Primary amine/CSA ion pair: A powerful catalytic system for the asymmetric enamine catalysis

Article abstract of DOI:10.1021/ol200747x

A novel ion pair catalyst containing a chiral counteranion can be readily derived by simply mixing cinchona alkaloid-derived diamine with chiral camphorsulfonic acid (CSA). A mixture of 9-amino(9-deoxy)epi-quinine 8 and (-)-CSA was found to be the best ca

Full text of DOI:10.1021/ol200747x

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2638–2641
Primary Amine/CSA Ion Pair: A Powerful
Catalytic System for the Asymmetric
Enamine Catalysis
Chen Liu,† Qiang Zhu,† Kuo-Wei Huang,‡ and Yixin Lu*,†
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Singapore 117543, and
KAUST Catalysis Center & Division of Chemical and Life Science and Engineering,
King Abdullah University of Science and Technology, Kingdom of Saudi Arabia
chmlyx@nus.edu.sg
Received March 21, 2011
ABSTRACT
A novel ion pair catalyst containing a chiral counteranion can be readily derived by simply mixing cinchona alkaloid-derived diamine with chiral
camphorsulfonic acid (CSA). A mixture of 9-amino(9-deoxy)epi-quinine 8 and (ꢀ)-CSA was found to be the best catalyst with matching chirality,
enabling the direct amination of R-branched aldehydes to proceed in quantitative yields and with nearly perfect enantioselectivities. A 0.5 mol %
catalyst loading was sufficient to catalyze the reaction, and a gram scale enantioselective synthesis of biologically important R-methyl
phenylglycine has been successfully demonstrated.
Aminocatalysis via the enamine mechanism has been
well-established in the field of asymmetric synthesis and
catalysis.1 Ever since the seminal discovery by List, Barbas,
and Lerner on the proline-catalyzed intermolecular aldol
reaction in 2000,2 proline and its structural analogues have
been utilized extensively in a wide range of asymmetric
organic reactions. Pyrrolidine-based secondary amine cata-
lysts were found to be extremely powerful in activating
carbonyl substrates, aldehydes in particular, via the enamine
intermediates. In the past few years, primary amines have
received much attention in the aminocatalysis.3 Notably,
ketones have been shown to be suitable substrates for the
primary amine-based enamine activation, which comple-
ments well with secondary amine-derived catalysts in this
important mode of activation. Our group has been investi-
gating primary amine-mediated enamine processes in the
past few years.4 While we have achieved a certain degree of
success in a number of asymmetric reactions, we indeed felt
the intrinsic limitation of chiral structural scaffolds in stereo-
control posed restriction to the effectiveness of our catalytic
† National University of Singapore.
‡ King Abdullah University of Science and Technology.
(1) For selected excellent reviews and books, see: (a) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (b) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Berkessel, A.;
Groger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005. (d)
Dalko, P. I. Enantioselective Organocatalysis: Reactions and Experimental
Procedures; Wiley-VCH: Weinheim, 2007. (e) Dondoni, A.; Massi, A. Angew.
Chem., Int. Ed. 2008, 47, 4638. (f) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(2) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395.
(4) For our recent examples on the primary amine-mediated enamine
catalysis, see: (a) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun.
2006, 2801. (b) Cheng, L.; Han, X.; Huang, H.; Wong, M. W.; Lu, Y.
Chem. Commun. 2007, 4143. (c) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol.
Chem. 2007, 5, 1018. (d) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. Adv.
Synth. Catal. 2007, 349, 812. (e) Zhu, Q.; Lu, Y. Chem. Commun. 2008,
6315. (f) Zhu, Q.; Lu, Y. Chem. Commun. 2010, 46, 2235. (g) Jiang, Z.;
Yang, H.; Han, X.; Luo, J.; Wong, M. W.; Lu, Y. Org. Biomol. Chem.
2010, 8, 1368.
(3) For reviews on asymmetric catalysis mediated by primary
amines/amino acids and synthetic peptides, see: (a) Xu, L.-W.; Luo,
J.; Lu, Y. Chem. Commun. 2009, 1807. (b) Xu, L.-W.; Lu, Y. Org.
