PtCl2-catalyzed transannular cycloisomerization of 1,5-enynes: A new efficient regio- and stereocontrolled access to tricyclic derivatives

Article abstract of DOI:10.1021/ol048463n

(Chemical Equation Presented) Transannular PtCl₂-catalyzed cycloisomerizations open a new route to cyclopropanic tricyclic systems. Ketones A or C were efficiently prepared from the same cycloundec-5-en-1-yne precursor B, depending on the subst

Full text of DOI:10.1021/ol048463n

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3771-3774
PtCl2-Catalyzed Transannular
Cycloisomerization of 1,5-Enynes:
A New Efficient Regio- and
Stereocontrolled Access to Tricyclic
Derivatives
Christophe Blaszykowski, Youssef Harrak, Maria-Helena Gonc¸alves,
Jean-Manuel Cloarec, Anne-Lise Dhimane,* Louis Fensterbank,* and
Max Malacria*
Laboratoire de Chimie Organique, UMR CNRS 7611, UniVersite´ Pierre et Marie
Curie, Case 229, 4 place Jussieu, 75252 Paris Cedex 05, France
adhimane@ccr.jussieu.fr; fensterb@ccr.jussieu.fr; malacria@ccr.jussieu.fr
Received August 3, 2004
ABSTRACT
Transannular PtCl2-catalyzed cycloisomerizations open a new route to cyclopropanic tricyclic systems. Ketones A or C were efficiently prepared
from the same cycloundec-5-en-1-yne precursor B, depending on the substituent at the propargylic position (either benzoate or methoxy).
Transannular processes constitute a unique opportunity for
achieving chemo-, regio-, and stereoselective synthesis.
Because ring constraints are more predictable than acyclic
ones and can also be tuned, versatile synthetic applications
have already been devised, notably for cycloadditions,1 and
also for radical processes.2 Our group, for instance, has
reported the diastereoselective and efficient synthesis of
polycyclic structures such as natural protoilludanes3 or linear
triquinanes4 via 4-exo/6-exo or 5-exo/5-exo transannular
radical cyclizations cascades. Surprisingly, besides coordina-
tion complexes incorporating polyunsaturated macrocycles
or macrocyclic Lewis bases serving as ligands,5 organome-
tallic reactivities have been rarely envisaged in transannular
fashion.6
In that context, PtCl2-catalyzed cycloisomerizations of
transannular enyne substrates appear as highly appealing
reacting systems to be explored.7,8 Further incentive was
gained by considering the following facts. We have recently
(5) (a) Diyne transannular reactivity with rhodium: King, R. B.;
Ackermann M. N. J. Organomet. Chem. 1974, 67, 431-441. (b) With
iron: King, R. B.; Haiduc, I.; Eavenson, C. W. J. Am. Chem. Soc. 1973,
95, 2508-2516. (c) With cobalt: King, R. B.; Efraty, A. J. Am. Chem.
Soc. 1972, 94, 3021-3025. (d) For a recent contribution: Pla-Quintana,
A.; Roglans, A.; Torrent, A.; Moreno-Man˜as, M.; Benet-Buchholz, J.
Organometallics 2004, 23, 2762-2767 and references therein.
(6) (a) Transannular oxypalladation: Sasaki, T.; Kanematsu, K.; Kondo
A. J. Chem. Soc., Perkin Trans. 1 1976, 2516-2520. (b) Transannular [3
+ 2] TMM-like cycloaddition: Yamago, S.; Nakamura, E. Tetrahedron
1989, 45, 3081-3088. (c) Transannular carbopalladation: Ohe, K.; Miki,
K.; Yanagi, S.-I.; Tanaka, T.; Sawada, S.; Uemura, S. J. Chem. Soc., Perkin
Trans. 1 2000, 3627-3634.
(1) For a review, see: Marsault, E.; Toro´, A.; Nowak, P.; Deslongchamps,
P. Tetrahedron 2001, 57, 4243-4260. See also: Caussanel, F.; Deslong-
champs, P.; Dory, Y. L. Org. Lett. 2003, 5, 4799-4802.
(2) Handa, S.; Pattenden, G. Contemp. Org. Synth. 1997, 4, 196-215.
See also: Dhimane, A. L.; Fensterbank, L.; Malacria, M. In Radicals in
Organic Synthesis; Renaud, P., Sibi M. P., Eds.; Wiley-VCH: Weiheim,
2001; Vol. 2, pp 350-382.
(3) Rychlet Elliott, M.; Dhimane, A. L.; Malacria, M. J. Am. Chem. Soc.
1997, 119, 3427-3428.
(4) Dhimane, A. L.; A¨ıssa, C.; Malacria M. Angew. Chem., Int. Ed. 2002,
41, 3284-3287.
10.1021/ol048463n CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/18/2004

