Asymmetric synthesis of new β-heterocyclic (S)-α-aminopropionic acids

Article abstract of DOI:10.1016/j.tetasy.2012.05.022

The asymmetric synthesis of novel non-proteinogenic β-heterocyclic α-amino acids via the diastereoselective conjugate addition of heterocyclic nucleophiles to the dehydroalanine moiety of chiral Ni(II) complexes has been studied. The complexes were formed from the Schiff base of dehydroalanine using (S)-2-N-(N-benzylprolyl)aminobenzophenone as a chiral auxiliary. After decomposition of the complexes, the α-amino acids were isolated with 30-99% ee.

Full text of DOI:10.1016/j.tetasy.2012.05.022

Tetrahedron: Asymmetry 23 (2012) 891–897
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of new b-heterocyclic (S)-a-aminopropionic acids
Ashot S. Saghyan a,b, , Hayarpi M. Simonyan b, Lala A. Stepanyan a, Samvel G. Ghazaryan a,
⇑
Arpine V. Geolchanyan b, Luiza L. Manasyan b, Vahe T. Ghochikyan a, Tariel V. Ghochikyan b,
Nelli A. Hovhannisyan a, Ashot Gevorgyan c, Viktor O. Iaroshenko c, Peter Langer c,d,
⇑
a Scientific and Production Center ‘Armbiotechnology’ of NAS RA, Gyurjyan str. 14, 0056 Yerevan, Armenia
b Department of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia
c Institute of Chemistry, University of Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
d Leibniz Institute of Catalysis at the University of Rostock e. V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2012
Accepted 25 May 2012
The asymmetric synthesis of novel non-proteinogenic b-heterocyclic a-amino acids via the diastereose-
lective conjugate addition of heterocyclic nucleophiles to the dehydroalanine moiety of chiral Ni(II)
complexes has been studied. The complexes were formed from the Schiff base of dehydroalanine using
(S)-2-N-(N-benzylprolyl)aminobenzophenone as a chiral auxiliary. After decomposition of the complexes,
the a-amino acids were isolated with 30–99% ee.
Ó 2012 Published by Elsevier Ltd.
1. Introduction
obtained from the Schiff base of dehydroalanine and (S)-BPB, while
NiII-(S)-BPB-
-Aba was prepared from the Schiff base of dehyd-
D
Optically active non-proteinogenic
a
-amino acids have shown a
roaminobutyric acid and (S)-BPB.
wide range of applications in biochemistry, pharmacology, syn-
thetic chemistry, and other fields.1 Among the most commonly
used drugs, more than 60% are heterocyclic compounds.2 For
example, pyrano(thiopyrano)[3,4-c]pyridine derivatives are known
to have anticonvulsive effects;3 1,2,4-triazole-containing drugs
have antitumor and antimicrobial activities,4 and piperazine deriv-
atives have been used in the treatment and prevention of anxiety,
depression, schizophrenia, Parkinson’s disease, delayed dyskinesia,
nausea, and gastroenteric tract function disorders.5 Therefore, ami-
no acids and peptides containing an N-heterocyclic substituent in
the side chain, are of considerable importance in medicinal chem-
istry because they combine the pharmacophoric groups of amino
acids and N-heterocycles. A prominent example is the essential
and natural amino acid tryptophan containing an indole moiety.
In recent years, Belokon6 and Saghyan7 have developed meth-
We have already studied the C-alkylation of Ni(II) complexes
NiII-(S)-BPB-Gly and NiII-(S)-BPB-(S)-Ala with alkyl halides. We
have also studied the addition of various nucleophiles (amines, thi-
ols, and alcohols) to Ni(II) complexes NiII-(S)-BPB- -Ala and NiII-
D
(S)-BPB-D
-Aba.8 The synthesis of heterocyclic amino acids using
this approach has only scarcely been reported on. We reported
the asymmetric synthesis of (R)-S-(1,2,4-triazol-3-yl)cysteines by
S-nucleophilic addition of thiotriazoles to a NiII complex with a chi-
ral dehydroalanine Schiff base.9a We also reported the asymmetric
synthesis of b-triazolyl-(S)-a-aminobutyric acids by N-nucleophilic
asymmetric addition reactions.9b Herein we report for the first
time, the synthesis of various novel heterocyclic amino acids via
asymmetric addition of various heterocycles, such as 6-amino-
2,4-dioxo-1,3-dimethyl-2,3,4-tetrahydropyrimdines, 6-morpholi-
nopyridine-2-thiols, 5-thioxo-1,2,4-triazoles, and piperazines, to
ods for the asymmetric synthesis of
a
- and b-substituted
L-
a-ami-
the dehydroalanine fragment of an NiII-(S)-BPB-
D-Ala complex.
no acids containing various aliphatic and aromatic substituents via
diastereoselective reactions of chiral Ni(II) complexes. (S)-2-N-(N0-
Benzylprolyl)aminobenzophenone [(S)-BPP] has been employed as
a ligand. The amino acids glycine (Gly), alanine ((S)-Ala)), dehydro-
These studies greatly extend the synthetic applicability of the
aforementioned methodology in the field of heterocyclic amino
acids.
alanine (D-Ala), and dehydroaminobutyric acid (D-Aba) have been
2. Results and discussion
used in the form of their Schiff bases with ligands. The Ni complex
NiII-(S)-BPB-Gly was prepared from the Schiff base of glycine and
(S)-BPB, while NiII-(S)-BPB-(S)-Ala was prepared from the Schiff
Our general strategy is outlined in Scheme 1. The addition of
heterocyclic nucleophiles 2a–n to the chiral dehydroalanine com-
base of alanine and (S)-BPB. The complex NiII-(S)-BPB-
D-Ala was
plex NiII-(S)-BPB-
D
-Ala 1, was carried out in acetonitrile in the
presence of K2CO3, and gave complexes 3a–n with good to very
good diastereoselectivities. The target -amino acids 4a–n were
isolated from the mixture of the diastereomeric complexes 3a–n
a
⇑
Corresponding authors. Tel./fax: +374 10 654183 (A.S.S.).
E-mail address: sagysu@netsys.am (A.S. Saghyan).
0957-4166/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetasy.2012.05.022

892
A. S. Saghyan et al. / Tetrahedron: Asymmetry 23 (2012) 891–897
O
O
O
O
CH2
H
O
Nu
NuH
Nu
N
(S)
L
Ni
N
HO
ii
N
2a-n
N
(S)
Ni
N
N
i
H2N
H
O
4a-n
H
O
NiII-(S)-BPB-D-Ala
3a-n
1
8d,e
Scheme 1. Synthesis of 3a–n and 4a–n; conditions: i, CH3CN, K2CO3, 25 or 50 °C; ii. See ref.
.
after acidic hydrolysis and ion-exchange demineralization. The chi-
ral auxiliary (S)-BPB was recovered in a quantitative yield (>95%)
without loss of enantiomeric purity and could be reused.
tilled. 1H NMR spectra were recorded on a ‘Mercury-300 Varian’
(300 MHz) in DMSO-d6/CCl4:1/3 (unless otherwise indicated). The
enantiomeric purity of the amino acids was determined by HPLC
on a 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 elu-
ent. The optical rotations were measured on a ‘Perkin Elmer-341’
polarimeter.
The reaction of 6-amino-2,4-dioxo-1,3-dimethyl-2,3,4-tetrahyd-
ropyrimdine 2a with 1 resulted in the formation of 3a with 85% de
and in 90% yield by regio- and diastereoselective attack of the carbon
atom of the enamine moiety of 2a to the double bond of 1 (Scheme 2,
Table 1). Hydrolysis afforded the novel (S)-amino acid 4a in quanti-
tative yield with 97% ee. The reaction of 1 with ethyl 2-mercapto-6-
morpholino-4-phenyl-nicotinic ester 2b and 3-mercapto-1-mor-
pholino-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile 2c afforded
3b and 3c, respectively, with very good diastereoselectivity. The
complexes were transformed into amino acids 4b and 4c. The struc-
ture of the products and the sulfur-regioselectivity was confirmed
by 1D and 2D NMR spectroscopy.
