A new approach to the efficient method for the asymmetric synthesis of (S)-O-, M-, P-fluorophenylalanines and their 2-methyl-substituted analogs

Article abstract of DOI:10.1080/00397911003587531

The reactions of asymmetric C-alkylation of glycine and alanine in NiII complexes of their Schiff's bases with modified chiral auxiliaries (S)-2-N-[(N0-2-chlorobenzylprolyl)- amino]benzophenone and (S)-2-N-[N′-(3, 4-dimethylbenzylprolyl)amino]benzophenone by fluorine-substituted benzyl halogenides have been studied. As a result, a highly stereoselective and relatively rapid method for the asymmetric synthesis of (S)-o-, m-, p-fluorophenylalanines and their 2-methyl substituted analogs has been developed.

Full text of DOI:10.1080/00397911003587531

This article was downloaded by: [Texas A&M University Libraries]
On: 10 September 2014, At: 23:05
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
A New Approach to the Efficient Method
for the Asymmetric Synthesis of (S)-O-,
M-, P-Fluorophenylalanines and Their 2-
Methyl-substituted Analogs
Ashot S. Saghiyan a , Satenik G. Petrosyan a , Luiza L. Manasyan a ,
Slavik A. Dadayan a , Arpine V. Geolchanyan a , Henry A. Panosyan b ,
Victor I. Maleev c & Victor N. Khrustalev c
a Chemistry Department , Yerevan State University , Yerevan,
Armenia
b Molecular Structure Research Center of National Academic of
Sciences , Yerevan, Armenia
c A. N. Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences , Moscow, Russia
Published online: 02 Feb 2011.
To cite this article: Ashot S. Saghiyan , Satenik G. Petrosyan , Luiza L. Manasyan , Slavik A. Dadayan ,
Arpine V. Geolchanyan , Henry A. Panosyan , Victor I. Maleev & Victor N. Khrustalev (2011) A New
Approach to the Efficient Method for the Asymmetric Synthesis of (S)-O-, M-, P-Fluorophenylalanines
and Their 2-Methyl-substituted Analogs, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:4, 493-506, DOI: 10.1080/00397911003587531
To link to this article: http://dx.doi.org/10.1080/00397911003587531
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,

proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 41: 493–506, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003587531
A NEW APPROACH TO THE EFFICIENT METHOD FOR
THE ASYMMETRIC SYNTHESIS OF (S)-O-, M-,
P-FLUOROPHENYLALANINES AND THEIR
2-METHYL-SUBSTITUTED ANALOGS
Ashot S. Saghiyan,1 Satenik G. Petrosyan,1
Luiza L. Manasyan,1 Slavik A. Dadayan,1
Arpine V. Geolchanyan,1 Henry A. Panosyan,2
Victor I. Maleev,3 and Victor N. Khrustalev3
1Chemistry Department, Yerevan State University, Yerevan, Armenia
2Molecular Structure Research Center of National Academic of Sciences,
Yerevan, Armenia
3A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, Moscow, Russia
Abstract The reactions of asymmetric C-alkylation of glycine and alanine in NiII complexes
of their Schiff’s bases with modified chiral auxiliaries (S)-2-N-[(N0-2-chlorobenzylprolyl)-
amino]benzophenone and (S)-2-N-[N0-(3,4-dimethylbenzylprolyl)amino]benzophenone by
fluorine-substituted benzyl halogenides have been studied. As
stereoselective and relatively rapid method for the asymmetric synthesis of (S)-o-, m-,
a result, a highly
p-fluorophenylalanines and their 2-methyl substituted analogs has been developed.
Keywords Asymmetric synthesis; c-alkylation; chiral NiII complex; fluorophenylalanine
Received October 29, 2009.
Address correspondence to Ashot S. Saghiyan, Professor, ScD, Corresponding Member of NAS
RA, Yerevan State University, Chemistry Department, 1 Manukyan str., 0049, Yerevan, Armenia.
E-mail: saghiyan@netsys.am
493

