N-Salicyl-β-aminoalcohols as a new class of ligand for catalytic asymmetric Strecker reactions

Article abstract of DOI:10.1016/S0040-4039(03)00735-4

An enantioselective Strecker synthesis employing novel chiral titanium complex catalysts derived from structurally simple chiral N-salicyl-β-amino alcohols is described. Reactions of N-benzylidenebenzylamine with trimethylsilyl cyanide in the presence of the catalyst (10 mol%) gave the corresponding α-aminonitrile in good to excellent yields, along with relatively high enantioselectivity (up to 86% ee). Similar reactions with various imines derived from aromatic aldehydes resulted in moderate to good enantioselectivity (44-81% ee).

Full text of DOI:10.1016/S0040-4039(03)00735-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3805–3808
N-Salicyl-b-aminoalcohols as a new class of ligand for catalytic
asymmetric Strecker reactions
Woraluk Mansawat, Worawan Bhanthumnavin and Tirayut Vilaivan*
Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road,
Patumwan, Bangkok 10330, Thailand
Received 15 January 2003; revised 6 March 2003; accepted 14 March 2003
Abstract—An enantioselective Strecker synthesis employing novel chiral titanium complex catalysts derived from structurally
simple chiral N-salicyl-b-amino alcohols is described. Reactions of N-benzylidenebenzylamine with trimethylsilyl cyanide in the
presence of the catalyst (10 mol%) gave the corresponding a-aminonitrile in good to excellent yields, along with relatively high
enantioselectivity (up to 86% ee). Similar reactions with various imines derived from aromatic aldehydes resulted in moderate to
good enantioselectivity (44–81% ee). © 2003 Elsevier Science Ltd. All rights reserved.
The Strecker reaction is one of the most general meth-
ods potentially useful for both laboratory and indus-
trial scale syntheses of a-amino acids. Typical Strecker
reactions involve addition of a cyanide ion to imines
which can be formed in situ from carbonyl compounds
and ammonia or primary amines. Due to the presence
of a prochiral CꢀN plane, the a-aminonitriles so formed
are racemic, which after hydrolysis yield a-amino acids
in racemic form. Although racemic a-aminonitriles and
a-amino acids may be converted to their optically
active forms by resolution with appropriate optically
active resolving agents or by enzymatic methods, direct
asymmetric synthesis of a-aminonitriles is still highly
desirable. A number of chiral auxiliaries successfully
used for this purpose mainly comprise optically active
amines.1 More recently, there has been interest in cata-
lytic asymmetric Strecker reactions.2 Some recent cata-
lysts successfully employed include metal complexes of
Scheme 1.
Keywords: catalytic asymmetric synthesis; Strecker; imines.
* Corresponding author. Tel.: +66-2-2187627; fax.: +66-2-2187598; e-mail: vtirayut@chula.ac.th
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00735-4

