C O M M U N I C A T I O N S
Table 3. Organocatalytic Reductive Amination of Alkyl-Alkyl
Ketones
simple fragment coupling has been accomplished with a wide range
of ketones in combination with aryl and heterocyclic amines. Further
mechanistic studies of this amination reaction will be reported
shortly.
Acknowledgment. Financial support was provided by the
NIHGMS (R01 GM66142-01) and kind gifts from Amgen and
Merck. This research was supported by a Marie Curie International
Fellowship (to R.I.S.) within the 6th European Community
Framework Programme. Joe Carpenter is thanked for catalyst
preparation.
Supporting Information Available: Experimental procedures,
structural proofs, and X-ray and spectral data. This material is available
References
(1) (a) For a general review, see: Ohkuma, T.; Noyori, R. In ComprehensiVe
Asymmetric Catalysis, Suppl. 1; Jacobsen, E. N., Pfaltz, A.; Yamamoto,
H., Eds.; Springer: New York, 2004. (b) For a review of asymmetric
reductive amination, see: Tararov, V. I.; Bo¨rner, A. Synlett 2005, 203.
(2) For reviews, see: (a) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.;
Steiner, H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103. (b) Tang, W.;
Zhang, X. Chem. ReV. 2003, 103, 3029. (c) Riant, O.; Mostefai, N.;
Courmarcel, J. Synthesis 2004, 2943. (d) Carpentier, J. F.; Bette, V. Curr.
Org. Chem. 2002, 6, 913. (e) Kadyrov, R.; Riermeier, T. H. Angew. Chem.,
Int. Ed. 2003, 42, 5472. (f) Nolin, K. A.; Ahn, R. W.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 12462. (g) Organocatalytic hydrosilylation of
imines: Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kocovsky, P.
Org. Lett. 2004, 6, 2253.
a Absolute stereochemistry determined by chemical correlation. b Enan-
tiomeric excess determined by chiral GLC or SFC-HPLC analysis.
Table 4. Organocatalytic Coupling of Aromatic and Heterocyclic
Amines
(3) (a) Blaser, H.-U.; Buser, H.-P.; Jalett, H.-P.; Pugin, B.; Spindler, F. Synlett
1999, 867. (b) Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003,
42, 5472. (c) Williams, G. D.; Pike, R. A.; Wade, C. E.; Wills, M. Org.
Lett. 2003, 5, 4227. (d) Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.;
Tararov, V.; Bo¨rner, A. J. Org. Chem. 2003, 68, 4067. (e) Chi, Y. X.;
Zhou, Y. G.; Zhang, X. M. J. Org. Chem. 2003, 68, 4120.
(4) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
(5) For the first asymmetric (63% ee) organocatalytic HEH reduction of
imines, see: (a) Singh, S.; Batra, U. K. Indian J. Chem., Sect. B 1989,
28, 1. Subsequent improvements in this ketimine reduction protocol were
published (b) during the preparation and (c) at the time of submission of
this manuscript: (b) Reuping, M.; Sugiono, E.; Azap, C.; Theissmann,
T.; Bolte, M. Org. Lett. 2005, 7, 378. (c) Hoffman, S.; Seayad, A. M.;
List, B. Angew. Chem., Int. Ed. 2005, 44, 7424.
(6) Alberts, B.; Bray, D.; Lewis, J.; Raff, M.; Roberts, K.; Watson, J. D.
Molecular Biology of the Cell; Garland: New York and London, 2002.
(7) For previous studies of asymmetric HEH reduction of enals, see: Ouellet,
S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
32.
(8) For reviews, see: (a) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062.
(b) Schreiner, P. Chem. Soc. ReV. 2003, 32, 289.
(9) For racemic acid-catalyzed reduction, see: Itoh, T.; Nagata, K.; Miyazaki,
M.; Ishikawa, H.; Kurihara, A.; Ohsawa, A. Tetrahedron 2004, 60, 6649.
(10) For examples, see: (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 1998, 120, 4901. (b) Yoon, T. P.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2005, 44, 466. (c) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2005, 127, 8964.
(11) (a) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157. (b) Huang, J.;
Corey, E. J. Org. Lett. 2004, 6, 5027.
(12) For examples, see: (a) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto,
Y. Org. Lett. 2004, 6, 625. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu,
X. N.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
(13) For examples, see: (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal,
V. H. Nature 2003, 424, 146. (b) Thadani, A. N.; Stankovic, A. R.; Rawal,
V. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5839. (c) Unni, A. K.;
Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005,
127, 1336.
(14) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004,
126, 3418.
(15) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
Ed. 2004, 43, 1566. (b) Akiyama, T.; Morita H.; Itoh J.; Fuchibe, K. Org.
Lett. 2005, 7, 2583.
a Enantiomeric excess determined by chiral SFC-HPLC.
this context, it is important to underscore a key benefit of reductive
amination versus imine reduction. Specifically, imines derived from
alkyl-alkyl ketones are unstable to isolation, a fundamental
limitation that is comprehensively bypassed using direct reductive
amination.
(16) (a) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. (b)
Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,
11804. (c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc.
2005, 127, 9360.
(17) Catalysts 1 and 3 were prepared using procedures outlined in refs 8 and
12. Catalyst 5 was first prepared and applied to this catalytic protocol on
October 13, 2004, to furnish the amine in Table 2, entry 1, in 94% ee.
(18) The crystallographic data have been deposited at the CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK, and copies can be obtain on request,
free of charge, by quoting the publication citation and the deposition
number 287655.
Last, a central tenet of this investigation was to develop an
enantioselective reductive amination that can be employed in
complex fragment couplings (eq 7). As revealed in Table 4, this
goal has now been accomplished using a variety of electronically
diverse aryl and heteroaromatic amines in combination with aryl
ketones (entries 1-5, 91-95% ee) as well as alkyl-alkyl carbonyls
(entry 6, 90% ee).
In summary, we have developed the first enantioselective
organocatalytic reductive amination. This mild and operationally
JA057222N
9
86 J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006