Chiral salen-metal complexes as novel catalysts for the asymmetric synthesis of α-amino acids under phase transfer catalysis conditions

Article abstract of DOI:10.1016/S0040-4020(01)00072-2

Chiral salen-metal complexes have been tested as catalysts for the C-alkylation of Schiff's bases of alanine and glycine esters with alkyl bromides under phase-transfer conditions (solid sodium hydroxide, toluene, ambient temperature, 1-10 mol% of the catalyst). The best catalyst, which was derived from a Cu(II) complex of (1R, 2R or 1S,2S)-[N,N′-bis(2′-hydroxybenzylidene)]-1,2-diaminocyclohexane, gave α-amino and α-methyl-α-amino acids with enantiomeric excesses of 70-96%.

Full text of DOI:10.1016/S0040-4020(01)00072-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2491±2498
Chiral salen±metal complexes as novel catalysts
for the asymmetric synthesis of a-amino acids
under phase transfer catalysis conditions
Yuri N. Belokon,a,p Michael North,b,p Tatiana D. Churkina,a Nikolai S. Ikonnikova
and Victor I. Maleeva
aA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813,
Vavilov 28, Moscow, Russian Federation
bDepartment of Chemistry, King's College, Strand, London WC2R 2LS, UK
Received 22 June 2000; revised 2 November 2000; accepted 6 November 2000
AbstractÐChiral salen±metal complexes have been tested as catalysts for the C-alkylation of Schiff's bases of alanine and glycine esters
with alkyl bromides under phase-transfer conditions (solid sodium hydroxide, toluene, ambient temperature, 1±10 mol% of the catalyst). The
best catalyst, which was derived from a Cu(II) complex of (1R, 2R or 1S,2S)-[N,N0-bis(20-hydroxybenzylidene)]-1,2-diaminocyclohexane,
gave a-amino and a-methyl-a-amino acids with enantiomeric excesses of 70±96%. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
ion-pair interactions inside the loose ion pairs, formed by
the carbanions and quaternary ammonium ions however, are
dif®cult to employ in rationally designed, stereochemically
controlled, electrophilic attack on the carbanion. In spite of
recent progress in the ®eld,3 it is still not possible to predict in
advance, which reaction conditions will give good enantio-
selectivity in a particular reaction.
Asymmetric catalysis is rapidly becoming an important tool
for both small scale laboratory syntheses1 and large scale
industrial productions of enantiomerically enriched
compounds.1a,b,c Amongst the many chiral catalysts, metal
complexes feature prominently. This is partly due to their
unique ability to ®x the mutual orientation of chiral ligands
and substrates in the coordination sphere of the complex and
thus provide the necessary chiral template for chiral recog-
nition in the transition state of the reaction.1a,b,c Another
industrially important reaction, asymmetric phase-transfer-
catalysis (PTC) of CH-acid alkylation, proceeds via ion-pair
formation and usually relies on the use of chiral, quaternary
ammonium salts derived from cinchona alkaloids to
promote the enantioselective version of the reactions.2 The
Recently, some of us reported the use of TADDOL [(4S,5S)-
2,2-dimethyl-a,a,a0,a0-tetraphenyl-1,3-dioxalane-4,5-
dimethanol] and NOBIN (2-hydroxy-20-amino-1,10-
binaphthyl) to promote the asymmetric PTC C-alkylation
of Schiff's bases of alanine esters with enantiometric
excesses as high as 82%.4 In this reaction, TADDOL func-
tioned as a chelating agent for the alkali ions and thus made
the ion-pair (formed by the corresponding carbanion and
Scheme 1. Reagents: (i), PhCH2Br/1-12/PhCH3/solid NaOH; (ii), HCl (aqueous), ambient temperature/ (iii), 6N HCl (aqueous) re¯ux.
Keywords: phase-transfer-catalysis; copper; Schiff-bases; asymmetric-catalysis; amino-acid.
Corresponding authors. Tel.: 17-095-135-63-56; fax: 17-095-135-50-85; e-mail: yubel@ineos.ac.ru
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00072-2

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Y. N. Belokon et al. / Tetrahedron 57 (2001) 2491±2498
alkali ions) soluble in organic solvents. This modi®cation
combined the synthetic simplicity of the PTC approach,
with the advantages of catalysis by metal complexes. We
expected that other types of preformed chiral metal
complexes might function in the same way: activating the
ion-pair by complexation of an alkali ion and/or forming a
complex with the carbanion itself. Our earlier attempts to
realize this principle, using positively charge complexes,
met with only limited success.5a We believed that neutral
chiral salen complexes known for their propensity of
chelating additional metal ions6 might be better catalysts
of asymmetric PTC alkylation of CH-acids. In this manu-
script, we report the use of chiral salen±metal complexes
1±12 as phase transfer catalysts for the asymmetric syn-
thesis of a-amino acids. Preliminary results of a part of
this work were published earlier.5b
ester) with benzyl bromide under PTC conditions (solid
NaOH/toluene) was chosen (Scheme 1). The advantages
of using this substrate were the stability to racemization of
product 14 and the importance of amino acids containing
quaternary a-carbon atoms.7
The reaction was conducted in toluene at ambient tempera-
ture, using solid MOH (or NaH) to activate the substrate
(usually 0.1 g in 4 ml of solvent) and chiral salen±metal
complexes (1±12) as promoters of the reaction (substrate/
catalyst ration from 10 /1 to 100/1). After 24 h, the reaction
was quenched with dilute hydrochloric acid and the liber-
ated amino ester was hydrolysed. The enantiomeric excess
of the resulting a-methyl-phenylalanine 15 was established
by chiral GLC, and the experimental results are summarized
in Table 1.
