New cascade reactions starting from acetylenic ω-ketoesters: An easy access to electrophilic allenes and to 1,3-bridgehead ketones

Article abstract of DOI:10.1016/S0040-4039(03)01023-2

Acetylenic ω-ketoesters bearing a three carbon-carbon bond spacer reacted smoothly with tetra-n-butylammonium fluoride and with potassium tert-butoxide to afford either electrophilic allenes or 1,3-bridgehead ketones, the latter being potentially useful m

Full text of DOI:10.1016/S0040-4039(03)01023-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4483–4485
New cascade reactions starting from acetylenic v-ketoesters: an
easy access to electrophilic allenes and to 1,3-bridgehead ketones
Aure´lie Klein and Michel Miesch*
Universite´ Louis Pasteur, Faculte´ de Chimie, Laboratoire de Chimie Organique Synthe´tique,
1, rue Blaise Pascal BP 296/R8 67008 Strasbourg Cedex, France
Accepted 17 April 2003
Abstract—Acetylenic v-ketoesters bearing a three carbonꢀcarbon bond spacer reacted smoothly with tetra-n-butylammonium
fluoride and with potassium tert-butoxide to afford either electrophilic allenes or 1,3-bridgehead ketones, the latter being
potentially useful molecules for the synthesis of biologically active compounds like Garsubellin A and Hispidospermidin. © 2003
Elsevier Science Ltd. All rights reserved.
The emergence of complex polycyclic natural products
induces new challenges in organic synthesis. One of
them is the development of new cascade reactions
which enables a very fast access to complex molecules
starting from easily available compounds. In this con-
text, we recently reported that acetylenic v-ketoesters
bearing a four carbonꢀcarbon bond spacer arm located
between the cycloalkanone moiety and the electrophilic
triple bond led either to electrophilic allenes or to
electrophilic oxetanes depending on whether tetra-n-
butylammonium fluoride (TBAF) or potassium tert-
butoxide (t-BuOK) was used as a base.1
When the acetylenic v-ketoesters 1 and 2 were treated
with TBAF, the reaction proceeded smoothly. Indeed,
the allene derivatives 3 and 4 bearing a cis ring junction
were isolated as major compounds4 along with the spiro
derivatives 5 and 6 as minor products.5 In all cases,
starting material was recovered and the increase of the
reaction time led only to the formation of several
unidentified side products. These results proved to be in
good accordance with our previously reported observa-
tions (Scheme 2).1
However, when the acetylenic v-ketoesters 1 and 2 were
reacted with t-BuOK in THF, we never observed the
formation of oxetane derivatives as previously.1 Indeed,
a new cascade reaction took place leading respectively
to the tricyclic derivative 7 along with the diester 8 and
to the tricyclic compound 9. It has to be noted that the
reaction occured very cleanly: indeed, according to
TLC analysis, no other products were formed except
the diester 8 (Scheme 3).
To further extend the utility of our cascade reactions,
we focused our attention on the influence of the spacer
length. For that purpose, the acetylenic v-ketoesters 1
and 2 bearing a three carbonꢀcarbon bond spacer were
synthesized starting, respectively, from the correspond-
ing cycloalkanones. After formation of the N,N-
dimethylhydrazones and subsequent treatment with
n-BuLi,2 the addition of 5-iodopentyne3 followed by an
acidic hydrolysis yielded the corresponding ketones
which were protected as dioxolanes. The latter were
treated with n-BuLi and the acetylides were quenched
with ethyl chloroformate followed by an acidic depro-
tection to afford the desired acetylenic v-ketoesters 1
and 2 (Scheme 1).
Keywords: tetra-n-butylammonium fluoride; potassium tert-butoxide;
intramolecular Michael addition; acetylenic v-ketoesters; allenes; 1,3-
bridgehead ketones.
* Corresponding author. Tel./fax: +33(0)390241752; e-mail: miesch@
chimie.u-strasbg.fr
Scheme 1. Reagents and conditions: (i) (CH3)2NNH2,
CF3COOH cat., C6H6 reflux; (ii) n-BuLi, THF, −5°C, 5-
iodopentyne; (iii) diethyleneglycol, pTsOH cat., C6H6, reflux;
(iv) n-BuLi, THF, −78°C, ClCO2Et, HCl 10%.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01023-2

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A. Klein, M. Miesch / Tetrahedron Letters 44 (2003) 4483–4485
the tricyclic derivative 7 was isolated in 10% yield.
Under the same reaction conditions, the spiro deriva-
tive 5 afforded diester 86 as a major compound (Scheme
4).
Thus, the formation of these compounds could be
explained as follows: the addition of t-BuOK to the
acetylenic v-ketoester 1 (2) could lead to carbanion A
which evolves via an intramolecular Michae¨l addition
toward carbanion B which is in equilibrium with carb-
anion D. The latter could then cyclize intramolecularly
(Claisen condensation) to give the bridgehead ketone 7
(9). During that process, ethylate is formed and adds to
the carbonyl group of the spiroketone to give E which
evolves by a fragmentation reaction to afford the
diester 8. Of course, carbanion C could also be formed
(either via an intra or intermolecular process) to afford
the allene derivatives 3 (4) (Scheme 5).
Scheme 2.
So, the shortening of the tether between the reacting
centers had virtually no effect on the TBAF catalyzed
reaction. However, the t-BuOK reaction led to interest-
ing tricyclic derivatives 7 and 9 isolated in 45% yield:
these yields proved to be modest but one has to recall
that not only the starting material are readily available
but also that these reactions are very ‘clean’ reactions.7
On the other hand, these polycyclic ring systems could
be considered as useful molecules and potentially uti-
Scheme 3.
Scheme 4. Reagents and conditions: (i) t-BuOK, THF, −78°C,
30 min; (ii) t-BuOK, THF, 50°C, 30 min; (iii) t-BuOK, THF,
20°C, 30 min.
Scheme 5.
In order to increase the yield of the tricyclic derivatives
7 and 9, a lot of different reaction conditions were
tested. Thus, we observed that no tricyclic derivatives
were formed when the reaction was carried out at
−78°C. On the contrary, either the spiro derivative 5 or
the allene 4 was isolated as major product, this being
probably due to subtle conformation change. However,
the tricyclic derivatives 7 and 9 were isolated as major
products in 45% yield when the t-BuOK reaction was
carried out at 50°C. On the other hand, when allene 3
was subjected to t-BuOK in THF at room temperature,
a complex reaction mixture was obtained from which
Scheme 6.

