Chemical Dynamic Thermodynamic Resolution and S/R Interconversion of Unprotected Unnatural Tailor-made α-Amino Acids

Article abstract of DOI:10.1021/acs.joc.5b01292

Described here is an advanced, general method for purely chemical dynamic thermodynamic resolution and S/R interconversion of unprotected tailor-made α-amino acids (α-AAs) through intermediate formation of the corresponding nickel(II)-chelated Schiff bases. The method features virtually complete stereochemical outcome, broad substrate generality (35 examples), and operationally convenient conditions allowing for large-scale preparation of the target α-AAs in enantiomerically pure form. Furthermore, the new type of nonracemizable axially chiral ligands can be quantitatively recycled and reused, rendering the whole process economically and synthetically attractive.

Full text of DOI:10.1021/acs.joc.5b01292

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Featured Article
Chemical Dynamic Thermodynamic Resolution and S/R Interconversion
of Unprotected Unnatural Tailor-Made alpha-Amino Acids
Shuni Wang, Shengbin Zhou, Jiang Wang, Yong Nian, Aki Kawashima, Hiroki
Moriwaki, José L. Aceña, Vadim Anatolievich Soloshonok, and Hong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01292 • Publication Date (Web): 09 Sep 2015
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The Journal of Organic Chemistry
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Chemical Dynamic Thermodynamic Resolution
and S/R Interconversion of Unprotected Unnatural
Tailor-Made α-Amino Acids
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Shuni Wang,† Shengbin Zhou,† Jiang Wang,† Yong Nian,† Aki Kawashima,‡ Hiroki Moriwaki,‡ José
L. Aceña,§ Vadim A. Soloshonok,*,§,ǁ and Hong Liu*,†
†CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
‡Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024, Japan
§Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country
UPV/EHU, Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain
ǁIKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza Bizkaia, 48011
Bilbao, Spain
hliu@simm.ac.cn (Hong Liu)
vadym.soloshonok@ehu.es (Vadim A. Soloshonok)
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Abstract
Described here is an advanced, general method for purely chemical dynamic thermodynamic
resolution (DTR) and S/R interconversion of unprotected tailor-made α-amino acids (α-AAs) through
intermediate formation of the corresponding nickel(II)-chelated Schiff bases. The method features
virtually complete stereochemical outcome, broad substrate generality (35 examples) and
operationally convenient conditions allowing for large-scale preparation of the target α-AAs in
enantiomerically pure form. Furthermore, the new type of non-racemizable axially chiral ligands can
be quantitatively recycled and reused, rendering the whole process economically and synthetically
attractive.
Introduction
Interest in the development of new methods for preparation of tailor-made α-amino acids (α-AAs)
in enantiomerically pure form is at an all-time high, because of their ever-increasing applications in
pharmaceutical and healthcare industries.1,2 In particular, the area of peptide-based drugs is the most
promising and fast-growing sector in the new pharmaceuticals design. Currently, substitution of a
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The Journal of Organic Chemistry
natural α-AA by an unnatural, tailor-made analog in polypeptide drugs is a widely used approach to
overcome the disadvantages related to poor chemical and pharmacokinetic profiles of natural
polypeptides. High pharmaceutical potential of unnatural, tailor-made α-AAs can be best illustrated
using examples of the most recently developed very successful drugs. For instance, telaprevir (1)
(Figure 1) is the all-tailor-made α-AAs tetra-peptide possesses remarkably strong anti-HCV
activity.3 Degarelix (2), the poly-peptide containing six key tailor-made α-AA residues, is an
exceptionally selective gonadotrophin releasing hormone (GnRH) receptor antagonist, prescribed for
the treatment of advanced prostate cancer.4 Both drugs were developed starting form all-natural AAs
peptides using tailor-made α-AA scan approach. Another notable example of a powerful
peptide-based drug is carfilzomib (3), which was developed from the natural product epoxomicin.5
Substitution of phenylalanine for tailor-made homophenylalanine resulted in a remarkable activity of
3 as chymotrypsin-like protease inhibitor. Furthermore, besides peptide-based drugs, there are a
number of important small-molecular-weight drugs containing fragments of tailor-made α-AAs, for
example, DDP-IV inhibitor saxagliptin (4) and antiepileptic agent lacosamide (5) (Figure 1).6,7
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Figure 1. Structures of current representative pharmaceuticals containing tailor-made α-AAs.
