Asymmetric synthesis of (2S,3S)- and (2R,3R)-α,β-dialkyl- α-amino acids via alkylation of chiral nickel(II) complexes of aliphatic α-amino acids with racemic α-alkylbenzyl bromides

Article abstract of DOI:10.1055/s-2008-1067172

This study has demonstrated that the stereochemical outcome of the direct alkylation of nickel(II) complexes derived from chiral Schiff bases of glycine, alanine, 2-aminobutyric acid, and leucine with racemic α-methylbenzyl bromide depends on the steric bulk of the corresponding amino acid residue. In particular, the alkylation of the alanine complex was found to proceed with a synthetically useful level (90% de) of stereoselectivity offering a concise synthesis of enantiomerically pure (2S,3S)- or (2R,3R)-α,α- dimethylphenylalanines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067172

2594
PAPER
Asymmetric Synthesis of (2S,3S)- and (2R,3R)-a,b-Dialkyl-a-amino Acids via
Alkylation of Chiral Nickel(II) Complexes of Aliphatic a-Amino Acids with
Racemic a-Alkylbenzyl Bromides
A
symmetric Synth
a
esis of (2
S
,
d
3
S
)- and (2
R
i
,3
R
)-
a
,
m
b
-Dialkyl-
a
-amino
AcidsA. Soloshonok,* Thomas U. Boettiger, Shawna B. Bolene
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
Fax +1(405)3256111; E-mail: vadim@ou.edu
Received 30 March 2008; revised 28 April 2008
H
O
H
N
O
H
N
O
φ
ω
N
H
φ
ω
N
H
Abstract: This study has demonstrated that the stereochemical out-
come of the direct alkylation of nickel(II) complexes derived from
chiral Schiff bases of glycine, alanine, 2-aminobutyric acid, and
leucine with racemic a-methylbenzyl bromide depends on the steric
bulk of the corresponding amino acid residue. In particular, the
alkylation of the alanine complex was found to proceed with a syn-
thetically useful level (90% de) of stereoselectivity offering a con-
cise synthesis of enantiomerically pure (2S,3S)- or (2R,3R)-a,b-
dimethylphenylalanines.
ψ
ψ
C
N
χ1
C
C
C
C
C
α
α
α
α
α
α
N
H
χ1
O
R'
O
O
H
H
R'
χ2
χ2
χ3
χ3
R
R
R
a
b
c
Figure 1 (a) Depiction of f, y, w, and c dihedral angles for amino
acid residues in peptides; (b) Restriction of f, y, w, angles by a-sub-
stitution; (c) restriction of c angles by b-substitution
Key words: sterically constrained amino acids, alkylation, asym-
metric synthesis, kinetic resolution
O
OH
R
O
O
R
R'
R"
X
+
H2N
In the post-genomic era, the medicine-related sciences are
currently exploring unprecedented opportunities in devel-
oping new approaches for detecting and treating human
health disorders and diseases. It is expected that the infor-
mation provided by the human genome sequence will rev-
olutionize various multidisciplinary research fields, in
particular, the rational design and synthesis of proteins,
peptides, and tailor-made amino acids.1–5 It is well estab-
lished that incorporation of tailor-made amino acids, in
particular sterically constrained derivatives, in a peptide
can allow for efficient alteration of the peptide’s native
secondary and/or tertiary structure by inducing specific
conformations.5–8 In this regard, a,b-dialkyl substituted a-
amino acids represent the least studied yet potentially
most powerful and important class of such tailor-made
sterically constrained amino acids.8–10 It has been demon-
strated that rational manipulation of the steric properties
of the a- and b-alkyl groups in such amino acids might al-
low for a rational simultaneous control of the peptide
backbone dihedral angles f (phi), y (psi), and w (omega),
and most importantly, the torsional angles (chi) c1, c2,
etc., determining the position of side-chain functional
groups (Figure 1).5–7 Taking into account that all these di-
hedral and torsional angles are of paramount importance
in determining the conformation of peptides, incorpora-
tion of these sterically constrained amino acids into pep-
tides might allow for a rational design of peptides with a
presupposed three-dimensional structure.5–7,11
Hal
racemic
N
Y
R"
R'
enantiomerically
pure at both stereogenic
centers
X, Y = protecting groups containing
chiral auxiliary
Scheme 1 Alkylation of chiral derivatives of a-amino acids with ra-
cemic sec-alkyl halides
Analysis of the relevant literature5,6,9–11 revealed that syn-
thesis of the enantiomerically pure a,b-dialkyl substituted
a-amino acids is virtually undeveloped. It is interesting to
note that structurally less complicated either a- or b-
monoalkyl substituted a-amino acids are readily available
by the recently developed quite synthetically efficient cat-
alytic and stoichiometric asymmetric approaches, most
notably represented by the work of Shibasaki,12 Maruoka
and Ooi,13 and Ohfune.14 In contrast, only a single method
reported by Davis allows for the preparation of a,b-di-
alkyl substituted a-amino acids in optically pure form via
a tedious multistep procedure starting from enantiomeri-
cally pure 2H-azirine-2-carboxylate esters.15
As one can envision, methodologically more straightfor-
ward and concise approach to the target a,b-dialkyl sub-
stituted a-amino acids might be realized via direct
alkylation of chiral derivatives of a-amino acids with ra-
cemic sec-alkyl halides (Scheme 1).
Feasibility of this approach was demonstrated by Seebach
and Hruby via alkylation of chiral glycine and alanine
equivalents BMI (1-Bz-, 1-Boc-, 1-Z- or 1-formyl-2-tert-
butyl-3-methyl-4-imidazolidinones) with racemic 1-(phe-
nyl)ethyl bromide (rac-5). The reactions were conducted
at low temperatures (–60 °C, –78 °C), and the correspond-
ing alkylation products were obtained in moderate to good
SYNTHESIS 2008, No. 16, pp 2594–2602
x
x.
x
x
.
