NH-type of chiral Ni(ii) complexes of glycine Schiff base: Design, structural evaluation, reactivity and synthetic applications

Article abstract of DOI:10.1039/c3ob41959b

The work being reported here deals with the design of a new type of "N-H" Ni(ii) complexes of glycine Schiff bases and study general aspects of their reactivity. It was confirmed that the presence of NH function in these Ni(ii) complexes does not interfere with the homologation of the glycine residue, rendering these derivatives of high synthetic value for the general synthesis of α-amino acids. In particular, the practical application of these NH-type complexes was demonstrated by asymmetric synthesis of various-substituted pyroglutamic acids via Michael addition reactions with chiral Michael acceptors.

Full text of DOI:10.1039/c3ob41959b

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NH-type of chiral Ni(II) complexes of glycine Schiff
base: design, structural evaluation, reactivity and
synthetic applications†
Cite this: DOI: 10.1039/c3ob41959b
Mackenzie Bergagnini,a Kazunobu Fukushi,b Jianlin Han,c Norio Shibata,b
Christian Roussel,d Trevor K. Ellis,a José Luis Aceñae and Vadim A. Soloshonok*e,f
The work being reported here deals with the design of a new type of “N–H” Ni(II) complexes of glycine
Schiff bases and study general aspects of their reactivity. It was confirmed that the presence of NH func-
tion in these Ni(II) complexes does not interfere with the homologation of the glycine residue, rendering
these derivatives of high synthetic value for the general synthesis of α-amino acids. In particular, the prac-
tical application of these NH-type complexes was demonstrated by asymmetric synthesis of various
β-substituted pyroglutamic acids via Michael addition reactions with chiral Michael acceptors.
Received 27th September 2013,
Accepted 6th December 2013
DOI: 10.1039/c3ob41959b
www.rsc.org/obc
methodology for preparation of structurally and functionally
varied α-AAs continues to evolve. One of the major challenges
Introduction
The synthesis of α-amino acids (α-AAs) has remained a topic of
special significance in organic chemistry for decades. The
importance of this subject is due to the remarkable multidisci-
plinary nature of α-AAs and related compounds. One of the key
aspects of α-AAs is their extraordinary versatility, as they have
been utilized in virtually all life/health-related areas, most
notably in pharmaceutical, food and agricultural industries.1
Currently, the commercial production of α-AAs is a multi-
billion industry heavily relying on isolation of α-AAs from
natural sources and enzymatic resolution of racemates.2 In
sharp contrast, the asymmetric synthesis of α-AAs is rarely
applied for the large-scale production. One of the key reasons
is that chemical synthesis is prohibitedly expensive,3 compared
to enzymatic methods which enjoy low cost-structure. Con-
sidering that the importance of tailor-made amino acids4 in
healthcare industries is rapidly increasing, the synthetic
being addressed is the application of operationally convenient
reaction conditions,5 resulting in the reduced cost of the target
compounds.
While the core-structure of amino acid is relatively simple
and remain unchanged throughout the family, the synthetic
challenge6 has remained in the development of a single syn-
thetic methodology which would include the flexibility neces-
sary to provide α-AAs with side chains which include various
structural, functional, stereochemical, electronic, and physical
properties.7 To date, the most robust of the synthetic
approaches offered in the literature is the derivatization of
nucleophilic glycine equivalents (NGE).6,7
There have been numerous NGEs introduced for the
general synthesis of α-AAs. They include examples, such as
nitroethanoic acid,8 dioxopiperazines,9 alkyl α-isocyano-
acetate10 and α-isocyanoacetamide,11 glycine derived oxazolidi-
nones12 and Schiff bases.13 Although each methodology has
demonstrated its advantages, each system does come with its
inherent limitations such as, reactivity, generality, cost of the
target α-AA and scalability. From the standpoint of operation-
ally convenient reaction conditions, the Ni(II) complex of
glycine Schiff base 114,15 (Fig. 1) is of particular practical
interest. The major advantage of Ni(II) complex 1 over other
NGEs is that its homologation via alkyl halide alkylations,16
Michael,17 aldol18 and Mannich19 addition reactions can
be conducted at ambient temperature under expedient
reaction conditions. An achiral analogue of 1, picolinic
acid derived Ni(II) complexes 220 has demonstrated similar
practicality as its asymmetric alkylations21 and Michael
aDepartment of Chemistry and Physics, Southwestern Oklahoma State University,
100 Campus Drive, Weatherford, OK 73096-3098, USA
bDepartment of Frontier Materials, Graduate School of Engineering, Nagoya Institute
of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
cSchool of Chemistry and Chemical Engineering, Nanjing University, Nanjing,
210093, China
dChirosciences, ISM2 UMR7313, Aix-Marseille University, France
eDepartment of Organic Chemistry I, Faculty of Chemistry, University of the Basque
Country UPV/EHU, 20018 San Sebastián, Spain. E-mail: vadym.soloshonok@ehu.es;
Fax: +34 943-015270; Tel: +34 943-015177
fIKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
†Electronic supplementary information (ESI) available: Crystallographic data of
18 and copies of NMR spectra. CCDC 962997. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c3ob41959b
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Results and discussion
The preparation of the Ni(II) complexed nucleophilic glycine
equivalents containing a secondary rather than a tertiary
amine was realized via a series of robust and high yielding
reactions.32 The synthesis was initiated by the condensation of
o-aminobenzophenone 5a, or its chlorinated analogue 5b, and
bromoacetyl bromide in acetonitrile with potassium carbonate
to quench the hydrobromic acid formed (Scheme 1). The
resulting 2-bromoacetamide intermediates 6a,b were treated
with a five-fold excess of a primary amine 7a–d in warm
(60 °C) acetonitrile. The resulting ligands 8a–d, 9 were trans-
formed in situ into the corresponding glycine Schiff bases and
complexed by the metal after exposure to the appropriate
α-amino acid and nickel(II) nitrate in methanol with excess pot-
assium hydroxide to facilitate the reaction. The target Ni(II)
complexes 10a–d, 11 were isolated in high yields and addition-
ally purified by column chromatography.
With ready access to a number of these Ni(II) complexed
NGE it was decided to explore their utility with regards to
preparation of α-AA derivatives via alkylation under phase
transfer catalysis (PTC) conditions. The initial complex
selected for the study was the N-benzyl derivative 10a
(Scheme 2). It was found that treating complex 10a with benzyl
bromide under basic PTC conditions at ambient temperature
resulted in the formation of three products (Table 1, entry 1).
Two of the compounds obtained from the reaction were
Fig. 1 Structures of various Ni(II) complexes of glycine Schiff base.
addition reactions22 can be conducted under operationally
convenient conditions.
Despite their practical potential, complexes 1 and 2 also
have some disadvantages, related mostly to their poor solubi-
lity in common organic solvents. Furthermore, the potential
for structural modification of complexes 1 and 2, to improve
their physicochemical properties and reactivity, is rather
restricted.23 Realizing the limitations of complexes 1 and 2, as
well as the broader consideration that a single nucleophilic
glycine equivalent will not be suitable for all of the synthetic
requirements, we developed a modular approach to Ni(II)
complex-based NGE.24 It is envisioned that this design will
allow for tailoring of the physicochemical properties as well as
chemical reactivity of the corresponding NGE required for a
particular synthetic application.25 For example, Ni(II) com-
plexes of type 3 (Fig. 1) can be tailored to become soluble in
virtually any solvent simply by choosing the appropriate (N,N-
di-alkyl)amine moiety.26 To date we have demonstrated the
practical nature of this design with respect to the preparation
of sterically constrained α,α-disubstituted α-amino acids27
and β-substituted pyroglutamic acid derivatives28 via highly
diastereoselective Michael addition reactions.29 Another
area of successful application of complexes of type 3 is the
deracemization or resolution of racemic α-AAs.30 Of the deriva-
tives that have been developed during these studies, the Ni(II)
complexes 4 (Fig. 1) which are derived from primary amines
rather than the traditional secondary amines are virtually
unstudied, however, they seem to be among the most
intriguing. From
a practical standpoint the availability
and cost of primary versus secondary amines makes these
complexes potentially valuable to the field. In addition,
the unusual chemoselectivity and stereochemical aspects
of these complexes add to the scientific interest of their
study.31
Scheme 1 Synthesis of NH-type Ni(II) complexes of glycine 10a–d
and 11.
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Scheme 2 PTC benzylation of Ni(II) complex 10a (TBAB: tetra-N-butylammonium bromide).
particular, the result observed at −10 °C, we can suggest that
the second approach, proceeding via formation of 15, is more
realistic as the alternative way does not afford complex 15 as
the end-product. If this rational is correct, it leads to another
very important assumption that NH-type Ni(II) complex 10a is
noticeably more reactive than N,N-di-alkyl-type 15. Thus, the
results obtained at low temperatures suggest that the for-
mation of enolate from 10a takes place at a much higher reac-
tion rate than that of the secondary amine derived complex 15.
To verify this assumption, we conducted standard PTC benzy-
lation of 1/1 mixture of 10a and 15 at 0 °C using only one equi-
valent of benzyl bromide. The result was overwhelmingly
convincing, as virtually all benzylation product obtained was a
mixture of diastereomeric complexes 12 and 13, resulting
exclusively from complex 10a.
The superior reactivity of NH-type complexes over pre-
viously used secondary amine derived complexes was rather
unexpected. One possible explanation for this noticeable
difference in reactivity might be based on the following steric
considerations. In the case of NH-type complexes, the corres-
ponding enolate has two non-equivalent diastereotopic faces.
One of which is totally open (NH face) and another slightly
shielded by the N-alkyl group. Obviously, the formation of the
corresponding transition state with an incoming electrophile
takes place faster on the NH-side, while approach from the
opposite N-alkyl face is disadvantaged by some repulsive steric
interactions. By contrast, in the case of secondary amine
derived complexes both sides of the corresponding enolate are
equivalent and shielded by N-alkyl groups. This conclusion
regarding reactivity of NH vs. N,N-di-alkyl types of Ni(II) com-
plexes is of great novelty and may have beneficial implications
for the design of more advanced types of Ni(II) complexes of
glycine Schiff bases.
