Michael addition reactions between various nucleophilic glycine equivalents and (S,E)-1-enoyl-5-oxo-N-phenylpyrrolidine-2-carboxamide, an optimal type of chiral Michael acceptor in the asymmetric synthesis of β-phenyl pyroglutamic acid and related compoun

Article abstract of DOI:10.1016/j.tetasy.2009.10.006

(S)-5-Oxo-N-phenyl-1-[(E)-3-phenylacryloyl]pyrrolidine-2-carboxamide, easily prepared from inexpensive and readily available, in both enantiomeric forms, glutamic/pyroglutamic acid was designed as an optimal type of chiral Michael acceptor for reactions w

Full text of DOI:10.1016/j.tetasy.2009.10.006

Tetrahedron: Asymmetry 20 (2009) 2629–2634
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Michael addition reactions between various nucleophilic glycine
equivalents and (S,E)-1-enoyl-5-oxo-N-phenylpyrrolidine-2-carboxamide,
an optimal type of chiral Michael acceptor in the asymmetric synthesis of
b-phenyl pyroglutamic acid and related compounds
*
*
Trevor K. Ellis , Hisanori Ueki, Rohit Tiwari, Vadim A. Soloshonok
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
(S)-5-Oxo-N-phenyl-1-[(E)-3-phenylacryloyl]pyrrolidine-2-carboxamide, easily prepared from inexpen-
sive and readily available, in both enantiomeric forms, glutamic/pyroglutamic acid was designed as an
optimal type of chiral Michael acceptor for reactions with a series of nucleophilic glycine equivalents.
A study of the corresponding Michael addition reactions revealed that the new generation of modular
glycine derivatives, as a counterpart to the Michael acceptor, provides for operationally convenient prep-
aration of b-phenyl pyroglutamic acids and related compounds with virtually complete chemical and
stereochemical outcomes.
Received 9 September 2009
Accepted 7 October 2009
Available online 10 November 2009
Published by Elsevier Ltd.
1. Introduction
family of the corresponding v-(chi)-constrained five-carbon-atom
amino acids including glutamines, prolines, ornithines, and argi-
nines.12 Therefore, one may envision that the development of prac-
tical, simple, and stereochemically reliable access to b-substituted
glutamic/pyroglutamic acids will also allow the preparation of vari-
ous types of other b-substituted amino acids and related biologically
important compounds.12
In the post-genomic era, the synthetic availability of tailor-
made a
-amino acids1 of desired structural and functional complex-
ity has become of critical importance in the development of a new
paradigm of peptide-based approaches to the treatment of dys-
function in human health.2 Of particular biological importance
are
derivatives substantially restrict the number of possible conforma-
tions in the
-(chi)-space,4 thus providing a powerful tool for the
preparation of peptides and peptidomimetics with a pre-supposed
3-D structure. However, the preparation of b-substituted- -amino
a
-amino acids containing substituents at the b-position.3 Such
2. Results and discussion
v
Recently, we have developed a new concept of organic base-cat-
alyzed, room-temperature Michael addition reactions between
a
nucleophilic glycine equivalents and
a,b-unsaturated carboxylic
acids, containing at least two stereogenic centers, presents a signif-
icant synthetic challenge in terms of control of the absolute as well
as relative stereochemistry.
acid derivatives as an operationally convenient and generalized
method for preparing b-substituted glutamic/pyroglutamic acids.13
In particular, we demonstrated that N-(E-enoyl)-4-phenyl-1,3-
oxazolidin-2-ones14 4 (Scheme 1) can be successfully used as
Michael acceptors in these organic base-catalyzed reactions, regard-
less of the fact that the usual application of derivatives 4 as chiral
electrophiles necessitates the presence of metals as chelating
agents.15 The most important feature in the concept of organic
base-catalyzed Michael addition reactions is the topographical
nature of the observed stereochemical outcome.16 A beneficial
consequence of this extremely rare mode of stereo-control in asym-
metric synthesis, is that the stereochemical outcome of these
Michael addition reactions does not depend on the structure of the
starting nucleophilic glycine equivalent or Michael acceptor.16 Thus,
glycine derivatives 1,17,18, 2a,b19,20, and 3a,b21 (Scheme 1) can be
used as nucleophilic glycine equivalents in the addition reactions
Recently, in response to the growing demand for b-substituted-
a
-amino acids, Kobayashi et al.,5 Kazmaier et al.,6 Szabó et al.,7 Ohfu-
ne et al.,8 Ooi and Maruoka et al.9 have developed synthetically
useful and methodologically elegant approaches to various struc-
tural types of amino acids, which belong to this family of tailor-made
a
-amino acids. The interest of our group in this area is the develop-
ment of operationally convenient10 methods for the preparation of
enantiomerically pure sterically constrained a-amino acids in gen-
eral,11 and b-substituted glutamic/pyroglutamic acids in particular.
