Rapid asymmetric synthesis of amino acids via NiII complexes based on new fluorine containing chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2010.11.024

New fluorine-containing chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(2- fluorobenzyl)-, (S)-N-(2-benzoylphenyl)-1-(3-fluorobenzyl)-, and (S)-N-(2-benzoylphenyl)-1-(4-fluorobenzyl)-pyrrolidine-2-carboxamide and their Ni^II complexes of Schiff bases with glycine and alanine have been synthesized. The greater efficiency of the complexes in terms of faster reaction rates and stereoselectivities in the asymmetric synthesis of (S)-α-amino acids has also been demonstrated.

Full text of DOI:10.1016/j.tetasy.2010.11.024

Tetrahedron: Asymmetry 21 (2010) 2956–2965
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
II
Rapid asymmetric synthesis of amino acids via Ni complexes based
on new fluorine containing chiral auxiliaries
Ashot S. Saghyan a, , Ani S. Dadayan , Slavik A. Dadayan , Anna F. Mkrtchyan , Arpine V. Geolchanyan ,
⇑
a
a
a
a
a
a
b
b
Luiza L. Manasyan , Hrant R. Ajvazyan , Victor N. Khrustalev , Hasmik H. Hambardzumyan ,
b
Victor I. Maleev
a
Institute of Biotechnology of National Academy of Sciences of Republic Armenia, 14 Gjurdjan, 0056 Yerevan, Armenia
Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, 28 Vavilov, 119991 Moscow, Russian Federation
b
a r t i c l e i n f o
a b s t r a c t
Article history:
New fluorine-containing chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(2-fluorobenzyl)-, (S)-N-(2-ben-
zoylphenyl)-1-(3-fluorobenzyl)-, and (S)-N-(2-benzoylphenyl)-1-(4-fluorobenzyl)-pyrrolidine-2-carbox-
amide and their Ni complexes of Schiff bases with glycine and alanine have been synthesized. The
Received 2 November 2010
Accepted 26 November 2010
Available online 13 January 2011
II
greater efficiency of the complexes in terms of faster reaction rates and stereoselectivities in the asym-
metric synthesis of (S)-
a-amino acids has also been demonstrated.
Ó 2010 Elsevier Ltd. All rights reserved.
1
. Introduction
or was very difficult to achieve in any reasonablechemical yield. Fur-
ther modification of BPB with the introduction of halogens onto the
aromatic ring of the N-benzylproline fragment of the initial Gly or
Ala complexes was carried out. Using BPB analogs that contained
chlorine atoms in various positions of the aromatic ring of the N-
benzylproline moiety and resulted in an increase in stereoselectivity
The asymmetric synthesis of enantiomerically pure
a-amino
acids using various chiral auxiliaries and catalysts is a well estab-
lished field in modern bioorganic chemistry. This can be seen by
the development of new methods for the synthesis of amino acids
by such approaches and their intensive use in practice.1 Recently,
a specialized issue of Tetrahedron: Asymmetry was devoted to the
use and synthesis of amino acids.3
,2
10
and a reduction of the reaction time of the amino acids synthesis.
The best results (complete alkylation time <15 min, ee of the iso-
lated amino acids >97%) were registered with the use of a chiral aux-
iliary, which contained a chlorine atom at the ortho-position of the
phenyl group of N-benzylproline–(S)-N-(2-benzoylphenyl)-1-(2-
chlorobenzyl)pyrrolidine-2-carboxamide (2-CBPB see Chart 1).1
II
The synthesis of enantiomerically enriched amino acid Ni com-
plexes of Schiff bases of amino acids (or dehydroamino acids) and a
chiral auxiliary (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-
2
0b
-carboxamide (BPB) have already been reported.4,5 The first
generation auxiliaries (S)-N-(2-formylphenyl)-1-benzylpyrrolidine-
-carboxamide (BPBA), and (S)-N-(2-acetylphenyl)-1-benzylpyr-
rolidine-2-carboxamide (BPA) (see Chart 1) were initially developed.
Thermodynamic and kinetic diastereoselectivities observed in a
BPBA
BPA
R = H, R'=H
2
6
R'
R = CH , R'=H
R
3
O
series of asymmetric C-alkylation reactions of the auxiliary derived
N
BPB
R = Ph, R'=H
H
N
II
complexes were modest ranging from 18–50% de.6,7 The next
N
2-CBPB
R = Ph, R'=Cl
generation auxiliary BPB was better with an average increase in
8
O
the stereoselectivities to 90%. Further modification of the BPB aux-
iliary led to the introduction of substituents into the phenyl groups
of either the aminobenzophenone9 or -benzylproline moieties.
The benzophenone modification was not productive, resulting in
unreactive complexes and low enantioselectivities of the reac-
Chart 1.
10
The short reaction time and greater than 95% ee of the reaction
product are important features related to the production of PET
radiopharmaceuticals. In particular, short lived isotope-labeled
1
0
tions. Modification of the N-benzyl moiety by the introduction of
1
1
12
naphthylmethyl or 2,4,6-trimethylbenzyl groups instead of the
benzyl group, led to either insoluble and thus unreactive complexes
18 11
16
(
F, C, and N) amino acids have found increasing use for PET
1,2,13
diagnostics of various diseases.
Herein we report the develop-
ment of a new generation of chiral auxiliaries based on BPB
modification, aimed at increasing the enantioselectivities of the
reactions and reducing the reaction time.
⇑
Corresponding author. Tel.: +3741 559355; fax: +3741 559355/654183.
E-mail addresses: saghiyan@netsys.am, sagysu@netsys.am (A.S. Saghyan).
0
957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.024

A. S. Saghyan et al. / Tetrahedron: Asymmetry 21 (2010) 2956–2965
2957
R3
R3
R2
R2
R1
R1
O
Gly or (R,S)-Ala
H
Ni(NO3)2
O
R
MeONa, MeOH
50°C, 1-1.5h
N
Ni
O
N
N
N
H
N
H
O
H
O
1
2
3
II
R = F, R =R =H; (S)-2-FBPB 1
Ni -(S)-2-FBPB-Gly
(R=H)
4
II
Ni -(S)-2-FBPB-(S)-Ala (R=Me) 5
2
1
3
II
R = F, R =R =H; (S)-3-FBPB 2
Ni -(S)-3-FBPB-Gly
(R=H) 6
II
Ni -(S)-3-FBPB-(S)-Ala (R=Me) 7
3
1
2
II
R = F, R =R =H; (S)-4-FBPB 3
Ni -(S)-4-FBPB-Gly
(R=H) 8
II
Ni -(S)-4-FBPB-(S)-Ala (R=Me) 9
Scheme 1.
2
. Results and discussion
The following modified analogs of chiral auxiliary BPB were
other two auxiliaries gave de of only 95%. Thus, the positioning
the fluorine atom at the o-position of the benzyl ring had an impor-
tant effect on the thermodynamic diastereoselectivity of the com-
plex, when compared with the m- and p-positions for 6 and 9,
respectively.
1
0
synthesized by analogy with a previously described procedure:
(S)-N-(2-benzoylphenyl)-1-(2-fluorobenzyl)-pyrrolidine-2-carbox-
amide (2-FBPB) 1, (S)-N-(2-benzoylphenyl)-1-(3-fluorobenzyl)
pyrrolidine-2-carboxamide (3-FBPB) 2, and (S)-N-(2-benzoylphe-
nyl)-1-(4-fluorobenzyl)pyrrolidine-2-carboxamide (4-FBPB) 3,
containing a fluorine atom at either the ortho-, meta,- or para-posi-
tions of the phenyl group of the N-benzylproline fragment (see
Scheme 1).
An increase in the thermodynamic stereoselectivity was previ-
ously observed in a number of modified chiral auxiliaries contain-
ing a chlorine atom in different positions of the benzyl ring. The
best results were observed in the case of a chiral auxiliary 2-CBPB
containing a chlorine atom at the o-position of the benzyl ring
(Table 1). It can be seen from the Table 1 that the diastereoselectivity
increased during the transition from the complexes with chiral
auxiliary BPB to its modified analog 2-CBPB.
In crystals of complex 5 two atropoisomers (A and B as pre-
sented in Fig. 1a) were detected. Atom numbering for complexes
(R)-7 and 9 (Fig. 1c and d) corresponds to their numbering in the
predominant atropoisomer of complex 5 (Fig. 1b). According to
the X-ray data, the introduction of substituents into the aromatic
ring of the N-benzylproline moiety significantly influenced the po-
sition of the group over the nickel coordination plane (see Fig. 1,
Table 2).
The auxiliaries easily form NiII complexes of their Schiff bases
II
II
with glycine or alanine; Ni -(S)-2-FBPB-Gly 4, Ni -(S)-2-FBPB-(S)-
II
II
II
Ala 5, Ni -(S)-3-FBPB-Gly 6, Ni -(S)-3-FBPB-(S)-Ala 7, Ni -(S)-4-
FBPB-Gly 8, Ni -(S)-4-FBPB-(S)-Ala 9 (Scheme 1). For the sake of
II
comparison, similarly designed chiral auxiliaries based on (R)-pro-
line and their Schiff base amino acid complexes were also synthe-
sized. The complexes were isolated from the reaction mixture
through precipitation with water followed by crystallization from
acetone.
As expected, complexes 5, 7, and 9, were obtained as a mix-
ture of two diastereomers of an (S,R)- and (S,S)-configuration.
To establish the absolute configuration of the
a
-carbon atom of
1. The distance of the benzyl aromatic ring from the Ni-atom [Ni–
II
the complexes’ amino acid moiety, a polarimetric method was
C(16)] is the shortest in 5 relative to 7, 9, and Ni -(S)-2-CBPB-
6
,7,11
employed.
The absolute configurations of some synthesized
(S)-Ala.
