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Synthesis of α-Amino Acids via Asymmetric Phase Transfer-Catalyzed Alkylation of Achiral Nickel(II) Complexes of Glycine-Derived Schiff Bases

30 Sep 2003-Journal of the American Chemical Society (American Chemical Society)-Vol. 125, Iss: 42, pp 12860-12871

TL;DR: An unusually large positive nonlinear effect was observed in these reactions, and implications of the association and self-association of NOBIN for the observed sense of asymmetric induction and nonlinear effects are discussed.

AbstractAchiral, diamagnetic Ni(II) complexes 1 and 3 have been synthesized from Ni(II) salts and the Schiff bases, generated from glycine and PBP (7) and PBA (11), respectively, in MeONa/MeOH solutions. The requisite carbonyl-derivatizing agents pyridine-2-carboxylic acid(2-benzoyl-phenyl)-amide 7 (PBP) and pyridine-2-carboxylic acid(2-formyl-phenyl)-amide 11 (PBA) were readily prepared from picolinic acid and o-aminobenzophenone or picolinic acid and methyl o-anthranilate, respectively. The structure of 1 was established by X-ray crystallography. Complexes 1 and 3 were found to undergo C-alkylation with alkyl halides under PTC conditions in the presence of beta-naphthol or benzyltriethylammonium bromide as catalysts to give mono- and bis-alkylated products, respectively. Decomposition of the complexes with aqueous HCl under mild conditions gave the required amino acids, and PBP and PBA were recovered. Alkylation of 1 with highly reactive alkyl halides, carried out under the PTC conditions in the presence of 10% mol of (S)- or (R)-2-hydroxy-2'-amino-1,1'-binaphthyl 31a (NOBIN) and/or its N-acyl derivatives and by (S)- or (R)-2-hydroxy-8'-amino-1,1'-binaphthyl 32a (iso-NOBIN) and its N-acyl derivatives, respectively, gave rise to alpha-amino acids with high enantioselectivities (90-98.5% ee) in good-to-excellent chemical yields at room temperature within several minutes. An unusually large positive nonlinear effect was observed in these reactions. The Michael addition of acrylic derivatives 37 to 1 was conducted under similar conditions with up to 96% ee. The (1)H NMR and IR spectra of a mixture of the sodium salt of NOBIN and 1 indicated formation of a complex between the two components. Implications of the association and self-association of NOBIN for the observed sense of asymmetric induction and nonlinear effects are discussed.

Topics: NOBIN (63%), Picolinic acid (54%), Alkylation (54%), Michael reaction (51%), Alkyl (50%)

Summary (1 min read)

Jump to: [Introduction][Results][Discussion] and [Conclusions]

Introduction

  • The synthesis of nonproteinogenicR-amino acids remains a subject of considerable interest because of their great importance in biology, medicine, and synthetic chemistry.
  • More recently, the authors employed NOBIN (2-amino-2′-hydroxy-1,1′-binaphthyl) as a novel type of PTC catalyst in the alkylation reaction ofN-alanine esters producingR-methyl-R-amino acids with modest enantioselectivity (68% ee).

Results

  • Complexes1 and3 were prepared from glycine, Ni(NO3)2, and the respective ligand precursors7 (PBP) and11 (PBA) in the presence of KOH or MeONa in methanol (Schemes 1 and 2).
  • The slight variation of the bond lengths in the ligand in1 and ( )-2 cannot be rationalized as the consequence of the presence of the methyl group at C(20) or the influence of crystal packing and seems to originate from a systematic bias introduced by the disorder in (-2.
  • In addition, the sense of chirality of the product was reversed, as compared with the alkyl halide alkylations catalyzed by31a (Table 5, entries 1-3; compare with Tables 3 and 4).