Our choice for this type of compounds as synthetic targets is based
on the proven feasibility of their transformation to a generalized
* Corresponding authors. Tel.: +1 405 325 3820; fax: +1 405 325 6111 (T.K.E.).
E-mail address: tellis@ou.edu (T.K. Ellis).
0957-4166/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2009.10.006

2630
T. K. Ellis et al. / Tetrahedron: Asymmetry 20 (2009) 2629–2634
Ph
According to X-ray analysis (Fig. 1), Michael acceptor 10 exists
Alk
Ni
Alk
exclusively in the s-cis conformation due to the strong electrostatic
repulsive interactions between the 2-enoyl and 5-oxo-pyrrolidine
carbonyl groups. Furthermore, the planes of the 2-enoyl and
5-oxo-pyrrolidine moieties are nearly coplanar, while the
N-(phenyl)carboxamide residue is pointed at about an angle of
90° relative to the 2-enoyl functionality. As one can reasonably
assume, in this position, being pointed away from the 2-enoyl res-
idue, the N-(phenyl)carboxamide group cannot exercise any effec-
tive stereo-control over the face selectivity of Michael acceptor 10.
However, due to the topographical nature16 of the stereochemical
outcome in these Michael addition reactions, the virtually perpen-
dicular position of the N-(phenyl)carboxamide group to the 2-en-
oyl residue, is efficient to completely prevent one side of Michael
acceptor 10 (as well as of types 4 and 7) from mutual approach
with enolates, derived from planar Ni(II) complexes 1–3, to a suffi-
cient close proximity for the addition reaction to take place. There-
fore, the observed geometry of compound 10 met our expectations
for an efficient Michael acceptor.
First, we studied the addition reaction between this new
Michael acceptor with picolinic acid derived Ni(II) complexes 11
and 12 (nucleophilic glycine equivalents of type 2, Scheme 1). As
shown in Scheme 3, the reactions were conducted at room temper-
ature in commercial-grade DMF, and in the presence of catalytic
(15 mol %) amounts of DBU. The reaction of benzophenone-derived
complex 11 with 10 proceeded very sluggishly, with it being less
than 50% complete after 24 h. The corresponding product 13 was
isolated in 30% yield, only for the purpose of structural and stereo-
chemical characterization. By contrast, the acetophenone-derived
complex 12, containing the less sterically shielded glycine moiety,
reacted with Michael acceptor 10 substantially faster allowing the
reaction to be completed in 4.5 h and furnishing the product 14 in
high (93%) yield. However, the isolation of product 14 should be
accomplished in an expeditious manner as compound 14 was
found to be partially soluble in DMF/water mixture.
N
N
O
N
O
N
O
N
O
N
N
O
N
O
Ni
Ni
or
O
O
N
O
or
R
Ph
(S)-1
R
2
3
R = Ph, Me
or
R = Ph, Me
Ph
MeOOC
O
R'
N
R'
N
O
O
O
O
7
4
R'
Ph
O
+
O
COOH
>93% yield
N
N
H
H
5
O
6
Scheme 1.
with oxazolidin-2-ones 4. Similarly, the structure of the chiral auxil-
iary in 4 can also be modified without any significant effect on the
stereochemical outcome of the corresponding Michael addition
reactions. In particular, Michael acceptors 7, derived from very inex-
pensive esters of naturally occurring pyroglutamic acid, can be effi-
ciently used in the addition reactions with different types of glycine
derivatives 1, 2a,b and 3a,b.22,23 Taking into account that natural (S)-
pyroglutamic acid, as well its (R)-enantiomer, are considerably less
expensive when compared with Evans-type oxazolidin-2-one auxil-
iary 6,24 the recovery of (S)- or (R)-pyroglutamic acids is not an issue,
thereby simplifying the procedure for isolation of the target b-
substituted amino acids 5.