II
II
major diastereomeric complexes [5, 9, and Ni -(R)-3-FBPB-(R)-
Ala (R)-7] were additionally confirmed by X-ray structure analysis
2. The Ni-halogen distance in case of 5 is shorter than in Ni -(S)-2-
CBPB-(S)-Ala, which may indicate some weak interaction of the
fluorine substituent with the Ni atom.
(
see Fig. 1).
The ratio of the (S,R)- and (S,S)-diastereomers of the complexes
3. The plane of the ring is greater skewed in 5 relative to the Ni-
coordination plane (Torsion angle N3–C15–C16–C17) relative
to all the other complexes (Table 2).
was determined by analysis of the mixtures of diastereomeric
1
complexes (before crystallization) by H NMR by the ratio of the
signal integrals of the methylene protons of the N-benzylproline
moiety in the region 3.45–3.86 ppm and 4.37–4.80 ppm, as well
as by chiral GLC and HPLC analyses of amino acids recovered after
decomposition of the mixture of diastereomeric complexes, sepa-
ration of the initial chiral auxiliary, and demineralization of the
amino acids. The results are presented in Table 1. For the sake of
comparison, Table 1 also presents data obtained earlier for the
thermodynamic diastereoselectivity of complex formation with
the chiral auxiliary (S)-BPB and modified analog (S)-2CBPB.
4. As a result of such interactions, the fluoro substituted phenyl
ring of 5 is closely situated over the ionized amide bond of 5.
Assuming that the dipole of the group has its positive charge
situated on the phenyl and the negative one at the fluorine
atom, one could expect an increase in electron withdrawing
capacity of the aminobenzophenone moiety by a partial induc-
tive effect through space neutralization of the negative charge
on the amide group.
Under the experimental conditions, the equilibrium between
the (S,S)- and (S,R)-diastereoisomers was established, as was usual
in other cases of similar Ni complexes. As was always observed in
the case of Ni-BPB-Aa complexes, the (S,S)-diastereoisomers were
Evidently, the greater acidity of the amino acid moiety of 5, and
thus that of 4, would be expected as compared to 6–9 and Ni -(S)-
2-CBPB-(S)-Ala.
II
To confirm the hypothesis, the rates of the deuteron exchange
6
,7,10
a H
-protons of the amino acid moiety of 3–9 were studied by 1
formed in excess.
As can be seen, 2-FBPB was the most effi-
of
NMR, monitoring the disappearance of the resonances of the
cient asymmetric auxiliary with 98% de at equilibrium of 5. The

2
958
A. S. Saghyan et al. / Tetrahedron: Asymmetry 21 (2010) 2956–2965
II
Figure 1. ORTEP structures of Ni -(S)-2-FBPB-(S)-Ala 5 (a) (mixture of atropoisomers A and B); (b) (atropoisomer A), hydrogen atoms are not presented for simplification; (c)
II
II
Ni -(R)-3-FBPB-(R)-Ala; (d) Ni -(S)-4-FBPB-(S)-Ala based on X-ray analysis.
Table 1
3
Results of complex formation of fluoro-containing modified chiral auxiliaries in CH OH in the presence of KOH, 55–60 °C
Initial chiral reagent
The synthesized complexes of
Schiff bases of amino acids
Chemical yield (%)
dra (%)
II
(
(
(
(
(
(
(
(
S)-2-FBPB 1
S)-2-FBPB 1
S)-3-FBPB 2
S)-3-FBPB 2
S)-4-FBPB 3
S)-4-FBPB 3
S)-BPBb
Ni -(S)-2-FBPB-Gly 4
86.2
89.7
78.4
81.5
74.8
82.6
80
—
II
Ni -(S)-2-FBPB-(S)-Ala 5
99.0/1.0
—
97.5/2.5
—
97.1/2.9
94/6
98.3/1.7
II
Ni -(S)-3-FBPB-Gly 6
II
Ni -(S)-3-FBPB-(S)-Ala 7
II
Ni -(S)-4-FBPB-Gly 8
II
Ni -(S)-4-FBPB-(S)-Ala 9
II
Ni -(S)-BPB-(S)-Ala
b
II
S)-2CBPB
Ni -(S)-BPB-(S)-Ala
92
a
Average ratio of the diastereomers according to 1H NMR and chiral GLC or HPLC analyses.
Literature data.
b
7,10b
protons in the presence of bases. The kinetic plots are presented in
Figure 2a (for a series of alanine complexes) and b (for a series of gly-
cine complexes). As expected, all of the glycine complexes had a
greater kinetic acidity relative to those of alanine. Evidently, the
lowest rate is observed in complexes based on an unsubstituted
BPB chiral auxiliary. The introduction of halogen substituents in-
creased the rate of exchange. Complexes with o-substitution were
more acidic than the other types of complexes. In full accordance
with the hypothesis, compound 5 was the most acidic in the series.
The modified glycine complexes 4, 6, 8, and (S)-alanine complex
ation of the amino acid moiety, with allyl and benzylbromides as
the alkylating agents (Scheme 2).
3
The reaction was conducted in either DMF or CH CN with finely
ground, solid NaOH or KOH at a room temperature or at 45–50 °C
(Scheme 2). The best results were obtained for a DMF mixture in
the presence of fresh finely ground NaOH. The alkylation reactions
2 3 3 2 5
were monitored by TLC [SiO , CHCl /CH COOC H (1:3)] following
the disappearance of the traces of the initial complexes and the
establishment of thermodynamic equilibrium between the diaste-
reomers of the alkylation products (in the case of glycine com-
plexes). The ratio of (S,S)- and (S,R)-diastereomers of alkylated
5
were then tested in model reaction of the asymmetric C-alkyl-

A. S. Saghyan et al. / Tetrahedron: Asymmetry 21 (2010) 2956–2965
2959
Table 2
X-ray data for modified F-containing alanine complexes
II
a
5b
(R)-7c
6.033/4.424d
3.122/3.087
51.52/48.36
Parameters of complexes
Ni -(S)-2-CBPB-(S)-Ala
9
Distance Niꢀ ꢀ ꢀhalogen
Distance Niꢀ ꢀ ꢀC(16)
Torsion angle
Ni–N3–C15–C16
Torsion angle
N3–C15–C16–C17
Torsion angle
N1–C3–C23–C24
3.149
3.403
ꢁ69.16
3.001 (4.651)
3.052
6.673
3.372
ꢁ62.1 (ꢁ44.5)
79.72 (86.25)
73.35
ꢁ70.4
86.51
68.49
87.75
69.97
ꢁ88.81/ꢁ89.23
ꢁ92.89/ꢁ84.11
a
NiII complex of Schiff base of (S)-alanine with chiral auxiliary (S)-N-(2-benzoylphenyl)-1-(2-chlorobenzyl)-pyrrolidine-2-
1
0b
carboxamide.
b
Data for B atropoisomer of complex 5 are given in brackets.
Complex on the basis of chiral (R)-proline derivative, that is why all angles are of opposite sign and with two independent molecules
c
in a crystal.
d
Before fluorine atom of the neighboring molecule.
a
60
Ni-2-F-BPB-(S)-Ala
Ni-2-Cl-BPB-(S)-Ala
Ni-4-F-BPB-(S)-Ala
Ni-3-F-BPB-(S)-Ala
Ni-BPB-(S)-Ala
5
4
3
2
1
0
0
0
0
0
0
0
10
20
30
40
50
60
70
80
90
t, min
50
40
30
20
10
0
b
Ni-2-F-BPB-Gly
Ni-2-Cl-BPB-Gly
Ni-BPB-Gly
0
2
4
6
8
10
12
14
16
18
20
t, min
3
Figure 2. Deuteration (a-hydrogen exchange) of the amino acid moiety of alanine (a) and glycine (b) complexes in CD OD and in the presence of base (see Section 4 for
details).
complexes was determined as usual (see above). As expected, the
alkylation of the glycine and alanine complexes resulted in a mix-
ture of diastereomeric complexes of alkylation products in high
excess of the (S,S)-diastereomers. The results of the alkylations
are presented in Table 3.
run with complexes based on the modified chiral auxiliary (S)-2-
FBPB. Comparison of the data with other modified BPB chiral
6
,7,10
auxiliaries
showed that the best results both in terms of stere-
oselectivities and the rate of syntheses were obtained for the chiral
auxiliaries (S)-2-CBPB and (S)-2-FBPB.
The data collected in Table 3 indicate that the asymmetric C-
alkylation of glycine and alanine complexes, are most efficiently
The alkylation reactions of similar glycine complexes with the
chiral auxiliary based on (R)-proline [Ni -(R)-2-FBPB-Gly, Ni -(R)-
II
II

2
960
A. S. Saghyan et al. / Tetrahedron: Asymmetry 21 (2010) 2956–2965
R3
R2
O
R1
O
H(Me)
R
aq. HCl in MeOH
RBr
O
a few minutes, 20-60°C
HO
H(Me)
4
, 6, 8 or 5
Ni
N
DMF, NaOH,
N
N
ion-exchange resin
2
0-50°C
R
H2N
H
O
1-3
major isomer 10a,b-13a,b
a) R=Bn; b) R=Allyl
Scheme 2.
