Catalytic enantioselective Strecker reaction of ketoimines using catalytic amount of TMSCN and stoichiometric amount of HCN

Article abstract of DOI:10.1016/j.tetlet.2004.02.077

Catalyst loading as low as 0.1mol% was achieved in the enantioselective Strecker reaction of ketoimines. Excellent enantioselectivity was obtained with a combined use of a catalytic amount of TMSCN and a stoichiometric amount of HCN as a reagent, and a chiral gadolinium complex as a catalyst.

Full text of DOI:10.1016/j.tetlet.2004.02.077

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3153–3155
Catalytic enantioselective Strecker reaction of ketoimines
using catalytic amount of TMSCN and stoichiometric
amount of HCN
a,
Nobuki Kato,a,b Masato Suzuki,a Motomu Kanaia,b, and Masakatsu Shibasaki
*
*
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—Catalyst loading as low as 0.1mol % was achieved in the enantioselective Strecker reaction of ketoimines. Excellent
enantioselectivity was obtained with a combined use of a catalytic amount of TMSCN and a stoichiometric amount of HCN as a
reagent, and a chiral gadolinium complex as a catalyst.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Gd(OiPr)3 (0.1–1 mol %)
1. Introduction
1 (0.2–2 mol %)
TMSCN (2.5–5 mol%)
HCN (1.5 equiv)
O
O
In the preceding paper, we disclosed a new method
for the catalytic enantioselective Strecker reaction of
ketoimines. Using 1–2.5 mol % of a chiral gadolinium
PPh2
H
N
NC N PPh2
R1
R2
up to 99% ee
R2
R1
°
CH3CH2CN, –40 C
complex generated from Gd(OiPr)3 and
D-glucose
Ph
O
Ph
derived ligand 1 in a 1:2 ratio, and 2,6-dimethylphenol
(DMP: 1equiv) as an additive, excellent enantioselect-
vity was obtained from a wide range of N-phos-
phinoylketoimines including aromatic, heteroaromatic,
alkyl, and cyclic ketoimines.1 This is currently the most
general catalytic enantioselective Strecker reaction of
ketoimines,2 which offers an efficient method for the
synthesis of very important chiral building blocks, chiral
a,a-disubstituted a-amino acids.3 Here we report the
more advanced reaction conditions. The new reaction
conditions using a catalytic amount of TMSCN (2.5–
5 mol %) and a stoichiometric amount of HCN allowed
us to reduce the catalyst amount to as low as 0.1mol %
with maintaining the high enantioselectivity. Reduction
of the amount of metals used in chemical reactions (in
this case, silicon and gadolinium) should be advanta-
geous for application to an industrial scale synthesis, in
terms of cost performance and atom economy.4
P
O
O
H
O
F
F
1
HO
ESI-MS studies of the active catalyst for the Strecker
reaction suggested that the beneficial effect of DMP
both on enantioselectivity and catalyst activity appeared
to stem from the generation of a proton-containing 2:3
complex 3 through the reaction of initially formed
double-silylated complex 2 with DMP (Scheme 1, Eq.
1).1 We expected that the same active catalyst 3 should
be generated through the reaction of HCN with 2
(Scheme 1, Eq. 2). In this protonolysis with HCN,
2 equiv of TMSCN is produced, concomitant with the
generation of the active catalyst 3. Because the Strecker
product is produced via a cyanide transfer from the
gadolinium cyanide in 3 to the activated substrate,5 it is
expected that only a catalytic amount of TMSCN would
be required for this catalysis.
Keywords: Asymmetric catalysis; Strecker reaction; Ketoimines; Di-
substituted amino acids; Atom economy.
As expected, the reaction of ketoimine 4a proceeded
rapidly using 2.5 mol % catalyst in the presence of
* Corresponding authors. Tel.: +81-3-5841-4830; fax: +81-3-5684-
5206; e-mail: mshibasa@mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.077

