Published on Web 12/14/2005

Enantioselective Organocatalytic Reductive Amination

R. Ian Storer, Diane E. Carrera, Yike Ni, and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received October 23, 2005; E-mail: dmacmill@caltech.edu

The reductive amination reaction remains one of the most ketone and amine coupling partners to a chiral hydrogen-bonding
powerful and widely utilized transformations available to practi- catalyst8 would result in the intermediate formation of an iminium
tioners of chemical synthesis in the modern era.1 A versatile species that in the presence of a suitable Hantzsch ester would
coupling reaction that enables the chemoselective union of diverse undergo enantioselective hydride reduction, thereby allowing asym-
ketone and amine containing fragments, reductive amination can metric reductive amination in an in vitro setting.9 This proposal
also provide rapid and general access to stereogenic C-N bonds, was further substantiated by the significant advances in hydrogen-
a mainstay synthon found in natural isolates and medicinal agents. bonding catalysis, arising from the pioneering studies of Jacobsen,10
While a variety of protocols have been described for the asymmetric Corey,11 Takemoto,12 Rawal,13 Johnston,14 Akiyama,15 and Terada.16
reduction of ketimines (a strategy that requires access to preformed,
bench stable imines),2 it is surprising that few laboratory methods
are known for enantioselective reductive amination.1b,3 Moreover,
the use of this ubiquitous reaction for the union of complex
fragments remains unprecedented in the realm of asymmetric
catalysis, a remarkable fact given the widespread application of
both racemic and diastereoselective variants. In this communication,
we report the first organocatalytic reductive amination, a biomimetic
reaction that allows the asymmetric coupling of complex fragments
using chiral hydrogen-bonding catalysts and Hantzsch esters.4,5

An initial evaluation of the proposed reductive amination was

performed with acetophenone, p-anisidine, ethyl Hantzsch ester
(HEH), and several classes of established hydrogen-bonding
catalysts (eq 1, Table 1). While thiourea 1 and taddol 2 did not
induce reductive amination, the binol phosphoric acid catalysts
3a-d (introduced by Terada and Akiyama) did indeed provide the
desired amine adduct, albeit with moderate conversion and stereo-
induction (entries 1-5, 7-65% ee). To our great delight, we found
that an unprecedented ortho-triphenylsilyl variant of the Terada-
Akiyama catalyst 5 facilitates the desired coupling in high conver-
sion and with excellent levels of enantiocontrol at 40 °C (entry 8,
94% ee).17 Importantly, preliminary studies have revealed that water,
generated in the initial condensation step, has a deleterious impact
on both iminium formation and the hydride reduction step. As such,
the introduction of 5 Å sieves was found to be critical to achieve
useful reaction rates and selectivities.
Having established the optimal conditions for hydrogen bond
It has long been established that nature has perfected reductive catalysis, we next examined the scope of the ketone component in
amination as an in vivo chemical tool for the enantioselective this organocatalytic reduction. As revealed in Table 2, a variety of
synthesis of essential biomonomers. As a preeminent example, substituted acetophenone derivatives can be successfully coupled
transferase enzymes utilize hydrogen bonding to selectively activate (eq 2), including electron-rich, electron-deficient, as well as ortho,
pyruvate-derived ketimines toward hydride delivery from NADH, meta, and para substituted aryl ketone systems (Table 2, entries
thereby ensuring the enantiocontrolled formation of naturally 1-9, 60-87% yield, 83-95% ee). Moreover, cyclic aryl ketones
occurring amino acids.6 With this in mind, we recently questioned (entry 10, 75% yield, 85% ee) and R-fluoromethyl ketones (entry
whether the conceptual blueprints of biochemical amination might 11, 70% yield, 88% ee) are also tolerated in this process without
be translated to an enantioselective reductive coupling wherein loss in reaction efficiencies or enantiocontrol.
enzymes and cofactors are replaced by small organic catalysts and Pleasingly, the pyruvic acid-derived cyclic imino ester (eq 3)
NADH analogues.7 Specifically, we proposed that exposure of also underwent facile reduction to yield the corresponding cyclic
84 9 J. AM. CHEM. SOC. 2006, 128, 84-86 10.1021/ja057222n CCC: $33.50 © 2006 American Chemical Society
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Table 1. Evaluation of Phosphoric Acid Catalyst Architecture tion wherein the CdN Si-face is exposed to hydride addition
entry cat. cat. substitution (R) additive temp (°C) % conva % eeb (MM3-7, green dot ) H). In contrast, the ethyl-containing
1 3a 2-naphthyl none 80 6 37
substrate (R2 ) Et, MM3-7, green dot ) Me) is conformationally
2 3a 2-naphthyl 5 Å MS 80 41 45 required to position the terminal CH3 of the ethyl group away from
3 3b H 5 Å MS 80 43 7 the catalyst framework, thereby ensuring that both enantiofacial
4 3c 3,5-NO2-phenyl 5 Å MS 80 45 16 sites of the iminium π-system are shielded (MM3-7, green dot )
5 3d 3,5-CF3-phenyl 5 Å MS 80 39 65 Me). As shown in Figure 1 (Supporting Information), we have
6 4 SitBuPh2 5 Å MS 80 35 61
7 5 SiPh3 5 Å MS 80 70 87 recently obtained a single-crystal X-ray structure of a catalyst-bound
8 5 SiPh3 5 Å MS 40 85 94 aryl imine that exhibits a remarkable correlation to MM3-7 in
terms of both hydrogen bond orientation and the specific architec-
a Conversion determined by GLC analysis. b Enantiomeric excess de-
tural elements that dictate iminium enantiofacial discrimination.18
termined by chiral GLC analysis (Varian CP-chirasil-dex-CB).