Analysis of the results indicated that in the absence of a
transition metal, the salen ligands did not produce any
asymmetric induction in the product (Table 1, run 1). In
other words, the disodium salt of the ligand, which would
from under the PTC condition, was not an ef®cient asym-
metric catalyst of the alkylation reaction under the reaction
conditions. Catalyst 1, derived from Ni(II) and a positively
charged Schiff's base was also quite inef®cient (Table 1, run
2), which may be due to the poor solubility of 1 in toluene.
The removal of one methyl group from the (Me)2S1-moiety
of 1 to give ligand 2, improved the performance of the
catalyst (Table 1, run 3), bringing the enantiomeric excess
of the product to 31% at a ratio of substrate/catalyst of 10/1.
Complex 3, the Ni(II) complex of a Schiff's base derived
from (1R,2R)-[N,N0-bis(20-hydroxybenzylidene)]-1,2-di-
aminocyclohexane, was also catalytically active, giving
the same level of asymmetric induction at the same concen-
tration of the catalyst (Table 1, run 4). The performance of
the catalyst was greatly improved when the Ni(II) ion in 3
was substituted by a Cu(II) ion to give complex 4, with the
enantiometric excess of the ®nal product reaching 85%
(Table 1, run 5). The introduction of tert-butyl groups into
the 30-position of the salen moiety of the catalyst to give
complex 5 was counterproductive, with the enantiomeric
excess of the product dropping to 6% (Table 1, run 6). On
the other hand, introduction of a tert-Bu substituent into
position 50 (catalyst 7) decreased the enantiomeric excess
to a much lesser degree (Table 1, run 18). Finally, the intro-
duction of two tert-Bu groups in positions 30 and 50 (catalyst
8) reduced the enantiomeric excess of the reaction to zero
(Table 1, run 19). In other cases of catalysis using salen
ligands, the introduction of substituents at the 30-position
greatly improved the enantioselectivity of the catalyst.8
The reaction could be scaled up to 5 g of substrate 13,
employing complex 4 as a catalyst without any signi®cant
decrease in the enantiomeric excess of the reaction but with
lower yield (Table 1, run 7). If the ratio of sodium hydroxide/
substrate was chosen in the range 1.2±2.0, the chemical
yield of the product was low (20±50%, Table 1, runs 1±7).
One reason for this might be the consumption of sodium
hydroxide in a side reaction such as hydrolysis of the
substrate. This was corroborated by the drop in the chemical
yield to 4% when aqueous sodium hydroxide was used
(Table 1, run 8). An almost quantitative chemical yield
could be achieved using tert-butyl N-benzylidene-alaninate
2. Results
As a model reaction, the alkylation of Schiff's base 13
(derived from benzaldehyde and R,S-alanine isopropyl

Y. N. Belokon et al. / Tetrahedron 57 (2001) 2491±2498
2493
Table 1. Asymmetric alkylation of Schiff's base 13 by benzyl bromide mediated by salen±metal complexes in toluene at ambient temperature under PTC
conditions
Run
Catalyst
Mol % of the catalyst
Base, equiv.
e.e. (%) (con®guration)a
Yield (%)a
1
2
3
4
5
6
Free ligand of catalyst 6
1
2
3
4
5
4
6
4
4
6
6
4
6
6
6
6
10
10
10
10
10
10
10
2
10
10
1
2
2
2
2
2
2
10
10
10
10
10
10
NaOH, 1.2
NaOH, 1.5
NaOH, 1.5
NaOH, 1.2
NaOH, 1.2
NaOH, 1.2
NaOH, 1.2
NaOH, 2.0
NaOH, 1.2
NaH, 1.2
NaOH, 3.0
NaOH, 3.5
NaOH, 4.0
NaOH, 3.0
LiOH, 2.0
KOH, 2.0
NaOH, 1.2
NaOH, 3.0
NaOH, 3.0
NaOH, 3.0
NaOH, 3.0
NaOH, 3.0
NaOH, 3.0
0.5
50
50
44
34
40
47
20
4
91
82
71c
91
99
95
7
87
48
80
80
76
61
22
90
1 (S)
31 (R)
30 (R)
85 (R)
6 (R)
80 (R)c
80 (S)
46 (R)
89 (R)
92 (S)c
88 (S)
76 (R)
53 (S)
0
63 (S)
90 (S)
65 (R)
0
3 (S)
3(S)
6(S)
7b
8d
9e
10
11b
12
13
14f
15
16
17g
18
19
20
21
22
23
7
8
9
10
11
12
8(S)
The concentration of the substrate was 0.2±0.3 M [usually 0.110 g (0.5 mmol) of substrate in 4 ml of the solvent, unless indicated otherwise]. The reaction was
conducted for 24 h under an argon atmosphere, solid MOH was used as base unless indicated otherwise, and the ratio of benzyl bromide to 13 was 1.2±2.
a
The enantiomeric excess of a-methyl-phenyalanine was determined by GLC of the N-tri¯uoroacetyl derivative of its propyl-ester, and the chemical yield was
determined by H NMR spectroscopy using leucine as an internal standard.
The experiment was scaled up to 5 g of 13 in 100 ml of toluene.
After crystallization, the enantiomeric excess of a-methyl-phenylalanine was increased to 98% and the yield decreased to 61%.
Aqueous NaOH (50%) was used as a base.
