Catalytic asymmetric Strecker synthesis. Preparation of enantiomerically pure α-amino acid derivatives from aldimines and tributyltin cyanide or achiral aldehydes, amines, and hydrogen cyanide using a chiral zirconium catalyst

Article abstract of DOI:10.1021/ja9935207

Catalytic enantioselective Strecker-type reactions of aldimines with tributyltin cyanide (Bu₃SnCN) proceeded smoothly in the presence of a novel chiral zirconium catalyst. High levels of enantioselectivities in the synthesis of α-amino nitrile

Full text of DOI:10.1021/ja9935207

762
J. Am. Chem. Soc. 2000, 122, 762-766
Catalytic Asymmetric Strecker Synthesis. Preparation of
Enantiomerically Pure R-Amino Acid Derivatives from Aldimines and
Tributyltin Cyanide or Achiral Aldehydes, Amines, and Hydrogen
Cyanide Using a Chiral Zirconium Catalyst
Haruro Ishitani, Susumu Komiyama, Yoshiki Hasegawa, and Shuj Kobayashi*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, CREST,
Japan Science and Technology Corporation (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and
Department of Applied Chemistry, Faculty of Science, Science UniVersity of Tokyo (SUT), Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan
ReceiVed September 30, 1999
Abstract: Catalytic enantioselective Strecker-type reactions of aldimines with tributyltin cyanide (Bu3SnCN)
proceeded smoothly in the presence of a novel chiral zirconium catalyst. High levels of enantioselectivities in
the synthesis of R-amino nitrile derivatives with wide substrate generality were obtained via these reactions.
In addition, hydrogen cyanide (HCN) was successfully used instead of Bu3SnCN as the cyanide source. Catalytic
asymmetric Strecker amino acid synthesis starting from achiral aldehydes, amines, and HCN using a chiral
zirconium catalyst has also been achieved. The three-component asymmetric process reported here significantly
improves upon the original Strecker reaction, and has advantages over previous reactions using unstable imines
(Schiff bases) as starting materials. Moreover, high yields and enantioselectivities have been obtained even in
the reactions using aliphatic aldehydes, and both enantiomers of various types of R-amino acid derivatives can
be prepared. As demonstrations to show the utility of this reaction, efficient syntheses of homophenylalanine,
leucine amide, and pipecolic acid derivatives have been performed. Finally, two novel binuclear zirconium
complexes (3 and 4) are postulated to be active chiral catalysts in the reactions of aldimines with Bu3SnCN
and the three-component reactions, respectively, and low loading levels of the chiral catalysts (1-2.5 mol %)
have been accomplished in both cases.
Introduction
Scheme 1. Classical Strecker Reaction (above) and
Asymmetric Version
Unnatural R-amino acids are expected to play key roles in
improving the original properties and functions of proteins,1 and
development of efficient methods for the preparation of various
types of R-amino acids is desired not only in the field of organic
chemistry but also in many biology-related areas. The Strecker
amino acid synthesis, treatment of aldehydes with ammonia and
hydrogen cyanide (or equivalents), and subsequent hydrolysis
of the intermediate R-amino nitriles providing R-amino acids
(Scheme 1) was first reported in 1850.2 While it has been applied
to the synthesis of racemic R-amino acids on an industrial scale,
recent demands have on the preparation of chiral R-amino acids.
Although several methods using chiral imines (Schiff bases)