The reaction of 1 with 3-thio-1,2,4-triazoles 2d–h afforded the
nickel complexes 3d–h in good yields and with very good diastere-
oselectivities (Scheme 3, Table 2). The reactions proceeded by reg-
ioselective attack of nitrogen (instead of the sulfur atom) of the
triazole to the double bond. The structure of the products and
the nitrogen-regioselectivity was confirmed by 1D and 2D NMR
spectroscopy. The hydrolysis of 3d–h afforded the S-configured
amino acids 4d–h with very good enantiomeric excess.
4.2. General method for the synthesis of 3a–n
To 6.6 g (13 mmol) of 1 in 30 ml of MeCN were added 5.4 g
(39 mmol) of K2CO3 and 26 mmol of the nucleophile 2a (8.4 g),
2b (9.0 g), 2c (7.2 g), 2d (5.18 g) 2e (6.01 g), 2f (5.5 g), 2g
(5.67 g), 2h (5.67 g), 2i (4.58 g), 2j (6.63 g), 2k (5.05 g), 2l
(3.28 g), 2m (8.54 g), 2n (5.31 g). The reaction mixture was stirred
at room temperature or at 50 °C (in case of 2a, 2g, 2h, 2m, and 2n)
under an argon atmosphere. The course of the reaction was moni-
tored by TCL (SiO2, CH3COCH3/CHCl3, 1:3) by following the disap-
pearance of the initial complexes 1. Upon completion of the
reaction, the mixture was filtered and extracted by CHCl3
(3 ꢀ 50 ml). A small part of the mixture (0.5 g) was separated by
column chromatography (20 ꢀ 30 cm, SiO2, CH3Cl/CH3COCH3
(5:1)) and the structure and absolute configuration of the pure ma-
jor diastereomer of complexes 3a–n were established by spectro-
scopic methods.
The reaction of 1 with piperazines 2i–n afforded the nickel com-
plexes 3i–n in good yields and with good diastereomeric excess
(Scheme 4, Table 3). The complexes were transformed into the
enantiomerically enriched amino acids 4i–n.
4.2.1. Complex 3a
Yield (90%, 7.78 g). Mp 183–185 °C: ½a D20
¼ þ1634 (c 0.05,
ꢁ
Most of the amino acids prepared are soluble in water. The anti-
microbial activities of
The effect of aqueous solutions (5 mM) on the lawn of test-cultures
sown on -agar was studied (Table 4).
a-amino acids 4i and 4j were investigated.
MeOH): Found: C 61.40; H 5.24; N 12.60. Calcd for C34H34N6O5Ni:
C 61.37; H 5.26; N 12.63: 1H NMR (CDCI3): 1.86 (1H, m,
2.91 (1H, m, -CH2); 1.92 (1H, m, d-CH2); 3.16 (1H, m, d-CH2);
3.33 (1H, dd, J = 9.0, J = 8.1, -CH); 4.14 (1H, dd, J = 4.8, J = 3.1,
c-CH2);
L
c
a
3. Conclusion
CHCH2); 3.77 (1H, d, J = 12.6, CH2C6H5); 4.14 (1H, d, J = 12.6,
CH2Ph); 3.26 (3H, s, CH3); 3.45 (3H, s, CH3); 2.49 (1H, dd, J = 15.0,
J = 3.1, CHCH2); 3.04 (1H, dd, J = 15.0, J = 4.8, CHCH2); 2.41–
2.51(2H, m, b-CH2); 5.42 (br. NH2); 6.99 (1H, m, C6H4); 6.68 (1H,
m, C6H4); 7.16 (1H, ddd, J = 8.6, J = 5.7, J = 3.1, C6H4); 7.21 (1H, m,
C6H5); 7.22 (1H, m, C6H5); 7.35 (2H, m, C6H5); 7.46–7.53 (3H, m,
C6H5); 7.73 (1H, m, C6H5); 7.97 (2H, m, C6H5); 8.34 (1H, d, J = 8.6,
C6H4).
Herein, a range of novel enantiomerically enriched b-heterocy-
clic a-amino acids have been synthesized by Michael additions of
heterocyclic nucleophiles onto the C@C bond of chiral dehydroala-
nine complexes. The products were formed in good to very good
yields and with very good enantiomeric excess.
4. Experimental
4.2.2. Complex 3b
Yield (82%, 9.1 g). Mp 158–160 °C. ½a D20
¼ þ642:0 (c 0.05,
ꢁ
4.1. Materials and methods
MeOH). Found: C 64.61; H 5.22; N 8.14. Calcd for C46H45S1O6N5Ni:
C 64.66; H 5.27; N 8.19. 1H NMR (DMSO): 0.88 (3H, t, Me, J = 7.5);
The silica gel L-40/100 was purchased from ‘Merck’ (Germany),
while (CH2O)n, CHCl3, (CH3CO)2O, CH3COOH, CH3COOC2H5, CH3CN,
Na2CO3, NH4OH, HCl, KOH, and 2-aminobenzophenone were
purchased from Aldrich (USA). All solvents used were freshly dis-
2.03 (2H, m, b,
NCH2Morph); 3.25 (1H, dd, SCH2, J = 13.2, J = 5.0); 3.54 (1H, dd,
-H Pro, J = 10.2, J = 7.0), 3.66 (1H, d, CH2Ph, J = 12.7); 3.67–3.79
c-H Pro); 2.65 (2H, m, b, c-H Pro); 3.21 (4H, m,
a

A. S. Saghyan et al. / Tetrahedron: Asymmetry 23 (2012) 891–897
893
CH3
O
N
O
O
O
O
O
N
H
CH3
O
O
N
L
HO
N
CH3
O
CH3
N
N
(S)
Ni
N
N
NH2
H2N
H2N
N
H2N
CH3
CH3
H
O
O
N
2a
3a
4a
O
N
O
N
N
O
O
N
H
O
S
C6H5
L
HO
N
COOC2H5
S
C6H5
COOC2H5
N
(S)
Ni
N
H2N
HS
C6H5
N
COOC2H5
H
O
2b
4b
3b
O
N
O
O
N
N
N
O
O
N
H
O
S
L
HO
N
CN
S
N
(S)
Ni
N
N
H2N
CN
HS
CN
H
O
4c
3c
2c
Scheme 2. Structures of 2a–c, 3a–c, and 4a–c.
1.73–1.97 (3H, m, b,b0-CH2C6H8); 2.05–2.18 (2H, m,
(2H, m,
a0-CH2C6H8); 2.89 (2H, m,
Pro); 3.10 (1H, m, b-H Pro); 3.21 (1H, dd, SCH2, J = 13.2, J = 5.0); 3.22
(4H, m, NCH2Morph); 3.43 (1H, dd, -H Pro, J = 10.2, J = 7.0);
3.63(1H, d, CH2Ph, J = 12.7); 3.63–3.79 (2H, m, ,d-H Pro); 3.74
(4H, m, OCH2 Morph); 3.86 (1H, dd, SCH2, J = 13.2, J = 3.6); 4.40
(1H, dd, CHCH2S, J = 5.0, J = 3.6); 4.42 (1H, d, CH2C6H5, J = 12.7);
6.59–6.67 (2H, m, Ar), 7.04 (1H, br.d., Ar, J = 7.6); 7.16 (1H, ddd,
Ar, J = 8.7, J = 6.0, J = 2.6); 7.20 (1H, m, Ar); 7.27–7.42 (4H, m, Ar);
c
,d-H Pro); 2.48
Table 1
Yields and enantiomeric purity of 3a–c and 4a–c
a,
a,
a0-CH2C6H8); 2.56 (1H, m, b-H
2,3,4
Reaction time (T)
dea
Config.
eeb
% 3c
a
a
b
c
180 (50 °C)
10 (25 °C)
40 (25 °C)
85
88
86
(S)
(R)
(R)
97
—
—
90
82
88
c
a
b
c
Diastereomeric purity (de) of 3a–c (by 1H NMR) in %.