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Considering the pharmaceutical potential of unnatural, tailor-made α-AAs, the development of
new approaches for preparation of structurally varied AAs in enantiomerically pure form has been
one of the most actively studied areas of organic synthesis.8,9 The current wealth of synthetic
methodology allows for preparation of virtually any structurally or stereochemically complex α-AAs.
On the other hand, the aspects of practicality and cost of target α-AAs have often been neglected
rendering the known chemical methods prohibitively expensive even for gram-scale preparations.10
Consequently, the cost-per-structure issue is currently the major key factor in the quality assessment
of a new synthetic method. Particularly, high yields and degree of stereocontrol accessible under
operationally convenient conditions, such as an easily maintainable temperature and the use of air-
and moisture-stable reagents, are unarguably essential requirements of a truly practical synthetic
method.11
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Considering the subject of preparation of enantiomerically pure α-AAs from the stand point of
practicality, it might be a general consensus that resolution of racemic α-AAs (rac-α-AAs), in
particular, dynamic resolution is the most economically feasible approach, including dynamic kinetic
resolution (DKR) and dynamic thermodynamic resolution (DTR). DKR of rac-α-AAs is mainly
dominated by the enzymatic approaches, while chemical methods, despite the intellectual brilliance
and reaction ingenuity, play a rather ornamental role. For example, state-of-the-art enzymatic
approach (Scheme 1) can involve up to three biocatalytic reactions including racemization, kinetic
resolution and deprotection stages.12 However, the whole process requires a purely chemical step for
proper protection of the starting rac-α-AAs 6.
Scheme 1. General biocatalytic approach for DKR of protected rac-α-AAs derivatives
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In the field of non-enzymatic, chemical DKR of rac-α-AAs,13,14 one of the outstanding methods is
a catalytic alcoholytic opening of oxazol-5(4H)-ones (Scheme 2).15 This approach makes use of very
high C-H acidity and reactivity of oxazolones 11, 12 allowing for quite efficient racemization and
catalytic ring opening under very mild conditions. This process also necessitates special preparation
of oxazolones 11, 12 and deprotection of the intermediate derivatives 14.
Scheme 2. An example of chemical approach for DKR of protected rac-α-AAs derivatives
Nevertheless, the direct dynamic resolution of unprotected α-AAs is difficult to realize, and there
are only two literature precedents based on the application of chiral ligands 15 and 16 can achieve
this (Figure 2).16 Both methods are purely chemical and make use of in situ formation of the
corresponding Schiff bases starting form unprotected α-AAs. While these reports have made a
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significant methodological breakthrough, the synthetic value of ligands 15 and 16 is rather limited
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Consistent with our longstanding interest in the development of synthetic methods for preparation
of tailor-made amino acids,17 we have been developed a modular approach to the design of new
ligands and the corresponding Ni(II)-complexes for general asymmetric synthesis of α- and β-AAs.18
One of the major breakthroughs in this research is the development of specially designed, axially
chiral ligands (S)- and (R)-17 (Figure 2) and their use for DTR of several natural proteinogenic
α-AAs based on thermodynamic equilibration of diastereomeric products.19-21 Here we report a
detailed account of our research on the application of (S)- and (R)-17 for general DTR of unprotected
rac-α-AAs. Furthermore, we demonstrate that ligands (S)- and (R)-17 can also be used for S/R
interconversion of unprotected α-AAs, underscoring synthetic range and flexibility of this approach.
In the present work we focus entirely on unnatural, tailor-made α-AAs of high pharmaceutical
potential. We demonstrate a remarkable generality of this method using 35 examples of
polyfunctional, structurally varied α-AAs and provide detailed mechanistic rationale for the
observed thermodynamically controlled stereochemical outcome. The chemical process presented in
this paper features virtually complete yields and diastereoselectivity, fully recyclable chiral ligands
(S)- and (R)-17 and operationally simple reaction conditions.
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Figure 2. Structural types of known 15, 16 and new 17 ligands for direct dynamic resolution of
unprotected α-AAs.
