Cascade cyclization: Carbopalladative cyclization followed by electrocyclic closure as a route to complex polycycles [12]

Full text of DOI:10.1021/ja0170495

J. Am. Chem. Soc. 2001, 123, 12107-12108
12107
Scheme 1
Cascade Cyclization: Carbopalladative Cyclization
Followed by Electrocyclic Closure as a Route to
Complex Polycycles
Jean Suffert,* Bahaˆa Salem, and Philippe Klotz
Laboratoire de Pharmacochimie de la Communication
Cellulaire (UMR 7081 CNRS/ULP), Faculte´ de Pharmacie
74, route du Rhin 67401 Illkirch-Cedex, France
ReceiVed September 11, 2001
The rapid and efficient synthesis of new complex molecules
requires the development of new methodologies shortening the
number of steps. In this context, the chemist is looking for
processes which involve several reactions in a one-pot operation.
Along these lines, several elegant cascade reactions have been
recently described in the literature showing their very high
potential.1 Particularly efficient in this field is the use of the
transition metal-catalyzed coupling reaction for the formation of
new carbon-carbon bonds.2 We recently found that polycyclic
ring systems could be easily produced for the synthesis of
biologically active natural products using a carbopalladation cross-
coupling reaction of vinyl halides with vinylstannanes. This
methodology could potentially be applied to the synthesis of
ascosalipyrrolidinone 1,3 which displays an unprecedented and
structurally unusual tetramic acid containing a cis-fused Decalin,
as well as to the tricyclic structure of trihydroxydecipiadiene 2.4
In a retrosynthetic analysis of 1, the central Decalin system could
be prepared from the highly functionalized hemiketal 3 and the
skeleton of 2 from the unusual strained tricyclic diol 7 containing
a cyclobutene moiety (Scheme 1).
We report herein a short synthesis (2 steps) of [4.4.0] and
[5.4.0] cis-fused bicyclic systems of type 3 and 4 and the first
synthesis of two new tricyclic structures, the tricyclo[5.3.1.05,11]-
undecadiene 7 and tricyclo[6.3.1.05,11] dodecadiene 8, including
a cyclobutenic bridgehead double bond respectively prepared from
bromocycloalkenones 5 and 6. The reaction pathway involves a
cascade of three different reactions including an unusual and quite
rare 4-exo-dig cyclization5 eventually leading stereospecifically
to a masked bicyclic ketone 3 and 4 (Scheme 2). The starting
material, diol 9anti, was prepared in large scale by addition of a
properly protected metalated propargylic alcohol6 on bromocyclo-
alkenones 5/6 followed by deprotection and chromatographic
separation of the two 9anti and 9syn diastereomers. The anti
relative stereochemistry of the diol was established by 1H-NOESY
experiments on a derivative of 9.7
Scheme 2
When the diol 9anti was heated with trans-bis(tributylstannyl)-
ethylene8 (10) and Pd(PPh3)4 for 2 h, a single product was formed
in 62% yield (Scheme 2). This compound was found to lack the
tributylstannyl group and the triple bond and to possess a cis-
fused Decalin system. The product was finally identified as
hemiketal 3, the structure of which was unambiguously confirmed
by X-ray diffraction analysis (Figure 1) as a single diastereomer.
By careful monitoring of the reaction, we observed after 30
min the formation of an intermediate that slowly reacts to give
3. After isolation of this compound by chromatography and
intensive 2D 1H NMR and NOESY experiments, its structure was
assigned to the bicyclo[4.2.0]octendiol (11). To our knowledge,
such a cyclobutane derivative has never been prepared previously
via a tandem 4-exo-dig carbopalladation/Stille cross-coupling
reaction. No trace of the corresponding direct Stille product was
observed in this case. However, related bicyclic [4.2.0]octadienes
or [3.2.0]heptene have been recently obtained from the intra-
molecular Heck reaction,9 from copper(I) chloride-mediated
internal conjugate addition of alkenyltrimethylstannane to the R,â-
alkenic ester unit10 or by intramolecular carbometalation of 1,6-
eneynes.11 To have an insight to the mechanistic aspect of the
formation of 3, the starting diol was submitted to the same reaction
conditions in the presence of the vinylic deuterated analogue 12.12
The two deuteriums were specifically incorporated at positions 4
and 5 in place of the two vinylic protons affording 13 and
indicating a clean isomerization of the starting double bond. Fur-
thermore, when pure 11 (n ) 1) was heated in benzene for 2 h
* Address correspondence to this author. E-mail: jeansu@aspirine.u-
strasbg.fr.
(1) (a) Wender, P. A.; Miller, B. L. Org. Synth. Theory Appl. 1993, 2, 27.
(b) Bertz, S. H.; Sommer, T. J. Org. Synth. Theory Appl. 1993, 2, 67. (c)
Malacria, M. Chem. ReV. 1996, 96, 289-306. (d) Ang, K. H.; Bra¨se, S.;
Steinig, A. G.; Meyer, F. E.; Llebaria, A.; Voigt, K.; de Meijere A. Tetrahedron
1996, 52, 11503-11528. (e) Henniges, H.; Meyer, F. E.; Schick, U.; Funke,
F.; Parsons, P. J.; de Meijere, A. Tetrahedron 1996, 52, 11545-11578.
(2) For reviews on palladium cascade reactions see: (a) de Meijere A.;
Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379-2411. (b) Bra¨se,
S.; de Meijere, A. In Metal-Catalysed Cross Coupling Reaction; Stang, P. J.,
Diederich, F., Eds.; Wiley-VCH: Weiheim, Germany, 1997. For examples
of palladium cascade reactions, see: (c) Grigg, R.; Major, J. P.; Martin, F.
M.; Whittake M. Tetrahedron Lett. 1999, 40, 7709-7712.
(3) Osterhage, C.; Kaminsky, R.; Koˆnig, G. M.; Wright, A. D. J. Org.
Chem. 2000, 65, 6412-6417.
(4) Ghisalberti, E. L.; Jefferies, P. R.; Sheppard, P. Tetrahedron Lett. 1975,
1775-1778.
(5) Bailey, W. F.; Ovaska, T. V. Tetrahedron Lett. 1990, 31, 627-630.
Breuil-Desvergnes, V.; Gore´, J. Tetrahedron 2001, 57, 1951-1960. Bogen,
S.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 1997, 119, 5037-5038.
(6) (a) Ushida, K.; Utimoto, K.; Nozaki, H. J. Org. Chem. 1976, 32, 2941-
2942. (b) Suffert, J.; Toussaint, D. Tetrahedron Lett. 1997, 38, 5507-5510.
(7) See Supporting Information
(8) Bottaro, J. C.; Hanson, R. N.; Seitz, D. E. J. Org. Chem. 1981, 46,
5221-5222.
(9) Bra¨se, S. Synlett 1999, 10, 1654-1656.
(10) Piers, E.; Boehringer, E. M.; Yee, J. G. K. J. Org. Chem. 1998, 63,
8642-8643.
(11) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1988, 110, 1636-
1638.
(12) 12 was prepared by deuteriostannylation of tributylstannylacetylene
in the presence of AIBN.
10.1021/ja0170495 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/08/2001