The substrate was derived from the tert- Bu ester of R,S-alanine.
The experiment was conducted in an open vessel without any Ar atmosphere.
The catalyst recovered from the previous experiments was used.
1
b
c
d
e
f
g
as a hydrolyticallly stable substrate (Table 1, run 9). Alter-
natively, use of 1.2 equiv. of sodium hydride gave a good
chemical yield and satisfactory enantiomeric excess (Table
1, run 10). Finally, increasing the amount of solid sodium
hydroxide to 3.5 equiv. improved the chemical yield with-
out compromising the enantiomeric excess of the product
(Table 1, runs 11,12) even if the amount of the catalyst was
decreased to 1% (Table 1, run 11). Further increase in the
amount of sodium hydroxide to 4.0 equiv. decreased the
enantiomeric excess of the product from 88 to 76% (Table
1, run 13). It was necessary to carry out these reactions
under an inert atmosphere, as an attempt to conduct the
reaction in an open vessel resulted in a low enantiomeric
excess of the product (Table 1, run 14). Sodium hydroxide
was found to be the base of choice since lithium hydroxide
was inef®cient (Table 1, run 15) and use of potassium
hydroxide gave a low enantiomeric excess (Table 1, run
16). Catalysts 6 or 4 could be recovered and successfully
reused in the reaction (Table 1, run 17).
Generally, any modi®cation of the catalyst's salen moiety
resulted in a decreased enantiomeric excess of the reaction.
The introduction of an electronegative Br-substituent at the
para-position (catalyst 10) was also detrimental for the cata-
lytic activity with the enantiomeric excess of the product
being close to zero (Table 1, run 21). Catalyst 9, differing
from complex 4 by the methyl substituents at the CvN
bonds, was active in the reaction, but lost its asymmetry
inducing properties (Table 1, run 20). Both catalysts 11
and 12 derived from (S,S)-1,3-oxa-2,2-dimethyl-4,5-di-
aminomethylcyclopentane and (R)-2,20-diamino-1,10-
dinaphthyl, respectively, catalysed the reaction, but the
asymmetric induction was very low 6 and 8% in both
cases (Table 1, runs 22, 23). A complex of Cu(II) of the
Schiff's base derived from (R,R)-1,2-diaminocyclohexane
and pyridine-2-aldehyde was not a very ef®cient catalyst
and did not induce any enantioselectivity in the reaction.
Thus, catalyst 4 (or its enantiomer 6) was the catalyst of
Table 2. Alkylation of substrate 13 with different alkylating agents catalysed by 4
Run
Alkylating agent
Chemical yield (%)
e.e.(%) (con®guration)
1
2
3
4
1-Chloromethylnaphthalene
Allyl bromide
EtBr
EtI
52
40
25
58
88 (R)
90 (R)
13 (R)
75 (R)
The experimental conditions are the same as in Table 1, run 12.

2494
Y. N. Belokon et al. / Tetrahedron 57 (2001) 2491±2498
Scheme 2. (i) RX, solid NaOH, catalyst 4, toluene, 48 h; (ii) aqueous HCl.
choice in the set of the complexes 1±12 under study. It was
of interest to broaden the scope of the reaction by including
other alkylating agents and/or other substrates in the reac-
tion under the optimal conditions of run 12 of Table 1. Table
2 summarizes the results of the alkylation of the alanine
derivative 13 with other alkylating agents. As can be seen
from the data, allyl bromide and 1-naphthylmethyl bromide
reacted with 13 with good enantioselectivity and moderate
chemical yield (Table 2, runs 1,2). Ethyl bromide proved to
be a slow reacting alkylating agent, but ethyl iodide was
reasonably active, giving 2-amino-2-methyl butyric acid
with an enantiomeric excess close to 75% (Table 2, runs
3,4).
making an achiral route more competitive. As the detri-
mental effect of the introduction of an electronegative Br-
substituent in the para-position indicates (Table 1, run 21) it
is the nucleophilicity of the coordinated metal atoms which
is essential for the asymmetric reactivity of the catalyst. The
data of Table 1 indicate that both the nature of the central
atoms of the catalysts (Table 1, runs 4, 5) and the cations of
the base (Table 1, runs 15, 16; Table 2, runs 8,9) were
important for high enantioselectivity of alkylation to be
observed. In addition, the conformation of the salen ligands
is crucial for both the magnitude and direction of the asym-
metric induction (compare catalysts 4, 11 and 12).
To further investigate the nature of the catalytically active
species, the presence of any non-linear effects was investi-
gated. As the plot of enatiomeric purity of the ligand versus
the enantiomeric purity of the product (Fig. 1) indicated,
there were positive non-linear effects9 observed for the
alkylation of both substrates with benzyl bromide catalysed
by 4 or 6. In other words more than one salenCu(II) complex
participated in the transition state of the alkylation and a
complex of (S,S)/(S,S)-type was a better catalyst than that of
(S,S)/(R,R)-con®guration.
Alkylation of the glycine derivative 16 was conducted
according to Scheme 2 under the optimal conditions
(Table 1, run 12) and the results are summarized in Table
3. The amino acids could be recovered from the reaction
mixture either by direct hydrolysis, or the intermediate
Schiff's base could ®rst be puri®ed on SiO2. As can be
seen from the results, benzyl bromide, allyl bromide, and
naphthylmethyl bromide participated in the catalyst 4
mediated alkylation of 16 and the resulting a-amino acids
had enantiomeric excesses in the 70±80% range (Table 3,
runs 1±3). There was no racemization of the intermediate
Schiff's base 17 during the reaction, as no decrease in the
enantiomeric excess of the amino acids was observed as
the time of the reaction was increased (Table 3, runs 6, 7).
