β,β′- and α,β,β′-annulation reactions of cyclic enamines: Enantioselective synthesis of bicyclo[3.n.1]alkenones (n = 2, 3) and Tricyclo[3.3.0.02,8]octanes from Fischer alkenyl carbene complexes [6]

Full text of DOI:10.1021/ja002905i

12874
J. Am. Chem. Soc. 2000, 122, 12874-12875
â,â′- and r,â,â′-Annulation Reactions of Cyclic
Enamines: Enantioselective Synthesis of
Bicyclo[3.n.1]alkenones (n ) 2, 3) and
Tricyclo[3.3.0.02,8]octanes from Fischer Alkenyl
Carbene Complexes
Jose´ Barluenga,* Alfredo Ballesteros, Javier Santamar´ıa,
Ramo´n Bernardo de la Ru´a, Eduardo Rubio, and
Miguel Toma´s
Figure 1.
Scheme 1
Instituto UniVersitario de Qu´ımica Organometa´lica
“Enrique Moles”, Unidad Asociada al CSIC
UniVersidad de OViedo, Julian ClaVer´ıa 8
33071-OViedo, Spain
ReceiVed August 4, 2000
Designing efficient, short routes for the stereoselective con-
struction of polycyclic molecules is currently one of the main
challenges in synthetic organic chemistry. Among polycyclic
targets, much work has been devoted to outline efficient entries
into the [3.2.1] and [3.3.1] bicyclic frameworks.1 In general, this
task has been accomplished by reaction of appropriate C3-
synthons with cyclic ketones (R,R′-annulation)2 or, to a lesser
extent, with their enamine derivatives (â,â′-annulation).3 In the
former case, a number of two-step processes based on R-alkeny-
lation or R-alkynylation followed by induced ring closure have
been disclosed.2 On the other hand, apart from the elegant [3+3]-
cyclization of nitroallylic esters and enamines discovered by
Seebach,3a no highly enantioselective approaches have been
reported.2f,3b Despite that transition metal complexes have played
a paramount role in the area of carbocyclization reactions,4 there
is still an important gap for the [3+3]-carbocyclization reaction
mediated or assisted by transition metals.5
While studying the potential of group 6 Fischer carbene
complexes we have discovered not only a new â,â′-annulation
([3+3] cyclization) but also a novel R,â,â′-annulation reaction
of cyclopentanone and cyclohexanone enamines (Figure 1).6 The
preliminary results of this study are reported now.
First 1-pyrrolidinylcyclopentene 2 was reacted with chromium
or tungsten alkenylcarbene complexes 1 in THF at 60 °C for 1.5
h to furnish substituted semibullvalenes 3a-c in around 90% yield
after column chromatography purification (Scheme 1). This
astonishing result entails the formation of three carbon-carbon
* Corresponding author: Phone and Fax: (34) 98 510 34 50. E-mail:
barluenga@sauron.quimica.uniovi.es.
bonds and five stereogenic centers with total selectivity in a
process that has no precedents in the chemistry of metal carbene
complexes. A series of NMR experiments clearly confirmed the
connectivity and stereochemistry of compounds 3 (HMQC,
HMBC, and NOESY experiments). Additionally, when the chiral,
nonracemic carbene complexes 1e-g, derived from (-)-menthol,
and 2 were heated in THF at 60 °C for 6 h the cycloadducts
3e-g were formed as a sole isomer.7 Interestingly, conducting
the reaction of complexes 1a-d and enamine 2 in hexane at room
temperature resulted in quantitative precipitation of the metal
complexes 4a-d.7 In turn, complexes 4a-c led to semibullvalene
derivatives 3a-c by heating in THF at 60 °C for 1.5 h. From a
synthetic point of view it was important to find that compounds
4 were transformed very efficiently into bicyclo[3.2.1]oct-2-en-
8-ones 5 by treatment with TFA/THF at 0 °C followed by
warming in the presence of water.8
(1) For reviews on bicyclo[3.2.1]- and [3.3.1]alkanes, see, respectively:
(a) Filippini, M.-H.; Rodriguez, J. Chem. ReV. 1999, 99, 27. (b) Peters, J. A.
Synthesis 1979, 321.
(2) For selenium-induced ring closure, see: (a) Nicolaou, K. C.; Pfefferkorn,
J. A.; Cao, G.-Q.; Kim, S.; Kessabi, J. Org. Lett. 1999, 1, 807. For Hg2+
-
mediated ring closure, see: (b) Frontier, A. L.; Raghavan, S.; Danishefsky,
S. J. J. Am. Chem. Soc. 1997, 119, 6686. (c) Huang, H.; Forsyth, C. J. J. Org.
Chem. 1995, 60, 5746. For Pd(II)-mediated ring closure, see: (d) Kende, A.