However, despite these advantageous characteristics of ester-
type Michael acceptors 7, we found that the physical properties of
derivatives 7 present some operational inconvenience. Most of the
esters of pyroglutamic acid are liquids (at ambient temperatures)
whiletheMichaelacceptors7 derivedfromthem haveverylowcrys-
tallinity. These factors make the derivatives 7 relatively unstable
upon storage under regular laboratory conditions and inconvenient
to manipulate. Therefore, we decided to find other derivatives of
pyroglutamic acid to overcome these shortcomings. After consider-
ation of several possibilities, our choice eventually fell on anilide-
type derivatives 10 (Scheme 2), which possess excellent physical
properties. Moreover, compounds of type 10 are even less expensive
than esters 7, as they can be prepared simply by heating glutamic 8a
or pyroglutamic acid 8b with aniline to form the corresponding
amide 9 in high (88%) chemical yield.25 Further transformation of
anilide 9 to the target Michael acceptor 10 can also be performed
under the standard conditions previously reported by us.14
Overall, the Michael acceptor 10 was found to be less reactive,
when compared to derivatives 4 and 7 (Scheme 1) in the additions
with 11 and 12, and therefore, these reactions can be considered
less synthetically attractive.
Next, we investigated the reaction of the Michael acceptor 10
with a series of a new generation of achiral nucleophilic glycine
equivalents (type 3, Scheme 1) 15 and 16. The addition reactions
(Scheme 4) were conducted under standard conditions at ambient
temperatures in the presence of 15 mol % of DBU. Dimethyl/ and
diethylamine/benzophenone-derived complexes 15a and 15b,
respectively, showed substantially improved reaction rates, when
compared with the reactions of 11 and 12, allowing a complete
conversion of the starting materials in less than 1 h (Table 1, en-
tries 1 and 2). However, the isolation of the corresponding prod-
ucts 17a,b was complicated by their physical properties. Thus,
compounds 17a,b were precipitated as very small, fine particles
significantly hindering their isolation via filtration. Due to this
property, the isolated yields of products 17a,b were only 70% and
75%, respectively.
HOOC
COOH
NH2
O
Ph
Cl
H
N
8a
Ph
N
O
Ph-NH2
°
or
O
Ph
N
H
O
O
LiCl; TEA;
CH2Cl2; 1 hr
175 C; 3.5 h
O
88%
N
H
O
COOH
N
Ph
9
10
91%
H
8b
Scheme 2.

T. K. Ellis et al. / Tetrahedron: Asymmetry 20 (2009) 2629–2634
2631
Table 1
O
Ph
N
Entry
Complex
Time (min)
Conversion (%)
Yield (%)
O
O
N
1
2
3
4
5
6
15a
15b
15c
15d
16a
16b
60
60
20
20
25
25
>98
>98
>98
>98
>98
>98
70
75
>95
>95
>95
>95
10
H
Ph
On the other hand, the di-n-butylamine/ and piperidine/benzo-
phenone-derived complexes 15c and 15d, respectively, demon-
strated even higher reactivity toward Michael acceptor 10,
allowing the formation of the corresponding addition products
17c,d in less than 20 min. Compounds 17c,d were found to be com-
pletely insoluble in the DMF/water mixture and precipitated as a
Figure 1. X-ray structure of Michael acceptor 10.
O
N
N
O
N
O
H
N
N
O
N
O
O
Ni
Ni
N
O
O
Ph
N
O
Ph
O
N
Ph
Ph
11
H
O
O
Ph
N
(2R,3S,2'S)-13
H
(S)-10
Ph
rt, DMF, DBU (15 mol%)
O
N
N
O
N
O
H
N
O
O
Ni
Ni
N
O
O
N
N
O
Ph
O
N
Me
Me
12
H
Ph
(2R,3S,2'S)-14
Scheme 3.
R
R
R
R
O
N
O
N
O
H
O
N
O
N
O
Ni
Ni
N
Ph
N
O
N
O
N
O
Ph
O
O
O
N
Ph
Ph
N
H
Ph
H
(S)-10
Ph
15
(2R,3S,2'S)-17
R = Me a ,Et b, n-Bu
c, (CH2)5 d
R = Me a, Et b, n-Bu
rt, DMF, DBU (15 mol%)
c, (CH2)5 d
R
R
R
R
O
N
N
O
N
O
H
N
N
O
N
O
Ni
Ni
N
O
O
O
Ph
O
N
Me
Me
16
R = n-Bu a, (CH2)5 b
H
Ph
(2R,3S,2'S)-18
R = n-Bu a, (CH2)5 b
Scheme 4.

2632
T. K. Ellis et al. / Tetrahedron: Asymmetry 20 (2009) 2629–2634
well-formed crystals leading to their isolation in quantitative
chemical yields.
All of the reactions were carried out under atmospheric conditions
without any special caution to exclude air. Unless indicated 1H and
13C NMR spectra, were taken in CDCl3 solutions at 299.95 and
75.42 MHz, respectively. Chemical shifts refer to TMS as the inter-
nal standard.