The cation of the base was important and NaOH was found
the base of choice (Table 3, runs 1, 8, 9) exactly as in the
case of the substrate 13.
Scheme 3 presents a hypothetical mechanism of the reaction
in which the ion pair derived from the substrate and MOH
forms on the surface of the solid MOH. Then, the ion pair
and the catalyst form a hydrophobic complex, which is
transferred to the solution. The key feature of the mecha-
nism is the formation of a mixed complex of two (or more)
salen Cu(II) complexes united by a cation of the base and
with the deprotonated substrate occupying the apical coor-
dination site of one of the Cu(II) ions of the complexes.
These features of the catalytic complex can account for
the in¯uence of the metal cations and the nature of the chiral
ligands on the enantioselectivity of the reaction. Further
alkylation of the coordinated carbanion occurs in the
complex followed by the liberation of the catalyst.
3. Discussion
The decrease in the enantioselectivity of the alkylation reac-
tion with the introduction of a tert-butyl group ortho to the
phenol oxygen atoms is highly unusual for other chiral salen
complex catalysed reactions.8 One possible explanation
might be the paramount importance of the phenol oxygen
atoms of the salen ligand for the asymmetric course of the
reaction, with any steric hindrance of the approach to them
There is a possibility that the initial alkylation of the
complex occurs on one of the phenolic oxygens of the
salen ligand in the catalytic complex, with the formation
of an alkylating agent which then intramolecularly attacks
the coordinated carbanion. Evidence to support this hypoth-
esis comes from an experiment employing (1R,2R)-bis-
(N,N0-20-benzyloxybenzylidene)-1,2-diaminocyclohexane,
which was capable of alkylating substrate 13 in the presence
of NaOH and CuBr2 to form (R)-15 with an enantiomeric
purity of 40%.
Table 3. Alkylation of substrate 16 (Scheme 2) with different alkylating
agents catalysed by 4
Run
Alkylating agent
Chemical yield (%) e.e. (con®guration)
1
2
3
4
5
6
7
8
9
PhCH2Br
Allyl bromide
1-Chloromethylnaphtalene .95
CH3I
(CH3)2CHI
PhCH2Br (4 h)
PhCH2Br (20 h)
PhCH2Br (KOH)
PhCH2Br (LiOH)
.95
.90
80 (R)
81 (R)
77 (R)
7 (R)
9 (R)
75 (R)
78 (R)
60 (R)
±
12
20
88
.90
.95
0
4. Conclusions
This work has resulted in the development of a new class of
asymmetric phase-transfer catalysts for the alkylation of
alanine and glycine enolates. The optimal catalyst is a
The experimental conditions are the same as in Table 1, run 12.

Y. N. Belokon et al. / Tetrahedron 57 (2001) 2491±2498
2495
Figure 1. Positive non-linear effects in the alkylations of substrate 13 and 16 catalysed by 4 with different degrees of enantiomeric purity.
Scheme 3. A mechanism for PTC alkylation of substrate 16 catalysed by a salen Cu(II) complex.

2496
Y. N. Belokon et al. / Tetrahedron 57 (2001) 2491±2498
(salen)Cu(II) derivative which produces the alkylated
product with up to 92% enantiomeric excess. Preliminary
mechanistic studies have shown that the introduction of
substituents onto the aromatic rings of the salen ligand is
detrimental to the activity of the catalyst, and that the
active form of the catalyst is not monomeric. Our work on
developing the synthetic applications of this chemistry and
in understanding the origin of the catalytic activity is
continuing, and further results will be reported in due
course.
oil) (4 g, 0.1 mol) whilst maintaining the reaction tempera-
ture below 558C followed by the dropwise addition of
benzyl bromide (12 ml, 17.3 g; 0.1 mol). The stirring was
continued for another 4 h and then H2O (75 ml) and benzene
(30 ml) were added to the mixture. The organic layer was
separated, washed with H2O (3£20 ml) and concentrated in
vacuo. The crude solid material was twice washed with H2O
and after drying additionally washed with hexane and dried
in air. Yield 39% (7.9 g). dH 5.21 (s, 2H, OCH2Ph), 7.0±
7.95 (m, 9H, Ar), 10.6 (s, 1H, CHO).
5.1.6. (1R, 2R)-[N,N0-bis-(20-benzyloxybenzylidene)]-1,2-
diaminocyclohexane. To a solution of (R,R)-cyclohexane-
diamine tartrate (1 g, 0.38 mmol) and K2CO3 (1.05 g,
0.76 mmol) in H2O (5 ml) were added ethanol (20 ml) and
the reaction mixture was heated until the solution became
transparent. Then, O-benzyl-salicylaldehyde (1.62 g, 0.76
mmol) was added to the mixture. The reaction mixture
was re¯uxed for 2 h and put into a freezer overnight. The
precipitated oil was separated and hexane (40 ml) was
added to it. The mixture was re¯uxed for 20 min and the
hot hexane solution separated from the residue. The solution
5. Experimental
5.1. General
1H NMR spectra were recorded on a Bruker WP-200 instru-
ment at 200 MHz with TMS (dˆ0.00) as an internal stan-
dard and CDCl3 as a solvent (unless indicated otherwise).