Table 1 Reaction conditions and ratio of products 12–15 in the PTC
benzylation of complex 10a
Entry
Temp (°C)
Time (h)
Ratio 12, 13/14/15a
1
2
3
25
0
−10
2
2
2
63.3/36.7/0
67.1/19.5/13.4
83.3/0/16.7
a Determined by NMR integration of the crude reaction mixtures.
expected products of the glycine CH2 group alkylation, diaster-
eomeric complexes 12 and 13, whereas the third product,
complex 14, resulted from the benzylation of the CH2 and ben-
zylamino groups. With a goal to eliminate the N-alkylation, we
conducted the reaction at a lower temperature (entry 2). As
expected, the amount of bis-benzylation product 14 was notice-
ably decreased, however, quite surprisingly, we observed the
formation of one more product, 15, resulting exclusively from
alkylation of the benzylamino group. Further decreases in reac-
tion temperature (−10 °C) (entry 3) provided even more sur-
prising results as the formation of bis-C-/N-alkylation product
14 was completely suppressed while the relative amount of
selectively N-benzylated complex 15 increased. To explain
these results we considered two possible reaction sequences
leading to the bis-benzylation product 14. One approach may
include: enolization of 10a, subsequent alkylation to form
complexes 12 and 13, followed by their N-benzylation; while
the alternative path may start with N-benzylation of 10a
forming the secondary amine containing complex 15, which
can be enolized and alkylated to produce the final product 14.
Considering the stereochemical outcome observed at ambient
temperature (entry 1) one may agree that it is impossible to
make a preference for either reaction sequence and therefore
both may take place. On the other hand, considering the reac-
tions conducted at lower temperatures (entries 2 and 3) in
Considering the results obtained, one more important con-
clusion can be made regarding the configurational stability of
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diastereomeric complexes 12 and 13. These products were achieve the desired chemoselectivity under the room temperature
obtained in a ratio close to 1/1 and can be easily seen as two PTC benzylation conditions. Thus, in the alkylation of complex 10b
well-separated spots on TLC. Therefore, we conducted column no products resulting from the corresponding N-benzylation
chromatography to isolate them in diastereomerically pure were detected in the crude reaction mixture (Table 2, entry 1).
form and determine their relative configurations. While we However, the phenylalanine containing complex 16 was
succeeded in separation of pure fractions of 12 and 13, evapor- obtained as a mixture of epimerizable diastereomers (67% de).
ation of the eluent (acetone–chloroform 1/5) at an elevated With this in mind, it was decided to further increase the steric
temperature resulted in their epimerization giving rise to the bulk around the stereogenic nitrogen via the incorporation of
mixtures of 12 and 13. This epimerization was also observed at a t-butyl moiety into the complex. Thus, benzylation of
ambient temperature, although at a slower rate. Considering complex 10c resulted in the formation of a single product, the
two stereogenic centers in diastereomers 12 and 13, we may phenylalanine containing Ni(II) complex 17a in excellent
confidently believe that the stereogenic carbon of the phenyl- chemical yield (93%) (entry 2).
alanine residue is completely configurationally stable under
To assign the relative configuration of the diastereomer 17a
neutral conditions in common organic solvents. This leads us we needed a crystallographic study. Taking advantage that
to a conclusion that the stereogenic nitrogen in complexes 12 Ni(II) complexes derived from m-Cl containing o-amino-benzo-
and 13 is rather configurationally unstable. This finding is of phenone 5b (Scheme 1) usually have significantly higher crys-
great novelty to be considered in the design of new generations tallinity, we performed synthesis of the corresponding glycine
of chiral Ni(II) complexes of glycine and higher amino acids.
complex 11 and its PTC benzylation. Similar to the reaction of
Intrigued by the results obtained, we decided to investigate 10c, alkylation of Cl-containing complex 11 gave only one dia-
these novel features of reactivity of NH-type Ni(II) complexes in stereomeric product 18 in excellent yield (Table 2, entry 3).
more detail (Scheme 3). During these investigations it was dis- Using the advantageous physicochemical properties of
covered that increasing the steric bulk of the substituent on the complex 18, we obtained suitable crystals and conducted X-ray
amine group from benzyl to isopropyl group was sufficient to analysis. The crystallographic structure of 18 is presented
in Fig. 2. As one may expect the N-t-Bu and Bn groups in
complex 18 are in trans-orientation, thus corresponding to
(RN*,R*) relative configuration.
The X-ray analysis has also revealed some striking structural
features of complex 18. First of all, while the three Ni(II)-
Scheme 3 PTC alkylations of complexes 10b–d and 11.
Fig. 2 X-ray structure of (RN*,R*)-18.
Table 2 Reaction conditions and stereochemical outcome of the PTC alkylations of complexes 10b–d and 11
Entry
Starting complex
R
R′
R″
Catalyst
Product
Time (h)
Yield (%)
dea (%)
1
2
3
4
5
6
7
8
9
10b
10c
11
10c
10c
10c
10d
10d
10d
H
H
Cl
H
H
H
H
H
H
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
1-Adamantyl
1-Adamantyl
1-Adamantyl
Bn
Bn
Bn
Allyl
Cinnamyl
Propargyl
Bn
Cinnamyl
Propargyl
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAI
TBAI
TBAI
16
17a
18
17b
17c
17d
19a
19b
19c
1.5
3
2
1
1
3
4
4
4
91
93
90
96
94
90
90
96
94
67
>98
>98
>98
>98
>98
>98
>98
>98
a The trans diastereomer is the favoured product.
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advance the design of subsequent generations of chiral Ni(II)
complexes of glycine Schiff bases. However, we were eager to
find some immediate useful applications of these NH-type
Ni(II) complexes for asymmetric synthesis of α-AAs. To this end
we considered the Michael addition reactions of complexes
10a–d and 11 with chiral oxazolidinone derived Michael accep-
tors 20 (Scheme 4). It is known that in the reactions of chiral
N-proline containing complex (S)- or (R)-133 (Fig. 1) or achiral
derivatives 2, 3,34 the chirality of Michael acceptors 20 controls
the stereochemical outcome giving rise to (S)(2S,3S) and
(R)(2R,3R) configured products in β-aliphatic and (S)(2S,3R)
and (R)(2R,3S) in β-aromatic series.35 In the case of NH-type
complexes 10a–d and 11 under study, we deal with new stereo-
chemical features due to the presence of stereogenic nitrogen
in 10a–d and 11. These derivatives are racemic and could
cause a situation in which matched and mismatched stereo-
chemical preferences in the reactions with chiral Michael
acceptors 20 could arise.
The initial reactivity comparison studies were conducted to
determine the effect of the alkyl group of the amino moiety of
the complexes 10a–d and 11 with respect to their differences
in lipophilicity, as well as their steric properties. The (R)-N-
(E-enoyl)-4-phenyl-1,3-oxazolidin-2-one ((R)-20a) chosen for these
experiments included a phenyl substituent in the β-position to
limit the reaction rate of the corresponding reactions, by virtue
of their corresponding steric contributions, to increase the
accuracy while determining the relative reactivity of each of the
complexes 10a–d and 11. Each of the following reactions dis-
cussed in this section were conducted under a set of standard
conditions at ambient temperature, which included the use of
commercial-grade DMF as the solvent and 15 mol% of DBU as
the catalyst (Scheme 4). It was found that the application of
Michael acceptor (R)-20a with the N-benzyl derived Ni(II)
complex 10a resulted in the formation of 21a in fairly good
yield (89%) and >98% de in one hour (Table 3, entry 1).
Repeating this reaction with the isopropyl derived NGE 10b
yielded similar results, 92% yield and >98% de, in approxi-
mately the same amount of time (entry 2). However, the appli-
cation of Ni(II) complexes with more sterically hindered groups
such as 10c containing N-t-Bu and 10d with N-Ad groups
resulted in longer reaction times in order to reach completion
(2 hours). In addition to the increased reaction time, these
reactions resulted in slightly decreased yields (84 and 81%
respectively) without compromising the diastereoselectivity of
the process (entries 3 and 4).
Fig. 3 A, B and C chelate rings in 18.
bonded/coordinated nitrogen and one oxygen atoms are nor-
mally positioned in the Ni(II) coordination plane, the chelate
rings A–C (Fig. 3) are remarkably puckered. Thus, the position
of the N-t-Bu group down the coordination plane pushes the
N-CH2 group and the whole chelate ring A up, with a torsion
angle Ni–N–CH2–CO of −33.55(17)°. Consequently, the six-
membered ring B is down, with a torsion angle (including
imine group) of 23.4(2)°. Finally, the phenylalanine containing
ring C is yet again down, providing a torsion angle of Ni–N–
CH–CvO −27.44(17)°. This deviation of the chelate rings from
planarity is believed to be the main reason for the observed
stereochemical outcome, trans-positioning the N-t-Bu and Bn
groups away from each other. Thus, considering that both the
substituent-bearing rings A and C are up, one may agree that
in a hypothetical cis-position, N-t-Bu and Bn groups will be
engaged in repulsive steric interactions destabilizing the
corresponding diastereomer.
It should be mentioned that in the alkylation chemistry of
Ni(II) complexes 1–3 (Fig. 1), the highest levels of diastereo-
selectivity are usually recorded around 90–95% de.16 There-
fore, the complete (>99% de) stereochemical outcome
observed in the PTC benzylations of complexes 10c and 11
present an obvious novelty deserving a more detailed study. As
one can see from Table 2, application of allyl (entry 4), cinna-
myl (entry 5) and propargyl (entry 6) bromides as alkylating
agents in the reactions with N-t-butyl derived Ni(II) complex
10c, resulted in the formation of single, diastereomerically
pure products 17b–d, respectively, isolated in chemical yields
above 90%.
In order to evaluate the generality of this stereocontrol and
its possible application for the synthesis of various α-AAs, we
also prepared the corresponding N–H complex 10d, derived
from 1-adamantylamine. In a series of alkylations of complex 10d
with benzyl (entry 7), cinnamyl (entry 8) and propargyl (entry
9) bromides, equally impressive, complete control over the
chemo and diastereoselectivity of the alkylation process was
observed. Products 19a–c, bearing the corresponding α-AA
moieties, were isolated as pure diastereomers with yields
greater than 90%.
Following the completion of the reactivity profile of the NH
Ni(II) complexes 10a–d it was decided to explore the generality
of this process with respect to the application of N-(E-enoyl)-4-
phenyl-1,3-oxazolidin-2-ones which contain various substitu-
ents in the β-position. The substituents, ranging from a methyl
group to a t-butyl group, will aid in generating a reactivity
profile with respect to the steric and electronic contributions
of the Michael acceptors. The reaction of the β-methyl substi-
tuted Michael acceptor (R)-20b resulted in the preparation of
the corresponding product 22 in greater than 95% yield in
about two hours (entry 5). However, increasing the steric bulk
The uncompromised diastereoselectivity in the PTC alky-
lations of N–H complexes 10c,d, discovered in this work, is
quite a novel and a very important feature of reactivity of this
new type of Ni(II) complexes which can be used in the future to
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Scheme 4 Michael additions of complexes 10b–d and 11 to acceptors 20.
