General and practical catalytic enantioselective Strecker reaction of ketoimines: Significant improvement through catalyst tuning by protic additives

Article abstract of DOI:10.1016/j.tetlet.2004.02.082

Significant improvement in enantioselectivity and catalyst activity was achieved for the catalytic enantioselective Strecker reaction. Using a catalyst (1-2.5mol%) prepared from Gd(OⁱPr)₃ and D-glucose derived ligand 1, and in the pr

Full text of DOI:10.1016/j.tetlet.2004.02.082

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3147–3151
General and practical catalytic enantioselective Strecker reaction
of ketoimines: significant improvement through catalyst
tuning by protic additives
Nobuki Kato,a,b Masato Suzuki,a Motomu Kanaia,b, and Masakatsu Shibasaki
a,
*
*
aGraduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
bPRESTO, Japan Science and Technology Corporation, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 29 January 2004; revised 12 February 2004; accepted 16 February 2004
Abstract—Significant improvement in enantioselectivity and catalyst activity was achieved for the catalytic enantioselective Strecker
reaction. Using a catalyst (1–2.5 mol %) prepared from Gd(OiPr)3 and
D-glucose derived ligand 1, and in the presence of 2,6-
dimethylphenol as an additive, high enantioselectivity was obtained from a wide range of ketoimines, including heteroaromatic and
cyclic ketoimines. The new method was applied to an efficient catalytic asymmetric synthesis of sorbinil, a therapeutic agent for
diabetic complications.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
compounds. We report herein the first example in cat-
alytic enantioselective Strecker reaction of ketoimines
that can be applied to these unprecedented, yet very
important substrates through developing a new proton-
containing catalyst. Substrate generality, catalyst load-
ing, and catalyst turnover frequency are significantly
improved. Using the new conditions, we developed an
efficient catalytic asymmetric synthesis of sorbinil, a
pharmaceutical lead for the treatment of diabetic neu-
ropathy.6
Chiral a,a-disubstituted a-amino acids are important
building blocks for pharmaceuticals and artificially
designed peptides.1 The catalytic enantioselective Strec-
ker reaction of ketoimines is one of the most direct and
practical methods for the synthesis of this class of
compounds.2 There are three examples reported previ-
ously on this reaction. Jacobsen and Vachal developed a
unique organocatalyst that promotes reactions with aryl
methyl and tert-butyl methyl ketoimines.3 Vallee and
ꢀ
co-workers reported a reaction with an acetophenone-
derived ketoimine, catalyzed by a chiral heterobimetallic
Gd(OiPr)3 (1–2.5 mol %)
1 (2–5 mol %)
TMSCN (1.5 equiv)
2,6-dimethylphenol (1 equiv)
complex.4 We recently reported
a
reaction with
N-phosphinoyl ketoimines using a catalyst prepared
from Gd(OiPr)3 and
-glucose-derived ligand 1 in a 1:2
O
O
PPh2
H
N
N
NC
R1
PPh2
D
R2
R2
R1
CH3CH2CN, –40 ˚C
Ph
ratio.5 Despite these contributions, there remains room
for improvement in terms of substrate generality and
catalyst loading, considering the high importance of
chiral disubstituted a-amino acids. For example, there
are no reports of an efficient catalysis for heteroaromatic
or cyclic ketoimines. Products from these substrates
should be useful for the synthesis of biologically active
up to 99% ee
(17 examples)
O
Ph
P
O
O
H
O
F
F
1
HO
Targeting heteroaromatic ketoimines as substrates, we
initially observed an intriguing dependency of enantio-
selectivity on the catalyst amount. The reaction with
3-pyridylketoimine 2m proceeded slowly using 10 mol %
catalyst, and product 3m was obtained with only 33% ee
Keywords: Asymmetric catalysis; Strecker reaction; Ketoimines;
Disubstituted amino acids; Additive effect.
* Corresponding authors. Tel.: +81-3-5841-4830; fax: +81-3-5684-52-
06; e-mail: mshibasa@mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.082