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Results and Discussion
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Synthesis of axially chiral ligands. Synthesis of ligands (S)- and (R)-17 (Scheme 3) is very
straightforward two-step process involving high-yielding reactions. First step, the acylation of
2-amino-5-chlorobenzophenone 18 with bromoacetyl bromide 19, is conducted at ambient
temperature affording the intermediate amide 20 in high yield. The second step consists of selective
N-alkylation of enantiomerically pure axially chiral secondary amine 21 which proceeds at room
temperature with quantitative yield. Enantiomerically pure amines (S)- and (R)-21 can be reliably
prepared on a large scale by resolution of inexpensive racemic 21 with L-(-)-tartaric acid.22 The
whole procedure is noticeably very simple, operationally convenient and can be reproduced on >300
g scale. For the large-scale synthesis, this route can be conducted as one-pot process without
purification of amide 20 affording ligands (S)- and (R)-17 of, at least, 85% chemical purity, which
can be directly used for the DTR or S/R interconversion of tailor-made α-AAs.
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Scheme 3. Synthesis of axially chiral ligands (S)- and (R)-17
Application of ligands (S)- and (R)-17 for DTR of tailor-made rac-α-AAs. With the aim to
optimize the reaction conditions and understand the mode of stereochemical preferences, we
conducted a series of experiments carefully monitoring the reaction composition over time using
HPLC analysis. As a representative example, we selected multifunctional rac-6-Cl-tryptophan 22a
(Figure 3). The reaction between ligand (R)-17 and unprotected rac-22a was conducted in methanol
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o
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at 40 C, using Ni(OAc)2 4H2O and K2CO3 as a base. As one can see from Figure 3, on the early
reaction stage the ratio between diastereomers (Ra)(Sc)-23a and (Ra)(Rc)-23a was about 3:1,
indicating rather low kinetic stereoselectivity. However, with the reaction progress over time, the
amount of major diastereomer (Ra)(Sc)-23a was rapidly increasing while the quantity of minor
stereoisomer (Ra)(Rc)-23a was correspondingly decreasing. Thus, at nearly 90% conversion of
starting ligand (R)-17, the ratio (Ra)(Sc)-23a/(Ra)(Rc)-23a was about 9:1, clearly suggesting that the
former diastereomer is thermodynamically preferred product. Final thermodynamic control was
achieved after almost 48 h furnishing diastereomers (Ra)(Sc)-23a and (Ra)(Rc)-23a in a ratio of
99.54:0.46 (see Table S1 in the Supporting Information). Major product (Ra)(Sc)-23a was isolated in
diastereomerically pure form (>99% de) with excellent 97% yield. It can be reasonably assumed that
under the reaction conditions minor diastereomer (Ra)(Rc)-23a undergoes base-catalyzed
α-epimerization, via the corresponding intermediate enolate, to form the thermodynamic product
(Ra)(Sc)-23a (see Figure S1 in the Supporting Information).
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%
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(Ra,Rc)-23a
(R)-17
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Figure 3. Reaction of ligand (R)-17 with rac-6-Cl-tryptophan 22a.
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Additional optimization of the reaction conditions revealed that the thermodynamic control can be
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considerably accelerated at elevated temperatures; in particular, 70 C was found most optimal, as
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virtually no byproducts were detected in the crude reaction mixture. Furthermore, we found that only
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10% excess of both the rac-α-AA and Ni(OAc)2 4H2O is needed for optimal reaction rates and
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complete consumption of the starting ligand (R)-17. Using these standard conditions, we advanced to
the substrate generality study and the most representative results are collected in Table 1.