Biomol. Chem. 2008, 6, 2047. (c) Davie, E. A. C.; Mennen, S. M.; Xu, Y.;
Miller, S. J. Chem. Rev. 2007, 107, 5759. (d) Peng, F.; Shao, Z. J. Mol. Catal.
A2008,285,1.(e)Chen, Y.-C.Synlett 2008,1919. (f) Bartoli, G.; Melchiorre,
P. Synlett 2008, 1759.
r
10.1021/ol200747x
Published on Web 04/21/2011
2011 American Chemical Society

reactions. Thus, we set out to develop more powerful
primary amine-based catalytic systems for the enamine
activations.
Asymmetric counteranion-directed catalysis (ACDC)
was recently introduced by List and co-workers as a
powerful strategy in asymmetric catalysis.5 The introduc-
tionof a chiral counteranion tothe catalytic systemenables
the reactions proceeding through cationic intermediates to
be conducted in a highly enantioselective manner; stereo-
chemical control could be effectively induced by the chiral
couteranion. To the best of our knowledge, efficient
catalytic systems engaging chiral counteranions for the
enamine catalysis are yet to be developed. We recently
showed that the combination of 9-amino-9-deoxy-epi-
cinchonine and (þ)-camphorsulfonic acid (CSA) yielded
a new primary amine-based organocatalyst useful for
iminium activation of R,β-unsaturated ketones.6 We rea-
soned that the introduction of a chiral counteranion to the
existing catalyst may result in a more efficient catalytic
system for the enamine activation. Thus, a chiral diamine7
and a chiral acid were selected for the creation of a new ion
pair catalyst (Figure 1).8 Such catalytic systems can be
easily derived via modular assembly of the amino and acid
components. The resulting ammonium moiety in the ion
pair catalyst serves as a Brønsted acid to interact with the
substrate. Moreover, the presence of a chiral counteranion
may further enhance the chiral communications between
the chiral diamine and the substrates. Compared to the
currently existing chiral primary amine catalysts, which
rely on the structural scaffolds of chiral amines for the
asymmetric induction, the proposed ion pair catalyst en-
gages an extra chiral counteranion for stereocontrol. We
hypothesize that judicious selection of the two chiral
components may create a powerful chiral diamineꢀacid
catalyst for an effective enamine catalysis. In this commu-
nication, we document that the combination of a cinchona
alkaloid-derived primary amine and chiral CSA results in a
powerful ion pair catalyst for the enamine activation.
Modified peptides are used extensively in medicinal
chemistry and biological sciences;9 thus, asymmetric
synthesis of optically enriched unnatural amino acids has
Figure 1. Primary amineꢀchiral acid catalytic system for the
enamine catalysis.
been an actively pursued research area in the past few
decades.10 In this context, R,R-disubstituted R-amino acids
are of extreme importance; the presence of a quaternary
carbon center renders these unnatural amino acids with
increased proteolytic stability, and they have been em-
ployed as inhibitors to probe enzymatic mechanisms.
Moreover, their incorporation into peptides provides con-
formational restrictions to the resulting peptides.11 In
particular, the derivatives of R-alkylated phenylglycine
have been shown to be selective group I/group II metabo-
tropic glutamate receptor antagonists,12 in addition to their
potential applications as enzyme inhibitors. Given their
biological significance, an efficient and practical synthesis
of this type of unnatural amino acids is highly desirable.
To demonstrate the power of diamineꢀchiral acid ion
pair catalysts in the enamine catalysis, and to develop an
efficient synthesis of R-alkylated phenylglycine derivatives,
we turnedour attention to the direct amination of branched
aldehydes. In 2002, List and Jørgensen disclosed their
pioneering studies on the proline-catalyzed asymmetric
R-amination of aldehydes.13 Shortly after, Brase showed
€
that proline could catalyze amination of R,R-disubstituted
aldehydes with moderate enantioselectivity.14 Recently, the
same group reported an improved protocol employing
microwave irradiation.15 Proline-derived thiourea was also
utilized by Wang et al. for the same reaction.16 Very
recently, Maruoka disclosed an organocatalytic conjugate
addition of heterosubstituted aldehydes to vinyl sulfones for
(10) (a) Barrett, G. C. In Amino Acids, Peptides and Proteins; The
Royal Society of Chemistry: 1998; Vol. 29. (b) Williams, R. M. Synthesis of
Optically Active R-Amino Acids; Pergamon: Oxford, 1989.
