Conjugate addition-Peterson olefination reactions: Expedient routes to cross conjugated dienones

Article abstract of DOI:10.1016/S0040-4039(03)01297-8

The synthesis of 5-alkylidenecyclopent-2-enones is readily achieved in two steps via a one-pot conjugate addition-Peterson olefination sequence, using exo-2-trimethylsilyl-3a,4,7,7a-tetrahydro-4,7-methanoinden-1-one, followed by a retro-Diels-Alder reaction.

Full text of DOI:10.1016/S0040-4039(03)01297-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5741–5745
Conjugate addition–Peterson olefination reactions: expedient
routes to cross conjugated dienones
Mazhar Iqbal and Paul Evans*
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Received 3 April 2003; revised 12 May 2003; accepted 22 May 2003
Abstract—The synthesis of 5-alkylidenecyclopent-2-enones is readily achieved in two steps via a one-pot conjugate addition–Peter-
son olefination sequence, using exo-2-trimethylsilyl-3a,4,7,7a-tetrahydro-4,7-methanoinden-1-one, followed by a retro-Diels–Alder
reaction.
©
2003 Elsevier Ltd. All rights reserved.
The cross conjugated dienone unit is present in various1
naturally occurring compounds of biological interest.
and on multi-gram scale via the Pauson–Khand cyclisa-
tion between trimethylsilyl acetylene and norbornadi-
ene. This species undergoes facile and chemoselective
2
9
For example, the clavulone 1 and 2 series of marine
1
2,14
natural products, the unsaturated prostaglandin D
-
1,4-conjugate addition with both organocuprate and
organomagnesium reagents in the presence of copper(I)
salts, generating the expected a-trimethylsilyl ketone
conjugate adducts on protonation. Classical Peterson
3
1
5-deoxy-PG-J 3, and the related C-18 chromomoric
2
4
acids 4 all contain this structural motif. Additionally
5
5
, an analogue of PG-A , is currently in pre-clinical
2
6
trials as an anticancer agent (Fig. 1).
olefination reactions were effected following treatment
of these conjugate adducts with LDA then benzalde-
hyde. However, the yields for this two-step process were
disappointingly low. Pleasingly, it was discovered that
addition of benzaldehyde (Table 1, entry 1) to an in situ
generated solution of the conjugate adduct 7 (from
We were attracted to the possibility of utilising a conju-
gate addition–Peterson olefination sequence as a novel
means of accessing this important structural motif (Fig.
6
2
). Surprisingly, this efficient transformation has been
7
virtually ignored following its disclosure in 1984. A
cyclopentene unit was chosen to mask the endocyclic
carbonꢀcarbon double bond in the cyclopentenone
moiety, since this group may be readily removed by a
Me CuLi, or MeMgBr and 10 mol% CuI) led to excel-
2
lent yields of the corresponding exocyclic enone 8a. In
1
the case of the reaction with Me CuLi, H NMR
2
spectroscopic analysis of the crude reaction mixture
indicated the formation of only one of the possible four
compounds. X-Ray structure analysis demonstrated
both the E-stereochemistry of the alkene formed and
the diastereoselectivity of the conjugate addition from
8
retro-Diels–Alder process.
Crucially, exo-2-trimethylsilyl-3a,4,7,7a-tetrahydro-4,7-
methanoinden-1-one 6 is readily available in high yield
Figure 1. Cross-conjugated cyclopentenones of biological interest.
*
Corresponding author. E-mail: pjevans@liv.ac.uk
0
040-4039/03/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01297-8

5
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M. Iqbal, P. E6ans / Tetrahedron Letters 44 (2003) 5741–5745
Figure 2. The one-pot conjugate addition–Peterson olefination reaction [M=metal].
the less hindered face of the enone 6. When MeMgBr
was used a small amount of the cis-alkene, separable by
flash column chromatography, was also formed (E:Z,
1,4-addition of the more sterically hindered iso-propyl-
magnesium chloride, and vinylmagnesium bromide pro-
ceeded smoothly using catalytic CuI (10 mol%) and in
both cases the corresponding magnesium enolate
reacted efficiently with benzaldehyde, affording enones
8d and 8e as separable mixtures of stereoisomers
(entries 4 and 5).
10
75:25). The addition of n-butyl- and n-octyl-
organometallics also successfully generated the
analogous Peterson products in good yield, following
the addition of benzaldehyde (entries 2 and 3). The
11
Table 1. Conjugate addition–Peterson olefination: synthesis of exocyclic enones 8a–8p