Table 1. DTR of unprotected tailor-made rac-α-AAs 22a-dd with axially chiral ligand (S)- or
(R)-17a
23
Entry
t (h)
17
22
yield (%)b
drc
99:1
98:2
96:4
97:3
>99:1
94:6
94:6
91:9
>99:1
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2
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
97
95
70
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77
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98
99
99
2
12
6
(a)
2-Br-benzyl (b)
2-MeO-benzyl (c)
2-OH-benzyl (d)
2-CN-benzyl (e)
3-Br-benzyl (f)
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4
3
5d
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5
12
3
7
3-OH-benzyl (g)
3-MeO-benzyl (h)
4-Br-benzyl (i)
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12
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12d
13d
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(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(R)
(R)
(S)
(R)
(S)
4-Cl-benzyl (j)e
4-F-benzyl (k)
99
99
92
78
98
98
92
97
97
62
98
98
99
97
99
99
97
99
96
88
98
99:1
99:1
12
12
6
1
2
3
4
5
6
7
8
4-CF3-benzyl (l)
4-acetyl-benzyl (m)
94:6
93:7
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>99:1
97:3
24
24
15
9
(n)
1,1'-biphenyl (o)
>99:1
>99:1
>99:1
99:1
(p)
(q)
(r)
7
5
(s)
allyl (t)
97:3
2
93:7
2
(u)
(v)
98:2
36
24
2
(w)f
>99:1
94:6
n-propyl (x)
n-butyl (y)e
n-hexyl (z)
93:7
2
92:8
2
96:4
2
(aa)
c-butyl (bb)e
96:4
2
t-butyl (cc)
phenyl (dd)
70:30
86:14
2
5
a
Reaction conditions: (S)-17 or (R)-17 (0.176 mmol), rac-α-AAs 22 (0.194 mmol),
.
Ni(OAc)2 4H2O (0.194 mmol), K2CO3 (1.06 mmol) were refluxed in methanol (6 mL) at 70
oC for 2-36 hrs. b Combined yield of isolated product 23. c Determined by LC/MS analysis of
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d
the crude reaction mixtures. Reactions rate was relatively high; therefore the reactions were
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conducted at 40 C. The reaction was performed with 500mg of ligand (S)-17 for the
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following disassembly process. The reaction was reproduced on large-scale starting with 10
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g of ligand (S)-17 (97% yield, >99:1 dr).
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Phenylalanine (Phe) derivatives represent one of the most frequently used types of tailor-made
α-AAs for modification of natural peptides.4,5 Therefore, we decided to study relatively large series
of various phenylalanine derivatives rac-22b-m. The reactions of ligand (S)-17 with unprotected
ortho-substituted phenylalanines rac-22b-e gave rise to products (Sa)(Rc)-23 with very good
stereochemical outcome (entries 2-5). The level of diastereoselectivity, ranging from 92 to 99% de,
was rather in the line with the optimized reaction (entry 1). On the other hand, the variable yields
may be attributed to generally lower reaction rates due to the steric effect of the ortho-substituents.
Quite agreeably with assumption, the yields obtained in the reactions of ligand (S)-17 with
meta-substituted derivatives rac-22f-h were truly excellent; albeit the diastereoselectivity was a bit
lower (entries 6-8). Virtually quantitative yields were obtained also in the reactions of
para-substituted phenylalanines rac-22i-m with ligand (S)-17 (entries 9-13), with an exception of
para-acetyl group containing rac-22m (78%, entry 13). In this case the lower yield might be
explained by rather special physicochemical properties of the products due to very polar nature of
acetyl moiety. Importantly, in this series of tailor-made phenylalanine derivatives neither electronic
nor steric properties of the substituents did not show any apparent effects on the stereochemical
outcome of the reactions. In particular, we would like to mention excellent stereochemical outcome
observed in the reactions of ligand (S)-17 with rac-22d,g (entries 4, 7), bearing free hydroxyl group,
which usually require proper protection in the corresponding enzymatic methods. Another example
worth mentioning is the DTR of para-Cl-phenylalanine rac-22j, used in the design of degarelix (2)
(Figure 1).4 Using our method this α-AA can be prepared quite efficiently (yield 99% with 98% de;
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entry 10) in both enantiomeric forms.
