.45 (m, 1 H, H-
5), 7.00–7.20 (m, 4 H).
33.6 (CH2), 34.0 (CH2), 38.1
(C-6), 45.2 (C-8), 49.8 (C-5),
126.2 (CH), 126.9, 127.1,
129.1 (CH), 132.5 (C-9a), 142.7
(C-4a), 221.1 (C-7).
172 (M+, 74%), 154
(5), 144 (8), 129
(100), 115 (53), 91
(11), 77 (10), 63 (15),
51 (16).
(R=H)
7
51–53
2.05 (ddd, J = 1.0, 2.1, 11.7, 1 H, H-10), 2.27
(dd, J = 3.4, 17.6, 1 H, H-6), 2.32 (m, 1 H, H-
10), 2.50 (dd, J = 6.6, 17.6, 1 H, H-6), 2.74 (m,
1 H, H-8), 2.94 (d, J = 17.5, H-9α), 3.15 (dd, J
= 5.5, 17.5, 1 H, H-9β), 3.83 (s, 3 H, MeO),
3.96 (m, 1 H, H-5), 6.69 (d, J = 7.8, 2 H, H-1 +
H-3), 7.12 (t, J = 7.8, 1 H, H-2).
30.0 (CH2), 33.4 (CH2), 34.2
(CH2), 45.1 (C-8), 49.0 (C-5),
55.4 (MeO), 107.7 (C-3), 121.3
(C-2 or C-1), 127.1 (C-1 or C-
2), 131.4 (C-9a), 133.9 (C-4a),
155.3 (C-4), 221.8 (C-7).
202 (M+, 92%), 187
(4), 174 (6), 159
(100), 144 (42), 129
(41), 115 (83), 103
(12), 91 (29), 77 (31),
63 (40), 51 (47).
(R=
4-OMe)
7
54–56
2.15 (dd, J = 3.3, 11.6, 1 H, H-10), 2.32 (dd, J
=3.4, 17.8, 1 H, H-6), 2.33 (m, obscured, 1 H,
H-10), 2.52 (dd, J = 6.4, 17.8, 1 H, H-6), 2.74
(m, 1 H, H-8), 2.90 (d, J = 17.5, H-9α), 3.07
(dd, J = 5.5, 16.5, 1 H, H-9β), 3.37 (m, 1H, H-
5), 3.78 (s, 3 H, MeO), 6.60 (d, J = 2.6, 1 H, H-
-4), 6.71 (dd, J = 2.6, 8.5, 1 H, H-2), 6.98 (d, J
= 8.5, 1 H, H-1).
33.3 (CH2), 33.6 (CH2), 38.5
(C-6), 45.3 (C-8), 49.6 (C-5),
55.3 (MeO), 112.3 (C-4 or C-
2), 112.5 (C-2 or C-4), 124.2
(C-9a), 1302 (C-1), 143.9 (C-
4a), 157.8 (C-3), 221.2 (C-7).
202 (M+, 100%), 187
(5), 174 (9), 159 (59),
144 (28), 128 (30),
115 (65), 103 (15), 91
(29), 77 (27), 63 (33),
51 (43).
(R=
3-OMe)
7
54–55
2.14 (dd, J = 3.2, 11.6, 1 H, H-10), 2.26–2.35
(m, 2 H, H-6 + H-10), 2.51 (dd, J = 6.0, 17.6,
1 H, H-6), 2.74 (m, 1 H, H-8), 2.93 (d, J = 17.2,
H-9α), 3.13 (dd, J = 5.6, 17.2, 1 H, H-9β), 3.41
(m, 1 H, H-5), 3.78 (s, 3 H, MeO), 6.61 (d, J =
2.3, 1 H, H-1), 6.68 (dd, J = 2.3, 8.5, 1 H, H-
3), 6.98 (d, J = 8.5, 1 H, H-4).
34.0 (CH2), 34.3 (CH2), 37.4
(C-6), 45.1 (C-8), 49.9 (C-5),
55.2 (MeO), 112.1 (C-1 or C-
3), 113.9 (C-3 or C-1), 128.0
(C-4), 133.7 (C-4a or C-9a),
135.0 (C-9a or C-4a), 158.5 (C-
2), 221.4 (C-7).
202 (M+, 56%), 187
(2), 174 (3), 159
(100), 144 (31), 128
(17), 115 (28), 91
(13), 77 (12), 63 (14),
51 (18).