494
A. S. SAGHIYAN ET AL.
INTRODUCTION
In a series of nonproteinogenic a-amino acids, b-phenyl-a-alanine derivatives,
especially o-, m-, p-fluorophenylalanines and their derivatives, which have a
broad spectrum of biological activity,[1] are of particular interest. For example,
p-fluorophenylalanine and its derivatives have antiviral and antitumor activities.[2,3]
It should be mentioned that individually pure optically active enantiomers of
amino acids are physiologically and pharmacologically active, and as a rule, the
optical antipode of a pharmacologically active compound has a negative pharmaco-
logical effect.[4] In this connection, the synthesis of new enantiomerically pure
analogs of phenylalanine, including derivatives with halogen substituents in the
aromatic ring, is an urgent task.
Among various approaches proposed for the syntheses of enantiomerically
pure (S)-o-, m-, p-fluorophenylalanines and their 2-methyl-substituted derivatives,
asymmetric C-alkylation of glycine and alanine moieties with the use of NiII
complexes of their Schiff base and chiral auxiliary (S)-2-N-(N0-benzylprolyl)amino-
benzophenone [(S)-BPB] as an amino acid synthon was the most efficient.[5] Stereo-
selectivities of the syntheses were reported as being 90% de on average, and the
duration of asymmetric reactions was 2–3 h. These complexes were also used for
the production of a wide spectrum of optically active, nonproteinogenic (S)-a-
amino acids containing aliphatic, aromatic, and heterocyclic substituents in the
side chain.[6]
Different modifications of the BPB auxiliary were recently introduced to
increase the stereoselectivity and to reduce the duration of the asymmetric reac-
tions.[7] Various electron-donating and acceptor substituents (Cl, Br, Me,
C6H5CH2O, NO2, etc.) were introduced in the aromatic ring of the N-benzylprolyl
moiety of BPB. For example, glycine and alanine Schiff base complexes with
modified chiral auxiliaries, 2-chloro [(S)-2-N-[N0-(2-chlorobenzylprolyl)amino]-
benzophenone [(S)-2-CBPB)] and 3,4-dimethyl [(S)-2-N-[N0-(3,4-dimethylbenzyl-
prolyl)amino]benzophenone [(S)-3,4-DMBPB], were prepared. Their use in reactions
of asymmetric C-alkylation of the amino acid moieties by alkyl halogenides
=
(C6H4Cl2Br, CH2 CH-CH2Cl) and carbonyl compounds [CH2O, CH3CHO,
(CH3)2CO], resulted in relatively high stereoselectivities of the reactions
[de ꢀ 95%).[8,9]
We put ourselves to the task of developing efficient methods to asymmetrically
synthesize enantiomerically enriched fluorine-substituted phenylalanines via NiII
complexes of glycine and alanine Schiff bases with [(S)-2-CBPB)] and [(S)-3,4-
DMBPB] auxiliaries.
RESULTS AND DISCUSSION
The initial complexes derived from (S)-2-CBPB and (S)-3,4-DMBPB, NiII-
(S)-2-CBPB-Gly (1), NiII-(S)-3,4-DMBPB-Gly (2), NiII-(S)-2-CBPB-Ala (3), and
NiII-(S)-3,4-DMBPB-Ala (4), have been obtained according the earlier method.[8d]
2-F-C6H4CH2Br, 3-F-C6H4CH2Cl, and 4-F-C6H4CH2Br were used as the alkylating
agents. The alkylation was conducted in dimethylformamide (DMF) at room
temperature with NaOH employed as a base (Scheme 1).

