Using the same organocatalyst for asymmetric synthesis of both enantiomers of glutamic acid-derived Ni(II) complexes via 1,4-additions of achiral glycine and dehydroalanine Schiff base Ni(II) complexes

Article abstract of DOI:10.1007/s00726-011-1076-y

(S)- and (R)-BIMBOL were efficient PT catalysts of asymmetric Michael addition of prochiral Ni-PBP-Gly (1) to acrylic esters and malonic esters to Ni-PBP-Δ-Ala (2) correspondingly. The salient feature of the catalysis is opposite configurations of Glu prepared via the two paths with BIMBOL of the same configuration and a perspective novel catalytic procedure for the synthesis of Gla derivatives.

Full text of DOI:10.1007/s00726-011-1076-y

Amino Acids (2012) 43:299–308
DOI 10.1007/s00726-011-1076-y
ORIGINAL ARTICLE
Using the same organocatalyst for asymmetric synthesis
of both enantiomers of glutamic acid-derived Ni(II) complexes
via 1,4-additions of achiral glycine and dehydroalanine Schiff base
Ni(II) complexes
Yuri N. Belokon
Margarita A. Moskalenko
Alan T. Tsaloev Kiryl K. Babievsky
•
Zalina T. Gugkaeva
•
Karine V. Hakobyan
•
•
Victor I. Maleev
•
•
•
Victor N. Khrustalev
Ashot S. Saghyan
•
Received: 27 June 2011 / Accepted: 2 September 2011 / Published online: 21 September 2011
Ó Springer-Verlag 2011
Abstract (S)- and (R)-BIMBOL were efficient PT catalysts
of asymmetric Michael addition of prochiral Ni–PBP–Gly (1)
to acrylic esters and malonic esters to Ni–PBP–D-Ala (2)
correspondingly. The salient feature of the catalysis is oppo-
site configurations of Glu prepared via the two paths with
BIMBOL of the same configuration and a perspective novel
catalytic procedure for the synthesis of Gla derivatives.
DCM
HMDSLi
Gly
Dichloromethane
Lithium hexamethyldisilaside
Glycine
Glu
Glutamic acid
Gla
c-Carboxyglutamic acid
Phase transfer catalysis
PTC
0
TADDOL
(2,2 -Dimethyl-1,3-dioxolan-4,5-
diyl)bis(diphenylmethanol)
0 0
Keywords c-Carboxyglutamic acid ꢀ Glutamic acid ꢀ
Asymmetric organocatalysis ꢀ Michael addition
NOBIN
2 -Amino-[1,1 -binaphthalen]-2-ol
0
0
iso-NOBIN
BINOL
8 -Amino-[1,1 -binaphthalen]-2-ol
0
[1,1 -Binaphthalene]-2,2’-diol
0
Abbreviation
PBP
BIMBOL
3,3 -Bis(hydroxydiphenylmethyl)-
0
0
N-(2-benzoylphenyl)pyridine-2-
carboxamide
[1,1 -binaphthalene]-2,2 -diol
Enantiomeric excess
ee
dr
Ni–PBP–Gly (1)
Ni(II) complex of a Schiff base of
glycine with PBP
Diastereomers ratio
Ni–PBP–D-Ala (2) Ni(II) complex of Schiff base of
dehydroalanine with PBP
MOM
DCE
Methoxymethylene group
Dichloroethane
Introduction
Enantiomerically pure (S)-Glu and its derivatives are very
important physiologically active compounds (Huffman and
Scelly 1963; Smith et al. 2011). Although Glu itself is
produced microbiologically and is a cheap industrial com-
modity (Huffman and Scelly 1963), its enantiomerically
pure derivatives, in particular Gla, are not easily available.
This was a reason why the methods of asymmetric synthesis
of Glu and its derivatives were sought. Presently, several
synthetic protocols have been elaborated based on both
stoichiometric (Williams 1989; Duthaler 1994; Cativiela
Electronic supplementary material The online version of this
article (doi:10.1007/s00726-011-1076-y) contains supplementary
material, which is available to authorized users.
Y. N. Belokon (&) ꢀ Z. T. Gugkaeva ꢀ V. I. Maleev ꢀ
M. A. Moskalenko ꢀ V. N. Khrustalev ꢀ A. T. Tsaloev ꢀ
K. K. Babievsky
Institute of Russian Academy of Sciences, A.N. Nesmeyanov
Institute of Organoelement Compounds, Russian Academy
of Sciences, Vavilov str. 28, 119991 Moscow, Russia
e-mail: yubel@ineos.ac.ru
´
and de DIaz Villegas 1998; Ma 2003) and catalytic versions
(
Maruoka and Ooi 2003; Corey et al. 1998; Vysko cˇ il et al.