Enantiomeric purity (ee) of 4a–c after crystallization (by chiral HPLC).
Isolated yields of 3a–c.
7.45–7.57 (2H, m, Ar); 8.04 (2H, m, Ar); 8.32 (1H, dd, Ar, J = 8.7,
13
J = 1.0). C NMR (DMSO): 22.1 and 22.9 (b,b0-CH2C6H8); 24.0 (
c
-C
a0-CH2C6H8); 31.4 (b-C Pro); 33.4 (SCH2);
49.6 (NCH2 Morph); 57.6 (d-C Pro); 63.5 (CH2Ph); 66.9 (OCH2
Morph); 68.6 (CHCH2S); 71.0 ( -C Pro); 100.4 (C6H4); 115.7
(2H, m, c,d-H Pro); 3.71 (4H, m, OCH2 Morph); 3.86 (1H, dd, SCH2,
J = 13.2, J = 3.6); 3.89 (2H, OCH2); 4.42 (1H, dd, CHCH2S, J = 5.0,
J = 3.6); 4.42 (1H, d, CH2Ph, J = 12.7); 6.1–8.35 (m, 20H, Ar).
Pro); 26.8 and 28.6 (a,
a
(C6H4); 119.4 (C6H4); 120.6 (C6H4); 124.1 (C6H4); 126.2 (Ph);
126.3 (Ph); 127.2 (Ph); 128.4 (Ph); 129.0 (Ph); 129.1 (Ph); 129.2
(Ph); 129.8 (Ph); 131.9 (Ph);132.8 (C);133.5 (C); 133.6(C); 134.5
(C); 143.7 (C); 151.5 (C); 156.7 (C); 161.4(C); 171.9 (C); 177.5 (C);
180.6 (C).
4.2.3. Complex 3c
Yield (88%, 8.99 g). Mp 183–185 °C. ½a D20
¼ þ1134:0 (c 0.05,
ꢁ
CH3OH). Found: C 64.29; H 5.31; N 10.73. Calcd for C42H42N6O4SNi:
C 64.22; H 5.35; N 10.70. 1H NMR (DMSO): 1.65 (1H, m, b-CH2C6H8);

894
A. S. Saghyan et al. / Tetrahedron: Asymmetry 23 (2012) 891–897
R2
S
O
N
O
S
H
O
R2
L
N
S
R1
HO
N
N
R2
N
N
N
(S)
Ni
N
N
N
H2N
N
H
R1
N
R1
H
O
4d-h
3d-h
Scheme 3. Structures of 2d–h, 3d–h, and 4d–h.
2d-h
Table 2
Yields and enantiomeric purity of 3d–h and 4d–h
2,3,4
Min (T)
R1
R2
dea
Config.
eeb
97
% 3c
d
180 (25 °C)
nBu
nPr
93
(86)
93
(84)
95
(S)
72
e
f
180 (25 °C)
60 (25 °C)
Bn
Allyl
(S)
(S)
97
98
68
60
nBu
2-Methallyl
(89)
96
97
g
h
180 (25 °C) 40 (50 °C)
200 (25 °C) 45 (50 °C)
3-Pyridyl
4-Pyridyl
Allyl
Allyl
(S)
(S)
—
—
62
58
a
Diastereomeric purity (de) of 3d–h by 1H NMR (in brackets: by chiral HPLC) in %.
Enantiomeric purity (ee) of 4d–h after crystallization (by chiral HPLC).
b
c
Isolated yields of 3d–h.
R1
O
N
O
H
O
N
L
HO
H
N
N
CH2R1
N
(S)
N
Ni
N
N
H2N
N
R1
H
O
2i-n
3i-n
4i-n
Scheme 4. Structures of 2i–n, 3i–n, and 4i–n.
Table 4
Table 3
Yields and enantiomeric purity of 3i–n and 4i–n
The effect of amino acids 4i and 4j on the growth of microorganisms
Strains
Medium
Compound
a
2,3,4
Min (T)
R1
de
Config.
eeb
% 3c
4i
4j
i
j
k
l
m
n
20 (25 °C)
30 (25 °C)
35 (25 °C)
35 (25 °C)
480 (50 °C)
300 (50 °C)
Ph
(81)
(74)
(84)
58
66
63
(S)
(S)
(S)
88
77
89
—
—
—
75
80
85
60
73
70
Escherichia coli DH5
Citrobacter freundii 62
Erwinia sp.
Corynebacterium glutamicum 191
Campylospermum flavum E 531
a
LA
LA
LA
LA
LA
+
+
—
—
—
+
—
+
+
+
4-BrC6H4
2-FC6H4
Vinyl
3,5-Ph2C6H3
3,5-Me2C6H3
+
Culture growth.
Diastereomeric purity (de) of 3i–n by 1H NMR (in brackets: by chiral HPLC) in %.
Enantiomeric purity (ee) of 4i–n after crystallization (by chiral HPLC).
Isolated yield of 3i–n.
a
b
c
m, d-H, Pro); 2.16 (1H, m,
c-H, Pro); 2.50 (2H, td,
a-CH2, C4H9,
J = 7.6, J = 3.0); 2.56 (1H, m, b-H Pro); 2.83 (1H, m, b-H, Pro); 3.43
(1H, dd, -H Pro, J = 10.6, J = 6.0); 3.59 (1H, d, CH2Ph, J = 12.8);
3.60 (1H, m, -H, Pro); 3.72 (1H, m, d-H Pro); 3.86 (2H, m, -CH2,
C3H7); 4.41 (1H, d, CH2Ph, J = 12.8); 4.42 (1H, dd, NCH2CH, J = 7.3,
J = 6.2); 4.66 (1H, dd, NCH2CH J = 13.5, J = 6.2); 4.95 (1H, dd,
NCH2CH, J = 13.5, J = 7.3); 6.61 (1H, m, Ar); 6.65 (1H, m, Ar); 7.03
(1H, d, Ar, J = 7.6); 7.15 (1H, ddd, Ar, J = 8.6, J = 6.6, J = 2.3); 7.20
a
4.2.4. Complex 3d
Yield (72%, 6.64 g). Mp 133–135 °C. ½a D20
ꢁ
¼ þ1734:0 (c 0.05,
c
a
CH3OH). Found: C 62.60; H 5.91; N 11.82. Calcd for C37H42O3N6SNi:
C 62.62; H 5.92; N 11.84. 1H NMR (CDCl3): 0.91 (t, 3H, CH3, C4H9
J = 7.3); 0.97 (t, 3H, CH3, C3H7, J = 7.4); 1.37 (m, 2H,
c-CH2, C4H9);
1.57 (2H, m, b-CH2, C4H9); 1.77 (2H, m, b-CH2, C3H7); 2.09 (1H,

A. S. Saghyan et al. / Tetrahedron: Asymmetry 23 (2012) 891–897
895
(1H, m, Ar); 7.27–7.43 (4H, m, Ar), 7.48–7.58 (2H, m, Ar); 8.02 (2H,
m, Ar); 8.24 (1H, d, Ar, J = 8.6).
7.19 (1H, m, Ar); 7.35 (2H, m, Ar); 7.35 (1H, m, Ar); 7.42 (1H, td,
J = 7.4, J = 1.4, Ar); 7.48 (2H, m, Ar); 7.51 (1H, m, Ar); 7.58 (1H,
m, Ar); 8.02 (2H, m, Ar); 8.25 (1H, dd, J = 8.7, J = 1.0, Ar); 8.71
(2H, m, Ar).
