[4+2] Cycloaddition reactions between 1,8-disubstituted cyclooctatetraenes and diazo dienophiles: Stereoelectronic effects, anticancer properties and application to the synthesis of 7,8-substituted bicyclo [4.2.0] octa-2,4-dienes

Article abstract of DOI:10.1002/chem.200903454

A detailed examination of [4+2] cycloaddition reactions between 1,8-disubstituted cyclooctatetraenes and diazo compounds revealed that 4-phenyl-1,2,4-triazole-3,5-dione (PTAD) reacts to form either 2,3- or 3,4-disubstituted adducts. The product distribution can be controlled by modulating the electron density of the cyclooctate-traene. Unprecedented [4+2] cycloadditions between diisopropyl azodicarboxylate (DIAD) and 1,8-disubstituted cyclooctatetraenes are also described and further manipulation of a resulting cycloadduct uncovered a new pathway to the synthetically challenging bicyclo[4.2.0]octa-2,4-diene family. Variation of the substituents resulted in a range of compounds displaying selective action against different human tumour cell types.

Full text of DOI:10.1002/chem.200903454

DOI: 10.1002/chem.200903454
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Rebecca L. Grange,[a] Michael J. Gallen,[a] Heiko Schill,[a] Jenny P. Johns,[b] Lin Dong,[a]
Peter G. Parsons,[b] Paul W. Reddell,[c] Victoria A. Gordon,[c] Paul V. Bernhardt,[a] and
Craig M. Williams*[a]
Abstract: A detailed examination of
[4+2] cycloaddition reactions between
traene. Unprecedented [4+2] cycload-
ditions between diisopropyl azodicar-
boxylate (DIAD) and 1,8-disubstituted
cyclooctatetraenes are also described
and further manipulation of a resulting
cycloadduct uncovered a new pathway
to the synthetically challenging bicyclo-
1,8-disubstituted
cyclooctatetraenes
and diazo compounds revealed that 4-
phenyl-1,2,4-triazole-3,5-dione (PTAD)
reacts to form either 2,3- or 3,4-disub-
stituted adducts. The product distribu-
tion can be controlled by modulating
the electron density of the cyclooctate-
AHCTUNGTRENNG[UN 4.2.0]octa-2,4-diene family. Variation
Keywords: antitumor agents · bicy-
clo compounds · cycloaddition · cy-
clooctatetraene · diazo compounds ·
Diels–Alder reaction
of the substituents resulted in a range
of compounds displaying selective
action against different human tumour
cell types.
Introduction
The 7,8-substituted bicycloACHTNUTRGNE[NUG 4.2.0]octa-2,4-diene motif 1 ap-
pears in a number of natural products, most notably in the
endiandric acids (e.g., endiandric acid D 2),[1] synthesised by
the Nicolaou group,[2] and the polyketide pyrone family
(e.g., ocellaACHTUNGTRENNUNGpyACHTUNGTRENNUNG
rone A 3),[3] synthesised by the Trauner,[4]
Baldwin,[5] Moses[6] and Parker[7] groups. All of these groups
masterfully accessed the requisite 7,8-substituted bicyclo-
ACHTUNGTRENNUNG[4.2.0]octa-2,4-dienes 1 for their total syntheses through a
biomimetically modelled 8p–6p electrocyclisation cascade
from tetraenes 4. These are typically[8] generated in situ by
Lindlar reduction of enynes 5, as demonstrated by Mar-
vell,[9] Huisgen[10] and Nicolaou,[2,11] palladium(0)-mediated
cross-coupling techniques (between 6 and 7), as disclosed by
the Trauner group,[4] and later by Parker,[7] or palladium(II)-
mediated isomerisation, as reported by Baldwin[5] and
Moses[6] (Scheme 1). Alternative methods to access this 7,8-
substituted bicyclic system (i.e., 1), however, are very few in
number[12,13] and most give rise to symmetrical substitution
patterns at these positions. Furthermore, efforts to convert
[a] Dr. R. L. Grange, Dr. M. J. Gallen, Dr. H. Schill, Dr. L. Dong,
Dr. P. V. Bernhardt, Dr. C. M. Williams
School of Chemistry and Molecular Biosciences
University of Queensland
Brisbane, 4072, Queensland (Australia)
Fax : (+61)7-3365-4299
E-mail: c.williams3@uq.edu.au
[b] J. P. Johns, Dr. P. G. Parsons
Queensland Institute of Medical Research
P O Royal Brisbane Hospital
Brisbane, 4029, Queensland (Australia)
derivatives, such as 7,8-dibromo-bicycloACTHNUTRGNE[UNG 4.2.0]octa-2,4-diene,
by using substitution reactions have generally failed,[14,15]
giving little hope that other heteroatom substitution patterns
(e.g., oxo)[16] will perform any better.
[c] Dr. P. W. Reddell, Dr. V. A. Gordon
EcoBiotics Limited
PO Box 1, Yungaburra, 4884, Queensland (Australia)
From a medicinal chemistry perspective, however, the 7,8-
substituted bicycloACTHNUTRGNEUNG[4.2.0]octa-2,4-diene fragment 1 has the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903454.
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FULL PAPER
Scheme 3.
products.[31,33] There are several reports of [4+2] cycloaddi-
tion reactions between electron-rich 1,8-disubstituted cyclo-
octatetraenes and tetracyanoethylene[30d,34,35] or maleic anhy-
dride.[36] Although up to eight regioisomeric adducts are
possible for these reactions, only 3,4-disubstituted products
were observed in each case. Similarly, Paquette isolated
solely 3,4-disubstituted adducts when PTAD (12) was react-
ed with a 1,2-bridged cyclooctatetraene[37] and 1,8-di-tert-bu-
tylcyclooctatetraene.[38,39]
Scheme 1.
potential to act as a privileged structure, template or scaf-
fold and, as such, is of interest for our drug discovery pro-
gram. Hence, research into a new method for constructing
However, cyclooctatetraenes bearing electron-withdraw-
ing substituents remain untested, as do cases in which R1 ¼
R2. Furthermore, a literature search failed to uncover any
examples of [4+2] cycloadditions involving cyclooctate-
traenes with other, less reactive, diazo dienophiles, such as
DIAD (diisopropyl azodicarboxylate, 16, R=iPr, which
must first be isomerised to 17).[40,41] [4+2] Cycloadditions in-
volving diazo dienophiles[42] are a powerful class of reac-
tions, because the hydrazide adducts are readily converted
into azo alkenes that subsequently undergo a cycloreversion
reaction[43] which regenerates the 1,3-diene moiety.[44] In this
capacity, PTAD (12) is often used as a protecting group for
1,3-dienes in natural product synthesis.[45] Inspired by this
body of work, we postulated that reduction of a double
bond in an appropriately substituted Diels–Alder adduct
13—itself obtained from a [4+2] cycloaddition reaction be-
tween a 1,8-disubstituted cyclooctatetraene 14 and a diazo
compound—followed by cycloreversion might constitute a
asymmetric 7,8-substituted bicycloACTHUNGTERN[NUNG 4.2.0]octa-2,4-dienes 1
was undertaken.