S.; Roth, B.; Sanfilippo, P. J.; Blacklock, T. J. J. Am. Chem. Soc. 1982, 104,
1784 and 5808. For free-radical ring closure, see: (e) Cole, B. M.; Han, L.;
Snider, B. B. J. Org. Chem. 1996, 61, 7832. (f) For enantioselective free-
radical ring closure, see: Garc´ıa-Ruano, J. L.; Rumbero, A. Tetrahedron:
Asymmetry 1999, 10, 4427.
(3) (a) Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. J. Am. Chem.
Soc. 1990, 112, 7625. (b) Butkus, E.; Stoncius, A. Synlett 1999, 234. (c) Byeon,
C.-H.; Hart, D. J.; Lai, C.-S.; Unch, J. Synlett 2000, 119.
(4) (a) Fru¨hauf, H.-W. Chem. ReV. 1997, 97, 523. (b) Lautens, M.; Klute,
W.; Tam, W. Chem. ReV. 1996, 96, 49.
(5) (a) While writing this manuscript the [3+3]-carbocyclization of TMM
and enamines has appeared, see: Buono, F.; Tenaglia, A. J. Org. Chem. 2000,
65, 3869. (b) For an isolated example involving Fischer alkenyl carbene
complexes, see: Barluenga, J.; Toma´s, M.; Rubio, E.; Lo´pez-Pelegr´ın, J. A.;
Garc´ıa-Granda, S.; Pe´rez-Priede, M. J. Am. Chem. Soc. 1999, 121, 3065.
(6) We have previously reported the R,â-annulation ([3+2] cyclization)
of carbene complexes with enamines of aldehydes as well as of 3-pentanone
and cycloheptanone. See: Barluenga, J.; Toma´s, M.; Ballesteros, A.; San-
tamar´ıa, J.; Brillet, C.; Garc´ıa-Granda, S.; Pin˜era-Nicola´s, A.; Va´zquez, J. T.
J. Am. Chem. Soc. 1999, 121, 4516.
Actually, the formation of 3 from 1 and 2 can be rationalized
via 1,4-addition of the Câ-enamine to the electrophilic alkene
carbene complex9 followed by intramolecular cyclopropanation
of the CR-Câ′ double bond of the newly formed enamine.
Importantly, the isolation of the zwitterionic species 4 does
represent an unprecedented feature for supporting the accepted
10.1021/ja002905i CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/05/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 51, 2000 12875
Scheme 2
Scheme 3
polar pathway for the cyclopropanation reaction of electron-rich
alkenes, like enamines, by Fischer carbene complexes.10 More-
over, the endo orientation of the M(CO)5 fragment precludes the
cyclopropanation reaction to involve the participation of a
metallacyclobutane species, but rather backside attack of the
carbanion-type metal-bonded carbon to the iminium function is
thought to occur.11
The asymmetric synthesis of bicyclo[3.2.1]oct-2-en-8-ones was
best accomplished by using cyclopentanone enamines derived
from readily available (S)-2-methoxymethylpyrrolidine (Scheme
2). Thus, stirring a solution of tungsten carbene complexes 1a-c
and enamine 6 (THF, -20 °C, 6.5 h) followed by TFA quenching
and warming with water resulted in the diastereoselective forma-
tion of the enantiomerically enriched endo-cycloadducts 5.
Column chromatography purification gave pure 5 with 85-90%
yield and high enantiomeric excess (88-93% ee).12
Cyclohexanone enamines 7a,b were also tested toward tungsten
complexes 1a,b (Scheme 3).13 We found that these enamines are
fairly less reactive than the former and that the selectivity of the
process is dependent on the reaction conditions and even on the
substituent R1 of the carbene complex. Thus, the reaction of 1a
(R1 ) 2-furyl) and 7a (THF, -20 °C, 72 h) led to the cycloadduct
8a (75% yield) as a 1:2 mixture of endo/exo isomers. Column
chromatography separation afforded pure endo-8a (73% ee) and
exo-8a (98% ee). On the contrary, the corresponding endo isomer
was efficiently formed (80%; endo-8a/exo-8a ) 15:1; 95% ee)
by reacting carbene 1a with enamine 7b in CH2Cl2 at -20 °C.14
In turn, the reaction of carbene 1b and enamine 7b in THF at
-30 °C afforded the endo-8b with moderate chemical yield
and excellent stereoselectivity (50%; endo-8b/exo-8b >50:1;
94% ee).12
In conclusion, we have demonstrated that alkenyl carbene
complexes of chromium and tungsten15 are very useful C3-
synthons for the [3+3] cycloaddition reaction toward cyclopen-
tanone and cyclohexanone enamines. This simple, one-step
protocol features a highly diastereo- and enantioselective synthesis
of functionalized bicyclo[3.2.1]octane and bicyclo[3.3.1]nonane
skeletons16 having three chiral and two prochiral centers. The
novel R,â,â′-annulation reaction of cyclopentanone enamines and
alkenyl carbene complexes described here represents the shortest
thermal access to tricyclo[3.3.0.02,8]octanes (semibullvalene de-
rivatives),17 systems known to be precursors of molecules of
interest, e.g. triquinanes.18 Moreover, diastereo- and enantiomeri-
cally pure semibullvalenes containing five chiral centers are
readily available from menthyl derived carbene complexes. The
isolation of intermediates supports the polar pathway for the
cyclopropanation of enamines by Fischer carbene complexes.19
(7) X-ray analyses were performed on compounds 4c, 10, and 11 (to be
published elsewhere). Compound 10 was obtained from 3g by thermal ring
opening to ketone 9 and derivatization with 2,4-dinitrophenylhydrazine.