4.2.5. Complex 3e
Yield (68%, 6.56 g). Mp 120–123 °C. ½½a D20
¼ þ514:0 (c 0.3,
ꢁ
MeOH). Found: C 64.53; H 4.51; N 11.99. Calcd for C38H33N6NiSO3:
4.2.9. Complex 3i
C 64.04; H 4.61; N 11.79. 1H NMR (CDCl3/CCl4 1/1): 2.06 (1H, m, d-
Yield (75%, 6.69 g). Mp 112–115 °C. Found: C 68.26; H 6.07; N
H Pro); 2.06 (1H, m,
H Pro); 3.44 (1H, dd,
J = 12.6); 3.62 (1H, m,
c
-H Pro); 2.50 (1H, m, b-H Pro); 2.78 (1H, m, b-
-H Pro, J = 10.7, J = 6.0); 3.58 (1H, d, CH2Ph,
-H Pro); 3.64 (1H, m, d-H Pro); 3.93 (2H,
10.26. Calcd for
C39H41O3N5Ni: C 68.24; H 6.02; N 10.20.
a 2D0
¼ þ1177:5 (c 0.0024, CH3OH). 1H NMR (CDCl3 /CCl4 = 1/1):
a
½ ꢁ
c
2.05 (1H, m,
c-H Pro); 2.07 (1H, m, d-H Pro); 2.40–2.56 (8H,
s, CH2Ph); 4.38–4.49 (5H, m, CH2Allyl, CH2Ph, NCH2CH); 5.09 (1H,
dq, @CH2, J = 17.2 J = 1.3); 5.15 (1H, dd, NCH2CH, J = 11.6, J = 6.7);
5.19 (1H, dq, @CH2, J = 10.4, J = 1.3); 5.73 (1H, ddt, @CH, J = 17.2,
J = 10.4, J = 5.3); 6.63 (1H, dd, Ar, J = 8.3, J = 2.2); 6.67 (1H, ddd,
Ar, J = 8.3, J = 6.5, J = 1.1); 7.04 (1H, m, Ar); 7.10–7.31 (8H, m, Ar);
8.04 (2H, m, Ar); 8.23 (1H, dd, Ar, J = 8.6, J = 1.1).
m,C4H8N2); 2.51 (1H, m, b-H Pro); 2.72 (1H, m, b-H Pro); 2.85
(1H, dd, J = 13.6, J = 5.5, CH2CH); 2.94 (1H, dd, J = 13.6, J = 4.9,
CH2CH); 3.42 (1H, dd, J = 10.8, J = 6.1,
azine-CH2Ph); 3.55 (1H, m, d-H Pro); 3.56 (1H, d, J = 12.6, CH2Ph);
3.67 (1H, m, -H Pro); 3.96 (1H, dd, J = 5.5, J = 4.9, CHCH2); 4.41
a-H Pro); 3.48 (2H, s, piper-
c
(H, d, J = 12.6, CH2Ph); 6.59 (1H, dd, J = 8.2, J = 2.2, Ar); 6.63 (1H,
ddd, J = 8.2, J = 6.5, J = 1.1, Ar); 6.95 (1H, m, Ar); 7.10 (1H, ddd,
J = 8.6, J = 6.5, J = 2.2, Ar); 7.15 (1H, m, Ar); 7.20–7.34 (8H, m, Ar),
7.38–7.51 (3H, m, Ar), 8.02 (2H, m, Ar); 8.20 (H, dd, J = 8.6,
4.2.6. Complex 3f
Yield (60%, 5.62 g). Mp 135–137 °C. Found: C 63.27; H 5.83; N
J = 0.9, Ar). 13C NMR: 24.01 (
c-C Pro); 30.93 (b-C Pro); 52.59 and
11.66. Calcd for
C38H42N6NiO3S: C 63.35; H 5.80. N 11.60.
½
a 2D0
ꢁ
¼ þ2064:0 (c 0.05, CH3OH). 1H NMR (CDCl3/CCl4 = 1/1) 0.90
54.67 (C); 57.17 (C Pro); 62.69 (CH2CH); 63.13 (CH2Ph); 63.15
(CH2Ph); 70.22 (CHCH2); 70.39 (C Pro); 120.65 (C); 123.60 (C);
126.39; 127.15 (CH); 127.40 (CH); 128.26 (2CH); 128.77 (CH);
128.81 (CH); 128.92 (3CH); 131.65 (2CH); 132.28 (C); 133.31;
133.47 (C); 134.29(C); 137.77(C); 142.82(C); 170.77(C);
178.36(C); 180.28(C).
(3H, t, CH3Bu, J = 7.3); 1.35(2H, m, CH2Bu); 1.57 (2H, m, CH2Bu);
1.74 (3H, s, CH3C@C); 2.09 (1H, m, d-H Pro); 2.19 (1H, m,
Pro); 2.46 (2H, -CH2Bu); 2.54 (1H, m, b-H Pro); 2.81 (1H, m, b-H
Pro); 3.44 (1H, dd, -H Pro, J = 10.8, J = 6.0); 3.58 (1H, d, CH2Ph,
J = 12.6); 3.64 (1H, m, d-H Pro); 3.78 (1H, m, -H Pro); 4.40 (1H,
c-H
a
a
c
m, CHCH2); 4.41 (1H, d, CH2Ph, J = 12.6); 4.44 (1H, m, CHCH2);
4.46 (1H, d, NCH2, J = 16.5); 4.57 (1H, d, NCH2, J = 16.5); 4.64 (1H,
s, @CH2); 4.90 (1H, s, @CH2); 5.16 (1H, dd, CHCH2, J = 15.0,
J = 10.3); 6.64 (1H, m, Ar); 6.66 (1H, m, Ar); 7.08 (1H, d, J = 7.6,
Ar); 7.15 (1H, ddd, Ar, J = 8.6, J = 5.5, J3 = 3.3); 7.20 (1H, m, Ar);
7.32 (1H, m, Ar); 7.36 (2H, m, Ar); 7.43–7.60 (3H, m, Ar); 8.03
(2H, m, Ar); 8.23 (1H, d, Ar, J = 8.7).
4.2.10. Complex 3j
Yield (80%, 7.96 g). Mp 122–125 °C. ½a D20
¼ þ1890 (c 0.02,
ꢁ
CH3OH). Found: C 61.26; H 5.31; N 9.19. Calcd for C39H40O3N5-
NiBr: C 61.20; H 5.27; N 9.15. 1H NMR (CDCl3 /CCl4 = 1/1): 2.05
(1H, m, d-H Pro); 2.06 (1H, m,
2.36–2.53 (7H, m, C4H8N); 2.45 (1H, m, b-H Pro); 2.71 (1H, m,
b-H Pro); 2.86 (1H, dd, J = 13.5, J = 5.6, NCHCH2N); 2.90 (1H, dd,
J = 13.5, J = 4.8, NCHCH2N); 3.40 (2H, s, CH2Ph); 3.41 (1H, dd,
c-H Pro); 2.09 (1H, m, C4H8N);
4.2.7. Complex 3g
Yield (62%, 5.87 g). Mp 165–167 °C. Found: C 62.25; H 4.66; N
J = 10.7, J = 6.1
a-H Pro); 3.55 (1H, m, d-H Pro); 3.56 (1H, d,
13.01. Calcd for
C38H35O3N7SNi: C 62.64; H 4.81; N 13.46.