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N. Kato et al. / Tetrahedron Letters 45 (2004) 3147–3151
Table 1. Additive effects on catalytic enantioselective Strecker reaction of heteroaromatic ketoimine 2m
Gd(OiPr)3 (x mol %)
O
1 (2x mol %)
TMSCN (1.5 equiv)
[additive]
O
PPh2
H
N
N
NC
PPh2
Me
Me
CH3CH2CN, –40 ˚C
N
N
2m
3m
Entry
Catalyst (x)
Additive (mol %)
Time (h)
14
192
Yield (%)b
Ee (%)c
33
1
2
3
4
5
6
7
8
9
10
20
30
5
––
––
100
78
89
81
80
87
88
81
84
––
0.5
5
88
69
95
95
99
99
99
MeOH(100)
iPrOH (100)
tBuOH (100)
Phenol (100)
DMPa (100)
DMPa (10)
5
0.5
1
5
5
0.3
0.3
2
5
5
a 2,6-Dimethylphenol.
b Isolated yield.
c Determined by chiral HPLC.
(Table 1, entry 1). When the catalyst amount was
increased to 20 and 30 mol %, the reaction was much
faster (0.5–1h), and the enantioselectivity was dramati-
cally improved to 78% and 88% ee, respectively (entries
2 and 3). A similar tendency was observed when 2-fur-
furylketoimine 2p was used as a substrate.
As shown in Table 1, entries 4–8, the reaction time was
significantly shortened in the presence of any protic
additives (100 mol %), even when using only 5 mol % of
catalyst. Enantioselectivity was improved up to 99% ee,
when phenol or 2,6-dimethylphenol (DMP) was used as
an additive. We selected DMP as the best additive,
based on the results of a dialkyl-substituted ketoimine
2c: 3c was obtained in 96% yield and 89% ee in the
presence of phenol, and 96% yield and 93% ee in the
presence of DMP (5 mol % catalyst, 2 h).
Having confirmed the lack of background reaction at
)40 °C, we hypothesized that the dramatic enhancement
of the enantioselectivity with an increase in the amount
of the catalyst might be due to the excess ligand, func-
tioning as a proton source.7 Although the best enantio-
selectivity was obtained with the catalyst prepared from
Gd(OiPr)3 and 1 in a 1:2 ratio, the actual catalyst in the
absence of additives is a 2:3 complex (4) of Gd and 1,
based on the NMR and ESI-MS studies (vide infra and
Ref. 9). Thus, the amount of the proton source increased
up to 30 mol %, when 30 mol % catalyst was used.
Therefore, we investigated the effects of protic additives.
This new method using DMP as an additive greatly
expanded the substrate scope of the catalytic enantio-
selective Strecker reaction with improved enantioselec-
tivity, catalyst turnover number, and catalyst turnover
frequency (Table 2). The catalyst amount could be
reduced to 1–2.5 mol %, and the products were obtained
with improved enantioselectivity in every case, com-
pared to the previous method. Specifically, excellent
Table 2. Catalytic enantioselective Strecker reaction using DMP as an additivea
Gd(OiPr)3 (x mol %)
1 (2x mol %)
Ph
P
O
Ph
O
TMSCN (1.5 equiv)
2,6-dimethylphenol (1 equiv)
O
O
PPh2
H
N
O
H
N
NC
R1
PPh2
O
F
F
R2
R2
R1
CH3CH2CN, –40 ˚C
HO
1
2
3
Entry
Substrate
Catalyst (x)
122
2.5
Time (h)
Yield (%)
Ee (%)
P(O)Ph2
P(O)Ph2
b
1
2
3
2a
2a
2a
92
0.3
134
92
94
70
N
98b
52b]c
[2.5
N
4
5
2b
2b
2.5
[2.5
48
158
98
67
97b
48b]c
P(O)Ph2
Me
6
7
8
2c
2c
2c
143
5
73
2
90
96
73
N
93
72]c
[5
65

N. Kato et al. / Tetrahedron Letters 45 (2004) 3147–3151
3149
Table 2 (continued)
Entry
Substrate
P(O)Ph2
Catalyst (x)
Time (h)
Yield (%)
Ee (%)
9
10
2d
2d
2.5
[5
2.5
48
9180
74
N
51]c
Me
b
11
12
13
P(O)Ph2
Me
2e
2e
2e
138
5
93
0.2
68
96
95
79
N
98b
83]c
Ph
[5
P(O)Ph2
14
15
16
2f
2f
2f
2.5
5
8
2
94
94
99
88b
N
94b
Me
[5
52
88b]c
P(O)Ph2
17
18
19
2g
2g
2g
152
2.5
[5
99
2
97
95
58
N
97
90]c
Me
67
b
20
21
22
23
24
25
R ¼ H (2h)
130
2.5
94
2
92
98
94
95
90
84
P(O)Ph2
Me
2h
2h
97b
95b]c
N
[2.5
1 3
2.5
24
93
0.7
67
R ¼ Cl (2i)
1
R
2i
2i
97
89]c
[2.5
b
26
27
28
R ¼ Me (2j)
138
2.5
89
0.7
52
87
96
93
2j
2j
99b
98b]c
[2.5
P(O)Ph2
N
29
30
31
2k
2k
2k
167
2.5
99
3.5
72
86
93
67
Me
98
94]c
[2.5
P(O)Ph2
Me
b
N
N
32
33
34
2l
2l
2l
19371
2.5
95
2
97
72
93b
85b]c
[10
14
P(O)Ph2
Me
35
36
2m
2m
1
2.5
6 1
90
95
0.3
92
99
N
P(O)Ph2
N
37
38
2n
2n
19231
2.5
93
1.3
98
94
99
96
Me
S
S
P(O)Ph2
N
N
39
40
2o
2p
2.5
2.5
10
6
Me
P(O)Ph2
98
98
Me
O
P(O)Ph2
41
42
2q
2q
2.5
10
16
6
73
91
53
69
N
Me
a For a representative procedure, see Section 2. Yields are isolated yields. EeÕs were determined by chiral HPLC.
b The absolute configuration was determined to be (S).
c Results in the absence of the additive (partly reported in Ref. 5).
enantioselectivity was obtained from heteroaromatic
ketoimines (entries 35–40) and cyclic ketoimines (entries
1–5). These results are the first examples of a catalytic
Strecker reaction that gives high enantioselectivity from
heteroaromatic and cyclic ketoimines.
that the additive might change the active catalyst
structure.8 Consistent with this expectation, the addition
of only 10 mol % of DMP was sufficient for providing
excellent enantioselectivity, although the reaction time
was longer than when using 100 mol % additive (Table 1,
entry 9). To gain preliminary insight into the protic
additive effects on the catalyst structure, we investigated
the catalyst constitution (molecular weight) using
The dramatic improvement in both enantioselectivity
and catalyst activity in the presence of DMP suggested

