Synthesis of β-alkyl cyclopentanones in high enantiomeric excess via copper-catalyzed asymmetric conjugate reduction [17]

Full text of DOI:10.1021/ja0009525

J. Am. Chem. Soc. 2000, 122, 6797-6798
Scheme 1
6797
Synthesis of â-Alkyl Cyclopentanones in High
Enantiomeric Excess via Copper-Catalyzed
Asymmetric Conjugate Reduction
Yasunori Moritani, Daniel H. Appella, Valdas Jurkauskas, and
Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed March 21, 2000
Lipshutz, and Hiyama demonstrated that achiral phosphine-
copper hydrides, such as [(Ph3P)CuH]6, preferentially reduce
enones via 1,4-reduction.9 We now report that chiral (bis-
phosphine)Cu catalysts can reduce â-substituted enones to afford
chiral ketones with very high ee’s. These catalysts are especially
effective for the asymmetric reduction of â-substituted cyclo-
pentenones.
In practice, efficient catalysts were generated in situ by first
combining a chiral bis-phosphine ((S)-p-tol-BINAP, (S)-BINAP,
or (S)-BIPHEMP),10 CuCl, and NaOt-Bu in toluene, followed by
the addition of PMHS. As shown in Table 1, cyclopentanones
were obtained in high yields and excellent ee’s. For most of the
â-substituted cyclopentenones, conjugate reductions were com-
plete in 24 h with 5 mol % catalyst and 1 equiv, relative to the
substrate, of PMHS. Lower catalyst loadings (1 mol %) could be
used without any effect on the ee of the product, but the reactions
took a longer time to go to completion. Previously, we reported
that 4 equiv of PMHS were necessary for the (S)-p-tol-BINAP-
derived catalyst to reduce R,â-unsaturated esters.7 However, for
the reduction of R,â-unsaturated ketones it was important to limit
the amount of PMHS such that 1 equiv of Si-H was present
relative to substrate.11 If extra PMHS was used, then overreduction
to the saturated alcohol was observed.
Cyclopentenones designed to test the tolerance of the catalyst
to functional groups and steric hindrance were subjected to the
reduction conditions. A cyclopentenone that contained an isolated
olefin was successfully reduced in high ee (entry 5). Substrates
with either a benzyl ether (entry 6) or an ester (entry 7) were
also reduced with high enantioselectivity. Examination of the
tolerance of the catalyst to steric hindrance on the substrate
revealed that longer reaction times were necessary as the steric
bulk of the substituent on the â-carbon increased. For instance,
the reduction of 3-isopropylcyclopentenone (entry 8) proceeded
to 90% completion after 3 days to afford 3-isopropylcyclopen-
tanone in 88% yield and 94% ee.13,14 To date, attempted reductions
Most synthetic routes to chiral â-substituted cyclic ketones are
based on the conjugate addition of nucleophiles to cyclic R,â-
unsaturated ketones (Scheme 1a).1 Recently, excellent catalysts
for the asymmetric conjugate addition of nucleophiles to cyclic
enones that contain a 6- or 7-membered ring have been discov-
ered.2 Highly enantioselective catalysts for conjugate addition of
aryl, vinyl,3 or enolate4 nucleophiles to cyclopentenone are also
known. However, catalysts for the asymmetric conjugate addition
of nucleophilic alkyl groups to cyclopentenone typically afford
products with enantiomeric excesses (ee’s) lower than 90%.2
Currently, the most enantioselective catalytic method to produce
â-alkylcyclopentanones utilizes Rh(Me-DUPHOS) and Rh(BINAP)
complexes to catalyze the asymmetric intramolecular hydro-
acylation of 4-substituted pent-4-enals.5 We felt that a procedure
based on asymmetric reduction of â-substituted enones, which
can be readily synthesized via the Stork-Danheiser procedure,6
could also provide a useful synthetic route to enantiomerically
enriched â-substituted cyclic ketones (Scheme 1b).
Recently, we described a new copper catalyst for the asym-
metric conjugate reduction of R,â-unsaturated esters.7 This catalyst
employs polymethylhydrosiloxane (PMHS), a safe and inexpen-
sive polymer, as the stoichiometric reductant. Other catalysts for
asymmetric conjugate reduction are based on chiral cobalt
complexes and utilize stoichiometric amounts of borohydrides,
such as NaBH4.8 Although the cobalt catalysts are very effective
for the asymmetric conjugate reduction of R,â-unsaturated esters
and amides, the same catalysts cannot be used for the asymmetric
conjugate reduction of enones because reduction by the borohy-
dride is rapid and nonselective. The pioneering work of Stryker,
(1) For reviews of conjugate addition, see: Rossiter, B. E.; Swingle, N.