(11) (a) Baldwin, J. E.; Lee, V.; Schofield, C. J. Heterocycles 1992, 34,
903. (b) Shrader, W. D.; Marlowe, C. K. Bioorg. Med. Chem. Lett. 1995,
5, 2207. (c) Badorrey, R.; Cativiela, C.; Diazde-Villegas, M. D.; Galvez,
J. A. Tetrahedron: Asymmetry 1995, 6, 2787. (d) Boyce, R. J.; Mulqueen,
G. C.; Pattenden, G. Tetrahedron 1995, 51, 7321. (e) Gershonov, E.;
Granoth, R.; Tzehoval, E.; Gaoni, Y.; Fridkin, M. J. Med. Chem. 1996,
39, 4833. (f) Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889.
(g) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
1996, 35, 2708. (h) Wirth, T. Angew. Chem., Int. Ed. 1997, 36, 225.
(12) (a) Bedingfield, J. S.; Kemp, M. C.; Jane, D. E.; Tse, H. W.;
Roberts, P. J.; Watkins, J. C. Br. J. Pharmacol. 1995, 116, 3323.
(b) Sekiyama, N.; Hayashi, Y.; Nakanishi, S.; Jane, D. E.; Tse, H. W.;
Birse, E. F.; Watkins, J. C. Br. J. Pharmacol. 1996, 117, 1493.
(13) (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (b) Bogevig, A.;
Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jorgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 1790.
(5) For the reports from the List group, see: (a) Mayer, S.; List, B.
Angew. Chem., Int. Ed. 2006, 45, 4193. (b) Martin, N. J. A.; List, B.
J. Am. Chem. Soc. 2006, 128, 13368. (c) Mukherjee, S.; List, B. J. Am.
Chem. Soc. 2007, 129, 11336. (d) Wang, X.; List, B. Angew. Chem., Int.
Ed. 2008, 47, 1119. (e) Garcıa-Garcıa, P.; Lay, F.; Garcıa-Garcıa, P.;
Rabalakos, C.; List, B. Angew. Chem., Int. Ed. 2009, 48, 4363. (f) Liao,
S.; List, B. Angew. Chem., Int. Ed. 2010, 49, 628. (g) Zhou, J.; List, B.
J. Am. Chem. Soc. 2007, 129, 7498. (h) Lifchits, O.; Reisinger, C. M.;
List, B. J. Am. Chem. Soc. 2010, 132, 10227. Also see: (i) Hamilton,
G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496.
(6) Liu, C.; Lu, Y. Org. Lett. 2010, 12, 2278.
(7) For an excellent review on the design of acidꢀbase catalysis, see:
Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
(8) For the iminium activations catalyzed by primary amineꢀchiral
acid catalysts, see: (a) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.;
Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403. (b) Carlone, A.;
Bartoli, G.; Bosco, M.; Pesciaioli, F.; Ricci, P.; Sambri, L.; Melchiorre,
P. Eur. J. Org. Chem. 2007, 5492. (c) Ricci, P.; Carlone, A.; Bartoli, G.;
Bosco, M.; Sambri, L.; Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49.
(d) Xie, J.-W; Huang, X.; Fan, L.-P.; Xu, D.-C.; Li, X.-S.; Su, H.; Wen,
Y.-H. Adv. Synth. Catal. 2009, 351, 3077.
€
(14) Vogt, H.; Vanderheiden, S.; Brase, S. Chem. Commun. 2003, 2448.