A. Klein, M. Miesch / Tetrahedron Letters 44 (2003) 4483–4485
4485
lized for the synthesis of biologically active natural
products and analogs like for example Garsubellin A8
and Hispidospermidin9 which are respectively a poten-
tial Alzheimer’s therapeutic and a potent inhibitor of
phospholipase C (Scheme 6).
(m, 2H), 4.16 (q, J=7.1 Hz); 13C NMR (CDCl3, 75 MHz):
l 14.2, 22.9, 28.5, 28.7, 30.8, 31.9, 33.1, 38.7, 52.5, 60.8,
86.1, 91.0, 118.0, 166.4, 207.0.
Spiro derivative 5: isomer A, yellow oil; IR (CCl4): 1709,
1
1657 cm−1; H NMR (CDCl3, 300 MHz) l 1.26 (t, J=7.1
Hz, 3H), 1.50–1.90 (m, 8H), 1.95–2.15 (m, 2H), 2.25–2.65
(m, 2H), 2.90 (ddd, J=2.5 Hz, 6.7 Hz, 7.7 Hz, 2H), 4.14
(q, J=7.3 Hz, 2H), 5.67 (t, J=2.6 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): l 14.3, 22.1, 22.8, 26.8, 33.0, 37.4, 38.1,
39.1, 59.6, 63.4, 114.3, 166.7, 168.3, 211.1. Spiro derivative
The scope and limitations of these cascade reactions as
well as some applications, especially the development of
new synthetic route toward Garsubellin A and Hispi-
dospermidin are currently being further investigated
and the results will be disclosed in the near further.
5: isomer B, yellow oil; IR (CCl4): 1739, 1709 cm−1
NMR (CDCl3, 300 MHz) l 1.24 (t, J=7.1 Hz, 3H), 1.50–
2.15 (m, 8H), 2.20–2.50 (m, 4H), 3.04 (ABXYZ, JA(B, C)X
;
1H
=
Acknowledgements
JA(B, C)Y=JA(B, C)Z=2.0 Hz, lA=3.18, lB=2.90, 2H),
5.77 (h, J=3.5 Hz, 2.3 Hz, 1.5 Hz, 1.3 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): l 14.1, 22.1, 26.4, 29.7, 34.4, 35.6, 35.8,
39.7, 60.5, 64.6, 130.3, 138.2, 171.7, 213.2.
We thank Professor Paul Wender for stimulating dis-
cussions, Dr. Jennifer Wytko for her help in preparing
the manuscript and the CNRS and the ULP for finan-
cial support.
Diester 8: colorless oil; IR (CCl4): 1733 cm−1 1H NMR
;
(CDCl3, 300 MHz) l 1.22 (t, J=7.1 Hz, 3H), 1.23 (t,
J=7.1 Hz, 3H), 1.40 (q, J=7.7 Hz, 2H), 1.57 (quint,
J=15.9 Hz, 7.6 Hz, 7.3 Hz, 2H), 1.77 (quint, J=15.0 Hz,
7.8 Hz, 7.5 Hz, 2H), 2.07 (t, J=7.5 Hz, 2H), 2.27 (t,
J=7.5 Hz, 4H), 2.30–2.40 (m, 2H), 3.05 (s, 2H), 4.09 (q,
J=6.9 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): l 14.2, 14.3, 21.6, 25.0, 27.4, 28.1, 34.2,
34.4, 35.5, 36.3, 60.1, 60.4, 128.1, 139.3, 171.5, 173.6.
Tricycle 9: yellow crystals mp 45–46°C; IR (CCl4): 1721,
References
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1H NMR (CDCl3, 300 MHz) l 1.23 (t, J=7.1 Hz, 3H),
1.30–2.00 (m, 12H), 2.05–2.15 (m, 2H), 2.50–2.65 (m, 2H),
4.13 (ABX3, JAB=10.8 Hz, JAX=7.1 Hz, JBX=7.3 Hz,
lA=4.10, lB=4.17, 2H); 13C NMR (CDCl3, 75 MHz): l
14.2, 22.9, 28.5, 28.8, 30.7, 31.7, 32.8, 38.8, 52.8, 60.6, 86.4,
90.8, 116.8, 166.0, 207.4.
Allene 4: most polar isomer; yellow oil; IR (CCl4): 1960,
1
1716 cm−1; H NMR (CDCl3, 300 MHz) l 1.26 (t, J=7.1
Hz, 3H), 1.35–2.00 (m, 12H), 2.10–2.25 (m, 2H), 2.45–2.80