2
0
0
8
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067172; Art ID: M01808SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of (2S,3S)- and (2R,3R)-a,b-Dialkyl-a-amino Acids
2595
O
Ph
H
N
OH
OH
Ref. 20
>95%
Ref. 20
>95%
N
H
N
N
O
O
O
Ph
Ph
(S)-1
(S)-2
(S)-3
Ni(NO2)2⋅6H2O
MeOH/NaOH
amino acid
>95%
Ph
N
N
O
N
O
R
1) HCl/MeOH
2) Dowex/NH4OH
R
COOH
Ni
recycled ligand (S)-3
(95% recovery)
+
O
NH2
target amino acid
Ph
4a–d
R = H (a), Me (b), Et (c), i-Bu (d)
Scheme 2
chemical yields (58–82%) and in respectable diastereo- inert atmosphere, rigorously dried and degassed solvents,
meric purity (80–85% de).16 Taking into account the po- air- or moisture-sensitive reagents and low temperatures.
tential synthetic value of this approach allowing for Another advantage of this design is that, in principle, any
straightforward preparation of enantiomerically pure a,b- other amino acid can be used instead of glycine for prepar-
dialkyl substituted a-amino acids, further investigation of ing the corresponding complexes of higher amino acids
the corresponding alkylation reactions between other under the standard reaction conditions. Thus complexes
chiral equivalents of amino acids and racemic sec-alkyl derived from glycine 4a, alanine 4b, a-aminobutyric acid
halides might be of great interest to develop a generalized 4c, and leucine 4d (Scheme 2) were prepared in high
and convenient synthesis of this virtually unknown and chemical yields simply by heating a methanolic solution
unstudied type of sterically constrained amino acids.
of ligand 3 and the corresponding amino acid in the pres-
ence of Ni(NO2)2·6H2O and NaOH. The alanine complex
4b was isolated and used for the alkylation as a mixture of
(S)(2S)- and (S)(2R)-diastereomers, while the complexes
4c,d, containing bulkier substituents, were obtained in
diastereomerically pure form.
Here we report a full account17 of our studies on the reac-
tions between chiral Ni(II) complexes of glycine (S)-4a,
alanine (S)(S,R)-4b, (S)(S,R)-a-aminobutyric acid 4c, and
(S)(S,R)-leucine 4d (Scheme 2) with bromide rac-5, and
provide a mechanistic rationale for the observed stereo-
chemical outcome.
Among the numerous chiral equivalents of a nucleophilic
glycine developed in the recent 25 plus years10,18 for gen-
eral asymmetric synthesis of a-amino acids, the N-benzyl-
proline-derived Ni(II) complex 4a, introduced by
Belokon19 represents one of the most successful designs.
Seemingly low atom economy of complex 4a, as a pro-
tected glycine derivative, is profoundly misleading as the
chiral ligand 3 can be quantitatively recovered and reused,
rendering the whole process as synthetically, practically,
and economically efficient as any catalytic process in
terms of chiral auxiliary consumption and cost of the final
products. Recently we reported a convenient procedure
for the large-scale synthesis of N-benzylproline 2, its
transformation to ligand 3, and preparation of the glycine
complex 4a.20 Practical asymmetric syntheses of various
a-amino acids using the glycine equivalent 4a is well doc-
umented by Belokon,21,22 our,22,23 and other24 groups. An
apparent synthetic advantage of complex 4a over other
chiral glycine equivalents is that it can be efficiently
(>90% de, >90 yield) homologated via alkyl halide alky-
lation, aldol and Michael addition reactions under opera-
tionally convenient conditions, that is, without recourse to
Alkylation of Complexes 4a–d with rac-5
The alkylation reactions (Scheme 3) of complexes 4a–d
with rac-5 were carried out under our standard conditions
using a three-fold excess of rac-5, commercial grade
DMF as a solvent, and powdered NaOH as a base. The re-
action temperature was varied to study its influence on the
stereochemical outcome. The results obtained are summa-
rized in Table 1. The alkylation of the glycine complex
4a, conducted at room temperature, occurred at a high rate
giving rise to a mixture of two major diastereomeric prod-
ucts (S)(2S,3R)-6a and (S)(2S,3S)-7a in a ratio of 1.2:1
(entry 1). Besides the major diastereomers 6a and 7a, up
to 20% of two a-R configured products were also detected
in the crude reaction mixture. Lowering the reaction tem-
perature expectedly decreased the rate of the alkylation
(entries 2, 3 vs. 1), however, the diastereoselectivity was
not markedly improved. Slow reaction rates brought about
formation of some by-products (up to 10%) lowering the
yield of the target products. We also tried the phase-trans-
fer conditions for the alkylation of the glycine complex 4a
Synthesis 2008, No. 16, 2594–2602 © Thieme Stuttgart · New York

2596
V. A. Soloshonok et al.
PAPER
Ph
Ph
Ni
Ph
Ni
Me
Ph
N
N
O
N
O
R
N
N
N
N
O
N
O
R
O
N
O
R
Br
rac-5
Ni
Ph
Ph
+
O
O
O
Me
Me
Ph
Ph
Ph
(S)-4a–d
(S)(2S,3R)-6a–d
(S)(2S,3S)-7a–d
R = H (a), Me (b), Et (c), i-Bu (d)
1) HCl/MeOH
2) Dowex/NH4OH
from 7b
from 6a
91%
Ni(NO2)2⋅6H2O
MeOH/NaOH
amino acid (R)
93%
O
Ph
Me
Me
Me
H
N
COOH
NH2
(2S,3R)-8a
Ph
Ph
COOH
NH2
N
O
Ph
(2S,3S)-9b
(S)-3
Scheme 3
Table 1 Reactions of Complexes 4a–d with rac-5a
with bromide rac-5. In this case (entry 4), the reaction
conducted at room temperature proceeded at a substantial-
ly slower rate resulting, however, in a clean formation of
diastereomers 6a and 7a in a ratio of 1.5:1, the same as the
stereochemical outcome of the alkylation carried out at
0 °C under the homogeneous conditions (entry 4 vs. 2).