have been reported in the literature, stoichiometric amounts of
chiral sources are needed according to these diastereoselective
approaches.3-7 In addition, the Schiff bases employed in these
reactions are limited to those derived from aromatic aldehydes
in most cases, because aliphatic Schiff bases are often unstable
and lower yields and selectivities have been observed. In this
paper, we report chiral zirconium-catalyzed Strecker reactions
of aldimines with tributyltin cyanide (Bu3SnCN), and also a
three-component asymmetric process using achiral aldehydes,
amines, and hydrogen cyanide (HCN).8 High yields and
enantioselectivities have been obtained even in the reactions
(6) Recently, catalytic asymmetric cyanation reactions of Schiff bases
have been reported. (a) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton,
M. J. Am. Chem. Soc. 1996, 118, 4910. (b) Sigman, M. S.; Jacobsen, E. N.
J. Am. Chem. Soc. 1998, 120, 4901. (c) Sigman, M. S.; Jacobsen, E. N. J.
Am. Chem. Soc. 1998, 120, 5315. (d) Ishitani, H.; Komiyama, S.; Kobayashi,
S. Angew. Chem., Int. Ed. Engl. 1998, 37, 3186. (e) Krueger, C. A.; Kuntz,
K. W.; Dzieba, C. D.; Wirschum, W. G.; Gleason, J. D.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284. (f) Corey, E. J.; Grogan,
M. J. Org. Lett. 1999, 1, 157. In all these cases, no example of the three-
component reactions that succeed to the original Strecker reaction was
reported. In addition, lower selectivities were obtained using Shiff bases
derived from aliphatic aldehydes, which restricts use of these reactions for
R-amino acid syntheses.
* Address correspondence to this author at The University of Tokyo.
(1) Barrett. G. C., Ed. Chemistry and Biochemistry of the Amino Acids;
Chapman and Hall: London, 1985.
(2) Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S. Russ. Chem. ReV.
1989, 58, 148. Cf.: Strecker, A. Liebigs Ann. Chem. 1850, 75, 27.
(3) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergamon Press: Oxford, 1989.
(7) For achiral Strecker reactions, see: (a) Ojima, I.; Inaba, S.; Nakat-
sugawa, K. Chem. Lett. 1975, 331. (b) Mai, K.; Patil, G. Tetrahedron Lett.
1984, 25, 4583. (c) Kobayashi, S.; Ishitani, H.; Ueno, M. Synlett 1997,
115.
(4) Williams, R. M.; Hendrix, A. J. Chem. ReV. 1992, 92, 889.
(5) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
10.1021/ja9935207 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/25/2000

Catalytic Asymmetric Strecker Synthesis
J. Am. Chem. Soc., Vol. 122, No. 5, 2000 763
Table 1. Effect of Ligands and Solvents
Scheme 2. Preparation of Chiral Zirconium Catalyst 3
ligand (equiv)
solvent
yield (%) ee (%)
(R)-6-Br-BINOL (0.2)
CH2Cl2
toluene-benzene (1:1)
70
72
92
55
69
91
(R)-6-Br-BINOL (0.1) + toluene-benzene (1:1)
(R)-3-Br-BINOL (0.1)
toluene
93
91
97
85
86
86
83
71
toluene-C2H5CN (1:1)
benzene-CH2Cl2 (1:1)
CH2Cl2
using aliphatic aldehydes, and both enantiomers of various types
of R-amino acid derivatives can be prepared based on these
reactions.
Results and Discussion
Recently, we have reported the first catalytic enantioselective
Mannich-type reactions9 and aza Diels-Alder reactions10 using
a chiral zirconium catalyst. In these reactions, the zirconium
catalyst effectively activates aldimines and efficient catalytic
processes have been accomplished. We then intended to use a
zirconium catalyst in asymmetric Strecker-type reactions. As a
cyanide source, we first chose Bu3SnCN11 because Bu3SnCN
is easy to handle in laboratories. Bu3SnCN is stable in water
and produces no HCN. This is in contrast to trimethylsilyl
cyanide (TMSCN) which easily hydrolyzes to form HCN even
in the presence of a small amount of water. In the presence of
10 mol % of a zirconium catalyst, which was prepared from
Zr(OtBu)4, 2 equiv of (R)-6,6′-dibromo-1,1′-bi-2-naphthol ((R)-
6-Br-BINOL),12 and 3 equiv of 1-methylimidazole (NMI),
aldimine 1a was treated with Bu3SnCN in dichloromethane at
-65 °C. The reaction proceeded smoothly to afford the
corresponding R-amino nitrile in 70% yield with 55% enantio-
meric excess (ee). After several reaction conditions were
examined, the best results (92% yield, 91% ee) were obtained
when the reaction was carried out in benzene-toluene (1:1)
using a chiral zirconium catalyst prepared from 1 equiv of Zr-
(OtBu)4, 1 equiv each of (R)-6-Br-BINOL and (R)-3,3′-dibromo-
1,1′-bi-2-naphthol ((R)-3-Br-BINOL),13 and 3 equiv of N-me-
thylimidazole (NMI) (Table 1). Use of other solvents slightly
decreased the selectivity. The free hydroxyl group of the
aldimine was important in obtaining both high yield and high
selectivity. When the aldimine prepared from aniline or 2-meth-
oxyaniline was used under the same reaction conditions, the
1
1
Figure 1. (a) H NMR spectra of 6-Br-BINOL, (b) H NMR spectra
1
of 3-Br-BINOL, and (c) H NMR spectra of chiral zirconium catalyst
3: (9) N-methylimidazole and (2) CD2Cl2 (internal standard).