Yields refer to isolated yields of products of greater than 95%
purity as estimated by 1H and 13C NMR spectrometry. All new com-
pounds were characterized by 1H, and 13C NMR, high-resolution
mass spectrometry (HRMS-ESI), melting point, and optical rotation,
when applicable.
With these successful results in hand, we studied the reactions of
Michael acceptor 10 with di-n-butylamine/ and piperidine/aceto-
phenone-derived complexes 16a,b, respectively. The corresponding
additions occurred at rates slightly slower, when compared with
15c,d, without compromising the virtually complete chemical and
stereochemical outcome furnishing products 18a,b in quantitative
yield.
The absolute (2R,3S,20S)-configuration of the b-phenyl-substi-
tuted glutamic acid residue in 17c was determined by the isolation
of the corresponding pyroglutamic acid (2R,3S)-20 (see Scheme 5).
Consequently the (2R,3S,20S) stereochemistry of products 13 and
14 and 17a,b,d and 18a,b was assigned based on similarity of their
spectral as well as chiroptical data to complex 17c. It should be
noted that in contrast to 4 and similarly to 7 (Scheme 1), the Mi-
4.1.1. (S)-5-Oxo-N-phenyl-1-((E)-3-phenylacryloyl)pyrrolidine-
2-carboxamide 10
Compound 10 was prepared according to the general procedure
previously described in Ref. 14. Yield (from glutamic or pyroglu-
tamic acid) 87%. Mp 148.8 °C. 1H NMR d 2.25 (1H, m), 2.40 (1H, t,
J = 9.3 Hz), 2.58 (1H, dq, J = 9.2, 2.4 Hz), 2.99 (1H, m), 4.99 (1H, dd,
J = 8.4, 2.1 Hz), 7.05 (1H, t, J = 8.7 Hz), 7.24 (1H, t, J = 6.9 Hz), 7.37–
7.41 (3H, m), 7.50 (2H, dd, J = 8.7, 1.2 Hz), 7.58–7.61 (2H, m), 7.92
(2H, q, J = 15.9 Hz), 8.81 (1H, s). 13C NMR d 21.5, 32.9, 60.1, 118.2,
118.3, 119.9, 120.1, 124.7, 128.7, 128.9, 129.1, 134.6, 137.5, 167.3,
168.1, 175.5. HRMS [M+Na] found m/s 357.1269, calcd for
chael acceptor (S)-10 induced the
a-(R) absolute configuration in
the addition products 13,14, 17a–d, and 18a,b. This difference in
the stereochemical outcome is simply due to the Cahn–Ingold–Pre-
log priority rules26 as compounds 4, 7, and 10 have the same rela-
tive stereochemistry in terms of the position of the substituent
above or beneath the oxazolidin-2-one or pyrrolidin-2-one ring,
respectively.
The isolation of the b-phenyl pyroglutamic acid 20 (Scheme 5)
from the addition products was demonstrated by disassembling
complex 17c under the standard conditions: heating of 17c in meth-
anol/3 M HCl, followed by neutralization of the reaction mixture
with 8 M ammonia and isolation of acid 20 using Dowex ion-ex-
change resin.21 Pyroglutamic acid 20 was obtained in 93% yield,
along with quantitative recovery of ligand 21, which can be recycled
and converted back to the corresponding Ni(II) complexes 15c.21d
Recovery of the corresponding chiral auxiliary, (S)-5-oxo-N-phenyl-
pyrrolidine-2-carboxamide, was not studied. The (2R,3S)-absolute
configuration of acid 20 was confirmed by comparison of its spectro-
scopic and chiroptical data with the literature data.16b,18e,21d
C20H18N2NaO3 is 357.1209. ½a D25
¼ ꢁ42:5 (c 0.0008, CHCl3).
ꢀ
4.2. The Michael addition reactions between the pyroglutamic
acid derived amide of cinnamic acid 10 and nucleophilic glycine
equivalents 1, 11, 12, 15, 16
4.2.1. General procedure
To a flask containing 1, 11, 12, 15 or 16 (1.00 equiv), (S)-5-oxo-N-
phenyl-1-((E)-3-phenylacryloyl)pyrrolidine-2-carboxamide (1.05
equiv)and 2.0 mL (per 1 g of the corresponding Ni(II) complex) of
DMF, DBU (15 mol %) was added to the reaction mixture, which
was stirred at room temperature and monitored by TLC. After the
disappearance of starting glycine equivalent (monitoring by TLC),
the reaction mixture was poured into a beaker containing 100 mL
ice water. After the ice had melted, the corresponding product
was filtered from the aqueous solution and dried in an oven to af-
ford the appropriate product in high (see text) chemical yields.
