[3 + 2] Cycloaddition of Fischer alkenyl carbene complexes to enamines: An efficient asymmetric approach to cyclopentanoids

Full text of DOI:10.1021/ja9825736

4516
J. Am. Chem. Soc. 1999, 121, 4516-4517
Communications to the Editor
[3 + 2] Cycloaddition of Fischer Alkenyl Carbene
Complexes to Enamines: An Efficient Asymmetric
Approach to Cyclopentanoids
Jose´ Barluenga,*,† Miguel Toma´s,† Alfredo Ballesteros,†
Javier Santamar´ıa,† Cecile Brillet,† Santiago Garc´ıa-Granda,‡
Alejandro Pin˜era-Nicola´s,‡ and Jesu´s T. Va´zquez§
Figure 1.
Scheme 1
Instituto UniVersitario de Qu´ımica
Organometa´lica “E. Moles”
Departamento de Qu´ımica F´ısica y Anal´ıtica
UniVersidad de OViedo, 33071-OViedo, Spain
Instituto UniVersitario de Bio-Orga´nica “A. Gonza´lez”
UniVersidad de La Laguna, 38206-La Laguna, Tenerife, Spain
ReceiVed July 20, 1998
Designing new strategies for the selective synthesis of five-
membered carbocycles continues to attract the interest of organic
chemists.1 The Pauson-Khand reaction constitutes a powerful
tool for the rapid construction of substituted cyclopentenones.2
Probably, the most efficient access to the cyclopentane ring is
based on the [3 + 2] cycloaddition which requires devising
appropriate C-C-C synthons of type I (C2-C1-C5 + C3-C4
coupling) (Figure 1). Thus, various synthons for dimethylene-
methane IA3 and trimethylenemethane IB4 have been elaborated
and successfully reacted with electron-deficient alkenes.1,5 Direct
entry into the cyclopentanone ring is not so straightforward and
has been accomplished either by ozonolysis of the cycloadducts
from IB or by cycloaddition of the oxyallyl species IC with
electron-rich alkenes.5,6 Studies on the asymmetric version have
centered mainly in species IB and high selectivity has been
reached in some occasions.4a Although Fischer carbene complexes
have been reported to form cyclopentadiene derivatives,7 the [3
+ 2] cycloaddition of complexes of type 1 toward alkenes leading
to cyclopentene derivatives has remained unknown until recently.8
Herein we report that tertiary achiral and homochiral enamines
smoothly undergo [3 + 2] carbocyclization to pentacarbonyl-
(alkoxyalkenylcarbene)tungsten(0) complexes 19 and that the
cycloaddition formally involves the carbene synthons IIA or IIB
(Figure 1) depending primarily on the nature of the enamine.10
Therefore the present cyclopentaannulation involves the coupling
of C1-C2-C3 and C4-C5 fragments.
The reaction of pyrrolidine enamines 2a,b, derived from
3-pentanone and cycloheptanone, with the tungsten alkenylcarbene
complex 1a in THF, went to completion after 6 h at 25 °C
affording cleanly the [3 + 2] cycloadducts 4a,b (Scheme 1).
Column chromatography of the crude reaction product furnished
pure methoxycyclopentenes 4a (95%; one diastereoisomer) and
4b (92%; C-3 epimers, 70% de). Interestingly, the formation of
two carbon-carbon single bonds and three stereogenic centers
occurred with regio- and stereochemical control. Hydrolysis of 4
with diluted acid provided cyclopentenones 6 (90% for 6a; 92%
for 6b). To test the facial selectivity of the process the corre-
sponding optically active enamines 3a,b, derived from (S)-2-
methoxymethylpyrrolidine,9 were reacted with carbene complex
1a in THF at 25 °C, affording 5a (88%) and 5b (90%) with more
than 80% de. Hydrolysis of the resulting diastereomeric mixtures
* Corresponding author. Telephone and Fax: (34) 98 510 34 50. E-mail:
barluenga@sauron.quimica.uniovi.es.
† Instituto Universitario de Qu´ımica Organometa´lica “E. Moles”.
‡ Departamento de Qu´ımica F´ısica y Anal´ıtica (X-ray analysis).
§ Instituto Universitario de Bio-Orga´nica “A. Gonza´lez” (CD studies).
(1) (a) Little, R. D. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 5, Chapter 3.1, pp 239-
270. (b) Chan, D. M. T. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 5, Chapter 3.2, pp 271-
314. (c) Hudlicky, T.; Price, J. D. Chem. ReV. 1989, 89, 1467. (d) Lautens,
M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49.