3150
N. Kato et al. / Tetrahedron Letters 45 (2004) 3147–3151
O
Gd(OiPr)3 (1 mol %)
1 (2 mol %)
TMSCN (1.1 equiv)
DMP (1 equiv)
O
PPh2
H
N
O
PPh2
N
NC
F
F
O
CH3CH2CN
–40 ˚C, 83h
2r
3r
recryst. from
CHCl3–hexane
10 g-scale
100%, 98% ee
93%, >99% ee
O
NH
HO2C NH2
1) KCNO
H2O, reflux
F
HN
HCl
90˚C
O
F
2) HCl, H2O
reflux
O
O
6
7 : 67% (3 steps)
Scheme 1. Catalytic enantioselective synthesis of sorbinil.
lowed by hydantoin formation gave 7 in high overall
yield. No silica gel chromatography was necessary from
2r to 7.
In conclusion, we developed a highly general and prac-
tical catalytic enantioselective Strecker reaction of
ketoimines, using DMP as a catalyst modulator. The
improvement appeared to stem from the generation of
new proton-containing catalyst, demonstrated by ESI-
MS studies. This new method made it possible to use
heteroaromatic and cyclic ketoimines as substrates for
the first time. The reported reaction is the most general
and practical catalytic enantioselective Strecker reaction
of ketoimines. The practicality was clearly demonstrated
by application to an efficient synthesis of an important
pharmaceutical lead, sorbinil.
Figure 1. ESI-MS observation in the absence (a) and in the presence
(b) of DMP.
ESI-MS. The catalyst prepared from Gd(OiPr)3 and 1 in
a 1:2 ratio, in the presence of TMSCN (15 equiv to the
catalyst) in acetonitrile as a solvent, afforded the peak at
1862 (calcd observed: 1867), which corresponds to the
previously proposed O-silylated 2:3 complex 4 (Fig.
1(a)).9 When DMP (10 equiv) was added to the catalyst
solution, the peak corresponding to 4 disappeared and a
new peak appeared at 1691, which corresponds to an O-
protonated 2:3 complex 5 (Fig. 1(b)). Therefore, the
protic additive changes the active catalyst structure from
the O-silylated form 4 to the O-protonated form 5.10
This proton containing complex should be the highly
active and enantioselective catalyst in this asymmetric
Strecker reaction of ketoimines.
2. Experimental
2.1. General procedure for catalytic enantioselective
Strecker reaction
As far as we know, this is one of the rare cases that
protic additives optimize the asymmetric environment of
the catalyst, as well as improve its activity.11 Thus, the
role of protic additives is to generate a new complex 5,
and is distinct from that reported in the catalytic enan-
tioselective Strecker reaction of aldoimines.7
A solution of Gd(OiPr)3 (0.2 M in THF, 1.37 mL,
0.274 mmol, purchased from Kojundo Chemical Labo-
ratory Co., Ltd. Fax: +81-492-84-1351) was added to a
solution of ligand 1 (256 mg, 0.556 mmol, commercially
available from Junsei Chemical Co., Ltd. Fax: +81-
3-3270-5461) in THF (5.5 mL) in an ice bath. The mix-
ture was stirred for 40 min at 45 °C, and then the solvent
was evaporated. After drying the resulting pre-catalyst
under vacuum (ꢀ5 mmHg) for 2 h, substrate 2r (10 g,
27.4 mmol) was added as a solid in one portion. Prop-
ionitrile (12.3 mL) was added at )40 °C, and after
20 min, TMSCN (4.15 mL, 30.1 mmol) was added. After
20 min, 2,6-dimethylphenol (3.35 g, 27.4 mmol) in pro-
pionitrile (12.3 mL) was added to start the reaction.
After 83 h, silica gel (10 g) was added to the reaction
mixture at )40 °C (caution! HCN is generated). The
mixture was carefully evaporated until no HCN gas
remained with monitoring by HCN sensor. The silica gel
was filtrated, and the filtrate was washed with MeOH/
CHCl3 (1:9). The combined liquid was evaporated, and
the resulting residue was recrystallized from CHCl3/
Success in the high enantio-induction from cyclic
ketoimines prompted us to apply this new method to a
catalytic asymmetric synthesis of sorbinil (7), a thera-
peutic agent for chronic complications of diabetes
mellitus, developed by the Pfizer group. Sorbinil con-
tains a chiral spirohydantoin structure, and its biological
activity resides in the (S)-enantiomer. A straightforward
synthesis of 7 was achieved using the catalytic asym-
metric Strecker reactions, as shown in Scheme 1. The
reaction with 2r proceeded using 1mol % catalyst in the
presence of 1equiv of DMP, and 3r was isolated as an
enantiomerically pure form by direct recrystallization of
the crude product. The reaction was performed on a
10 g-scale without any difficulty. Acid hydrolysis fol-