Table 3 Reaction conditions and stereochemical outcome of the Michael additions of complexes 10b–d and 11 to acceptors 20
Starting
complex
Michael
acceptor
Entry
R
R′
R″
Product
Time (h)
Yield (%)
de (%)
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10c
11
11
11
11
11
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
H
H
H
Bn
i-Pr
t-Bu
1-Adamantyl
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
(S)-20a
(S)-20a
(S)-20a
(S)-20a
(R)-20b
(S)-20c
(R)-20d
(S)-20e
(S)-20f
(S)-20g
(R)-20d
(R)-20f
(S)-20g
Ph
Ph
Ph
Ph
21a
21b
21c
21d
22
23
24a
25
26a
27a
24b
26b
27b
1
1
2
2
2
89
92
84
81
95
72
61
0
89
85
73
66
85
>98
>98
>98
>98
>98
>98
>98
NA
>98
>98
>98
>98
>98
Me
i-Pr
α-Naphthyl
t-Bu
4-CF3-C6H4
4-MeO-C6H4
α-Naphthyl
4-CF3-C6H4
4-MeO-C6H4
4
24
24
2
3
2
1
1
9
10
11
12
13
t-Bu
10d
10d
10d
1-Adamantyl
1-Adamantyl
1-Adamantyl
of the β-substituent on the Michael acceptor via the substi- Therefore, N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones which
tution of the methyl group by an isopropyl group increased the included a 4-trifluoromethylphenyl 20f and 4-methoxyphenyl
reaction time necessary to obtain the appropriate product 23 group 20g in the β-position were utilized for this purpose.
in 72% yield to four hours (entry 6). Increasing the steric hin- These investigations found that the application of a phenyl
drance contributed by the β-position of the Michael acceptor group with an electron withdrawing (CF3) or electron donating
via the incorporation of an α-naphthyl group drastically (OMe) group results in the formation of the expected glutamic
decreased reaction rates, 24 hours, however, the expected acid derivatives 26a, 27a in high chemical yield, 89 and 85%
product was recovered in acceptable yield, 61%, without com- yield respectively (entries 9 and 10). However, as expected,
promising the diastereoselectivity of the process (entry 7). shorter reaction times were necessary to reach complete con-
Increase in the steric contribution of the Michael acceptor cul- sumption of the starting glycine Ni(II) complex in the reactions
minated with the incorporation of a t-butyl group; however, no with the Michael acceptors bearing the electron withdrawing
product 25 could be identified from the reaction mixture group.
(entry 8). To this point the focus of these studies has been con-
With the aim to confirm the absolute configuration of the
centrated on the steric factors associated with the Michael addition products and to demonstrate the preparation of the
acceptors; however, an evaluation with respect to the electronic corresponding enantiomerically pure pyroglutamic acids, we
properties of the Michael acceptors also required evaluation. carried out the disassembly of compounds 21d, 26a and 27a.
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Optical rotations were measured on JASCO P-1010 and P-2000
polarimeters. Melting points (m.p.) are uncorrected and were
obtained in open capillaries. All reagents and solvents, unless
otherwise stated, are commercially available and were used as
received. Chiral (S)- or (R)-N-(E-enoyl)-4-phenyl-1,3-oxazoline-2-
ones 20 were prepared according to the general method given
in ref. 36. Unless otherwise stated, yields refer to isolated
yields of products of greater than 95% purity as estimated by
1H, 19F and 13C NMR spectrometry. All new compounds were
characterized by 1H, 19F, 13C NMR and HRMS.
General procedure for the synthesis of bromoacetamides 6
A solution of 2-bromoacetyl bromide (104.64 mmol) in aceto-
nitrile (21 mL) was slowly added to a slurry of aminoacetophe-
none 5 (102.32 mmol) and potassium carbonate (70.71 g,
511.6 mmol) in acetonitrile (240 mL). The reaction was stirred
at ambient temperature (room temperature water bath) for one
hour, and upon completion (monitored by TLC), the aceto-
nitrile was evaporated in vacuo. Water (200 mL) was then
added to the crude mixture and extracted with dichloro-
methane (200 mL) three times. The organic portions were com-
bined, dried and concentrated in vacuo to afford the
corresponding α-bromoamide product 6 in 98% yield and
greater than 99% chemical purity.
N-(2-Benzoylphenyl)-2-bromoacetamide (6a). M.p. 71.7 °C.
1H NMR (300 MHz, CDCl3): δ 4.20 (2 H, s), 7.15 (1 H, m),
7.43–7.53 (2 H, m), 7.53–7.63 (3 H, m), 7.63–7.75 (2 H, m), 8.61
(1 H, dd, J = 8.8, 1.2 Hz), 11.60 (1 H, br). 13C NMR (75.5 MHz,
CDCl3): δ 43.0, 121.3, 122.9, 124.0, 128.1, 129.8, 132.4, 133.3,
133.9, 138.1, 139.0, 165.1, 198.8. HRMS: calcd for
C15H12BrNNaO2 [M + Na+] 339.9949, found 339.9955.
Scheme 5 Disassembly of products 21d, 26a and 27a.
Heating in 3 N HCl–MeOH resulted in a clean decomposition
of the Ni(II) complexes and the formation of the target pyroglu-
tamic acids 28–30 along with chiral auxiliary (S)-31 and NH
ligands 8d or 9 (Scheme 5). Similar to the procedure esta-
blished for the disassembly of the corresponding glutamic acid
derivatives obtained from complexes 1–3,17 compounds 8d, 9
and 31 were isolated by extraction while pyroglutamic acids
28–30 were obtained using ion-exchange resin. Comparison of
spectral and chiroptical properties of thus obtained amino
acids 28–30 confirmed their expected (2S,3R) absolute
configuration.
Conclusions
N-(2-Benzoyl-4-chlorophenyl)-2-bromoacetamide (6b). M.p.
The data reported in this work, clearly demonstrate that new
N–H type of Ni(II) complexes of glycine Schiff bases holds
advantageous structural features and reactivity profile. In par-
ticular, they are readily available, very inexpensive, self-stable
and can be easily prepared on a large scale. The N–H stereo-
genic centre in these compounds is relatively configurationally
unstable in solution; however, in the case of sterically bulky
groups (t-Bu, Ad) attached to the N–H function, homologation
1
125.5 °C. H NMR (300 MHz, CDCl3): δ 4.02 (2 H, s), 7.45–7.80
(7 H, m), 8.53–8.64 (1 H, m), 11.30 (1 H, br). 13C NMR
(75.5 MHz, CDCl3): δ 29.3, 123.0, 125.4, 128.3, 128.6, 130.0,
132.6, 133.1, 133.8, 137.5, 137.9, 164.9, 197.9. HRMS: calcd for
C15H12BrClNO2 [M + H+] 351.9740, found 351.9747.
General procedure for the synthesis of ligands 8a–d, 9
of the glycine fragment occurs with complete (>99%) diastereo- To a solution of the corresponding bromoacetamide 6 (1
selectivity giving rise to a single reaction product with excellent equiv.) and acetonitrile (10 mL per 1 g of 6) was added the
chemical yield. The synthetic potential of these N–H Ni(II) corresponding primary amine 7a–d (5 equiv.). The reaction
complexes is demonstrated by an advanced asymmetric syn- was allowed to proceed for 24 hours at 60–70 °C (monitored by
thesis of β-substituted pyroglutamic acids via Michael addition TLC) before the reaction mixture was concentrated in vacuo.
reactions with chiral oxazolidinone derived Michael acceptors.
Water was added to the viscous liquid, followed by extraction
with dichloromethane. The organic portions were combined,
dried with magnesium sulfate, and concentrated in vacuo to
afford the corresponding alkylamino-acetamide product 8a–d,
9 in nearly quantitative yield and high chemical purity >99%.
Experimental
General methods
N-(2-Benzoylphenyl)-2-(benzylamino)acetamide
(8a). 1H
1H, 13C and 19F NMR were performed on Varian Unity-300 NMR (300 MHz, CDCl3): δ 1.95 (1 H, br), 3.45 (2 H, s), 3.86 (2
(299.94 MHz), Gemini-200 (199.98 MHz) and Brüker Avance H, s), 7.10 (1 H, t, J = 7.2 Hz), 7.13–7.29 (3 H, m), 7.03–7.43 (2
300 spectrometers using TMS, CDCl3 and CCl3F as internal H, m), 7.46–7.60 (5 H, m), 7.77 (2 H, d, J = 8.4 Hz), 8.64 (1 H,
standards. High resolution mass spectra (HRMS) were d, J = 8.4 Hz), 11.66 (1 H, br). 13C NMR (75.5 MHz, CDCl3): δ
recorded on JEOL HX110A and Agilent Synapt G2 instruments. 52.9, 54.1, 121.7, 122.3, 124.8, 127.3, 128.3, 128.5, 128.5, 130.2,
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132.6, 132.8, 133.7, 138.5, 139.1, 139.3, 171.2, 198.3. HRMS: 129.7, 129.8, 132.6, 133.6, 134.7, 142.8, 171.8, 178.0. HRMS:
calcd for C22H21N2O2 [M + H+], 345.1603, found 345.1606.
calcd for C24H22N3NiO3 [M + H]+ 458.1015, found 458.1020.
Ni(II) complex of glycine Schiff base with N-(2-benzoylphe-
N-(2-Benzoylphenyl)-2-(isopropylamino)acetamide (8b). 1H
NMR (300 MHz, CDCl3): δ 1.13 (6 H, d, J = 6.3 Hz), 1.77 (1 H, nyl)-2-(isopropylamino)acetamide (10b). M.p. 292.3 °C
1
br), 2.84 (1 H, hept, J = 6.3 Hz), 3.42 (2 H, s), 7.10 (1 H, t, J = (decomp.). H NMR (300 MHz, CDCl3): δ 1.56 (3 H, d, J = 6.3
7.8 Hz), 7.45–7.62 (5 H, m), 7.74 (2 H, d, J = 8.1 Hz), 8.68 (1 H, Hz), 1.66 (3 H, d, J = 6.3 Hz), 2.76 (1 H, br), 3.12 (1 H, dq, J =
d, J = 8.4 Hz), 11.65 (1 H, br). 13C NMR (75.5 MHz, CDCl3): δ 13.2, 6.3 Hz), 3.29 (1 H, d, J = 17.7 Hz), 3.75 (2 H, s), 3.99 (1 H,
22.9, 49.6, 51.2, 121.6, 122.2, 125.0, 128.3, 128.4, 130.0, 130.1, dd, J = 17.7, 7.5 Hz), 6.83 (1 H, m), 6.93 (1 H, m), 7.01 (1 H, m),
132.5, 132.7, 133.5, 138.5, 139.2, 172.4, 198.1. HRMS: calcd for 7.19 (1 H, m), 7.35 (1 H, m), 7.53–7.59 (3 H, m), 8.55 (1 H, d,
C18H21N2O2 [M + H+], 297.1603, found 297.1601.