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Another structural group of α-AAs used in this study are poly-aromatic derivatives represented by
β-naphthylalanine rac-22n, used in the design of degarelix (2) (Figure 1)4 and
para-(phenyl)-phenylalanine rac-22o (entries 14, 15). The corresponding reactions with ligand
(S)-17 proceeded with excellent stereochemical outcome allowing preparation of target products
(Sa)(Rc)-23n,o in diastereomerically pure form with 98% yield. Tailor-made α-AAs containing
aromatic heterocyclic moieties are usually quite formidable targets, but they are in a great demand as
key structural features in the peptide-base drugs design.4 To explore this special structural type, we
selected four α-AAs rac-22p-s and performed their reactions with both (S)- and (R)-17. The results
obtained were exceptionally good in terms of both diastereoselectivity and chemical yields (entries
16-19). One more unusual and synthetically challenging structural type of tailor-made α-AAs is
represented by allyl group containing rac-22t,u (entries 20, 21). Gratifyingly, we found that the
reactions of unprotected rac-22t,u with ligand (R)-17 proceeded quite smoothly affording products
(Ra)(Sc)-23t,u with excellent stereochemical outcome. Another relatively large group of tailor-made
α-AAs studied in this work, represents aliphatic derivatives containing various linear as well as
sterically constrained cyclic fragments. For example, unprotected rac-22v,w (entries 22, 23), bearing
cyclo-propyl and –hexyl rings, reacted with (S) configured ligand 17 exceptionally well, furnishing
major diastereomers (Sa)(Rc)-23v,w with excellent yields and stereoselectivity. On the other hand,
the reactions of α-AAs rac-22x-z, bearing linear alkyl groups (entries 24-26), and rac-22aa,
possessing phenethyl moiety (entry 27), also gave satisfactory yields and stereoselectivity. Of
particular interest was the reaction of α-AA rac-22bb containing sterically constrained cyclo-butyl
ring (entry 28). The outcome was quite satisfactory affording diastereomer (Sa)(Rc)-23bb in very
good yield and diastereomeric excess. Finally, we believe it is very important to mention a few less
successful results pointing to some limitations of this method. For example, the reaction of sterically
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bulky rac-tert-leucine 22cc with ligand (R)-17 proceeded at slow rate and with far form incomplete
thermodynamic control (entry 29). On the other hand, rac-phenylglycine 22dd (entry 30) reacted
with ligand (S)-17 at rather good rate but with noticeably lower diastereoselectivity. Taking
advantage of the nearly perfect stereochemical outcome in the case of cyclo-hexane containing AA
rac-22w (entry 23), we performed large-scale experiment using 10 g of the starting ligand (S)-17.
The reaction proceeded without any complication furnishing diastereomerically pure (Sa)(Rc)-23w
with 94% isolated yield.
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To conclude this part of the study, we would like to emphasize that axially chiral ligands (S)- and
(R)-17 were evidently proven to be very efficient reagents for direct DTR of various unprotected
tailor-made rac-α-AAs. In the most of cases reported in Table 1, the reactions took place under
operationally convenient conditions affording the major products with synthetically valuable
diastereoselectivity and chemical yields. It should be mentioned that due to the significant
differences in physicochemical properties between major (Sa)(Rc)-23 and minor (Sa)(Sc)-23
diastereomers the purification of the former can be readily achieved by recrystallization or regular
gravity-driven column chromatography.
Application of ligands (S)- and (R)-17 for S/R interconversion of tailor-made α-AAs. Inspired
by the exciting results obtained for the DTR of tailor-made rac-α-AAs, we decided to explore an
additional methodological opportunity such as S/R interconversion of α-AAs. Compared to the DTR
of rac-α-AAs, conversion of (S)-α-AAs to (R) enantiomers and vice versa, is obviously of much
lesser general use for production of enantiomerically pure α-AAs. However, in some cases, such as
utilization of undesired enantiomers, availability of the S/R-interconversion method can be of critical
practical importance. Furthermore, a synthetic concept allowing the use of the same chiral ligands,
reagents and even conditions to pursue simply by choice either DTR or S/R interconversion, has
never been realized to date. Thus, the obvious novelty of this idea was an additional motivation to
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conduct the present study.
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As we did in the research on DTR, we decided to investigate first the reaction progress and the
chemical composition over time. As a model reaction, we chose (R)-6-Cl-tryptophan 22a as the
expected products (Ra)(Sc)-23a and (Ra)(Rc)-23a were already characterized and monitored by HPLC
(Table S2). The reaction of (R)-22a with ligand (R)-17 was conducted under the standard conditions:
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o
heating reagents in methanol at 40 C. Composition of starting ligand (R)-17 and products
(Ra)(Sc)-23a and (Ra)(Rc)-23a were carefully monitored by HPLC analysis; the results are presented
in Figure 4.