M. Chem. ReV. 1992, 92, 771. Tomioka, K.; Nagaoka, Y. Conjugate Addition
of Organometallic Reagents. In ComprehensiVe Asymmetric Catalysis; Ja-
cobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol.
3, Chapter 31.1, pp 1105-1120. For recent examples of chiral additives for
asymmetric conjugate addition, see: Kanai, M.; Nakagawa, Y.; Tomioka, K.
Tetrahedron 1999, 55, 3831. Chong, J. M.; Shen, L.; Taylor, N. J. J. Am.
Chem. Soc. 2000, 122, 1822. For a recent example of a chiral auxiliary for
asymmetric conjugate addition, see: Funk, R. L.; Yang, G. Tetrahedron Lett.
1999, 40, 1073.
(2) (a) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988. (b) Hu,
X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. Engl. 1999, 38, 3518. (c)
Yan, M.; Chan, A. S. C. Tetrahedron Lett. 1999, 40, 6645. (d) Arnold, L. A.;
Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L.
Tetrahedron 2000, 56, 2865. (e) Escher, I. H.; Pfaltz, A. Tetrahedron 2000,
56, 2879. (f) Krause, N. Angew. Chem., Int. Ed. Engl. 1998, 37, 283 and
references sited within.
(3) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1999, 40,
6957.
(4) (a) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T. Chem. Lett.
1994, 97. (b) Arai, T.; Sasai, H.; Aoe, K.-I.; Okamura, K.; Date, T.; Shibasaki,
M. Angew. Chem., Int. Ed., Engl. 1996, 35, 104.
(5) (a) Bardhart, R. W.; McMorran, D. A.; Bosnich, B. Chem. Commun.
1997, 589. (b) Fujio, M.; Tanaka, M.; Wu, X.-M.; Funakoshi, K.; Sakai, K.;
Suemune, H. Chem. Lett. 1998, 881.
(6) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775.
(7) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473.
(9) (a) Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989, 111, 8818.
(b) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett. 1998,
39, 4627. (c) Mori, A.; Fujita, A.; Kajiro, H.; Nishihara, Y.; Hiyama, T.
Tetrahedron 1999, 55, 4573.
(10) p-tol-BINAP ) 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl, BINAP
) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, BIPHEMP ) 2,2′-bis(diphen-
ylphosphino)-6,6′-dimethyl-1,1′-biphenyl.
(11) PMHS from Aldrich has an average molecular weight between 3200
and 17 000, and a density of 1.006 g/mL. From these values, 0.06 mL of
PMHS/mmol of Si-H was calculated and this value was used to determine
the volume of PMHS to add to the reaction so that there was only 1 equiv of
Si-H relative to substrate.
(12) We are in the process of developing reaction conditions that do not
require a drybox by trying to replace CuCl with a copper salt that is less
sensitive to air.
(13) Isolation of the volatile product in high yield could only be ac-
complished by Kugelrohr distillation to remove toluene followed by chro-
matography with ether/pentane (a high vacuum pump could not be used to
remove solvents without losing substantial amounts of the product).
(14) Cyclopentenones with substituents larger than an isopropyl group on
the â-carbon did not react with the catalyst; for instance, 3-tert-butylcyclo-
pentenone could not be reduced. Additionally, at present we are unable to
reduce 2,3-disubstituted cyclopentenones.
(8) (a) Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem., Int. Ed., Engl.
1989, 28, 60. (b) Misun, M.; Pfaltz, A. HelV. Chim. Acta 1996, 79, 961. (c)
Yamada, T.; Ohtsuka, Y.; Ikeno, T. Chem. Lett. 1998, 1129.
10.1021/ja0009525 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/27/2000

6798 J. Am. Chem. Soc., Vol. 122, No. 28, 2000
Communications to the Editor
Table 1. Asymmetric Conjugate Reductions with (S)-p-tol-BINAP,
CuCl, NaOt-Bu, and PMHSa
Scheme 2
1,2-reduction of the substrate was a problem in this reduction; in
addition to the desired product, 3-phenethylcycloheptenol (9%)
was also isolated. The p-tol-BINAP and BIPHEMP derived
catalysts produced the same mixture of the desired product and
the product of 1,2-reduction.