3. Conclusion
In conclusion, we have demonstrated that inexpensive, and
readily available in both enantiomeric forms Michael acceptor 10
can be efficiently used in the corresponding addition reactions
with the new generation of achiral nucleophilic glycine equivalents
15c,d, 16a,b and chiral glycine derivative (S)-1. High chemical and
stereochemical yields as well as operationally convenient condi-
tions10 for each synthetic step render these Michael addition reac-
tions as a practical and scalable generalized approach for the
preparation of enantiomerically pure b-phenyl glutamic/pyroglu-
tamic acid and related compounds.
4.2.1.1. Ni(II) complex of (2R,3S,20S)-3-phenyl-5-[50oxo-N-phenyl-
pyrrolidine-20-carboxamide] glutamic acid Schiff base with 2-
(picolinoylamino)-benzophenone 13.
Mp 163.2 °C. 1H NMR d
1.42 (1H, d, J = 6.6 Hz), 1.97–2.27 (3H, m), 2.42 (1H, m), 2.77 (1H,
m), 3.48 (1H, t, J = 5.4 Hz), 4.57 (1H, dd, J = 8.4, 1.8 Hz), 4.66 (1H, d,
J = 4.8 Hz), 6.72–6.80 (2H, m), 7.02–7.13 (3H, m), 7.16–7.60 (13H,
m), 7.69 (1H, d, J = 7.2 Hz), 7.85 (2H, m), 8.59 (1H, s), 8.62 (2H, d,
J = 6.3 Hz). 13C NMR d 21.3, 32.3, 37.7, 44.6, 59.7, 74.3, 121.3, 123.5,
124.4, 126.4, 127.5, 127.6, 127.7, 128.1, 128.2, 128.3, 128.6, 128.8,
128.9, 129.2, 129.3, 129.7, 129.8, 130.0, 130.2, 130.3, 133.2, 133.5,
134.6, 137.9, 139.0, 139.9, 143.0, 146.5, 153.1, 168.6, 168.9, 171.6,
172.3, 175.0, 177.2. HRMS [M+Na] found m/s 772.1743, calcd for
4. Experimental
4.1. General methods
C41H33N5NaNiO6 is 772.1676. ½a D25
¼ ꢁ413:2 (c 0.006, CHCl3).
ꢀ
Unless otherwise noted, all reagents and solvents were obtained
from commercial suppliers and used without further purification.
4.2.1.2. Ni(II) complex of (2R,3S,20S)-3-phenyl-5-[50oxo-N-phenyl-
pyrrolidine-20-carboxamide] glutamic acid Schiff base with 2-
(picolinoylamino)-acetophenone 14.
Mp 193.6 °C. 1H NMR d
n-Bu
n-Bu
2.18 (1H, m), 2.26 (2H, m), 2.49 (1H, d, J = 8.6 Hz), 2.81 (3H, s), 3.55
(1H, d, J = 5.6 Hz), 3.77 (1H, m), 4.40 (1H, dd, J = 8.6, 1.4 Hz), 4.86
(2H, m), 6.74 (1H, t, J = 6.3 Hz), 6.92 (1H, m), 7.70 (3H, m), 7.29 (4H,
m), 7.44 (3H, m), 7.64 (2H, d, J = 6.2 Hz), 7.69 (1H, d, J = 8.2 Hz), 7.86
(1H, t, J = 9.4 Hz), 8.49 (1H, m), 9.12 (1H, s). 13C NMR d 18.7, 22.2,
29.3, 32.1, 38.0, 44.8, 59.7, 74.3, 119.9, 121.8, 123.5, 124.0, 124.3,
126.3, 127.3, 127.8, 128.2, 129.0, 130.2, 130.5, 132.6, 138.2, 139.0,
139.8, 141.9, 146.5, 153.3, 168.6, 169.4, 173.3, 175.3, 177.8. HRMS
Ph
N
1. 3M HCl/MeOH
2. NH4OH
+
NH
O
3. Dowex
17c
O
COOH
O
N
H
Ph
21
(2R,3S)-20
Scheme 5.

T. K. Ellis et al. / Tetrahedron: Asymmetry 20 (2009) 2629–2634
2633
[M+Na] found m/s 710.1449, calcd for C36H31N5NaNiO6 is 710.1520.