12108 J. Am. Chem. Soc., Vol. 123, No. 48, 2001
Communications to the Editor
Scheme 5
Figure 1. X-ray crystal structures showing the two ORTEP views of
compounds 3 and 8.
Scheme 3
properly positions the triple bond in proximity to the vinyl
palladium intermediate. The carbopalladation of the triple bond
is then kinetically favored. This is not the case in 16. No further
rearrangement of 17 was observed and again only decomposition
occurred.
The proposed mechanism for the formation of 3 is shown in
Scheme 5. A six-electron disrotatory electrocyclization results in
the strained tricyclic diol 19. The anti stereochemistry between
the proton 6 and the tributylstannyl group is fixed by the
electrocyclization process. Intermediate 19 undergoes a concerted
elimination of SnBu3 and ring opening of the cyclobutenediol
leading to the enol 21.
The formation of the conjugated diene 22 is then followed after
prototropy by an intramolecular attack of the alcoholate on the
ketone from the concave face to form the last stereocenter,
resulting in the hemiketal 3. Strong evidence for this mechanism
is supported by the isolation and characterization of the strained
tricyclic compounds 7 and 8 obtained respectively in 32% and
62% yield when 9anti (n ) 1 and 2) is treated with tributylstannyl-
ethylene. The unusual structure of 8 was unambiguously con-
firmed by an X-ray diffraction analysis (Figure 1).7 The reaction
was also applied to the synthesis of [5.4.0] cis-fused bicyclic
hemiketal 4 isolated with 24% yield as a pure diastereomer.
We have described a new process that converts simple
propargylic anti diols to functionalized polycyclic products via
an unprecedented cascade reaction summarized as follows: (1)
4-exo-dig carbopalladation of an alkyne, (2) disrotatory electro-
cyclization, (3) concerted SnBu3 elimination/cyclobutene ring
opening, and (4) face selective cyclic hemiketal formation. The
syntheses of the cyclobutanediol 11, cyclobutanol 17, and the two
tricyclic compounds 7 and 8 through an intramolecular carbo-
palladation are presented for the first time. Efforts are currently
underway to probe the scope and limitations of this new protocol
cascade reaction and to its application to the synthesis of
ascosalipyrrolidinone 1, trihydroxydecipiadiene 2, and analogues.
These results will be disclosed in the future.
Scheme 4
in the absence of the catalyst, compounds 3 and 14 were obtained
in 46% and 26% yield, respectively (Scheme 3). This fact strongly
supports a thermal rearrangement of the strained molecule 11
leading to 3 via a cascade reaction. The formation of 14 can be
explained by an opening of the hemiketal 3 followed by a
spontaneous oxidative aromatization of the cyclohexadiene al-
though the reaction occurred under rigorously inert conditions.
This is further supported by the reactivities of other structurally
related analogues. When a similar procedure was employed for
diol 9syn (n ) 1), no trace of the related product 3 or Stille cross-
coupling product was isolated. After 6 h, the reaction gave mainly
decomposition of the starting diol and traces of a new unidentified
compound. If the propargylic alcohol 16, easily prepared from
15 by a [2,3]-Wittig rearrangement in 98% yield with complete
control of the stereoselectivity, was submitted to the same
conditions, a mixture of two products (assigned as 17 and 18)
was isolated in 23% yield with a ratio of 65:35, respectively
(Scheme 4). The different reactivity of compound 16 vs 9anti
could be explained by the presence of the diol function and the
formation of an intramolecular hydrogen bond in 9anti which
Acknowledgment. We thank Professors P. A. Wender and M. L.
Snapper for fruitful discussions, the CNRS for financial support, and the
MNERT (B.S.) for fellowship.
Supporting Information Available: Experimental procedures, physi-
cal data and NMR spectra for 3-18 and synthetic intermediates, and
X-ray data for 3 and 8 (n ) 2) (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org. The structures of 3 and 8
have been deposited at the Cambridge Crystallographic Data Centre under
the numbers CCDC 172736 and 172737 respectively.
JA0170495