Table 3
Alkylation of complexes 4, 6, 8, and 5 with allyl and benzyl bromides
a
Initial complex
Alkylating agent
CH Br
@CH–CH
CH Br
@CH–CH
CH Br
@CH–CH
CH Br
@CH–CH
Reaction time (min)
Alkylated complex
Amino acids recovered from complexes
eeb (%)
Chem. yieldc (%)
4
4
5
5
6
6
8
8
C
CH
C
CH
C
CH
C
CH
6
H
5
2
3–5
7
8
7
12
15
15–20
18–20
10a
10b
11a
11b
12a
12b
13a
13b
(S)-Phe
(S)-Allyl-Gly
(S)-a-MePhe
(S)-Allyl-Ala
(S)-Phe
(S)-Allyl-Gly
(S)-Phe
96.8
97.1
96.4
97.0
92.3
93.5
93.7
90.3
74.6
75.6
79.2
77.0
77.4
76.5
75.4
77.5
2
2
2
2
2
Br
Br
Br
Br
6
H
5
2
2
6
H
5
2
2
6
H
5
2
2
(S)-Allyl-Gly
a
Reaction conditions: 0.055 mol of the initial complex, 15 ml of DMF, 0.055 mol of alkyl bromide, 0.0825 mol NaOH, 20–25 °C, (45–50 °C in the case of complex 5
alkylation), Ar atmosphere.
b
Enantiomeric purity (ee) of the isolated amino acid according to data from chiral GLC analysis.
Chemical yield at the stage of alkylation.
c
II
3
-FBPB-Gly, and Ni -(R)-4-FBPB-Gly] were also conducted. The
4. Experimental
II
synthesis of (R)-a-amino acids with the Ni -(R)-2-FBPB-Gly com-
plex was also highly efficient in yielding (R)-amino acids. The re-
sults of the alkylations are presented in Table 4.
The amino acids were purchased from ‘Reanal’ (Hungary); silica
gel L-40/100 ‘Chemapol’ (Praha, Czech Republic), CHCl , (CH CO) O,
3
3
2
The aldol condensation of 4 with formaldehyde and acetalde-
3 3 2 3 3
CH COOH, (CH ) CO, CH CN, i-PrOH, CH OH, NaOH, and ROH from
hyde was carried out under strongly basic conditions (see
‘Reachim’ (Russia); 2-fluorobenzylbromide, 3-fluorobenzylbro-
mide, 4-fluorobenzylbromide, benzylchloride, 2-chlorobenzylbro-
mide, and 2-aminobenzophenone from ‘Aldrich’. All solvents used
were freshly distilled. The enantiomeric GLC analysis of the amino
acids as the N-trifluoroacetyl derivatives of their isopropyl esters
was performed using a ‘Chirasil Val’ type chiral phase on quartz cap-
Scheme 3) similar to a previously described procedure6
,8,10b
with
the formation of the corresponding serine and threonine com-
plexes with an (R)-absolute configuration.
The results are presented in Table 5. The data shows that the
stereoselectivities of the aldol condensation reactions of 4 (Table 5,
runs 1 and 2) are similar to those of complexes with (S)-2-CBPB
illary columns (40 m ꢂ 0.23 mm) with 0.12
lm film thickness at
column temperature 125 °C, using helium as the carrier gas. The
1
0b
(Table 5, runs 3 and 4).
However, the reactions proceeded faster
1
in the case of 4 (see Table 5, runs 1 and 2).
H NMR spectra were recorded on a ‘Mercury-300 Varian’ (300
MHz) in DMSO-d
6 4
/CCl 1:3 (unless otherwise indicated). Deutero
exchange was studied in an ampoule of the NMR-spectrometer by
ꢁ4
t
3
. Conclusion
adding 3 ꢂ 10 mol of Bu OK (for alanine complexes) or 0.05 ml
of a 0.5 M molar solution of DABCO in CDCl (for glycine complexes)
3
ꢁ5
In conclusion we have reported the synthesis of a novel modi-
to a solution of 2 ꢂ 10 mol complexes in 0.5 ml of CD OD. The spe-
3
fied chiral auxiliary 2-FBPB 1 which may be used for the rapid
cific rotations were measured on ‘Perkin–Elmer-341’ polarimeter, in
and highly selective asymmetric syntheses of amino acids.
a 5 cm thermostated cell with an accuracy of 0.1%.
Table 4
II
II
II
a
Alkylation of complexes Ni -(R)-2-FBPB-Gly, Ni -(R)-3-FBPB-Gly, and Ni -(R)-4-FBPB-Gly with allyl and benzyl bromides
Initial complex
Alkylating agent
CH Br
@CH–CH
CH Br
@CH–CH
CH Br
@CH–CH
Reaction time (min)
Amino acids recovered from complexes
eeb (%)
Chem. yieldc (%)
II
Ni -(R)-2-FBPB-Gly
C
CH
C
CH
C
CH
6
H
5
2
7–9
9
10
9
15
20
(R)-Phe
(R)-Allyl-Gly
(R)-a-MePhe
(R)-Allyl-Ala
(R)-Phe
(R)-Allyl-Gly
95.6
96.3
94.1
95.5
90.8
92.5
70.2
71.4
76.0
72.2
72.5
73.6
II
Ni -(R)-2-FBPB-Gly
2
2
2
2
Br
Br
Br
II
Ni -(R)-3-FBPB-Gly
6
H
5
2
II
Ni -(R)-3-FBPB-Gly
2
II
Ni -(R)-4-FBPB-Gly
6
H
5
2
II
Ni -(R)-4-FBPB-Gly
2
a
b
c
Reaction conditions: 0.055 mol of the initial complex, 15 ml of DMF, 0.055 mol of alkyl bromide, 0.0825 mol NaOH, 20–25 °C, Ar atmosphere.
Enantiomeric purity (ee) of the isolated amino acid according to chiral GLC analysis.
Chemical yield at the stage of alkylation.

A. S. Saghyan et al. / Tetrahedron: Asymmetry 21 (2010) 2956–2965
2961
Na+
F
F
H
R
O
OH
O
H
HO
O
H
MeCHO or HCHO
MeONa in MeOH
aq. HCl
H
1
) HCl in MeOH, 50°C
CO2-
R
HO C
2
4
N
Ni
H
2) ion-exchange resin
R
N
N
Ni
N
N
N
H2N
H
H
O
H
O
1
4, R=H
5, R=Me
1
1
Scheme 3.
Table 5
a,b
Asymmetric aldol condensation of 4 and (S)-2-CBPB derived complex glycine with formaldehyde and acetaldehyde
Run
Initial complex
Aldehyde
Reaction time
The resulting complex
(chemical yield %)
Recovered amino acid
(chemical yield %)
Amino acid eeb (%)
97
95
99
(
min)
1
2
3
4
4
4
(CH
CH
(CH
CH
2
O)n
CHO
O)n
CHO
70–75
95–100
90
14 (80)
15 (71)
(72)
(R)-Ser (65)
(R)-Thr (ratio syn/anti) (56)
(R)-Ser (60)
c
3
II
Ni -(S)-2-CBPB-Gly
2
II
Ni -(S)-2-CBPB-Gly
3
120
(65)
(R)-Thr (52)
96.6
a
b
c
The experiments were conducted in 4.7 M CH
Enantiomeric excesses (ee) were determined by chiral GLC analysis of the amino acids recovered after decomposition of the mixture of diastereomeric complexes.
Less than 2% of allo-isomer was detected.
3
ONa solution in CH
3
OH at ambient temperatures.
4
.1. The synthesis of chiral auxiliaries 1–3
3J = 9.8 Hz, 3J = 4.4 Hz); 3.54 (1H, d, CH
2
C
H
6 4
F, 2J = 12.9 Hz); 3.87
2
(
1H, d, CH
2
C
6
H
4
F, J = 12.9 Hz); 6.78 (2H, m, Ar); 7.08 (1H, td, Ar,
3
4
Chiral auxiliaries 1–3 were synthesized by a previously de-
J = 7.5 Hz, J = 1.0 Hz); 7.36 (2H, m, Ar); 7.49 (2H, m, Ar); 7.53
4
,10b
3
4
signed method.
ture was stirred at room temperature for 15 h.
After adding all components, the reaction mix-
(2H, m, Ar); 7.64 (1H, tt, Ar, J = 7.4 Hz, J = 1.3 Hz); 7.76 (2H, m,
3
4
Ar); 8.56 (1H, dd, Ar, J = 8.3 Hz, J = 0.9 Hz); 11.41 (1H, s, NH).
4
.1.1. (S)-N-(2-Benzoylphenyl)-1-(2-fluorobenzyl)pyrrolidine-2-
4.2. The synthesis of complexes 4–9 were carried out according
to the previously described method
1
0b
carboxamide 1
2 2
Yield 81.5%. Calcd for C25H23FN O (402.46): C, 74.61; H, 5.76;
N, 6.96. Found: C, 74.64; H, 5.80; N, 6.91. Mp 208–210 °C.
4.2.1. (S)-{({2-[1-(2-Fluorobenzyl)pyrrolidine-2-carboxamide]-
20
1
0
00
½
a
ꢃ
¼ ꢁ48:6 (c 1.0, MeOH). H NMR d: 1.75–1.92 (3H, m, b,
c
-H
phenyl}phenylmethylene)-glycinato-N,N ,N ,O}nickel(II) 4
Yield: 86.2%. Calcd for C27 NiO (516.19): C, 62.82; H,
D
Pro); 2.21 (1H, m,
c
-H Pro); 2.46 (1H, m, d-H Pro); 3.18 (1H, m,
H24FN
3
3
d-H Pro); 3.24 (1H, dd,
d, CH
6
a
-H Pro, 3J = 9.7 Hz, 3J = 3.6 Hz); 3.71 (1H,
4.69; N, 8.14. Found: C, 62.85; H, 4.73; N, 8.16. Mp 125–127 °C.