¼ ꢁ582:6 (c 0.0007, CHCl3).
dd, J = 19.3, 11.3 Hz), 4.56 (1H, d, J = 4.67 Hz), 4.78 (1H, dd, J = 7.70,
2.75 Hz), 6.90–7.06 (2H, m), 7.14–7.32 (3H, m), 7.36–7.45 (2H, m),
7.45–7.60 (5H, m), 7.63 (1H, d, J = 8.26 Hz), 8.22 (1H, d, J = 8.52 Hz),
8.83 (1H, br s). 13C NMR d 13.8, 14.0, 18.7, 20.4, 20.7, 22.2, 22.8,
29.3, 32.1, 38.4, 44.4, 54.1, 56.8, 59.6, 63.8, 72.8, 119.5, 121.5, 123.8,
124.2, 126.7, 128.2, 128.8, 129.0, 129.6, 130.7, 132.2, 138.1, 139.6,
141.5, 168.7, 168.7, 173.4, 175.0, 175.3, 177.7. HRMS [M+Na] found
½ ꢀ
a 2D5
4.2.1.3. Ni(II) complex of (2R,3S,20S)-3-phenyl-5-[50oxo-N-phenyl-
pyrrolidine-20-carboxamide] glutamic acid Schiff base with N-(2-
benzoyl-phenyl)-2-dimethylamino-acetamide
17a.
Mp
177 °C. 1H NMR d 1.62 (3H, s), 1.88–2.18 (2H, m), 2.26–2.45 (1H, m),
2.37 (3H, m), 2.45–2.80 (2H, m), 2.56 (1H, d, J = 15.8 Hz), 3.20 (1H,
d, J = 15.5 Hz), 3.28–3.60 (2H, m), 4.43 (1H, d, J = 4.98 Hz), 4.49 (1H,
dd, J = 8.70, 2.35 Hz), 6.64–6.72 (2H, m), 6.96–7.06 (2H, m), 7.08–
7.48 (14H, m), 8.40 (1H, d, J = 8.50 Hz), 8.74 (1H, br s). 13C NMR d
21.3, 32.1, 37.7, 44.1, 47.4, 49.5, 59.4, 66.9, 73.0, 119.7, 121.0, 123.1,
124.1, 126.7, 127.0, 127.8, 128.0, 128.7, 128.8, 129.0, 129.1, 129.8,
130.2, 132.7, 133.4, 134.0, 137.9, 139.3, 142.5, 168.5, 171.2, 171.8,
174.6, 174.9, 177.2. HRMS [M+Na] found m/s 752.2152, calcd for
m/s 774.2629, calcd for C40H47N5NaNiO6 is 774.2772. ½a D25
¼ ꢁ974
ꢀ
(c 0.08, CHCl3).
4.2.1.8. Ni(II) complex of (2R,3S,20S)-3-phenyl-5-[50oxo-N-phenyl-
pyrrolidine-20-carboxamide] glutamic acid Schiff base with N-(2-
acetyl-phenyl)-2-piperidyl-acetamide 18b.
Mp 218.6 °C. 1H
NMR d 1.31 (2H, m), 1.47 (2H, m), 1.60 (1H, dt, J = 6.9, 3.6 Hz), 2.02
(1H, m), 2.27 (4H, m), 2.72 (3H, s), 2.86 (3H, m), 3.01 (1H, m), 3.15
(2H, t, J = 8.2 Hz), 3.52 (1H, dd, J = 8.6, 2.4 Hz), 3.63 (1H, m), 4.44
(1H, dd, J = 9.4, 1.4 Hz), 4.66 (1H, d, J = 4.5 Hz), 4.88 (1H, t,
J = 5.4 Hz), 6.97 (1H, dt, J = 6.9, 1.2 Hz), 7.04 (1H, m), 7.26 (3H, m),
7.44 (2H, m), 7.60 (5H, m), 7.65 (1H, dd, J = 8.4, 1.5 Hz), 8.28 (1H, dd,
J = 8.4, 1.2 Hz), 9.31 (1H, s). 13C NMR d 18.6, 19.6, 19.8, 22.0, 22.9,
32.1, 38.3, 44.2, 54.8, 55.6, 59.5, 60.5, 72.7, 119.6, 121.6, 123.8,
124.1, 126.6, 128.3, 128.8, 128.9, 129.0, 129.7, 130.7, 132.2, 138.2,
139.5, 141.5, 168.8, 169.1, 173.2, 174.8, 175.4, 178.1. HRMS [M+Na]
found m/s 730.2189, calcd for C37H39N5NaNiO6 is 730.2146.