M. Iqbal, P. E6ans / Tetrahedron Letters 44 (2003) 5741–5745
5743
11
Table 2. retro-Diels–Alder: synthesis of cross-conjugated cyclopentenones 9a–9o and 5
Additional aromatic and heteroaromatic aldehydes
were shown to be successful reaction partners, although
it was found that the reaction was sensitive to the
electronic nature of the aldehyde. Thus, employment of
(83%) (entry 9). Similarly 2-furfural gave the enone 8k
in 94% yield (entry 10) stereoselectively. The process
described also proceeded efficiently with a,b-unsatu-
rated aldehydes (entries 11 and 12), thereby providing a
strategy for the installation of the exocyclic dienone
unit present in natural products 1 to 4 (Fig. 1).
4-methoxybenzaldehyde led to a sluggish reaction with
low yields of the corresponding alkene 8g (entry 7). In
contrast use of 4-nitrobenzaldehyde led to a rapid
reaction and the enone 8f was isolated in excellent yield
At this stage it was of interest to ascertain whether
aldehydes possessing acidic a-protons would participate
in the process, or if the carbanionic intermediate 7
might prove to be incompatible with such reaction
partners. However, this concern proved to be
unfounded and freshly distilled isobutyraldehyde gave
good yields of the corresponding adducts 8n and 8o
(entries 13 and 14). Interestingly, the stereochemical
integrity of the double bond formed was much less well
(
8
entry 6). 2-Pyridyl carboxaldehyde afforded the enone
h in 45% yield (entry 8). This moderate yield may
reflect competing complexation of the azo-functional
group with the copper species present after the conju-
gate addition. The electron rich N-methyl indole 3-carb-
oxaldehyde, gave a low yield (13%) of the exocyclic
enone 8i; however, the corresponding N-tosyl indole
carboxaldehyde afforded the adduct 8j in excellent yield

5
744
M. Iqbal, P. E6ans / Tetrahedron Letters 44 (2003) 5741–5745
Figure 3.
defined in these instances and significant amounts of the
readily separable Z-stereoisomers were formed. As
before (entries 1, 4 and 5) this lack of stereoselectivity
was most marked when organomagnesium reagents
were employed in the conjugate addition reaction. It
seems reasonable to speculate that this phenomenon is
partly due to a change in counterion in the intermediate
conjugate addition reaction proceeds with very high
diastereoselectivity; consequently in order to generate
enantioenriched, or homochiral products the corre-
sponding enantioenriched, or homochiral Pauson–
Khand adduct could be employed. Future work will
involve the development of the process described for the
synthesis of homochiral dienones and the application of
this method for the synthesis of 3 and 4.
14
7
(Li“MgBr) and that the counterion influences the
path of the Peterson reaction.
This reaction sequence described was then applied to a
Acknowledgements
5
rapid synthesis of (±)-TEI-9826 5. Thus, addition of
n
n
either ( Oct) CuLi, or OctMgBr (10 mol% CuI) to 6,
2
12
followed by addition of methyl 7-oxoheptanoate
Charterhouse Therapeutics, Oxford are thanked for the
provision of a Lectureship (P.E.), as are the Ministry of
Science and Technology and NIBGE, Pakistan for a
Ph.D. scholarship awarded to M.I. Dr. Herve Siendt
and Professor Stan Roberts, University of Liverpool are
thanked for helpful advice and discussions.
afforded the exocyclic enone 8p in good yield (entry 15).
The retro-Diels–Alder reactions of the norbornadiene
adducts 8a–p described in Table 2 were performed in
DCM at 40°C using MeAlCl and an excess of maleic
2
8
b
anhydride as a cyclopentadiene trap. Generally, this
method provided good yields of the corresponding cross
conjugated cyclopentenones 9a–o (see Table 2). Notable
exceptions were compounds containing basic azo-func-
tionality (entries 8 and 9), in these examples none of the
cyclopentenone products 9h and 9i were detected. It was
of interest that following employment of this Lewis acid
methodology the purified Z-exocyclic enones 8a and 8o
underwent significant alkene isomerisation, affording
predominantly the E-cross conjugated cyclopentenone
products 9a and 9o. For example, treatment of Z-8o
under these conditions gave 9o in 67% yield (E:Z, 88:12)
and 22% of isomerised starting material E-8o. Similarly,
the functionalised adduct 8p was smoothly converted to
the target dienone 5 in 86% yield.
References
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Preliminary experiments demonstrate that this process
may be applied in a more general sense. For example,
under the standard conditions indicated in Table 1,
13
cyclohexenone 10
afforded the trans-enone 11
stereoselectively in 46% yield. Additionally, it was found
that nucleophiles other than carbanions may be used:
PhSLi and benzaldehyde generated an undetermined
diastereomeric mixture of 12 (60:40) in 96% yield, result-
ing from an initial conjugate addition–Peterson olefina-
tion process followed by nucleophilic attack at the
exocyclic double bond and elimination. Optimum yields
for this process were achieved following a one-pot
reaction protocol in which all the reagents were added
simultaneously (Fig. 3).
In conclusion, we have developed an efficient and novel
method for the synthesis of cross-conjugated cyclopen-
tadienones in two high yielding steps. Significantly the
7. (a) Tsuge, O.; Kanemasa, S.; Ninomiya, Y. Chem. Lett.
1984, 1993; (b) Tanaka, J.; Kanemasa, S.; Ninomiya, Y.;