ASYMMETRIC SYNTHESIS OF FLUOROPHENYLALANINES
495
Scheme 1. Synthesis of complexes 5–8(a–c).
The reaction of alkylation was monitored by thin-layer chromatography (TLC)
[SiO2, CHCl3–CH3COCH3 (3:1)] following the disappearance of traces of the initial
complexes 1–4.
As expected, a mixture of two (S,S)- and (S,R)-diastereoisomeric complexes
were obtained in all the cases. The major diastereomers of the alkylation products
were separated by preparative chromatography [SiO2, 20 ꢁ 20 cm, CHCl3–
CH3COCH3 (3:1)], and their absolute configuration was determined by the sign of
optical rotation at 589 nm wavelength. It was established earlier that the complexes
of (S)-a-amino acids based on the BPB chiral auxiliaries and their modified analogs
had a positive sign of rotation and the complexes of (R)-a-amino acids had a nega-
tive one.[10] The signs of the optical rotation of the major diastereomeric complexes
5–8 had positive values, which reflected their (S,S)-absolute configuration.
The ratio of (S,S)- and (S,R)-diastereomers of alkylation products was determ-
ined by chiral high-performence liquid chromatographic (HPLC) analysis of the
amino acid mixture recovered after decomposition of the mixture of diastereomeric
complexes (before chromatography) and ion-exchange demineralization. The data

496
A. S. SAGHIYAN ET AL.
Table 1. Results of alkylation of glycine complexes (1, 2) by fluorine-substituted benzyl halogenides in
DMF=NaOH at 20–25 ꢃC
Ratio of products (%)c
Initial
complex
Alkylating
agent
Chemical
yield (%)b
Duration
(min)
Product of
bis-alkylation
Runa
(S,S)
(S,R)
1
2
3
4
5
6
7
8
9
1
2-F-BnBr
3-F-BnCl
4-F-BnBr
2-F-BnBr
3-F-BnCl
4-F-BnBr
2-F-BnBr
3-F-BnCl
4-F-BnBr
70
82
81
62
72
85
72
70
71
15
5
76.8
9.32
2.71
10.43
5.03
2.16
4.00
5.01
4.36
7.20
13.88
0.55
3.10
1
96.74
86.47
60.99
82.36
50.62
80.24
95.08
77.44
1
8
2
20
12
20
30
30
30
33.98
15.48
45.38
14.74
0.55
2
2
NiII-(S)-BPB-Gly
NiII-(S)-BPB-Gly
NiII-(S)-BPB-Gly
15.36
aReaction conditions: the reactions were run in DMF, concentration of initial complex was 1.4 M, ratio
of the initial complex–alkylating agent–NaOH ¼ 1:1.2:2.5, at 20–25 ꢃC, under Ar.
bChemical yield on the stage of alkylation (mixture of diastereomeric complexes).
cData obtained by chiral HPLC analysis.
are presented in Tables 1 and 2. In addition, in the case of unmodified BPB, the
determination of the ratio of diastereomeric complexes of the alkylation products
1
was also carried out by H NMR. The HPLC analyses of the same amino acids
are also presented in the tables.
As seen from the data of Table 1, the best results were registered in the case of
alkylation of the chiral auxiliary complex (S)-2-CBPB (1) by 3-F-benzyl chloride
(run 2); stereoselectivity of the syntheses was 94%. The chiral auxiliary (S)-3,4-
DMBPB (2) was less effective (runs 4, 5, and 6). A significant shortening of
asymmetric reaction (ꢂ5–15 min) was also observed in the case of complex 1 (runs
1, 2, and 3).
Table 2. The results of alkylation of alanine complexes (3, 4) by fluorine-substituted benzyl halogenides in
DMF=NaOH at 20–25 ꢃC
Ratio of products (%)c
Alkylating
agent
Chemical
yield (%)b
Duration
(min)
Runa
Initial complex
(S,S)
(S,R)
1
2
3
4
5
6
7
8
9
3
2-F-BnBr
3-F-BnCl
4-F-BnBr
2-F-BnBr
3-F-BnCl
4-F-BnBr
2-F-BnBr
3-F-BnCl
4-F-BnBr
70
82
74
62
78
65
72
70
63
120
70
94.57
96.07
93.65
94.03
95.23
93.48
86.90
87.41
84.72
5.43
3.93
3
3
90
6.35
5.97
4
120
90
4
4.77
6.52
4
110
120
120
120
NiII-(S)-BPB-(S)-Ala
NiII-(S)-BPB-(S)-Ala
NiII-(S)-BPB-(S)-Ala
13.10
12.59
15.28
aReaction conditions: the reactions were run in DMF, was concentration of initial complex 0.3 M, ratio
of the initial complex–alkylating agent–NaOH ¼ 1:3.5:5, at 20–25 ꢃC, under Ar.
bChemical yield on the stage of alkylation (mixture of diastereomeric complexes).
cData obtained by chiral HPLC analysis.