(R=
2-OMe)
7
–
–
2.14 (dd, J = 3.2, 11.6, 1 H, H-10), 2.26–2.35
(m, 2 H, H-6 + H-10), 2.51 (dd, J = 6.0, 17.6, 1
H, H-6), 2.74 (m, 1 H, H-8), 2.93 (d, J = 17.2,
1 H, H-9α), 3.13 (dd, J = 5.6, 17.2, 1 H, H-9β),
3.41 (m, 1 H, H-5), 3.78 (s, 3 H, MeO), 6.61 (d, J
= 2.3, 1 H, H-1), 6.68 (dd, J = 2.3, 8.5, 1 H,
H-3), 6.98 (d, J = 8.5, 1 H, H-4).
29.6 (CH2), 33.4 (CH2), 38.0
(C-6), 44.9 (C-8), 49.5 (C-5),
55.1 (MeO), 108.2 (C-2), 119.3
(C-3), 121.0 (C-4), 133.7 (C-4a
or C-9a), 135.0 (C-9a or C-4a),
158.5 (C-1), 221.4 (C-7).
202 (M+, 100%), 187
(5), 174 (8), 159 (75),
144 (40), 128 (40),
115 (85), 103 (16), 91
(32), 77 (32), 63 (34),
51 (48).
(R=
1-OMe)
7
[R=
1,3-(OMe)2]
2.10 (dd, J = 3.0, 11.6, 1 H, H-10), 2.25 (m,
1 H, H-10), 2.32 (dd, J = 3.3, 17.6, 1 H, H-6),
2.50 (dd, J = 6.0, 17.6, 1 H, H-6), 2.70-2.90
(m, 3 H, H-8 + H-9 × 2), 3.35 (m, 1 H, H-5), 3.78
(s, 3 H, MeO), 3.80 (s, 3 H, MeO), 6.22 (d, J = 1.5, 9a), 144.5 (C-4a), 158.5, 159.1
1 H, H 2), 6.30 (d, J = 1.5, 1 H, H-4).
29.1 (CH2), 33.5 (CH2), 38.5
(CH2), 44.9 (C-8), 49.4 (C-5),
55.2 (MeO), 55.3 (MeO), 96.4
(C-2), 103.1 (C-4), 113.1 (C-
232 (M+, 100%), 191
(82), 175 (23), 159
(17), 128 (20), 115
(65), 103 (29), 91
(39), 77 (46), 63 (33),
51 (47).
(C-1, C-3), 221.2 (C-7).
8
[R=
2,3-(OMe)2]
125–126 2.15 (dd, J = 3.0, 11.6, 1 H, H-10), 2.30 (dd, J
= 3.3, 17.6, 1 H, H-6), 2.32 (m, 1 H, H-10),
2.51 (dd, J = 6.0, 17.6, 1 H, H-6), 2.74 (m,
1 H, H-8), 2.88 (d, J = 17.0, 1 H, H-9α), 3.09
(dd, J = 5.7, 17.0, 1 H, H-9β), 3.35 (m, 1 H,
H-5), 3.63 (s, 3 H, MeO), 3.66 (s, 3 H, MeO), 6.56
(s, 2 H, H-1 + H-4).
33.8 (CH2), 34.1 (CH2), 37.8
(CH2), 45.2 (C-8), 49.9 (C-5),
55.7 (MeO), 55.9 (MeO)
110.2, 111.9, (C-1, C-4), 124.6
(C-9a), 134.9 (C-4a), 147.3 (C-
2 or C-3), 147.9 (C-3 or C-2),
221.4 (C-7).
232 (M+, 100%), 217
(7), 189 (71), 175
(18), 158 (14), 128
(18), 115 (43), 103
(26), 91 (28), 77 (31),
63 (22), 51 (34).
8
Ð
1.705 (m, 1 H, H-3β), 2.06 (m, 1 H, H-3α), 2.65
(m, 2 H, H-4 × 2), 2.79 (m, 1 H, H-1α), 3.52 (m, 1
H, H-1β), 3.69 (m, 1 H, H-2a), 3.85 (s, 3 H, MeO),
3.87 (m, 1 H, H-8b), 6.64 (d, J = 2.3, 1 H, H-
4), 6.74 (dd, J = 2.3, 8.4, 1 H, H-2), 6.99 (d, J
= 8.4, 1 H, H-1).
(R=
6-OMe)
8
Ð
1.75 (m, 1 H, H-3β), 2.10 (m, 1 H, H-3α), 2.68
(m, 2 H, H-4 × 2), 2.75 (m, 1 H, H-1α), 3.59 (m, 1
H, H-1β), 3.72 (m, 1 H, H-2a), 3.84 (s, 3 H, MeO),
3.86 (m, 1 H, H-8b), 6.76 (d, J = 7.9, 2 H, H-5
+ H-7), 7.15 (t, J = 7.9, 1 H, H-6).