Complexes 6a and 7a were easily isolated in diastereo-
merically pure form by column chromatography on silica
gel. Complex 6a was disassembled, under standard condi-
tions, to afford enantiomerically pure (2S,3R)-b-methyl-
phenylalanine (8a) (Scheme 3).
Entry
4a–d
Temp
(°C)
Time
(min)
Yield (%)b Ratio of 6/7c
1
2
a
a
a
a
b
b
b
c
25
0
10
25
95
84
89
96
96
90
94
87
87
–
1.2:1
1.5:1
1.9:1
1.5:1
1:4.0
1:6.5
1:20.0
1:1.6
1:1.7
–
3
–15
25d
25
0
75
4
240
70
5
In sharp contrast to the reactions of the glycine complex
4a, the alkylation of the alanine derivative 4b with rac-5,
conducted at room temperature, occurred with apprecia-
ble diastereoselectivity (entry 5). Moreover, the formation
of the a-R configured products was substantially reduced
(<5%) allowing direct isolation of the major product
(S)(2S,3S)-7b in good (75%) chemical yield. Once again,
in contrast to the alkylation of the glycine complex 4a,
lowering the reaction temperature lead to a noticeable in-
crease in the diastereoselectivity (entries 6, 7 vs. 2, 3).
Thus, the reaction conducted at –15 °C gave rise to the
major diastereomer 7b with synthetically useful (entry 7)
6
110
180
90
7
–15
25
0
8
9
c
210
540
180
480
10
11
12
c
–10
25
0
d
d
81
–
1:1.7
–
a All reactions were run in commercial grade DMF under N2.
stereoselectivity. Taking into account that in this reaction b Combined yield of all diastereomeric products.
c Ratio of diastereomeric products (S)(2S,3R)-6/(S)(2S,3S)-7 was de-
we used the racemic alkyl halide 5 for alkylation of the
diastereomeric mixture of the alanine complex 4b, the ob-
tained stereochemical outcome of >90% de was truly
remarkable. Decomposition of the complex 7b afforded
the enantiomerically pure a,b-dimethylphenylalanine
(9b) (Scheme 3), which is not directly available by the lit-
erature methods.
termined on the crude reaction mixtures by 1H NMR spectra (500
MHz). In particular, characteristic and well-separated signals of aro-
matic protons in the region 8.00–8.25 ppm were used for the determi-
nation.
d The reaction was conducted under phase-transfer conditions.
and (S)(2S,3S)-7c in a low ratio of 1:1.6 (entry 8). At-
tempts to improve the stereochemical outcome by lower-
ing the reaction temperature were unsuccessful. Thus, the
reaction conducted at 0 °C gave virtually the same ratio of
the diastereomers as was observed in the room tempera-
ture reaction (entry 9 vs. 8), while the alkylation at –10 °C
was too sluggish (entry 10) to isolate the products in
With these encouraging results, we next studied the alky-
lations of complexes 4c,d, assuming that bulkier ethyl
and, in particular, isobutyl groups might allow for in-
creased stereoselectivity. Surprisingly, the alkylation of
the ethyl-containing 4c with rac-5 occurred at a notice-
ably slower rate giving rise to a mixture of (S)(2S,3R)-6c
Synthesis 2008, No. 16, 2594–2602 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of (2S,3S)- and (2R,3R)-a,b-Dialkyl-a-amino Acids
2597
amount suitable for reliable determination of the stere- the corresponding amino acids in 6c,d and 7c,d was as-
ochemical outcome. Even slower reaction rates and lower signed as 2S. Absolute configuration of the b-stereogenic
stereoselectivity were observed in the alkylation of the centers of the amino acids in 6c,d and 7c,d was made con-
1
leucine-derived complex 4d (entries 11, 12), indicating sidering clear similarity of their H NMR spectra with
1
that an increase in the steric bulk of the amino acid residue those registered for 6a,b and 7a,b. Thus, in all H NMR
interferes with the reactivity of the Ni(II) complexes and spectra of 2S,3R-configured products 6a,b the doublet of
stereoselectivity of the alkylation.
the b-methyl appears at the expected 1.15–1.20 ppm,
while in the spectra of products 7a–d of 2S,3S absolute
configuration, the doublet of the b-methyl group is shifted
downfield to the region of 2.00–2.20 ppm. As shown in
the previous work,21–23 such downfield shift is character-
Assignment of the Absolute Configuration
The absolute configuration of products 6a–d, 7a–d, and 8, istic for the alkyl groups situated directly under the Ni(II)
9 was assigned using chiroptical properties of the prod- atom. On the other hand, in the 1H NMR spectra of 2S,3R-
ucts, 1H NMR patterns, and correlations with literature da- diastereomers 6a–d, in which the phenyl of the side chain
ta. The absolute configuration of the a-stereogenic carbon is located under the Ni(II) atom, one of the g-protons of
of the corresponding amino acid residues in all Ni(II) the proline ring is shifted about 0.5–0.6 ppm upfield, due
complexes can be easily assigned on the basis of their op- to the effect of the diamagnetic ring current of the phe-
tical rotation. As it has been established in numerous stud- nyl.26
ies of the Ni(II) complexes of this type derived form
various amino acids,25 the complexes containing a-S con-
figured amino acids have a positive sign of optical rota-
tion with magnitude ranging from +1500 to +3000, while
Rationale for the Stereochemical Outcome
the complexes containing amino acids of a-R absolute Explanation of the observed stereochemical outcome in
configuration show the negative sign of –1000 to –2000. the alkylation reactions under study, can be divided into
Thus products 6a and 7a, obtained in the alkylation of the three separate major questions: 1) in the reaction of the
glycine complex 4a, showed optical rotations of +1980 glycine complex 4a with rac-5, why is the (S)(2S,3R)-
and +2350, suggesting that both contained residues of b- configured diastereomer 6a preferred over the (S)(2S,3S)-
methylphenylalanine of a-S absolute configuration. The 7a one; 2) why does the alkylation of the alanine complex
relative configuration of the amino acid residue in 6a and 4b show overwhelming preference for the opposite
7a was assigned based on their 1H NMR spectra. Thus, in (S)(2S,3S)-stereochemistry giving rise to the diastereomer
6a the a-proton at 4.12 ppm appears as a doublet with 7b in synthetically useful chemical yield; and 3) why does
JaH,bH = 3.0 Hz, while in the 1H NMR spectrum of 7a the the further increase in the steric bulk of the amino acid
a-proton at 4.06 ppm is a doublet with JaH,bH = 6.0 Hz. A side chain, the reactions of the complexes 4c,d with rac-
comparison of these chemical shifts and coupling con- 5, result in an unexpected decrease in diastereoselectivity?