Discussion

  • Evidently, the glycine-derived complex1 is a very convenient substrate for the synthesis of racemicR-amino acids, retaining oneR-proton of the original glycine moiety.
  • Clearly, in addition to the probable decrease in theR-CH acidity of the amino acid moiety in the mono-alkylated complexes derived from1, further steric hindrance to the approach of the second alkylating agent also contributes to the predominant mono-alkylation of1.
  • As the NH2 group of free NOBIN (31a) was shown by IR not to be involved in any coordination prior to the reaction, it seems that the phenolate oxygen atom replaced the carboxyl group in the coordination sphere of Ni(II), and thus, the group became partially or fully liberated, forming a strong ionic bond with Na+.
  • In fact,31f and 31h failed to catalyze the reaction entirely.

Conclusions

  • The authors have developed a new series of efficient nucleophilic substrates for the synthesis ofR-amino acids, both chiral and achiral, employing very simple and easily reproducible modes of operation.
  • Combined with the use of the chiral catalysts, (S)- and (R)-NOBIN,19 (S)and (R)-iso-NOBIN,7b and their derivatives (31 and 32), this method opens a convenient synthetic route to the enantiomerically pureR-amino acids of both configurations.
  • Further experiments will be needed to shed more light on this complex problem; work toward this direction is underway in these laboratories.