€
(15) (a) Baumann, T.; Vogt, H.; Brase, S. Eur. J. Org. Chem. 2007,
€
€
266. (b) Baumann, T.; Bachle, M.; Hartmann, C.; Brase, S. Eur. J. Org.
€
€
Chem. 2008, 2207. (c) Hartmann, C. E.; Baumann, T.; Bachle, M.; Brase,
S. Tetrahedron: Asymmetry 2010, 21, 1341.
(16) Fu, J.-Y.; Xu, X.-Y.; Li, Y.-C.; Huang, Q.-C.; Wang, L.-X. Org.
(9) (a) Crommelin, D. J. A.; Storm, G. Eur. J. Pharm. Sci. 1994, 2, 17.
(b) Kompella, U. B.; Lee, V. H. L. Adv. Drug Delivery Rev. 1992, 8, 115.
Biomol. Chem. 2010, 8, 4524.
Org. Lett., Vol. 13, No. 10, 2011
2639

the construction of R,R-dialkylamino aldehydes.17 Our
group recently reported a primary amine-mediated con-
jugate addition of branched aldehydes to vinyl sulfone
for the asymmetric creation of quaternary carbon
centers.4f,18 Given the steric hindrance of R-branched
aldehydes, we reasoned primary amines may serve as
suitable catalysts for the activation of such challenging
substrates in the enamine catalysis, and herein we demon-
strate that our novel ion pair catalyst with a chiral counter-
anion could promote the aminations of R-branched
aldehydes in a highly enantioselective manner.
Table 1. Screening of Chiral Primary Amines/Acids for the
Amination of 2-Phenylpropanal 1a with Di-tert-butyl Azodi-
carboxylate 2aa
We began our investigation by choosing the amination
reaction of 2-phenylpropanal 1 with di-tert-butyl azodi-
carboxylate 2 (DBAD) as a model reaction, and the
catalytic effects of various primary amine catalysts were
studied (Table 1). Different amino acids, L-serine-derived
4, L-threonine-derived 5, and diamine-based 6, were found
to be effective, affording the desired products in moderate
yields and enantioselectivities (entries 1ꢀ3). 9-Amino(9-
deoxy)epi-cinchonidine 7, in combination with different
acids, could promote the amination, and good chemical
yield and enantioselectivity were achieved when TFA was
employed (entry 6). However, the inclusion of methanesul-
fonic acid (MsOH), p-toluenesulfonic acid (TsOH), or tri-
fluoromethanesulfonic acid (TfOH) in the catalytic system
resulted in being ineffective (entries 7ꢀ10).19 To our delight,
the introduction of a chiral CSA resulted in highly efficient
catalytic systems (entries 11ꢀ12). The (þ)-CSA/7 ion pair
induced better enantioselectivity than the (ꢀ)-CSA/7 ion
pair; this prompted us to consider the matching chirality
between the diamine and CSA may play an important role in
the stereocontrol. The use of 9-amino(9-deoxy)epi-quinine 8
with CSA led to further improvement, and the (ꢀ)-CSA/8
ion pair afforded the desired amination product in quanti-
tative yield and with 97% ee (entry 14). The molar equiva-
lence of CSA to diamine 8 can be varied, but more than 2
equiv of CSA were found to be detrimental (entries 15ꢀ18).
Mixing 9-amino(9-deoxy)epi-cinchonine 9 or 9-amino(9-
deoxy)epi-qunidine 10 with chiral CSA resulted in mis-
matched chiral pairs, and the products were formed in low
ee, and with opposite configurations, suggesting the stereo-
chemical outcome of the reaction was mainly controlled by
the chiral scaffolds of the cinchona alkaloid (entries 19ꢀ22).