(2) (a) The Pauson-Khand reaction has been highlighted, see: Geis, O.;
Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1997, 36, 2801
(3) For recent examples of dimethylene synthons, see: (a) Zhu, G.; Chen,
Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119,
3836. (b) Kno¨lker, H.-J.; Foitzik, N.; Goesmann, H.; Graf, R.; Jones, P. G.;
Wanzl, G. Chem.sEur. J. 1997, 3, 538. (c) Choi, G. M.; Yeon, S. H.; Jin, J.;
Yoo, B. R.; Jung, I. N. Organometallics 1997, 16, 5158.
(4) (a) Binger, P.; Fox, D. In Houben-Weyl: StereoselectiVe Synthesis;
Helmchen, G., Hoffmann, R., Mulzer, J., Schaumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, 1996; Vol. E 21-5, pp 2997-3059. (b) Harrington, P. J.
In ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. G.
A., Wilkinson, G., Eds.; Pergamon: New York, 1995; Vol. 12, Chapter 8.4,
pp 923-958. (c) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1. For
recent examples of trimethylene synthons, see: (d) Rosenstock, B.; Gais, H.-
J.; Herrmann, E.; Raabe, G.; Binger, P.; Freund, A.; Wedemann, P.; Kru¨ger,
C.; Lindner, H. J. Eur. J. Org. Chem. 1998, 257, 7. (e) Trost, B. M.; Higuchi,
R. I. J. Am. Chem. Soc. 1996, 118, 10094. (f) Lautens, M.; Ren, Y. J. Am.
Chem. Soc. 1996, 118, 9597, 10668. (g) Ghera, E.; Yechezkel, T.; Hassner,
A. J. Org. Chem. 1996, 61, 4959. (h) Yamago, S.; Ejiri, S.; Nakamura, E.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2154. (i) Takahashi, Y.; Tanino, K.;
Kuwajima, I. Tetrahedron Lett. 1996, 37, 5943.
(7) (a) Yamashita, A. Tetrahedron Lett. 1986, 27, 5915. (b) Wulff, W. D.;
Bax, B. M.; Brandvold, T. A.; Chan, K. S.; Gilbert, A. M.; Hsung, R. P.;
Mitchell, J.; Clardy, J. Organometallics 1994, 13, 102. (c) Flynn, B. L.; Funke,
F. J.; Silveira, C. C.; de Meijere, A. Synlett 1995, 1007. (d) Aumann, R.;
Heinen, H.; Dartmann, M.; Krebs, B. Chem. Ber. 1991, 124, 2343. (e) Aumann,
R.; Meyer, A. G.; Fro¨hlich, R. Organometallics 1996, 15, 5018.
(8) (a) Hoffmann, M.; Reissig, H.-U. Synlett 1995, 625. (b) Hoffmann,
M.; Buchert, M.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1997, 36, 283.
(9) Poorer results were reached for chromium carbene complexes. All
attempts with tungsten carbene complexes derived from homochiral alcohols
[R2OHd (+)- and (-)-menthol, (-)-8-phenylmenthol)] failed.
(10) For isolated examples of [3 + 2] cyclopentaannulations based on
synthons of type IIA, see: (a) Huart, C.; Ghosez, L. Angew. Chem., Int. Ed.
Engl. 1997, 36, 634. (b) Takeda, K.; Fujisawa, M.; Makino, T.; Yoshii, E.;
Yamaguchi, K. J. Am. Chem. Soc. 1993, 115, 9451.
(5) Fru¨hauf, H.-W. Chem. ReV. 1997, 97, 523.
(6) For instance, see: Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I.
J. Am. Chem. Soc. 1998, 120, 1724.
10.1021/ja9825736 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/24/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 18, 1999 4517
Scheme 2
Figure 2.
Figure 3.
derivative of its reduced alcohol 17 (λmax ) 243 nm) (Figure 2).
On the basis of the CD allylic benzoate method,14 the observed
negative exciton Cotton effect at 242 nm (∆ꢀ ) -10.7)
established the absolute configuration shown for these compounds.
On the other hand, the absolute configuration of 11b was
established by an X-ray analysis performed on its methylammo-
nium iodide 18 (Figure 2).
A possible reaction course is outlined in Figure 3. The
formation of cycloadducts 4,5 and 10,11 implies 1,2-addition (via
III) and 1,4-addition (via IV), respectively, followed by cyclization
and (CO)5W elimination.15 The structure of 5 is in agreement
with a carbene complex-to-enamine anti-(s-cis) approach accord-
ing to the Seebach model for the addition of ketone enamines to
nitroalkenes.16 The absolute stereochemistry of 11 would result
from an anti-(s-trans) approach, a finding that might provide
further insight when applying the Seebach model to aldehyde
enamines.