21.6 (C-3), 21.7 (C-8b), 27.6
(C-4), 53.9 (C-1), 55.4 (MeO),
57.9 (C-2a), 108.0 (C-7), 121.1
(C-6), 126.6 (C-8a), 127.8 (C-
5), 138.3 (C-4a), 157.6 (C-8),
213.4 (C-2).
202 (M+, 2%), 160
(100), 145 (20), 129
(21), 115 (29), 91
(15), 77 (12), 63 (13),
51 (16).
(R=
8-OMe

SYNTHESIS
Papers
466
1 H, H-7), 3.44 (m, 1 H, H-8), 3.68 (s, 3 H, OMe), 4.58 (d, J = 4.6 Hz,
1 H, H-6), 6.18 (m, 1H, H-10).
N2. H2O was added to quench the reaction and the aqueous layer was
extracted with EtOAc (3 × 10 mL). The organic extracts were washed
with H2O (5 mL) and brine (5 mL). The solvent was removed in vacuo
to afford a white solid (9.5 mg). 1H NMR spectroscopy revealed that
21 was now the minor product in a 10:1 mixture. The 1H NMR signals
of the major product 22 corresponded to the second isomer (11%) ob-
tained from the preceding experiment.
13C NMR (75 MHz, CDCl3): δ = 19.7 (C-1), 24.9 (C-2), 27.5 (C-11),
27.7 (C-9), 34.3 (C-4a), 36.8 (C-4b or C-10b), 40.2 (C-10b or C-4b),
40.4 (C-3), 41.1 (C-7), 45.1 (C-6a), 46.4 (C-8), 55.0 (OMe), 89.1 (C-
6), 123.5 (C-10), 138.1 (C-10a), 153.0 (C-5), 170.2 (C-12 or C-13),
173.9 (C-13 or C-12), 212.3 (C-4).
MS (EI) m/z (%) = 326 (M+, 14%), 298 (6), 253 (13), 228 (100), 200
(21), 185 (28), 172 (27), 158 (40), 141 (24), 128 (30), 115 (38), 91
(30), 84 (100), 77 (27), 55 (41), 51 (25).
1H NMR (300 MHz, CDCl3): δ = 1.60–1.75 (m, 2 H), 1.88 (d, J = 12.7
Hz, 1 H, H-11α), 1.90–2.45 (m, 9 H), 2.65–2.83 (m, 3 H), 2.86 (s, 1
H, H-4a), 3.74 (s, 3 H, OMe), 5.82 (m, 1 H, H-10).
IR (CHCl3) ν = 2970, 1850, 1780, 1720 cm-1.
13C NMR (75 MHz, CDCl3): δ = 18.6 (CH2), 24.8 (CH2), 25.1 (CH2),
26.8 (CH2), 27.9 (CH2), 29.7 (CH2), 31.0 (C-4a), 40.3 (CH), 40.8
(CH), 45.4 (C-4b or C-10b), 46.9 (C-10b or C-4b), 47.7 (CH), 52.1
(OMe), 122.8 (C-10), 132.7 (C-10a), 174.9 (CO2Me), 203.4 (C-5),
210.8 (C-3).
HRMS (EI) m/z calcd for C19H18O5: 326.1154, found 326.1154.
Diels–Alder Reaction of Vinylnorcaradiene 16 with Methyl Acrylate
(a) The norcaradiene 16 (26 mg, 0.114 mmol) and freshly distilled
methyl acrylate (0.3 mL) in anhyd benzene (3 mL) were heated at
80˚C for 24 h, then the solvent removed in vacuo. The white solid was
purified by MPLC, using 20% EtOAc/hexane as the eluent, to afford
the Diels–Alder adducts as a white solid (20 mg, 56%). Attempts to
separate the isomers resulted in their decomposition. There appeared
to be three diastereoisomers in a 71:17:12 ratio (but vide infra) as de-
termined by integration of the alkenic proton (H10) and the enol ether
proton (H6) resonances in the 1H NMR spectrum. The respective
chemical shifts for these protons for each isomer were: A (δ 5.62,
4.22); B (δ, 5.89, 4.42); C (δ 5.79, 4.18). Spectroscopic data for the
major isomer were:
MS (EI) m/z (%) = 300 (M+, 100%), 241 (52), 213 (25), 185 (16), 128
(16), 73 (62), 59 (19).
IR (CHCl3) ν = 2950, 1725, 1685 cm–1.
HRMS (EI) m/z calcd for C18H20O4: 300.1362, found 300.1365.