stants with the literature data26 reported for the diastereo- As an approach to the mechanistic rationale for the stereo-
meric Ni(II)-complexes containing (2S,3R)- and (2S,3S)- chemical preferences observed, we constructed all six the-
3-phenylglutamic acids reveals very close similarity, sug- oretically possible transition states (TSs), representing the
gesting that product 6a has 2S,3R and 7a 2S,3S absolute interactions between the si-face of the corresponding eno-
configuration. These assignments are also in perfect ac- late and the S- and R-enantiomers of the bromide 5
cord with the optical and physicochemical properties re- (Figure 2). Based on the substantial experimental data and
corded for the free amino acids 8 obtained from complex mechanistic rationale for the stereochemical preferences
6a, which showed sign and magnitude of optical rotation we previously obtained in the Michael addition reactions
as well as 1H NMR pattern matching the literature data re- of complex 4a and its analogues with (S)- or (R)-3-(E-
ported for the (2S,3R)-b-methylphenylalanine.27
enoyl)-4-phenyl-1,3-oxazolidin-2-ones,28 we can rule out
the possibility of TSs B and D formation, since the phenyl
group cannot be sterically accommodated directly under
the nickel. Formation of the TSs C and E, in which the
phenyl group points toward the ketimine phenyl, also
seems to be unlikely due to the apparent steric repulsive
interactions between these two phenyl groups. Therefore,
we can assume that TSs A and F, which allows for mini-
mization of all steric interactions, might be the most plau-
sible candidates. Considering the steric interaction of the
methyl group in the reaction of the glycine complex 4a
(R = H), we can conclude that TS F should be more ther-
modynamically favorable than TS A. Thus, in TS F the
methyl interacts with the enolate hydrogen and nitrogen,
while in TS A the methyl is located between the enolate
oxygen and nitrogen. Accordingly, the observed prefer-
The absolute configuration of the complexes 6b and 7b,
containing residue of the a,b-(dimethyl)phenylalanine
was assigned as a-S on the basis of their positive optical
rotations (+2254 and +2095, respectively). The configura-
tion of the b-stereogenic carbon of the amino acid residue
was determined by comparison of the chiroptical and 1H
NMR data recorded for free amino acid 9, obtained from
complex 7b, with those reported in the literature for
(2S,3S)-a,b-dimethylphenylalanine.15b Finally, the abso-
lute configuration of the amino residues in complexes
6c,d and 7c,d was determined based on their chiroptical
1
properties as well as pattern of H NMR spectra. Since
products 6c,d and 7c,d showed positive optical rotation,
the absolute configuration of the a-stereogenic carbon of
Synthesis 2008, No. 16, 2594–2602 © Thieme Stuttgart · New York

2598
V. A. Soloshonok et al.
PAPER
Transition states A–C leading to the products of (2S,3S) configuration
Na
O
Na
O
Na
O
O
H
O
O
Ni
Me
Ni Me
Ph
Ni
H
Ph
N
N
R
R
N
R
N
N
N
Ph
Me
H
C
A
B
Transition states D–F leading to the products of (2S,3R) configuration
Na
O
Na
Na
O
O
H
O
O
O
Ni
Ph
Ni
Me
Ni Me
H
Ph
N
N
N
R
R
R
N
N
N
Me
Ph
H
F
D
E
Figure 2 Transition states A–F in the reactions between complexes 4a–d and rac-5
ence of about 2:1 of the 2S,3R-diastereomer can be rea- Unless otherwise noted, all reagents and solvents were obtained
from commercial suppliers and used without further purification.
sonably accounted for on the basis of steric interactions in
TSs A and F. When the R group is Me, the reactions of the
alanine complex 4b with bromide 5, the mode of the ste-
reochemical preferences in TSs A and F is reversed. Thus,
All the reactions were carried out under atmosphere without any
1
special caution to exclude air. Optical rotations, H and 13C NMR
spectra were taken in CDCl3 solutions at 299.95 and 75.42 MHz, re-
spectively, on instruments available in the University of Oklahoma
in the enolate derived from the glycine complex the hy-
drogen is the smallest substituent, while for alanine the
methyl is the largest group of the corresponding enolate
moiety. Considering the TSs A and F, we can expect that
the TS F might be significantly disfavored relative to TS
A, thus accounting for the observed high 2S,3S-diastereo-
selectivity. Finally, we can suggest that an increase in the
steric bulk of the substituent R might interfere with the
formation of both TSs A and F. Thus, substitution of the
methyl (alanine complex 4b) for ethyl (4c) or isobutyl
(4d) might lead to increased repulsive steric interactions
with the Ni(II) complex ketimine phenyl, as well as with
the phenyl group of the incoming electrophile, disfavoring
the formation of both TSs A and F. This detrimental effect
NMR Spectroscopy Laboratory. Chemical shifts refer to TMS as
the internal standard. Yields refer to isolated yields of products
1
greater than 95% purity as estimated by H, 13C NMR, and high-
resolution mass spectrometry (HRMS-ESI).