2
2
20
D
1
2
C H
6 4
F, J = 13.3 Hz); 3.86 (1H, d, CH
C
2 6
4
H F, J = 13.3 Hz);
½
a
ꢃ
¼ þ1300:0 (c 0.05, CHCl
3
). H NMR d: 2.05–2.21 (2H, m, c,
3
H,F = 10.3 Hz, 3J = 8.3 Hz, 4J = 0.8 Hz); 6.89 (1H,
.79 (1H, ddd, Ar,
J
d-H Pro); 2.48 (1H, m, b-H Pro); 2.67 (1H, m, b-H Pro); 3.36 (1H,
3
4
3
3
td, Ar, J = 7.5 Hz, J = 1.0 Hz); 7.05–7.15 (2H, m, Ar); 7.45–7.55
5H, m, Ar); 7.61 (1H, m, Ar); 7.72 (2H, m, Ar); 8.51 (1H, dd, Ar,
m,
c
-H Pro); 3.45 (1H, dd,
a
-H Pro, J = 10.4 Hz, J = 5.4 Hz); 3.67
Gly, J = 20.2 Hz); 3.70 (1H, m, d-H Pro); 3.75 (1H, d,
2
(
(1H, d, CH
2
2
3
4
2
J = 8.3 Hz, J = 0.8 Hz); 11.30 (1H, s, NH).
2 2 6 4
CH Gly, J = 20.2 Hz); 3.96 (1H, d, CH C H F, J = 13.0 Hz); 4.50
2
3
(
1H, d, CH
2
4
C H
6 4
F, J = 13.0 Hz); 6.72 (1H, ddd, Ar, J = 8.3 Hz,
3
J = 7.2 Hz, J = 1.1 Hz); 6.81 (1H, dd, Ar, J = 8.3 Hz, 4J = 1.4 Hz);
3
4
.1.2. (S)-N-(2-Benzoylphenyl)-1-(3-fluorobenzyl)pyrrolidine-2-
carboxamide 2
7.01 (1H, m, Ar), 7.09–7.37 (5H, m, Ar); 7.49–7.57 (3H, m, Ar);
3
3
Yield 70.3%. Calcd for C25
H
23FN
2
O
2
(402.46): C, 74.61; H, 5.76;
8.34 (1H, d, Ar, J = 8.6 Hz); 8.37 (1H, ddd, Ar, J = 7.4 Hz,
4
4
N, 6.96. Found: C, 74.63; H, 5.80; N, 6.94. Mp 200–202 °C.
J
H,F = 7.4 Hz, J = 1.5 Hz).
2
D
0
1
½
a
ꢃ
¼ ꢁ40:2 (c 1.0, MeOH). H NMR d: 1.77–1.96 (3H, m, b,
c-H
Pro); 2.24 (1H, m,
J = 7.2 Hz); 3.18 (1H, m, d-H Pro); 3.23 (1H, dd,
J = 9.7 Hz, J = 4.5 Hz); 3.56 (1H, d, CH
c
-H Pro); 2.38 (1H, td, d-H Pro, 2J = 8.9 Hz,
4.2.2. (S)-{({2-[1-(3-Fluorobenzyl)pyrrolidine-2-carboxamide]-
3
3
0
00
a
-H Pro,
phenyl}phenylmethylene)-glycinato-N,N ,N ,O}nickel(II) 6
Yield: 78.4%. Calcd for C27 NiO (516.19): C, 62.82; H,
3
2
C H
2 6 4
F, J = 13.2 Hz); 3.86
H24FN
3
3
2
(
1H, d, CH
2
C
6
H
4
F, J = 13.2 Hz); 6.84 (1H, m, Ar); 7.06–7.17 (3H,
4.69; N, 8.14. Found: C, 62.84; H, 4.66; N, 8.20. Mp 178–180 °C.
m, Ar); 7.28 (1H, ddd, Ar, J = 10.0 Hz, 3J = 2.4 Hz, 2J = 1.3 Hz);
3
½
aꢃ
20
D
¼ þ1726:7 (c 0.05, CHCl
1
3
). H NMR: 2.06 (1H, m, c-H Pro);
.48–7.56 (4H, m, Ar); 7.61 (1H, tt, Ar, J = 7.4 Hz, 4J = 1.3 Hz);
.75 (2H, m, Ar); 8.57 (1H, d, Ar, J = 8.3 Hz); 11.51 (1H, s, NH).
3
2.13 (1H, ddd, d-H Pro, J = 10.8 Hz, J = 10.8 Hz, J = 6.0 Hz); 2.42
2
3
3
7
7
3
(1H, m, b-H Pro); 2.55 (1H, m, b-H Pro); 3.32 (1H, m, d-H Pro);
3
3
3
.40 (1H, dd, a-H Pro, J = 10.7 Hz, J = 5.5 Hz); 3.57 (1H, d,
2
2
4
.1.3. (S)-N-(2-Benzoylphenyl)-1-(4-fluorobenzyl)pyrrolidine-2-
CH
(1H, m,
CH
C
2 6
H
4
F, J = 12.6 Hz); 3.65 (1H, d, CH
2
Gly, J = 20.1 Hz); 3.72
2
carboxamide 3
c
4
-H Pro); 3.72 (1H, d, CH
2
Gly, J = 20.1 Hz); 4.39 (1H, d,
2
3
Yield 75.2%. Calcd for C25
H
23FN
2
O
2
(402.46): C, 74.61; H, 5.76;
C
2 6
H
F, J = 12.6 Hz); 6.67 (1H, ddd, Ar, J = 8.2 Hz, 3J = 6.9 Hz,
4
3
4
N, 6.96. Found: C, 74.63; H, 5.79; N, 6.99. Mp 203–205 °C.
J = 1.2 Hz); 6.76 (1H, dd, Ar, J = 8.2 Hz, J = 1.9 Hz); 6.96 (2H, m,
Ar), 7.10 (1H, br d, Ar, J = 7.1 Hz); 7.18 (1H, ddd, Ar, J = 8.8 Hz,
J = 6.8 Hz, J = 1.9 Hz); 7.37 (1H, ddd, Ar, J = 8.4 Hz, J = 7.4 Hz,
J = 5.8 Hz); 7.45–7.56 (3H, m, Ar); 7.78 (1H, br d., Ar, J = 7.7 Hz);
2
D
0
1
3
3
½
a
ꢃ
¼ ꢁ42:2 (c 1.0, MeOH). H NMR d: 1.75–1.95 (3H, m, b,
c
-H
3
3
4
3
3
Pro); 2.23 (1H, m,
J = 7.6 Hz); 3.14 (1H, m, d-H Pro); 3.20 (1H, dd,
c
-H Pro); 2.38 (1H, td, d-H Pro, 2J = 8.9 Hz,
3
3
a
-H Pro,

2
962
A. S. Saghyan et al. / Tetrahedron: Asymmetry 21 (2010) 2956–2965
3
4
3
dd, Ar, J = 8.3 Hz, J = 2.0 Hz); 6.68 (1H, ddd, Ar, 3J = 8.3 Hz,
3
4
8
.00 (1H, ddd, Ar, J = 9.4 Hz, J = 2.5 Hz, J = 1.5 Hz); 8.33 (1H, dd,
3
4
3
4
3
4
Ar, J = 8.7 Hz, J = 1.1 Hz).
J = 6.7 Hz, J = 1.2 Hz); 6.97 (1H, dt, Ar, J = 6.7 Hz, J = 1.8 Hz);
.04 (2H, m, Ar); 7.18 (1H, ddd, Ar, J = 8.7 Hz, J = 6.7 Hz,
J = 2.0 Hz); 7.27 (1H, m, Ar); 7.43–7.57 (3H, m, Ar); 8.10 (2H, m,
Ar); 8.14 (1H, dd, Ar, J = 8.6 Hz, J = 1.2 Hz).
3
3
7
4
4
.2.3. (S)-{({2-[1-(4-Fluorobenzyl)pyrrolidine-2-carboxamide]-
phenyl}phenylmethylene)-glycinato-N,N ,N ,O}nickel(II) 8
Yield: 74.8%. Anal. Calcd for C27 NiO (516.19): C, 62.82;
0
00
3
4
H
24FN
3
3
H, 4.69; N, 8.14. Found: C, 62.81; H, 4.66; N, 8.16. Mp 128–
4.3. General method of alkylation of 4–9 complexes with alkyl
bromides
2
0
1
1
30 °C. ½
a
ꢃ
¼ þ2006:7 (c 0.05, CHCl
3
). H NMR: 2.10 (1H, m,
c
-H
D
Pro); 2.16 (1H, ddd, d-H Pro, J = 11.0 Hz, J = 10.2 Hz, 3J = 6.0 Hz);
2
3
2
.45 (1H, m, b-H Pro); 2.59 (1H, m, b-H Pro); 3.39 (1H, m, d-H
To the DMF solution of complexes 4–9 under an argon atmo-
sphere an alkylating agent and finely ground solid NaOH were
added. The reaction mixture was stirred under argon at either room
temperature or at 45–50 °C. The course of reaction was monitored
Pro); 3.42 (1H, dd,
a
-H Pro, 3J = 10.7 Hz, 3J = 5.4 Hz); 3.61 (1H, d,
2
Gly, 2J = 20.1 Hz); 3.76
CH
1H, m,
CH
C
2 6
H
4
F, J = 12.8 Hz); 3.67 (1H, d, CH
2
(
c
4
-H Pro); 3.77 (1H, d, CH
2
Gly, 2J = 20.1 Hz); 4.48 (1H, d,
C
2 6
H
F, J = 12.8 Hz); 6.72 (1H, ddd, Ar, J = 8.3 Hz, 3J = 6.8 Hz,
2
3
by TLC (SiO
the initial complexes. Upon completion of the reaction, the mixture
was neutralized by AcOH and diluted in H O. The precipitate of the
mixture was filtered and washed with water. A small part of mixture
(0.5g) was separated by column chromatography (20 ꢂ 30 cm, SiO
AcOEt/CHCl , 4:1) and the structure and absolute configuration of
2 3
, AcOEt/CHCl , 4:1) by following the disappearance of
4
J = 1.3 Hz); 6.80 (1H, dd, Ar, J = 8.3 Hz, 4J = 1.9 Hz); 7.01 (1H, m,
3
Ar); 7.13 (2H, m, Ar); 7.13 (1H, m, Ar); 7.24 (1H, ddd, Ar,
2
3
3
4
J = 8.6 Hz, J = 6.9 Hz, J = 1.9 Hz); 7.49–7.59 (3H, m, Ar); 8.07
3
4
(
2H, m, Ar); 8.34 (1H, dd, Ar, J = 8.6 Hz, J = 1.3Hz).