Optical rotations were measured with a Perkin±Elmer-241
polarimeter in a thermostated cell at 258C. Toluene was
distilled from sodium prior to use. Enantiomeric analyses
of amino acids were performed by GLC on their N-tri¯uoro-
acetyl n-propyl esters using a Chirasil-L-Val type phase on a
fused silica capillary column 40 m£0.23 mm ID, ®lm
0.12 mm, column temperature 1258C, and He carrier-gas
at 1.80 bar. N-(Diphenylmethylene)glycine tert-butyl ester,
was concentrated in vacuo and the resulting oil was used
without additional puri®cation. Yield 53% (1.0 g). [a]D
25
ˆ
1231 (cˆ0.39, CHCl3). dH 1.51 (m, 2H, CH2), 1.86 (m, 6H,
CH2), 3.47 (m, 2H,.CH±Nv), 5.03 (s, 4H, PhCH2O), 6.8±
8.0 (m, 18H, Ar), 8.75 (s, 2H, CHN).
5-t-butyl-salicilaldehyde,
3,5-di-t-lbutyl-salicilaldehyde,
5.1.7. (4S, 5S)-1,3-oxa-2,2-dimethyl-[N,N0-bis(20-hydroxy-
(R)-(1)-2,20-diamino-1,10-binaphthalene and alkyl halides
were available from Aldrich, (4S, 5S)-4,5-di(aminomethyl)-
2,2-dimethyldioxalane was available from ACROS
Chimica; all reagents were used without additional puri®-
cation.
benzylidene)]-4,5-diaminometycyclopentane.
MgSO4
(2 g) was suspended in a solution of (4S,5S)-4,5-di(amino-
methyl)-2,2-dimethyldioxalane (0.3 g, 1.88 mmol) and
salicylaldehyde (0.46 g, 3.75 mmol) in dry benzene
(20 ml). The reaction mixture was stirred for 6 h, the inor-
ganic salts ®ltered off and the ®ltrate evaporated in vacuo.
The resulting oil solidi®ed after standing for 2 days. The
solid Schiff's base was used without additional puri®cation.
dH 1.34 (s, 6H, 2CH3), 3.83 (m, 4H, CH2Nv), 4.18 (m, 2H,
.CHO), 7.21±7.34 (m, 8H, Ar), 8.35 (s, 2H, CHvN), 12.9
(s, 2H, OH).
5.1.1. (1R, 2R)-diaminocyclohexane. This was resolved
according to the literature procedure10 and had satisfactory
25
elemental analysis and [a]D ˆ215 (cˆ5, aq. 1N HCl),
{lit.11 [a]D ˆ215.8}.
25
5.1.2. (1S, 2S)-diaminocyclohexane. This was resolved in
the same manner, using the enantiomeric tartaric acid.
5.1.8.
(R)-[N,N0-bis-(200-hydroxybenzylidene)]-2,20-di-
amino-1,10-binaphthalene. (R)-2,20-Diamino-1,10-binaph-
thalene (0.2 g, 0.702 mmol) was dissolved in absolute
ethanol (30 ml), then salicylaldehyde (0.172 g, 1.408
mmol) was added and the mixture re¯uxed with stirring
for 5 h. After adding water (2 ml), a precipitate was formed
which was ®ltered, washed with absolute ethanol (5 ml), and
5.1.3. (1R, 2R)-[N,N0-bis(20-hydroxybenzylidene)]-1,2-
diaminocyclohexane. This and all the other Schiff's bases
were synthesized according to a literature procedure.10
5.1.4. Schiff's bases of (R,S)-alanine. These were synthe-
sized from benzaldehyde and the appropriate amino esters,
as described earlier.12 tert-Butyl N-benzylidene-(R,S)-alani-
nate was obtained as a colourless oil with bp 105±1078C/
1.5 mm Hg in 58% yield. dH 1.48 (s, 9H, (CH3)3), 1.50 (d,
Jˆ6.3 Hz, 3H, CH3), 4.02 (q, Jˆ6.3 Hz, 1H, CH), 7.34±
7.86 (m, 5H, Ph), 8.3 (s, 1H, CHvN); nmax 1650,
1740 cm21. Isopropyl N-benzylidene-(R,S)-alaninate was
obtained as a colourless oil with bp 120±1218C/2 mm Hg
in 71% yield. nD15 1.5168. dH 1.23 (d, Jˆ6.2 Hz, 3H, CH3),
1.27 (d, Jˆ6.2 Hz, 3H, CH3), 1.51 (d, Jˆ7.1 Hz, 3H, CH3),
4.09 (q, Jˆ7.1 Hz, 1H, CH), 5.05 (m, 1H, OCH), 6.3±7.3
25
dried in air. Yield 87% (0.32 g). Mp 2568C. [a]D ˆ2455
(cˆ1, CHCl3). Found: C, 82.89; H, 5.01; N, 5.52. Calculated
for C34H24N2O2: C, 82.91; H, 4.91; N, 5.69.
5.1.9. (1S,2S)-[N,N0-bis-((20-pyridine)-methylene)]-1,2-di-
aminocyclohexane. (1S,2S)-1,2-Diaminocyclohexane (1 g,
8.77 mmol) was dissolved in methanol (5 ml) and 2- pyri-
dine carboxaldehyde (1.88 g, 17.55 mmol) was added. The
stirring was continued for another 5 h. The precipitated
product was ®ltered, recrystallized from hexane/methanol
and dried in air. Yield 2.2 g (86%). Mp 127±1298C.
(m, 5H, Ph), 8.29 (s, 1H, CHvN); nmax 1644, 1735 cm21
.