shown that such processes can be extended to a variety of
partners such as allenynes9 and ene-tosylynamides.10 More-
over, as was the case for dienynol derivatives,11 it has been
shown that in acyclic 5-en-1-yn-3-ol precursors 1 the nature
of the hydroxy protecting group at the propargylic position
is a very practical handle for controlling the outcome of the
reaction.12 When this function is free, or appears as a silyl
ether, bicyclic compound 3 is formed, while bicyclic enol
ester 2 is isolated when an O-acyl group is present (Scheme
1). Electrophilic activation of the alkyne moiety triggers at
products possess a related tricycloundecane framework (n
) 5, m ) 1) such as anastreptene15 or myliol16 isolated from
liverwort plants. Some others, such as euphanginol17 (n )
2, m ) 4) and favelanone18 (n ) 4, m ) 2), are obtained
from Euphorbia species which present some antitumoral or
cytotoxic activities (Scheme 2).
Scheme 2. Transannular PtCl2-Catalyzed Cyclopropanation
Strategy
Scheme 1. PtCl2-Catalyzed Cyclizations of Acyclic 1,5-Enyne
Derivatives 1
will a hydride or an O-acyl migration yielding to regioiso-
meric derivatives.
Since the macrocycles we have designed originate from
the macrocylization of R,ω-ynal precursors by using the
Nozaki-Hiyama-Kishi-Takai (NHKT) chromium(II)-
mediated process,13 they display the pivotal propargyl alcohol
motif and so constitute ideal test substrates.
Thus, we anticipated that enyne macrocycle precursors of
type 4 would undergo transannular cyclopropanations which
would constitute a straightforward, modular, and unprec-
edented access to highly valuable tricyclic derivatives 5
incorporating an inner cyclopropane moiety.14 Various natural
Herein, we report the application of this transannular
strategy to various 1,5-unsaturated eleven-membered rings
such as cycloundecenynes 10 and 11 (Scheme 3) and
cycloundecadienynes Z,E- and E,E-17 (Scheme 6) whose
syntheses are, as previously mentioned, based on the efficient
NHKT macrocyclization conditions. Thus, following the
synthesis of the already described heptenal 6 as a TBS-
ether,19 we prepared it as a THP derivative. This one was
first submitted to Horner-Wadsworth-Emmons olefination
conditions modified by Masamune and Roush20 to reach
stereoselectively the corresponding E,E-nonadienoate 7.
Then, a five-step sequence including a LAH total reduction-
iodination-alkynylation-alkyne deprotection-ether depro-
tection furnished undecenynol 8 in 47% overall yield.
The macrocyclization precursor was prepared by mild
iodination of the triple bond, followed by IBX oxidation of
the alcohol moiety. Slow addition of the resulting unde-
cenynal to a suspension of chromium(II) chloride in THF
was performed to produce cleanly cycloundecenynol E-9 in
38% overall yield in three steps (Scheme 3).
(7) For reviews, see: (a) Aubert, C.; Buisine, O.; Malacria, M. Chem.
ReV. 2002, 102, 813-834. (b) Me´ndez, M.; Mamane, V.; Fu¨rstner, A.
Chemtracts-Org. Chem. 2003, 16, 397. (c) Lloyd-Jones, G. C. Org. Biomol.
Chem. 2003, 1, 215-236.
(8) For recent publications, see: (a) Nevado, C.; Ca´rdenas, D. J.;
Echavarren, A. M. Chem. Eur. J. 2003, 9, 2627-2635. (b) Chatani, N.;
Kataoka, K.; Murai, S.; Furukawa, N.; Seki, Y. J. Am. Chem. Soc. 1998,
120, 9104-9105. (c) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000,
122, 3801-3810. (d) Charruault, L.; Michelet, V.; Taras, R.; Gladiali, S.;
Geneˆt, J.-P. Chem. Commun. 2004, 850-851. (e) Fu¨rstner, A.; Stelzer, F.;
Szillat, H. J. Am. Chem. Soc. 2001, 123, 11863-11869. (f) Me´ndez, M.;
Mun˜oz, M. P.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem.
Soc. 2001, 123, 10511-10520.
(9) Cadran, N.; Cariou, K.; Herve´, G.; Aubert, C.; Fensterbank, L.;
Malacria, M.; Marco-Contelles, J. J. Am. Chem. Soc. 2004, 126, 3408-
3409.
(10) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria,
M. Org. Lett. 2004, 6, 1509-1511.
(11) Mainetti, E.; Mourie`s, V.; Fensterbank, L.; Malacria, M. Marco-
Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132-2135.
(12) (a) Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou, K.; Mainetti,
E.; Mourie`s, V.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am.
Chem. Soc. 2004, 126, 8656-8657. For similar findings, see: (b) Mamane,
V.; Gress, T.; Krause, H.; Fu¨rstner A. J. Am. Chem. Soc. 2004, 126, 8654-
8655.
(13) (a) Takai, K.; Kuroda, T.; Nakatsukasa, S.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1985, 26, 5585-5588. (b) Rychlet Elliott, M.; Dhimane,
A. L.; Hamon, L.; Malacria, M. Eur. J. Org. Chem. 2000, 155-163.
(14) For other access to these intriguing skeletons, see: (a) Hannah, D.
J.; Smith, R. A. J.; Teoh, I.; Weavers, R. T. Aust. J. Chem. 1981, 34, 181-
188. (b) Marshall, J. A.; Peterson, J. C.; Lebioda, L. J. Am. Chem. Soc.
1984, 106, 6006-6015. (c) Ricci, A.; Fasani, E.; Mella, M.; Albini, A. J.
Org. Chem. 2003, 68, 4361-4366.
(15) Warmers, U.; Ko¨nig, W. A. Phytochemistry 1999, 52, 1519-1524.
(16) Hayashi, K.-I.; Asano, K.-I.; Tanaka, M.; Takaoka, D.; Nozaki, H.
Phytochemistry 1998, 48, 461-466.
(17) Shi, J.-G.; Shi, Y.-P.; Jia, Z.-J. Phytochemistry 1997, 45, 343-
347.
(18) Endo, Y.; Ohta, T.; Nozoe, S. Tetrahedron Lett. 1991, 32, 5555-
5558.
(19) A¨ıssa, C.; Dhimane, A.-L.; Malacria, M. Synlett 2000, 1585-1588.
(20) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
3772
Org. Lett., Vol. 6, No. 21, 2004