3RS,4aSR,4bRS,6aSR,7RS,8RS,10bRS-5-Methoxy-7-methyl-
2,3,6a,7,8,9-hexahydro-1H-3,4b-methanobenzo[1,3]cyclopro-
pa[1,2-a]naphthalene-4(4aH)-one-7,8-dicarboxylic Anhydride (23):
A solution of the diazo ketone 15 (1.15 g, 4.49 mmol) in ClCH2CH2Cl
(40 mL) was added via syringe pump (0.3 mL min–1) to a solution of
Cu(acac)2 (ca 3 mol%, 35 mg) in ClCH2CH2Cl (40 mL) at reflux.
Once this addition was complete, the mixture was allowed to cool to
r.t. and citraconic anhydride (1.21 mL, 13.5 mmol) was added. The
solution was then stirred at r.t. for 18 h before the solvent was re-
moved under reduced pressure and the residue was submitted to flash
chromatography (25–50% EtOAc/hexane ). The Diels–Alder adduct
23 (1.15 g, 75%) was obtained as a colourless solid which could be
further purified by recrystallisation from EtOAc to provide fine col-
ourless needles; mp 193–199˚C.
1H NMR (500 MHz, CDCl3): δ = 1.60–2.00 (m, 4 H), 1.82 (d, J = 12.0
Hz, 1 H, H-11α), 2.05–2.35 (m, 5 H), 2.50 (s, 1H, H-4a), 2.63 (m, 1
H, H-11β), 2.84 (m, 1 H), 2.90 (m, 1 H, H-6a), 3.48 (s, 3 H, 5-OMe),
3.67 (s, 3 H, CO2Me), 4.22 (m, 1 H, H-6), 5.62 (m, 1 H, H-10).
13C NMR (75 MHz, CDCl3): δ = 18.8 (CH2), 22.2 (CH2), 24.5 (CH2),
27.7 (CH2), 27.9 (CH2), 32.7 (CH), 39.4 (C), 41.4 (CH), 43.5 (C),
43.8 (CH), 54.9 (OMe), 91.4 (C-6), 121.4 (C-10), 133.7 (C-10a),
153.5 (C-5), 174.2 (CO2Me), 213.4 (C-4)
MS (EI) m/z (%) = 314 (M+, 47%), 255 (38), 141 (31), 128 (43), 115
(46), 91 (43), 71 (100), 58 (91).
1H NMR (300 MHz, CDCl3): δ = 1.57 (s, 3 H, Me), 1.69 (d, J =
1.5 Hz, 1 H, H-4a), 1.75 (d, J = 12.3 Hz, 1 H, H-11α), 1.82–1.96 (m,
3 H, H-1α and H-2), 2.15–2.28 (m, 2 H, H-3 and H-9β), 2.38 (m, 1
H, H-1β), 2.66 (m, 1 H, H-6a), 2.73 (m, 1 H, H-11β), 2.90 (m, 1 H,
H-9a), 3.02 (dd, J = 2.2, 5.8 Hz, 1 H, H-8), 3.67 (s, 3 H, OMe), 4.68
(d, J = 3.0 Hz, 1 H, H-6), 6.24 (m, 1H, H-10).
(b) One Pot Cyclopropanation/Diels–Alder/Hydrolysis
Methyl (3RS,4aSR,4bRS,6aSR,7RS,10bRS)-2,3,6a,7,8,9-Hexahy-
dro-1H-3,4b-methanobenzo[1,3]cyclopropa[1,2-a]naphthalene-
4(4aH),5(6H)-dione-7-carboxylate (21):
1H NMR (500 MHz, d6-acetone): δ = 1.59 (d, J = 1.5 Hz, 1 H, H-4a),
1.60 (s, 3 H, Me), 1.71 (d, J = 12.1 Hz, 1 H, H-11α), 1.74-1.90 (m, 3
H, H1α and H-2), 2.03 (m, 1 H, H-3), 2.31 (m, 1 H, H-9β), 2.44 (m,
1 H, H-1β), 2.63 (m, 1 H, H-11β), 2.75 (m, 1 H, H-9α), 2.78 (m, 1 H,
H-6a), 3.30 (dd, J = 2.3, 5.5 Hz, 1 H, H-8), 3.64 (s, 3 H, OMe), 4.84
(d, J = 3.3 Hz, 1 H, H-6), 6.31 (m, 1 H, H-10).