Complexes 4a,b were prepared according to the literature proce-
dure.20 For preparing new complexes 4c,d the same procedure was
followed except that rac-2-aminobutyric acid and (S)-leucine were
used in the place of glycine or alanine.
Ni(II) Complex 4c of the Schiff Base of (S)-BPB {[(S)-o-[N-(N-
Benzylprolyl)amino]benzophenone} with (S)-2-Aminobutyric
Acid
Rf = 0.25 (acetone–hexanes, 1:1); mp 290–291 °C; [a]D25 +2565 (c
0.144, CHCl3).
1H NMR (CDCl3): d = 1.36 (3 H, t, J = 6.9 Hz), 1.50–2.23 (5 H, m),
of the substituents bulkier than methyl on the formation of 2.48–2.60 (1 H, m), 2.69–2.85 (1 H, m), 3.42–3.58 (2 H, m), 3.60,
the TS seems quite plausible to account for the low reac-
4.45 (2 H, AB, J = 12 Hz), 3.85–3.93 (1 H, m), 6.60–7.55 (11 H, m),
8.04 (2 H, d, J = 7.2 Hz), 8.15 (1 H, d, J = 7.5 Hz).
tivity and diastereoselectivity observed in the reactions of
HRMS: m/z calcd for C29H29N3NiO3 [M + H]+: 526.1614; found:
complexes 4c,d with bromide rac-5.
526.1652.
In summary, this study has demonstrated that the stere-
ochemical outcome of the direct alkylation of Ni(II) com-
plexes derived from chiral Schiff bases of glycine 4a,
alanine 4b, 2-aminobutyric acid 4c and leucine 4d with ra-
cemic a-methylbenzyl bromide (5) dramatically depend-
ed on the steric bulk of the amino acid residue. In
particular the reaction of the alanine complex 4b, was
found to proceed with a high level (90% de) of stereose-
lectivity offering a methodologically advantageous ap-
proach for preparing enantiomerically pure (2S,3S)- or
(2R,3R)-a,b-dimethylphenylalanine, depending on the
(S)- or (R)-proline containing starting Ni(II) complex 4b.
Ni(II) Complex 4d of the Schiff Base of (S)-BPB with (S)-Leu-
cine
Rf = 0.35 (acetone–hexanes, 1:1); mp 254–257 °C; [a]D25 +2448 (c
0.175, CHCl3).
1H NMR (CDCl3): d = 0.33 (3 H, d, J = 6.6 Hz), 0.86 (3 H, d, J = 6.6
Hz), 1.29–1.41 (1 H, m), 1.85–2.28 (3 H, m), 2.42–2.62 (2 H, m),
2.68–2.81 (1 H, m), 3.43–3.51 (2 H, m), 3.55, 4.45 (2 H, AB,
J = 12.6 Hz), 3.61–3.80 (1 H, m), 3.88 (1 H, dd, J = 10.8, 7.2 Hz),
6.59–6.69 (2 H, m), 6.90–6.96 (1 H, m), 7.08–7.54 (8 H, m), 8.05 (3
H, d, J = 7.2 Hz).
HRMS: m/z calcd for C31H33N3NiO3 [M + Na]+: 576.1773; found:
576.1757.
Synthesis 2008, No. 16, 2594–2602 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of (2S,3S)- and (2R,3R)-a,b-Dialkyl-a-amino Acids
2599
Alkylation of Complexes 4a–d with rac-5; General Procedure
Powdered NaOH (100 mmol, 10 equiv) was added to a solution of
Ni(II) complex 4a–d (10 mmol, 1 equiv) in DMF (20 mL) under
stirring. Then, the bromide rac-5 (25 mmol, 3 equiv) dissolved in
DMF (5 mL) was added to the solution. The mixture was stirred un-
der N2 and the reaction progress was monitored by TLC. Upon com-
pletion [complete consumption of the Ni(II) complex], the mixture
was poured over ice, and the precipitated material was collected by
filtration and dried in vacuo. A small amount of the crude mixture
was used to determine the diastereomeric ratio of the products, the
rest was subjected to column chromatography on silica gel using
acetone–hexanes (1:1) as an eluent to isolate the diastereomerically
pure products.
130.0, 130.3, 132.0, 132.1, 132.9, 134.0, 134.4, 141.4, 143.4, 171.0,
177.2, 182.0.
HRMS: m/z calcd for C35H33N3NiO3 [M + Na]+: 624.1773; found:
624.1772.
Ni(II) Complex (S)(2S,3R)-6b of the Schiff Base of (S)-BPB with
(2S,3R)-2,3-Dimethylphenylalanine
Rf = 0.43 (acetone–hexanes, 1:1); mp 121–123 °C; [a]D25 +2254 (c
0.178, CHCl3).
1H NMR (CDCl3): d = 1.15 (s, 3 H), 1.43 (3 H, d, J = 7.0 Hz), 1.49–
1.56 (1 H, m), 1.94–2.03 (2 H, m), 2.11–2.22 (2 H, m), 3.02–3.05 (1
H, m), 3.25 (1 H, dd, J = 7.9, 9.3 Hz), 3.48 (1 H, d, J = 12.6 Hz),
3.47–3.51 (1 H, m), 4.27 (1 H, d, J = 12.6 Hz), 6.54–6.60 (2 H, m),
7.03–7.05 (1 H, m), 7.07–7.09 (1 H, m), 7.10–7.16 (1 H, m), 7.27–
7.51 (11 H, m), 8.01 (2 H, d, J = 7.1 Hz), 8.22 (1 H, d, J = 8.4 Hz).
13C NMR (CDCl3): d = 16.3, 22.9, 28.0, 30.2, 48.8, 57.3, 63.8, 69.9,
81.3, 120.1, 122.9, 127.1, 127.3, 127.6, 127.7, 127.8, 128.6, 129.2,
129.6, 130.9, 131.5, 131.8, 133.4, 133.9, 137.3, 142.3, 142.5, 171.8,
179.7, 180.3.