2
,
3
4
.2.4. (S)-{({2-[1-(2-Fluorobenzyl)pyrrolidine-2-carboxamide]-
the pure major diastereomer of complexes 10–13 were established
by spectroscopic methods. The ratio of the diastereomers (de) was
determined by using chiral GLC analysis of the amino acid mixture
isolated after decomposition of the mixture of diastereomeric com-
plexes (without chromatographic purification).
0
00
phenyl}phenylmethylene)-alaninato-N,N ,N ,O}nickel(II) 5
Yield: 89.7%. Anal. Calcd for C28 NiO (530.22): C, 63.43; H,
.94; N, 7.93. Found: C, 63.46; H, 4.92; N, 7.95. Mp 283–285 °C.
H26FN
3
3
4
2
D
0
1
½
a
ꢃ
¼ þ3126:6 (c 0.05, CHCl
3 3
). H NMR d 1.59 (3H, d, CH ,
3
2
3
J = 7.0 Hz); 2.08 (1H, ddd, d-H Pro, J = 11.6 Hz, J = 10.4 Hz,
J = 6.0 Hz); 2.24 (1H, m,
3
c
-H Pro); 2.58 (1H, m, b-H Pro); 2.84 (1H,
4.3.1. (S)-{({2-[1-(2-Fluorobenzyl)pyrrolidine-2-carboxamide]-
-H Pro, J = 11.0 Hz, 3J = 5.8 Hz); 3.55
3
phenyl}phenylmethylene)-(S)-3-phenylalaninato-N,N ,N ,O}-
nickel(II) 10a
0
00
m, b-H Pro); 3.48 (1H, dd,
a
2
3
(
1H, dd, d-H Pro, J = 10.4 Hz, J = 6.2 Hz); 3.72 (1H, m,
c-H Pro);
2
4
3
.86 (1H, dd, CH
2
C
6
H
4
F, J = 12.9 Hz, JH,F = 1.2 Hz); 3.89 (1H, q, CH–
, J = 7.0 Hz); 4.42 (1H, dd, CH
To 2 g (3.88 mmol) of 4 in 15 ml DMF were added 0.47 ml
3
2
4
CH
3
2 6
C
H
4
F, J = 12.9 Hz, JH,F = 1.5 Hz);
(3.88 mmol) C
diastereomeric complex 10a (second fraction) was isolated with
a yield of 80%. Anal. Calcd for C34 NiO (606.31): C, 67.35;
6 5 2
H CH Br, and 0.23 g (5.81 mmol) of NaOH. Major
3
4
3
6
.64 (1H, dd, Ar, J = 8.2 Hz, J = 2.1 Hz); 6.68 (1H, ddd, Ar, J = 8.2 Hz,
3
4
3
4
J = 6.6 Hz, J = 1.3 Hz); 6.98 (1H, dt, Ar, J = 6.6 Hz, J = 1.9 Hz); 7.07
H30FN
3
3
3
3
4
(
1H, ddd, Ar, JC,F = 10.0 Hz, J = 7.9 Hz, J = 1.5 Hz); 7.14–7.30 (4H, m,
H, 4.99; N, 6.93. Found: C, 67.38; H, 4.96; N, 6.98. Mp 119–
3
4
20
D
1
Ar); 7.44–7.57 (3H, m, Ar); 8.18 (1H, dd, Ar, J = 8.6 Hz, J = 1.0 Hz);
121 °C. ½
a
ꢃ
¼ þ1101 (c 0.25, CH
3
OH). H NMR: 1.68 (1H, m,
-H Pro); 2.81
-Ph, J = 13.7 Hz, J = 5.6 Hz,); 3.08 (1H, dd, CH -Ph,
-H
F, J = 12.9 Hz,
c-H
3
4
8
.36 (1H, ddd, Ar, J = 7.3 Hz, J = 1.9 Hz,).
Pro); 1.90 (1H, m, d-H Pro); 2.25–2.39 (3H, m, b, c
1H, dd, CH
J = 13.7 Hz, J = 4.4 Hz); 3.09 (1H, m, d-H Pro); 3.27 (1H, dd, a
Pro, J = 9.6 Hz, J = 7.1 Hz); 3.73 (1H, dd, CH
H,F = 1.1 Hz); 4.24 (1H, dd, CHCH
(1H, dd, CH
Ar); 6.88 (1H, dt, Ar, J = 7.6 Hz, J = 1.6 Hz); 6.99 (1H, ddd, Ar,
2
3
(
2
3
2
2
4
.2.5. (S)-{({2-[1-(3-Fluorobenzyl)pyrrolidine-2-carboxamide]-
0
00
3
3
2
phenyl}phenylmethylene)-alaninato-N,N ,N ,O}nickel(II) 7
Yield: 81.5%. Anal. Calcd for C28 NiO (530.22): C, 63.43;
H, 4.94; N, 7.93. Found: C, 63.49; H, 4.98; N, 7.91. Mp 298–
C
2 6
H
4
4
3
3
H26FN
3
3
J
2
Ph, J = 5.6 Hz, J = 4.4 Hz), 4.28
2
4
2
C H
6 4
F; J = 12.9 Hz,
J
C,F = 1.4 Hz); 6.65–6.71 (2H, m,
2
D
0
1
3
4
3
CH
00 °C. ½
a
ꢃ
¼ þ2366:7 (c 0.05, CHCl
3
). H NMR: d 1.59 (3H, d,
3
J = 7.0 Hz); 2.08 (1H, ddd, d-H Pro, J = 11.8 Hz, 2J = 10.4 Hz,
3
3
3
4
3
,
J = 10.0 Hz, J = 8.0 Hz, J = 1.5 Hz); 7.09–7.23 (5H, m, Ar); 7.30–
7.46 (5H, m, Ar); 7.49–7.59 (2H, m, Ar); 8.29 (1H, ddd, Ar,
3
J = 5.9 Hz); 2.25 (1H, m,
c
-H Pro); 2.57 (1H, m, b-H Pro); 2.77
-H Pro, 3J = 11.1 Hz, 3J = 5.5 Hz);
F, J = 12.7 Hz); 3.60 (1H, dd, d-H Pro,
J = 10.4 Hz, J = 6.2 Hz); 3.74 (1H, m, -H Pro); 3.89 (1H, q, CH–
3
3
4
3
(
1H, m, b-H Pro); 3.45 (1H, dd,
a
J = 7.2 Hz, J = 7.3 Hz, J = 2.0 Hz), 8.30 (1H, d, Ar, J = 8.4 Hz).
2
3
2 6 4
.50 (1H, d, CH C H
2
3
c
4.3.2. (S)-{({2-[1-(2-Fluorobenzyl)pyrrolidine-2-carboxamide]-
3
2
0
00
CH
3
,
J = 7.0 Hz,); 4.38 (1H, d, CH
C
2 6
H
4
F, J = 12.7 Hz); 6.62 (1H,
phenyl}phenylmethylene)-(S)-2-allylglycinato-N,N ,N ,O}-
nickel(II) 10b
3
4
3
dd, Ar, J = 8.2 Hz, J = 2.0 Hz); 6.67 (1H, ddd, Ar, J = 8.2 Hz,
3
4
4
3
4
J = 6.6 Hz, J = 1.3 Hz); 6.87 (1H, tdd, Ar, J = 8.4 Hz, J = 2.7 Hz,
To 2 g (3.88 mmol) of 4 in 15 ml DMF were added 0.34 ml
J = 0.8 Hz); 7.16 (1H, ddd, Ar, J = 8.7 Hz, J = 6.7 Hz, 4J = 2.0 Hz);
3
3
(3.88 mmol) CH
jor diastereomeric complex 10b (second fraction) was isolated
with a yield of 79.5%. Anal. Calcd for C30 NiO (556.25): C,
2 2
@CH–CH Br and 0.23 g (5.81 mmol) of NaOH. Ma-
3
4
7
.28 (1H, ddd, Ar, J = 7.5 Hz, J = 2.0); 7.33 (1H, ddd, Ar,
3
3
3
J = 8.7 Hz, J = 7.5 Hz, J = 5.8 Hz); 7.43–7.58 (3H, m, Ar); 7.80
H28FN
3
3
1H, dt, Ar J = 7.7 Hz, 4J = 1.2 Hz); 7.99 (1H, ddd, Ar, J = 9.3,
J = 2.5 Hz, J = 1.7 Hz); 8.19 (1H, dd, Ar, J = 8.7 Hz, J = 1.2 Hz).