J = 7.8 Hz). 13C NMR (75.5 MHz, CDCl3): δ 20.6, 21.7, 51.7,
N-(2-Benzoylphenyl)-2-(tert-butylamino)acetamide (8c). 1H 53.3, 60.6, 121.3, 128.3, 125.7, 125.8, 136.2, 129.4, 129.7, 129.9,
NMR (300 MHz, CDCl3): δ 1.16 (9 H, s), 3.42 (2 H, s), 7.09 (1 H, 132.7, 133.6, 134.7, 142.6, 173.2, 177.9, 178.2. HRMS: calcd for
t, J = 8.1 Hz), 7.44–7.61 (5 H, m), 7.75 (2 H, d, J = 6.9 Hz), 8.61 C20H21N3NaNiO3 [M + Na+] 432.0834, found 432.0837.
(1 H, d, J = 8.4 Hz), 11.67 (1 H, br). 13C NMR (75.5 MHz,
Ni(II) complex of glycine Schiff base with N-(2-benzoylphe-
CDCl3): δ 28.8, 47.1, 51.2, 121.5, 122.2, 125.2, 128.3, 130.1, nyl)-2-(tert-butylamino)acetamide (10c). M.p. >300 °C
132.5, 132.6, 133.5, 138.6, 139.1, 173.0, 198.0. HRMS: calcd for (decomp.). 1H NMR (300 MHz, CDCl3): δ 1.54 (9 H, s), 2.60
C19H23N2O2 [M + H+] 311.1760, found 311.1764.
(1 H, d, J = 7.8 Hz), 3.41 (1 H, d, J = 17.1 Hz), 3.73 (2 H, d, J =
N-(2-Benzoylphenyl)-2-((adamant-1-yl)amino)acetamide (8d). 3.9 Hz), 4.17 (1 H, dd, J = 17.1, 7.5 Hz), 6.84 (1 H, m), 6.93
1H NMR (300 MHz, CDCl3): δ 1.60 (6 H, q, J = 13.7 Hz), 1.68 (6 (1 H, dd, J = 8.1, 1.8 Hz), 6.99 (1 H, m), 7.23 (1 H, m), 7.38
H, br), 2.04 (3 H, br), 3.47 (2 H, s), 4.10 (1 H, br), 7.12 (1 H, td, (1 H, m), 7.53–7.60 (3 H, m), 8.37 (1 H, d, J = 7.5 Hz). 13C NMR
J = 7.6, 1.1 Hz), 7.46–7.64 (5 H, m), 7.76–7.82 (2 H, m), 8.62 (1 (75.5 MHz, CDCl3): δ 28.0, 51.0, 58.2, 60.4, 121.3, 124.2, 125.7,
H, d, J = 8.3 Hz), 11.59 (1 H, br). 13C NMR (75.5 MHz, CDCl3): δ 126.3, 129.4, 129.8, 129.9, 132.7, 133.5, 134.5, 142.4, 171.7,
29.3, 36.3, 42.0, 44.7, 51.4, 121.6, 122.3, 125.5, 128.2, 130.0, 177.4, 177.7. HRMS: calcd for C21H23N3NaNiO3 [M + Na+]
132.2, 132.5, 133.2, 138.4, 138.7, 172.6, 197.9. HRMS: calcd for 446.0991, found 446.1015.
C25H29N2O2 [M + H]+ 389.2229, found 389.2240.
N-(2-Benzoyl-4-chlorophenyl)-2-(tert-butylamino)acetamide (9). nyl)-2-((adamant-1-yl)amino)acetamide
Ni(II) complex of glycine Schiff base with N-(2-benzoylphe-
(10d). 1H
NMR
1H NMR (300 MHz, CDCl3): δ 1.17 (9 H, s), 3.41 (2 H, s), 7.49 (300 MHz, CDCl3): δ 1.71 (6 H, br), 2.11 (6 H, br), 2.17 (3 H,
(1 H, d, J = 2.5 Hz), 7.51–7.58 (3 H, m), 7.66 (1 H, tt, J = 7.4, br), 3.03 (1 H, d, J = 7.4 Hz), 3.44 (1 H, d, J = 17.0 Hz), 3.68
1.3 Hz), 7.70–7.82 (2 H, m), 8.66 (1 H, d, J = 8.9 Hz), 11.60 (1 H, (1 H, d, J = 20.4 Hz), 3.71 (1 H, d, J = 20.3 Hz), 4.07 (1 H, dd, J =
br). 13C NMR (75.5 MHz, CDCl3): δ 28.4, 46.6, 50.7, 122.5, 17.0, 7.6 Hz), 6.80 (1 H, td, J = 7.6, 1.0 Hz), 6.90 (1 H, dd, J =
126.2, 126.9, 128.2, 129.7, 131.2, 132.7, 137.1, 137.4, 172.6, 8.2, 1.5 Hz), 6.93–6.99 (1 H, m), 7.23 (1 H, d, J = 6.6 Hz), 7.34
196.0. HRMS: calcd for C19H22ClN2O2 [M + H]+ 345.1370, (1 H, ddd, J = 7.7, 7.0, 1.6 Hz), 7.46–7.58 (3 H, m), 8.39 (1 H,
found 345.1374.
dd, J = 8.5, 0.6 Hz). 13C NMR (75.5 MHz, CDCl3): δ 29.3, 35.7,
40.7, 49.0, 58.1, 60.3, 120.9, 124.2, 125.6, 126.0, 126.2, 129.2,
129.5, 129.6, 132.3, 133.2, 134.5, 142.4, 171.3, 177.7, 177.8.
HRMS: calcd for C27H30N3O3Ni [M + H]+ 502.1641, found
General procedure for the synthesis of Ni(II) complexes
10a–d, 11
A solution of potassium hydroxide (10 equiv.) in methanol 502.1646.
(7 mL per 1 g of KOH) was added to the corresponding ligand
Ni(II) complex of glycine Schiff base with N-(2-benzoyl-4-
8a–d, 9 (1 equiv.), glycine (5 equiv.), nickel nitrate hexahydrate chlorophenyl)-2-(tert-butylamino)acetamide
(11). M.p.
1
(2 equiv.) in methanol (10 mL per 1 g of ligand) at 60–70 °C. >300 °C (decomp.). H NMR (300 MHz, CDCl3): δ 1.51 (9 H, s),
Upon complete consumption of the ligand (monitored by 2.98 (1 H, br), 3.36 (1 H, d, J = 17.1 Hz), 3.55–3.75 (2 H, m),
TLC), the reaction mixture was poured over slurry of ice and 4.16 (1 H, dd, J = 17.0, 7.5 Hz), 6.85 (1 H, d, J = 2.5 Hz),
5% acetic acid. After the complete precipitation, the corres- 6.93–6.99 (1 H, m), 7.22 (1 H, d, J = 6.3 Hz), 7.31 (1 H, dd, J =
ponding product 10a–d, 11 was filtered and dried, in a low 9.1, 2.5 Hz), 7.52–7.65 (3 H, m), 8.38 (1 H, d, J = 9.1 Hz). 13C
temp. oven (50 °C) overnight. The product was obtained in NMR (75.5 MHz, CDCl3): δ 30.8, 54.4, 58.0, 60.4, 125.6, 126.1,
high chemical yield (99%) and high chemical purity without 127.3, 128.6, 129.3, 129.6, 130.1, 132.1, 132.5, 133.9, 141.2,
further purification.
171.0, 177.7, 178.1. HRMS: calcd for C21H23ClN3NiO3 [M + H+]
Ni(II) complex of glycine Schiff base with N-(2-benzoylphe- 458.0781, found 458.0780.
nyl)-2-(benzylamino)acetamide (10a). M.p. >300 °C (decomp.).
General procedure for the PTC alkylations of Ni(II) complexes
10a–d, 11
1H NMR (300 MHz, CDCl3): δ 3.08 (1 H, br), 3.25 (1 H, d, J =
16.9 Hz), 3.68 (1 H, dd, J = 17.0, 7.3 Hz), 3.79 (2 H, s), 3.97
(1 H, dd, J = 13.6, 10.0 Hz), 4.45 (1 H, d, J = 13.7 Hz), 6.83 (1 H, To a flask containing the corresponding Ni(II) complex 10a–d,
t, J = 7.5 Hz), 6.94 (1 H, d, J = 8.2 Hz), 7.00–7.07 (1 H, m), 7.18 11 (0.10 g), tetra-n-butylammonium iodide (25 mol%), 15 ml of
(1 H, d, J = 7.0 Hz), 7.34–7.49 (6 H, m), 7.52–7.62 (3 H, m), 8.64 dichloromethane and 5 ml of 30% aqueous sodium hydroxide,
(1 H, d, J = 8.5 Hz). 13C NMR (75.5 MHz, CDCl3): δ 53.0, 55.6, alkyl bromide (1.0 equiv.) was added and the reaction mixture
60.8, 121.2, 124.3, 125.5, 125.7, 126.2, 128.8, 129.1, 129.4, was stirred at room temperature. After disappearance of the
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starting complex by TLC, 10 mL of water was added and the 1.07 (3 H, d, J = 6.3 Hz), 2.16 (1 H, br), 2.64–2.76 (1 H, m), 2.87
organic layer was extracted with CHCl3 three times. The com- (1 H, dd, J = 13.7, 5.8 Hz), 3.04 (1 H, dd, J = 13.6, 3.6 Hz),
bined organic layer was dried over magnesium sulfate, and 3.20–3.31 (2 H, m), 4.26 (1 H, dd, J = 5.7, 3.7 Hz), 6.81–6.87
concentrated in vacuo to afford the corresponding products (1 H, m), 6.91 (1 H, dd, J = 8.2, 1.8 Hz), 7.12–7.17 (1 H, m),
12–16, 17a–d, 18, 19a–c.