J = 12.6, CH2Ph); 3.66 (1H, m,
c-H Pro); 3.94 (1H, dd, J = 5.6,
½
a 2D0
ꢁ
¼ þ1801:4 (c 0.07, CH3OH). 1H NMR (CDCl3/CCl4 = 1/1): 2.11
J = 4.8, CH); 4.40 (1H, d, J = 12.6, CH2Ph); 6.58 (1H, dd, J = 8.2,
J = 2.2, Ar); 6.62 (1H, ddd, J = 8.2, J = 6.6, J = 1.1, Ar); 6.95 (1H,
m, Ar); 7.09 (1H, ddd, J = 8.7, J = 6.6, J = 2.2, Ar); 7.13 (2H, m,
Ar); 7.14 (1H, m, Ar); 7.24 (1H, m, Ar); 7.30 (2H, m, Ar); 7.38
(2H, m, Ar); 7.38–7.52 (3H, m, Ar); 8.01 (2H, m, Ar); 8.20 (1H,
(1H, m, d-H Pro); 2.08 (1H, m,
c-H Pro); 2.49 (1H, m, b-H Pro);
2.76 (1H, m, b-H Pro); 3.43 (1H, dd, J = 10.7, J = 6.0,
3.57 (1H, d, J = 12.6, CH2Ph); 3.58 (1H, m, d-H Pro); 3.67 (1H, m,
-H Pro); 4.39 (1H, d, J = 12.6, CH2Ph); 4.48 (1H, dd, J = 7.9,
a-H Pro);
c
J = 6.1, CHCH2N); 4.58 (1H, dd, J = 13.2, J = 6.1, NCH2CH); 4.66
(1H, ddt, J = 16.5, J = 4.7, J = 1.6, CH2Allyl); 4.72 (1H, ddt, J = 16.5,
J = 4.7, J = 1.6, CH2Allyl); 5.13 (1H, dt, J = 17.2, J = 1.6, @CH2Allyl);
5.17 (1H, dd, J = 13.2, J = 7.9, NCH2CH); 5.30 (1H, dt, J = 10.5,
J = 1.6, CHAllyl); 5.93 (1H, ddt, J = 17.3, J = 10.5, J = 4.7, @CH2Allyl);
6.63 (1H, m, Ar); 6.66 (1H, m, Ar); 7.16 (1H, m, Ar); 7.16 (1H, m,
Ar); 7.19 (1H, m, Ar); 7.30–7.60 (7H, m, Ar); 7.87 (1H, dd, J = 8.0,
J = 2.2, J = 1.6, Ar); 8.03 (2H, m, Ar); 8.23 (1H, d, J = 8.7, Ar); 8.72
(2H, dd, J = 4.9, J = 1.6, Ar); 8.08 (1H, d, J = 2.2, Ar).
dd, J = 8.7, J = 1.1, Ar); 13C NMR: 24.0 (
c
-C, Pro); 30.9 (b-C Pro);
52.6 (C4H8N2); 54.6 (C4H8N2); 57.2 (d-C Pro); 62.4 (CH2C6H4Br);
62.6 (NCH2CHN); 63.2 (CH2Ph); 70.1 (NCHCH2N); 70.3 ( -C Pro);
a
120.6 (C6H4); 121.0 (C); 123.6 (C6H4); 126.3 (C); 127.4 (C6H5);
128.7 (CH); 128.8 (CH); 128.9 (Ph); 128.9 (CH); 129.0 (CH);
129.7 (CH); 130.8 (C6H4Br); 131.4 (C6H4Br);; 131.7 (Ph); 132.3
(C6H4); 133.3 (C); 133.4 (C6H4); 134.3 (C); 137.0 (C); 142.9 (C);
170.7 (C); 178.2 (C); 180.2(C).
4.2.11. Complex 3k
4.2.8. Complex 3h
Yield (85%, 7.78 g). Mp 130–132 °C. ½a D20
¼ þ2042:1 (c 0.057,
ꢁ
Yield (58%, 5.49 g). Mp 168–170 °C. Found: C 62.25; H 4.66; N
CH3OH). Found: C 66.51; H 5.78; N 9.91. Calcd for C39H40O3N5NiF:
13.01. Calcd for
C38H35O3N7SNi: C 62.64; H 4.81; N 13.46.
C 66.49; H 5.72; N 9.94. 1H NMR (CDCl3/CCl4 = 1/1): 2.00 (1H, m,
c-
½
a 2D0
ꢁ
¼ þ1892:25 (c 0.07, CH3OH). 1H NMR (CDCl3 /CCl4 = 1/1):
H Pro); 2.04 (1H, m, d-H Pro); 2.38–2.56 (8H, m, C4H8N2); 2.49 (1H,
m, b-H Pro); 2.68 (1H, m, b-H Pro); 2.79 (1H, dd, J = 13.6, J = 5.4,
CHCH2); 2.91 (1H, dd, J = 13.6, J = 4.8, CHCH2); 3.39 (H, dd,
2.07 (1H, m, d-H Pro); 2.08 (1H, m,
c-H Pro); 2.48 (1H, m, b-H
Pro); 2.74 (m, 1H, b-H Pro); 3.42 (1H, dd, 3J = 10.7, 3J = 6.0,
Pro); 3.58 (1H, d, 2J = 12.6, CH2Ph); 3.60 (1H, m, d-H Pro); 3.65
(1H, m, -H Pro); 4.39 (1H, d, J = 12.6, CH2Ph); 4.46 (1H, dd,
a-H
J = 10.7; J = 6.2,
a-H Pro); 3.53 (1H, m, d-H Pro); 3.55 (1H, d,
c
J = 12.7, CH2Ph); 3.56 (2H, s, CH2Ph); 3.65 (1H, m,
c-H Pro); 3.94
J = 7.9, 6.1, CHCH2N); 4,57 (1H, dd, J = 13.2, J = 6.1, NCH2CH); 4.69
(1H, ddt, J = 16.5, J = 4.8, J = 1.7, CH2Allyl); 4.74 (1H, ddt, J = 16.5,
J = 4.5, J = 1.7, CH2Allyl); 5.14 (1H, dt, J = 17.2, J = 1.7, @CH2); 5.15
(1H, dd, J = 13.2, J = 7.9, NCH2CH); 5.32 (1H, dt, J = 10.5, J = 1.7,
@CH2); 5.94 (1H, ddtd, J = 17.2, J = 10.5, J = 4.8, J = 4.5, @CH); 6.63
(1H, m, Ar); 6.66 (1H, m, Ar); 7.12 (1H, m, Ar); 7.15 (1H, m, Ar);
(1H, dd, J = 5.4, J = 4.8, CHCH2); 4.39 (1H, d, J = 12.7, CH2Ph); 6.57
(1H, dd, J = 8.2, J = 2.1, Ar); 6.61 (1H, ddd, J = 8.2, J = 6.5, J = 1.1,
Ar); 6.91–7.20 (6H, m, Ar); 7.23 (1H, m, Ar); 7.29 (1H, m, Ar);
7.29 (2H, m, Ar); 7.36–7.51 (3H, m, Ar); 8.00 (2H, m, Ar); 8.21
(1H, dd, J = 8.7, J = 1.1, Ar). 13C NMR: 24.0 (
c-C Pro); 30.9 (b-C

896
A. S. Saghyan et al. / Tetrahedron: Asymmetry 23 (2012) 891–897
Pro); 52.3 and 54.7 (C4H8N2); 55.2 (d, J = 2.0, CH2-Ar); 57.1 (d-C
Pro); 62.5 (CH2CH); 63.1 (CH2Ph); 70.3 (CHCH2); 70.3 ( -C Pro);
19.9 (CH3); 24.1 (
54.8 (CH2 C4H8N2); 57.2 (d-C, Pro); 62.8 (CH2CH); 63.0 (CH); 63.2
(CH2Ph); 70.4 (CHCH2N); 70.4 ( -C Pro); 120.6 (C); 123.7 (C);
126.4 (C); 127.0 (C6H5); 127.5 (CH); 128.8 (CH); 129.0 (CH);
129.0 (Ph); 129.0 (C); 129.0 (C); 129.6 (C); 129.8 (C); 130.8 (C);
131.8 (Ph); 132.4 (C6H4); 133.3 (C).
c-C Pro); 31.0 (b-C Pro); 52.7 (CH2 C4H8N2);
a
115.3 (d, J = 22.4, C6H4F); 120.6 (C6H4); 123.6 (C6H4); 123.8 (d,
J = 3.6, C6H4F); 124,4 (d, J = 14.7, C6H4F); 126.3 (C); 127.4 (CH);
128.7 (CH); 128.8 (d, J = 3.6, C6H4F); 128.9 (Ph); 128.9 (CH);
129.7 (CH); 131.6 (Ph); 131.7(d, J = 4.5, C6H4F); 132.2 (C6H4);
133.3 (C); 133.4 (C6H4); 134.4 (C); 142,9 (C); 161.5 (d, C6H4F);
170.7 (C); 178,2 (C); 180.2 (C).