3
3
64.78; H, 5.07; N, 7.55. Found: C, 64.79; H, 5.11; N, 7.58. Mp
(
4
3
3
4
20
D
1
138–140 °C. ½
a
ꢃ
¼ þ1188 (c 0.03, CHCl
-H Pro); 2.36 (1H, m, CHCH
); 2.54 (1H, m, b-H Pro); 2.87 (1H, m, b-H Pro); 3.42
3
). H NMR: 2.04 (1H, m,
c
-H Pro); 2.12 (1H, m,
m, CHCH
(1H, dd,
3.53 (1H, m, d-H Pro); 3.88 (1H, dd, CH
c
2
); 2.42 (1H,
4
.2.6. (S)-{({2-[1-(4-Fluorobenzyl)pyrrolidine-2-carboxamide]-
2
0
00
3
3
phenyl}phenylmethylene)-alaninato-N,N ,N ,O}nickel(II) 9
Yield: 82.6%. Anal. Calcd for C28 NiO (530.22): C, 63.43;
H, 4.94; N, 7.93. Found: C, 63.48; H, 4.96; N, 7.96. Mp 296–
a-H Pro, J = 10.6 Hz, J = 6.4 Hz), 3.47 (1H, m, d-H Pro);
2
H26FN
3
3
2
C H
6 4
F, J = 12.9 Hz,
J = 6.6, J = 4.0); 4.41 (1H, dd,
C,F = 1.2 Hz); 5.18 (1H, dd, CH CH@CH
4
3
3
J
H,F = 1.0 Hz); 3.99 (1H, dd, CHCH
F, J = 12.9 Hz,
J = 17.0 Hz, J = 1.4Hz); 5.39 (1H, ddt, CH
2
,
2
D
0
1
2
4
2
98 °C. ½
aꢃ
¼ þ2333:3 (c 0.05, CHCl
3
)
H NMR 1.60 (3H, d, CH
3
,
CH
C
2 6
H
4
J
2
2
,
3
3
2
3
2
3
J = 7.0 Hz); 2.07 (1H, ddd, d-H Pro, J = 11.9 Hz, J = 10.4 Hz,
J = 5.9 Hz); 2.24 (1H, m,
2
CH@CH
CH@CH
2
2
,
,
J = 10.2 Hz,
J = 17.0 Hz,
3
2
3
3
4
2
3
c
-H Pro); 2.56 (1H, m, b-H Pro); 2.76
-H Pro, 3J = 11.1 Hz, 3J = 5.6 Hz);
2 6 4
.49 (1H, d, CH C H F, J = 12.7 Hz); 3.58 (1H, dd, d-H Pro,
J = 1.5 Hz, J = 1.0 Hz); 6.43 (1H, ddt, CH
2
3
(
1H, m, b-H Pro); 3.42 (1H, dd,
a
J = 10.2 Hz, J = 7.4 Hz); 6.62–6.71 (2H, m, Ar); 6.97 (1H, dt, Ar,
2
J = 6.5 Hz, J = 1.9 Hz); 7.06 (1H, ddd, Ar, J = 10.0 Hz, 3J = 8.1Hz,
4
3
3
2
3
J = 10.4 Hz, J = 6.0 Hz); 3.76 (1H, m,
c
-H Pro); 3.90 (1H, q, CH–
J = 1.2 Hz); 7.14–7.31 (4H, m, Ar), 7.45–7.57 (3H, m, Ar), 8.25
(1H, d, Ar, J = 8.6 Hz); 8.31 (1H, ddd, Ar, J = 7.3 Hz, J = 2.0 Hz).
3
2
3
3
4
CH
3
,
J = 7.0 Hz); 4.38 (1H, d, CH
C
2 6
H
4
F, J = 12.7 Hz); 6.62 (1H,

A. S. Saghyan et al. / Tetrahedron: Asymmetry 21 (2010) 2956–2965
2963
4
.3.3. (S)-{({2-[1-(2-Fluorobenzyl)pyrrolidine-2-carboxamide]-
64.75; H, 5.07; N, 7.55. Found: C, 64.78; H, 5.11; N, 7.58. Mp
2
0
1
phenyl}phenylmethylene)-(S)-2-methyl-3-phenylalaninato-
N,N ,N ,O}nickel(II) 11a
158–160 °C. ½
a
ꢃ
¼ þ1262:5 (c 0.04, CHCl
3
). H NMR: 2.06 (1H,
-H Pro); 2.36 (1H, m, CH CH ); 2.43
2
(1H, m, CH CH ); 2.55 (1H, m, b-H Pro); 2.79 (1H, m, b-H Pro);
D
0
00
m, d-H Pro); 2.15 (1H, m,
c
2
To 2 g (3.77 mmol) of 5 in 15 ml DMF were added 1.35 ml
3
3
(
11.32 mmol) C
diastereomeric complex 11a (second fraction) was isolated with a
yield of 79.3%. Anal. Calcd for C35 NiO (620.34): C, 67.77; H,
.20; N, 6.77. Found: C, 67.79; H, 5.22; N, 6.81. Mp 208–210 °C.
H CH
6 5 2
Br and 0.45 g (11.32 mmol) of NaOH. Major
3.40 (1H, dd,
a
-H Pro, J = 10.8 Hz, J = 6.1 Hz); 3.50 (1H, d,
2
CH C
2 6
H
4
F, J = 12.6 Hz); 3.55 (1H, m,
c
-H Pro); 3.55 (1H, m, d-H
3
3
H32FN
3
3
2
Pro); 3.98 (1H, dd, CHCH , J = 6.6 Hz, J = 3.9 Hz); 4.36 (1H, d,
2
3
5
CH
C
2 6
H
4
F, J = 12.6 Hz); 5.18 (1H, ddt, CH
2
–CH@CH
2
,
,
,
J = 17.0 Hz,
J = 10.1 Hz,
J = 17.0 Hz,
2
D
c
0
1
4
4
3
3
½
a
m,
ꢃ
¼ þ1802 (c 0.065 CHCl
3
). H NMR: 1.15 (3H, s, CH
3
); 1.58 (1H,
-H Pro); 1.82 (1H, ddd, d-H Pro, J = 10.4 Hz, 3J = 6.3 Hz); 2.04
1H, m, -H Pro); 2.21–2.29 (2H, m, b-H Pro); 3.07 (1H, ddd, d-H
J = 1.6 Hz, J = 1.3 Hz); 5.40 (1H, ddt, CH
2
–CH@CH
–CH@CH
2
2
4
3
4
J = 1.6 Hz, J = 0.9 Hz); 6.44 (1H, ddt, CH
2
2
3
(
c
J = 10.1Hz, J = 7.4 Hz); 6.62 (1H, m, Ar); 6.65 (1H, m, Ar); 6.83
2
3
3
3
3
4
4
Pro, J = 10.4 Hz, J = 6.3 Hz, J = 3.1 Hz); 3.13 (2H, s, CH
2
-Ph); 3.21
-H Pro, J = 9.5 Hz, 3J = 7.8 Hz); 3.81 (1H, dd, CH
F,
F, J = 12.9 Hz,
(1H, tdd, Ar, J = 8.4 Hz, JH,F = 8.4 Hz, J = 2.6 Hz, J = 1.0 Hz); 6.94
3
(1H, m, Ar); 7.14 (1H, ddd, Ar, J = 8.7 Hz, 3J = 6.5 Hz, 4J = 2.2 Hz);
7.27 (1H, m, Ar); 7.29 (1H, m, Ar); 7.48 (1H, m, Ar); 7.50 (1H, m,
Ar); 7.54 (1H, m, Ar); 7.75 (1H, ddd, Ar, J = 7.6 Hz, 4J = 1.6 Hz,
3
(
1H, dd,
J = 12.9 Hz,
a
2 6 4
C H
2
4
2
2 6 4
JH,F = 1.0 Hz); 4.31 (1H, dd, CH C H
4JC,F = 1.4 Hz); 6.55–6.64 (2H, m, Ar); 6.96–7.04 (2H, m, Ar); 7.10–
3
3
5
4
3
4
7
.25 (3H, m, Ar); 7.32–7.50 (9H, m, Ar); 8.19 (1H, dd, Ar, J = 8.7 Hz,
J
H,F = 1.0 Hz); 7.99 (1H, ddd, Ar,
JH,F = 9.3 Hz, J = 2.6 Hz,
4
3
3
4
3
4
J = 1.2 Hz); 8.24 (1H, ddd, Ar, J = 7.4 Hz, J = 7.4 Hz, J = 1.9 Hz).
J = 1.6 Hz); 8.25 (1H, dd, Ar, J = 8.7 Hz, J = 1.0 Hz).
4
.3.4. (S)-{({2-[1-(2-Fluorobenzyl)pyrrolidine-2-carboxamide]-
4.3.7. (S)-{({2-[1-(4-Fluorobenzyl)pyrrolidine-2-carboxamide]-
phenyl}phenylmethylene)-(S)-3-phenylalaninato-N,N ,N ,O}-
nickel(II) 13a
0
00
phenyl}phenylmethylene)-(S)-2-methyl-3-allylalaninato-
N,N ,N ,O}nickel(II) 11b
0
00
To 2 g (3.77 mmol) of 5 in 15 ml DMF were added 0.98 ml
To 2 g (3.88 mmol) of 8 in 15 ml DMF were added 0.47 ml
(
11.32 mmol) CH
Major diastereomeric complex 11b (second fraction) was isolated
with a yield of 77.1%. Anal. Calcd for C31 NiO (570.28): C,
5.29; H, 5.30; N, 7.37. Found: C, 65.33; H, 5.35; N, 7.35. Mp
2
@CH–CH
2
Br and 0.45 g (11.32 mmol) of NaOH.
(3.88 mmol) C
diastereomeric complex 13a (second fraction) was isolated with
a yield of 76.1%. Anal. Calcd for C34 NiO (606.31): C,
6 5 2
H CH Br and 0.23 g (5.81 mmol) of NaOH. Major
H30FN
3
3
H30FN
3
3
6
2
CH
67.35; H, 4.99; N, 6.93. Found: C, 67.37; H, 5.01; N, 6.96. Mp
2
0
1
20
D
1
02–204 °C. ½
); 1.96–2.21 (2H, m,
m, b-H Pro); 2.82 (1H, m, b-H Pro); 3.31 (2H, m, d-H Pro); 3.38
a
ꢃ
¼ þ742:3 (c 0.29 CHCl
3
). H NMR: 1.20 (3H, s,
102–104 °C. ½
aꢃ
¼ þ1000 (c 0.05, CHCl
3
). H NMR: 1.68 (1H, m,
D
3
c
-H Pro); 2.49 (2H, m, CHCH ); 2.54 (1H,
2
c
-H Pro); 1.93 (1H, m, d-H Pro); 2.32 (2H, m, b-H Pro); 2.34 (1H,
c-H Pro); 2.84 (1H, dd, CH -Ph, J = 13.7 Hz, J = 5.5 Hz); 3.10
2
2
-Ph, J = 13.7 Hz, J = 4.5 Hz); 3.12 (1H, m, d-H Pro);
3.24 (1H, dd, a-H Pro, J = 9.1 Hz, J = 7.4 Hz); 3.38 (1H, d,
2
3
m,
3
3
2
3
(
1H, dd,
J = 12.9 Hz,
a
-H Pro, J = 10.5 Hz, J = 6.6 Hz), 3.98 (1H, dd, CH
2
C
6
H
4
F,
(1H, dd, CH
2
4
2
3
3
J
H,F = 1.0 Hz); 4.50 (1H, dd, CH
2
C
6
H
4
F, J = 12.9 Hz,
4JC,F = 1.2 Hz); 5.36 (1H, dd, CH
5
CH
Ar); 7.04–7.50 (9H, m, Ar); 8.10 (1H, d, Ar, J = 8.5 Hz); 8.30 (1H,
dt, Ar, J = 7.3 Hz, J = 1.9 Hz).