Table 2. Organocatalytic Reductive Amination of Aromatic

Ketones

Both these X-ray and calculated structures suggest that catalyst

5 should be generically selective for the reduction of iminium ions
derived from methyl ketones. To test this hypothesis, we next
examined the amination of para substituted aryldiketone 8. In accord
with our torsional-control hypothesis, diketone 8 underwent chemo-
selective reduction to yield monoaminated 9 with a 18:1 preference
for coupling at the methyl ketone site (eq 4, 85% yield, 96% ee).

a Absolute stereochemistry determined by chemical correlation. b Enan-

tiomeric excess determined by chiral GLC or SFC-HPLC analysis. We next proposed to test this methyl versus ethyl chemoselec-
c Performed at 5 °C. d Reduction of preformed cyclic imine.
tivity in a productive fashion via the amination of butanone, a
prochiral ketone that contains both such alkyl substituents on the
alanine amino ester with excellent enantioselectivity (Table 2, entry same carbonyl (eq 5). In the event, the corresponding 2-amino
12, 82% yield, 97% ee). However, implementation of the corre- butane product 10 was furnished with notable levels of enantio-
sponding ethyl substituted imine 7 resulted in a dramatic decrease control (83% ee), thereby revealing that ketones that contain dialkyl
in efficiency (82 vs 27% yield). Computational studies reveal that substituents of similar steric and electronic character are viable
this remarkable change in reaction rate as a function of alkyl substrates for this process (e.g., A values: Me )1.7 vs Et ) 1.75).
substituent likely arises from catalyst imposed torsional constraints Indeed, the capacity of catalyst 5 to selectively function with a
on substrate conformation. More specifically, imines that incorporate broad range of methyl alkyl substituted ketones has now been
a methyl group are predicted to undergo selective catalyst associa- established (Table 3, entries 1-4, 49-75% yield, 83-94% ee). In

J. AM. CHEM. SOC. 9 VOL. 128, NO. 1, 2006 85

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Table 3. Organocatalytic Reductive Amination of Alkyl-Alkyl simple fragment coupling has been accomplished with a wide range
Ketones 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
free of charge via the Internet at http://pubs.acs.org.

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.; Börner, 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.;
a Absolute stereochemistry determined by chemical correlation. b Enan- 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.,
tiomeric excess determined by chiral GLC or SFC-HPLC analysis. 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
Table 4. Organocatalytic Coupling of Aromatic and Heterocyclic imines: Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kocovsky, P.
Amines Org. Lett. 2004, 6, 2253.
(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.; Börner, 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.
a Enantiomeric excess determined by chiral SFC-HPLC. (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.;
this context, it is important to underscore a key benefit of reductive Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005,
127, 1336.
amination versus imine reduction. Specifically, imines derived from (14) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004,
alkyl-alkyl ketones are unstable to isolation, a fundamental 126, 3418.
limitation that is comprehensively bypassed using direct reductive (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.
amination. Lett. 2005, 7, 2583.
Last, a central tenet of this investigation was to develop an (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,
enantioselective reductive amination that can be employed in 11804. (c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc.
complex fragment couplings (eq 7). As revealed in Table 4, this 2005, 127, 9360.
(17) Catalysts 1 and 3 were prepared using procedures outlined in refs 8 and
goal has now been accomplished using a variety of electronically 12. Catalyst 5 was first prepared and applied to this catalytic protocol on
diverse aryl and heteroaromatic amines in combination with aryl October 13, 2004, to furnish the amine in Table 2, entry 1, in 94% ee.
ketones (entries 1-5, 91-95% ee) as well as alkyl-alkyl carbonyls (18) The crystallographic data have been deposited at the CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK, and copies can be obtain on request,
(entry 6, 90% ee). free of charge, by quoting the publication citation and the deposition
In summary, we have developed the first enantioselective number 287655.
organocatalytic reductive amination. This mild and operationally JA057222N
86 J. AM. CHEM. SOC. 9 VOL. 128, NO. 1, 2006