Dynamic kinetic resolution via asymmetric conjugate reduction: Enantio- and diastereoselective synthesis of 2,4-dialkyl cyclopentanones

Article abstract of DOI:10.1021/ja025603k

Herein, we report the kinetic and the dynamic kinetic resolutions of racemic 3,5-dialkyl-2-cyclopenten-1-ones. Kinetic resolution, with good selectivity factors (25-52), was achieved by conjugate reduction with catalytic CuCl/NaOt-Bu/(S)-p-tol-BINAP and s

Full text of DOI:10.1021/ja025603k

Published on Web 03/01/2002
Dynamic Kinetic Resolution via Asymmetric Conjugate Reduction: Enantio-
and Diastereoselective Synthesis of 2,4-Dialkyl Cyclopentanones
Valdas Jurkauskas and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received January 15, 2002
Table 1. Kinetic Resolution of 3,5-Dialkylcyclopentenones
The majority of methods to access chiral â-substituted cyclic
ketones employ conjugate addition reactions.1 Several selective
systems have been developed for the asymmetric catalytic conjugate
addition of alkylmetals to R,â-unsaturated esters and ketones.2 We
have recently reported that chiral bidentate phosphine complexes
of copper (I) serve as effective asymmetric conjugate reduction
catalysts for enoates and cyclic enones,3-5 offering a complementary
enantioselective method to access such compounds. In this paper,
we describe the kinetic resolution6 (KR) and dynamic kinetic
resolution7 (DKR) of racemic 3,5-dialkylcyclopentenones employ-
ing catalytic (S)-p-tol-BINAP/CuCl/NaOt-Bu and poly(methyl-
hydrosiloxane) (PMHS) as a stoichiometric reductant. This process
is a unique approach to simultaneously establish two nonadjacent
stereocenters in dialkylcyclopentanones (eq 1).
a See Supporting Information for the absolute stereochemistry determi-
nation of 1a. b Determined by HPLC. c Reaction time ) 4-12 h. d Selec-
tivity factors (s) (averages of two or more runs). The % ee and conversion
reported are for specific runs. e Reaction at -78 °C. f Reaction at 0 °C.
g Reaction at -50 °C. h Reaction time ) 72 h.
tivities. Fortuitously, stoichiometric NaOt-Bu could effect the
racemization of 1 at temperatures as low as -50 °C. Unfortunately,
this epimerization was too slow relative to the rate of conjugate
The different rates of reaction for the enantiomers of racemic
3,5-dialkylcyclopentenones in the asymmetric copper-catalyzed
conjugate reduction enabled us to perform efficient kinetic resolu-
tion of these substrates. As is evident in Table 1, high selectivity
factors8 (s) were obtained under the kinetic resolution conditions
regardless of the alkyl substituent at the 5-position. In cases where
primary alkyl and methyl groups were at the 5-position (entries 1,
2, 5-7), the reductions were performed at low temperatures to
obtain high selectivity. Notably, high diastereomeric ratios were
observed for all reduction products 2 under the KR conditions
(dr g 92:8).9 It is important to note that the kinetic resolution of
3,4-dialkylcyclopentenones gave lower s values (<10).
Scheme 1
Encouraged by our kinetic resolution results, we sought to extend
this method to the dynamic kinetic resolution of 3,5-dialkylcyclo-
pentenones (Scheme 1). We previously postulated5b that upon
asymmetric conjugate reduction of the enone, a copper enolate10
intermediate is formed. Subsequent σ-bond metathesis with silane11
yields silyl enol ether5b 4 and regenerates the Cu-hydride catalyst.
We reasoned that if the reduction was performed under basic
conditions (e.g, NaOt-Bu, LiHMDS), rapid racemization of the
starting material should occur. Furthermore, since the product ketone
is masked as silyl enol ether 4, epimerization at the R-stereocenter
of the desired product would be obviated.
In our initial studies, we determined that the use of amide bases
in the DKR resulted in low conversions and poor enantioselec-
* Address correspondence to this author. E-mail: sbuchwal@mit.edu.
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10.1021/ja025603k CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Dynamic Kinetic Resolution of
3,5-Dialkylcyclopentenones
conjugate reduction as well as mechanistic investigations of this
catalyst system.
Acknowledgment. We thank the National Institutes of Health
(GM 46059) for funding and Pfizer, Merck and Bristol-Myers
Squibb for additional unrestricted support. V.J. thanks Natural
Sciences and Engineering Research Council (NSERC) of Canada
for a predoctoral fellowship. The authors also thank Professor
Gregory C. Fu, Dr. Daniel H. Appella, and Dr. Alexander R. Muci
for helpful discussions as well as Dr. Jeffrey H. Simpson for
assistance with NMR measurements.
Supporting Information Available: Preparation and characteriza-
tion of all substrates and products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) Reviews on conjugate addition: (a) Feringa, B. L. Acc. Chem. Res. 2000,
33, 346. (b) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (c)
Hayashi, T. Synlett 2001, 879.
(2) Leading references on asymmetric conjugate addition: (a) Takaya, Y.;
Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120, 5579. (b)