CH@CH
,
3
J = 17.2 Hz, J = 1.6Hz);
2
2
2
2
2
2 6 4 2 6 4
CH C H F, J = 12.8 Hz); 4.25 (1H, d, CH C H F, J = 12.8 Hz); 4.27
3
2
3
3
.47 (1H, dd, CH
2
CH@CH
2
,
J = 10.1 Hz, J = 1.5Hz); 6.61 (1H, ddt,
2
(1H, dd, CH–CH –, J = 5.5 Hz, J = 4.5 Hz); 6.67 (1H, m, Ar); 6.69
3
J = 17.2 Hz, J = 10.2 Hz, 3J = 6.8 Hz); 6.63 (2H, m,
3
(1H, m, Ar); 6.87 (1H, dddd, Ar, J = 7.6 Hz, J = 1.9 Hz, 4J = 1.3 Hz,
3
4
2
CH@CH
2
,
3
4
J = 0.7 Hz); 6.98 (2H, m, Ar); 7.18 (1H, m, Ar); 7.19 (2H, m, Ar);
3
4
7.31 (1H, m, Ar); 7.40 (1H, m, Ar); 7.40 (2H, m, Ar); 7.45 (1H, m,
Ar); 7.53 (1H, m, Ar); 7.57 (1H, m, Ar); 8.03 (2H, m, Ar); 8.27
3
4
4
.3.5. (S)-{({2-[1-(3-Fluorobenzyl)pyrrolidine-2-carboxamide]-
(1H, dd, Ar, J = 8.7 Hz, J = 1.1Hz).
0
00
phenyl}phenylmethylene)-(S)-3-phenylalaninato-N,N ,N ,O}-
nickel(II) 12a
4.3.8. (S)-{({2-[1-(4-Fluorobenzyl)pyrrolidine-2-carboxamide]-
0
00
To 2 g (3.88 mmol) of 6 in 15 ml DMF were added 0.47 ml
phenyl}phenylmethylene)-(S)-2-allylglycinato-N,N ,N ,O}-
nickel(II) 13b
(
3.88 mmol) C
diastereomeric complex 12a (second fraction) was isolated with
a yield of 75.8%. Anal. Calcd for C34 NiO (606.31): C,
7.35; H, 4.99; N, 6.93. Found: C, 67.39; H, 4.95; N, 6.96. Mp
6 5 2
H CH Br and 0.23 g (5.81 mmol) of NaOH. Major
To 2 g (3.88 mmol) of 8 in 15 ml DMF were added 0.34 ml
H30FN
3
3
(3.88 mmol) CH
jor diastereomeric complex 13b (second fraction) was isolated
with a yield of 73.4%. Anal. Calcd for C30 NiO (556.25): C,
2 2
@CH–CH Br and 0.23 g (5.81 mmol) of NaOH. Ma-
6
1
m,
2
D
0
1
23–125 °C. ½
-H Pro); 1.92 (1H, m, d-H Pro); 2.25–2.38 (3H, m, b,
Pro); 2.81 (1H, dd, CH
-Ph, 2J = 13.7 Hz, 3J = 5.5 Hz); 3.09 (1H, dd,
aꢃ
¼ þ1138:9 (c 0.06, CHCl
3
). H NMR: 1.67 (1H,
H28FN
3
3
c
c
-H
64.78; H, 5.07; N, 7.55. Found: C, 64.80; H, 5.03; N, 7.59. Mp
20
D
1
2
101–103 °C. ½
a
ꢃ
¼ þ936:4 (c 0.055, CHCl
-H Pro); 2.40 (2H, m, CH
(1H, m, b-H Pro); 2.80 (1H, m, b-H Pro); 3.38 (1H, dd,
3
). H NMR 2.05 (1H, m,
–CH@CH ); 2.53
-H Pro,
F, J = 12.7 Hz); 3.55
2
-H Pro); 4.01 (1H, dd, CH CH ,
2
3
CH
t,
2
-Ph, J = 13.7 Hz, J = 4.4 Hz); 3.12 (1H, m, d-H Pro), 3.25 (1H,
-H Pro, J = 8.2 Hz); 3.36 (1H, d, CH
d-H Pro); 2.16 (1H, m,
c
2
2
3
2
a
2
C H
6 4
F, J = 12.5 Hz); 4.22
a
2
3
3
3
2
(
1H, d, CH
2
C
6
H
4
F, J = 12.5 Hz); 4.24 (1H, dd, CH–CH
2
,
J = 5.5 Hz,
2 6 4
J = 10.7 Hz, J = 6.2 Hz); 3.51 (1H, d, CH C H
(1H, m, d-H Pro); 3.59 (1H, m,
J = 6.6 Hz, J = 4.1 Hz); 4.39 (1H, d, CH
3
3
3
J = 4.4 Hz); 6.66 (1H, m, Ar); 6.68 (1H, m, Ar); 6.80 (1H, tdd, Ar,
c
4
4
3
3
2
J = 8.4 Hz, J = 2.6 Hz, J = 1.0 Hz); 6.87 (1H, dddd, 2-H, C
6
H ,
5
2 6
C H
4
F, J = 12.7 Hz); 5.19
J = 7.6 Hz, J = 1.9 Hz, 4J = 1.3 Hz, 4J = 0.6 Hz); 7.15 (1H, m, Ar);
4
3
J = 17.0 Hz, J = 1.4 Hz); 5.40 (1H, dq,
J = 10.1 Hz, J = 1.4 Hz); 6.43 (1H, ddt, CH
4
2 2
(1H, dq, CH –CH@CH ,
3
4
7
.18–7.28 (4H, m, Ar); 7.32 (1H, m, Ar); 7.38–7.46 (4H, m, Ar);
CH
CH@CH
6.67 (1H, m, Ar); 6.96 (1H, m, Ar); 7.03 (2H, m, Ar); 7.18 (1H,
2
–CH@CH
2
,
2
–
3
3
J = 17.0 Hz, 3J = 10.1 Hz, 3J = 7.4 Hz); 6.65 (1H, m, Ar);
7
.53 (1H, m, Ar); 7.57 (1H, m, Ar); 7.67 (1H, ddd, Ar, J = 8.4 Hz,
2
,
4
4
2
4
J = 2.6 Hz, J = 1.0 Hz); 8.03 (1H, ddd, Ar, J = 9.4 Hz, J = 2.6 Hz,
4
3
4
4
3
3
4
J = 1.0 Hz); 8.32 (1H, ddd, Ar, J = 8.7 Hz, J = 1.0 Hz, J = 0.6 Hz).
ddd, Ar, J = 8.7 Hz, J = 6.6 Hz, J = 2.2 Hz); 7.29 (1H, m, Ar); 7.47
1H, m, Ar); 7.51 (1H, m, Ar); 7.55 (1H, m, Ar); 8.07 (2H, m, Ar);
8.21 (1H, dd, Ar, J = 8.7 Hz, J = 1.1 Hz).
(
3
4
4
.3.6. (S)-{({2-[1-(3-Fluorobenzyl)pyrrolidine-2-carboxamide]-
0
00
phenyl}phenylmethylene)-(S)-2-allylglycinato-N,N ,N ,O}-
nickel(II) 12b
4.4. The aldol condensation of complex 4 was carried out by a
1
0
To 2 g (3.88 mmol) of 6 in 15 ml DMF were added 0.34 ml
previously designed method
(
3.88 mmol) CH
jor diastereomeric complex 12b (second fraction) was isolated
with a yield of 74.2%. Anal. Calcd for C30 NiO (556.25): C,
2 2
@CH–CH Br and 0.23 g (5.81 mmol) of NaOH. Ma-
The (R)-serine 14 complex was crystallized from a heptane/
acetone mixture (1:1), while the (R)-threonine complex 15 was
H28FN
3
3

2
964
A. S. Saghyan et al. / Tetrahedron: Asymmetry 21 (2010) 2956–2965
Table 6
Crystallographic data for 5, enantiomer-7 and 9
Compound
5
(R)-7 ꢂ ½CHCl
3
ꢂ ½H
2
O
9
Empirical formula
C
28
H
26
3
N O
3
FNi
C
28.5
H
27.5
N
3
O
3.5FCl1.5Ni
C
28 26 3 3
H N O FNi
f
w
530.23
100
598.92
293
530.23
120
T (K)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
Rhombic
P2
9.5229(4)
9.9635(5)
25.4816(11)
90
90
Monoclinic
P2
9.3442(3)
24.0402(7)
12.4545(4)
90
90.833(1)
90
2797.44(15)
4
Rhombic
P2
9.1541(7)
10.2051(7)
25.6532(18)
90
90
90
2396.5(3)
4
1.470
1104
1
2
2
1 1
1
1 1 1
2 2
a
(deg)
b (deg)
(deg)
c
90
3
V (Å )
25.4816(11)
4
1.457
1104
0.846
60
Z
d
(g sm 3
ꢁ
)
1.422
1240
0.880
57.5
c
F(0 0 0)
l
(mmꢁ1)
0.854
60
2h
max (deg)
No. rflns collected
No. of unigue rflns
No. of rflns with I > 2
21155
7020
5844
33851
14468
11455
690
27317
6851
5788
r
(I)
Data/restraints/parameters
317
326
R
R
1
; wR
1;wR
2
(I > 2
r
(I))
0.0466
0.1159
1.016
0.01(5)
0.842; 0.884
0.0373
0.0871
1.002
0.006(7)
0.844; 0.844
0.0452
0.1092
1.003
0.045(13)
0.784; 0.958
2
(all data)
2
GOF on F
Absolute structure parameter
Tmin; Tmax
crystallized from
a
mixture of heptane/acetone/methanol
4.5. Deuteration (a-hydrogen exchange) of the amino acid
(
1:1:1).