Ni(II) complex of phenylalanine Schiff base with N-(2-ben- 7.46–7.52 (2 H, m), 7.54–7.65 (3 H, m), 8.49 (1 H, d, J = 8.6 Hz).
zoylphenyl)-2-(benzylamino)acetamide (upper diastereomer) Ni(II) complex of phenylalanine Schiff base with N-(2-ben-
7.26–7.33 (4 H, m), 7.37 (1 H, ddd, J = 8.6, 5.3, 1.8 Hz),
(12). M.p. 219.7 °C (decomp.). 1H NMR (300 MHz, CDCl3): δ zoylphenyl)-2-(tert-butylamino)acetamide (17a). M.p. 272.9 °C
2.00 (1 H, t, J = 7.5 Hz), 2.72–2.84 (2 H, m), 3.08–3.16 (2 H, m), (decomp.). 1H NMR (300 MHz, CDCl3): δ 1.30 (9 H, s), 1.78
3.66 (1 H, ABX, J = 13.8, 10.2 Hz), 4.04 (1 H, AB, J = 13.8 Hz), (1 H, d, J = 7.2 Hz), 2.66 (1 H, dd, J = 13.5, 6.0 Hz), 3.03 (1 H, d,
4.37 (1 H, m), 6.84 (1 H, m), 7.08–7.19 (2 H, m), 7.23–7.48 (6 H, J = 16.5 Hz), 3.07 (1 H, dd, J = 13.5, 2.7 Hz), 3.37 (1 H, dd, J =
m), 7.49 (1 H, m), 7.52–7.65 (6 H, m), 7.74 (1 H, dd, J = 6.6, 2.4 16.5, 7.2 Hz), 4.33 (1 H, dd, J = 5.4, 3.0 Hz), 6.84 (2 H, d, J =
Hz), 8.42 (1 H, d, J = 8.4 Hz). 13C NMR (75.5 MHz, CDCl3): δ 3.9 Hz), 7.14 (1 H, m), 7.32–7.43 (4 H, m), 7.55–7.63 (6 H, m),
39.5, 53.1, 54.7, 71.3, 121.0, 124.3, 127.1, 127.4, 127.8, 128.8, 8.26 (1 H, d, J = 8.7 Hz). 13C NMR (75.5 MHz, CDCl3): δ 27.8,
129.0, 129.1, 129.3, 129.7, 130.1, 131.7, 132.5, 133.8, 133.9, 39.0, 50.9, 57.7, 70.8, 121.0, 123.3, 127.3, 127.6, 127.8, 128.0,
134.4, 136.5, 143.0, 170.4, 176.8, 178.3. HRMS: calcd for 128.8, 129.1, 129.3, 130.2, 131.4, 132.9, 133.7, 133.9, 136.1,
C31H27N3NaNiO3 [M + Na+] 570.1304, found 570.1312.
Ni(II) complex of phenylalanine Schiff base with N-(2-ben- [M + Na+] 536.1460, found 536.1472.
142.8, 170.4, 176.3, 178.7. HRMS: calcd for C28H29N3NaNiO3
zoylphenyl)-2-(benzylamino)acetamide (lower diastereomer)
Ni(II) complex of phenylalanine Schiff base with N-(2-
(13). M.p. 219.7 °C (decomp.). 1H NMR (300 MHz, CDCl3): δ benzoyl-4-chlorophenyl)-2-(tert-butylamino)acetamide (18). 1H
2.43 (1 H, m), 2.75–2.91 (2 H, m), 3.12–3.23 (2 H, m), 3.65 (1 H, NMR (300 MHz, CDCl3): δ 1.29 (9 H, s), 1.95 (1 H, d, J = 7.3
ABX, J = 13.5, 9.6 Hz), 3.96 (1 H, AB, J = 13.5 Hz), 4.35 (1 H, m), Hz), 2.64 (1 H, dd, J = 13.5, 5.6 Hz), 3.00 (1 H, d, J = 16.6 Hz),
6.77–6.83 (2 H, m), 7.08–7.16 (2 H, m), 7.26–7.37 (5 H, m), 3.08 (1 H, dd, J = 13.5, 2.9 Hz), 3.35 (1 H, dd, J = 16.6, 7.4 Hz),
7.42–7.48 (2 H, m), 7.51–7.63 (6 H, m), 7.72 (1 H, dd, J = 5.7, 4.31 (1 H, dd, J = 5.6, 2.9 Hz), 6.77 (1 H, d, J = 2.5 Hz),
2.4 Hz), 8.38 (1 H, d, J = 8.4 Hz). 13C NMR (75.5 MHz, CDCl3): δ 7.10–7.15 (1 H, m), 7.28 (1 H, dd, J = 9.1, 2.5 Hz), 7.36–7.42
39.6, 52.7, 55.4, 71.2, 121.0, 123.7, 126.9, 127.4, 127.7, 127.8, (3 H, m), 7.56–7.67 (6 H, m), 8.26 (1 H, d, J = 9.1 Hz). 13C NMR
128.7, 128.8, 128.9, 128.9, 129.1, 129.7, 130.1, 131.5, 132.7, (75.5 MHz, CDCl3): δ 27.6, 38.9, 50.7, 57.6, 70.8, 124.5, 125.6,
133.4, 133.8, 136.2, 143.0, 170.4, 176.7, 179.1. HRMS: calcd for 127.1, 127.7, 127.7, 128.7, 129.2, 129.4, 130.4, 131.1, 132.3,
C31H27N3NaNiO3 [M + Na+] 570.1304, found 570.1307.
Ni(II) complex of phenylalanine Schiff base with N-(2-ben- C28H29ClN3NiO3 [M + H]+ 548.1251, found 548.1263.
zoylphenyl)-2-(dibenzylamino)acetamide (14). M.p. 295.2 °C Ni(II) complex of 2-aminopent-4-enoic acid Schiff base with
132.6, 133.0, 135.8, 141.4, 169.5, 176.5, 178.4. HRMS: calcd for
(decomp.). 1H NMR (300 MHz, CDCl3): δ 2.64 (1 H, d, J = N-(2-benzoylphenyl)-2-(tert-butylamino)acetamide (17b). M.p.
16.4 Hz), 2.73 (1 H, dd, J = 13.5, 5.3 Hz), 3.02 (1 H, d, J = 12.3 116.3 °C (decomp.). 1H NMR (300 MHz, CDCl3): δ 1.46 (9 H, s),
Hz), 3.04 (1 H, dd, J = 13.3, 3.4 Hz), 3.17 (1 H, d, J = 14.1 Hz), 2.32 (1 H, m), 2.48 (1 H, m), 2.73 (1 H, d, J = 7.5 Hz), 3.41 (1 H,
3.49 (1 H, d, J = 14.2 Hz), 3.58 (1 H, d, J = 16.3 Hz), 3.83 (1 H, d, J = 16.8 Hz), 4.08 (1 H, dd, J = 6.3, 3.6 Hz), 4.28 (1 H, dd, J =
d, J = 12.3 Hz), 4.31 (1 H, dd, J = 5.3, 3.4 Hz), 6.60–6.68 (2 H, 16.8, 7.5 Hz), 5.26 (1 H, dd, J = 17.1, 1.5 Hz), 5.56 (1 H, dd, J =
m), 6.96–7.09 (3 H, m), 7.17–7.80 (17 H, m), 8.20–8.28 (2 H, 10.1, 1.5 Hz), 6.63 (1 H, m), 6.81 (1 H, m), 6.99 (1 H, m),
m). 13C NMR (75.5 MHz, CDCl3): δ 39.0, 62.3, 62.7, 62.8, 71.3, 7.32–7.38 (2 H, m), 7.48–7.55 (3 H, m), 8.33 (1 H, d, J = 8.1 Hz).
120.5, 123.5, 126.2, 127.1, 127.3, 127.5, 128.4, 128.5, 128.6, 13C NMR (75.5 MHz, CDCl3): δ 28.0, 38.1, 51.4, 58.0, 69.4,
128.7, 128.9, 129.7, 130.2, 131.2, 131.6, 131.8, 132.8, 133.5, 120.0, 121.1, 123.3, 127.1, 127.7, 128.0, 129.0, 129.2, 130.0,
134.0, 136.3, 142.0, 170.2, 175.5, 177.6. HRMS: calcd for 132.3, 132.9, 133.7, 133.8, 142.6, 170.6, 176.8, 179.0. HRMS:
C38H33N3NaNiO3 [M + Na+] 660.1773, found 660.1781.
Ni(II) complex of phenylalanine Schiff base with N-(2-ben- 486.1308.
zoylphenyl)-2-(isopropylamino)acetamide (16) (major diaster- Ni(II) complex of (E)-2-amino-5-phenylpent-4-enoic acid
calcd for C24H27N3NaNiO3 [M +
Na+] 486.1304, found
1
eomer). M.p. 245.9 °C (decomp.). H NMR (300 MHz, CDCl3): Schiff base with N-(2-benzoylphenyl)-2-(tert-butylamino)aceta-
δ 1.28 (3 H, d, J = 6.3 Hz), 1.46 (3 H, d, J = 6.3 Hz), 1.74 (1 H, mide (17c). M.p. 198.3 °C (decomp.). 1H NMR (300 MHz,
br), 2.67–2.73 (2 H, m), 2.93 (1 H, d, J = 16.5 Hz), 3.08 (1 H, dd, CDCl3): δ 1.37 (9 H, s), 2.26 (1 H, d, J = 7.5 Hz), 2.34 (1 H, m),
J = 13.5, 3.0 Hz), 3.32 (1 H, dd, J = 16.5, 7.2 Hz), 4.33 (1 H, dd, 2.64 (1 H, m), 2.98 (1 H, d, J = 16.8 Hz), 3.23 (1 H, dd, J = 16.8,
J = 5.4, 3.0 Hz), 6.82 (2 H, d, J = 3.6 Hz), 7.14 (1 H, m), 7.5 Hz), 4.19 (1 H, dd, J = 5.7, 3.3 Hz), 6.72 (1 H, d, J = 15.9
7.31–7.37 (2 H, m), 7.43–7.46 (2 H, m), 7.55–7.62 (6 H, m), 8.39 Hz), 6.82 (2 H, d, J = 4.2 Hz), 7.04–7.15 (2 H, m), 7.30–7.38 (3
(1 H, d, J = 9.0 Hz). 13C NMR (75.5 MHz, CDCl3): δ 20.4, 21.7, H, m), 7.44 (2 H, t, J = 7.2 Hz), 7.50–7.60 (3 H, m), 7.66 (2 H, d,
39.2, 52.0, 53.1, 71.2, 121.1, 123.6, 127.3, 127.3, 127.7, 127.9, J = 7.5 Hz), 8.34 (1 H, d, J = 8.4 Hz). 13C NMR δ 27.9, 36.6, 50.7,
128.7, 129.1, 129.3, 130.1, 131.5, 132.8, 133.8, 133.8, 136.2, 58.0, 69.9, 121.0, 123.2, 124.0, 126.4, 127.2, 127.7, 128.0, 128.0,
142.9, 170.3, 176.8, 178.8. HRMS: calcd for C27H28N3NiO3 129.1, 129.3, 130.1, 133.0, 133.7, 133.8, 135.4, 137.3, 142.9,
[M + H+] 500.1484, found 500.1490. Data for the minor diaster- 170.5, 176.9, 179.0. HRMS: calcd for C30H31N3NaNiO3
1
eomer: H NMR (300 MHz, CDCl3): δ 1.05 (3 H, d, J = 6.3 Hz), [M + Na+] 562.1617, found 562.1620.