Ni(II) Complex (S)(2S,3R)-6a of the Schiff Base of (S)-BPB with
(2S,3R)-3-Methylphenylalanine
Rf = 0.36 (acetone–hexanes, 1:1); mp 253–258 °C; [a]D25 +1980 (c
0.15, CHCl3).
1H NMR (CDCl3): d = 1.145 (3 H, d, J = 7.5 Hz), 1.35–1.49 (1 H,
m), 1.71–1.87 (1 H, m), 1.89–1.98 (1 H, m), 2.17–2.27 (2 H, m),
2.74–2.91 (2 H, m), 3.25 (1 H, t, J = 8.7 Hz), 3.40, 4.24 (2 H, AB,
J = 12.8 Hz), 4.12 (1 H, d, J = 3.3 Hz), 6.63–6.74 (2 H, m), 7.01–
7.05 (1 H, m), 7.09–7.17 (2 H, m), 7.23–7.34 (3 H, m), 7.36–7.58 (8
H, m), 7.97 (2 H, d, J = 6.9 Hz), 8.27 (1 H, d, J = 8.7 Hz).
HRMS (FAB): m/z calcd for C36H35N3O3Ni [M + H]+: 616.2110;
found: 616.2106.
Ni(II) Complex (S)(2S,3S)-7b of the Schiff Base of (S)-BPB with
(2S,3S)-2,3-Dimethylphenylalanine
HRMS: m/z calcd for C35H33N3NiO3 [M + H]+: 602.1954; found:
602.1956.
Rf = 0.36 (acetone–hexanes, 1:1); mp 277–279 °C; [a]D25 +2095 (c
0.125, CHCl3).
1H NMR (CDCl3): d = 0.67 (3 H, s), 1.66 (3 H, d, J = 6.7 Hz), 2.08–
2.13 (1 H, m), 2.18–2.23 (1 H, m), 2.63–2.73 (1 H, m), 2.99–3.06 (1
H, m), 3.41–3.50 (1 H, m), 3.52–3.56 (3 H, m), 4.45 (1 H, d,
J = 12.7 Hz), 4.85 (1 H, d, J = 7.7 Hz), 6.09–6.13 (1 H, m), 6.30–
6.32 (1 H, m), 6.48–6.51 (1 H, m), 6.83–6.87 (1 H, m), 7.00–7.03 (1
H, m), 7.07–7.11 (2 H, m), 7.17–7.33 (9 H, m), 8.13 (2 H, d, J = 7.2
Hz), 8.21 (1H, d, J = 8.7 Hz).
13C NMR (CDCl3): d = 16.7, 20.6, 23.1, 30.5, 52.8, 56.6, 63.0, 70.6,
81.9, 120.0, 122.2, 125.9, 126.8, 127.0, 127.1, 127.6, 128.0, 128.3,
128.4, 128.5, 129.2, 129.6, 131.0, 131.5, 133.1, 133.5, 135.7, 139.6,
141.4, 169.7, 178.5, 179.4.
Ni(II) Complex (S)(2S,3S)-7a of the Schiff Base of (S)-BPB with
(2S,3S)-3-Methylphenylalanine
Rf = 0.31 (acetone–hexanes, 1:1); mp 213–216 °C; [a]D25 +2350 (c
0.15, CHCl3).
1H NMR (CDCl3): d = 2.00 (3 H, d, J = 7.2 Hz), 2.05–2.23 (2 H, m),
2.53–2.69 (1 H, m), 2.87–2.98 (1 H, m), 3.46–3.58 (3 H, m), 3.58,
4.45 (2 H, AB, J = 12.8 Hz), 3.73–3.84 (1 H, m), 4.06 (1 H, d,
J = 6.0 Hz), 6.20 (1 H, d, J = 7.8 Hz), 6.51–6.56 (1 H, m), 6.58–6.65
(1 H, m), 6.66–6.73 (2 H, m), 7.04–7.33 (9 H, m), 7.42–7.49 (2 H,
m), 8.04 (2 H, d, J = 7.2 Hz), 8.22 (1 H, d, J = 8.7 Hz).
13C NMR (CDCl3): d = 16.3, 23.4, 30.8, 45.4, 56.7, 63.1, 70.5, 76.2,
120.5, 123.0, 126.3, 126.8, 127.5, 127.8, 128.2, 128.3, 128.7, 128.8,
129.4, 131.4, 132.2, 133.1, 133.5, 133.6, 140.9, 142.1, 170.6, 176.9,
180.1.
HRMS (FAB): m/z calcd for C36H35N3O3Ni [M + H]+: 616.2110;
found 616.2106.
HRMS: m/z calcd for C35H33N3NiO3 [M + H]+: 602.1954; found:
602.1951.
Ni(II) Complex (S)(2S,3R)-(6c) of the Schiff Base of (S)-BPB
with (2S,3R)-2-Ethyl-3-methylphenylalanine
Rf = 0.40 (acetone–hexanes, 1:1); mp 216–222 °C; [a]D25 +1492 (c
0.204, CHCl3).
1H NMR (CDCl3): d = 0.98 (3 H, t, J = 7.2 Hz), 1.251 (3 H, d,
J = 7.2 Hz), 1.41–1.55 (2 H, m), 1.66–1.81 (1 H, m), 1.85–1.95 (1
H, m), 1.97–2.23 (3 H, m), 2.87–2.97 (1 H, m), 3.21 (1 H, dd,
J = 9.3, 7.7 Hz), 3.37, 4.11 (2 H, AB, J = 12.3 Hz), 3.48 (1 H, q,
J = 7.2 Hz), 6.49–6.62 (2 H, m), 7.04–7.11 (1 H, m), 7.13–7.20 (1
H, m), 7.24–7.34 (4 H, m), 7.41–7.53 (8 H, m), 8.02 (1 H, d, J = 8.4
Hz), 8.13 (2 H, d, J = 6.9 Hz).