ASYMMETRIC SYNTHESIS OF FLUOROPHENYLALANINES
497
Kinetic stereoselectivity of the synthesis was controlled by the relative rate
of the alkylating agent attack on the re- or si- sides of the sp2-carbanion of alanine
moieties of the complexes. The relative thermodynamic stability of the formed
diastereomeric complexes (thermodynamic stereoselectivity) was established in case
of glycine alkylation via the base induced equilibration of the diastereoisomers.
Table 2 summarizes the data of alanine complex (3,4) alkylation. As can be
seen from the data collected in Table 2, the increase of the stereoselectivities of
the alkylations was observed in the modified complexes 3 and 4, as compared with
the unsubstituted complex NiII-(S)-BPB-(S)-Ala [runs 1–6 and 7–9].
The results on C-alkylation of modified complexes 1–4 with fluorine-
substituted benzyl halogenides were in full agreement with the previously obtained
data on the alkylation by other alkylating agents of the same complexes obtained
earlier.[8] As was suggested earlier, the increase in the stereoselectivity in the case
of alkylation of the modified complexes based on 2-CBPB and 3,4-DMBPB was
caused by the change in the sizes of the torsion angle C4–C11–C12–N formed by
=
the phenyl substituent at the -C N- bond. The torsion angle for these complexes
was 81.7ꢃ for NiII-(S)-3,4-DMBPB-(S)-Ala (4) and 70ꢃ for NiII-(S)-2-CBPB-
(S)-Ala (3) (see Fig. 1) (In the case of the unmodified NiII-(S)-BPB-(S)-Ala complex,
this angle was 90ꢃ.)
The decrease of the angle from a 90ꢃ value was accompanied with the inevitable
increase in the shielding of the re- side of the flat carbanion formed in the initial stage
of the reaction. This leads to greater kinetic diastereoselectivity of alkylation in the
case of complexes 3 and 4 (and to greater thermodynamic diastereoselectivity in the
case of complexes 1 and 2 also). Hence, the ratio of (S,S)=(S,R) becomes greater.
The most significant deviation of the C4–C11–C12–N torsion angle from a 90ꢃ value
is observed in the case of amino acid complexes based on a modified chiral auxiliary
(S)-2-CBPB. As a result, high efficiency of the asymmetric reaction is registered
exactly in the case of these complexes. This can also be facilitated by a decrease in
the distance between the Cl and Ni atoms in the case of complex 3 (see Fig. 1).
Figure 1. Structures of 3(a) and exo- and endo-conformers of 4(b) based on PCA data.