002; Belokon et al. 2003; Lygo et al. 2001; N a´ jera and
Sansano 2007; Tsubogo et al. 2010; Kobayashi and
K. V. Hakobyan ꢀ A. S. Saghyan
2
Department of Pharmaceutical Chemistry, Yerevan State
University, A. Manoogian str. 1, 0025 Yerevan, Armenia
123

3
00
Y. N. Belokon et al.
Yamashita 2011) of Michael additions of chiral or achiral
activated Gly derivatives to acrylic acid derivatives. In
particular, some of us developed an asymmetric procedure
of Michael addition of an achiral Ni–PBP–Gly complex (1)
to acrylic esters, (Scheme 1) catalyzed by (R or S)-NOBIN
some CH-acids to cyclohex-2-enone and nitrostyrene
(Belokon et al. 2011). We envisaged that the application of
the catalytic system to the reactions of Scheme 1 could
lead to a novel synthetic protocol for the preparation of
both Glu and Gla.
(
Vysko cˇ il et al. 2002) and (R or S)-iso-NOBIN (Belokon
et al. 2003). Another synthetic path to Glu includes Michael
Herein, we found that (S)- or (R)-BIMBOL were effi-
cient PT catalysts of both reactions, yielding enantiomeri-
cally enriched Glu via both paths. The salient feature of the
catalysis is opposite configurations of Glu prepared via the
two paths with BIMBOL of the same configuration and a
perspective novel catalytic procedure for the synthesis of
Gla.
addition of malonic esters to Ni–PBP–D-Ala (2)
(
Scheme 1) catalyzed by (R, R)-TADDOL earlier devel-
oped by some of us (Belokon et al. 2004). The stereode-
termining stage of path (a) is the C–C bond formation,
whereas that of path (b) is the asymmetric protonation of the
transient carbanionic species. The latter type of asymmetric
catalytic reactions is becoming a popular subject of research
(
Pracejus et al. 1977; Kumar et al. 1991; Emori et al. 1998;
Results and discussion
Fehr 1996; Yanagisawa and Yamamoto 1999; Yanagisawa
et al. 2000; Mu n˜ oz-Mu n˜ iz and Juaristi 2003; Nishimura
et al. 2001; Cheon and Yamamoto 2008; Navarre et al.
Complexes 1 and 2 were prepared as earlier described
(Vysko cˇ il et al. 2002; Belokon et al. 2004). The structure
of 1 was also established and discussed earlier (Vysko cˇ il
et al. 2002). The X-ray structure of 2 (Fig. 1) suggests that
the complex is neutral with the two positive charges at the
central Ni atom neutralized by two negative charges of the
tetradentate PBP ligand. Bond lengths and angles (see
Table in experimental section in supporting information)
2
008), in particular, as applied to amino acid syntheses
(
Tsubogo et al. 2010; Kobayashi and Yamashita 2011;
Belokon et al. 2004; Leow et al. 2008)
Recently, we elaborated a chiral salt of (R or S)-BIM-
BOL (Wang et al. 2007) (see Chart 1) as an efficient
multifunctional catalyst of enantioselective addition of
Scheme 1 Catalytic
asymmetric synthesis
of Glu and Gla
1
23

Synthesis of both enantiomers of Glu-derived Ni(II) complexes
301
Chart 1
Fig. 1 X-ray structure of 2 with two enantiomeric conformations of the complex in crystals
1
Figure 2 illustrates the changes that occur in the H
are similar to those observed for the complexes of that type
Vysko cˇ il et al. 2002).
(
NMR spectra of both (S)-BIMBOL (spectrum A) and 2
(spectrum B) in CDCl when mixed at a 1:1 ratio (spectrum
The salient feature of the complex is chiral puckering of
3
the ligand with two enantiomeric conformations of the
amino acid moieties d and k (Fig. 1, right section, top and
bottom correspondingly), restoring racemic crystal
arrangement in the crystal cell. As a result of the puckering,
the plane of the phenyl substituent at the C=N bond is
skewed relative to the expected perpendicular position
relative to the plane of the bond and equals 107°. Such an
arrangement means shielding of the C=C bond of the
dehydroalanine moiety either from the re or si-side. A
similar situation existed for 1 where it was the glycine
moiety that was chirally shielded, as earlier discussed
C). The most salient features of the spectra are the sig-
nificant shifts of the resonances of both OH protons of
BIMBOL (4.74 and 6.70 ppm) to lower fields (5.08 and
6.89 ppm, respectively) in the 2/BIMBOL mixture.