3154
N. Kato et al. / Tetrahedron Letters 45 (2004) 3153–3155
and additive 2,6-dimethylphenol (Table 1, entry 4), and
2
2
+ HCN
OTMS
under the current reaction conditions using a catalytic
amount of TMSCN and a stoichiometric amount of
HCN (entries 2 and 3). Because TMSCN/protic additive
ratio is higher in the case of entry 4 compared to entries
2 and 3, the concentration of the desired proton-con-
taining catalyst 3 should be higher under the conditions
in entries 2 and 3.7 This might result in the improvement
of the reactivity and enantioselectivity. It is also
important to note that the reaction in the absence of
TMSCN did not proceed at all at )40 ꢁC, even using
high catalyst amount with the prolonged reaction time
(entry 5). This feature is crucial for the success of the
current reaction.8
OH
Gd(OiPr)3 + 1 + TMSCN
1
eq. 1
eq. 2
O
O
O
Gd
O
O
O
Gd
O
O
O
O
O
O
Gd
CN NC
Gd
O
O
O
H
O
O
O
NC
3
TMS
2
TMS
HCN
2 TMSCN
Scheme 1. Active catalyst generation.
High reactivity under the combination of a catalytic
amount of TMSCN and a stoichiometric amount of
HCN allowed us to reduce the catalyst amount as low as
0.1mol % with maintaining the excellent enantioselec-
tivity (Table 1, entries 7 and 8).9 Although Jacobsen
et al. reported one example using 0.1mol % catalyst, the
product was obtained with only 69% ee from acetoph-
enone-derived ketoimine.2a Therefore, this is the first
example to achieve excellent enantioselectivity with very
high catalyst turnover number. HCN produced from
protonolysis of TMSCN10 could also be used as well
(entry 9). Most of the Strecker products are crystalline
compounds, and enantiomerically pure amidonitriles
were easily obtained by recrystallization.
10 mol % TMSCN and 150 mol % HCN, and product 5a
was obtained with 99% ee (Table 1, entry 1). When the
catalyst amount was reduced to 1mol % with maintain-
ing the amount of TMSCN and HCN (entry 2), slight
decrease in enantioselectivity was observed (97% ee). The
product with 99% ee, however, was again obtained when
reducing the amount of TMSCN to 5 mol % (entry 3).
These results suggested that there exists an equilibrium
between the proton-containing catalyst 3 with high
reactivity/enantioselectivity and the silylated catalyst 2
with moderate reactivity/enantioselectivity,6 and the
undesired reaction pathway promoted by 2 might con-
taminate when the TMSCN/HCN ratio was increased.
These considerations might explain the dramatic reac-
tivity difference between under the previous reaction
conditions using stoichiometric amounts of TMSCN
In conclusion, we developed an efficient method for the
catalytic enantioselective Strecker reaction of keto-
Table 1. Catalytic enantioselective Strecker reaction of ketoiminesa
Ph
P
O
Gd(OiPr)3 (x mol %)
O
O
Ph
O
1 (2x mol %)
PPh2
H
O
H
N
TMSCN, HCN
NC N PPh2
O
F
F
CH CH CN, –40 C
R1
R2
R2
˚
R1
3
2
5
HO
1
4
Entry
Substrate
Cat. (·mol %) TMSCN (mol %)
HCN (mol %) Time (h)
Yield (%)
Ee (%)
1
2
3
4
5
2.5
1
10
10
150
150
0.5
2
99
99
99
97
P(O)Ph2
N
15 50
11
5
13
99
99
4a
Me
b
50
0
20
21
93
0
93
––
S
0
150
P(O)Ph2
N
6
7
8
1
10
150
99
0.6
99
97
95
4b: R = Cl
0.12.5 50
0.1
154
93
19
4b: R = Cl
4c: R = H
Me
5
150
90d
R
P(O)Ph2
N
c
4d
9
5
20
1
500.25
99
96
94
Me
N
P(O)Ph2
N
93d
F
10
0.5
5
150
1.3
4e
O
a For a representative procedure, see Experimental Section. Yields are isolated yields. EeÕs were determined by chiral HPLC.
b 2,6-Dimethylphenol (100 mol %) was added instead of HCN (Ref. 1).
c
i
HCN was prepared by mixing TMSCN with PrOH.
d The absolute configuration was determined to be (S).