Compound 11 was obtained by derivatization of ketone 5c with (S)-(-)-1-
amino-2-(methoxymethyl)pyrrolidine (SAMP).
The presence of a sole stereoisomer for compounds 3e-g was deduced from
the 1H and 13C NMR of the reaction crude. This was also confirmed from the
formation of derivatives 9 and 10 as single isomers.
(8) We agree with a referee who noted that this transformation presumably
involves elimination of the alkoxy group to provide a nonstabilized carbene
complex which then decomposes via a 1,2 proton shift. See: (a) Casey, C.
P.; Brunsvold, W. R. Inorg. Chem. 1977, 16, 391. (b) Rudler, H.; Audouin,
M.; Parlier, A.; Martin-Vaca, B.; Goumont, R.; Durand-Re´ville, T.; Vaisser-
mann, J. J. Am. Chem. Soc. 1996, 118, 12045.
Acknowledgment. This research was supported by DGICYT (PB97-
1271). Predoctoral (FYCYT) and postdoctoral (DGCYT) fellowships to
J.S. are gratefully acknowledged.
Supporting Information Available: Characterization data for 3-5
and 8-12 and HPLC data for racemic 5,8 and enantioenriched 5,8 (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
(9) The Michael adduct intermediate 12 was obtained (45%) in the reaction
of enamine 2 and pentacarbonyl[2-methylpropenylidene(methoxy)]tungsten
complex followed by SiO2 treatment.
JA002905I
(14) Running the reaction at -50 °C resulted in increasing the endo/exo
ratio to >20:1 and the ee to 98%, though the chemical yield dropped to 52%.
The replacement of enamine 7b with 7a led to poorer selectivity toward endo-
8a (endo/exo ) 5:1; 83% ee).
(15) Either chromium or tungsten complexes 1 were found to work equally
well in the formation of racemic 3-5. All the assays leading to (+)-5 and
(+)-8 were performed with tungsten complexes 1.
(10) Casey, C. P.; Cesa, M. C. Organometallics 1982, 1, 87.
(11) This conclusion was previously reached by Brookhart in a sound study
on the cyclopropanation reaction by cationic nonstabilized iron carbene
complexes. See: Brookhart, M.; Liu, Y.; Goldman, E. W.; Timmers, D. A.;
Williams, G. D. J. Am. Chem. Soc. 1991, 113, 927. (We thank a referee for
this observation.) In our case, despite that the endo stereochemical orientation
of the anion metal center of 4 is exclusively observed both in the solid state
and in THF-d8 solution, an endo-exo equilibration cannot be definitively ruled
out.
(16) The bicyclo[3.3.1]nonan-2-one skeleton is the central part of a number
of terpenes. For instance, see refs 2a-d.
(17) (a) For the arene-alkene photocyclization, see: Wender, P. A.; Siggel,
L.; Nuss, J. M. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: New York, 1991; Vol. 5, pp 645-673. (b) For the oxa-
di-π-methane rearrangement of bicyclo[2.2.2]octenones to semibullvalenes,
see: Lee, T.-H.; Rao, P. D.; Liao, C.-C. Chem. Commun. 1999, 801.
(18) Singh, V. Acc. Chem. Res. 1999, 32, 324.
(19) Studies aiming to rationalize the different pathways found for cyclic
and acyclic enamines toward alkenyl carbenes are being completed. In
particular, it can be anticipated that the formation of complexes 4 is a reversible
process.
(12) The enantiomeric excesses of 5 and 8 were determined by HPLC
(Chiracel OB-H and OJ columns).
(13) The reaction of the nonchiral cyclohexanone pyrrolidine enamine and
carbene complexes 1a,b takes place in THF (0 °C, 12 h) to furnish a ca. 5:1
mixture of racemic endo-8/exo-8 in 80-85% yield.