Simultaneously, a proton of the pyridine moiety of 2 (at
C12, Fig. 1) was shifted to stronger fields (from 8.25 to
8.15 ppm). The observation can be rationalized, assuming
formation of H-bonded complex of BIMBOL and 2. Most
likely, both substances were connected by the BIMBOL
phenol OH group hydrogen bonding with O3 oxygen atom
of 2.
(
Belokon et al. 2003). Evidently, any chiral catalyst capa-
The ability to stabilize a chiral conformation of 2 by
BIMBOL was confirmed by running the CD spectra of the
mixture (Fig. 3). The appearance of a positive Cotton
effect at 548 nm unequivocally supports our notion of
ble of fixing either chiral conformations of the substrate in
the transition state of the reaction would be an effective
asymmetry inducing agent.
123

3
02
Y. N. Belokon et al.
1
Fig. 2 H NMR spectra of (S)-BIMBOL, 2 and a mixture of both at a 1:1 ratio. (from bottom to the top)
BIMBOL ability to shift the equilibrium between the two
enantiomeric conformations of 2. This represented another
case of Pfeiffer effect (Pfeiffer and Quell 1931; Kirshner
et al. 1968). The CD spectra of enantiomerically enriched
complexes 3 (Belokon et al. 2003) indicated that the
positive effect at 536 nm corresponded to (S)-3, which had
the k-conformation of the amino acid chelate ring.
According to X-ray data, the similar complexes of alanine
had the same type of chiral puckering (Belokon et al. 2003)
as 2. Thus, other closely related chiral complexes, such as
3
, can be used as a model to compare their Cotton effects
with those of 2. Evidently, one can assume that (S)-BIM-
BOL stabilized a conformational enantiomer with k-con-
formation of the dehydroalanine moiety in 2 (Fig. 1, right,
bottom structure). Undoubtedly, the strongly basic nega-
tively charged carbanions generated from either 1 or 2 will
be more strongly coordinated by BIMBOL and their con-
formational preferences might be different. However, the
Pfeiffer effect observed in the case of a mixture of 2 and
Fig. 3 CD spectra of a 1:1 mixture of (S)-BIMBOL and 2 (Fig. 2
1
shows the H spectra of the mixture)
The reaction was stopped after 5 min with aqueous
acetic acid and the yield of the Michael adduct estimated
1
by H NMR. The ee of product was assessed using the
(S)-BIMBOL serves as a proof of principle experiments,
supporting our general concept.
optical rotation of the forming complex, as described ear-
lier (Belokon et al. 2003). The values were corroborated by
chiral GLC analysis of the amino acid recovered from the
complex (Table 2, run 9). The results are summarized in
Table 1.
The Michael addition of 1 to methyl acrylate (Scheme 1)
was carried out in DCM at ambient temperature with NaH
as a base and with 10% mol of one of the catalysts presented
in the Chart 1 (Table 1, runs 1–4).
1
23

Synthesis of both enantiomers of Glu-derived Ni(II) complexes
303
Evidently, BIMBOL was the most efficient of the series
of catalysts, affording 60% chemical yield of the product
only 40–50% chemical yield of the Michael adduct and a
meager 1–3% ee after 15 min (Table 2, runs 3, 4). Both ee
and the chemical yields were improved on switching to
HMDSLi and NaH (Table 2, runs 5, 6). Even better
(
Table 1, run 4), whereas the chemical yields were only
0–15% in cases of (R)-BINOL, (R)-MOM-BINOL or (R)-
1
t
MOM-BIMBOL (Table 1, runs 1–3). Some asymmetric
induction was also detected for the BIMBOL catalysis that
was completely absent in other cases.
asymmetric induction was achieved with BuOK and KOH
(Table 2, runs 8, 9 and 14, 15). The maximum ee was 68%
with 10% mol of BIMBOL and one equivalent of KOH
(Table 2, run 14). Further fourfold decrease in the amount
of the catalyst resulted in diminished ee of the product
(Table 2, runs 9, 12, 13). Even more dramatically, the
sense of chirality was reversed when Li or Na cations were
substituted with K cation (Table 2, runs 5 and 6, as com-
pared to 8–10, 12–15). Evidently, both cations and anions
of the base were involved in the stereochemical arrange-
ment of the transition state of the C–C bond formation.