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University of Groningen
Synthesis of α-Amino Acids via Asymmetric Phase Transfer-Catalyzed Alkylation of Achiral
Nickel(II) Complexes of Glycine-Derived Schiff Bases
Belokon, Yuri N.; Bespalova, Natalia B.; Churkina, Tatiana D.; Císařová, Ivana; Ezernitskaya,
Marina G.; Harutyunyan, Syuzanna R.; Hrdina, Radim; Kagan, Henri B.; Kočovský, Pavel;
Kochetkov, Konstantin A.
Published in:
Journal of the American Chemical Society
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Publication date:
2003
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Citation for published version (APA):
Belokon, Y. N., Bespalova, N. B., Churkina, T. D., Císařová, I., Ezernitskaya, M. G., Harutyunyan, S. R.,
Hrdina, R., Kagan, H. B., Kočovský, P., Kochetkov, K. A., Larionov, O. V., Lyssenko, K. A., North, M.,
Polášek, M., Peregudov, A. S., Prisyazhnyuk, V. V., & Vyskočil, Š. (2003). Synthesis of α-Amino Acids via
Asymmetric Phase Transfer-Catalyzed Alkylation of Achiral Nickel(II) Complexes of Glycine-Derived Schiff
Bases.
Journal of the American Chemical Society
,
125
(42), 12860-12871.
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Synthesis of r-Amino Acids via Asymmetric Phase
Transfer-Catalyzed Alkylation of Achiral Nickel(II) Complexes
of Glycine-Derived Schiff Bases
Yuri N. Belokon,*
,†
Natalia B. Bespalova,
Tatiana D. Churkina,
Ivana ´sarˇova´,
Marina G. Ezernitskaya,
Syuzanna R. Harutyunyan,
Radim Hrdina,
‡,¶
Henri B. Kagan,
§
Pavel Kocˇovsky´,*
Konstantin A. Kochetkov,
Oleg V. Larionov,
Konstantin A. Lyssenko,
Michael North,
Miroslav Pola´sˇek,
Alexander S. Peregudov,
Vladimir V. Prisyazhnyuk,
and Sˇ teˇpa´n Vyskocˇil*
,‡,¶,
Contribution from A. N. NesmeyanoV Institute of Organo-Element Compounds,
Russian Academy of Sciences, 117813, Moscow, VaViloV 28, Russian Federation,
Department of Organic Chemistry, Faculty of Science, Charles UniVersity, HlaVoVa 2030,
12840 Prague 2, Czech Republic, Department of Chemistry, Joseph Black Building, UniVersity
of Glasgow G12 8QQ, United Kingdom, Institut de Chimie Moleculaire d’Orsay, Laboratoire de
Synthe`se Asyme´trique (UPRESA 8075), UniVersite´ de Paris Sud, 91405-Orsay Cedex, France,
Department of Chemistry, King’s College, Strand, London, WC2 R2LS, United Kingdom, and
J. HeyroVsky´ Institute of Physical Chemistry, Academy of Sciences of the Czech Republic,
18223 Prague 8, Czech Republic
Received April 4, 2003; E-mail: yubel@ineos.ac.ru; P.Kocovsky@chem.gla.ac.uk; stepanv@natur.cuni.cz
Abstract:
Achiral, diamagnetic Ni(II) complexes 1 and 3 have been synthesized from Ni(II) salts and the
Schiff bases, generated from glycine and PBP (7) and PBA (11), respectively, in MeONa/MeOH solutions.
The requisite carbonyl-derivatizing agents pyridine-2-carboxylic acid(2-benzoyl-phenyl)-amide 7 (PBP) and
pyridine-2-carboxylic acid(2-formyl-phenyl)-amide 11 (PBA) were readily prepared from picolinic acid and
o
-aminobenzophenone or picolinic acid and methyl
o
-anthranilate, respectively. The structure of 1 was