% 100
90
80
70
(Ra,Sc)-23a
60
(Ra,Rc)-23a
(R)-17
50
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10
0
0
5
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30
35
hrs
Figure 4. Reaction of ligand (R)-17 with (R)-22a; progress and stereochemical outcome over time.
As expected, diastereomer (Ra)(Rc)-23a was a kinetic product on the early reaction stage. From the
data obtained, it was apparently clear that the rate of (Ra)(Rc)-23a formation was a bit faster than the
rate of its based-catalyzed α-epimerization (via intermediate enolate) to form the thermodynamic
product (Ra)(Sc)-23a, rendering (Ra)(Rc)-23a as a major product until about 50% consumption of the
starting ligand (R)-17. However, quite rapidly the relative amounts of (Ra)(Rc)-23a were gradually
decreasing, while diastereomer (Ra)(Sc)-23a became a major product after about 1.5 h of the reaction
time. Ultimately, after 33 h under full thermodynamic control, kinetic (Ra)(Rc)-23a was virtually
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completely transformed to (Ra)(Sc)-23a with the final ratio of 99.63:0.37 (see Table S2 in the
Supporting Information).
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With these data in hand, we next proceeded to study the substrate generality of S/R-interconversion
method; some selected results are presented in Table 2.
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Table 2. S/R Interconversion of unprotected tailor-made α-AAs using ligand (S)- or (R)-17a
23
t
(h)
2
Entry
17
22
yield (%)b
drc
1
2
3
4
5
(R)
(S)
(S)
(S)
(R)
(R)
(S)
(S)
(S)
(R)
97
98
99
98
97
99:1
(a)
(a)
>99:1
>99:1
>99:1
97:3
2
4-Cl-benzyl (j)
4-CH3-benzyl (ee)
3,4-di-F-benzyl (ff)
2
4
7
6
(S)
(S)
99
90:10
28
(gg)
(hh)e
7
8d
9
(R)
(R)
(S)
(R)
(R)
(S)
88
97
99
97:3
93:7
94:6
7
8
4
propargyl (ii)
n-butyl (y)
a
Reaction conditions: (S)-17 or (R)-17 (0.176 mmol), (S)- or (R)-α-AAs 22 (0.194 mmol),
.
Ni(OAc)2 4H2O (0.194 mmol), K2CO3 (1.06 mmol) were refluxed in methanol (6 mL) for 2-28
b
c
hrs. Combined yield of isolated product 23. Determined by LC/MS analysis of the crude
d
o
e
reaction mixtures. Reactions conducted at 40 C. The reaction was performed with 500mg of
ligand (R)-17 for the following disassembly process.
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First, we reproduced the described above procedure using optically pure AA 22a and ligand 17 of
both opposite absolute configurations. The reaction of ligand (S)-17 with (S) configured 22a gave
virtually identical stereochemical outcome allowing preparation of product (Sa)(Rc)-23a with
virtually complete chemical yield and diastereoselectivity (entry 1 vs. 2). Similarly excellent results
were obtained in the reactions of 4-Cl-Phe (S)-22j (entry 3) and 4-Me-Phe (S)-22ee (entry 4) with
ligand (S)-17 furnishing diastereomerically pure products (Sa)(Rc)-23j,ee. Interesting example of
disubstituted derivative, 3,4-difluoro-Phe 22ff is presented in entry 5. In this case the reaction of
(R)-22ff with (R)-17 resulted in a complete inversion of the α-configuration giving rise to complex
(Ra)(Sc)-23ff with excellent yield and stereoselectivity. Sterically bulky β-Ph-Phe (S)-22gg reacted
with ligand (S)-17 at relatively high rate, however, the diastereoselectivity was less than expected
(entry 6). Three more examples featuring (R)-to-(S) conversion of thienylalanine (R)-22hh (entry 7),
propargylglycine (R)-22ii (entry 8) and (S)-to-(R) transformation of n-butylglycine (S)-22y (entry 9)
provide some additional evidence of wide structural generality of this method.