498
A. S. SAGHIYAN ET AL.
After decomposition of the complexes 5–8(a–c) with 2N HCl solution, the
target amino acids were isolated from the solution by a routine cation-exchange pro-
cedure followed by crystallization of the raw amino acids from aqueous alcohols.[8]
The initial chiral auxiliaries (S)-2CBPB and (S)-3,4-DMBPB were recovered with
>95% yield with full retention of the initial enantiomeric purity and could be reused
repeatedly without any further purification.
Optically active o-, m-, p-fluorine-substituted derivatives of phenylalanine 9(a–c)
and (S)-b-phenyl-2-methyl-a-alanine 10(a–c) have been obtained in >75% yields and
>99.5% enantiomeric purity.
CONCLUSION
A relatively fast and highly selective asymmetric synthesis of (S)-o-, m-,
p-fluorine-substituted phenylalanines and their 2-methyl-substituted analogs has
been elaborated.
EXPERIMENTAL
The amino acids were purchased from Reanal (Hungary); silica gel L-40=100
from Chemapol (Praha, Czech Republic); CHCl3, CH3CN, CH3OH, NaOH, and
ROH, from Reakhim (Russia); and 2-fluorobenzylbromide, 3-fluorobenzylchloride,
and 4-fluorobenzylbromide from Aldrich. All used solvents were freshly distilled.
Enantiomeric purity of amino acids was determined by HPLC on the chiral phase
Diaspher-110-Chirasel-E-PA 6.0 mkm 4.0 ꢁ 250 mm with 20% MeOH–80% 0.1 M
NaH2PO4 ꢁ 2H2O used as an eluent. A 254-nm ultraviolet (UV) detector was used.
The 1H NMR and 13C NMR spectra were recorded on a Mercury-300 Varian
(300-MHz)instrument in CDCl3 (unless otherwise indicated). The optical rotations
were measured on Perkin-Elmer-341 polarimeter in a 5-cm thermostated cell with
an accuracy of 0.1%.
Alkylations of the initial complexes (1–4) were conducted as previously
described.[5]
Upon completion of the reaction, the mixture was neutralized with AcOH and
diluted with H2O. The precipitate of the mixture of diastereomer complexes was fil-
tered and washed with water. A small part of the mixture (ꢂ0.5 g) was separated by
preparative chromatography [20 ꢁ 20 cm, SiO2, CHCl3–CH3COCH3 (3:1)], and the
structure and absolute configuration of the pure major diastereomer of complexes
5–8(a–c) were established by spectral methods. The ratio of the diastereomers was
determined with chiral HPLC analysis of the amino acid mixture isolated after the
decomposition of the mixture of diastereomeric complexes (without chromato-
graphic purification).
1
Rating of signals in NMR H spectra to hydrogen atoms of methylene groups
CH2-aryl does not present any difficulties, whereas rating of signals of proline
protons and aromatic rings is significantly complicated because of the overlapping
multiplet signals from several nuclei of hydrogen atoms. This requires application
of modern methods of two-dimensional correlation spectroscopy (COSY). The same
methods are also necessary for rating carbon atoms in 13C NMR. Rating of signals
presented in Tables 3 and 4 is based on COSY, heteronuclear multiple quantum