Since a cyclooctatriene ring (i.e., 8) is formed in the 8p–
6p electrocyclisation cascade from tetraenes 4 (Scheme 1),
we wondered if a 1,8-substituted cyclooctatetraene could act
as a vehicle to target bicycles 1.[17] It is known that cyclooc-
tatetraenes 9 react with dienophiles via their bicyclo-
ACHTUNGTRENNUNG
[4.2.0]octa-2,4,7-triene valence tautomers 10,[18] which are
present in the equilibrium in minute concentrations, to
afford tetracycles 11 (Scheme 2).
novel route to 7,8-disubstituted bicycloACTHNUTRGNE[UNG 4.2.0]octa-2,4-dienes
1 (Scheme 4).
Scheme 2.
For the unsubstituted parent compound (9, R=H) the re-
action proceeds in high yield with a range of dienophiles, in-
cluding singlet oxygen,[19] maleic anhydride,[18,20,21] male-
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
imides,[20,22] tetracyanoethylene,[23] dimethyl acetylene
A
(DMAD),[24]
Scheme 4.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
cycloaddition between a monosubstituted cyclooctatetraene
(9, R¼H) and a symmetrical dienophile could, in principle,
result in four regioisomeric products, as there are four dif-
ferent possible regioisomers for bicycle 10. When R is elec-
tron donating the rate-determining step is the tautomerisa-
tion (k2 >k1) and, for all dienophiles previously investigated,
3-substituted products predominate.[30] In contrast, when R
is electron withdrawing the reaction outcome depends upon
the 2p component: tetracyanoethylene yields 3-substituted
products,[31] whereas, the more reactive dienophile, PTAD
(12, Scheme 3)[32] gives rise to mixtures of regioisomeric
The prospect that the adducts from [4+2] cycloaddition
reactions between 1,8-disubstituted cyclooctatetraenes 14
and diazo compounds (e.g., 12, 15[29b,46] and 16, Scheme 3)
could find a niche synthetic application, coupled with the
unanswered questions about the reaction itself, led us to un-
dertake a comprehensive survey of the transformation. Such
an investigation has the added advantage of generating an
ordered array of novel nitrogen-containing compounds (i.e.,
13) for structure activity relationship studies. The results of
this odyssey are reported herein, along with the conversion
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C. M. Williams et al.
of one of the major adducts to an, otherwise elusive, 7,8-di-
substituted bicyclo[4.2.0]octa-2,4-diene.
exist predominantly as the monocyclic tautomer and the
equilibrium concentration of the bicyclic tautomer is less
than 5%, as judged by H NMR spectroscopy. This is in con-
G
E
ACHTUNGTRENNUNG
1
trast to 1,8-di-tert-butylcylcooctatetraene, which has been in-
vestigated by Paquette, but is an atypical cyclooctatetraene,
as its bicyclic tautomer predominates.[38] Since the results for
the monosubstituted series depended, in part, upon the di-
enophile, both diisopropyl azodicarboxylate (DIAD, 16, R=
iPr) and PTAD (12) were screened as the 2p component.
Results and Discussion
A range of electron-poor and electron-rich 1,8-disubstituted
cyclooctatetraenes were examined, that is, 18,[47] 19, 20,
21,[36b] 22, 23 and 24 (Table 1). All of the substrates tested
Table 1. The reaction of 1,8-disubstituted cyclooctatetraenes with diazo compounds 12 and 16.[a]
Entry
Cyclooctatetraene
Dienophile
Solvent
t [h]
T [8C]
Product(s)
1
PTAD
EtOAc
1[b]
70
2
PTAD
EtOAc
16
55
3
4
PTAD
PTAD
EtOAc
EtOAc
1[b]
70
55
68
5
6
PTAD
PTAD
EtOAc
EtOAc
2
1
8
55
55
55
7
8
PTAD
DIAD
EtOAc
EtOAc
16[f]
4[b]
35
70
No reaction
No reaction
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Cyclooctatetraenes
Table 1. (Continued)
FULL PAPER
Entry
Cyclooctatetraene
Dienophile
DIAD
Solvent
EtOAc
t [h]
T [8C]
Product(s)
9
16[f]
35
10
DIAD
cyclohexane
46[f]
35
11
12
DIAD
DIAD
cyclohexane/EtOAc, 1:1
cyclohexane
8[f]
35
35
16[f]
No reaction
[a] 1.2 equivalents of the diazo compound, unless stated otherwise. PTAD=4-phenyl-1,2,4-triazole-3,5-dione (12); DIAD=diisopropyl azodicarboxylate
(16, R=iPr); TBS=tert-butyldimethylsilyl. [b] Microwave irradiation (150 W). [c] 1.7 equivalents of PTAD. [d] Yield calculated by using the NMR spec-
trum. [e] Yield for the uncharacterised component was calculated by using the NMR spectrum. [f] UV irradiation (1000 W).
Unfortunately, the sulfur derivative 15 could not be generat-
ed in significant quantities and no reaction was observed
with di-tert-butyl azodicarboxylate (16, R=tBu). Reactions
involving DIAD were performed in the presence of UV ir-
oxymethyl]cyclooctatetraene (24) with 12 was complicated
by the formation of substantial quantities of an unidentified
product that appeared to contain two PTAD moieties. It
was, however, possible to ascertain that the 2,3-diACTHNUTRGNENGsU ubACHTUNGTRENNUNGstituted
A
isomer 41 is favoured to an even greater extent with this
substrate.
bond to the cis geometry (i.e., 16 to 17, Scheme 3) as report-
ed by Askani.[48] The results of these reactions are summar-
ised in Table 1.