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Ni(II) complex of 2-aminopent-4-ynoic acid Schiff base with to the reaction mixture, which was stirred at room temperature
N-(2-benzoylphenyl)-2-(tert-butylamino)acetamide (17d). M.p. and monitored by TLC. After the disappearance of the starting
236.7 °C (decomp.). 1H NMR (300 MHz, CDCl3): δ 1.47 (9 H, s), glycine equivalent by TLC, the reaction mixture was poured
2.28 (1 H, dq, J = 19.8, 2.7 Hz), 2.67 (1 H, dt, J = 17.4, 2.7 Hz), into a beaker containing 100 mL of ice water. After the ice had
2.81–2.86 (2 H, m), 3.41 (1 H, d, J = 16.5 Hz), 4.05 (1 H, dd, J = melted the solid was filtered from the aqueous solution and
6.3, 3.0 Hz), 4.27 (1 H, dd, J = 16.5, 7.2 Hz), 6.81 (2 H, m), 7.05 dried in an oven to afford the appropriate product in high
(1 H, m), 7.31–7.39 (2 H, m), 7.48–7.58 (3 H, m), 8.32 (1 H, d, chemical yields.
J = 8.1 Hz). 13C NMR (75.5 MHz, CDCl3): δ 23.9, 27.9, 51.5,
58.0, 67.2, 74.2, 79.5, 121.1, 123.5, 126.9, 127.7, 127.7, 129.3, zolidinonyl)]glutamic acid Schiff base with N-(2-benzoylphe-
130.2, 133.0, 133.6, 133.7, 142.9, 171.4, 176.9, 178.5. HRMS: nyl)-2-(benzylamino)acetamide (21a). M.p. 146.3 °C. [α]D25
Ni(II) complex of (2S,3R,4′S)-3-phenyl-5-[3′-(4′-phenyl-2′-oxa-
=
calcd for C24H25N3NaNiO3 [M
484.1172.
+
Na+] 484.1147, found +1867.2 (c 0.021, CHCl3). 1H NMR (300 MHz, CDCl3): δ
2.66–2.89 (4 H, m), 3.25–3.42 (3 H, m), 3.85 (1 H, dd, J = 16.2,
Ni(II) complex of phenylalanine Schiff base with N-(2-ben- 6.0 Hz), 4.18 (1 H, dd, J = 8.7, 3.9 Hz), 4.43 (1 H, d, J = 4.2 Hz),
zoylphenyl)-2-((adamant-1-yl)amino)acetamide (19a). 1H NMR 4.60 (1 H, t, J = 8.7 Hz), 5.18 (1 H, dd, J = 8.7, 3.9 Hz), 6.71–6.84
(300 MHz, CDCl3): δ 1.64 (6 H, br), 1.77 (1 H, d, J = 6.8 Hz), (3 H, m), 6.97–7.01 (2 H, m), 7.05 (1 H, d, J = 6.9 Hz), 7.11–7.14
1.88 (6 H, br), 2.11 (3 H, br), 2.67 (1 H, dd, J = 13.4, 5.5 Hz), (2 H, m), 7.23–7.47 (10 H, m), 7.56–7.59 (2 H, m), 7.67–7.73 (3
3.07 (1 H, dd, J = 13.7, 2.7 Hz), 3.13 (1 H, d, J = 16.7 Hz), 3.30 H, m), 8.38 (1 H, d, J = 8.7 Hz). 13C NMR (75.5 MHz, CDCl3): δ
(1 H, dd, J = 16.4, 7.1 Hz), 4.29–4.34 (1 H, m), 6.81–6.85 (2 H, 36.4, 45.2, 53.1, 54.7, 57.5, 69.7, 73.4, 121.0, 123.8, 125.7,
m), 7.14 (1 H, d, J = 6.6 Hz), 7.31–7.44 (4 H, m), 7.52–7.64 (6 H, 125.9, 126.9, 127.0, 127.2, 128.0, 128.3, 128.4, 128.75, 128.9,
m), 8.28 (1 H, d, J = 8.5 Hz). 13C NMR (75.5 MHz, CDCl3): δ 129.1, 129.6, 129.8, 130.7, 132.6, 133.5, 133.6, 134.0, 138.7,
29.2, 35.6, 38.9, 40.6, 48.9, 57.9, 70.6, 120.8, 123.4, 127.2, 132.8, 139.2, 142.9, 169.9, 171.0, 175.9, 176.6, 177.4. HRMS:
127.5, 127.6, 127.9, 128.6, 129.0, 129.2, 130.0, 131.2, 132.7, calcd for C42H36N4NaNiO6 [M
133.6, 133.8, 135.9, 142.8, 170.2, 176.5, 178.7. HRMS: calcd for 773.1886.
Ni(II) complex of (2S,3R,4′S)-3-phenyl-5-[3′-(4′-phenyl-2′-oxa-
Ni(II) complex of (E)-2-amino-5-phenylpent-4-enoic acid zolidinonyl)]glutamic acid Schiff base with N-(2-benzoylphe-
Schiff base with N-(2-benzoylphenyl)-2-((adamant-1-yl)amino)- nyl)-2-(isopropylamino)acetamide (21b). M.p. 183.1 °C. [α]D25
+
Na+] 773.1886, found
C34H36N3O3Ni [M + H]+ 592.2110, found 592.2117.
=
acetamide (19b). 1H NMR (300 MHz, CDCl3): δ 1.67 (6 H, br), +1124.9 (c 0.018, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.29
1.96 (6 H, br), 2.14 (3 H, br), 2.29–2.40 (2 H, m), 2.60–2.70 (3 H, d, J = 6.6 Hz), 1.37 (3 H, d, J = 6.6 Hz), 2.67 (1 H, s), 2.74
(1 H, m), 3.09 (1 H, d, J = 16.7 Hz), 3.20 (1 H, dd, J = 16.7, (1 H, h, J = 6.6 Hz), 2.86 (1 H, d, J = 16.5 Hz), 3.18–3.30 (2 H,
7.0 Hz), 4.18 (1 H, dd, J = 5.5, 3.4 Hz), 6.70 (1 H, d, J = 15.9 m), 3.56 (1 H, dd, J = 18.6, 8.7 Hz), 3.72 (1 H, dd, J = 18.6,
Hz), 6.82 (2 H, d, J = 3.9 Hz), 7.03–7.08 (1 H, m), 7.12 (1 H, dd, 8.7 Hz), 4.20 (1 H, dd, J = 8.7, 3.9 Hz), 4.49 (1 H, d, J = 4.5 Hz),
J = 15.7, 7.8 Hz), 7.29–7.46 (5 H, m), 7.49–7.60 (3 H, m), 7.65 4.63 (1 H, t, J = 9.0 Hz), 5.18 (1 H, dd, J = 8.7, 3.9 Hz), 6.74
(2 H, d, J = 7.2 Hz), 8.36 (1 H, d, J = 8.5 Hz). 13C NMR (1 H, d, J = 2.7 Hz), 6.99–7.05 (3 H, m), 7.24 (1 H, d, J = 2.7 Hz),
(75.5 MHz, CDCl3): δ 29.3, 35.7, 36.6, 40.7, 48.7, 58.2, 69.8, 7.27 (1 H, d, J = 2.7 Hz), 7.28–7.33 (5 H, m), 7.37 (1 H, t, J =
120.9, 123.3, 123.9, 126.3, 127.1, 127.6, 127.9, 129.0, 129.1, 7.2 Hz), 7.47–7.52 (3 H, m), 7.56–7.62 (3 H, m), 8.40 (1 H, d, J =
129.9, 132.8, 133.6, 133.9, 135.2, 137.2, 142.9, 170.3, 177.0, 9.3 Hz). 13C NMR (75.5 MHz, CDCl3): δ 20.2, 21.4, 29.3, 44.9,
179.0. HRMS: calcd for C36H38N3O3Ni [M + H]+ 618.2267, 52.7, 53.8, 57.5, 69.8, 73.3, 124.7, 125.7, 125.9, 127.3, 127.9,
found 618.2271.
128.3, 128.4, 128.5, 128.7, 128.9, 129.3, 129.4, 130.3, 130.8,
Ni(II) complex of 2-aminopent-4-ynoic acid Schiff base with 132.6, 132.7, 132.9, 138.8, 139.2, 141.6, 153.3, 169.8, 170.0,
N-(2-benzoylphenyl)-2-((adamant-1-yl)amino)acetamide (19c). 176.9, 177.1. HRMS: calcd for C38H36N4NaNiO6 [M + Na+]
1H NMR (300 MHz, CDCl3): δ 1.73 (6 H, br), 2.09 (6 H, br), 2.21 725.1886, found 725.1884.
(3 H, br), 2.31 (1 H, dd, J = 6.0, 2.6 Hz), 2.57 (1 H, d, J =
6.9 Hz), 2.68 (1 H, dt, J = 17.0, 2.7 Hz), 2.80 (1 H, t, J = 2.5 Hz), zolidinonyl)]glutamic acid Schiff base with N-(2-benzoylphe-
3.54 (1 H, d, J = 16.6 Hz), 4.06 (1 H, dd, J = 6.0, 2.6 Hz), 4.20 nyl)-2-(tert-butylamino)acetamide (21c). M.p. 183.1 °C. [α]D25
Ni(II) complex of (2S,3R,4′S)-3-phenyl-5-[3′-(4′-phenyl-2′-oxa-
=
(1 H, dd, J = 16.6, 7.4 Hz), 6.79–6.86 (2 H, m), 7.06 (1 H, d, J = +734.2 (c 0.012, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.28
6.7 Hz), 7.33–7.41 (2 H, m), 7.49–7.60 (3 H, m), 8.36 (1 H, d, J = (9 H, s), 2.67 (1 H, s), 2.97 (1 H, d, J = 16.8 Hz), 3.20–3.37 (2 H,
8.4 Hz). 13C NMR (75.5 MHz, CDCl3): δ 23.8, 29.4, 35.8, 40.8, m), 3.51 (1 H, dd, J = 17.7, 8.4 Hz), 3.74 (1 H, dd, J = 17.7,
49.6, 58.2, 67.2, 74.1, 79.5, 120.9, 123.6, 126.8, 127.7, 129.2, 8.4 Hz), 4.17 (1 H, dd, J = 9, 3.9 Hz), 4.46 (1 H, d, J = 4.5 Hz),
130.1, 132.9, 133.6, 133.7, 143.0, 171.1, 177.0, 178.4. HRMS: 4.61 (1 H, t, J = 8.7 Hz), 5.18 (1 H, dd, J = 8.7, 3.6 Hz), 6.79
calcd for C30H32N3O3Ni [M + H]+ 540.1797, found 540.1804.