M. Iqbal, P. E6ans / Tetrahedron Letters 44 (2003) 5741–5745
5745
3
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(2×25 cm ). The combined organic extracts were then
dried over MgSO4. Filtration, followed by solvent
removal in vacuo and flash column chromatography
(Hex–EtOAc; 19:1) afforded the title compound 8c (604
mg, 84%) as a viscous yellow liquid. R =0.25 (Hex–
EtOAc; 19:1); lH (400 MHz, CDCl ) 0.88 (3H, t, J 6.5
Hz, CH ), 1.18–1.52 (15H, m, CH ), 1.64–1.73 (1H, m,
CH ), 2.05 (1H, d, J 7.5 Hz, CH), 2.47 (1H, d, J 7.5 Hz,
CH), 2.82 (1H, s, CH), 3.01–3.09 (1H, m, CH), 3.12 (1H,
s, CH), 6.23 (1H, dd, J 2.75, 5.5 Hz, CH), 6.28 (1H, dd,
J 3.0, 5.5 Hz, CH), 7.30 (1H, d, J 2.0 Hz, CH), 7.34–7.44
3H, m, ArH), 7.56 (2H, d, J 7.0 Hz, ArH); lC (100
MHz, CDCl ) 14.1, 22.6, 26.9, 29.2, 29.5, 29.6, 31.8, 34.7,
3.3, 44.4, 46.5, 48.4, 49.8, 53.7, 128.7, 129.4, 130.7,
33.4, 135.0, 137.6, 138.9, 144.3, 209.2; m/z (CI) 349
MH , 10%), 283 (MH−C H , 100%); Found 349.25394,
C H O requires 349.25314 (+2.5 ppm); Found C, 85.9;
f
8
9
3
3
2
2
. Iqbal, M.; Vyse, N.; Dauvergne, J.; Evans, P. Tetra-
hedron Lett. 2002, 43, 7859.
0. Representative procedure: 3-octyl-2-[1-phenyl-meth-(E)-
1
ylidene]-2,3,3a,4,7,7a-hexahydro-4,7-methanoinden-1-one
(
8
c: Under N2 a 1.7 M solution of tert-butyllithium in
3
3
pentane (4.9 cm , 8.33 mmol, 4 equiv.) was added drop-
wise to a solution of n-octyl iodide (0.75 cm , 4.15 mmol,
2
cm ) at −78°C. Stirring was continued at −78°C for 0.25
h before warming to room temperature over 1 h. The
solution of n-octyl lithium was re-cooled to −78°C and
4
1
(
3
3
equiv.) in a mixture of pentane (17 cm ) and Et O (10
2
+
+
3
5 6
25
33
H, 9.4%, C H O requires C, 86.2; H, 9.2%.
25
32
1
1
1. All new compounds were fully characterised by H and
added to a slurry of CuI (395 mg, 2.07 mmol, 1 equiv.) in
13
3
C NMR spectroscopic techniques, by microanalysis
Et O (10 cm ) at −78°C via cannula. The mixture was
2
and/or high resolution mass spectroscopy.
2. Suzuki, M.; Kawagishi, T.; Yanagisawa, A.; Suzuki, T.;
Okamura, N.; Noyori, R. Bull. Chem. Soc. Jpn. 1988, 61,
1299.
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Maestro, M. A.; Mahia, J. J. Am. Chem. Soc. 2000, 122,
10242.
warmed to −20°C over 1 h and the resultant cuprate was
1
cooled to −40°C before a solution of the enone 6 (452
3
mg, 2.07 mmol, 1 equiv.) in Et O (5 cm ) was added
2
3
dropwise [washed with Et O (2 cm )]. After stirring for 1
h (−40°C“−20°C) benzaldehyde (0.42 cm , 4.13 mmol, 1
2
3
1
equiv.) was added and the reaction was stirred for 18 h
and allowed to warm to room temperature. Saturated
1
3
3
NH Cl (25 cm ) and EtOAc (25 cm ) were added and the
4
resultant aqueous layer was further extracted with EtOAc