N. Kato et al. / Tetrahedron Letters 45 (2004) 3147–3151
3151
hexane (1:1) to give colorless needles in 93% yield
(10.0 g).
References and notes
1. For reviews, see: (a) Cativiela, C.; Diaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517; (b) Ohfune, Y.;
Shinada, T. Bull. Chem. Soc. Jpn. 2003, 76, 1115.
2.2. Sorbinil synthesis from Strecker product 3r
€
2. Groger, H. Chem. Rev. 2003, 103, 2795.
3. (a) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867; (b)
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
10012.
ꢀ
4. Chavarot, M.; Byrne, J. J.; Chavant, P. Y.; Vallee, Y.
Tetrahedron: Asymmetry 2001, 12, 1147.
5. Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634.
6. Sarges, R.; Howard, H. R.; Kelbaugh, P. R. J. Org. Chem.
1982, 47, 4081, and references cited therein.
7. For beneficial additive effects of the proton source on
catalytic enantioselective Strecker reaction of aldoimines,
see: (a) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.;
Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284; (b)
Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 11594; (c)
Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.;
Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650. In
these cases, protic additives do not change the active
catalyst structure. The enantioselectivity was not affected
by the protic additives.
Enantiomerically pure 3r (10.0 g, 25.5 mmol) was treated
with concd HCl (500 mL) under reflux for 16 h. Volatiles
were evaporated, and the residue was purified through
ion exchange chromatography [Dowex 50Wx8-100
(acidic) (300 g)], loading and eluting with MeOH (1.5 L)
to get rid of Ph2P(O)OH, and then eluting with 1.4 M
NH4 OH aq (1.5 L)] to give quaternary amino acid 6 as a
white solid in 86% yield (4.63 g). A mixture of 6 (4.63 g,
21.9 mmol) and KCNO (6.09 g, 75 mmol) in H2O
(130 mL) was heated at 80 °C for 14 h. After cooling to
room temperature, 6 M HCl was added to acidify the
solution. The resulting white solid was filtrated and
washed with EtOH (100 mL). The filtrate white solid
was treated with 3 M HCl (100 mL) under reflux for 8 h.
Evaporation of volatiles and recrystallization from
iPrOH gave sorbinil 7 in 67% yield (three steps: 3.98 g,
23
25
½aꢁ +53.5 (c ¼ 1.0, MeOH): lit.6 ½aꢁ +53.1( c ¼ 1.0,
D
MeOH)).
D
8. The possibility that HCN generated from TMSCN and the
additive acts as the catalyst modulator can not be denied.
9. Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.;
Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 9908.
10. Addition of BuOH (10 equiv) also gave the same peak
corresponding to 5, however with lower intensity than
when DMP was added.
11. For examples of beneficial effects of protic additives on
catalyst structures, see: Yamashita, Y.; Ishitani, H.;
Shimizu, H.; Kobayashi, S. J. Am. Chem. Soc. 2002,
124, 3292, and references cited therein.
Acknowledgements
t
Financial support was provided by RFTF of the Japan
Society for the Promotion of Science (JSPS) and PRE-
STO of the Japan Science and Technology Corporation
(JST). We thank Mr. Usuda and Mr. Takita for helpful
discussions.