(1 H, m), 6.98–7.03 (3 H, m), 7.26–7.38 (7 H, m), 7.43–7.49 (3
H, m), 7.54–7.63 (4 H, m), 8.23 (1 H, d, J = 8.4 Hz). 13C NMR
(75.5 MHz, CDCl3): δ 27.8, 36.5, 44.9, 50.8, 57.4, 59.7, 69.7,
72.5, 120.9, 123.1, 125.8, 127.3, 127.6, 128.2, 128.3, 128.8,
General procedure for the Michael addition of complexes
10a–d, 11 to acceptors 20
To a flask containing the starting complex 10a–d, 11 (0.10 g), 128.9, 129.0, 129.2, 130.0, 130.6, 132.9, 133.6, 133.9, 138.8,
the corresponding 3-((E)-3-alkylacryloyl)oxazolidin-2-one (R)- or 139.1, 142.8, 153.3, 170.0, 170.8, 176.4, 177.2. HRMS: calcd for
(S)-20 (1.05 equiv.) and 3 ml of DMF, DBU (15 mol%) was added C39H38N4NaNiO6 [M + Na+] 739.2043, found 739.2078.
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Ni(II) complex of (2S,3R,4′S)-3-phenyl-5-[3′-(4′-phenyl-2′-oxa- 49.7, 57.5, 57.7, 69.7, 72.9, 124.4, 125.5, 125.6, 126.7, 126.8,
zolidinonyl)]glutamic acid Schiff base with N-(2-benzoylphe- 127.3, 127.7, 128.1, 128.2, 128.3, 128.4, 128.6, 128.7, 129.3,
nyl)-2-((adamant-1-yl)amino)acetamide (21d). [α]2D5 = +1751.3 129.5, 130.4, 132.6, 132.8, 132.9, 133.3, 133.5, 136.1, 138.5,
1
(c 0.052, CHCl3). H NMR (300 MHz, CDCl3): δ 1.64 (6 H, br), 141.6, 153.4, 170.0, 170.1, 176.6, 177.1. HRMS: calcd for
1.85 (6 H, br), 2.11 (3 H, br), 3.08 (1 H, d, J = 16.5 Hz), C43H40ClN4NiO6 [M + H+] 801.1990, found 801.1981.
3.21–3.31 (2 H, m), 3.46 (1 H, dd, J = 18.0, 8.0 Hz), 3.74 (1 H,
dd, J = 17.9, 6.7 Hz), 4.16 (1 H, dd, J = 8.8, 3.7 Hz), 4.46 (1 H, d, 5-[3″-(4″-phenyl-2″-oxazolidinonyl)]glutamic acid Schiff base
J = 4.7 Hz), 4.60 (1 H, t, J = 8.7 Hz), 5.18 (1 H, dd, J = 8.6, 3.6 with N-(2-benzoyl-4-chlorophenyl)-2-(tert-butylamino)aceta-
Ni(II) complex of (2S,3R,4″S)-3-(4′-trifluoromethylphenyl)-
Hz), 6.75–6.84 (2 H, m), 6.97–7.05 (3 H, m), 7.25–7.39 (6 H, m), mide (26a). [α]2D5 = +506.5 (c 0.007, CHCl3). 1H NMR (300 MHz,
7.42–7.50 (3 H, m), 7.53–7.66 (4 H, m), 8.26 (1 H, d, J = 8.4 Hz). CDCl3): δ 1.25 (9 H, s), 1.96 (1 H, m), 3.00 (1 H, d, J = 16.9 Hz),
13C NMR (75.5 MHz, CDCl3): δ 29.2, 35.6, 36.5, 40.5, 44.8, 48.8, 3.29 (3 H, m), 3.91 (1 H, dd, J = 19.1, 9.1 Hz), 4.17 (1 H, m),
57.3, 57.8, 69.6, 72.4, 120.7, 123.1, 125.6, 127.2, 127.5, 128.2, 4.41 (1 H, m), 4.60 (1 H, t, J = 8.6 Hz), 5.17 (1 H, dd, J = 7.6,
128.7, 128.9, 129.1, 129.8, 130.5, 132.7, 133.5, 133.8, 138.7, 2.9 Hz), 6.71 (1 H, m), 6.93 (3 H, m), 7.41 (10 H, m), 7.77 (2 H,
138.9, 142.7, 153.2, 169.9, 170.6, 176.5, 171.2. HRMS: calcd for m), 8.26 (1 H, d, J = 8.9 Hz). 13C NMR (75.5 MHz, CDCl3):
C45H45N4O6Ni [M + H]+ 795.2693, found 795.2695.
δ 27.7, 36.5, 44.8, 50.3, 57.5, 58.0, 69.8, 72.5, 77.1, 124.3, 125.7,
Ni(II) complex of (2R,3R,4′R)-3-methyl-5-[3′-(4′-phenyl-2′-oxa- 125.8, 127.2, 128.0, 128.5, 128.9, 129.4, 129.6, 130.5, 130.6,
zolidinonyl)]glutamic acid Schiff base with N-(2-benzoyl- 132.8, 132.9, 133.0, 138.5, 141.6, 143.0, 153.4, 169.6, 170.7,
phenyl)-2-(tert-butylamino)acetamide (22). M.p. 153.7 °C. 176.5, 176.7. HRMS: calcd for C40H37ClF3N4NiO6 [M + H+]
[α]2D5 = –1467.9 (c 0.005, CHCl3). 1H NMR (300 MHz, CDCl3): 819.1707, found 819.1704.
δ 1.43 (9 H, s), 1.91 (3 H, s), 3.04 (1 H, dd, J = 18.3, 7.2 Hz),
3.24 (1 H, dd, J = 18.3, 7.2 Hz), 3.39 (1 H, d, J = 17.1 Hz), 4.16 phenyl-2″-oxazolidinonyl)]glutamic acid Schiff base with N-(2-
(1 H, d, J = 4.5 Hz), 4.22 (1 H, dd, J = 9.0, 3.6 Hz), 4.39 (1 H, q, benzoyl-4-chlorophenyl)-2-(tert-butylamino)acetamide (27a).
Ni(II) complex of (2S,3R,4″S)-3(4′-methoxyphenyl)-5-[3″-(4″-
J = 17.1, 7.2 Hz), 4.61 (1 H, t, J = 8.7 Hz), 5.28 (1 H, dd, J = 8.7, [α]2D5 = +316.4 (c 0.003, CHCl3). 1H NMR (300 MHz, CDCl3):
3.3 Hz), 6.78 (2 H, d, J = 4.8 Hz), 6.94 (1 H, d, J = 7.8 Hz), 7.25 δ 1.25 (9 H, m), 2.98 (1 H, d, J = 16.8 Hz), 3.13 (1 H, m), 3.37
(2 H, m), 7.30–7.47 (7 H, m), 7.53 (1 H, t, J = 7.8 Hz), 8.37 (1 H, (1 H, dd, J = 16.8, 7.6 Hz), 3.44 (1 H, dd, J = 17.8, 8.2 Hz), 3.63
d, J = 8.4 Hz). 13C NMR (75.5 MHz, CDCl3): δ 16.8, 28.0, 33.7, (1 H, dd, J = 17.8, 6.5 Hz), 3.89 (3 H, s), 4.16 (1 H, dd, J = 8.8,
38.9, 51.5, 57.5, 57.9, 69.9, 72.3, 121.0, 123.0, 126.1, 127.3, 3.4 Hz), 4.40 (1 H, d, J = 4.9 Hz), 4.59 (1 H, t, J = 8.8 Hz), 5.16
127.8, 128.6, 128.8, 129.0, 129.1, 129.8, 132.9, 133.7, 134.0, (1 H, dd, J = 8.6, 3.3 Hz), 5.30 (1 H, s), 6.72 (1 H, d, J = 2.2 Hz),
139.2, 142.7, 153.5, 170.5, 171.2, 177.1, 177.8. HRMS: calcd for 6.99 (3 H, m), 7.09 (2 H, m), 7.29 (8 H, m), 7.46 (1 H, t, J =
C34H36N4NaNiO6 [M + Na+] 677.1886, found 677.1918.
7.4 Hz), 7.56 (1 H, t, J = 7.6 Hz), 8.18 (1 H, d, J = 9.1 Hz). 13C
Ni(II) complex of (2S,3R,4′S)-3-isopropyl-5-[3′-(4′-phenyl-2′- NMR (75.5 MHz, CDCl3): δ 27.7, 29.3, 31.0, 44.1, 50.5, 55.5,
oxazolidinonyl)]glutamic acid Schiff base with N-(2-benzoyl-4- 57.4, 57.8, 69.7, 114.0, 124.3, 125.6, 129.9, 127.3, 128.0, 128.3,
chlorophenyl)-2-(tert-butylamino)acetamide
(23). [α]2D5
=
128.8, 129.2, 129.4, 130.4, 130.6, 131.5, 132.6, 132.9, 138.8,
+766.7 (c 0.015, CHCl3). 1H NMR (300 MHz, CDCl3): δ 0.39 141.4, 153.3, 159.7, 170.0, 176.6, 177.1. HRMS: calcd for
(3 H, d, J = 6.7 Hz), 0.81 (3 H, d, J = 6.7 Hz), 1.37 (9 H, s), 2.49 C40H40ClN4NiO7 [M + H+] 781.1939, found 781.1929.
(2 H, m), 2.71 (1 H, d, J = 7.3 Hz), 3.10 (2 H, m), 3.38 (1 H, d,
J = 16.6 Hz), 3.83 (1 H, d, J = 8.2 Hz), 4.15 (1 H, dd, J = 8.8, oxazolidinonyl)]glutamic acid Schiff base with N-(2-benzoyl-
2.8 Hz), 4.25 (1 H, t, J = 8.5 Hz), 4.52 (1 H, dd, J = 16.5, 7.4 Hz), phenyl)-2-((adamant-1-yl)amino)acetamide (24b). [α]D25
Ni(II) complex of (2R,3S,4′R)-3-α-naphthyl-5-[3′-(4′-phenyl-2′-
=
–
5.34 (1 H, dd, J = 8.2, 2.6 Hz), 6.79 (1 H, d, J = 2.4 Hz), 7.21 1584.5 (c 0.074, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.63
(4 H, m), 7.38 (4 H, m), 7.52 (3 H, m), 8.45 (1 H, d, J = 9.1 Hz). (6 H, br), 1.87 (6 H, br), 2.01 (1 H, d, J = 6.0 Hz), 2.10 (3 H, br),
13C NMR (75.5 MHz, CDCl3): δ 15.8, 21.8, 27.5, 27.9, 31.5, 44.4, 3.12–3.42 (4 H, m), 3.98 (1 H, dd, J = 16.8, 7.2 Hz), 4.16 (1 H,
51.7, 57.3, 57.9, 70.5, 70.9, 123.9, 125.9, 128.1, 128.4, 128.7, dd, J = 8.9, 3.9 Hz), 4.40 (1 H, d, J = 4.3 Hz), 4.60 (1 H, t, J =
129.1, 129.2, 129.5, 129.7, 130.5, 132.8, 132.9, 133.2, 139.3, 8.8 Hz), 5.19 (1 H, dd, J = 8.7, 3.9 Hz), 6.78–6.82 (2 H, m),
141.3, 153.9, 170.5, 172.1, 177.7, 178.7. HRMS: calcd for 6.94–7.00 (3 H, m), 7.20–7.28 (3 H, m), 7.28–7.44 (5 H, m),
C36H40ClN4NiO6 [M + H+] 717.1990, found 717.1988.