499

500

501

502

ASYMMETRIC SYNTHESIS OF FLUOROPHENYLALANINES
503
correlation (HMQC), and nuclear Overhauser effect spectrosleaopy (NOESY)
experiments.
As can be seen from Table 3, one of hydrogen atoms of the NCH2 proline
group is noticeably shielded and developed in the range of 1.80–1.90 ppm. Values
of J constants show that the given hydrogen atom has an axial configuration. The
other hydrogen atom of this group is developed in the range of 3.15–3.20 ppm, which
is more typical of protons of the NCH2 group. In 13C NMR spectrum this group is
developed in the range of ꢄ57 ppm. The hydrogen atom of proline in the a-position
also occupies the axial position and shows a strong nuclear Overhauser effect (NOE)
with proton in position 6 of the chloro-substituted aromatic ring.
Both 1H and 13C NMR spectra show that positions 2 and 20 as well as 3 and 30
in the phenyl ring are not equivalent, which proves the absence of free rotation of the
whole phenyl group about an axis passing through C–C1–C4. Moreover, as is evi-
dent from the NOESY spectra, hydrogen atoms in positions 2 and 20 have differ-
ent-intensity NOE with proton 3-H of the neighboring aromatic ring. NOE, closer
in intensity, are observed in compound 5a, in which fluorine atom is in the ortho-
position. The torsion angle C4–C11–C12–N is closer to 90ꢃ. Substitution of hydro-
gen atom by a methyl group turns the phenyl ring in such a way that the torsion
angle C4–C11–C12–N decreases thus reducing the distance, between 20-H and 3-H
while the distance between 2-H and 3-H increases. In spectra, this is reflected by
the growth and decrease of intensities of the corresponding NOE signals. In com-
pounds 5b and 5c, where the fluorine atom is in meta- or para-positions, the phenyl
ring is turned in such a way that the distance between 20-H and 3-H is shorter than
the distance between 2-H and 3-H, and introduction of the methyl group (com-
pounds 7b and 7c) strengthens this tendency, resulting in a decrease of the torsion
angle C4–C11–C12–N.
Complex 5a
Yield: 70%. Calcd. for C34H29ClFN3NiO3 (640.76): C, 63.73; H, 4.56; N, 6.56.
20
Found: C, 63.69; H, 4.62; N, 6.59. Mp 238–240 ꢃC. ½aꢅD þ 1951.67 ꢃ (c 0.06, MeOH).
Complex 5b
Yield: 82%. Calcd. for C34H29ClFN3NiO3 (640.76): C, 63.73; H, 4.56; N, 6.56.