The additions of other activated olefins to 1 were con-
ducted under the optimal conditions of run 14 of Table 2.
The data are summarized in Table 3.
To improve the catalytic performance of BIMBOL, a
series of alkali metal bases was tested under the same cata-
lytic conditions. The results are summarized in Table 2.
Under the conditions, no bis-alkylation products were
detected in the reaction mixture. The reason for this has
been already discussed in our previous paper on 1 alkyl-
ation (Belokon et al. 2003) and, generally, is similar to
the reasoning for rationalizing similar behavior of glycine
ester benzophenone imines, as discussed by O’Donnell
(
O’Donnell et al. 1988). In short, the first alkylation results
in greater puckering of the chelated amino acid moiety in 3,
as compared to the initial 1 (because of the interaction of
the alkyl group in 3 with the phenyl substituent at the C=N
bond). A consequence of it was greater pseudo-equatorial
orientation of the amino acid a-proton in 3, as compared to
those of 1. This results in diminished acidity of 3 relative to
The addition of 1 to other acrylic esters resulted in
somewhat lower enantioselectitvity as compared to methyl
acrylate (Table 2, run 14 and Table 3, runs 1, 2). 1 was added
to methylvinylketone also under the same conditions
(Table 3, runs 3–5). However, the process was accompanied
by racemization of the final product. The notion was sup-
ported by the greater enantiomeric purity of the product in
case of smaller concentrations of the base (Table 3, runs
3–5). The effect could be rationalized by assuming faster
C–C bond formation relative to the racemization of the final
adduct. Thus, at smaller concentrations of the base, it was
easier to detect greater amounts of the unracemized adduct
even at great conversions of 1. The phenomena was already
observed and discussed in the case of NOBIN-catalyzed
addition of 1 to acrylic esters (Belokon et al. 2003). The same
tendency was observed in case of 1 addition to acrylonitrile
1
due to the stereoelectronic effects. Thus, it is the initial 1
and not 3 that produced a sufficient amount of reactive
transient carbanions under the same alkalinity of the
reactive solution. Eventually, this led to the reaction being
effectively stopped at the mono-alkylation step.
The data summarized in Table 2 support the notion of
the paramount importance of the alkali metal ion of the
base on the efficiency of the catalysis.
The performance of the catalytic system increased in the
order Li \ Rb \ Na \ K (Table 2, runs 3–5, 6, 9, 11). Use
of PhOLi and BuLi produced low efficiency catalysts with
n
a
Table 1 Catalyst structure–activity relationship study in the addition of 1 to acrylate
b
Run
Catalysts
Yield (%)
ee (%)
1
2
3
4
a
(R)-BINOL
10
10
15
60
0
(R)-MOM-BINOL
(R)-MOM-BIMBOL
(R)-BIMBOL
-6
0
0
14 (R)
-5
-4
-5
Reaction conditions: catalyst (7.2 9 10 mol), 1 (7.2 9 10 mol), methyl acrylate (4.32 9 10 mol), NaH (7.2 9 10 mol), 1 mL of
DCM, 5 min at ambient temperature under Ar
b
Determined by the optical rotation of the final complex; product configuration in parentheses
123