corresponding R-amino nitrile derivatives were obtained in much
lower yields and lower ee’s (aniline, 29% yield, 1% ee;
2-methoxyaniline, 45% yield, 5% ee).
It was quite interesting to find that use of a mixture of (R)-
6-Br-BINOL and (R)-3-Br-BINOL gave the best results. We
then carefully examined the structure of the zirconium catalyst,
and it was indicated from NMR studies that a zirconium
binuclear complex (3) was formed under the conditions used
(Scheme 2). The binuclear complex consists of 2 equiv of
zirconium, (R)-6-Br-BINOL, and NMI and 1 equiv of (R)-3-
Br-BINOL. The structure appears to be very stable as the same
complex was formed even when different molar ratios of Zr-
(OtBu)4, (R)-6-Br-BINOL, (R)-3-Br-BINOL, and NMI were
combined. Formation of 3 was confirmed by 1H and 13C NMR
spectra when 1 equiv of Zr(OtBu)4 and (R)-6-Br-BINOL, 0.5-1
equiv of (R)-3-Br-BINOL, and 2-3 equiv of NMI were
combined (Figure 1).14
(8) For a preliminary communication using Bu3SnCN as a cyanation
source, see 6d.
(9) (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997,
119, 6984. (b) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc.
1998, 120, 431.
(10) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int. Ed.
Engl. 1998, 37, 979.
(11) Commercially available (Aldrich, etc.). (a) Luijten, J. G. A.; van
der Kerk, G. J. M. InVestigations in the Field of Organotin Chemistry; Tin
Research Institute: Greenford, 1995; p 106. (b) Tanaka, M. Tetrahedron
Lett. 1980, 21, 2959. (c) Harusawa, S.; Yoneda, R.; Omori, Y.; Kurihara,
T. Tetrahedron Lett. 1987, 28, 4189.
We then examined several examples of the Strecker-type
reactions, and the results are summarized in Table 2. Aldimines
(12) For the use of 6,6′-dibromo-1,1′-bi-2-naphthol, see: (a) Terada, M.;
Motoyama, Y.; Mikami, K. Tetrahedron Lett. 1994, 35, 6693. (b) Sasai,
H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org.
Chem. 1995, 60, 7388.
(13) Cox, P. J.; Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 33,
2253.
(14) This could be partially due to the lower reactivity of (R)-3-Br-BINOL
compared to (R)-6-Br-BINOL and equilibrium of the coordination of NMI
to the zirconium center. After careful examination, the best results and
reproducibility were obtained when the catalyst was prepared by combining
1 equiv of Zr(OtBu)4, 1 equiv of (R)-6-Br-BINOL and (R)-3,3′-dibromo-
1,1′-bi-2-naphthol ((R)-3-Br-BINOL), and 3 equiv of NMI.

764 J. Am. Chem. Soc., Vol. 122, No. 5, 2000
Ishitani et al.
Table 2. Catalytic Asymmetric Strecker-Type Reactions Using
Table 3. Effect of Solvents and Concentration
Bu3SnCN
entry
solvent
additive
concn (M)
yield (%)
ee (%)
1b
2c
3c
4c
toluene
toluene
CH2Cl2
CH2Cl2
MS 4A
MS 4A
MS 4A
none
0.04
0.04
0.04
0.01
63
49
63
99
65
79
85
94
a See text. b Aldehyde, amine, and HCN were added to catalyst 3.
c HCN was added to catalyst 3 first and this catalyst solution was added
to the mixture of aldehyde and amine.