Scheme 3. Synthesis of Cycloundecadienynol Derivatives 10
and 11
Scheme 5. PtCl2-Catalyzed Transannular Cyclization of
Cycloundecenyne Derivative 11
The corresponding 4-nitrobenzoate and methyl ether
derivatives 10 and 11 were then exposed to a catalytic
amount of PtCl2 in toluene at rt. In both cases, a clean
reaction took place giving, respectively, compounds 12 and
14 as single isomers21 in good yields (Schemes 4 and 5).
two different pathways according to the nature of the hydroxy
protecting group. In the case of ester precursor 10, a [1,2]-
migration of the benzoate group11,22 via an oxocarbenium
species B gives birth to an allylic platinacarbene C (Scheme
4). Cyclopropanation could then proceed and generate
diastereoselectively the tricyclic enol ester 12 in 85% isolated
yield.
Alternatively, in the case of the methoxy precursor 11,
the η2-alkyne platinum complex A′ would undergo a 1,2-
hydride migration23 to form, via oxonium of type D, an allylic
carbene E which is stabilized by the donor methoxy group,
followed by a diastereoselective cyclopropanation step which
gives labile enol ether intermediate 15. Tricyclo[5.4.0.0.1,8]-
undecan-10-one 14 is finally obtained as the isolated product
in 55% yield after purification on silica gel (Scheme 5).
Scheme 4. PtCl2-Catalyzed Transannular Cyclization of
Cycloundecenyne Derivative 10
We next turned our attention to check the reactivity of
cycloundecadienyne systems. By using the same synthetic
approach, precursors Z,E- and E,E-cycloundecadienynols 16
and their corresponding nitrobenzoate derivatives 17 were
prepared and submitted to PtCl2 (Scheme 6).
Z,E-Dienyne precursor 17 followed the same reactivity
pattern as its enyne equivalent 10. After methanolysis, it gave
the expected tricyclic ketone 19 diastereoselectively with the
carbonyl moiety R to the junction of the rings. Stereochem-
ical assignment of the isolated unique diastereomer of
tricyclo[5.4.0.0.1,8]undeca-3,10-diene 18 was established by
X-ray analysis.24 The spectroscopic data for 12 and 18 being
similar, this confirmed the stereochemistry deduced from the
NOE for 12.
We could readily determine that product 12 was an enol ester
and 14 a ketone. This led us to run a methanolysis on 12.
Careful spectroscopic analysis showed that the resulting
products 13 and 14 were regioisomeric ketones that possess
the same 5,3,7-tricyclic skeleton. Thus, as anticipated from
the acyclic series, a completely different behavior for
methoxy and acyloxy derivatives is observed.12
Based on the previous mechanistic rationale, we propose
that an initial electrophilic π-complexation of the alkyne by
the Pt(II) entity, shown in species A and A′, would trigger
(22) (a) For pioneering findings, see: Rautenstrauch, V. J. Org. Chem.
1984, 49, 950-952. (b) For an intermolecular version, see: Miki, K.; Ohe,
K.; Uemura, S. J. Org. Chem. 2003, 68, 8505-8513.
(23) Whether involving carbenoid or carbocationic intermediates, similar
1,2-hydrogen transfers have been observed by Echavarren, Fu¨rstner, and
us on several precursors; see refs 8e,f and 12a,b.
(24) CCDC 243389 contains the supplementary crystallographic data for
18 that can be obtained, free of charge, from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/conts/retrieving.html.
(21) Stereochemical assignments were performed by using NOE studies.
See the Supporting Information.
Org. Lett., Vol. 6, No. 21, 2004
3773