3
04
Y. N. Belokon et al.
a
Table 2 BIMBOL catalyzed asymmetric addition of 1 to methyl acrylate
b
Base (eq )
b
Catalyst (% mol )
c
Run
Yield (%)
ee (%)
t
1
2
BuOK (1)
No catalyst
70
60
50
40
80
98
95
99
99
60
80
90
90
99
99
99
0
KOH (1)
No catalyst
0
d
3
PhOLi (2)
n
BuLi (0.2)
(R)-BIMBOL (10)
(R)-BIMBOL (10)
(R)-BIMBOL (10)
(R)-BIMBOL (10)
(S)-BIMBOL (10)
(R)-BIMBOL (10)
(S)-BIMBOL (10)
(S)-BIMBOL (10)
(R)-BIMBOL (10)
(S)-BIMBOL (5)
(S)-BIMBOL (2.5)
(S)-BIMBOL (10)
(S)-BIMBOL (10)
(S)-BIMBOL (10)
3 (R)
0
d
4
5
6
HMDSLi (1)
NaH (2)
35 (R)
31 (R)
2 (S)
47 (S)
e
7
NaOH (0.5)
t
BuOK (1)
8
9
t
f
60 (60 ) (R)
BuOK (0.5)
t
10
11
12
13
14
15
16
a
BuOK (0.2)
45 (R)
2 (S)
RbOH(1)
t
BuOK (0.5)
46 (R)
41 (R)
68 (R)
60 (R)
11 (S)
t
BuOK (0.5)
KOH (1)
KOH (0.5)
NaOH (0.5)
g
For the reaction conditions see the footnote to Table 1, unless indicated otherwise
b
Equivalents of the base or mol percent of the catalyst relative to 1
c
Product ee was determined by the optical rotation of the final complex, unless indicated otherwise; product configuration in parentheses
The reaction was conducted for 15 min
d
e
The reaction was conducted for 50 min
f
Determined by chiral GLC analysis on chiral Chirasil-Val columns for the amino acid released from the crude complex
The reaction was carried out at 80°C in DCE
g
a
Table 3 (R)-BIMBOL-catalyzed asymmetric addition of 1 to different acrylates
b
Run
EWG
KOH (eq)
Time (min)
Yield (%)
ee (%)
1
2
–COOMe
1
1
5
99
90
68 (S)
49 (S)
–COOC
4
H
9
60
3
4
5
–COMe
1
8
7
95
95
95
3 (S)
34 (S)
44 (S)
0.5
0.25
90
6
–CN
1
30
30
80
85
25
1 (S)
7 (S)
0
.5
0
.25
120
10 (S)
7
8
a
–CONH
–COOC
2
1
1
20
10
95
95
0
0
4 8
H OH
For the reaction conditions, see the footnote to Table 1, unless indicated otherwise
b
Relative to 1
1
23

Synthesis of both enantiomers of Glu-derived Ni(II) complexes
305
a
Table 4 Catalyst structure–activity relationship study in the case of malonate addition to 2
b
c
Run
Catalyst
Yield (%)
ee (%)
1
2
3
4
a
None
95
[95
[95
[95
-5
–
(R)-BINOL
6 (R)
0
(R)-MOM-BIMBOL
(S)-BIMBOL
23 (S)
-6
-5
The reaction conditions: 10% mol of the catalysts (5.8 9 10 mol), 1 mL of DCM, 5.8 9 10 mol of 2, 1.16 9 10 mol of malonate, 1 eq
of NaH (relative to 2), 5–10 min at an ambient temperature under Ar
b
c
1
Esimated by H NMR
Estimated by the specific rotation at 589 nm of the recovered final adduct. The correctness of the determination was in some cases supported by
the analysis of glutamic acid recovered from the adduct; product configuration in parentheses
a
Table 5 (S)-BIMBOL-catalyzed asymmetric addition of malonic ester to 2
b
c
Run
Base (eq)
Solvent
T (°C)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
BuLi (0.1)
BuLi (0.4)
LiOH (0.5)
NaH (0.5)
NaOH (0.5)
NaOH (0.5)
KOH (0.5)
RbOH (0.7)
DCE
DCE
DCE
DCM
DCM
DCE
DCM
DCM
DCM
80
99
99
99
99
99
99
99
99
99
15
99
99
99
99
99
30 (S)
17 (S)
35 (S)
37 (S)
63 (S)
35 (S)
65 (S)
13 (S)
41 (S)
20 (S)
64 (S)
80
80
20–25
20–25
80
20–25
20–25
20–25
-20
80
9
CsOH 9 H
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.25)
2
O (0.5)
e
10
11
12
13
14
15
a
2 2
CH Cl
Toluene
DCE
80
76 (S)
d
DCM
DCE
25
62/62 (S)
70 (S)
f
f
Mono-K salt of BIMBOL (0.1)
Tetra-K salt of BIMBOL (0.1)
80
DCE
80
80 (S)
For the reaction conditions see the footnote to Table 4, unless indicated otherwise
b
Relative to 2
c
Estimated by the angle of rotation at 589 nm of the recovered final adduct. The correctness of the determination was in some cases supported
by the analysis of glutamic acid recovered from the adduct (see run 13); product configuration in parentheses
d
Determined by chiral GLC analysis of the final glutamic acid recovered from the complex
e
The reaction was run for 8 h
f
The catalyst was prepared by the reaction of metallic potassium with (S)-BIMBOL
(
Table 3, run 6). Probably, greater electron withdrawing
The addition of malonic ester to 2 was promoted by NaH
in DCM at an ambient temperature even without any chiral
catalyst added (Table 4, run 1).
properties of CN group, increasing the racemization rate of
the adduct, led to a very low ee in case of acrylonitrile
addition reactions (Table 3, run 6). Acrylamide also added to
There were practically noasymmetricinductions observed
when 10% mol of (R)-BINOL or (R)-MOM-BIMBOL was
added (Table 4, runs 2, 3). Noticeable ee was detected when
(S)-BIMBOL was employed under the conditions.