Table 4. Catalytic Asymmetric Strecker Reactions Using HCN
R1
R2
catalyst (mol %)
yield (%)
ee (%)
a When 2.5 mol % of 3 was used, 94% yield and 87% ee were
obtained. b ent-3 (5 mol %) was used. c The imine was prepared from
the corresponding aldehyde and 2-amino-3-methylphenol in situ in the
presence of MS 4A.
Ph
H
H
5
5
80
83
85
76
83
86
93
99
94
95
quant
quant
86
85
94
R-Nap
Ph(CH2)2
Ph(CH2)2
C8H17
C8H17
C8H17
iBu
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2.5
2.5
2.5
1
2.5
5
2.5
5
5
93 (S)b
90
84
derived from various aromatic aldehydes as well as aliphatic
and heterocyclic aldehydes reacted with Bu3SnCN smoothly to
afford the corresponding R-amino nitrile derivatives in high
yields with high enantiomeric excesses. Since both enantiomers
of the chiral sources (6-Br-BINOL and 3-Br-BINOL) are readily
available, both enatiomers of R-amino nitrile derivatives can
be easily prepared according to this protocol. In addition, it is
noteworthy that Bu3SnCN has been successfully used as a safe
cyanide source,15 and that, after the reaction was completed,
all tin sources were quantitatively recovered as bis(tributyltin)
oxide, which has been converted to tributyltin chloride16 and
then to Bu3SnCN.11,17
We then decided to develop a catalytic asymmetric version
of the Strecker synthesis (three-component reactions)18 and to
use HCN instead of Bu3SnCN. Although HCN is very toxic, it
is cheap and suitable for industrial use. To a chiral zirconium
catalyst prepared from 2 equiv of Zr(OtBu)4, 2 equiv of (R)-
6,6′-dibromo-1,1′-bi-2-naphthol ((R)-6-Br-BINOL), 1 equiv of
(R)-3,3′-dibromo-1,1′-bi-2-naphthol ((R)-3-Br-BINOL), and 3
91c
94
iBu
91
94
c-C6H11
tBu
86
tBu
2.5
88c
a See text. b (S)-3-Br-BINOL and (S)-6-Br-BINOL were used. c Zr(On-
Pr)4 was used instead of Zr(OtBu)4.
equiv of N-methylimidazole (NMI) in toluene (5 mol %, 0.04
M) were added isobutylaldehyde, 2-amino-3-methylphenol, and
HCN at -45 °C in the presence of molecular sieves (4A), and
the mixture was stirred for 12 h. After a typical workup, the
desired R-amino nitrile was obtained in 63% yield with 65%
ee. To improve the yield and selectivity, several reaction
conditions were examined (Table 3). It was found that the
selectivity was improved when HCN was added to the catalyst
first and this solution was then added to the mixture of the
aldehyde and the amine. The best results (99% yield, 94% ee)
were obtained when the catalyst was prepared at lower
concentration (0.01 M) in dichloromethane and the reaction was
performed in the same solvent without molecular sieves. The
same levels of yield and selectivity were achieved when 2.5
mol % of the Zr catalyst was used, and it was noted that an
excellent yield and enantiomeric excess were obtained in the
Strecker reaction using an aliphatic aldehyde.
(15) When TMSCN was used in this system, moderate yields and
moderate enantiomeric excesses were observed. The reaction of the aldimine
prepared from 1-naphthaldehyde and 2-aminophenol with TMSCN, 33%
yield, 63% ee; with triethylsilyl cyanide, 65% yield, 63% ee (not optimized).
(16) (a) Brown, J. M.; Chapman, A. C.; Harper, R.; Mowthorpe, D. J.;
Davies, A. G.; Smith, P. J. J. Chem. Soc., Dalton 1972, 338. (b) Davies, A.
G.; Kleinschmidt, D. C.; Palan, P. R.; Vasishtha, S. C. J. Chem. Soc. C
1971, 3972.