Optimized conditions afforded 19% of allene 20 after 3 h of
reflux conditions. More drastic conditions yielded to com-
plete degradation. An explanation for the formation of this
intriguing bis-allylic allene 20 resides in the E-stereochem-
istry of the disubstituted double bond. Due to this geometric
constraint, formation of the E-seven-membered ring from
Z-allyl carbene F becomes impossible. Instead, another
oxocarbenium species G could be generated from E-F.
O-Acyl migration would occur one more time and yield to
the formation of the allenyl ester moiety present in 20.
In conclusion, we have reported the first examples of a
transannular PtCl2-catalyzed reactivity of 1,5-enynes. This
particularly efficient synthetic strategy opens a diastereose-
lective access to various tricyclic ketones possessing an
internal cyclopropane motif. By simple variation of the
hydroxy protecting group, the regioselectivity of the carbonyl
group incorporation is completely controlled. Modeling the
adequate precursor to reach natural bioactive products is
under active investigation in our laboratory.
Scheme 6. PtCl2-Catalyzed Transannular Cyclization of Z,E-
and E,E-Cycloundecadienyne Derivatives 17
Acknowledgment. M.M. thanks the Institut Universitaire
de France for financial support. C.B. acknowledges the
M.R.E.S. for a Ph.D. grant and Y.H. the U.P.M.C. for a
postdoctoral grant. We extend special thanks to Dr. Y.
Dromze´e (UPMC) for the X-ray analysis of 18 and Dr.
Christophe A¨ıssa for valuable discussions regarding prepara-
tion of macrocycles.
Moreover, E,E-cycloundecadienyne benzoate 17, submit-
ted to the same conditions as its Z,E-diastereomer, showed
a different behavior. After 6 h at rt, no conversion was
observed. So we pursued the reaction overnight at 80 °C
and one product appeared slowly. After an additional 3 h
under reflux, cycloundeca-1,2,5,9-tetraene 2025 was isolated
in 15% yield along with 60% of recovered material. No trace
of the corresponding tricyclic compound was detected.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL048463N
(25) For related formation of allenes, see refs 9 and 23b and references
therein.
3774
Org. Lett., Vol. 6, No. 21, 2004