1
, but the final product was racemic (Table 3, run 7). Sur-
prisingly, 1 added to d-hydroxybutyl acrylate without any
asymmetric induction (Table 3, run 8).
123

3
06
Y. N. Belokon et al.
Scheme 2 Stereochemical model rationalizing opposite configurations of the adducts formed in case of 1 and 2, as catalyzed by BIMBOL of the
same configuration
a
Table 6 (S)-BIMBOL-catalyzed asymmetric addition of different CH-acids to 2
b
Run
CH-acids
Time (min.)
Yield (%)
ee (%)
t
(COO Bu)
1
2
3
4
5
6
a
CH
CH
CH
2
2
2
2
45
7
90
45 (S)
(COOEt)
(COOMe)
2
[95
[95
[95
[95
85
76 (S)
2
7
83 (S)
Diethyl 2-acetamidomalonate
MeCOCH COOEt
Naphthalen-2-ol
7
(dr 1/9) 61 (S)
(dr 1/4) 88 (S)
0
2
7
80
The reaction conditions: 1 mL of DCE, temperature 80°C, 0.058 mmol of 2, CH-acids 2 eq (relative to 2), ROH 0.5 eq (relative to 2), 10% mol
of a catalyst (S)-BIMBOL
b
Estimated by the angle of rotation at 589 nm of the recovered final adduct; product configuration in parentheses
Scheme 3 Catalytic asymmetric synthesis of derivatives of glutamic acid and 2-hydroxynaphthalen-1-yl-alanine
The data summarized in Table 5 indicate that potassium-
derived bases gave the best induction in case of (S)-BIM-
BOL-catalyzed reaction (Table 5, runs 1–9, 11–15). The
temperature increase from -20 to 25°C and 80°C led to
greater ee of the product, the complex of Gla (Table 5, runs 7,
of the alkali base used (compare Table 2 and 5). In addition,
in the presence of KOH (S)-BIMBOL catalyzed the addition
of 1 to acrylates furnishing the complex of (R)-Glu (Table 2,
runs 9, 10, 12–15), whereas the addition of malonic ester to 2,
catalyzed by (S)-BIMBOL, gave complexes of (S)-Gla
(Table 5, runs 7, 10–14), after hydrolysis of which (S)-Glu
was recovered (Scheme 1).
1
0, 11, 12). The best results were obtained with mono- and
tetra-potassium salts of (S)-BIMBOL (Table 5, runs 14, 15).
The recovery of a protected version of Gla from closely
related chiral BPB copper complexes has been recently
described (Smith et al. 2011) and was not pursued in this
work.
The observation can be rationalized, applying the ste-
reochemical model depicted in Scheme 2.
Hypothetically, chiral BIMBOL might stabilize similar
chiral conformations (see a model chiral conformation of 2
in Fig. 1 and Scheme 2) of the carbanions, derived either
from 1 by the abstraction of its a-proton by KOH or from 2
The salient feature of the condensation was independence
of the sense of the asymmetric induction on the metal cation
1
23

Synthesis of both enantiomers of Glu-derived Ni(II) complexes
307
complexes under PTC conditions. We hope to further
modify the BIMBOL molecule to improve its performance,
and work to this end is ongoing in our laboratory.
Acknowledgments The support of this work by RFBR Grants No.
1
1-03-00206-a and 09-03-00730 is gratefully acknowledged. The
authors thank Prof. K. A. Lyssenko (A. N. Nesmeyanov Institute of
Organoelement Compounds RAS) for performing the X-ray structure
analysis of compound 2 and Dr. M. G. Ezernitskaya for IR studies.