(17) Quite recently, we have developed scandium triflate-catalyzed
Strecker-type reactions of aldehydes, amines, and Bu3SnCN (achiral
reactions). In these reactions, complete recovery of tin compounds toward
environmentally friendly chemical processes has been achieved. Kobayashi,
S.; Busujima, T.; Nagayama, S. J. Chem. Soc., Chem. Commun. 1998, 981.
(18) For utility and advantages of three-component reactions, see: (a)
Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett. 1995, 36, 5773.
(b) Kobayashi, S.; Busujima, T.; Nagayama, S. J. Chem. Soc., Chem.
Commun. 1998, 981.
Several examples of the zirconium-catalyzed asymmetric
Strecker reaction are summarized in Table 4. The following
characteristics of these reactions are noted. (1) Catalytic
asymmetric three-component reactions, which succeed the
original Strecker reaction, have been accomplished. (2) In all
cases, chiral R-amino nitriles were obtained from both achiral
aldehydes and amines using a small amount of a chiral source.

Catalytic Asymmetric Strecker Synthesis
J. Am. Chem. Soc., Vol. 122, No. 5, 2000 765
Scheme 3. A Key Catalyst in the Three-Component
Reactions
Scheme 4. Conversion of Enantiomerically Pure R-Amino
Acid Esters
High yields and selectivities were obtained even when 1 mol
% of the catalyst was employed. (3) Aromatic aldehydes as well
as aliphatic aldehydes including primary, secondary, and tertiary
aldehydes worked well to afford the corresponding R-amino
nitriles in excellent enantiomeric excesses. (4) Not only mi-
croscale experiments but also larger scale syntheses (>10 mmol)
were successfully performed. (5) Both enantiomers of R-amino
nitriles could be readily prepared by using the enantiomeric
zirconium catalyst. (6) Less expensive Zr(OnPr)4 could be used
instead of Zr(OtBu)4.
Scheme 5. Conversion to Leucinamide
In general, it has been regarded that the Strecker three-
component reactions proceed via two possible pathways:
cyanation of aldimines and cyanohydrine pathways.19 The
former pathway was suggested in the present enantioselective
Strecker reactions, because no cyanohydrine formation was
observed during the reaction courses. As for the chiral catalyst,
formation of zirconium cyanide 4 is assumed. After combining
Zr(OtBu)4, (R)-6-Br-BINOL, (R)-3-Br-BINOL, NMI, and HCN,
all solvents were removed under reduced pressure and the
1
catalyst was dried (12 h/0.1 mmHg). H NMR experiments
revealed that the tBuO groups were removed from the catalyst.
On the other hand, no significant change of NMR spectra was
observed when the similar procedure was performed using Bu3-
SnCN instead of HCN.20 Control experiments also revealed that
the cyano groups attached to the zirconium center did not work
as cyanide nucleophiles in this Strecker reaction. Formation of
4 would be fast because similar high selectivities were obtained
when HCN was added after an aldehyde and an amine were
injected to the catalyst (78% yield, 90% ee; cf. Table 3, entry
4).
Scheme 6. Synthesis of Pipecolic Acid
R-Amino nitriles thus prepared were successfully converted
to R-amino acid derivatives. Methylation of the phenolic
hydroxyl group followed by acidic methanolysis provided the
corresponding methyl esters (5). Oxidative cleavages were
performed using cerium ammonium nitrate (CAN)21 to give
R-amino acid methyl esters (6). Their hydrochloric acid salts
were recrystallized to afford the enantiomerically pure R-amino
acid esters (Scheme 4). Homophenylalanine (2-amino-4-phen-
ylbutanoic acid) derivatives thus prepared may serve as potential
constituents of many medicinally important compounds.23-25
Similarly, D-leucine amide (8) was prepared (Scheme 5). Thus,
after methylation of the phenolic OH of 2b using methyl iodide
and potassium bicarbonate, the nitrile group was converted to
an amide moiety.22 Treatment of 7 with cerium ammonium
nitrate (CAN)21 gave leucinamide 8. The absolute configuration
assignment (R) was made by comparison of its hydrochloride
with the authentic sample. The present catalytic asymmetric
Strecker reaction could be also used for the synthesis of other
biologically important amino acid derivatives. For example, the
synthesis of D-pipecolic acid methyl ester (12) is shown in
Scheme 6. Pipecolic acid is an interesting member of the class
of lysine-related compounds. The key Strecker reaction using
5-tert-butyldimethylsiloxypentanal was successfully carried out
in the presence of 4 (2.5 mol %) to afford R-amino nitrile 9.