25
[a]D ˆ185.44 (cˆ1, CHCl3); dH 1.95 (m, 4H, ±CH2±
CH2), 3.55 (m, 2H,.CH±Nv), 7.17±8.55 (m, 8H, Ar),
8.33 (s, 2H, CHvN). Found: C, 74.14; H, 7.24; N, 19.25.
Calculated for C18H20N4: C, 73.94; H, 6.89; N, 19.16.
5.1.5. 2-O-Benzyloxy-benzaldehyde (O-Benzyl-salicylalde-
hyde). To a solution of salicylaldehyde (10 ml, 0.096 mol)
in DMF (25 ml) was slowly added NaH (60% suspension in

Y. N. Belokon et al. / Tetrahedron 57 (2001) 2491±2498
2497
5.1.10. Cu(II) complex 4. To a solution of (1R,2R)-[N,N0-
bis(20-hydroxybenzylidene)]-1,2-diaminocyclohexane (1.32 g,
4.1 mmol) in MeOH (20 ml) were added CuBr2 (0.92 g,
4.1 mmol) and NaOMe (0.9 ml of 4.6 N solution in
MeOH). The reaction mixture was stirred for 3 h at ambient
temperature and then the solvent was removed in vacuo. The
4.98. Calculated for C34H22N2O2Cu: C, 73.70; H, 4.00; N,
5.06.
5.1.17. Cu(II) complex of (1R,2R)-[N,N0-bis-(20-benzyl-
oxybenzylidene)]-1,2-diaminocyclohexane. This was
synthesized in situ by dissolving (1R,2R)-[N,N0-bis-(20-
benzyloxybenzylidene)]-1,2-diaminocyclohexane (0.137 g,
0.27 mmol) in methanol (2 ml) followed by the addition
of CuBr2 (0.060 g, 0.27 mmol). The reaction mixture was
stirred at room temperature for 4 h after which time the
inorganic salts were ®ltered off and the brown solution
concentrated in vacuo. The brown solid complex was used
in alkylation reactions without any puri®cation.
complex was puri®ed by chromatography on LH-20 (EtOH/
ˆ
25
C6H6 1:3). Yield 1 g (63%); mp 315±3198C (dec.); [a]D
2917 (cˆ0.048, CHCl3). Found: C, 62.97; H, 5.43; N, 7.47.
Calculated for C20H20N2O2Cu: C, 62.57; H, 5.25; N, 7.30.
5.1.11. Cu(II) complex 6. This was synthesized as
described for complex 4 in a chemical yield of 68%.
25
Mp 313±318C (dec.); [a]D ˆ1915 (cˆ0.04, CHCl3).
Found: C, 61.78; H, 5.27; N, 7.21. Calculated for
C20H20N2O2Cu£0.25H2O: C, 61.84; H, 5.32; N, 7.21.
5.1.18. Cu(II) complex of (1S,2S)-[N,N0-bis-((20-pyri-
dine)-methylene)]-1,2-diaminocyclohexane.
(1S,2S)-
[N,N0-bis-((20-pyridine)-methylene)]-1,2-diaminocyclo-
hexane (0.050 g, 0.17 mmol) and CuBr2 (0.038 g, 0.17
mmol) were mixed and stirred for 8 h. The reaction product
was ®ltered, washed with methanol, benzene and ether, and
then dried in air. Yield 87% (0.093 g). Mp 228±2308C.
5.1.12. Cu(II) complex 5. This was synthesized as
described for complex 4 in a chemical yield of 75%. Mp
25
256±2578C; [a]D ˆ2237 (cˆ0.04, CHCl3). Found: C,
67.61; H, 7.50; N, 5.45. Calculated for C28H36N2O2Cu: C,
67.78; H, 7.31; N, 5.65.
25
[a]D ˆ1168 (cˆ1, CHCl3). Found: C, 34.45; H, 3.02; N,
8.92. Calculated for C18N4Br2Cu£0.5CuBr2: C, 34.46; H,
5.1.13. Cu(II) complex of (1R, 2R)-[N,N0 bis(20-hydroxy-
50-t-butyl-benzylidene)]-1,2-diaminocyclohexane 7. This
was synthesized as described for complex 4 with additional
puri®cation using LH-20 in benzene/i-propyl alcohol (3:1)
in a chemical yield of 75%. Mp dec. .2608C without
3.21; N, 8.93.
5.1.19. Ni(II) complex 3. This was synthesized as described
for 4, starting with Ni(NO3)2£6H2O in a yield of 60%. Mp
25
.3458C (dec); [a]D ˆ2610 (cˆ0.04, CHCl3); dH 1.31±
25
melting; [a]D ˆ2613 (cˆ0.04, CHCl3). Found: C, 67.51;
2.39 (m, 8H, CH2CH2CH2CH2), 3.29 (m, 2H, CHNv),
6.47±7.19 (m, 8H, Ph), 7.24 (s, 2H, PhCHvN).
Found: C, 62.50; H, 5.36; N, 6.99. Calculated for
C20H20N2O2Ni£0.5H2O: C, 62.38; H, 5.41; N, 7.27.
H, 7.14; N, 5.61. Calculated for C28H36N2O2Cu: C, 67.78; H,
7.31; N, 5.65.