Interestingly, no products arising from the 1,4-cycloaddi-
tion of 12 to the monocyclic cyclooctatetraene tautomer
were observed with any of the substrates investigated. This
is despite the propensity of 12 to give rise to such products
Moving through the PTAD (12) series (Table 1, entries 1–
7), it is apparent that the ratio of 3,4-disubstitued adducts to
2,3-disubstituted adducts increases as the cyclooctatetraenes
become more electron rich. The series begins with the exclu-
sive formation of the 2,3-disubstituted adduct 25 from di-
methyl cyclooctatetraene-1,8-dicarboxylate (18) (Table 1,
entry 1) and culminates with the isolation of the 3,4-disubsti-
tuted adduct 34 as the major product from cyclooctatetraene
22 (Table 1, entry 5). When two regioisomeric 2,3-disubsti-
tuted adducts were possible (Table 1, entries 2, 3 and 5), ad-
ducts with the more electron-withdrawing substituent occu-
pying the bridgehead position (compounds 27, 30 and 35)
were isolated in higher yields than adducts with the less
electron-withdrawing substituent at the bridgehead position
(compounds 28, 31 and 36). The tert-butyldimethylsilyl-con-
taining (TBS) substrate 23, which was the most electron-rich
cyclooctatetraene examined, generated results that deviate
from these trends (Table 1, entry 6). It would appear that, in
this instance, steric factors compete with the electronic ef-
fects to increase the formation of the 2,3-disubstituted
adduct 38, in which steric hindrance between the bulky TBS
group and the ethyl group is now a considerable factor. An
attempt to further extend the series by reacting the even
more sterically demanding 1,8-bis[(tert-butyldimethylsilyl)-
when reacted with unsubstituted cyclo
ene[26a,30] and
ACHTUNGTRENNUoGN ctaACHTUNGTREGtNNUN etraCAHTNUGTRENNGUN
monosubstituted cyclooctatetraenes.[30d]
DIAD (16, R=iPr) was less tolerant of highly electron-
rich or -deficient cyclooctatetraenes than PTAD (12; com-
pare entries 8 and 12 with entries 1 and 5, Table 1). For the
three substrates that did react, the trend observed in the
PTAD series appears to be inverted. Cyclooctatetraenes 19
and 20 produced only 3,4-disubstituted adducts (Table 1, en-
tries 9 and 10), whereas a mixture of both possible re-
gioisomers (44 and 45) was obtained from the more elec-
tron-rich
1,8-di(acetoxymethyl)cyclooctatetraene
(21;
Table 1, entry 11). To the best of our knowledge, these are
the first examples of [4+2] cycloaddition reactions between
cyclooctatetraenes and diazo dicarboxylates.
For a given cyclooctatetraene, 12 tended to give rise to
higher ratios of 2,3-disubstituted adducts than 16 (R=iPr;
compare entries 2 and 3 with 9 and 10, Table 1). Particularly
striking are the results for ethyl 8-ethylcyclooctatetraene-1-
carboxylate (20); reaction with 12 yielded an almost 1:1
ratio of 2,3-disubstituted adducts to 3,4-disubstituted adduct,
while addition to 16 (R=iPr) led exclusively to the 3,4-dis-
ubstituted adduct 43 (Table 1, entries 3 and 10). This finding
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C. M. Williams et al.
parallels Huisgenꢁs[31] observation that the reaction of mono-
substituted cyclooctatetraenes with 12 results in a more di-
verse range of products than reactions with less reactive di-
enophiles. (Note: the standard protocol for PTAD reactions
is to cease the reaction when the red colour has been dis-
charged, which results in differing reaction times and tem-
peratures.[31,33]) Although there are reports detailing the syn-
thesis of 1-cyanocyclooctatetraene[33,49] and 1,2-dicyanocy-
clooctatetraene,[50] all attempts to synthesise nitrile-substitut-
ed cyclooctatetraenes to use in this reaction failed.
The structures of the adducts were determined by using a
combination of 1D and 2D NMR experiments. If R1 =R2,
the 2,3-disubstituted adducts could be unambiguously identi-
fied from the 1H NMR spectra alone. For unsymmetrical
substrates, COSY and NOESY spectra were needed for
structure elucidation. COSY experiments were also used to
confirm the structures of the 3,4-disubstituted adducts; cross
peaks between the olefin protons and the bridgehead me-
thine protons (H1 and H6) ruled out the possibility of 9,10-
disubstituted adducts. Single-crystal X-ray diffraction analy-
ses of several adducts [from both 12 and 16 (R=iPr)] veri-
fied that the relative configurations at C1 and C6 are as de-
picted. As shown in Figure 1 for adducts 25, 28 and 43 the
dienophile adds to the less hindered face of the diene. Simi-
lar observations have been documented for the cyclooctate-
traene–maleic anhydride adduct.[51]
With the survey of the key transformation complete, our
focus shifted to converting one of the cycloadducts into a
7,8-disubstituted bicycloACTHNUGRTENUNG[4.2.0]octa-2,4-diene 1. Inspection of
Table 1 reveals that adducts with the correct regiochemistry
were isolated in good yields in two instances (Table 1, en-
tries 5 and 10). Adduct 43, which was isolated in high yield
from ethyl 8-ethylcyclooctatetraene-1-carboxylate (20) and
16 (R=iPr), without purification by preparative HPLC, was
selected for further elaboration, mainly because its conjugat-
ed ester functionality should facilitate selective reduction of
the desired double bond (Scheme 5). Reduction of the con-
jugated double bond in ester 43 was achieved by using mag-
nesium in methanol.[52] Treatment with sodium methoxide
completed epimerisation and furnished alkenes 46 as an in-
Figure 1. ORTEP diagrams of compounds 25, 28 and 43 at the 30% prob-
ability level.
Scheme 5. a) Mg, MeOH, sonication, 3 h, RT; b) Na, MeOH, 4 h, 0–5 8C; c) LiBEt3H, THF, 1 h ꢀ20–5 8C; d) KOH, EtOH, microwave irradiation
(50 W), 80 8C, 5 psi, 5 h; e) NaH, PMB-Cl, Bu4NI, THF, 0 8C–RT, overnight.
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Cyclooctatetraenes
FULL PAPER
separable mixture of diastereomers (Scheme 5). The ester
functionality was then smoothly reduced with Super-Hy-
drideꢂ (LiBEt3H) to provide alcohols 47 in good yield.