References
Belokon YN, Bespalova NB, Churkina TD, C ´ı sa rˇ ov a´ I, Ezernitskaya
MG, Harutyunyan SR, Hrdina R, Kagan HB, Ko cˇ ovsk y´ P,
Kochetkov KA, Larionov OV, Lyssenko KA, North M, Pol a´ sˇ ek
M, Peregudov AS, Prisyazhnyuk VV, Vyskoil S (2003) Synthe-
sis of a-amino acids via asymmetric phase transfer-catalyzed
alkylation of achiral nickel(II) complexes of glycine-derived
schiff bases. J Am Chem Soc 125:12860–12871
Fig. 4 X-ray structure of 4d
Belokon YN, Harutyunyan S, Vorontsov EV, Peregudov AS,
Chrustalev VN, Kochetkov KA, Pripadchev D, Sagyan AS,
Beck AK, Seebach D (2004) Nucleophilic addition to an achiral
dehydroalanine Schiff base Ni(II) complex as a route to amino
acids. A case of stereodetermining asymmetric protonation in the
presence of TADDOL. ARKIVOC iii:132–150
by the addition of the potassium malonate salt. Thus, the
same si-side (or re-side) of both transient carbanions will
be shielded by the phenyl substituent. It would correspond
to opposite configurations in case of the addition and
protonation (most likely by BIMBOL) in spite of the same
preference of the attack because of the resulted priorities of
the groups in the final chiral compounds. It would imply
the (S)-configuration of the adduct in case of protonation,
leading to Gla complex, and (R)-configuration of Glu in
case of the Michael addition of 1 to acrylate (as depicted in
Scheme 2) or vice versa, depending on which carbanion
conformation was stabilized.
Belokon YN, Gugkaeva ZT, Maleev VI, Moskalenko MA, Tsaloev AT,
Khrustalev VN, Hakobyan KV (2011) Four hydroxyls are better
0
than two. The use of a chiral lithium salt of 3, 3 -bis-methanol-2,
0
2
-binaphthol as a multifunctional catalyst of enantioselective
Michael addition reactions. Tetrahedron Asymmetr 22:167–172
Cativiela C, de D ´ı az Villegas MD (1998) Stereoselective synthesis of
quaternary a-amino acids. Part 1. Acyclic compounds. Tetrahe-
dron Asymmetr 9:3517–3599
Cheon CH, Yamamoto H (2008) A brønsted acid catalyst for the
enantioselective protonation reaction. J Am Chem Soc 130:
Naphthalen-2-ol added to 2 by its a-carbon atom (Fig. 4),
as shown by the X-ray structure analysis of the adduct 4d.
Unfortunately, the product was racemic (Table 6, run 6).
Other nucleophiles also added to 2 under the optimal
conditions in the presence of KOH (see Schemes 1, 3). The
results are summarized in Table 6. The values of ee of the
adduct was inversely dependent on the size of the malonic
ester (Table 6, runs 1–3), increasing from t-butyl malonate
9
246–9247
Corey EJ, Noe MC, Xu F (1998) Highly enantioselective synthesis of
cyclic and functionalized a-amino acids by means of a chiral
phase transfer catalyst. Tetrahedron Lett 39:5347–5350
Duthaler RO (1994) Recent developments in the stereoselective
synthesis of a-aminoacids. Tetrahedron 50:1539–1650
Emori E, Arai T, Sasai H, Shibasaki M (1998) A catalytic michael
addition of thiols to a, b-unsaturated carbonyl compounds:
asymmetric michael additions and asymmetric protonations.
J Am Chem Soc 120:4043–4044
(
45%) to ethyl (76%) and methyl malonates (83%). Diethyl
-acetamidomalonate was also active giving 61% ee of the
Fehr C (1996) Enantioselective protonation of enolates and enols.
Angew Chem Int Ed Engl 35:2566–2587
2
Huffman CW, Scelly WG (1963) Glutamic acid: chemical syntheses
and resolutions. Chem Rev 63:625–644
Kirshner S, Ahmad N, Magnell K (1968) Optical rotatory dispersion
and the Pfeiffer effect in coordination compounds. Coord Chem
Rev 3:201–206
adduct (Table 6, run 4). Ethyl acetylacetate was also active
with 88% ee and dr 1/4 of the product (Table 6, run 5).