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W. Mansawat et al. / Tetrahedron Letters 44 (2003) 3805–3808
Table 1. Optimization of the conditions for asymmetric Strecker reaction of 1aa
Entry
4a (mol%)
Ti(OiPr)4 (mol%)
Solvent
Temp. (°C)
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
5
10
20
10
10
10
10
5
10
20
10
10
10
10
Toluene
Toluene
Toluene
Hexane–toluene (1:1)
THF
0
0
0
0
0
90
90
91
95
83
69
89
46
79
75
72
48
8
Toluene
Toluene
−20
25
62
a The reactions were performed at a 0.2 mmol scale. Reaction time: 6 h.
b Yields were estimated from 1H NMR integration of the crude products.
c Ee values were determined by integration of the CaH
6 signals of 2 in the presence of (S)-camphorsulfonic acid in CDCl3 (estimated error < 5%).
Schiff’s bases,3 BINOL and related ligands4 and certain
The optimal reaction temperature was found to be
between −5 and 0°C. TMSCN was the preferred source
of cyanide since poorer selectivities were obtained when
HCN (generated in situ from TMSCN by the addition
purely organic catalysts.5
Oguni and co-workers have pioneered the use and
investigated the mechanism of reactions of Ti com-
plexes of chiral Schiff’s bases derived from b-amino
alcohols which lead to asymmetric cyanosilylation of
aldehydes giving silyl protected cyanohydrins in good
yields and ee’s.6 In view of the similar mechanistic
aspects of trimethylsilylcyanation of aldehydes and
imines, it is surprising that no equivalent cyanation
reactions of imines using this class of ligands has ever
been reported. This prompted us to investigate this
possibility.
i
of 1 equiv. of PrOH) was employed.10,11
In order to investigate the effect of the structure of the
ligands on the selectivity of the reaction, the related
N-salicyl-b-amino alcohol ligands 4b–f were synthesized
by NaBH4 reduction of the corresponding Schiff’s bases
3b–f.12 These ligands were screened under the best
conditions obtained for 4a and the results are summa-
rized in Table 2. It is evident that the bulkiness of the
substituent on the chiral b-amino alcohol plays an
important role in determining the degree of selectivity.
The Strecker reaction of N-benzylidenebenzylamine 1a
(Scheme 1) was chosen as a model reaction since the
optical purity of the resulting a-aminonitrile 2a can be
i
t
Ligands 4b,c bearing the highly branched Pr and Bu
groups showed the highest selectivities (82 and 86% ee)
followed by those containing benzyl, phenyl, isobutyl
and methyl substituents, respectively. Attempts to
increase the steric bulk of the salicyl part by using
ligand 4g resulted in a disappointingly poor ee. In all
cases the configuration of the major a-aminonitrile was
S as determined by comparison of the [h]D and 1H
NMR spectra in the presence of (S)-CSA with litera-
ture data.7
1
measured conveniently by H NMR in the presence of
(S)-camphorsulfonic acid in CDCl3.7 Initially the reac-
tion between 1a and trimethylsilyl cyanide (TMSCN)
was carried out in the presence of 10 mol% of the
non-C2 symmetric Schiff’s base ligands 3a and 3b and
Ti(OiPr)4. Unfortunately, the enantioselectivity of the
product 2a was disappointingly poor (ca. 10%; condi-
tions: 2 equiv. TMSCN, 10 mol% Ti(OiPr)4, −5 to 0°C
in toluene). However, the reduced Schiff’s base ligand
4a8 showed much better catalytic activity and gave the
desired a-aminonitriles with better ee’s.
Table 2. Effects of catalyst structurea
Entry
Ligand
Yieldb (%)
Eec (%)
Configurationd
The conditions for the asymmetric Strecker reaction of
1a in the presence of ligand 4a were optimized (Table
1). Ti(OiPr)4 was found to be the most effective co-cat-
alyst at a co-catalyst:ligand ratio of 1:1.9 The optimal
amount of catalyst used was 10 mol% since poorer ee’s
were obtained with lower catalyst loadings and
improvement in neither yield nor ee was observed with
higher catalyst loadings (up to 20 mol%) (entries 1–3).
Solvent polarity appears to have some effect on the
stereoselectivity of the reaction. The reaction proceeded
with higher enantioselectivities in less polar solvents
including toluene or a hexane–toluene mixture (entry 4)
while a reaction in THF gave a somewhat lower ee
(entry 5). The reactions were initially performed at 0°C.
Decreasing the temperature to −20°C led to a very slow
reaction rate and, surprisingly, very poor selectivity
(entry 6). At higher temperature, the reaction was
faster, but proceeded with lower selectivity (entry 7).
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
98
99
98
98
97
84
83
76
82
86
66
48
20
8
S
S
S
S
S
S
S
4g
a The reaction was performed at a 0.2 mmol scale. Conditions: 2
equiv. TMSCN; 10 mol% ligand; 10 mol% Ti(OiPr)4; toluene; 0°C;
6 h.
b Yields were estimated from 1H NMR integration of the crude
products.
c Ee values were determined by integration of the CaH
6 signals of 2 in
the presence of (S)-camphorsulfonic acid in CDCl3 (estimated error
< 5%).
d The absolute configuration was determined by comparison of the
[h]D and 1H NMR chemical shifts of the CaH
6
proton in the
presence of (S)-camphorsulfonic acid with the literature data.7

W. Mansawat et al. / Tetrahedron Letters 44 (2003) 3805–3808
Table 3. Effects of substrate structurea
3807
Entry
Ligand
Substrate
Product
R
Yieldb (%)
Eec,d (%)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4c
4a
4c
1b
1c
1d
1e
1f
1g
1h
1i
2b
2c
2d
2e
2f
2g
2h
2i
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-BrC6H4
3-NO2C6H4
4-CH3C6H4
3-PhOC6H4
4-MeOC6H4
4-MeOC6H4
2-MeOC6H4
2-MeOC6H4
84
98
86
72 (S)
80 (S)
71 (S)
81 (S)
64 (S)
67 (S)
75 (S)
44 (S)
48 (S)
51 (S)
39 (S)
98
\99
\99
90
98
92
9
10
11
1i
1j
1j
2i
2j
2j
92
\99
a The reaction was performed at 0.2 mmol scale. Conditions: 2 equiv. TMSCN; 10 mol% ligand; 10 mol% Ti(OiPr)4; toluene; 0°C; 9 h.
b Yields were estimated from 1H NMR integration of the crude products.
c Ee values were determined by integration of the CaH
6 signals of 2 in the presence of (S)-camphorsulfonic acid in CDCl3 (estimated error < 5%).
d The absolute configuration was proposed to be (S) by analogy with R=Ph.
Finally, the substrate generality of this class of ligand
was investigated using the crystalline ligand 4a as a
model. In all cases, optically active a-aminonitriles were
obtained in excellent yields and with enantioselectivities
ranging from fair to good (44–81% ee) (Table 3). Poor
ee values were obtained with methoxy-substituted
imines, and employing the more bulky ligand 4c did not
improve significantly the selectivity (entries 8–11). The
scope and applications of these N-salicylaminoalcohol-
catalyzed asymmetric Strecker reactions as well as
mechanistic details of the catalysis are currently being
explored, details of which will be disclosed elsewhere.
References
1. For examples, see: (a) Kunz, H.; Sager, W. Angew.
Chem., Int. Ed. Engl. 1987, 26, 557–559; (b) Kunz, H.;
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Tetrahedron 1995, 51, 9179–9190.
In conclusion, we have demonstrated that N-salicyl
b-amino alcohol ligands 4 may be used successfully in
conjunction with Ti(OiPr)4 as effective catalysts for
catalytic asymmetric Strecker reactions. To the best of
our knowledge, this is the first report of asymmetric
Strecker reactions being catalyzed by this class of lig-
and. The availability of the relatively inexpensive start-
ing materials together with the simplicity of the reaction
should provide a convenient and efficient access to
optically active a-aminonitriles.
2. For a recent review, see: Yet, L. Angew. Chem., Int. Ed.
Engl. 2001, 40, 875–877.
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Acknowledgements
This work was supported partly by the Ministry of
University Affairs, The Royal Thai Government
(W.M.). Additional support from the Development
Grants for New Faculty/Researchers, Chulalongkorn
University (T.V. and W.B.) is gratefully acknowledged.
We thank Vorawit Banphavichit for technical
assistance.
5. (a) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 10012–10014; (b) Sigman, M. S.; Vachal, P.; Jacob-