When alcohols 47 were subjected to microwave irradiation
in the presence of potassium hydroxide, the hitherto un-
dative stress,[55] these compounds may inhibit a relevant cel-
lular defence mechanism. The leukaemia cell line K562 and
normal fibroblasts NFF tended to be insensitive to these
structures. To determine whether potency would increase
with pure enantiomers as opposed to racemates 25 was re-
solved by using chiral chromatography, however, neither
enantiomer improved potency.
known bicyclo
in yields of up to 50%. Elaboration of alcohols 48 to para-
methoxybenzyl ethers (PMBO) 49 enabled separation of the
ACHTUNGTRENNUNG[4.2.0]octa-2,4-dienes 48 were formed cleanly
AHCTUNGTRENNUNG
diastereomers through careful flash column chromatogra-
phy. The relative stereo configurations were determined
from the NOESY spectra of PMB ethers 49 (key correla-
tions shown in Scheme 5). It is important to note that sub-
stantial efforts to generate a suitable precursor for bicycles
48, either through the dienediyne or cross-coupling[53] ap-
proaches, failed. Also, when the conjugate reduction was
performed on cyclooctatetraene 20 a complex mixture was
obtained and the expected [4.2.0] bicycle was not isolated,
even after preparative HPLC. This indicates that protection
of the 1,3-diene unit in 20 through a [4+2] cycloaddition re-
action with 16 (R=iPr) is a crucial step in the sequence. An
attempt was made to extend the protocol to access a 1,8-dis-
Conclusion
In summary, a survey of the [4+2] cycloaddition reaction be-
tween 1,8-disubstituted cyclooctatetraenes and diazo dieno-
philes revealed that if PTAD (12) is the dienophile, 3,4-di-
ACHUTNGRENsNUG ubACHUTNGTRENsNNGU tituted products predominate for electron-rich cyclooc-
tatetraenes, while electron-deficient cyclooctatetraenes are
mainly converted into 2,3-disubstituted adducts. The reac-
tions between 1,8-disubstituted cyclooctatetraenes and
DIAD (16, R=iPr), which are reported here for the first
time, lead predominantly to 3,4-disubstituted adducts. Also
detailed is a novel protocol for the preparation of 7,8-disub-
ubstituted bicyclo
G
stituted bicycloACHTGUNTERNNU[G 4.2.0]octa-2,4-dienes that utilises one of the
25 (Table 1, entry 1). However, when compound 25 was ex-
posed to magnesium in methanol, conjugate addition of
methoxide was observed instead of double bond reduction
and the trisubstituted product 50 was deemed to be incom-
patible with the basic[45a] or reducing[45h,i] conditions that are
typically required for PTAD deprotection.
[4+2] cycloaddition products as a key intermediate. This
structure class may constitute a platform for achieving vary-
ing potencies against a range of human tumour types.
Experimental Section
Since our recent focus has been on cancer treatments,[54]
a
range of cell lines were treated with the compounds listed in
Table 2. The responses of different cell types varied consid-
erably. The most notable feature was the sensitivity of the
melanoma cell line MM96 L to 25, 28, 29, 36, and 43, fol-
lowed by moderate sensitivity of the breast cancer cell line
MCF7 to compound 25. The nature of the diimide substitu-
ents appears to be irrelevant to potency, which seems to
depend on the identity and location of substituents in the
unsaturated butane ring. Since MM96 L is susceptible to oxi-
Representative procedure: the reaction of cyclooctatetraenes with PTAD
(12): Compound 12 (13.6 mg, 0.08 mmol) was added to a solution of 22
(13.6 mg, 0.067 mmol) in ethyl acetate (0.8 mL) and the mixture was
stirred at 558C until thin-layer chromatography (TLC) indicated com-
plete consumption of the starting material (~2 h). The solution was con-
centrated in vacuo and the residue was subjected to flash column chro-
matography (petroleum ether/Et2O, 1:3 then Et2O). The resulting mixture
of regioisomeric adducts was further purified by preparative HPLC in
the following order:
2-(Acetoxymethyl)-3-ethyl-7,8-diazatricyclo[4.2.2.02,5]deca-3,9-diene-7,8-di-
carboxylic acid phenylimide (35): White solid, 14% yield; m.p. 80–818C;
1H NMR (500 MHz, CDCl3): d=0.97 (t, J=7.5 Hz, 3H), 1.84–1.92 (m,
1H), 2.01–2.09 (m, 1H), 2.09 (s, 3H), 2.82–2.83 (m, 1H), 4.38 (d, J=
11.2 Hz, 1H), 4.56 (d, J=11.2 Hz, 1H), 4.97–5.01 (m, 2H), 5.62–5.63 (m,
1H), 6.16–6.19 (m, 1H), 6.27–6.30 (m, 1H), 7.32–7.35 (m, 1H), 7.41–
7.45 ppm (m, 4H); 13C NMR (101 MHz, CDCl3): d=10.3, 20.9, 22.3, 40.0,
48.7, 54.7, 55.2, 64.3, 125.6, 126.9, 127.0, 127.5, 128.3, 129.1, 131.4, 156.45,
156.54, 156.7, 170.8 ppm; MS (ESI): m/z: 402 [M+Na]+; HRMS (ESI):
m/z: calcd for C21H21N3O4Na [M+Na]+: 402.1424; found: 402.1425.
3-(Acetoxymethyl)-4-ethyl-7,8-diazatricyclo[4.2.2.02,5]deca-3,9-diene-7,8-di-
carboxylic acid phenylimide (34): Colourless oil, 47% yield; 1H NMR
(400 MHz, CDCl3): d=0.98 (t, J=7.6 Hz, 3H), 2.01–2.07 (m, 2H), 2.07
(s, 3H), 3.13–3.14 (m, 2H), 4.40 (d, J=13.3 Hz, 1H), 4.50 (d, J=13.3 Hz,
1H), 5.01–5.04 (m, 2H), 6.15–6.18 (m, 2H), 7.32–7.35 (m, 1H), 7.40–
7.43 ppm (m, 4H); 13C NMR (101 MHz, CDCl3): d=11.6, 20.8, 21.1, 37.0,
38.0, 54.2, 54.4, 58.7, 125.6, 126.5, 128.2, 129.1, 131.4, 136.5, 150.1, 156.05,
156.13, 170.6 ppm; MS (ESI): m/z: 402 [M+Na]+; HRMS (ESI): m/z:
calcd for C21H21N3O4Na [M+Na]+: 402.1424; found: 402.1424.