Hayashi, T.; Senda. T.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc.
1999, 121, 11591. (c) Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int.
Ed. 1999, 38, 3518. (d) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999,
64, 2988. (e) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H.;
Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865. (f) Escher, I. H.;
Pfaltz, A. Tetrahedron 2000, 56, 2879. (g) Chataigner, I.; Gennari, C.;
Ongeri, S.; Piarulli, U.; Ceccarelli, S. Chem. Eur. J. 2001, 7, 2628. (h)
Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 755. (i) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem.
Soc. 2002, 124, 779.
a See Supporting Information for the determination of relative and
absolute stereochemistry of 2a. Absolute stereochemistry of all other
products was assigned by analogy to 2a. b Isolated yield (sum of both
diastereomers; average of at least two runs of >95% purity as determined
by GC, 1H, and 13C NMR). c Determined by HPLC. Average % ee and dr
for at least two runs. d Reaction at -50 °C. e Reaction at -30 °C. f Reaction
at 0 °C. g 3.1 equiv of PMHS and 2.4 equiv of NaOt-Bu, reaction time )
48 h.
(3) Pioneering studies on Cu-H phosphine complexes: (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.
reduction under these conditions. The addition of t-BuOH (5 equiv)
as a kinetically labile proton source enhanced the rate of racem-
ization, resulting in the isolation of 2 with high enantiomeric and
diastereomeric excesses (Table 2). PMHS proved to be the silane
of choice; the use of more reactive silanes (e.g., Ph2SiH2) resulted
in diminished enantioselectivities. In most cases where the R-sub-
stituent was either Me or 1° alkyl, it was necessary to perform the
dynamic kinetic resolutions at higher temperatures than the corre-
sponding kinetic resolutions, presumably to achieve efficient
racemization of 1 (entries 1, 5-6). In contrast, performing the DKR
of isopropyl-substituted ketone 1c at 0 °C (the optimum temperature
for the KR) resulted in a diminished diastereomeric ratio (85:15).
We hypothesized that this was due to competitive partial decom-
position of silyl enol ether 4 and subsequent epimerization. Thus,
lowering the reaction temperature to -30 °C allowed for the clean
conversion of (()-1c (94% yield, 93% ee, 93:7 dr). Greater than
95% conversion of the starting material to the desired reduction
product was observed in all reactions.
(4) Asymmetric conjugate reductions using cobalt catalysts and NaBH
4: (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 and references
therein.
(5) (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473. (b) Moritani, Y.; Appella, D.
H.; Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 6797.
(c) Yun, J.; Buchwald, S. L. Org. Lett. 2001, 3, 1129.
(6) Leading references on kinetic resolution: (a) Kagan, H. B.; Fiaud, J. C.
Top. Stereochem. 1988, 18, 249. (b) Hoveyda, A. H.; Didiuk, M. T. Curr.
Org. Chem. 1998, 2, 489. (c) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N.
AdV. Synth. Catal. 2001, 343, 5. (d) Blackmond, D. G. J. Am. Chem. Soc.
2001, 123, 545. For a recent example of kinetic resolution of cyclo-
hexenones, see: Naasz, R.; Arnold, L. A.; Minnaard, A. J.; Feringa,
B. L. Angew. Chem., Int. Ed. 2001, 40, 927.
(7) Reviews on dynamic kinetic resolution: (a) Noyori, R.; Tokunanga, M.;
Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36. (b) Ward, R. S.
Tetrahedron: Asymmetry 1995, 6, 1475. (c) Caddick, S.; Jenkins, K. Chem.
Soc. ReV. 1996, 25, 447. (d) Stecher, H.; Faber, K. Synthesis 1997, 1. (e)
Huerta, F. F.; Minidis, A. B. E.; Ba¨ckvall, J.-E. Chem. Soc. ReV. 2001,
30, 321.
In conclusion, the method we report here represents an example
of a dynamic kinetic resolution with simultaneous creation of two
nonadjacent chiral centers. The combination of catalytic amounts
of CuCl, a commercially available chiral bis-phosphine, and NaOt-
Bu with PMHS generates a highly enantio- and diastereoselective
complex that reacts exclusively via 1,4-reduction. The dynamic
kinetic resolution conditions for this catalytic system were achieved
by employing stoichiometric amounts of NaOt-Bu and t-BuOH.
Our current efforts are focused on the discovery of new copper
complexes that will improve the substrate scope of the asymmetric
(8) Selectivity factor, s ) kf/ks ) ln[(1 - C)(1 - ee)]/[(1 - C)(1 + ee)],
where ee is the percent enantiomeric excess of 1 and C is the conversion.
For each substrate, comparable selectivity factors (s) were observed at
low (24-30%) and at high (45-57%) conversions.
(9) Selectivity factors (s) calculated using the enantiomeric excess of reduction
product 2 were consistent with values calculated using the % ee of
unreacted 1 for the several cases examined. (In these cases, s ) kf /ks )
ln[1 - C(1 + ee)]/[(1 - C(1 - ee)], where ee is the percent enantiomeric
excess of 2 and C is the conversion.)
(10) Pagenkopf, B. L.; Kru¨ger, J.; Stojanovic, A.; Carreira, E. M. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 3124.
(11) Lorenz, C.; Schubert, U. Chem. Ber. 1995, 128, 1267.
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