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Disassembly of products 23, isolation of free amino acids 22 and recovery/reuse of chiral
ligands 17. To demonstrate the isolation of free α-AAs from products 23, we selected para-Cl-Phe
(R)-22j (Scheme 4) of known pharmaceutical importance4, quite interesting long-chain n-butyl
(R)-24y and sterically constrained cyclo-butyl (R)-24bb containing AAs, as well as an example of
heterocyclic thienylalanine (S)-22hh, representing both the DTR and S/R-interconversion approaches.
Disassembly of Ni(II) complexes of amino acid Schiff bases is usually conducted under acidic
conditions with an option to isolate the target free amino acid or conduct its N-derivatization in
situ.8h-k Taking advantage of truly exceptional stereochemical outcome (DTR approach; Table 1,
entry 10) obtained in preparation of (Sa)(Rc)-23j, we performed its disassembly without any
additional purification. Due to a relatively high solubility of Ni(II) complex (Sa)(Rc)-23j in methanol
(Scheme 4), its disassembly under the action of 6 N HCl occurred at very high rate affording
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enantiomerically pure (>99% ee) free (R)-4-Cl-phenylalanine 22j in excellent isolated yield (95%).
Similarly, diastereomerically pure Ni(II) complexes (Sa)(Rc)-23y, (Sa)(Rc)-23bb, obtained using DTR
and (Ra)(Sc)-23hh, using the S/R-interconversion approach, were disassembled to furnish free amino
acids (R)-22y, (R)-22bb and (S)-22hh in >90% yields.
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Scheme 4. Disassembly of (Sa)(Rc)-23j, y, bb and (Ra)(Sc)-hh: isolation of the target AAs (R)-22j,
y, bb and (S)-22hh, recycling, and reuse of the chiral ligands (S)-17 and (R)-17
DTR approach
(Sa)(Rc)-23j
6 N HCl/MeOH
(rac)- -AA 22j (1.1 equiv)
Ni(OAc)2.4H2O (1.1 equiv)
K2CO3 (6 equiv)
COOH
NH2
(R)-22j
95% yield; >99% ee
Cl
(S)-17
97% yield
(Sa)(Rc)-23y
6 N HCl/MeOH
(rac)- -AA 22y (1.1 equiv)
Ni(OAc)2.4H2O (1.1 equiv)
K2CO3 (6 equiv)
COOH
Cbz-OSU
COOH
NH2
NaHCO3
Na2CO3
NHCbz
(R)-24y
(R)-22y
(S)-17
90% yield;
>99% ee
93% yield
97% yield
(Sa)(Rc)-23bb
6 N HCl/MeOH
(rac)- -AA 22bb (1.1 equiv)
Ni(OAc)2.4H2O (1.1 equiv)
K2CO3 (6 equiv)
COOH
Cbz-OSU
COOH
NaHCO3
Na2CO3
NHCbz
NH2
(R)-22bb
(R)-24bb
(S)-17
95% yield
95% yield
91% yield;
>99% ee
S/R-interconversion
approach
(Ra)(Sc)-23hh
6 N HCl/MeOH
(R)- -AA 22hh (1.1 equiv)
Ni(OAc)2.4H2O (1.1 equiv)
K2CO3 (6 equiv)
COOH
S
NH2
(S)-22hh
96% yield; >99% ee
(R)-17
96% yield
It should be specially emphasized that along with the target AAs (R)-22j, y, bb and (S)-22hh,
ligands (S)-17 and (R)-17 were virtually quantitatively (>95% yield) recovered. Without any
additional purification ligands (S)-17 and (R)-17 can be successfully reused for DTR or S/R
interconversion of any target α-AA. One may agree that convenient recycling and reuse of the chiral
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ligands 17 render the present approach economically very attractive surpassing efficiency and
practicality of biocatalytic approaches.
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Assignment of the absolute configurations and rationale for the observed stereochemical
outcome. Absolute configuration of α-AA residues in products (Sa)(Rc)-23j, y, bb and (Ra)(Sc)-23hh
was made by comparison of the optical properties of isolated AAs (R)-22j, y, bb and (S)-22hh with
the literature data. Furthermore, we performed a crystallographic analysis of Ni(II) complex 23j,
confirming its (Sa)(Rc) configuration (see CIF and Figure S2 in the Supporting Information).