3-(Acetoxymethyl)-2-ethyl-7,8-diazatricyclo[4.2.2.02,5]deca-3,9-diene-7,8-di-
carboxylic acid phenylimide (36): Colourless oil, 5% yield; 1H NMR
(500 MHz, CDCl3): d=1.00 (t, J=7.5 Hz, 3H), 1.81–1.88 (m, 1H), 1.98–
2.05 (m, 1H), 2.08 (s, 3H), 2.86–2.87 (m, 1H), 4.42 (dt, J=2.0, 14.2 Hz,
1H), 4.50 (dt, J=1.3, 14.2 Hz, 1H), 4.76 (dd, J=1.6, 5.9 Hz, 1H), 4.98–
Table 2. Inhibition of the growth of cultured human cells (IC50 mgmLꢀ1).
Compound[a]
MCF7
MM96 L
NFF
K562
27
26
46
44
34
32
47
42
45
30
33
29
43
28
36
25[b]
12
20
>100
>100
21
48
>100
41
27
28
69
67
57
>100
38
19
68
>100
>100
91
>100
>100
>100
>100
>100
>100
29
>100
>100
>100
>100
>100
>100
>100
>100
>100
49
>100
>100
69
>100
13
>100
12
5
6
32
5.5
12
2.1
>100
9
1.8
0.64
12
79
11
>100
5
61
11
>100
1.7
4.8
[a] Dissolved in ethanol, unless specified otherwise. [b] Dissolved in ace-
tone.
Chem. Eur. J. 2010, 16, 8894 – 8903
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8899

C. M. Williams et al.
5.00 (m, 1H), 5.86 (s, 1H), 6.10–6.13 (m, 1H), 6.28–6.31 (m, 1H), 7.33–
7.35 (m, 1H), 7.42–7.43 ppm (m, 4H); 13C NMR (126 MHz, CDCl3): d=
9.6, 20.7, 22.9, 41.3, 50.4, 54.8, 58.3, 60.1, 125.6, 125.9, 128.19, 128.22,
129.1, 131.5, 131.6, 148.3, 156.3, 156.5, 170.3 ppm; MS (ESI): m/z: 402
[M+Na]+; HRMS (ESI): m/z: calcd for C21H21N3O4Na [M+Na]+:
402.1424; found: 402.1424.
(100 mL) and brine (100 mL), dried (MgSO4) and concentrated in vacuo.
The residue was subjected to flash column chromatography (petroleum
ether/Et2O, 1:1 then Et2O) and the resulting mixture of methyl and ethyl
esters was taken up in anhydrous methanol (59 mL). Sodium (0.421 g,
18.3 mmol) was added at 08C under argon. The mixture was stirred at 0–
58C for 4 h and then quenched with saturated ammonium chloride
(75 mL). The product was extracted into diethyl ether (3ꢃ50 mL) and
the combined organic phase was washed with water (75 mL) and brine
(75 mL). Drying (MgSO4) followed by concentration in vacuo afforded
compounds 46a and 46b as a white foam (1.17 g, 82%); 1H NMR
(300 MHz, CDCl3): d=0.74 (t, J=7.3 Hz, 3H), 1.14–1.19 (m, 12H), 1.27–
1.40 (m, 2H), 2.46–2.27 (m, 2H), 2.69 (brs, 1H), 3.13 (brs, 1H), 3.57 (s,
3H), 4.79–4.91 (m, 4H), 6.37–6.73 ppm (m, 2H); GC/MS (EI): m/z (%):
394 (7) [M]+, 308 (17), 266 (21), 115 (35), 91 (25), 83 (22), 81 (59), 79
(34), 78 (84), 44 (29), 43 (100), 41 (58); HRMS (EI): m/z: calcd for
C20H30N2O6 [M]+: 394.2098; found: 394.2111.
Representative procedure: the reaction of cyclooctatetraenes with PTAD
under microwave irradiation:
A solution of compounds 20 (20 mg,
0.098 mmol) and 12 (18 mg, 0.10 mmol) in ethyl acetate (1.2 mL) was
subjected to microwave irradiation (708C, 150 W, 1 h) and then concen-
trated in vacuo. Flash column chromatography (petroleum ether/Et2O,
10:1 then Et2O) furnished a mixture of regioisomers. The resulting mix-
ture of regioisomeric adducts was further purified by preparative HPLC
in the following order:
2-Carboethoxy-3-ethyl-7,8-diazatricyclo[4.2.2.02,5]deca-3,9-diene-7,8-dicar-
boxylic acid phenylimide (30): Yellow oil, 26% yield; 1H NMR
(300 MHz, CDCl3): d=0.98 (t, J=7.5 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H),
1.86–2.06 (m, 2H), 3.56–3.58 (m, 1H), 4.27 (qd, J=1.1, 7.1 Hz, 2H),
4.99–5.03 (m, 1H), 5.38 (dd, J=1.8, 5.8 Hz, 1H), 5.81–5.83 (m, 1H),
6.18–6.30 (m, 2H), 7.29–7.37 (m, 1H), 7.41 ppm (d, J=4.5 Hz, 4H);
13C NMR (126 MHz, CDCl3): d=10.2, 14.3, 22.2, 39.7, 54.6, 55.4, 56.5,
61.6, 125.6, 126.3, 127.3, 128.2, 129.1, 131.0, 131.4, 154.2, 156.2,
170.6 ppm; MS (ESI): m/z: 402 [M+Na]+; HRMS (ESI): m/z: calcd for
C21H21N3O4Na [M+Na]+: 402.1424; found: 402.1424.