established by X-ray crystallography. Complexes 1 and 3 were found to undergo C-alkylation with alkyl
halides under PTC conditions in the presence of β-naphthol or benzyltriethylammonium bromide as catalysts
to give mono- and bis-alkylated products, respectively. Decomposition of the complexes with aqueous HCl
under mild conditions gave the required amino acids, and PBP and PBA were recovered. Alkylation of 1
with highly reactive alkyl halides, carried out under the PTC conditions in the presence of 10% mol of (
S
)
-
or (
R
)
-
2-hydroxy-2-amino-1,1-binaphthyl 31a (NOBIN) and/or its
N
-acyl derivatives and by (
S
)
-
or (
R
)
-
2-
hydroxy-8-amino-1,1-binaphthyl 32a (
iso
-NOBIN) and its
N
-acyl derivatives, respectively, gave rise to
R-amino acids with high enantioselectivities (90-98.5% ee) in good-to-excellent chemical yields at room
temperature within several minutes. An unusually large positive nonlinear effect was observed in these
reactions. The Michael addition of acrylic derivatives 37 to 1 was conducted under similar conditions with
up to 96% ee. The
1
H NMR and IR spectra of a mixture of the sodium salt of NOBIN and 1 indicated
formation of a complex between the two components. Implications of the association and self-association
of NOBIN for the observed sense of asymmetric induction and nonlinear effects are discussed.
Introduction
The synthesis of nonproteinogenic R-amino acids remains a
subject of considerable interest because of their great importance
in biology, medicine, and synthetic chemistry.
1
An increasingly
popular approach to chiral R-amino acids with a tertiary
R-carbon atom relies on the C-C bond formation via alkylation
of glycine derivatives, such as N-(diphenylmethylene)glycine
tert-butyl ester with alkyl halides, developed by O’Donnell et
al.
2
Catalytic asymmetric versions of this reaction are being
sought, and following the seminal work by O’Donnell et al.
2c
on asymmetric alkylations with cinchona alkaloid derivatives
as chiral phase-transfer catalysts (PTC), dramatic improvements
have been achieved.
3
Purely synthetic, chiral C
2
symmetrical
ammonium salts have recently been prepared and shown to be
highly efficient in the same set of reactions.
4
Nevertheless,
A. N. Nesmeyanov Institute.
Charles University.
University of Glasgow.
§
Universite´ de Paris Sud.
King’s College.
J. Heyrovsky´ Institute.
Current address: Department of Chemistry, The Scripps Research
Institute, La Jolla, CA 92037.
(1) (a) Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 238-264. (b)
Williams, R. M.; Hendrix, J. A. Chem. ReV. 1992, 92, 889. (c) Duthaler,
R. O. Tetrahedron 1994, 50, 1539. (d) Wirth, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 225. (e) Gibson, S. E.; Guillo, N.; Tozer, M. J. Tetrahedron
1999, 55, 585. (f) Diaz-de-Villegas, M. D.; Cativiela, C. Tetrahedron:
Asymmetry 1998, 9, 3517. (g) Cativiela, C.; Diaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2000, 11, 645.
Published on Web 09/30/2003
12860
9
J. AM. CHEM. SOC. 2003,
125
, 12860-12871 10.1021/ja035465e CCC: $25.00 © 2003 American Chemical Society