The influence of different ester moieties in the
azodicarboxylates on the reactions was next investigated
(Scheme 1). Di-isopropyl azodicarboxylate offered a slightly
decreased enantioselectivity, and the employment of dibenzyl
entry
cat.
additive
none
yield (%)b
ee (%)c
1
4
5
6
7
7
7
7
7
7
7
7
7
8
8
8
8
8
8
9
9
10
10
74
57
ꢀ77
ꢀ60
76
2
none
3
none
73
4
benzoic acid
4-NO2-PhCOOH
TFA
50
49
5
47
75
6
89
81
7
MsOH
30
88
8
TsOH H2O
<10
<10
<10
90
ꢀ
3
9
TsOH
ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
TfOH
ꢀ
(þ)-CSA
(ꢀ)-CSA
(þ)-CSA
(ꢀ)-CSA
(ꢀ)-CSAd
(ꢀ)-CSAe
(ꢀ)-CSAf
(ꢀ)-CSAg
(þ)-CSA
(ꢀ)-CSA
(þ)-CSA
(ꢀ)-CSA
93
99
87
98
91
99
97
97
97
97
97
70
93
<10
96
ꢀ
ꢀ14
ꢀ13
ꢀ26
ꢀ42
99
83
97
a Reaction conditions: di-tert-butyl azodicarboxylate 2a (0.1 mmol),
2-phenylpropanal 1a (0.15 mmol), the catalyst (0.02 mmol), the acid
(0.04 mmol), CHCl3 (0.2 mL), room temperature. b Isolated yield.
c Determined by 1H NMR analysis of the crude reaction mixture. d With
0.02 mmol of acid. e With 0.03 mmol of acid. f With 0.045 mmol of acid.
g With 0.05 mmol of acid.
Scheme 1. Effects of Different Azodicarboxylates
(17) Moteki, S. A.; Xu, S.; Arimitsu, S.; Maruoka, K. J. Am. Chem.
Soc. 2010, 132, 17074.
(18) For our recent examples of creation of quaternary stereocenters,
see: (a) Zhu, Q.; Lu, Y. Angew. Chem., Int. Ed. 2010, 49, 7753. (b) Han, X.;
Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed.
2009, 48, 7604. (c) Han, X.; Luo, J.; Liu, C.; Lu, Y. Chem. Commun. 2009,
2044. (d) Luo, J.; Xu, L.-W.; Hay, R. A. S.; Lu, Y. Org. Lett. 2009, 11, 437.
(e) Jiang, Z.; Lu, Y. Tetrahedron Lett. 2010, 51, 1884. (f) Han, X.; Zhong, F.;
Lu, Y. Adv. Synth. Catal. 2010, 352, 2778. (g) Zhong, F.; Chen, G.-Y.; Lu, Y.
Org. Lett. 2011, 13, 82. (h) Luo, J.; Wang, H.; Han, X.; Xu, L.-W.;
Kwiatkowski, J.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50,
1861. (i) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. J. Am. Chem. Soc. 2011, 133,
1726. For a recent review, see: (j) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(19) Extensive decompositions were observed; we suspect the alde-
hyde substrate may decompose under the reaction conditions.
azodicarboxylate led to a substantial decrease in enantios-
electivity. Thus, DBAD was used as the aminating reagent
for our following studies.
Having identified the best catalytic system, we next
proceeded to examine the generality of the reaction
2640
Org. Lett., Vol. 13, No. 10, 2011

Table 2. Direct Aminations of Various Branched Aldehydesa
Table 3. Lowing the Catalyst Loading of the Reactiona
entrya
mol % 8
t (h)
yield (%)b
ee (%)c
entrya
R1/R2
Ph/Me
3
yield (%)b
ee (%)c
1
2
3
4
5
20
10
1
24
24
24
36
72
99
99
99
96
47
97
97
96
95
3
1
3a
3d
3e
3f
99
91
95
97
97
92
80
99
83
99
99
99
82
85
99
99
97
99
96
98
97
99
96
99
97
95
99
96
96
99
97
68
2
Ph/Et
3
Ph/iPr
0.5
0.1
4
1-naphthyl/Me
2-naphthyl/Me
2-BrC6H4/Me
2-NO2C6H4/Me
2-OMeC6H4/Me
3-BrC6H4/Me
3- NO2C6H4/Me
3,5-OMeC6H3/Me
4-BrC6H4/Me
4-NO2C6H4/Me
4-MeC6H4/Me
4-OMeC6H4/Me
Pr/Me
5
3g
3h
3i
6
a Reaction conditions: di-tert-butyl azodicarboxylate 2a (0.1 mmol),
aldehyde 1 (0.15 mmol), the molar ratio of 8 to CSA is 1 to 2, CHCl3 (0.2
mL), room temperature. b Isolated yield c The ee value was determined
by HPLC analysis on a chiral stationary phase.