Our current view is that a (bis-phosphine)CuH complex is the
key intermediate in the catalytic cycle of the reduction. Conjugate
reduction of cyclopentenones by such a complex should result in
formation of a copper enolate that subsequently undergoes
metathesis with a silane15 to form a silyl enol ether (Scheme 2).
Circumstantial evidence supporting this mechanism was obtained
when the silyl bis-(enol ethers) 1-3 were isolated from the
catalytic reduction of the corresponding cyclopentenones with 0.53
equiv of diphenylsilane. Treatment of 1-3 with TBAF afforded
the 3-alkylcyclopentanone with the same ee as the catalytic
reduction with PMHS.
In conclusion, the combination of catalytic amounts of CuCl,
NaOt-Bu, and a chiral bis-phosphine with PMHS generates a
highly enantioselective catalyst for the asymmetric conjugate
reduction of R,â-unsaturated ketones. The catalysts examined in
this study produce â-substituted cyclopentanones with ee’s that
have not been obtained via asymmetric conjugate addition. These
catalysts react with cyclopentenones exclusively via 1,4-reduction.
The reductions of cyclohexenones and cycloheptenones also give
the products of 1,4-reduction in high ee’s; however, in these
reactions competing 1,2-reduction occurs to a minor extent.
Stryker and co-workers have reported that the reactivity of copper
hydride complexes is highly dependent on the nature of the
phosphine ligand.16 We are currently exploring copper hydride
complexes with new ligands to access catalysts with increased
selectivity for asymmetric conjugate reduction of a wide variety
of substrates.
a Reactions were performed at 0.5 M [enone], with 1.05 equiv of
PMHS, 5 mol % CuCl, 5 mol % NaOt-Bu, 5 mol % (S)-p-tol-BINAP,
for 24 h, at the temperature specified. Note: The reactions were set up
with the aid of a nitrogen filled drybox.12 b See Supporting Information
for details on substrate preparation. c Yields are the average of two
1
isolated yields of >95% purity as determined by GC and H NMR.
d The average ee for two reactions is reported for each entry. The
absolute stereochemistry of the products in entries 1, 2, 8, 9, and 10
was assigned by comparing the sign of their optical rotations to
published values (see Supporting Information for details). The absolute
stereochemistry of all other products was assigned by analogy. e Low
isolated yield due to volatility of the product, GC yield was 86%.
f Reaction time was 12 h. g (S)-BINAP was the ligand. h Reaction time
was 3 days. In addition to the desired product,10% starting material
was recovered. i Low isolated yield due to volatility of the product,
GC yield was 85%. j (S)-BIPHEMP was the ligand. k The reaction time
was 2 days. In addition to the desired product, 6% of 3-butylcyclo-
hexanol was isolated. l The reaction time was 4 days. In addition to
the desired product, 9% of 3-phenethylcycloheptenol was isolated.
of cyclopentenones with vinyl or alkynyl groups conjugated to
the enone gave mixtures of products resulting from competing
1,4- and 1,6-reductions.
The conjugate reductions of â-substituted cyclohexenones and
cycloheptenones produced the desired products in high ee. For
cyclohexenones, the BIPHEMP-derived catalyst produced prod-
ucts in higher ee than the catalysts derived from the other two
ligands. In some cases, minor amounts of overreduced products
were isolated. For instance, the reduction of 3-methylcyclohex-
enone (entry 9) produced the product cleanly (92% ee), but the
reduction of 3-butylcyclohexenone (entry 10) afforded the desired
product (87% ee) along with 3-butylcyclohexanol (6%). Similar
problems with competing overreduction were observed with the
catalysts derived from p-tol-BINAP and BINAP. For 3-pheneth-
ylcycloheptenone, BINAP was the ligand of choice, and the
desired product was obtained in 96% ee (entry 11). Competing
Acknowledgment. Y.M. was supported by the Tanabe Seiyaku Co.,
Ltd. D.H.A. is an NIH postdoctoral fellow (GM19551). We thank the
National Institutes of Health (GM46059) for funding and Pfizer and Merck
for additional unrestricted support. We are grateful to Pfizer for a gift of
(S)-BINAP and to Dr. Rudy Schmid of Hoffmann-LaRoche for a gift of
(S)-BIPHEMP.
Supporting Information Available: Preparation and characterization
of all substrates and products (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA0009525
(15) Lorenz, C.; Schubert, U. Chem. Ber. 1995, 128, 1267.
(16) Chen, J.-X.; Daeuble, J. F.; Stryker, J. M. Tetrahedron 2000, 56, 2789.