The diazo ketone 15 (77 mg, 0.301 mmol) in anhyd CH2ClCH2Cl (4
mL) was added, at a rate of 0.15 mL/min, to a solution of Cu(acac)2
(1 mg, 2 mole %) in anhyd CH2ClCH2Cl (2 mL) at reflux. Upon ad-
dition, methyl acrylate (5 drops) was added to the mixture and the so-
lution heated at 80˚C for a further 21 h. The solvent was removed in
vacuo to afford a green/yellow oil, which was dissolved in acetone
(5 mL). Upon addition of 2 M HCl (10 drops) the solution turned an
orange colour. After 5 min the solution was diluted with H2O (15 mL)
and extracted with EtOAc (3 × 20 mL). After washing with H2O
(10 mL) and brine (10 mL), the solvent was removed in vacuo to give
an orange oil. The residue was purified by MPLC, using 25% EtOAc/
hexane as the eluent, to afford a white solid (57 mg, 63% for the three
steps). The 1H NMR spectrum revealed a ratio of 60:11:18:10 (based
on integration of H-10). Two recrystallisations from Et2O/hexane
gave the major adduct 21 as white needles; mp 149–151˚C.
1H NMR (300 MHz, CDCl3): δ = 1.48–1.62 (m, 2 H), 1.69 (d, J = 12.7
Hz, 1 H, H-11α), 1.85–2.35 (m, 8 H), 2.65–2.82 (m, 3 H), 3.00 (d, J
= 1.4 Hz, 1 H, H-4a), 3.69 (s, 3 H, OMe), 5.77 (m, 1 H, H-10).
13C NMR (75 MHz, CDCl3): δ = 18.6 (CH2), 19.2 (CH2), 25.1 (CH2),
26.7 (CH2), 27.5 (CH2), 29.2 (C-4a), 40.2 (CH2), 40.7 (CH), 40.9
(CH), 42.8 (CH), 45.2, 48.0 (C-4b, C-10b), 51.8 (OMe), 123.2 (C-10),
133.9 (C-10a), 173.5 (CO2Me), 203.7 (C-5), 210.9 (C-3).
13C NMR (75 MHz, CDCl3): δ = 20.3 (C1), 22.2 (Me), 24.0 (C-2),
27.4 (C-9 or C-11), 27.6 (C-11 or C-9), 36.8 (C-4b or C-10b), 40.0 (C-
10b or C4-b), 41.0 (C-4a), 41.2 (C-3), 45.1 (C-6a), 49.1 (C-8), 50.9
(C-7), 54.8 (OMe), 86.6 (C-6), 125.6 (C-10), 137.8 (C-10a), 153.6 (C-
5), 172.8 (C-12 or C-13), 173.3 (C-13 or C-12), 212.2 (C-4).
MS (EI) m/z (%) = 340 (M+, 10%), 298(6), 228 (100), 200 (26), 185
(35), 172 (33), 159 (35), 158 (37), 128 (22), 115 (18).
IR (CHCl3) ν = 2970, 1850, 1780, 1720 cm–1.
Anal. Calcd for C20H20O5: C, 70.58; H, 5.92. Found: C, 70.25; H,
6.33. HRMS (EI) m/z calcd for C20H20O5: 340.1311, found 340.1311.
X-ray Structural Determination of 20:
C19H18O5, M = 326.35, T = 296(1) K, orthorhombic, space group
P212121, a = 9.786(2), b = 10.106(3), c = 32.043(3) Å, U = 3168.9(10)
Å3, Dc (Z = 8) = 1.368 g cm-3, F(000) = 1376, µ(CuKα) = 8.20 cm–1,
semi-empirical absorption correction; 2731 unique data (2Θmax
120.2˚), 1741 with I > 3σ(I); R = 0.049, wR = 0.043, GOF = 2.66.
=
MS (EI) m/z (%) = 300 (M+, 100%), 241 (52), 213 (25), 185 (16), 128
(16), 73 (62), 59 (19).
Data were measured on a Rigaku AFC6R rotating anode diffractome-
ter (graphite crystal monochromator, λ = 1.54178 Å). The structure
was solved by direct methods52 and expanded using Fourier tech-
niques.53 Refinement was by full-matrix least squares analysis on F
using the teXsan Structure analysis Software of Molecular Structure
Corporation.54 Atomic coordinates, bond lengths and angles, and
thermal parameters have been deposited at the Cambridge Crystallo-
graphic Data Centre, deposition number: CSD-100669.
IR (CHCl3) ν = 2950, 1725, 1685 cm–1.
HRMS (EI) m/z calcd for C18H20O4: 300.1362, found 300.1363.
Epimerisation of the major adduct 21:
Adduct 21(10 mg) in 0.3M NaOMe (5 mL; prepared by adding 35 mg
of Na metal to 5 mL of anhyd MeOH) was stirred at r.t. for 70 h under

SYNTHESIS
April 1998
467
The authors are indebted to Professor Michael Doyle for the gener-
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