despite the recent progress in the catalytic asymmetric synthesis
of R-amino acids,
5
asymmetric PTC alkylation of glycine or
alanine derivatives still represents the simplest and most
straightforward route to a variety of enantiomerically enriched
R-amino acids.
Previously, we have reported on the synthesis and application
of the square-planar nickel(II) complex 1 (Chart 1) in asym-
metric Michael reaction, catalyzed by (R,R)-TADDOL [(4R,5R)-
2,2-dimethyl-1,3-dioxolane-4,5-bis(diphenylmethanol)], which
led to 4-methylglutamic acid with low enantioselectivity (28%
ee).
6a
More recently, we employed NOBIN (2-amino-2-hy-
droxy-1,1-binaphthyl) as a novel type of PTC catalyst in the
alkylation reaction of N-(phenylmethylene)alanine esters pro-
ducing R-methyl-R-amino acids with modest enantioselectivity
(68% ee).
6b
Herein, we report on the introduction of one or two alkyl
groups (identical or different) into the achiral Ni(II) complex
1, derived from the Schiff base of glycine and pyridine-2-
carboxylic acid(2-benzoyl-phenyl)-amide 7 (PBP), in a selective,
stepwise manner. This approach represents a viable route to the
preparation of either racemic or enantiomerically enriched
R-monosubstituted R-amino acids or R,R-disubstituted R-amino
acids. Also reported is the achiral Ni(II) complex 3, obtained
from the Schiff base of glycine and pyridine-2-carboxylic acid-
(2-formyl-phenyl)-amide 11 (PBA) as a convenient substrate
for the preparation of achiral, highly constrained R,R-disubsti-
tuted R-amino acids. Finally, we explore asymmetric catalytic
C-alkylation of 1 with alkyl halides and Michael acceptors under
PTC conditions, using NOBIN, iso-NOBIN, and their deriva-
tives as catalysts.
7
Results
Synthesis and Structure of Ni(II) Complexes 1 and 3.
Complexes 1 and 3 were prepared from glycine, Ni(NO
3
)
2
, and
the respective ligand precursors 7 (PBP) and 11 (PBA) in the
presence of KOH or MeONa in methanol (Schemes 1 and 2).
The red-colored, crystalline, diamagnetic complexes 1 and 3
can be purified by chromatography or crystallization from
CHCl
3
. Racemic complexes 2 and 4 were obtained in the same
way, using (()-alanine instead of glycine. The ketone precursor
7 (PBP) was obtained by condensation of the in situ-generated
chloride of R-picolinic acid (5) with o-aminobenzophenone (6),
(2) (a) O’Donnell, M. J.; Boniece, I. M. Tetrahedron Lett. 1978, 19, 2641. (b)
O’Donnell, M. J.; Eckrich, T. M. Tetrahedron Lett. 1978, 19, 4625. (c)
Scott, W. L.; Zhou, Ch.; Fang, Z.; O’Donnell, M. J. Tetrahedron Lett. 1997,
38, 3695. (d) Griffith, D. L.; O’Donnell, M. J.; Pottorf, R. S.; Scott, W. L.;
Porco, J. A. Tetrahedron Lett. 1997, 38, 8821. (e) O’Donnell, M. J.; Bennett,
W.; Bruder, W.; Jacobsen, W.; Knuth, K.; LeClef, B.; Polt, R.; Bordwell,
F.; Mrozack, S.; Cripe, T. J. Am. Chem. Soc. 1988, 110, 8520. (f)
O’Donnell, M. J.; Delgano, F.; Pottorf, R. S. Tetrahedron 1999, 55, 6347.
(g) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989,
111, 2353. (h) O’Donnell, M. J.; Dominguez, E.; Scott, W. L.; Delgado,
F.; de Blas, J. Tetrahedron: Asymmetry 2001, 12, 821. (i) O’Donnell, M.
J.; Delgano, F.; Hostettler, C.; Schwesinger, R. Tetrahedron Lett. 1998,
39, 8775.
(3) (a) Corey, E. J.; Xu, F.; Noe, M. J. Am. Chem. Soc. 1997, 119, 12414. (b)
Corey, E. J.; Noe, M.; Xu, F. Tetrahedron Lett. 1998, 39, 5347. (c) Corey,
E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1998, 120, 13000. (d)
Lygo, B.; Crosby, J.; Lowdon, T. R.; Wainwright, P. G. Tetrahedron Lett.
1997, 38, 2343. (e) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997,
38, 8595. (f) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998, 39, 1599.
(g) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671.
(h) Chinchilla, R.; Mazon, P.; Najera, C. Tetrahedron: Asymmetry 2000,
11, 3277.
(4) (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519.
(b) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
2000, 122, 5228. (c) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K.
Angew. Chem., Int. Ed. 2002, 41, 1551.
(5) (a) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2002, 41, 1790 and references therein. (b)
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315. (c)
Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason,
J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284.
(d) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2000, 122, 762 and references therein.
(6) (a) Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.;
Orlova, S. A.; Smirnov, V. V.; Chesnokov, A. A. MendeleeV Commun.
1997, 137. (b) Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Singh, I.; Parmar,
V. S.; Vyskocˇil, Sˇ.; Kagan, H. B. J. Org. Chem. 2000, 65, 7041.
Chart 1.
Ketimine and Aldimine Ni(II) Complexes
Scheme 1.
Synthesis of Ni(II) Complexes 1 and 2
Scheme 2.
Synthesis of Ni(II) Complexes 3 and 4
Synthesis of R-Amino Acids ARTICLES
J. AM. CHEM. SOC.
9
VOL. 125, NO. 42, 2003 12861