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W. Mansawat et al. / Tetrahedron Letters 44 (2003) 3805–3808
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racemic product 2a. However, if the concentration of
HCN was kept low at all time by slow addition of the
HCN solution to 1a under the same conditions, (S)-2a
was obtained in 94% yield and 63% ee.
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157–160; (d) Sigman, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 1998, 120, 4901–4902; (e) Iyer, M. S.;
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Chem. Soc. 1996, 118, 4910–4911.
11. General procedure for ligand screening: The chiral ligand
(0.02 mmol) and Ti(OiPr)4 (0.02 mmol) were placed in an
oven-dried 10 mL round bottom flask. The mixture was
dissolved in dried toluene (0.3 mL). The reaction flask
was capped with a rubber septum, sealed with Teflon tape
and the solution was stirred for 10 min at room tempera-
ture. Subsequently, N-benzylidenebenzylamine 1a (0.2
mmol) in 0.4 mL of dried toluene was added. The clear
yellow solution was then stirred at −5 to 0°C (ice–salt
bath). TMSCN (50 mL, 2 equiv.) was added to the
solution and the mixture was stirred for 6–8 h. The
solution was diluted with toluene and the solvent
removed by distillation at reduced pressure to give a
crude product. The crude material was passed through a
short plug of neutral aluminum oxide (Activity I) in a
Pasteur pipette using hexane/ethyl acetate (9/1) as eluent.
N-Benzylaminophenylacetonitrile 2a was obtained and
6. (a) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J.
Chem. Soc., Chem. Commun. 1991, 1752–1753; (b)
Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Org.
Chem. 1993, 58, 1515–1522; (c) Hayashi, M.; Inoue, T.;
Miyamoto, Y.; Oguni, N. Tetrahedron 1994, 50, 4385–
4398.
7. Hassan, N. A.; Bayer, E.; Jochims, J. C. J. Chem. Soc.,
Perkin Trans. 1 1998, 3747–3757.
8. Prepared in 68% yield as a white crystalline solid by
reduction of 3a with NaBH4. Ligand 4a has been previ-
ously synthesized from the Zr(BH4)4 reduction of the
salicylimine derived from an a-amino ester. See:
Narasimhan, S.; Balakumar, R. Synth. Commun. 2000,
30, 4387–4396.
9. Although Shibasaki (Refs. 4a,b) and Jacobsen (Ref. 3a)
have shown that Al complexes were effective catalysts for
asymmetric Strecker reactions, only a racemic product
was obtained from the cyanation reaction of the imine 1a
with 1:1 Al(OiPr)3–4a catalyst system at 10 mol%.
10. The poor enantioselectivity when TMSCN was replaced
by HCN can probably be accounted for by the high
background rate of HCN addition to the imine (Ref. 3d).
Addition of a toluene solution of HCN to 1a in the
presence of 10 mol% Ti(OiPr)4–4a gave a completely
1
analyzed for percent conversion by integration of the H
NMR signal of the imine and CaH. Enantioselectivity
was determined after addition of 1 equiv. of (S)-CSA by
integration of the now split CaH signals.
12. Ligands 4b and 4d are known compounds. 4b: see Ref. 8.
4d: Suwa, T.; Sugiyama, E.; Shibata, I.; Baba, A. Synthe-
sis 2000, 789–800. All new ligands showed the expected
1H and 13C NMR and elemental analyses.