In conclusion, a new protocol for the selective synthesis of
cyclopentane derivatives is reported which is based on the rich
reactivity and flexibility of group 6 alkenyl carbene complexes.
The chemical yields (e.g., the cyclopentanones 15 are formed in
>55% unoptimized overall yield from carbenes 1), the regiose-
lectivity and the relative and absolute stereocontrol are intriguing.
In our opinion, these annulation reactions are complementary to
previous methodologies for cyclopentenone and cyclopentanone
synthesis.
permitted the isolation of enantiomerically enriched cyclopen-
tenones 7a (88%, 87% ee) and 7b (93%, 83% ee).11
The reaction of complexes 1 with enamines derived from
aldehydes took place in THF at 25 °C (for 1c,d) or 60 °C (for
1a,b,e) (Scheme 2). Although a 2:1 regioisomeric mixture of
cycloadducts (not shown) formed from enamine 8b (R3 ) n-Hex),
the reaction of carbene complexes 1a-d and enamine 8a (R3 )
i-Pr) gave rise to cycloadducts 10a-d (72-95%) with excellent
regiocontrol (12:1 for 10a; >20:1 for 10b-d). Fortunately, we
found that the bulkiness of the ultimately removable alkoxy group
OR2 of 1 does play a definitive role in the cyclization and dictates
the sense of the regiochemistry. Thus, the carbene complex 1e
(R2 ) t-Bu) and the enamine 8b yielded exclusively 10e (94%).
Remarkably, the cycloadducts 10 were produced as diastereo-
chemically pure materials.11 Compounds 10a,b,e were elaborated
into 3,4-disubstituted cyclopentanones 14a,b,e by sequential
enolether hydrolysis (concentrated HCl, AcOH; 82-89%) to give
12a,b,e followed by reductive carbon-nitrogen bond cleavage
(SmI2, THF, MeOH; 78-90%).11,12 This protocol was applied
successfully to the asymmetric synthesis of cyclopentanones using
enantiopure enamines 9 (Scheme 2).9 Thus, the expected substi-
tuted cyclopentenes 11a-e were obtained as single regioisomers
with excellent chemical yield (74-91%) and complete relative
and absolute stereocontrol. Hydrolysis of 11a,b,e furnished
cyclopentanones 13a,b,e (80-84%) which gave rise to enantio-
merically enriched trans-3,4-disubstituted cylopentanones 15a,b,e
(90-92%; 92-99% ee) upon reductive cleavage.11,12 Finally,
compound (+)-16 was efficiently synthesized (30% overall yield,
>97% ee) from carbene complex 1a and malonaldehyde mono-
acetal enamine.11,13
Acknowledgment. This research was supported by DGICYT (Grants
PB94-1313 and PB97-1271). Fellowships to J.S. and A.P.N. (FICYT)
and C.B. (MEC) are gratefully acknowledged.
Supporting Information Available: Characterization data for 4-22,
including HPLC assays, X-ray figure and crystallographic data for
compound 18 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
The absolute configuration of compound 7a was determined
by circular dichroism (CD) analysis of the p-bromobenzoyl
(11) The relative stereochemistry of 4 and 10 was determined by 2D-
NOESY spectra. The diastereomeric excesses were analyzed by 1H NMR
(4,5: >80%; 10-13: >90%) and GC-MS (11c: 98.6%; 11d: 97%). The
enantiomeric excess of 7 and 15 was determined by HPLC (Chiracel columns).
The enantiomeric excess of 16 was established by 13C NMR (100 MHz) of
the acetal derived from (2S,3S)-2,3-butanediol.
(12) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
(13) Cyclopentanones with two orthogonally masked carbonyl function-
alities are highly useful synthons in natural products (ref 1b, pp 308-312).
See also: Trost, B. M.; Lynch, J.; Renaut, P.; Steinman, D. H. J. Am. Chem.
Soc. 1986, 108, 284.
JA9825736
(14) Harada, N.; Iwabuchi, J.; Yokota, Y.; Uda, H.; Nakanishi, K. J. Am.
Chem. Soc. 1981, 103, 5590.
(15) For the cyclization model of III to 4,5, see: Barluenga, J.; Toma´s,
M.; Ballesteros, A.; Santamar´ıa, J.; Carbajo, R. J.; Lo´pez-Ortiz, F.; Garc´ıa-
Granda, S.; Pertierra, P. Chem.sEur. J. 1996, 2, 88.
(16) (a) Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. J. Am. Chem.
Soc. 1990, 112, 7625. (b) Seebach, D.; Imwinkelried, R.; Weber, T. In Modern
Synthetic Methods; Scheffold, R., Ed.; Springer-Verlag: Berlin 1986; Vol. 4,
pp 125-259.