Super hydrideꢀ reduction of compounds 46a and 46b: Super hydride
(LiBHEt3; 1.0m in tetrahydrofuran, 2.04 mL, 2.04 mmol) was added to a
solution of the esters 46a and 46b (0.361 g, 0.916 mmol) in anhydrous tet-
rahydrofuran (6.4 mL) at ꢀ208C under an argon atmosphere. The reac-
tion was stirred at 08C for 1 h and then poured into ice-cold hydrochloric
acid (2n, 10 mL). The product was extracted into ethyl acetate (2ꢃ
10 mL). The aqueous phase was treated with brine (10 mL) and addition-
al product was extracted into ethyl acetate (2ꢃ10 mL). The combined or-
ganic phase was washed with brine (20 mL) and dried (MgSO4). Concen-
tration in vacuo followed by flash column chromatography (petroleum
ether/Et2O, 1:1 then Et2O) furnished alcohols 47a and 47b as a white
3-Carboethoxy-2-ethyl-7,8-diazatricyclo[4.2.2.02,5]deca-3,9-diene-7,8-dicar-
1
boxylic acid phenylimide (31): Yellow oil, 4% yield; H NMR (500 MHz,
CDCl3): d=0.99 (t, J=7.5 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H), 2.02 (q, J=
7.5 Hz, 2H), 2.96 (d, J=4.6 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 4.94 (dd,
J=1.6, 5.5 Hz, 1H), 5.06–5.08 (m, 1H), 6.09–6.12 (m, 1H), 6.32–6.35 (m,
1H), 6.59 (d, J=0.6 Hz, 1H), 7.33–7.36 (m, 1H), 7.41–7.45 ppm (m, 4H);
13C NMR (126 MHz, CDCl3): d=14.2, 23.0, 29.7, 41.7, 50.5, 54.5, 58.0,
60.6, 125.6, 125.7, 128.3, 128.9, 129.1, 131.4, 143.5, 144.3, 156.4, 156.5,
161.2 ppm; MS (ESI): m/z: 402 [M+Na]+; HRMS (ESI): m/z: calcd for
C21H21N3O4Na [M+Na]+: 402.1424; found: 402.1421.
3-Carboethoxy-4-ethyl-7,8-diazatricyclo[4.2.2.02,5]deca-3,9-diene-7,8-dicar-
boxylic acid phenylimide (29): White solid, 35% yield; 1H NMR
(300 MHz, CDCl3): d=1.04 (t, J=7.7 Hz, 3H), 1.27 (t, J=6.9 Hz, 3H),
2.32–2.48 (m, 2H), 3.22 (t, J=4.2 Hz, 1H), 3.31–3.34 (m, 1H), 4.16 (qd,
J=1.5, 6.9 Hz, 2H). 5.08–5.12 (m, 1H), 5.17–5.21 (m, 1H), 6.13–6.25 (m,
2H), 7.31–7.36 (m, 1H), 7.40–7.43 ppm (m, 4H); 13C NMR (126 MHz,
CDCl3): d=11.0, 14.3, 22.5, 36.1, 38.4, 53.8, 60.2, 125.5, 125.6, 127.1,
128.3, 129.1, 131.4, 131.9, 156.0, 156.2, 161.9, 164.9 ppm; MS (ESI): m/z:
402 [M+Na]+; HRMS (ESI): m/z: calcd for C21H21N3O4Na [M+Na]+:
402.1424; found: 402.1421.
1
foam (0.241 g, 72%); H NMR (300 MHz, CDCl3): d=0.71 (t, J=7.4 Hz,
3H), 1.10–1.18 (m, 12H), 1.23–1.35 (m, 2H), 1.87 (quint, J=6.8 Hz, 1H),
2.02 (quint, J=8.5 Hz, 1H), 2.67 (brs, 2H), 3.40–3.44 (m, 2H), 4.78–4.87
(m, 4H), 6.34–6.69 ppm (m, 2H); GC/MS (EI): m/z (%): 366 (4) [M]+,
280 (8), 86 (33), 81 (43), 57 (22), 43 (100), 41 (47); HRMS (EI): m/z:
calcd for C19H30N2O5 [M]+: 366.2149; found: 366.2162;
Diene deprotection of alcohols 47a and 47b: Potassium hydroxide
(0.742 g, 13.2 mmol) was added to a solution of alcohols 47a and 47b
(0.445 g, 1.21 mmol) in anhydrous ethanol (10 mL) and the mixture was
heated in a microwave reactor (5 psi, 808C, 50W) for 5 h. On cooling,
water (30 mL) was added and the product was extracted into diethyl
ether (3ꢃ20 mL). The combined organic phase was dried (MgSO4) and
concentrated in vacuo. Flash column chromatography (petroleum ether/
Et2O/NEt3, 50:50:0.5) afforded dienes 48a and 48b as a colourless oil
(0.099 g, 50%); 1H NMR (400 MHz, CDCl3): d=0.78–0.86 (m, 6H),
1.23–1.29 (m, 2H), 1.42–1.65 (m, 4H), 2.17–2.22 (m, 1H), 2.41–2.47 (m,
2H), 2.52–2.58 (m, 2H), 2.65–2.72 (m, 1H), 3.11–3.13 (m, 1H), 3.19–3.21
(m, 1H), 3.53–3.66 (m, 2H), 3.74–3.83 (m, 2H), 5.54–5.68 (m, 6H), 5.82–
5.86 ppm (m, 2H); 13C NMR (101 MHz, CDCl3): d=12.2, 12.6, 23.4, 29.0,
32.3, 33.1, 33.9, 36.2, 48.6, 50.6, 51.9, 53.8, 63.7, 65.8, 121.2, 121.8, 124.0,
124.4, 125.3, 126.4, 126.8, 127.9 ppm; GC/MS (EI): m/z (%): 164 (3) [M]+,
133 (1), 80 (20), 78 (65), 57 (100); HRMS (EI): m/z: calcd for C11H16O
[M]+: 164.1196; found: 164.1200;
Representative procedure: the reaction of cyclooctatetraenes with DIAD
(16, R=iPr): A solution of 20 (1.96 g, 9.60 mmol) and 16 (R=iPr;
2.25 mL, 11.4 mmol) in cyclohexane (100 mL) in a pyrex reaction vessel
was exposed to UV irradiation (Hanovia high pressure mercury–xenon
vapour lamp, 1000 W; note: the light was passed through a 30 cm long
ꢁ58C water filter) for 46 h. The solvent was removed in vacuo and the
residue was purified by flash column chromatography (petroleum ether/
Et2O, 1:1 then Et2O) to yield compound 43[60] as a colourless oil (2.75 g,
71%) that solidified into a crystalline solid (m.p. 70–728C) suitable for
X-ray crystallography when stored at ꢀ208C; 1H NMR (300 MHz,
[D6]DMSO): d=0.92 (t, J=7.6 Hz, 3H), 0.97 (t, J=7.6 Hz, 3H), 1.15–
1.21 (m, 30H), 2.21–2.36 (m, 4H), 2.85–3.20 (m, 4H), 4.03–4.11 (m, 4H),
4.74–4.82 (m, 4H), 4.93 (brs, 2H), 5.04 (brs, 2H), 6.10–6.16 (m, 2H),
6.31–6.35 ppm (m, 2H); GC/MS (EI): m/z (%): 406 (5) [M]+, 320 (12),
131 (21), 81 (86), 43 (100), 41 (52); HRMS (EI): m/z: calcd for
C21H30N2O6 [M]+: 406.2098; found: 406.2086.