a
4.3. Isolation of the target amino acids 4a–n
Decomposition of the diastereomeric complexes 3a–k and iso-
4.2.12. Complex 3l
lation of the target b-substituted
a-amino acids 4a–k were carried
Yield (60%, 4.96 g). Mp 177–180 °C. ½a D20
¼ þ1639:2 (c 0.18,
ꢁ
out according to the literature.8d,e
CH3OH). Found: C 65.66; H 5.96; N 11.28. Calcd for C34H37O3N5Ni:
C 65.61; H 5.99; N 11.25. 1H NMR (CDCl3/CCl4 1/1): 2.06 (1H, m, d-
4.3.1. (S)-2-Amino-3-(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-
H Pro); 2.12 (1H, m,
H Pro); 2.73 (1H, m, b-H Pro); 2.81–2.95 (4H, m, CH2CH, CH2Allyl);
3.40 (1H, dd, J = 10.7, J = 6.0 -H Pro); 3.54 (1H, d, J = 12.5, CH2Ph);
3.55 (1H, m, d-H Pro); 3.67 (1H, m, -H Pro); 3.93 (1H, t, J = 5.3,
CHCH2); 4.39 (1H, d, J = 12.5, CH2Ph); 5.05–5.15 (2H, m, @CH2);
5.76 (1H, ddt, J = 17.0, J = 10.3, J = 6.5, CH@CH2); 6.54–6.63 (2H,
m, Ar); 6.94 (1H, m, Ar); 7.07 (1H, ddd, J = 8.6, J = 6.4, J = 2.3, Ar);
7.12 (1H, m, Ar); 7.23 (1H, m, Ar); 7.28 (2H, m, Ar); 7.37–7.50
(3H, m, Ar); 8.00 (2H, m, Ar); 8.18 (1H, d, J = 8.6, Ar). 13C NMR:
c-H Pro); 2.42 (8H, m, C4H8N2); 2.48 (1H, m, b-
tetrahydropyrimidine-5-yl) propionic acid 4a
Yield (40%, 1.16 g). Mp 224–226 °C, ½a D20
¼ ꢂ13:5 (c 0.2, 6 M
ꢁ
a
HCl). Found: C 44.52; H 5.72; N 23.18. Calcd for C9H14N4O4: C
44.6; H 5.78; N 23.13. 1H NMR (DMSO/CF3COOD): 2.75 (dd,
J = 15.2, J = 8.2, CH2); 2.97 (dd, J = 15.2, J = 5.6, CH2); 3.15 (s,
NNCH3); 3.32 (s, NCH3); 3.89 (dd, J = 8.2, J = 5.6, CH).
c
4.3.2. (R)-2-Amino-3-(3-ethoxycarbonyl)-6-morpholino-4-phe-
nylpyridin-2-ylthio)propionic acid 4b
24.0 (
(d-C Pro); 61.8 (NCH2); 62.7 (NCH2); 63.1 (NCH2); 70.1 (CHCH2);
70.3 ( -C Pro); 118.0 (@CH2); 120.6 (C); 123.6 (C); 126.3 (C);
c-C Pro); 30.9 (b-C Pro); 52.6 (C4H8N2); 54.5 (C4H8N2); 57.2
Yield (35%, 1.66 g). Mp 78–80 °C. ½a D20
¼ þ16:5 (c 0.46, 6 M HCl).
ꢁ
Found: C 58.41; H 5.4; N 9.69. Calcd for C21H25S1O5N3: C 58.46; H
5.8; N 9.74. 1H NMR (DMSO + CF3COOD): 0.74 (3H, t, J = 7.1, CH3),
3.18 (1H, dd, J = 14.3, J = 9.5, SCH2), 3.55–3.70 (8H, m, CH2Morph),
3.75–3.90 (2H, m, OCH2), 3.99 (1H, dd, J = 14.3, J = 3.8, SCH2), 4.08
(1H, dd, J = 9.5, J = 3.8, CH), 6.32 (1H, s, CHPyr), 7.18 (2H, m), 7.29–
7.36 (3H, m, C6H5).
a
127.4 (C); 128.7 (C); 128.8 (C); 128.9 (Ph); 128.9 (C); 129.7 (C);
131.6 (Ph); 132.2 (C); 133.3 (C); 133.4 (C); 134.9 (C); 142.8 (C);
170.7 (C); 178.1 (C); 180.2 (C).
4.2.13. Complex 3m
Yield (73%, 7.24 g). Mp 133–137 °C. ½a D20
¼ þ1392:3 (c 0.16,
ꢁ
4.3.3. (R)-2-Amino-3-(4-cyano-1-morpholino-5,6,7,8-tetrahy-
CH3OH). Found: C 73.09; H 5.94; N 8.31. Calcd for C51H49O3N5Ni:
C 73.04; H 5.89; N 8.35. 1H NMR (CDCl3/CCl4 1/1): 2.04 (1H, m,
droisoquinolin-3-ylthio)propionic acid 4c
Yield (33%, 1.446 g). Mp 170–172 °C. ½a D20
¼ þ20:7 (c 0.27, 6 M
ꢁ
c-H Pro); 2,05 (1H, m, d-H Pro); 2,44 (4H, m, CH2 piperazine);
HCl). Found: C 56.39, H 6.04, N 15.49, Calcd for C17H22N4O3S: C
56.35, H 6.07, N 15.46. 1H NMR (DMSO + CF3COOD): 1.67 (2H, m)
and 1.81 (2H, m, CH2C6H8), 2.49 (2H, t, J = 6.3, CH2C6H8), 2.79
(2H, t, J = 6.5, CH2C6H8), 3.30 (4H, m, NCH2 Morph), 3.43 (1H, dd,
J = 14.4, J = 8.7, SCH2), 3.69 (4H, m, OCH2 Morph), 3.99 (1H, dd,
J = 14.4, J = 4.3, SCH2), 4.12 (1H, dd, J = 8.7, J = 4.3, CHNH2).
2.52 (1H, m, CH2 piperazine); 2.54 (1H, m, b-H Pro); 2.70 (1H, m,
b-H Pro); 2.83 (1H, dd, J = 13.6, J = 5.3, NCH2CH); 2.99 (1H, dd,
J = 13.6, J = 4.9, NCH2CH); 3.41 (1H, dd, J = 10.8, J = 6.1,
3.56 (1H, m, d-H Pro); 3.58 (1H, d, J = 12.6, CH2Ph); 3.66 (1H, m,
-H Pro); 3.96 (1H, dd, J = 5.3, J = 4.9, CHCH2N); 4.27 (1H, s,
a-H Pro);
c
NCH(Ph)2); 4.43 (1H, d, J = 12.6, CH2Ph); 6.59 (1H, dd, J = 8.2,
J = 1.9, Ar); 6.63 (1H, ddd, J = 8.2, J = 6.7, J = 0.9, Ar); 6.97 (1H, d,
3J = 7.4, Ar); 7.08–7.50 (18H, m, Ar); 8.01 (2H, m, Ar); 8.23 (1H, d,
4.3.4. (S)-2-Amino-(3-butyl-4-propyl-5-thio-1,2,4-triazol-1-yl)-
propionic acid 4d
3J = 8.6, Ar). 13C NMR: 24.1 (
piperazine); 55.2(CH2
62.8(NCH2CH);63.2(CH2Ph); 70.4(CHCH2N);70.5 (
c
-C Pro); 31.1 (b-C Pro); 51.5 (CH2
piperazine); 57.2 (d-C Pro);
-C Pro); 76.1
Yield (48%, 1.29 g). Mp 192–194 °C. Found: C 50.32; H 7.67; N
19.56. Calcd for
C12H22N4O2S: C 50.35; H 7.69; N 19.58.
a
½
a 2D0
ꢁ
¼ ꢂ10:4 (c 0.5, 4.9 M HCl). 1H NMR (D2O): 0.97–1.03 (6H, m,
(CH(Ph)2); 120.7(C); 123.7(C); 126.5(C); 127.1(C); 127.5(C);
128.2(C); 128.3(C); 128.5(C); 128.6(C); 128.8(C); 129.0 (C);
129.0(C); 129.8(C); 131.8(C); 132.4(C); 133.3(C); 133.6(C);
134.5(C); 142.4(C); 142.4(C); 143.0(C); 170.8(C); 178.4(C); 180(C).