as reported in our preliminary communication;
7a
an improved
procedure is described in the Experimental Section of the
Supporting Information. The aldehyde precursor 11 was syn-
thesized as follows: condensation of the in situ-generated
chloride of R-picolinic acid (5) with methyl o-anthranilate (8)
afforded amide 9, which was reduced with LiBH
4
to give alcohol
10. Swern oxidation of the latter alcohol provided the required
aldehyde 11.
The X-ray structure of 1 and (()-2 (Figures 1 and 2, Table
1) suggests that the complexes are neutral, with the two positive
charges at the central Ni ion neutralized by two negative charges
(CON
-
and COO
-
) of the tetradentate ligand. The ligand is
slightly puckered with two enantiomeric conformations of two
molecules of 1 and (()-2 in the crystal cell, restoring the overall
racemic crystal arrangement. The principal bond lengths and
angles in complexes 1 and (()-2 are close to each other and
are typical for this type of compound (see Table 1). The slight
variation of the bond lengths in the ligand in 1 and (()-2 cannot
be rationalized as the consequence of the presence of the methyl
group at C(20) or the influence of crystal packing and seems to
originate from a systematic bias introduced by the disorder in
(()-2.
The dihedral angles between the Ni(1)O(1)N(1)N(2)N(3)
plane and the phenyl ring in 1 and (()-2 differ slightly (90.8°
and 108.8°, respectively). The difference most likely originates
in the steric interaction of the methyl substituent and the Ph
group in (()-2 that is absent in 1. The effect of the methyl
group is also reflected in the supramolecular assembly of the
complexes. Although both complexes 1 and (()-2 are assembled
into centrosymmetric dimers, the nature of the interaction
between the stacks is different. The heterochiral dimer of 1 is
interconnected by the weak Ni(1)‚‚‚N(1) contacts [Ni(1A)‚‚‚
N(1A) 3.287(2)Å] and by the interaction of the N(3) atom with
the π-system of the pyridine ring [N(3)‚‚‚C(2A) 3.319(3)Å]
(Figure 1). By contrast, the presence of the methyl group in
(()-2 makes this stacking-type interaction impossible, and as a
result, the interdimer interactions are limited to only a weak
contact of the nickel atom with the carbonyl group (Ni(1)‚‚‚
O(3A) 3.287(2)Å) (Figure 2).
Synthesis of Racemic Amino Acids by Alkylation of Ni-
(II) Complexes 1 and 3. The alkylation of both 1 and 3 with
alkyl halides was carried out in the presence of Bu
4
NBr, Bu
4
-
NCl, or β-naphthol as PTC catalysts in CH
2
Cl
2
with solid NaOH
as a base (Scheme 3), and the reaction was monitored by TLC.
After completion, the reaction mixture was neutralized and the
red-colored solid residue was purified either by chromatography
or crystallization. In most cases the yields exceeded 95%, and