N. Kato et al. / Tetrahedron Letters 45 (2004) 3153–3155
3155
imines, using the combination of a catalytic amount of
Acknowledgements
TMSCN and a stoichiometric amount of HCN. The
catalyst amount was reduced as low as 0.1mol %. This
new procedure should be advantageous for a large-scale
synthesis of chiral a,a-disubstituted a-amino acids.
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).
2. Experimental
References and notes
2.1. General procedure for catalytic enantioselective
Strecker reaction using a catalytic amount of TMSCN
and a stoichiometric amount of HCN
1. See the preceding paper. Tetrahedron Lett. 2004, 45, 3147–
3151.
2. For previous examples for catalytic enantioselective
Strecker reaction of ketoimines, see: (a) Vachal, P.;
Jacobsen, E. N. Org. Lett. 2000, 2, 867; (b) Vachal, P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012; (c)
A solution of Gd(OiPr)3 (0.2 M in THF, 18.8 lL,
3.8 lmol, purchased from Kojundo Chemical Labora-
tory Co., Ltd. Fax: +81-492-84-1351) was added to a
solution of ligand 1 (3.5 mg, 7.6 lmol, commercially
available from Junsei Chemical Co., Ltd. Fax: +81-3-
3270-5461) in THF (75 lL) in an ice bath. The mixture
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 1h, substrate 4b (1.33 g,
3.8 mmol) was added as a solid in one portion. Propio-
nitrile (1mL) was added at )40 ꢁC, and after 30 min,
TMSCN (12.5 lL, 0.094 mmol) was added. After 5 min,
HCN11 (4 M in propionitrile stock solution, 1.4 mL,
5.6 mmol) was added to start the reaction. After com-
pletion of the reaction, silica gel 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 purified by silica gel column
chromatography.
ꢀ
Chavarot, M.; Byrne, J. J.; Chavant, P. Y.; Vallee, Y.
Tetrahedron: Asymmetry 2001, 12, 1147; (d) Masumoto,
S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2003, 125, 5634; For an excellent
€
review, see: (e) Groger, H. Chem. Rev. 2003, 103, 2795.
3. Catalytic asymmetric alkylation is another powerful
methodology for disubstituted a-amino acid synthesis.
For recent examples, see: (a) Ooi, T.; Takeuchi, M.;
Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122,
5228; (b) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002,
124, 7256.
4. Trost, B. M. Science 1991, 254, 1471.
5. The gadolinium cyanide, not TMSCN itself, is the actual
nucleophile in the catalytic cyanosilylation of ketones,
confirmed by labeling studies: Yabu, K.; Masumoto, S.;
Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du, W.;
Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001,
123, 9908, See also the proposed catalytic cycle in Ref. 8
(Scheme 2).
6. For the reactivity and enantioselectivity differences
between in the absence and presence of protic additive,
see Tetrahedron Lett. 2004, 45, 3147–3151.
7. Other factors such as the fact that the substrates are more
readily soluble to the reaction media under the TMSCN
(cat.)-HCN conditions than under TMSCN-DMP condi-
tions, and/or the retardation effect of the trimethylsilylated
DMP, cannot be excluded as origins of the reactivity
difference.
8. Lack of reactivity using only HCN is also important from
the mechanistic point of view, that is, the pre-catalyst 6
cannot be directly converted to the active catalyst 3
(Scheme 2). Working hypothesis for the catalytic cycle is
postulated in Scheme 2, based on these new experimental
results and previous mechanistic studies (Ref. 5). The
catalytic cycle should always proceed through the inter-
mediary of silylated 2. Thus, TMSCN produced in the
active catalyst (3) formation step functions as a catalyst
re-generator (from 6 to 3 through 2).
Gd(OiPr)3 + 1
O
H
NC N PPh2
RL RS
O
O
O
O
O
2 TMSCN
Gd
Gd
O
O
O
O
6
O
O
O
O
O
O
O
O
Gd
Gd
O
O
O
O
O
O
Gd
Gd
O
O
O
CN NC
O
O
P
H
NC
RL
2
Ph
N
TMS
TMS
HCN
2 TMSCN
HCN
Ph
RS
8
F
F
Ph
O
9. High purity of the substrate N-phosphinoylketoimines is
very important especially when catalyst loading was
reduced. Substrate purification through flash column
chromatography followed by recrystallization using anhy-
drous solvents under argon atmosphere was effective to
obtain the substrates with high purity.
P
O
O
O
O
Ph
O
O
O
O
O
Gd
Gd
O
O
O
O
O
Gd
CN
Gd
O
O
O
O
NC
3
H
O
O
O
PPh2
H
P
N
N
10. Mai, K.; Patil, G. J. Org. Chem. 1986, 51, 3545. For in situ
i
Ph
RL
Ph
7
RS
RL RS
preparation of HCN, we treated TMSCN with PrOH
(1:1) in propionitrile (1.1 M) under ice bath for 2 h.
11. Slatta, K. H. Ber. 1934, 67, 1028.
Scheme 2. Proposed catalytic cycle.