CH3); 1.48 (2H, m,
c-CH2, C4H9); 1.73–1.90 (4H, m, b-CH2, C4H9
and b-CH2, C3H7); 2.83 (2H, t,
a-CH2, C4H9, J = 7.5); 4.04 (2H, t, a-
CH2, C3H7, J = 7.7); 4.32 (1H, t, NCH, J = 6.0); 4.75 (2H, m, NCH2CH).
4.3.5. (S)-2-Amino-3-(3-benzyl-4-allyl-5-thio-1,2,4-triazol-1-yl)-
propionic acid 4e
4.2.14. Complex 3n
Yield (70%, 6.50 g). Mp 105–110.
½
a 2D0
ꢁ
¼ þ1137:1 (c 0.23,
Yield (44%, 1.24 g). Mp 225–228 °C. Found: C 56.38; H 5.32; N
CH3OH). Found: C 68.95; H 6.38; N 9.85. Calcd for C41H45O3N5Ni:
17.73. Calcd for
C15H18O2N4S: C 56.60; H 5.66; N 17.61.
C 68.92; H 6.35; N 9.80. 1H NMR (CDCl3/CCl4 1/1): 2.07 (1H, m,
½
a 2D0
ꢁ
¼ ꢂ4:2 (c 1.0, 6 M HCl). 1H NMR (DMSO + CF3COOD): 4.04
c-H Pro); 2.07 (1H, m, d-H Pro); 2.23 (3H, s, CH3); 2.24 (3H, s,
(2H, s, CH2Ph); 4.42 (1H, dd, J = 7.6, J = 5.6, CHNH2); 4.48 (2H, dt,
J = 5.5, J = 1.5 CH2Allyl); 4.51 (1H, dd, J = 14.0, J = 7.6, CH2CH);
4.70 (1H, dd, J = 14.0, J = 5.6 CH2CH), 5.06 (1H, dq, J = 17.1, J = 1.5,
@CH2); 5.12 (1H, dq, J = 10.5, J = 1.5, @CH2); 5.69 (1H, ddt,
J = 17.1, J = 10.5, J = 5.5, @CH); 7.19–7.32 (5H, m, Ar).
CH3); 2.37–2.57 (8H, m, C4H8N2); 2.50 (1H, m, b-H Pro); 2.73
(1H, m, b-H Pro); 2.83 (1H, dd, J = 13.5, J = 5.5, CHCH2); 2.95 (1H,
dd, J = 13.5, J = 4.9, CHCH2); 3.41 (2H, s, CH2C6H3); 3.42 (1H, dd,
J = 10.6, J = 6.2,
a-H Pro); 3.57 (1H, m, d-H Pro); 3.59 (1H, d,
J = 12.6, CH2Ph); 3.68 (1H, m,
c
-H Pro); 3.95 (1H, dd, J = 5.5,
J = 4.9, CHCH2); 4.44 (1H, d, J = 12.6, CH2Ph); 6.59 (1H, dd, J = 8.3,
J = 2.1, Ar); 6.63 (1H, ddd, J = 8.3, J = 6.6, J = 1.1, Ar); 6.93–7.03
(4H, m, Ar); 7.11 (1H, ddd, J = 8.7, J = 6.6, J = 2.1, Ar); 7.16 (1H, tt,
J = 7.5, J = 1.2, Ar); 7.26 (3H, m, Ar); 7.32 (2H, m, Ar); 7.38–7.53
(3H, m, Ar); 8.24 (1H, dd, J = 8.7, J = 1.1, Ar). 13C NMR: 19.6 (CH3);
4.3.6. (S)-2-Amino-3-(3-butyl-4-(2-methallyl)-5-thio-1,2,4-triazol-1-
yl)propionic acid 4f
Yield (46%, 1.07 g). Mp 218–220 °C. Found: C 56.93; H 8.03; N
20.44. Calcd for C13H22N4O2S:
C 56.90; H 8.08; N 20.40.
½
a 2D0
ꢁ
¼ ꢂ2:2 (c 0.5, 6 M HCl). 1H NMR (DMSO/CF3COOD): 1.02

A. S. Saghyan et al. / Tetrahedron: Asymmetry 23 (2012) 891–897
897
(3H, m, Me); 1.24 (3H, m,Me); 1.48–1.54 (2H, m, –C–CH2–C–);
1.61–1.73 (2H, m, –C–C–CH2–); 2.48–2.56 (2H, m, –C–CH2–C–);
3.94–4.00 (1H, m, -CH); 4.39–4.43 (2H, m, CH2–C(CH3)@)); 4.62
(1H, m, b-H CH2), 4.80 m (1H, b-H CH2); 5.14 (1H, d, –CH2–
C(CH3) @CH2, J = 10.2), 5.24 (1H, d, –CH2–C(CH3) @CH2, J = 10.2 Hz).
Acknowledgments
a
This work was supported by the International Science and Tech-
nology Center Grants #A-356, #A-1247, and #A-1677. The authors
thank Professor Yuri N. Belokon for helpful discussions.
4.3.7. (S)-2-Amino-3-(3-pyridine)-4-allyl-5-thio-1,2,4-triazol-1-
yl)propionic acid 4g
References
1. (a) Izumi, Y.; Chibata, I. Angew. Chem., Int. Ed. Engl. 1978, 17, 176–183; (b)
Williams, R. M.; Sinclair, P. J.; Zhai, D.; Chen, D. J. Am. Chem. Soc. 1989, 110,
1547–1557; (c) Cativiela, C.; Dıáz de Villegas, M. D. Tetrahedron: Asymmetry
1998, 9, 3517–3599; (d) Cativiela, C.; Dıáz de Villegas, M. D. Tetrahedron:
Asymmetry 2000, 11, 645–732; (e) Wirth, T. Angew. Chem., Int. Ed. 1997, 36, 225–
227; (f) North, M. Contemp. Org. Synth. 1996, 3, 323–343; (g) Duthaler, R. O.
Tetrahedron 1994, 50, 1539–1650; (h) Abellan, T.; Chinchilla, R.; Galindo, N.;
Guillena, G.; Najera, C.; Sansano, J. M. Eur. J. Org. Chem. 2000, 2689–2697; (i)
O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506–517; (j) Aurelio, L.; Brownlee, R. T.;
Hughes, A. B. Chem. Rev. 2004, 104, 5823; (k) Lygo, B.; Andrews, B. I. Acc. Chem.
Res. 2004, 37, 518–525; (l) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013–3028;
(m) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290–4299; (n) Kotha, S. Acc. Chem.
Res. 2003, 36, 342–351; (o) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584–
4671.
Yield (50%, 1.23 g). Mp 218–219 °C. Found: C 50.89; H 4.91; N
22.83. Calcd for
C13H15N5O2S: C 51.15; H 4.92; N 22.95.
½
a 2D0
ꢁ
¼ þ4:5 (c 1.0, 4.9 M HCl). 1H NMR (DMSO + CF3COOD): 4.48
(1H, m,
a-H CH); 4.62 (1H, m, b-H CH2); 4.73 (1H, m, –CH2–
CH@CH2); 4.80 (1H, m, b-H CH2); 4.84 (1H, d, –CH2–CH@CH2,
J = 10.5); 5.04 (1H, d, –CH2–CH@CH2, J = 17.2); 5.19 (1H, d, –CH2–
CH@CH2, J = 10.5); 5.88 (1H, m, –CH2–CH@CH2); 7.42–8.96 (4H,
m, Ar).
4.3.8. (S)-2-Amino-3-(4-pyridine)-4-allyl-5-thio-1,2,4-triazol-1-
yl)propionic acid 4h
2. Gilchrist, T. Heterocyclic Chemistry; Pitman Publishing Ltd. London, 1997.
3. Paronikyan, E. G.; Sirakanyan, S. N.; Noravyan, A. S.; Paronikyan, R. G.;
Dzhagatspanyan, I. A. Pharm. Chem. J. 2001, 35, 8–10.