5.1.14. Cu(II) complex of (1R,2R)-[N,N0-bis(20-hydroxy-
30,50-di-t-butyl-benzylidene)]-1,2-diamino-cyclohexane
8. This was synthesized as described for complex 4 in a
chemical yield of 85 %. Mp dec. .2808C without melting;
5.1.20. Ni(II) complex 2. This was prepared from the corre-
sponding Schiff's base10b and Ni(NO3)2£6H2O as described
25
for 4 in a yield of 58%. Mp 224±2258C; [a]D ˆ21350
25
[a]D ˆ2275 (cˆ0.04, CHCl3). Found: C, 71.24; H, 8.56;
(cˆ0.0011, CHCl3); dH 2.02 (s, 3H, CH3S), 1.8±2.5 (m,
4H, CH2CH2S), 2.84 and 3.20 (AB part of ABX system,
2H, CH2Nˆ), 4.05 (X part of ABX system, 1H, CHNv),
6.36±7.12 (m, 8H, Ph), 7.15 (s, 1H, PhCHvN±), 7.20 (s,
1H, PhCHvN±). Found: C, 57.40; H, 5.53; N, 6.93. Calcu-
lated for C19H20N2O2NiS: C, 57.10; H, 5.05; N, 7.02.
N, 4.55. Calculated for C36H52N2O2Cu: C, 71.07; H, 8.62; N,
4.60.
5.1.15. Cu(II) complex of (4S,5S)-1,3-oxa-2,2-dimiethyl-
[N,N0-bis(20hydroxybenzylidene)]-4,5-diaminomethy-
cyclopentane 11. To a solution of the Schiff's base of
salicylaldehyde and (4S,5S)-1,3-oxa-2,2-dimethyl-4,5-
diaminomethycyclopentane (0.1 g, 0.27 mmol) in methanol
(5 ml) were added Cu(OAc)2£H2O (0.053 g, 0.265 mmol)
and the reaction mixture was stirred under re¯ux for 2 h.
The precipitated complex was washed with methanol and
dissolved in benzene (10 ml). The solution was ®ltered
and the complex precipitated by the addition of methanol
5.1.21. Ni(II) complex 1 (as an iodide). To complex 2
(0.99 g, 2.5 mmol) in CH2Cl2 (4 ml) at room temperature
was added MeI (1.6 ml. 3.65 g, 25.7 mmol). The reaction
mixture was stirred for 18 h at ambient temperature, then
complex 1 was separated by ®ltration, washed with CH2Cl2
(2£3 ml) and dried in air. Yield 1.25 g (92%). Mp 152±
25
1558C; [a]D ˆ21042, (cˆ0.037, CHCl3); dH (CD3OD)
25
and dried in air. Yield 65%. Mp 228±2308C, [a]D ˆ2462
2.34±3.54 (m, 6H, CH2Nv, CH2CH2S1), 2.98 (s, 3H,
SCH3), 3.00 (s, 3H, SCH3), 3.83 (m, 1H, CHNv), 6.62±
7.29 (m, 8H, Ph), 7.78 (s, 1H, CHvN), 7.86 (s, 1H,
CHvN). Found: C, 44.29; H, 4.22; N, 5.18. Calculated
for C20H23N2O2NiSI: C, 44.40; H, 4.28; N, 5.18.
(cˆ0.52, CHCl3). Found: C, 58.58; H, 5.21; N, 6.55. Calcu-
lated for C21H20N2O4Cu: C, 58.66; H, 5.16; N, 6.52.
5.1.16. Cu(II) complex of (R)-[N,N0-bis(200-hydroxybenzyl-
idene)]-2,20-diamino-1,10-binaphthalene 12. To a stirring
solution of Cu(OAc)2£H2O (0.061 g, 0.305 mmol) in
methanol (5 ml) was added (R)-1,10-(2,20-diamino)bi-
naphthalene (0.15 g, 0.305 mmol) after which the reaction
mixture was stirred for 1 h. The precipitate of complex 12
5.1.22. Catalytic asymmetric alkylation procedure. A
¯ask, containing catalyst 1±12 (3.3 mg, 0.0086 mmol)
was ¯ame dried and ®lled with argon. NaOH (40 mg,
1 mmol), toluene (2 ml) and substrate 13 or 16 (110 mg,
0.5 mmol), were added to the ¯ask under argon. The reac-
tion mixture was deoxygenated at 2788C under vacuum and
then, under argon, a solution of 0.1 ml of alkyl halide in
was washed with methanol (2£5 ml), dried in air and used
25
without additional puri®cation. Mp 277±2808C. [a]D
1775 (cˆ0.04, CHCl3). Found: C, 73.46; H, 3.82; N,
ˆ

2498
Y. N. Belokon et al. / Tetrahedron 57 (2001) 2491±2498
Soc. 1989, 111, 2353±2355. For use of other type ammonium
salts see; Ooi, T.; Kameda, M.; Maruoka, K.
J. Am. Chem. Soc. 1999, 121, 6519±6520. Manabe, K.
Tetrahedron Lett. 1998, 39, 5807±5810. Ooi, T.; Takeuchi,
M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 121,
5228±5229.
2 ml of toluene was added with stirring. The temperature
was allowed to rise to room temperature and the stirring was
continued for another 5±12 h. Then, the mixture was ®ltered
and the ®ltrate treated as described earlier for recovery of
the a-amino acids.4 The procedure for the alkylation of 16
differed, as sometimes the ®nal product of the alkylation, the
corresponding benzophenone Schiff's bases, could be
puri®ed by TLC (SiO2, acetone/hexane, 1/8). The isolated
amino acids were analysed by chiral GLC without any puri-
®cation. In the case of scale up experiments a-methyl-a-
phenylalanine was additionally recrystallized from PrOH/
H2O, to obtain almost enantiomerically pure amino acid
3. Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39,
5347±5350. Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc.