20
Found: C, 63.78; H, 4.52; N, 6.60. Mp 192–195 ꢃC. ½aꢅD þ 936.25 ꢃ (c 0.08, MeOH).
Complex 5c
Yield: 81%. Calcd. for C34H29ClFN3NiO3 (640.76): C, 63.73; H, 4.56; N, 6.56.
20
Found: C, 63.69; H, 4.59; N, 6.59. Mp 207–209 ꢃC. ½aꢅD þ 1618.00 ꢃ (c 0.03, MeOH).
Complex 6a
Yield: 62%. Calcd. for C36H34FN3NiO3 (634.37): C, 68.16; H, 5.40; N, 6.62.
20
Found: C, 68.07; H, 5.48; N, 6.55. Mp 258–260 ꢃC. ½aꢅD þ 2056.68 ꢃ (c 0.09, MeOH).

504
A. S. SAGHIYAN ET AL.
Complex 6b
Yield: 72%. Calcd. for C36H34FN3NiO3 (634.37): C, 68.16; H, 5.40; N, 6.62.
20
Found: C, 68.22; H, 5.34; N, 6.67. Mp 205–207 ꢃC. ½aꢅD þ 1025.14 ꢃ (c 0.08, MeOH).
Complex 6c
Yield: 85%. Calcd. for C36H34FN3NiO3 (634.37): C, 68.16; H, 5.40; N, 6.62.
20
Found: C, 68.11; H, 5.38; N, 6.57. Mp 196–198 ꢃC. ½aꢅD þ 1802.02 ꢃ (c 0.03, MeOH).
Complex 7a
Yield: 70%. Calcd. for C35H31ClFN3NiO3 (654.78): C, 64.20; H, 4.77; N, 6.42.
20
Found: C, 64.27; H, 4.69; N, 6.48. Mp 200–202 ꢃC. ½aꢅD þ 1711.25 ꢃ (c 0.08, MeOH).
Complex 7b
Yield: 82%. Calcd. for C35H31ClFN3NiO3 (654.78): C, 64.20; H, 4.77; N, 6.42.
20
Found: C, 64.13; H, 4.65; N, 6.46. Mp 177–179 ꢃC. ½aꢅD þ 1190.0 ꢃ (c 0.09, MeOH).
Complex 7c
Yield: 74%. Calcd. for C35H31ClFN3NiO3 (654.78): C, 64.20; H, 4.77; N, 6.42.
20
Found: C, 64.29; H, 4.82; N, 6.37. Mp 122–124 ꢃC. ½aꢅD þ 2181.25 ꢃ (c 0.08, MeOH).
Complex 8a
Yield: 62%. Calcd. for C37H36FN3NiO3 (648.39): C, 68.54; H, 5.60; N, 6.48.
20
Found: C, 68.47; H, 5.53; N, 6.55. Mp 162–164 ꢃC. ½aꢅD þ 1450.0 ꢃ (c 0.08, MeOH).
Complex 8b
Yield: 75%. Calcd. for C37H36FN3NiO3 (648.39): C, 68.54; H, 5.60; N, 6.48.
20
Found: C, 68.59; H, 5.67; N, 6.41. Mp 218–220 ꢃC. ½aꢅD þ 1395.56 ꢃ (c 0.08, MeOH).
Complex 8c
Yield: 65%. Calcd. for C37H36FN3NiO3 (648.39): C, 68.54; H, 5.60; N, 6.48.
20
Found: C, 68.43; H, 5.56; N, 6.59. Mp 129–131 ꢃC. ½aꢅD þ 2020.05 ꢃ (c 0.03, MeOH).
ACKNOWLEDGMENT
This work was supported by ISTC Grants 2780 and A-1247.
REFERENCES
1. (a) Wildes, R. A.; Pitman, M. G.; Schaefer, N. Comparison of isomers of fluorophenyla-
lanine as inhibitors of ion transport across barley roots. Austral. J. Plant Physiol. 1975, 2,
659–661; (b) Wheatley, D. N.; Henderson, J. Y. p-Fluorophenylalanine and ‘‘division-
related proteins.’’ Nature 1974, 247, 281–283; (c) Gillam, S. S.; Woo, S. L. C.; Woolf, L. I.