PMB derivatisation of dienes 48a and 48b: Sodium hydride (60% sus-
pension in mineral oil, 14 mg, 0.35 mmol), 4-methoxybenzyl chloride
(30 mL, 0.22 mmol) and tetrabutylammonium iodide (8.1 mg, 0.022 mmol)
were added to a solution of dienes 48a and 48b (22 mg, 0.14 mmol) in
anhydrous tetrahydrofuran at 08C under an argon atmosphere. The mix-
ture was warmed to room temperature overnight and then diluted with
diethyl ether (5 mL). The solution was then washed with water (5 mL)
and brine (5 mL), dried (Na2SO4) and concentrated in vacuo. Flash
column chromatography (petroleum ether/Et2O, 19:1) provided ethers
49a and 49b as a mixture of diastereomers (17 mg, 45%). Careful flash
column chromatography of this mixture (petroleum ether/Et2O, 39:1, no
pressure) provided analytically pure samples of each diastereomer. Sig-
nificant decomposition occurred during separation of the diastereomers.
Magnesium reduction of compound 43: Magnesium turnings, in three
equal portions, (0.742 g, 30.5 mmol in total) were added to a solution of
diene 43 (1.48 g, 3.64 mmol) in anhydrous methanol (63 mL) under an
argon atmosphere. After each addition the suspension was briefly heated
to reflux (heat gun) and then sonicated until all of the metal had dis-
solved (ca. 1 h each time). The reaction was quenched with 10% citric
acid solution (100 mL) and the product was extracted into diethyl ether
(3ꢃ70 mL). The combined organic phase was washed with water
7-Ethyl-8-[(4-methoxybenzyloxy)methyl]bicycloACTHNUTRGNE[UNG 4.2.0]octa-2,4-diene (49a):
Rf =0.32; 1H NMR (400 MHz, CDCl3): d=0.82 (t, J=7.4 Hz, 3H), 1.49–
1.62 (m, 2H), 2.42 (quint, J=8.1 Hz, 1H), 2.50–2.57 (m, 1H), 2.68 (ddd,
J=5.2, 8.3, 10.7 Hz, 1H), 3.07–3.13 (m, 1H), 3.36 (dd, J=6.6, 9.8 Hz,
1H), 3.43 (dd, J=5.3, 9.8 Hz, 1H), 3.79 (s, 3H), 4.39 (d, J=11.7 Hz, 1H),
8900
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 8894 – 8903

Cyclooctatetraenes
FULL PAPER
4.43 (d, J=11.8 Hz, 1H), 5.53–5.61 (m, 2H), 5.65 (dd, J=5.2, 9.4 Hz,
1H), 5.80–5.84 (m, 1H), 6.86 (d, J=8.7 Hz, 2H), 7.22 ppm (d, J=8.7 Hz,
2H); 13C NMR (101 MHz, CDCl3): d=12.6, 23.4, 33.7, 34.0, 49.2, 51.4,
55.3, 72.4, 73.0, 113.7, 121.6, 123.9, 126.5, 127.0, 129.0, 130.9, 159.0 ppm;
GC/MS (EI): m/z (%): 284 (1) [M]+, 175 (2), 162 (1), 145 (1), 136 (24),
121 (100) 78 (20); HRMS (EI): m/z: calcd for C19H24O2 [M]+: 284.1771;
found: 284.1776.
[5] a) J. E. Moses, J. E. Baldwin, R. M. Adlington, A. R. Cowley, R.
Marquez, Tetrahedron Lett. 2003, 44, 6625–6627; b) J. E. Moses,
J. E. Baldwin, S. Brꢄckner, S. J. Eade, R. M. Adlington, Org.
Biomol. Chem. 2003, 1, 3670–3684; c) J. E. Moses, J. E. Baldwin, R.
Marquez, R. M. Adlington, Org. Lett. 2002, 4, 3731–3734.
[6] a) S. J. Eade, M. W. Walter, C. Byrne, B. Odell, R. Rodriguez, J. E.
Baldwin, R. M. Adlington, J. E. Moses, J. Org. Chem. 2008, 73,
4830–4839; b) P. Sharma, B. Lygo, W. Lewis, J. E. Moses, J. Am.
Chem. Soc. 2009, 131, 5966–5972.
7-Ethyl-8-[(4-methoxybenzyloxy)methyl]bicycloACTHNUTRGNE[UNG 4.2.0]octa-2,4-diene (49b):
Rf =0.21; 1H NMR (300 MHz, CDCl3): d=0.80 (t, J=7.4 Hz, 3H), 1.38–
1.48 (m, 2H), 2.09–2.19 (m, 1H), 2.52 (ddd, J=5.0, 8.0, 11.1 Hz, 1H),
2.67 (ddd, J=5.5, 9.0, 17.9 Hz, 1H), 3.13–3.17 (m, 1H), 3.61 (dd, J=5.5,
9.0 Hz, 1H), 3.62 (t, J=9.0 Hz, 1H), 3.79 (s, 3H), 4.40 (s, 2H), 5.54–5.64
(m, 3H), 5.77–5.82 (m, 1H), 6.85 (d, J=8.8 Hz, 2H), 7.24 ppm (d, J=
8.8 Hz, 2H); 13C NMR (101 MHz, CDCl3): d=12.3, 28.9, 32.7, 36.4, 49.5,
51.3, 55.3, 70.9, 72.7, 113.7, 121.3, 123.9, 126.1, 127.4, 129.3, 130.7,
159.1 ppm; GC/MS (EI): m/z (%): 284 (1) [M]+, 255 (1), 175 (3), 162 (1),
145 (1), 136 (23), 121 (100); HRMS (EI): m/z: calcd for C19H24O2 [M]+:
284.1771; found: 284.1767.
[7] a) K. A. Parker, Y.-H. Lim, J. Am. Chem. Soc. 2004, 126, 15968–
15969; b) K. A. Parker, Y.-H. Lim, Org. Lett. 2004, 6, 161–164.