The following standard transformations gave 10 in a good yield.
Bromination of the hydroxyl group induced spontaneous cy-
(19) (a) Leblanc, J.-P.; Gibson, H. W. Tetrahedron Lett. 1992, 33, 6295.
(b) Walia, J. S.; Bannor, S. N.; Walia, A. S.; Guillot, L. Chem. Lett. 1974,
1005. (c) Jacobsen, R. A. J. Am. Chem. Soc. 1946, 68, 2628. (d) Jacobsen,
R. A. J. Am. Chem. Soc. 1945, 67, 1996. See also ref 7b.
(20) This indicates formation of different catalysts in the catalytic Strecker
reactions using Bu3SnCN and HCN. For catalysts 3 and 4, 4 is more active
than 3, presumably because of the two cyano groups.
(21) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
47, 2765.
(22) McGrath, M. E.; Klaus, J. L.; Barnes, M. G.; Bro¨mme, D. Nature
Struct. Biol. 1997, 4, 105.
(23) Sahoo, S. P.; Caldwell, C. G.; Chapman, K. T.; Durette, P. L.; Esser,
C. L.; Kopka, I. E.; Polo, S. A.; Sperow, K. M.; Nisdzwiechki, L. M.;
Izquierdo-Martin, M.; Chang, B. C.; Harrison, R. K.; Stein, R. L.; MacCoss,
M.; Hagmann, W. K. Bioorg. Med. Chem. Lett. 1995, 5, 2441.
(24) Yamada M.; Nagashima N.; Hasegawa, J.; Takahashi S. Tetrahedron
Lett. 1998, 39, 9019.
(25) Cacchi, S.; Misiti, D.; Torre, F. L. Synthesis 1980, 243.

766 J. Am. Chem. Soc., Vol. 122, No. 5, 2000
Ishitani et al.
solution (3.0 mL) of 6-Br-BINOL (0.04 mmol), 3-Br-BINOL (0.04
mmol), and NMI (0.12 mmol) was added a dichloromethane solution
(1.0 mL) of Zr(OtBu)4 (0.04 mmol) at room temperature. After the
mixture was stirred for 1 h, a dichloromethane solution (0.2 mL) of
HCN (0.8 mmol) was added at 0 °C and the mixture was further stirred
for 3 h at the same temperature. The resulting solution was then added
to a mixture of an aldehyde (0.4 mmol) and an amine (0.4 mmol) in
dichloromethane (1 mL) at -45 °C. After the mixture was stirred for
12 h, HCN was added if the reaction was not completed. Saturated
aqueous NaHCO3 was then added to quench the reaction, and after a
usual workup, the crude product was chromatographed on silica gel to
give the desired adduct. The optical purity was determined by HPLC
analysis using a chiral column (see the Supporting Information).
Since some of the adducts were unstable, they were characterized
after methylation of the phenolic OH group as shown above.
Chiral Zirconium Catalyst 3. To the solution of Zr(OtBu)4 (0.04
mmol) in toluene (0.25 mL) was added (R)-6,6′-dibromo-BINOL (0.04
mmol) and (R)-3,3′-dibromo-BINOL (0.04 mmol) in toluene (0.5 mL)
and 1-methylimidazole (0.12 mmol) in toluene (0.25 mL) at room
temperature. After the mixture was stirred for 1 h at the same
temperature, solvent was removed and then dried for 3 h at 50 °C in
vacuo.
clization, and acid treatment afforded N-protected D-pipecolic
acid methyl ester (11). Deprotection under standard conditions
gave 12 in a good yield.
Conclusion
Catalytic enantioselective Strecker-type reactions of aldimines
with Bu3SnCN have been developed using a novel chiral
zirconium binuclear catalyst. High levels of enantioselectivities
in the synthesis of R-amino nitrile derivatives with wide
substrate generality were obtained according to these reactions.