the purification was not necessary. Decomposition of the
resulting complexes 12, 13-16, and 22-24 was effected by
diluted methanolic HCl within 5 min at 50 °C to produce the
corresponding mono- and bis-alkylated amino acids 17, 18-
21, 25, and 26, respectively. The process was easily followed
by the change of the solution color from red to blue. The
hydrochlorides of 7 (PBP) and 11 (PBA) were removed by
filtration in almost quantitative yields, and NiCl
2
and the amino
acid were easily isolated by ion exchange chromatography. The
results of the alkylations are summarized in Table 2.
At a 1:1 molar ratio of the alkylating agent to the substrate,
the monoalkylation of the ketimine complex 1 proceeded
quantitatively both in CH
2
Cl
2
under PTC conditions and in DMF
in the presence of NaOH or NaH (Table 2, entries 1-4). The
use of sterically hindered alkyl halides such as i-PrI gave rise
to mono-alkylated products with 1, even at a 3:1 ratio to the
substrate in DMF (Table 2, entry 5). On the other hand, bis-
alkylation of 1 can be performed by employing 2-3 equiv of
the more reactive alkylating agents, such as benzyl and allyl
bromide (Table 2, entries 6 and 7) in DMF. R,R-Dibromo-o-
xylene can be employed to give cleanly the corresponding
(7) Preliminary data on the asymmetric alkylation of 1 under PTC conditions,
catalyzed by NOBIN, have been reported by us earlier: (a) Belokon, Y.
N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.; Larionov, O. V.;
Harutyunyan, S.; North, M.; Vyskocˇil, Sˇ.; Kagan, H. B. Angew. Chem.,
Int. Ed. 2001, 40, 1948. (b) Vyskocˇil, Sˇ.; Meca, L.; Tisˇlerova´, I.; ´sarˇova´,
I.; Pola´sˇek, M.; Harutyunyan, S.; Belokon, Y. N.; Stead, R. M. J.; Farrugia,
L.; Kocˇovsky´, P. Chem.-Eur. J. 2002, 8, 4633.
Figure 1.
Scheme illustrating the formation of the heterochiral dimers in
the crystal of 1.
Figure 2.
Scheme illustrating the formation of the heterochiral dimers in
the crystal of (()-2. The other position of the disordered ligand is omitted
for clarity.
Table 1.
Selected Bond Lengths (Å) and Angles in Complexes 1
and (()-2
(bond/angles)
atoms 12
Ni(1)-O(1) 1.851(2) 1.857(2)
Ni(1)-N(1) 1.876(3) 1.881(3)
Ni(1)-N(2) 1.861(3) 1.874(3)
Ni(1)-N(3) 1.843(2) 1.846(3)
O(1)-C(21) 1.289(4) 1.299(4)
O(2)-C(21) 1.231(4) 1.217(4)
O(3)-C(6) 1.220(4) 1.217(4)
N(1)-C(1) 1.333(4) 1.353(8)
N(1)-C(5) 1.352(4) 1.323(4)
N(2)-C(6) 1.381(4) 1.370(4)
N(2)-C(7) 1.395(4) 1.402(5)
N(3)-C(13) 1.292(4) 1.297(4)
N(3)-C(20) 1.486(4) 1.486(4)
O(1)-Ni(1)-N(1) 90.8(1) 90.7(1)
O(1)-Ni(1)-N(2) 176.7(1) 173.3(1)
O(1)-Ni(1)-N(3) 87.6(1) 87.1(1)
N(1)-Ni(1)-N(2) 86.0(1) 86.1(1)
N(1)-Ni(1)-N(3) 176.0(1) 175.4(2)
N(2)-Ni(1)-N(3) 95.6(1) 96.5(1)
ARTICLES Belokon et al.
12862 J. AM. CHEM. SOC.
9
VOL. 125, NO. 42, 2003