[8] The serendipitous formation of the 7,8-disubstituted bicyclo-
AHCTUNGERTG[NNUN 4.2.0]octa-2,4-diene motif has been observed, see, for example:
R. A. S. Chandraratna, W. H. Okamura, J. Am. Chem. Soc. 1982,
104, 6114–6115 and A. C. Cope, N. A. Nelson, D. S. Smith, J. Am.
Chem. Soc. 1954, 76, 1100–1104; calculations describing the forma-
tion of this bicycle have also been reported, see: A. J. Fry, Tetrahe-
dron 2008, 64, 2101–2103.
[9] a) E. N. Marvell, J. Seubert, J. Am. Chem. Soc. 1967, 89, 3377–3378;
b) E. N. Marvell, J. Seubert, Tetrahedron Lett. 1969, 10, 1333–1336;
see also: c) H. Meister, Chem. Ber. 1963, 96, 1688–1696.
[10] a) R. Huisgen, A. Dahmen, H. Huber, J. Am. Chem. Soc. 1967, 89,
7130–7131; b) R. Huisgen, A. Dahmen, H. Huber, Tetrahedron Lett.
1969, 10, 1461–1464; c) A. Dahmen, R. Huisgen, Tetrahedron Lett.
1969, 10, 1465–1469.
[11] The “superior” Lindlar catalyst used by Nicolaou and co-workers
was a gift from Hoffman-La Roche, Inc. (see, for example, ref. [2d]).
This catalyst is not commercially available and extensive literature
searches failed to uncover preparation procedures. However, a P-2
Nickel catalyst has found applications in this area, see a) C. Hulot,
G. Blond, J. Suffert, J. Am. Chem. Soc. 2008, 130, 5046–5047; b) C.
Hulot, S. Amiri, G. Blond, P. R. Schreiner, J. Suffert, J. Am. Chem.
Soc. 2009, 131, 13387–13398.
Biological testing: Cells were cultured at 3000 cells per well in 96 well
plates by using 10% FCS (fetal calf serum) in RPMI (Roswell Park Me-
morial Institute) media and incubated for 24 h at 378C. Cells were treat-
ed with the following concentrations of drug: 100 mgmLꢀ1, 30 mgmLꢀ1
,
10 mgmLꢀ1, 3 mgmLꢀ1, 1 mgmLꢀ1, 0.3 mgmLꢀ1, 0.1 mgmLꢀ1 (solvent as in-
dicated in Table 2), allowed to grow until 90–95% confluent and fixed
with ethanol. Attached cell lines (NFF, MCF7, MM96 L) were stained
with 0.4% sulforhodamine B solution and read at 560 nm on a VERSA-
max microplate reader. The non-adherent cell line K562 was treated by
using [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sul-
fophenyl)-2H-tetrazolium] (MTS) assay, Promegaꢁs Celltiter 96 AQ One
solution cell proliferation assay, and read at 490 nm.
[12] Photoaddition to benzenes: a) E. J. Grovenstein, D. V. Rao, J. W.
Taylor, J. Am. Chem. Soc. 1961, 83, 1705–1711; b) B. E. Job, J. D.
Littlehailes, J. Chem. Soc. C 1968, 886–889; c) R. J. Atkins, G. I.
Fray, A. Gilbert, Tetrahedron Lett. 1975, 16, 3087–3088; d) R. J.
Atkins, G. I. Fray, A. Gilbert, M. W. bin Samsudin, A. J. K. Steward,
G. N. Taylor, J. Chem. Soc. Perkin Trans. 1 1979, 3196–3202; e) D.
Bryce-Smith, A. Gilbert, B. Orger, H. Tyrrell, J. Chem. Soc. Chem.
Commun. 1980, 334–335; f) A. Gilbert, P. Yianni, Tetrahedron 1981,
37, 3275–3283; g) A. Gilbert, P. Yianni, Tetrahedron Lett. 1982, 23,
4611–4614; h) D. Bryce-Smith, A. Gilbert, N. Al-Jalal, R. R. Desh-
pande, J. Grzonka, M. A. Hems, P. Yianni, Z. Naturforsch. B 1983,
38, 1101–1112; i) For reviews, see, J. Mattay, Angew. Chem. 2007,
119, 674–677; Angew. Chem. Int. Ed. 2007, 46, 663–665 and J.
Mattay, Tetrahedron 1985, 41, 2405–2417.
[13] Acylation and alkylation of cyclooctatetraenyl dianions, see:
a) D. A. Bak, K. Conrow, J. Am. Chem. Soc. 1966, 88, 3958–3965;
b) T. S. Cantrell, Tetrahedron Lett. 1968, 9, 5635–5638; c) T. S. Can-
trell, J. Am. Chem. Soc. 1970, 92, 5480–5483.
[14] a) H. Straub, J. M. Rao, E. Mꢄller, Liebigs Ann. Chem. 1973, 1339–
1351; b) E. Mꢄller, H. Straub, J. M. Rao, Tetrahedron Lett. 1970, 11,
773–776; c) H. Hoever, Tetrahedron Lett. 1962, 3, 255–256; d) L.
Moegel, W. Schroth, B. Werner, J. Chem. Soc. Chem. Commun.
1978, 57–58.
Acknowledgements
We thank EcoBiotics Ltd and the University of Queensland for financial
support. Dr. L. Lambert is acknowledged for assistance with NMR ex-
periments and the University of Queensland Enantioselective Chroma-
tography Facility for assistance with ee determinations and preparative
separations.
[1] a) W. M. Bandaranayake, J. E. Banfield, D. S. C. Black, G. D. Fallon,
B. M. Gatehouse, J. Chem. Soc. Chem. Commun. 1980, 162–163;
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5560–5562; d) K. C. Nicolaou, N. A. Petasis, Strategies Tactics Org.
Synth. 1984, 155–173; e) N. A. Petasis, PhD Thesis, University of
Pennsylvania (USA), 1983; f) R. E. Zipkin, PhD Thesis, University
of Pennsylvania (USA), 1984; g) K. C. Nicolaou, E. J. Sorensen in
Classics in Total Synthesis, VCH, Weinheim, 1996 and references
therein.
[15] With the exception of TMSCCMgBr, see: S. J. Harris, D. R. M.
Walton, Tetrahedron 1978, 34, 1037–1042, and acetate, see referen-
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8902
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Cyclooctatetraenes
FULL PAPER
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Received: December 17, 2009
Published online: June 22, 2010
Chem. Eur. J. 2010, 16, 8894 – 8903
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