1997, 119, 12414±12415. Lygo, B.; Winewright, P. G.
Tetrahedron Lett. 1997, 38, 8595±8598. O'Donnel, M. J.;
Delgado, F.; Hostettler, C.; Schwesinger, R. Tetrahedron
Lett. 1998, 39, 8775±8778. Lygo, B.; Crosby, J.; Peterson,
J. A. Tetrahedron Lett. 1999, 40, 1385±1388. Horikawa, M.;
Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40,
3843±3846. For a short review see: Nelson, A. Angew. Chem.,
Int. Ed. 1999, 38, 1583±1585.
25
(yield 2.58 g. 61%) with [a]D ˆ217.2 (cˆ1, H2O) lit.
4,13 117.8 (cˆ0.2, H2O); 217.8 (cˆ0.2, H2O). The catalyst
could be recovered in 30±50% yield from the solid pre-
cipitate by washing it with water, after which procedure
the catalyst could be collected as the remaining insoluble
material.
4. Belokon', Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Parmar,
V. S.; Kumar, R.; Kagan, H. B. Tetrahedron: Asymmetry
1998, 9, 851±857. Belokon, Y. N.; Kochetkov, K. A.;
Churkina, T. D.; Ikonnikov, N. S.; Vyskocil, S.; Kagan, H.
Tetrahedron: Asymmetry 1999, 10, 1723±1726.
5.1.23. Non-linear effects. These were investigated
employing the same procedure, using the mixture of the
appropriate amounts of 4 and 6 catalysts.
5. (a) Belokon', Y. N.; Maleev, V. I.; Videnskaja, S. O.;
Saporovskaja, M. B.; Tsyryapkin, V. A.; Belikov, V. M. Izv.
Akad. Nauk, Ser. Khim. SSSR 1991, 126±134 (Bull. Acad. Sci.
USSR, Div. Chim. Sci., 1991, 40, 110±118). (b) Belokon,
Y. N.; North, M.; Kublitski, V. S.; Ikonnikov, P. E.; Krasik,
P. E.; Maleev, V. I. Tetrahedron Lett. 1999, 40, 6105±6108.
6. Gleizes, A.; Julve, M.; Kuzmina, N.; Alikhanyan, A.; Lloret,
F.; Malkerova, J.; Sanz, J.; Senocq, F. Eur. J. Inorg. Chem.
1998, 1169±1174.
Acknowledgements
The research described in this publication was made pos-
sible in part by Award No RC1-2205 of the US Civilian
Research and Development Foundation for the Independent
States of the Former Soviet Union (CRDF), and also by the
Russian Fund for Fundamental Sciences (Grant No 99-03-
32970).
7. For recent references see: (a)Wirth, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 225±227. (b) Chinchill, R.; Falvello, L.;
Galindo, N.; Najera, C. Angew. Chem., Int. Ed. Engl. 1997,
36, 995±997.
References
8. Pospisil, P. J.; Carsten, D. H.; Jacobsen, E. N. Chem. Eur. J.
1996, 2, 974 (and references cited therein). Moscalenko, M.;
North, M.; Orlova, S.; Tararov, V.; Yashkina, L. Tetrahedron:
Asymmetry 1996, 7, 851±855.
1. (a) Kagan, H. B. Bull. Soc. Chem. Fr 1988, 5, 846±852.
(b) Davies, I. W.; Reider, P. J. Chemistry and Industry 1996,
6, 412±415. (c) Trost, B. M. Angew. Chem., Int. Ed. Engl.
1995, 34, 258±281. (d) Noyori, R. Asymmetric Catalysis in
Organic Synthesis, Wiley: Chichester, 1994. For recent
reviews see: (e)Ito, Y. N.; Katsuki, T. Bull. Chem. Soc. Jpn
1999, 72, 603±619. (f) Vogl, E. M.; Groger, H.; Shibasaki, M.
Angew. Chem., Int. Ed. 1999, 38, 1570±1577.
9. Girard, C.; Kagan, H. Angew. Chem., Int. Ed. 1998, 37, 2923±
2959.
10. (a) Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C.
J. Org. Chem. 1994, 59, 1939±1942. (b) Amundsen, A. R.;
Whelan, J.; Bosnich, B. Inorg. Chem. 1979, 18, 206±208.
11. Asperger, R.; Liu, C. Inorg. Chem. 1965, 4, 1492±1494.
12. Grigg, R.; Gunaratne, H. Q. N.; Kemp, J. J. Chem. Soc., Perkin
Trans. 1 1984, 41±46.
2. O'Donnel, M. J.; Wu, Sh.; Hauffman, J. C. Tetrahedron 1994,
50, 4507±4518. Dolling, U.; Hughes, H.; Bhattacharya, A.;
Ryan, K.; Karady, S.; Weinstock, L.; Grabovski, E. In Phase
Transfer Catalysis, New Chemistry, Catalysis and Appli-
cations, Starks, M., Ed.; ACS Symposium Series: 326,
American Chemical Society: Washington DC, 1987; 326, pp
67±73. O'Donnel, M. J.; Bennet, W.; Wu, Sh. J. Am. Chem.
13. Belokon', Y. K.; Bakhmutov, V. I.; Chernoglazova, N. I.;
Kochetkov, K. A.; Vitt, S. V.; Garbalinskaya, N. S.; Belikov,
V. M. J. Chem. Soc., Perkin Trans. 1 1988, 305±312.