7.45–7.63 (5 H, m), 7.79 (2 H, d, J = 8.1 Hz), 8.31 (1 H, d, J =
Ni(II) complex of (2R,3S,4′R)-3-α-naphthyl-5-[3′-(4′-phenyl-2′- 8.4 Hz). 13C NMR (75.5 MHz, CDCl3): δ 29.2, 35.6, 36.5, 40.5,
oxazolidinonyl)]glutamic acid Schiff base with N-(2-benzoyl-4- 44.8, 48.5, 57.3, 58.1, 69.7, 72.2, 120.8, 122.3, 123.1, 125.5,
chlorophenyl)-2-(tert-butylamino)acetamide (24a). [α]D25
=
125.9, 126.1, 126.7, 127.2, 128.1, 128.3, 128.5, 125.6, 128.7,
–720.0 (c 0.002, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.15 129.0, 129.2, 130.0, 130.4, 133.0, 133.4, 133.9, 138.4, 143.0,
(9 H, s), 1.66 (1 H, m), 1.85 (1 H, dd, J = 16.7, 7.4 Hz), 2.47 143.0, 153.3, 169.6, 171.1, 176.4, 176.9. HRMS: calcd for
(1 H, d, J = 16.7 Hz), 3.38 (2 H, m), 3.95 (1 H, m), 4.11 (1 H, dd, C49H47N4O6Ni [M + H]+ 845.2849, found 845.2831.
J = 8.8, 3.8 Hz), 4.43 (1 H, d, J = 4.2 Hz), 4.58 (1 H, t, J =
Ni(II) complex of (2R,3S,4″R)-3-(4′-trifluoromethylphenyl)-5-
8.8 Hz), 5.15 (1 H, dd, J = 4.9, 3.8 Hz), 6.73 (1 H, d, J = 2.4 Hz), [3″-(4″-phenyl-2″-oxazolidinonyl)]glutamic acid Schiff base
6.86 (2 H, m), 6.99 (2 H, t, J = 7.7 Hz), 7.10 (2 H, m), 7.21 (1 H, with N-(2-benzoylphenyl)-2-((adamant-1-yl)amino)acetamide
dd, J = 9.1, 2.4 Hz), 7.46 (7 H, m), 7.95 (2 H, m), 8.19 (1 H, d, (26b). [α]2D5 = –2560.6 (c 0.088, CHCl3). 1H NMR (300 MHz,
J = 9.1 Hz). 13C NMR (75.5 MHz, CDCl3): δ 27.6, 36.4, 45.2, CDCl3): δ 1.58 (6 H, br), 1.73 (6 H, br), 1.80–1.91 (2 H, m), 2.04
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(3 H, br), 2.63 (1 H, d, J = 16.7 Hz), 3.35–3.49 (2 H, m), J = 9.3, 6.1, 4.9 Hz), 4.11 (1 H, d, J = 4.9 Hz), 7.11–7.25 (5 H,
3.96–4.08 (1 H, m), 4.12 (1 H, dd, J = 8.8, 3.8 Hz), 4.46 (1 H, d, m). 13C NMR (75.5 MHz, CD3OD): δ 39.5, 45.5, 64.5, 128.0,
J = 4.1 Hz), 4.58 (1 H, t, J = 8.8 Hz), 5.18 (1 H, dd, J = 8.6, 128.4, 130.1, 143.7, 174.8, 179.9. HRMS: calcd for C11H12NO3
3.7 Hz), 6.76–6.91 (4 H, m), 7.00 (2 H, t, J = 7.6 Hz), 7.08–7.17 [M + H]+ 206.0817, found 206.0809.
(2 H, m), 7.30 (1 H, ddd, J = 7.5, 6.6, 2.1 Hz), 7.35–7.44 (2 H,
(2S,3R)-3-(p-Trifluoromethylphenyl)pyroglutamic
acid
m), 7.50 (2 H, t, J = 7.5 Hz), 7.55–7.65 (3 H, m), 7.93–8.04 (4 H, (29). Yield 93%; m.p. 172.0–172.5 °C; [α]2D5 = +76.0 (c 1.0,
m), 8.26 (1 H, d, J = 8.5 Hz). 13C NMR (75.5 MHz, CDCl3): CHCl3); lit.17b {[α]2D5 = +73.3 (c 1.3, CHCl3)}. H NMR (CD3OD):
1
δ 29.2, 35.6, 36.5, 40.5, 45.3, 47.9, 57.4, 57.9, 69.6, 72.8, 120.7, δ 2.48 (1 H, dd, J = 17.0, 6.6 Hz), 2.88 (1 H, dd, J = 17.0, 9.3
123.2, 125.5, 126.5, 126.6, 127.3, 127.4, 127.6, 128.0, 128.1, Hz), 3.82 (1 H, ddd, J = 9.3, 6.0, 5.6 Hz), 4.27 (1 H, d, J = 5.4
128.2, 128.3, 128.5, 128.6, 129.0, 129.1, 129.9, 132.8, 133.2, Hz), 7.55, 7.66 (4 H, d, J = 8.3 Hz). 19F NMR (CD3OD): δ −65.5
133.5, 133.7, 133.8, 136.3, 138.5, 143.0, 153.2, 170.1, 170.7, (3 F, s). 13C NMR (CD3OD): δ 39.2, 45.4, 64.1, 126.9 (q, J = 4.0
176.4, 177.1 (the CF3 peak was obscured due to low intensity). Hz), 126.7, 128.8, 148.1, 174.5, 179.2. HRMS: calcd for
19F NMR (376.4 MHz, CDCl3): δ −62.1 (s, 3F). HRMS: calcd for C12H11F3NO3 [M + H]+ 274.0691, found 274.0691.
C46H44F3N4O6Ni [M + H]+ 863.2566, found 863.2564.
(2S,3R)-3-(p-Methoxyphenyl)pyroglutamic acid (30). Yield
Ni(II) complex of (2S,3R,4″S)-3(4′-methoxyphenyl)-5-[3″-(4″- 90%; m.p. 184.0–186.0 °C; [α]D25 = +85.9 (c 1.0, CHCl3); lit.17b
phenyl-2″-oxazolidinonyl)]glutamic acid Schiff base with N- {[α]2D5 = +87.1 (c 1.6, CHCl3)}. 1H NMR (CD3OD): δ 2.41 (1 H,
(2-benzoylphenyl)-2-((adamant-1-yl)amino)acetamide (27b). dd, J = 17.2, 6.0 Hz), 2.81 (1 H, dd, J = 17.1, 9.3 Hz), 3.64 (1 H,
1
[α]2D5 = +1576.2 (c 0.061, CHCl3). H NMR (300 MHz, CDCl3): δ ddd, J = 9.4, 6.0, 5.1 Hz), 3.76 (3 H, s), 4.16 (1 H, d, J = 5.1 Hz),
1.64 (6 H, br), 1.69 (1 H, d, J = 6.8 Hz), 1.87 (6 H, br), 2.11 (3 H, 6.90, 7.23 (4 H, d, J = 8.8 Hz). 13C NMR (CD3OD): δ 39.5, 45.1,
br), 3.10–3.33 (3 H, m), 3.42 (1 H, dd, J = 17.8, 8.0 Hz), 3.71 (1 55.7, 64.8, 115.3, 129.1, 135.7, 160.2, 179.8, 179.9. HRMS:
H, dd, J = 17.8, 7.0 Hz), 3.92 (3 H, s), 4.16 (1 H, dd, J = 8.8, 3.6 calcd for C12H14NO4 [M + H]+ 236.0923, found 236.0921.
Hz), 4.41 (1 H, d, J = 4.9 Hz), 4.59 (1 H, t, J = 8.7 Hz), 5.18 (1 H,
dd, J = 8.6, 3.6 Hz), 6.75–6.84 (2 H, m), 6.98–7.04 (3 H, m), 7.11
(2 H, d, J = 8.7 Hz), 7.25–7.40 (8 H, m), 7.46 (1 H, t, J = 7.5 Hz),
Acknowledgements
7.56 (1 H, t, J = 7.0 Hz), 8.24 (1 H, d, J = 8.3 Hz, 1H). 13C NMR
(75.5 MHz, CDCl3): δ 29.3, 35.7, 36.5, 40.6, 44.2, 48.7, 55.5, We thank IKERBASQUE, Basque Foundation for Science;
57.4, 57.9, 69.6, 72.4, 113.9, 120.7, 123.1, 125.7, 127.3, 127.5, Basque Government (SAIOTEK S-PE12UN044), Spanish Minis-
128.2, 128.7, 129.9, 130.7, 131.5, 132.7, 133.6, 133.8, 138.8, try of Science and Innovation (CTQ2010-19974) and Hamari
142.8, 153.2, 159.6, 170.0, 170.4, 176.4, 177.2. HRMS: calcd for Chemicals (Osaka, Japan) for generous financial support. We
C46H47N4O7Ni [M + H]+ 825.2798, found 825.2797.
also thank SGIker (UPV/EHU) for HRMS analyses.
General procedure for the disassembly of complexes
(S)(2S,3R)-21d, 26a, 27a
Notes and references
To a suspension of complex 21d, 26a or 27a (10 mmol) in
MeOH (40 mL), a mixture of 3 N HCl and MeOH (80 mL, ratio
1/1) was added with stirring at 70 °C. Red color of the reaction
mixture gradually disappeared (∼2 h) indicating complete
decomposition of the Ni(II) complexes. The reaction mixture
was evaporated in vacuo to dryness. Water (75 mL) and conc.
NH4OH were added to the crystalline residue to obtain a trans-
parent solution which was extracted with CH2Cl2 (3 × 50 mL).
The CH2Cl2 extracts were dried over MgSO4 and evaporated in
vacuo to afford a 1 : 1 mixture (∼96%) of chiral auxiliary (S)-31
and ligands 8d or 9. The aqueous solution was evaporated
in vacuo, dissolved in a minimum amount of water, and
loaded on a column with cation exchange resin Dowex 50X2
100. The column was washed with water and the target pyro-
glutamic acids 28–30 were collected in an acidic fraction. Evap-
oration of water and drying in vacuo of the crystalline residue
afforded amino acids of at least 95% chemical purity. For
analytical purpose products 28–30 were recrystallized from
THF–n-hexane (1 : 5).
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