complex of 2-amino-2-carboxy-indane 15 (Table 2, entry 8)
from which the amino acid 21 can be released. Notably, the
alkylation of a chirally modified O’Donnell substrate with this
alkyl halide was reported as being accompanied by simultaneous
N-alkylation of the nitrogen atom of the glycine moiety, giving
rise to the corresponding heterocyclic derivative of amino acid.
8
A procedure for the stepwise bis-alkylation of 1 was
elaborated, starting with mono-alkylation of 1 with an alkyl
bromide under PTC conditions in CH
2
Cl
2
, followed by a second
alkylation with another activated alkyl halide in DMF. In this
way, alkylation of 1 with EtBr, followed by the alkylation of
the resulting mono-alkylated complex with benzyl bromide, gave
R-ethylphenylalanine 20 after the decomposition of the bis-
alkylated complex (Table 2, entry 9).
The glycine moiety of the aldimine complex 3 is much less
sterically hindered, and only bis-alkylated complexes were
formed selectively under PTC in CH
2
Cl
2
or DMF even at a 1:1
ratio of the alkylating agent to the substrate. The increase of
the latter ratio to 2.5 led to the formation of the bis-alkylated
complexes in quantitative yields (Table 2, entries 10 and 11).
Even the sterically hindered iso-propyl iodide reacted readily
to give the corresponding bis-alkylated complex (Table 2, entry
11), from which R,R-diisopropylglycine 26 was released in a
very good chemical yield.
9
The Ni chelation serves as a means of protection for both
the amino and carboxyl groups of the amino acid moiety so
that various reactions could be easily performed on the groups
of the side chains. As an illustration, a ruthenium-catalyzed ring-
closing metathesis was carried out with the diallylglycine
complex 14, which resulted in a ready formation of 1-amino-
1-carboxycyclopent-3-ene 28 after decomplexation of the in-
termediate 27 (Scheme 4).
Synthesis of Enantiomerically Enriched r-Amino Acids
by Asymmetric Alkylation of the Ni(II) Complex 1 with
Alkyl Halides, Catalyzed by NOBIN, iso-NOBIN and Their
Congeners 31-32. Asymmetric alkylation of 1 in CH
2
Cl
2
(Scheme 5) was carried out in the presence of cinchonine
derivative 29,(R,R)-TADDOL 30, NOBIN 31a (and its deriva-
tives 31d-h), and iso-NOBIN 32a (and its derivatives 32b-g)
as catalysts (Chart 2). Catalysts 29 and 30 gave low chemical
yields (less than 50%) even after prolonged treatment (1 h),
and the ee of the resulting phenylalanine (17a) was in the range
of 5-16% (Table 3, entries 1-3). By contrast, NOBIN-type
binaphthyls 31 and 32 proved much more efficient.
Thus, benzylation of 1, catalyzed by (R)-NOBIN 31a (or its
enantiomer) in toluene (Scheme 5), gave the mono-alkylated
complex 12a in a 50% chemical yield, and the released
phenylalanine (17a) was of 89% ee (Table 3, entry 4). The
reaction carried out in CH
2
Cl
2
gave (R)-Phe [or (S)-Phe] in 88-
90% chemical yield with 96-97% ee within 8 min (Table 3,
entries 5 and 6). As expected, the increase in solvent polarity
(MeCN) diminished the ee of the alkylation (Table 3, entry 7),
whereas (CH
2
)
2
Cl
2
served as a good substitute for CH
2
Cl
2
(Table
3, entries 8 and 9), allowing the reaction to be carried out at
higher temperatures (up to 70 °C) without a significant loss in
the product ee (Table 3, entry 9).
The nature of the base was important in these reactions as
the transition from solid NaOH to KOH and then to CsOH
H
2
O brought the ee of the reaction progressively from 96% to
16% and finally to 10% (Table 3, compare entries 6, 10, and
11). Switching from solid NaOH to 50% aqueous NaOH was
detrimental to the enantioselectivity, which fell from 96% ee
to 55% ee; simultaneously, the chemical yield dropped to a
meager 5% after 1 h (Table 3, entry 12). Significantly, solid
NaH proved to be almost as efficient as NaOH (Table 3,
compare entries 6 and 13).
An attempt at using BINOL (31b)or2,2-diamino-1,1-
binaphthyl (31c) as catalysts resulted in both low ee and
chemical yields of the product (Table 3, entries 14 and 15).
The modifications of 31a by replacing the NH
2
group with
NMe
2
(31d) or NHPh (31e) invariably decreased the efficiency
of the reaction by slowing the rate and decreasing the enantio-
selectivity to 3-5% ee (Table 3, entries 16 and 17). N-Formyl
NOBIN 31f was also inactive (Table 3, entry 18), whereas
modest restoration of reactivity was observed for the (R)-N-
acetyl derivative 31g, which gave the final (S)-Phe of 28% ee
(Table 3, entry 19). Interestingly, the latter instance constitutes
the reversal of the sense of chirality as compared to the catalysis
by (R)-NOBIN (Table 3, compare entries 6 and 19). The
introduction of three fluorine atoms into the N-acyl-moiety (31h)
resulted in a total loss of catalytic activity (Table 3, entry 20).
(S)-iso-NOBIN (32a) proved to be a fairly efficient catalyst
for the production of (S)-Phe with 87.5% ee and 36% chemical
(8) Guillena, G.; Najera, C. J. Org. Chem. 2000, 65, 7310.
(9) The Schiff base derived from benzaldehyde and i-propyl glycinate gave
no products of bis-C-alkylation under the same conditions; only a mixture
of the mono-alkylated product, i.e., ValO-i-Pr Schiff base, and unidentified
material was detected by
1
H NMR in the reaction mixture.
Scheme 3.
Alkylation of Ni(II) Complexes 1 and 3
a
a
For catalysts, conditions, and results, see Table 2.
Synthesis of R-Amino Acids ARTICLES
J. AM. CHEM. SOC.
9
VOL. 125, NO. 42, 2003 12863

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References
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Frequently Asked Questions (2)
Q1. What are the contributions in "University of groningen synthesis of α-amino acids via asymmetric phase transfer-catalyzed alkylation of achiral nickel(ii) complexes of glycine-derived schiff bases belokon," ?

Implications of the association and self-association of NOBIN for the observed sense of asymmetric induction and nonlinear effects are discussed. 

However, further experiments will be needed to shed more light on this complex problem ; work toward this direction is underway in these laboratories.