Yield (52%, 1.19 g). Mp 220–222 °C. Found: C 50.87; H 4.60; N
22.81. Calcd for
C13H15N5O2S: C 51.15; H 4.92; N 22.95.
a 2D0
ꢁ
¼ þ9:4 (c 1.0, 4.9 M HCl). 1H NMR (DMSO + CF3COOD): 4.42
4. Sztanke, K.; Tuzimski, T.; Rzymowska, J.; Pasternak, K.; Kandefer-Szerszen´ , M.
½
Eur. J. Med. Chem. 2008, 43, 404–419.
5. Vinaya, K.; Naveen, S.; Kumar, C. S.; Benakaprasad, S. B.; Sridhar, M. A.;
Shashidhara, J.; Rangappa, K. S. Struct. Chem. 2008, 19, 765–770.
(1H, m,
a-H CH); 4.64 (1H, m, b-H CH2); 4.78 (1H, m, –CH2–
CH@CH2); 4.82 (1H, m, b-H CH2); 4.86 (1H, d, –CH2–CH@CH2,
J = 10.5); 5.18 (1H, d, –CH2–CH@CH2, J = 17.2); 5.21 (1H, d,–CH2–
CH@CH2, J = 10.5); 5.88 (1H, m, –CH2–CH@CH2); 7.62–8.84 (4H,
m, Ar).
6. (a) Belokon, Y. N.; Bulychev, A. G.; Vitt, S. V.; Struchkov, Y. T.; Batsanov, A. S.;
Timofeeva, T. V.; Tsyryapkin, V. A.; Ryzhov, M. G.; Lysova, L. A.; Bakhmutov, V. I.;
Belikov, V. M. J. Am. Chem. Soc. 1985, 107, 4252–4259; (b) Belokon, Y. N.; Maleev,
V. I.; Vitt, S. V.; Ryshov, M. G.; Kondrashov, Y. D.; Golubev, S. N.; Vauchskii, Y. P.;
Kazika, A. I.; Novikova, M. I.; Krasutskii, P. A.; Yurchenko, A. G.; Dubchak, I. L.;
Shklover, V. E.; Struchkov, Y. T.; Bakhmutov, V. I.; Belikov, V. M. J. Chem. Soc.,
Dalton Trans. 1985, 17–26; (c) Belokon, Y. N.; Chernoglazova, N. I.; Kochetkov, C.
A.; Garbalinskaya, N. S.; Belikov, V. M. J. Chem. Soc., Chem. Commun. 1985, 171–
172; (d) Belokon, Y. N.; Bakhmutov, V. I.; Chernoglazova, N. I.; Kochetkov, C. A.;
Vitt, S. V.; Garbalinskaya, N.; Belikov, V. M. J. Chem. Soc., Perkin Trans. 1 1988,
305–311.
4.3.9. (S)-2-Amino-3-(4-benzylpiperazin-1-yl)propionic acid 4i
Yield (40%, 1.03 g). Mp 230–235 °C. ½a D20
¼ þ21:5 (c 0.16, 6 M
ꢁ
HCl). 1H NMR (DMSO + CF3COOD): 2.73 (4H, br.,) and 3.20 (4H,
m, C4H8N2); 2.84 (H, dd, J = 13.6, J = 8.6, NCH2CH); 2.89 (H, dd,
J = 13.6, J = 4.9, NCH2CH); 4.03 (H, dd, J = 8.6, J = 4.9, NCH2CH);
4.28 (2H, s, CH2Ph); 7.38–7.42 (3H, m) and 7.47–7.53 (2H, m,
C6H5); 8.37 (2H, br., NH2).
7. Belokon, Y. N.; Saghiyan, A. S.; Djamgaryan, S. M.; Bakhmutov, B. I.; Belikov, V.
M. Tetrahedron 1988, 44, 5507–5514.
8. (a) Saghiyan, A. S.; Manasyan, L. L.; Geolchanyan, A. V.; Hovhannisyan, A. M.;
Ghochikyan, T. V.; Haroutunyan, V. S.; Avetisyan, A. A.; Mirzoyan, K. S.; Maleev,
V. I.; Khrustalev, V. N. Tetrahedron: Asymmetry 2006, 17, 2743–2753; (b)
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.
Tetrahedron: Asymmetry 2006, 17, 455–467; (c) Saghiyan, A. S.;
Hambardzumyan, H. H.; Manasyan, L. L.; Petrosyan, A. A.; Maleev, V. I.;
Peregudov, A. S. Synth. Commun. 2005, 35, 449–459; (d) Saghiyan, A. S.;
Avetisyan, A. E.; Djamgaryan, S. M.; Djilavayan, L. R.; Gyulumyan, E. A.;
Grigoryan, S. K.; Kuzmina, N. M.; Orlova, S. A.; Ikonnikov, N. S.; Larichev, V. S.;
Tararov, V. I.; Belokon, Y. N. Russ. Chem. Bull. Int. Ed. 1997, 46, 483–486; (e)
Saghiyan, A. S.; Geolchanyan, A. V.; Djamgaryan, S. M.; Vardapetyan, S. M.;
Tararov, V. I.; Kuzmina, N. A.; Ikonnikov, N. S.; Belokon, Y. N.; North, M. Russ.
Chem. Bull. Int. Ed. 2000, 49, 1460–1463.
9. (a) Saghiyan, A. S.; Geolchanyan, A. V.; Manasyan, L. L.; Mkrtchyan, G. M.;
Martirosyan, N. R.; Dadayan, S. A.; Khochikyan, T. V.; Harutyunyan, V. S.;
Avetisyan, A. A.; Tararov, V. I.; Maleev, V. I.; Belokon, Y. N. Russ. Chem. Bull. Int.
Ed. 2004, 53, 932–935; (b) Saghiyan, A. S.; Manasyan, L. L.; Geolchanyan, A. V.;
Hovhannisyan, A. M.; Ghochikyan, T. V.; Haroutunyan, V. S.; Avetisyan, A. A.;
Mirzoyan, K. S.; Maleev, V. I.; Khrustalev, V. N. Tetrahedron: Asymmetry 2006, 17,
2743–2753.
4.3.10. (S)-2-Amino-3-(4-bromobenzylpiperazin-1-yl)propionic
acid 4j
Yield (36%, 1.28 g). Mp 185–190 °C. ½a D20
¼ þ23:9 (c 0.26, 6 M
ꢁ
HCI) 1H NMR (D2O + CF3COOD): 3.11 (4H, br., C4H8N2); 3.15 (H,
dd, J = 14.0, J = 8.2 CH2CH); 3.27 (H, dd, J = 14.0, J = 5.5, CH2CH);
3.42 (4H, br, C4H8N2); 4.31 (H, dd, J = 8.2, J = 5.5, CHCH2); 4.34
(2H, s, CH2-C6H4Br); 7.39 (2H, m, C6H4Br); 7.68 (2H, m, C6H4Br).
4.3.11. (S)-2-Amino-3-(2-fluorobenzylpiperazin-1-yl)propionic
acid 4k
Yield (34%, 1.06 g). Mp 245–250 °C. ½a D20
¼ þ24:5 (c 0.20, 6 M
ꢁ
HCl). 1H NMR (D2O + CF3COOD): 2.74 (2H, m, C4H8N2); 2.88 (2H,
m, C4H8N2); 3.24 (H, m, C4H8N2); 2.84 (H, dd, J = 13.6, J = 8.7,
CHCH2); 2.90 (H, dd, J = 13.6, J = 4.7, CHCH2); 4.03 (H, dd, J = 8.7,
J = 4.7, CH); 4.34 (2H, s, CH2C6H4); 7.16–7.28 (2H, m, C6H4F); 7.48
(H, m, C6H4F); 7.63 (H, td, J = 7.5, J = 1.5, C6H4F).