C39H37N5NaNiO6 is 752.1990. ½a D25
¼ ꢁ1088 (c 0.05, CHCl3).
ꢀ
4.2.1.4. Ni(II) complex of (2R,3S,20S)-3-phenyl-5-[50oxo-N-phenyl-
pyrrolidine-20-carboxamide] glutamic acid Schiff base with N-(2-
benzoyl-phenyl)-2-diethylamino-acetamide 17b.
Mp 183 °C.
1H NMR d 0.74 (3H, t, J = 7.03 Hz), 1.65 (3H, t, J = 7.03 Hz), 1.80–2.40
(6H, m), 2.50–2.80 (2H, m), 2.68 (1H, d, J = 15.5 Hz), 3.29 (1H, d,
J = 15.8 Hz), 3.33–3.68 (3H, m), 4.41 (1H, d, J = 4.10 Hz), 4.44 (1H,
m), 6.64–6.72 (2H, m), 6.96–7.08 (2H, m), 7.10–7.55 (14H, m), 8.30
(1H, d, J = 8.50 Hz), 8.77 (1H, br s). 13C NMR d 5.78, 12.7, 21.3, 32.1,
37.9, 44.3, 47.9, 50.7, 59.4, 62.8, 72.9, 119.6, 121.0, 123.3, 124.0,
126.8, 127.1, 127.8, 128.0, 128.7, 128.8, 129.0, 129.1, 129.9, 130.0,
132.6, 133.4, 133.9, 138.0, 139.4, 142.3, 168.6, 171.2, 171.8, 175.0,
175.3, 177.1. HRMS [M+Na] found m/s 780.2086, calcd for
½
a 2D5
ꢀ
¼ ꢁ432:8 (c 0.002, CHCl3).
4.2.2. X-ray data for compound 10
The data were collected at 120(2) K on a Bruker Apex diffractom-
eter27 using MoK
a
(k = 0.71073 A) radiation. Intensity data, which
approximately covered the full sphere of the reciprocal space, were
measured as a series of oscillation frames each 0.3° for 35 s/frame.
C41H41N5NaNiO6 is 780.2305. ½a D25
¼ ꢁ416 (c 0.05, CHCl3).
ꢀ
4.2.1.5. Ni(II) complex of (2R,3S,20S)-3-phenyl-5-[50oxo-N-phenyl-
pyrrolidine-20-carboxamide] glutamic acid Schiff base with N-(2-
x
The detector was operated in 512 ꢂ 512 mode and was positioned
6.12 cm from the crystal. Coverage of unique data was 97.6% com-
plete to 55.0°(2h). Cell parameters were determined from a non-lin-
ear least squares fit of 6283 reflections in the range of 2.6 < h < 27.5°.
A total of 8276 reflections were measured. The structure was solved
by the direct method using SHELXTL system,28 and refined by full-ma-
trix least squares on F2 using all reflections. All the non-hydrogen
atoms were refined anisotropically. All the hydrogen atoms were in-
cluded with idealized parameters. Final R1 = 0.058 is based on 3190
benzoyl-phenyl)-2-dibutylamino-acetamide
17c.
Mp
142.3 °C. 1H NMR d 0.93 (3H, t, J = 7.2 Hz), 0.97 (3H, t, J = 6.9 Hz),
1.13–1.31 (4H, m), 1.35–1.53 (2H, m), 1.60–1.89 (2H, m), 1.92–2.23
(4H, m), 2.30–2.47 (3H, m), 2.68–2.91 (3H, m), 3.42–3.56 (4H, m),
3.64 (1H, m), 3.35 (1H, d, J = 5.1 Hz), 4.51 (1H, d, J = 6.6 Hz), 6.73–
6.79 (3H, m), 7.10–7.15 (2H, m), 7.26–7.54 (13H, m), 8.22 (1H, s),
8.38 (1H, d, J = 9.0 Hz). 13C NMR d 13.9, 14.1, 20.4, 20.8, 21.2, 23.1,
29.3, 29.7, 32.4, 38.3, 44.7, 54.5, 57.4, 59.6, 63.8, 118.8, 119.8, 121.1,
123.5, 124.5, 127.0, 127.6, 128.0, 128.4, 128.9, 129.0, 129.2, 129.3,
129.9, 130.1, 132.8, 134.0, 137.6, 139.6, 142.6, 168.0, 171.0, 172.9,
174.9, 175.7, 176.7. HRMS [M+Na] found m/s 836.2889, calcd for
‘observed reflections’ [I > 2
reflections (3629 reflections).
r
(I)], and wR2 = 0.140 is based on all
Empirical formula: C20H18N2O3; formula weight: 334.36; wave-
length: 0.71073 Å; crystal system: monoclinic; space group: Pc; unit
C45H44N5NaNiO6 is 836.2929. ½a D25
¼ ꢁ2270:0 (c 0.0011, CHCl3).