ASYMMETRIC SYNTHESIS OF FLUOROPHENYLALANINES
505
The isolation and properties of phenylalanine hydroxylase from rat liver. Biochem. J.
1974, 139, 731–739; (d) Poillon, W. N. Noncovalent inhibitors of sickle hemoglobin
gelation: Effects of aryl-substituted alanines. Biochemistry 1982, 21, 1400–1406.
2. Bikshapathy, E.; Sitaram, N.; Nagaranj, R. Effect of Introducing p-fluorophenylalanine
and multiple tryptophan residues in a 13-residue antibacterial peptide. Protein Peptide
Lett. 1999, 6, 67–71.
3. (a) Gullbo, J.; Lindhagen, E.; Bashir-Hassan, S.; Tullberg, M.; Ehrsson, H.; Lewensohn,
R.; Nygren, P.; Torre, M.; Luthman, K.; Larsson, R. Antitumor efficacy and acute
toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1)
in vivo. Invest. New Drugs 2004, 22, 411–420; (b) Gullbo, J.; Wallinder, C.; Tullberg,
M.; Lovborg, H.; Ehrsson, H.; Lewensohn, R.; Nygren, P.; Luthman, K.; Larsson, R.
¨
Antitumor activity of the novel melphalan containing tripeptide J3 (l-prolyl-l-melphalanyl-
p-l-fluorophenylalanine ethyl ester): Comparison with its m-l-sarcolysin analogue P2.
Mol. Cancer Ther. 2003, 2, 1331–1339.
4. Lourens, D. R.; Benett, P. N. Clinical Pharmacology; Medicina: Moscow, 1993.
5. Soloshonok, V. A.; Belokon, Y. N.; Kukhar, V. P.; Chernoglazova, N. I.; Saporovskaya,
M. B.; Bakhmutov, V. I.; Kolycheva, M. T.; Belikov, V. M. Asymmetric synthesis of
heteroorganic analogs of natural compounds: A convenient preparative method for the
synthesis of enantiomerically pure (S)-(ꢆ)-o-, m-, and p-fluorophenylalanines and their
2-methylsubstituted analogs. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya
1990, 7, 1630–1636.
6. (a) Belokon, Y. N. Chiral complexes of Ni(II), Cu(II), and Cu(I) as reagents, catalysts and
receptors for asymmetric synthesis and chiral recognition of amino acids. Pure Appl.
Chem. 1992, 64, 1917–1924; (b) Soloshonok, V. A.; Ohkura, H.; Sorochinsky, A.;
Voloshin, N.; Markovsky, A.; Belik, M.; Yamazaki, T. Convenient, large-scale asymmetric
synthesis of b-aryl-substituted a,a-difluoro-b-amino acids. Tetrahedron Lett. 2002, 43,
5445–5448.
7. (a) Belokon, Y. N.; Maleev, V. I.; Saporovskaya, M. B.; Bakhmutov, V. I.; Timofeeva, T.
V.; Batsanov, A. S.; Struchkov, Y. T. Ni(II) complexes of Schiff’s base of glycine and ala-
nine with (S)-N-(a-naphtyl)proline derivatives for asymmetric synthesis of amino acids.
Koordinats. Khim. 1988, 11, 1565–1575; (b) Popkov, A.; Gree, A.; Nadvornık, M.; Lycka.
´ ´ ˇ
A. Chiral nucleophilic glycine and alanine synthons: Nickel (II) complexes of Schiff bases
of (S)-N-(2,4,6-trimethylbenzyl)proline (2-benzoylphenyl)amide and glycine or alanine.
Trans. Metal Chem. 2002, 27, 884–887; (c) Belokon’, Y. N.; Maleev, V. I.; Petrrosyan,
A. A.; Savel’eva, T. F.; Ikonnikov, N. S.; Peregudov, A. S.; Khrustalev, V. N.; Saghiyan,
A. S. Halo-substituted (S)-N-(2-benzoylphenyl)-1-benzylpyrolidine-2-carboxamides as
new chiral auxiliaries for the asymmetric synthesis of (S)-a-amino acids. Russ. Chem. Bull.
Int. Ed. 2002, 51, 1593–1599.
8. Saghiyan, A. S.; Dadayan, S. A.; Petrosyan, S. G.; Manasyan, L. L.; Geolchanyan, A. V.;
Djamgaryan, S. M.; Andreasyan, S. A.; Maleev, V. I.; Khrustalev, V. N. New chiral NiII
complexes of Schiff’s bases of glycine and alanine for efficient asymmetric synthesis of a-
amino acids. Tetrahedron: Asymmetry 2006, 17, 455–467.
9. Saghiyan, A. S.; Manasyan, L. L.; Dadayan, S. A.; Petrosyan, S. G.; Petrosyan, A. A.;
Maleev, V. I.; Khrustalev, V. N. Novel modified chiral NiII complexes with the Schiff
bases of (E)- and (Z)-2-aminobut-2-enoic acids. Russ. Chem. Bull. Internat. Ed. 2006,
55, 442–450.
10. (a) Belokon, Y. N.; Bulychev, A.; Vitt, S.; Struchkov, Y.; Batsanov, A.; Timofeeva, T.;
Tsyrypkin, V.; Ryzhov, M.; Lysova, L.; Bakhmutov, V.; Belikov, V. General method of
diastereo- and enantioselective synthesis of b-hydroxy-a-amino acids by condensation
of aldehydes and ketones with glycine. J. Am. Chem. Soc. 1985, 107, 4252–4259; (b)
Belokon, Y. N.; Saghyan, A. S.; Djamgaryan, S. M.; Bakhmutov, V. I.; Vitt, S. V.;

506
A. S. SAGHIYAN ET AL.
Batsanov, A. S.; Struchkov, Y. T.; Belikov, V. M. General method of the asymmetric syn-
thesis of anti-diastereoisomers of b-substituted L-2-aminobutanoic acids via chiral Ni(II)
Schiff’s base complexes of dehydroaminobutanoic acid. X-ray crystal and molecular struc-
ture of the nickel(II) complex of the Schiff’s base from [(benzylprolyl)amino]benzophe-
none and dehydroaminobutanoic acid. J. Chem. Soc. Perkin Trans. 1 1990, 2301–2310;
(c) Saghyan, A. S.; Geolchanyan, A. V.; Petrosyan, S. G.; Ghochikyan, T. V.;
Haroutunyan, V. S.; Avetisyan, A. A.; Belokon, Y. N.; Fisher, F. Asymmetric synthesis
of b-heterocycle substituted L-a-amino acids. Tetrahedron: Asymmetry 2004, 15, 705–711.