13C NMR (CDCl3): d = 0.2, 9.8, 16.0, 22.9, 30.1, 30.4, 45.8, 57.9,
64.4, 70.7, 86.1, 120.1, 123.2, 127.0, 127.1, 127.6, 128.0, 128.1,
128.3, 128.4, 128.5, 129.2, 129.4, 131.2, 131.3, 133.4, 134.0, 137.0,
142.0, 143.2, 171.1, 179.1, 180.0.
HRMS: m/z calcd for C37H37N3NiO3 [M + H]+: 630.2267; found
630.2256.
Besides the major products 6a and 7a, the a-R configured diastereo-
mer was isolated in up to 20% yield. The (S)(2R,3S) absolute con-
figuration was determined by its conversion to the corresponding
(S)(2S,3S)-7a by the a-epimerization under the action of NaOH in
DMF.
Ni(II) Complex of the Schiff Base of (S)-BPB with (2R,3S)-3-
Methylphenylalanine
Rf = 0.44 (acetone–hexanes, 1:1); mp 207–213 °C; [a]D25 –1996 (c
0.122, CHCl3).
1H NMR (CDCl3): d = 0.82–0.98 (1 H, m), 1.18 (3 H, d, J = 7.2 Hz),
1.25–1.42 (1 H, m), 1.78–1.88 (1 H, m), 1.98–2.15 (1 H, m), 2.42–
2.53 (1 H, m), 2.96 (1 H, dq, J = 7.2, 3.6 Hz), 3.32, 3.45 (2 H, AB,
J = 14.2 Hz), 3.34 (1 H, dd, J = 9.3, 3.2 Hz), 3.78 (1 H, ddd,
J = 11.4, 7.5, 3.8 Hz), 4.11 (1 H, d, J = 3.6 Hz), 6.73–6.79 (1 H, m),
6.82–6.87 (1 H, dd, J = 8.3, 1.6 Hz), 7.09–7.19 (3 H, m), 7.25–7.36
(6 H, m), 7.44–7.51 (1 H, m), 7.52–7.99 (6 H, m), 8.46 (1 H, d,
J = 8.7 Hz).
Ni(II) Complex (S)(2S,3S)-7c of the Schiff Base of (S)-BPB with
(2S,3S)-2-Ethyl-3-methylphenylalanine
Rf = 0.37 (acetone–hexanes, 1:1); mp 257–260 °C; [a]D25 +1719 (c
0.203, CHCl3).
13C NMR (CDCl3): d = 18.0, 24.1, 31.8, 45.9, 55.3, 59.5, 69.0, 76.3,
121.0, 123.8, 126.5, 127.5, 128.1, 128.2, 128.9, 129.0, 129.1, 129.5,
Synthesis 2008, No. 16, 2594–2602 © Thieme Stuttgart · New York

2600
V. A. Soloshonok et al.
PAPER
1H NMR (CDCl3): d = 0.83 (3 H, t, J = 7.2 Hz), 1.09–1.25 (1 H, m),
1.62–1.76 (1 H, m), 2.00–2.18 (2 H, m), 2.37 (3 H, d, J = 7.2 Hz),
2.47–2.64 (1 H, m), 2.67–2.79 (1 H, m), 3.22–3.38 (1 H, m), 3.40–
3.50 (2 H, m), 3.63, 4.43 (2 H, AB, J = 12.6 Hz), 3.69–3.79 (1 H,
m), 6.58–6.68 (4 H, m), 7.02–7.14 (5 H, m), 7.16–7.22 (1 H, m),
7.36 (2 H, t, J = 7.8 Hz), 7.41–7.49 (2 H, m), 7.52–7.60 (2 H, m),
7.93 (1 H, d, J = 8.4 Hz), 8.19 (2 H, d, J = 6.9 Hz).
1H NMR (H2O, dioxane as internal standard at d = 3.55): d = 1.18
(3 H, d, J = 7.2 Hz), 3.33 (1 H, qd, J = 7.2, 5.0 Hz), 3.74 (1 H, d,
J = 5.0 Hz), 7.13–7.23 (m, 5 H).
(2S,3S)-2,3-Dimethylphenylalanine (9b)15b
Mp 263–265 °C; [a]D25 –31.42 (c 0.3472, MeOH) [Lit.15b –31.7 (c
0.492, MeOH)].
13C NMR (CDCl3): d = 0.4, 9.7, 18.2, 23.6, 31.0, 32.9, 45.5, 57.8,
64.7, 71.2, 85.7, 120.9, 124.2, 127.0, 127.3, 127.6, 128.2, 128.5,
128.9, 129.1, 129.4, 129.7, 129.9, 131.6, 131.7, 133.4, 134.4, 136.9,
140.5, 141.6, 172.4, 179.3, 180.6.
1H NMR (DMSO-d6/DCl): d = 0.94 (3 H, d, J = 5.4 Hz), 1.07 (3 H,
s), 2.95 (1 H, q, J = 5.6 Hz), 6.84–6.91 (5 H, m).
(2R,3R)-2,3-Dimethylphenylalanine
This compound was prepared according to the above procedures,
starting form the complex 4b derived from (R)-proline;
[a]D25 +31.38 (c 0.2679, MeOH)}
HRMS: m/z calcd for C37H37N3NiO3 [M + Na]+: 652.2086; found:
652.2097.
Ni(II) Complex (S)(2S,3R)-6d of the Schiff Base of (S)-BPB with
(2S,3R)-2-Isobutyl-3-methylphenylalanine
Rf = 0.56 (acetone–hexanes, 1:1); mp 268–272 °C; [a]D25 +1602 (c
0.175, CHCl3).