moiety of alanine (a) and glycine (b) complexes
4
.4.1. (S)-{({2-[1-(2-Fluorobenzyl)pyrrolidine-2-
The rate of the deutero exchange of the -hydrogen atom of
a
carboxamide]phenyl}phenylmethylene)-(R)-serinato-
N,N ,N ,O}nickel(II) 14
amino acid moiety in complexes of glycine and alanine and the
new chiral auxiliaries was studied. The deuterium exchange was
studied in an ampoule of the NMR-spectrometer by adding
0
00
3 4
Yield: 2 g (3.6 mmol) 79.6%. Anal. Calcd for C28H26FN NiO
ꢁ4
t
(
7
1
544.22): C, 61.57; H, 4.80; N, 7.69. Found: C, 61.55; H, 4.85; N,
0.05 ml 5.45 ꢂ 10 mol Bu OK (for alanine complexes) and
0.05 ml 0.5 M of DABCO in CDCl (for glycine complexes) to a solu-
OD. Data on the
20
1
.63. Mp 175–177 °C. ½
aꢃ
¼ ꢁ2243 (c 0.05, CHCl
3
). H NMR:
-H Pro); 2.30 (1H, m, -H
3
D
ꢁ5
.92 (1H, m, b-H Pro); 2.11 (1H, m,
c
c
tion of 3.7 ꢂ 10 mol complex in 0.5 ml of CD
3
Pro); 2.52 (1H, m, d-H Pro); 2.67 (1H, m, d-, b-H Pro); 3.46 (1H,
change of the amount of the deuterated product versus time are
presented in Figure 2a (for a series of alanine complexes) and b
(for a series of glycine complexes).
3
3
dd,
a
-H Pro, J = 9.3 Hz, J = 4.8 Hz); 3.64 (1H, dd, CH
2
–OH,
–OH, J = 10.8 Hz,
F, J = 13.2 Hz); 3.90 (1H, dd,
H Ser, J = 5.7 Hz, J = 4.1 Hz); 4.10 (1H, m, d-H Pro); 4.46 (1H, dd,
2
3
2
J = 10.8 Hz, J = 4.1 Hz); 3.72 (1H, dd, CH
J = 5.7 Hz); 3.77 (1H, d, CH
2
3
2
2
C H
6 4
a-
3
3
4.6. X-ray diffraction study of complexes 5, (R)-7, and 9
2
4
3
2 6 4
CH C H F, J = 13.2 Hz, J = 1.5 Hz); 6.65 (1H, ddd, Ar, J = 8.4 Hz,
3
J = 6.8 Hz, J = 1.2 Hz); 6.75 (1H, dd, Ar, 3J = 8.4 Hz, 4J = 1.9 Hz);
4
Parameters of elementary cells and reflection intensities for
7
.09–7.22 (4H, m, Ar); 7.30–7.42 (2H, m, Ar); 7.47–7.53 (3H, m,
compounds 5, (R)-7, and 9 were measured on a Bruker SMART
Ar); 8.46 (1H, dd, Ar, J = 8.7 Hz, 4J = 1.2 Hz); 8.72 (1H, td, Ar,
3
1K CCD three-circle automated diffractometer (kMoK
a
-radiation,
-scan mode) (for compounds
-radiation,
, and x-scan mode) (for compound
3
4
J = 7.4 Hz, J = 2.1 Hz).
graphite monochromator,
u
and x
(R)-7 and 9) and Bruker SMART APEX II CCD (kMoKa
4
.4.2. (S)-{({2-[1-(2-Fluorobenzyl)pyrrolidine-2-
graphite monochromator,
u
carboxamide]phenyl}phenylmethylene)-(R)-threoninnato-
N,N ,N ,O}nickel(II) 15
5). Absorption records of X-radiation for the obtained data were
0
00
14
performed by the SADABS program (versions 2.01 in the case of en-
1
5
Yield: 2 g (3.6 mmol) 71.0%. Anal. Calcd for C29
H28FN
3
NiO
4
ant-7 and 9 and 2.03 in the case of compound 5). The major crys-
tallographic data are presented in Table 6.
(
7
1
560.24): C, 62.17; H, 5.04; N, 7.50. Found: C, 62.15; H, 5.09; N,
20
1
.55. Mp 188–190 °C. ½
a
ꢃ
¼ ꢁ471:5 (c 0.035, CHCl
3
). H NMR
-H Pro); 2.15 (1H, m,
-H Pro); 2.53 (1H, ddd, d-H Pro,
J = 11.2 Hz, J = 9.6 Hz, J = 6.2 Hz); 2.73 (1H, m, b-H Pro); 3.50
The structures of all compounds were determined by the direct
method and verified by full-matrix least squares refinement with
anisotropic thermal approximation for non-hydrogen atoms. The
crystal of compound (R)-7 contains solvate molecules of chloro-
form and water. In compound 5 the ortho-fluorophenyl fragment
is statistically disordered over two sites related by the rotation
on 180° around the C(15)–C(16) bond with equal occupancies.
The hydrogen atoms of the solvate molecule of water in compound
(R)-7 are revealed in different Fourier syntheses and refined in iso-
tropic approximation with fixed positional and thermal parame-
ters (Uiso(H) = 1.5Ueq(O)). Positions of other hydrogen atoms are
calculated geometrically and refined in isotropic approximation
with fixed positional (riding model) and thermal parameters
D
3
3
.73 (3H, d, CH , J = 6.3 Hz); 1.91 (1H, m, c
b-H Pro); 2.32 (1H, m,
c
2
3
3
-H Pro, J = 9.9 Hz, 3J = 4.6 Hz); 3.59 (1H, br d, OH,
3
(
1H, dd,
a
3
J = 10.3 Hz); 3.78 (1H, m, CHCH ); 4.02 (1H, ddd, d-H Pro,
3
2
3
3
3
J = 11.2 Hz, J = 6.8 Hz, J = 4.0 Hz); 4.05 (1H, d, CHCHOH,
2
4
J = 5.1 Hz); 4.12 (1H, dd, CH
2
6
C H
4
F, J = 13.3 Hz,
J
H,F = 1.0 Hz);
2
4
4
.80 (1H, dd, CH
2
C H
6 4
F, J = 13.3 Hz,
J
H,F = 1.1 Hz); 6.75 (1H, ddd,
3
3
4
3
Ar, J = 8.3 Hz, J = 6.9 Hz, J = 1.2 Hz); 6.86 (1H, dd, Ar, J = 8.3 Hz,
4
J = 1.7 Hz); 7.16–7.32 (5H, m, Ar); 7.43 (1H, m, Ar); 7.51–7.57
3
(
3H, m, Ar); 8.15 (1H, td, Ar, J = 7.5 Hz, 4J = 1.7 Hz); 8.49 (1H, dd,
3
4
Ar, J = 8.7 Hz, J = 1.1 Hz).

A. S. Saghyan et al. / Tetrahedron: Asymmetry 21 (2010) 2956–2965
2965
(
U
iso(H) = 1.5Ueq(C) for the CH
3
-groups and Uiso(H) = 1.2Ueq(C) for
I.; Kochetkov, C. A.; Garbalinskaya, N. S.; Ryzhov, M. G.; Bakhmutov, V. I.;
Saprovskaya, M. B.; Paskonova, E. A.; Maleev, V. I.; Vitt, S. V.; Belikov, V. M. Russ.
Chem. Bull. 1984, 33, 738–746.
Belokon’, Y. N.; Bakhmutov, V. I.; Chernoglazova, N. I.; Kochetkov, C. A.; Vitt, S.
V.; Garbalinskaya, N. S.; Belikov, V. M. J. Chem. Soc. Perkin. Trans. I 1988, 305–
all other groups). All calculations were carried out by using the
SHELXT program package.
1
6
7
.
.
311; Belokon’, Y. N.; Djamgaryan, S. M.; Saghiyan, A. S.; Ivanov, A. S.; Belikov, V.
Acknowledgments
M. Izv. AN USSR, Ser. Chim. 1988, 7, 1618–1624.
8
Soloshonok, V. A.; Ohkura, H.; Sorochinsky, A.; Voloshin, N.; Markovsky, A.;
Belik, M.; Yamazaki, T. Tetrahedron Lett. 2002, 43, 5445; Saghiyan, A. S.;
Geolchanyan, A. V.; Petrosyan, S. G.; Chochikyan, T. V.; Haroutyunyan, V. S.;
Avetisyan, A. A.; Belokon’, Y. N.; Fisher, K. Tetrahedron: Asymmetry 2004, 15,
This work was supported by ISTS Grant # A-1677. The authors
thank Professor Yuri Belokon for helpful discussions.
7
05–711; Saghiyan, A. S.; Avetisyan, A. E.; Djamgaryan, S. M.; Djilavayan, L. R.;
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