7
8
3j
9
3k
3l
10
11
12
13
14
15
16
3m
3n
3o
3p
3q
3r
Scheme 2. A Gram-Scale Synthesis of R-Methyl Phenylglycine
a Reaction conditions: di-tert-butyl azodicarboxylate 2a (0.1 mmol),
aldehyde 1 (0.15 mmol), the catalyst (0.01 mmol), (ꢀ)-CSA (0.02 mmol),
CHCl3 (0.2 mL), room temperature, 24 h. b Isolated yield. c Determined
by HPLC analysis on a chiral stationary phase.
phenylglycine 12 was obtained in good yield at a gram
scale.
(Table 2). In addition to methyl-substituted phenylglycine,
other alkyl-substituted phenylglycines could be prepared
in excellent yields and with nearly perfect enantioselectiv-
ities (entries 1ꢀ3). The reaction proved to be versatile for
the synthesis of various R-aryl-substituted phenylglycine
analogues; a wide range of 2-arylpropanals could be
employed, and very high chemical yields and excellent
enatioselectivities were attainable (entries 4ꢀ15). Nota-
bly, this reaction could even offer a certain degree of
stereochemical differentiation between the two alkyl
groups; R-methylpentanal could be aminated with
68% ee (entry 16).
The turnover numbers of organocatalytic reactions are
in general lower than those of transition-metal-mediated
processes, and high catalyst turnovers are certainly ideal
for industrial applications. The feasibility of reducing our
catalyst loading to a more practical level was examined
(Table 3). The loading of diamine 8 could be reduced to
1 mol % with little effects on the chemical yield and
enantioselectivity (entry 3). When the catalyst loading
was further decreased to 0.5 mol %, the yield and stereo-
selectivity of the reaction were virtually maintained,
although a longer reaction time was required (entry 4).
To demonstrate the value of our catalytic asymmetric
synthetic method in the scaleable synthesis of unnatural
R,R-disubstituted amino acids, a gram-scale synthesis
of R-methyl phenylglycine was performed (Scheme 2).
Aldehyde 3a, prepared via our amination protocol with
only a 0.5 mol % catalyst loading, was readily con-
verted into methyl ester 11. The NꢀN bond was cleaved
by treatment with SmI2, and the N-Boc R-methyl
In conclusion, we designed novel ion pair catalysts
containing a chiral counteranion for the enamine catalysis
for the first time, and suchcatalystscan be easily derived by
simply mixing a cinchona alkaloid-derived diamine with
chiral CSA. Our ion-pair catalysts were found to be very
effective in promoting the direct amination reactions of
R-branched aldehydes. A mixture of 9-amino(9-deoxy)epi-
quinine 8 and (ꢀ)-CSA was shown to be the best catalyst
with matching chirality, affording the desired amination
product in quantitative yield and nearly perfect enantios-
electivity. Remarkably, a catalyst loading of as little as 0.5
mol % was sufficient for maintaining an excellent chemical
yield and stereoselectivity. A gram-scale asymmetric synthesis
of biologically important R-methyl phenylglycine was realized,
suggesting the great potential of the chiral ion-pair catalyst
for industrial applications. We believe the novel ion-pair
catalysts described in this report will find wide applications
in the enamine catalysis, and we are currently extending their
applications to other important organic transformations.
Acknowledgment. We are grateful for the generous
financial support from the National University of Singapore
and the Ministry of Education (MOE) of Singapore (R-
143-000-362-112).
Supporting Information Available. Representative ex-
perimental procedures, determination of the absolute
configurations of the products, HPLC chromatogram,
and NMR spectra of the products. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 10, 2011
2641