1H NMR (CDCl3): d = 0.99 (3 H, d, J = 7.2 Hz), 1.23 (6 H, dd,
J = 7.2, 4.2 Hz), 1.35–1.49 (1 H, m), 1.55–2.24 (7 H, br m), 2.77 (1
H, dt, J = 12.3, 6.6 Hz), 3.22 (1 H, t, J = 8.9 Hz), 3.38, 4.32 (2 H,
AB, J = 12.6 Hz), 3.51 (1 H, q, J = 7.2 Hz), 6.54–6.64 (2 H, m),
7.08 (1 H, ddd, J = 8.4, 6.0, 2.5 Hz), 7.17–7.35 (5 H, m), 7.38–7.60
(8 H, m), 7.83 (1 H, d, J = 7.8 Hz), 8.06 (2 H, d, J = 6.9 Hz).
Acknowledgment
This work was supported by the Department of Chemistry and Bio-
chemistry, University of Oklahoma and by the Undergraduate Re-
search Opportunities Program, Honors College, University of
Oklahoma. T.U.B. and S.B.B. thank Yamanouchi Pharma (current-
ly Astellas), U.S.A., for generous fellowships. The authors grateful-
ly acknowledge generous financial support from Central Glass
Company (Tokyo, Japan) and Ajinomoto Company (Tokyo, Japan).
13C NMR (CDCl3): d = 16.1, 21.0, 23.1, 24.1, 25.3, 30.7, 44.7, 45.6,
58.2, 64.2, 70.2, 83.5, 120.6, 124.1, 127.2, 127.5, 127.9, 128.6,
128.7, 128.8, 128.9, 129.2, 129.5, 129.8, 131.3, 131.7, 133.4, 137.2,
141.9, 143.5, 172.4, 180.2, 180.6.
HRMS: m/z calcd for C39H41N3NiO3 [M + H]+: 658.2580; found:
658.2584.
References
(1) As we recently pointed out (see ref. 2), the terms unnatural,
unusual, or nonproteinogenic, noncoded amino acids depend
on the success of specific scientific achievements. For
instance, amino acids containing the most xenobiotic
element fluorine were shown to be synthesized by
microorganisms (see ref. 3), and also new amino acids can
be added to genetic code of microorganisms (see ref. 4).
Therefore, the time-independent term tailor-made, meaning
rationally designed/synthesized amino acids, in the absence
of a better definition, is used in this paper and generally
recommended for use in the corresponding literature.
(2) Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Meervelt, L.
Tetrahedron 1999, 55, 12045.
(3) (a) Fluorine-Containing Amino Acids. Synthesis and
Properties; Kukhar’, V. P.; Soloshonok, V. A., Eds.; Wiley:
Chichester, 1994. (b) O’Hagan, D.; Schaffrath, C.; Cobb, S.;
Hamilton, J. T. G.; Murphy, C. D. Nature 2002, 416, 279.
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(6) Gibson, S. E.; Guillo, N.; Tozer, M. J. Tetrahedron 1999, 55,
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(7) For monographs, see: (a) Molecular Conformation and
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Ni(II) Complex (S)(2S,3S)-7d of the Schiff Base of (S)-BPB with
(2S,3S)-2-Isobutyl-3-methylphenylalanine
Rf = 0.44 (acetone–hexanes, 1:1); mp 131–135 °C.
1H NMR (CDCl3): d = 0.73–3.88 (38 H, m), 4.12 (1 H, d, J = 12.9
Hz), 4.29 (0.4 H, d, J = 12.3 Hz), 4.58 (0.6 H, d, J = 12.3 Hz), 6.55–
6.77 (7.4 H, m), 7.03–7.83 (35.4 H, m), 8.02 (0.4 H, d, J = 8.4 Hz),
8.15 (1 H, d, J = 6.9 Hz), 8.23 (0.6 H, d, J = 6.9 Hz).
HRMS: m/z calcd for C39H41N3NiO3 [M + H]+: 658.2580; found:
658.2596.
Decomposition of Compounds 6a and 7b and Isolation of Free
Amino Acids 8a and 9b; General Procedure22m
A solution of the complex 6a or 7b (22.5 mmol) in MeOH (90 mL)
was slowly added to a mixture of aq 3 N HCl and MeOH (180 mL,
1:1) at 70 °C with stirring. When the red color of the Ni(II) complex
had disappeared, the mixture was evaporated to dryness under vac-
uum. H2O (120 mL) was added, and the resultant mixture was treat-
ed with an excess of NH4OH and extracted with CHCl3. The CHCl3
extracts were dried (MgSO4) and evaporated under vacuum to af-
ford the free chiral ligand (93–98%). The aqueous phase was evap-
orated under vacuum and redissolved in a minimum amount of H2O
and loaded on a Dowex 50 × 2 100 ion-exchange column, which
was washed with H2O until neutral. The column was then washed
with 8% aq NH4OH. First fraction (350 mL) was collected and
evaporated under vacuum to afford the corresponding amino acids
8a (91%) or 9b (93%), respectively.
(2S,3R)-3-Methylphenylalanine (8a)
(9) For a recent collection of papers, see the Special Issue:
Asymmetric Synthesis of Novel Sterically Constrained
Amino Acids, Tetrahedron Symposia-in-Print # 88; Guest
Editors Hruby, V. J.; Soloshonok, V. A. Tetrahedron 2001,
57, 6329–6650.
Mp 193–194 °C; [a]D25 –5.9 (c 1.0, H2O) [Lit.13a –5.3 (c 0.75,
H2O)].
Synthesis 2008, No. 16, 2594–2602 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of (2S,3S)- and (2R,3R)-a,b-Dialkyl-a-amino Acids
2601
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Synthesis 2008, No. 16, 2594–2602 © Thieme Stuttgart · New York

2602
V. A. Soloshonok et al.
PAPER
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conformation of the polycyclic system of chelate rings.
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stituted a-amino acid, the pseudoaxial orientation of the
amino acid side chain, corresponding to a-L configuration of
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Synthesis 2008, No. 16, 2594–2602 © Thieme Stuttgart · New York