Kobayashi S, Yamashita Y (2011) Alkaline Earth metal catalysts for
asymmetric reactions. Acc Chem Res 44:58–71
Conclusion
Kumar A, Salunkhe RV, Rane RA, Dike SY (1991) Novel catalytic
enantioselective protonation (proton transfer) in Michael addi-
tion of benzenethiol to a-acrylacrylates: synthesis of (S)-
naproxen and a-arylpropionic acids or esters. J Chem Soc Chem
Commun 485–486
Leow D, Lin S, Chittimalla SK, Fu X, Tan CH (2008) Enantiose-
lective protonation catalyzed by a chiral bicyclic guanidine
derivative. Angew Chem Int Ed Engl 47:5641–5645
BIMBOL proved to be an efficient catalyst of asymmetric
synthesis of glutamic acid and its derivatives via Michael
addition of achiral glycine Ni-complexes to acrylic esters
under PTC conditions. It was efficient as a catalyst of
asymmetric protonation of the intermediate carbanions
formed by the addition of CH-acids to Ni-dehydroalanine
123

3
08
Y. N. Belokon et al.
Lygo B, Crosby J, Lowdon TR, Peterson JA, Wainwright PG (2001)
Studies on the enantioselective synthesis of a-amino acids via
asymmetric phase-transfer catalysis. Tetrahedron 57:2403–2409
Ma J-A (2003) Recent developments in the catalytic asymmetric
synthesis of a-and b-amino acids. Angew Chem Int Ed Engl
Pracejus H, Wilcke FW, Hanemann
K
(1977) Asymmetrisch
katalysierte Additionen von Thiolen an a-Aminoacryls a¨ ure-
Derivate und Nitroolefine. J Prakt Chem 319:219–229
Smith DJ, Yap GPA, Kelley JA, Schneider JP (2011) Enhanced
stereoselectivity of a Cu(II) complex chiral auxiliary in the
synthesis of Fmoc-l-c-carboxyglutamic acid. J Org Chem
76:1513–1520
Tsubogo T, Kano Y, Ikemoto K, Yamashita Y, Kobayashi S (2010)
Synthesis of optically active, unnatural a-substituted glutamic
acid derivatives by a chiral calcium-catalyzed 1, 4-addition
reaction. Tetrahedron Asymmetr 21:1221–1225
4
2:4290–4299
Maruoka K, Ooi T (2003) Enantioselective amino acid synthesis by
chiral phase-transfer catalysis. Chem Rev 103:3013–3028
Mu n˜ oz-Mu n˜ iz O, Juaristi E (2003) Enantioselective protonation of
prochiral enolates in the asymmetric synthesis of (S)-naproxen.
Tetrahedron Lett 44:2023–2026
N a´ jera C, Sansano JM (2007) Catalytic asymmetric synthesis of
a-amino acids. Chem Rev 107:4584–4671
Navarre L, Martinez R, Genet JP, Darses S (2008) Access to
enantioenriched a-amino esters via Rhodium-catalyzed 1,
Vysko cˇ il S, Meca L, Ti sˇ lerov a´ I, C ´ı sa ˇr ov a´ I, Pol a´ sˇ ek M, Harutyunyan
SR, Belokon YN, Stead RMJ, Farrugia L, Lockhart SC, Mitchell
0
0
WL, Ko cˇ ovsk y´ P (2002) 2, 8 -Disubstituted-1, 1 -binaphthyls: a
new pattern in chiral ligands. Chem Eur J 8:4633–4648
4
1
-addition/enantioselective protonation.
30:6159–6169
J
Am Chem Soc
Wang Q, Chen X, Tao L, Wang L, Xiao D, Yu XQ, Pu L (2007)
Enantioselective fluorescent recognition of amino alcohols by a
chiral tetrahydroxyl 1,1 -binaphthyl compound. J Org Chem
97–101
Williams RM (1989) Synthesis of optically active a-amino acids.
Pergamon Press, Oxford
0
Nishimura K, Ono M, Nagaoka Y, Tomioka K (2001) Catalytic
Enantioselective protonation of Lithium ester enolates generated
by conjugate addition of arylthiolate to enoates. Angew Chem
Int Ed Engl 40:440–442
O’Donnell MJ, Bennett WD, Bruder WA, Jacobsen WN, Knuth K,
LeClef B, Polt RL, Bordwell FG, Mrozack SR, Cripe TR (1988)
Acidities of glycine Schiff bases and alkylation of their
conjugate bases. J Am Chem Soc 110:8520–8525
¨
Pfeiffer P, Quell K (1931) Uber einen neuen Effekt in L o¨ sungen
optisch-aktiver Substanzen. Ber 64: 2667–2671
Yanagisawa A, Yamamoto H (1999) Protonation of Enolates. In:
Jacobsen EN, Pflatz A, Yamamoto H (eds) Comprhensive
asymmetric catalysis. Springer, Heidelberg, pp 1295–1306
Yanagisawa A, Watanabe T, Kikuchi T, Yamamoto H (2000)
Catalytic enantioselective protonation of Lithium enolates with
Chiral imides. J Org Chem 65:2979–2983
1
23