ꢀ
cell dimensions: a = 15.114(3) Å,
a = 90°; b = 6.3646(14) Å,
b = 93.565(3)°; c = 8.6912(19) Å,
c
= 90°; volume: 834.4(3) Å3; Z: 2;
4.2.1.6. Ni(II) complex of (2R,3S,20S)-3-phenyl-5-[50oxo-N-phenyl-
pyrrolidine-20-carboxamide] glutamic acid Schiff base with N-(2-
density (calculated): 1.331 Mg/m3; absorption coefficient:
0.091 mmꢁ1; F(0 0 0): 352; crystal size: 0.40 ꢂ 0.08 ꢂ 0.04 mm3; h
range for data collection: 2.70–27.49°; index ranges: ꢁ19 6 h 6 19,
ꢁ8 6 k 6 8, ꢁ11 6 l 6 11; reflections collected: 8276; independent
reflections: 3629 [R(int) = 0.0396]; completeness to h = 27.49°
97.6%; absorption correction: semi-empirical from equivalents,
max. and min. transmission: 0.9964 and 0.9647; refinement method:
full-matrix least-squares on F2; data/restraints/parameters: 3629/2/
benzoyl-phenyl)-2-piperidyl-acetamide 17d.
Mp 186.1 °C. 1H
NMR d 1.46 (7H, m), 2.02 (1H, q, J = 6.6 Hz), 2.19 (2H, m), 2.40 (2H,
m), 2.77 (1H, m), 2.92 (1H, d, J = 6.8 Hz), 3.21 (3H, m), 3.52 (2H, m),
3.65 (2H, t, J = 12.6 Hz), 4.44 (1H, d, J = 3.9 Hz), 4.51 (1H, d,
J = 7.8 Hz), 6.73 (2H, m), 7.07 (2H, dt, J = 17.1, 6.3 Hz), 7.39 (13H, m),
8.39 (1H, d, J = 8.4 Hz), 8.49 (1H, m), 9.15 (1H, s). 13C NMR d 19.9,
21.3, 22.8, 32.3, 38.0, 44.4, 53.5, 54.6, 55.6, 56.1, 59.6, 73.1, 119.8,
123.4, 124.4, 125.9, 127.4, 128.2, 128.9, 129.0, 129.2, 129.3, 129.6,
129.9, 130.3, 132.7, 133.7, 134.0, 137.9, 139.5, 168.4, 171.2, 172.4,
175.0, 175.4, 177.1. HRMS [M+Na] found m/s 792.2393, calcd for
226; goodness-of-fit on F2: 1.133; final
R1 = 0.0578, wR2 = 0.1357; indices (all data) R1 = 0.0662,
R indices [I > 2r(I)]:
R
wR2 = 0.1402; absolute structure parameter: 0.4(13); largest diff.
peak and hole: 0.387 and ꢁ0.285 e Åꢁ3
.
C42H41N5NaNiO6 is 792.2308. ½a D25
¼ ꢁ405:2 (c 0.0007, CHCl3).
ꢀ
4.2.1.7. Ni(II) complex of (2R,3S,20S)-3-phenyl-5-[50oxo-N-phenyl-
pyrrolidine-20-carboxamide] glutamic acid Schiff base with N-(2-
Acknowledgements
This work was supported by the Department of Chemistry and
Biochemistry, University of Oklahoma. The authors gratefully
acknowledge generous financial support from Central Glass Com-
pany (Tokyo, Japan) and Ajinomoto Company (Tokyo, Japan).
acetyl-phenyl)-2-dibutylamino-acetamide 18a.
Mp 167 °C.
1H NMR d 0.87–1.00 (6H, m), 1.00–1.20 (1H, m), 1.30–1.50 (3H, m),
1.70–2.50 (9H, m), 2.60–2.95 (4H, m), 2.70 (3H, s), 3.19 (1H, d,
J = 14.7 Hz), 3.49 (1H, dd, J = 19.3, 2.48 Hz), 3.61 (1H, m), 4.38 (1H,

2634
T. K. Ellis et al. / Tetrahedron: Asymmetry 20 (2009) 2629–2634
Synthesis 2008, 2594; (b) Soloshonok, V. A.; Yamada, T.; Ueki, H.; Moore, A. M.;
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