Moreover, we have demonstrated the catalytic asymmetric
Strecker amino acid synthesis, which can be achieved starting
from achiral aldehydes, amines, and HCN using a chiral
zirconium catalyst. It is noted that 150 years after the first
discovery of the Strecker reaction, a truly efficient three-
component asymmetric version has been accomplished. While
the former reactions using Bu3SnCN are suitable for laboratory-
scale experiments, industrial applications are expected in the
three-component catalytic asymmetric Strecker process.
t
1H NMR (CD2Cl2) δ 1.22 (s, BuO), 2.60 (s, 3H, NMe), 5.63 (d,
Experimental Section
2H, J ) 29.9 Hz, H4 and H5 of 1-methylimidazole), 6.02 (s, 1H, H2 of
1-methylimidazole), 6.33 (d, 1H, J ) 8.5 Hz), 6.41 (d, 1H, J ) 9.1
Hz), 6.52 (d, 1H, J ) 9.1 Hz), 6.55 (dd, 1H, J ) 7.0, 8.5 Hz), 6.78 (d,
1H, J ) 9.1 Hz), 6.82 (d, 1H, J ) 9.1 Hz), 6.90 (t, 1H, J ) 7.0, 8.0
Hz), 7.33 (d, 1H, J ) 8.0 Hz), 7.67 (d, 1H, J ) 8.9 Hz), 7.69 (d, 1H,
J ) 8.9 Hz), 7.72 (s, 1H), 7.78 (s, 1H), 8.03 (s, 1H), 8.08 (d, 1H, J )
8.9 Hz), 8.20 (d, 2H, J ) 8.9 Hz); 13C NMR (CD2Cl2) δ 30.6 (tBuO),
34.0 (NMe), 114.2, 114.4, 117.6, 117.7, 118.7, 118.8, 119.1 (C4 and
C5 of 1-methylimidazole), 122.0, 124.6, 124.7, 125.7, 126.1, 126.5,
126.6, 126.7, 126.8, 126.9, 127.0, 1217.1, 127.2, 127.6, 128.86, 128.90,
128,93, 129.0, 139.5, 132.0, 132.9 (C2 of 1-methylimidazole), 155.5,
159.3, 159.9.
A Typical Experimental Procedure for the Catalytic Enantiose-
lective Strecker-Type Reactions of Aldimines with Bu3SnCN. To
Zr(OtBu)4 (0.04 mmol) in toluene (0.25 mL) was added (R)-6-Br-
BINOL (0.04 mmol), (R)-3-Br-BINOL (0.04 mmol), and NMI (0.12
mmol) in toluene (0.75 mL) at room temperature. The mixture was
stirred for 1 h at the same temperature, and then cooled to -65 °C. A
benzene solution (1.0 mL) of 1 (0.4 mmol) and Bu3SnCN (0.44 mmol)
was added. The mixture was stirred and warmed from -65 to 0 °C
over 12 h, and saturated aqueous NaHCO3 was then added to quench
the reaction. The aqueous layer was extracted with dichloromethane.
After a usual workup, the crude product was chromatographed on silica
gel to give the desired adduct. The optical purity was determined by
HPLC analysis using a chiral column (see the Supporting Information).
Since some of the adducts were unstable, they were characterized
after methylation of phenolic OH group as follows: The adduct was
treated with 20% MeI-acetone (5 mL) and K2CO3 (200 mg). After the
mixture was stirred at room temperature for 6 h, saturated aqueous
NH4Cl was added to quench the reaction. After extraction of the aqueous
layer with dichloromethane, the crude product was chromatographed
on silica gel to afford the corresponding methylated product (quant).
A Typical Experimental Procedure for the Catalytic Enantiose-
lective Three-Component Strecker Reactions. A typical experimental
procedure of the Strecker reactions follows: To a dichloromethane
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan, and a SUT
Special Grant for Research Promotion.
Supporting Information Available: Experimental Section
and 1H and 13C NMR data of products (PDF). This material is
available free of charge via the Internet at hppt://pubs.acs.org.
JA9935207