C O M M U N I C A T I O N S
Table 1. Catalytic Asymmetric Hydrogenation of 2,3,5-Trisubstituted Pyrrolesa
entry
R1
R2
R3
1
convn (%)b
2:3b
yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
9
Me
Me
MeO2C
MeO2C
Ph
Me
MeO2C
Me
-(CH2)4-
C3H7
Ph
Ph
Ph
Ph
Ph
MeO2C
Me
Me
1b
1c
1d
1e
1f
1g
1h
1i
100
100
100
100
100
100
100
100
100
100
54:46
98:2
2b: 52, 3b: 42
2c: 91
2b: 11, 3b: 75
2c: 74, 3c: 43
2d: 96
2e: 91, 3e: 95
2f: 93
3g: 99.7
3h: 99.3
3i: 98
3j: 99.6
100:0
16:84
100:0
0:100
0:100
0:100
0:100
0:100
2d: 85
2e: 8,e 3e: 70
2f: 96
Me
Ph
Ph
Ph
p-CF3C6H4
p-MeOC6H4
Ph
3g: >99
3h: 99
3i: 96
3j: >99
3k: 97
p-FC6H4
p-MeOC6H4
Ph
1j
1k
10
Ph
3k: 99.2
a Reactions were conducted on a 0.2 mmol scale in 1.0 mL of EtOAc. The ratio of 1:[Ru]:PhTRAP:Et3N was 40:1:1.1:10. b Determined by 1H NMR
analysis of crude product. In all cases, no side product was observed in the spectra. c Isolated yields. d Determined by chiral GC or HPLC analysis. e The
product 2e was obtained as a mixture of two diastereomers (89% de).
Scheme 1
References
(1) Recent reviews: (a) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.;
Steiner, H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103-151. (b) Cui,
X.; Burgess, K. Chem. ReV. 2005, 105, 3272-3296. (c) Ja¨kel, C.; Paciello,
R. Chem. ReV. 2006, 106, 2912-2942.
(2) (a) Besson, M.; Pinel, C. Top. Catal. 2003, 25, 43-61. (b) Glorius, F.
Org. Biomol. Chem. 2005, 3, 4171-4175.
(3) Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani, M.
Organometallics 1998, 17, 3308-3310.
Scheme 2
(4) (a) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem.
Soc. 2000, 122, 7614-7615. (b) Kuwano, R.; Kashiwabara, M.; Sato,
K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron: Asymmetry 2006, 17, 521-
535.
(5) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653-2655.
(6) Representative examples: (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han,
X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536-10537. (b) Lu,
S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed.
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hydrogenation would produce achiral intermediate 3a (Scheme 1).
The chiral center of 2a would be created during the hydrogenation
of enamide 3a.16 By contrast, 2,3,5-trisubstituted pyrroles 1b-k
are reduced enantiomerically to chiral enamides in the initial step
(Scheme 2). The stereoselectivity in the additional reduction of 3
must be controlled by the chirality at the 5-position rather than the
chiral catalyst: if the stereoselectivity had been dictated by the chiral
catalyst, preferential formation of trans-2,5-substituted pyrrolidines
would have been observed in the reactions of 1b-f (Table 1, entries
1-5). The difference of the enantiodiscrimination step between the
hydrogenations of 1a and others suggests that the PhTRAP-
ruthenium catalyst is suitable for asymmetric hydrogenation of
pyrroles rather than for that of cyclic enamides.
Q.-H.; Zhou, H.-F.; Lam, K.; Chan, A. S. C. Chem. Commun. 2007, 613-
615.
(7) High enantioselectivity was achieved in the reduction of quinolines with
organocatalysis; see: Rueping, M.; Antonchick, A. P.; Theissmann, T.
Angew. Chem., Int. Ed. 2006, 45, 3683-3686.
(8) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966-
8967.
(9) Very recently, high enantioselectivity has been reported in the organo-
catalytic transfer hydrogenation of pyridines; see: Rueping, M.; Anton-
chick, A. P. Angew. Chem., Int. Ed. 2007, 46, 4562-4565.
(10) Highly stereoselective hydrogenation of pyridines modified with a chiral
oxazolidinone with heterogeneous catalysis has been reported; see:
Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.; Lehmann, C. W.
Angew. Chem., Int. Ed. 2004, 43, 2850-2852.
(11) (a) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Angew. Chem., Int. Ed. 2006, 45,
5194-5197. (b) Feiertag, P.; Albert, M.; Nettekoven, U.; Spindler, F. Org.
Lett. 2006, 8, 4133-4135.
In conclusion, we were successful in developing the highly
enantioselective hydrogenation of N-Boc-pyrroles by using chiral
Ru(η3-methallyl)2(cod)-(S,S)-(R,R)-PhTRAP catalyst. In particular,
2,3,5-trisubstituted pyrroles bearing a large substituent at the
5-position were hydrogenated with high ee values to give chiral
4,5-dihydropyrroles 3 or pyrrolidines 2 in high yields. This is the
first successful enantioselective reduction of pyrroles. Of note is
the fact that the asymmetric hydrogenation of 1d creates three chiral
centers with high level of stereocontrol in a single process.
(12) Highly stereoselective hydrogenation of a pyrrole modified with chiral
auxiliary had been reported; see: Hada, V.; Tungler, A.; Szepesy, L. Appl.
Catal. A 2001, 210, 165-171.
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Organometallics 1995, 14, 4549-4558. (b) Kuwano, R.; Sawamura, M.
In Catalysts for Fine Chemical Synthesis, Volume 5: Regio- and Stereo-
Controlled Oxidations and Reductions; Roberts, S. M.; Whittall, J., Eds.;
John Wiley & Sons: West Sussex, 2007; pp 73-86.
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J. A. Tetrahedron: Asymmetry 1991, 2, 555-567. (b) Geneˆt, J. P.; Pinel,
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(15) See Supporting Information for details.
Acknowledgment. This work was supported by the Uehara
Memorial Foundation and KAKENHI (No. 18032056 and 19685008)
from MEXT.
Supporting Information Available: Experimental procedures and
characterization data for all compounds. This material is available free
(16) When the hydrogenation of ethyl 2-pyrrolecarboxylate using the PhTRAP-
ruthenium catalyst was stopped at 2 h (29% conversion, 58% ee), the
resulting mixture contained only the staring material and the desired
pyrrolidine (by 1H NMR). No enamide 3a was detected. The observation
suggests that the conversion of enamide 3a into 2a will be much faster
than the first hydrogenation of 1a because 3a lacks aromaticity.
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J. AM. CHEM. SOC. VOL. 130, NO. 3, 2008 809