Stereochemistry of other products 23a-i, k-x, z-aa, cc-gg and ii was assigned based on their
matching spectroscopic and optical properties with complexes (Sa)(Rc)-23j, y, bb and (Ra)(Sc)-23hh.
Crystallographic structure of Ni(II) complex (Sa)(Rc)-23j, containing (R)-4-Cl-Phe moiety, has
several unexpected, rather unique features. First of all, what is quite striking, there are no any
stereochemical contacts between the chiral auxiliary’s bisnaphthyl frame and the amino acid residue.
What is evident from the structure is that the observed preference for the (R) absolute configuration
of the (R)-4-Cl-Phe moiety is not directly controlled by the chiral auxiliary. Another prominent
peculiarity of crystallographic structure of (Sa)(Rc)-23j is a notably severe twisting of the chelate
rings around the Ni(II). Thus, while the coordinating to Ni(II) three nitrogen and one oxygen atoms
are nearly perfectly coplanar, the chelate rings A, B, and C (Figure 5) are noticeably puckered out of
this plane. In particular, the ring A is puckered up above the plane showing the torsion angle
(N-Ni-N-CH2) of 36.10o. By contract, the ring B is puckered down out of this plane with torsion
angle (N-Ni-N-C) of -30.19o. Subsequently, the ring C is puckered up above the plane. As a result of
this sterically congested arrangement, the benzophenone phenyl ring is skewed by -70.65o and
located right below the chelate ring C. The distance between the phenyl ortho-hydrogen and the
hydrogen of amino acid C-H group is only 2.38 Å, strongly indicating that the position of
4-Cl-benzyl group up and away from the phenyl is the only stereochemically feasible option. Based
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on these structural features, one can assume the following mode of the observed stereocontrol. First,
the helical chirality of the bisnaphthyl moiety induces the chiral puckering of the three chelate rings
A, B, and C up and down the Ni(II) coordination plane. Second, the phenyl group of the ring B is
positioned underneath of the amino acid bearing ring C forcing the R substituent to be pointed in the
opposite direction, avoiding any repulsive stereochemical interactions. One might agree that this
type of indirect asymmetric induction is rather distinctive to these Ni(II) complexes.
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Figure 5. Mechanistic rationale for the observed stereochemical outcome in the DTR and
S/R-interconversion methods.
Conclusions
In summary, we have developed an advanced purely chemical DTR and S/R-interconversion
methods for preparation of tailor-made, unnatural α-AAs using novel axially chiral ligands (S)- and
(R)-17. These approaches can be used starting directly from unprotected α-AAs. All reactions can be
conducted under operationally convenient conditions with good-to-excellent chemical yields and
stereoselectivity (up to > 99:1). These methods show broad structural generality as demonstrated on
35 examples including various α-benzyl-, α-alkyl-, α-alkenyl, and α-heteroaryl-containing
tailor-made α-AAs. The source of chirality in the presented methods, specially designed chiral and
non-racemizable ligands (S)-17 and (R)-17, can be virtually completely recycled and reused for
continuous production of the target enantiomerically pure α-AAs. Overall, the operational ease of the
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presented methods coupled with structural generality and attractive stereochemical outcome bode
well for their widespread practical applications.
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Experimental Section
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General Information. The chemicals were purchased from commercial sources and used without
further purification. Analytical thin layer chromatography (TLC) was performed on HSGF 254
1
(0.15−0.2 mm thickness). All products were characterized by NMR and MS spectra. H and 13C
NMR spectra were recorded in deuterochloroform (CDCl3), dimethyl sulfoxide-d6 (DMSO-d6) or
deuterium oxide (D2O) on 400 or 500 MHz instrument. Chemical shifts were reported in parts per
million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns were described as
singlet (s), doublet (d), triplet (t), quartet (q), quintet (p), doublet of triplets (dt) and multiplet (m).
High-resolution mass spectra (HRMS) was measured on Q-TOF spectrometer. The determination of
dr was performed via LC/MS analysis. The determination of ee was performed via HPLC analysis or
UFLC analysis. Optical rotations were measured using a 1 mL cell with a 10 mm path length on
25
matic polarimeter and were reported as follows: [α]
(c: g/100 mL, in solvent). Melting points
D
were measured on melting point apparatus. All physicochemical data reported for the Ni(II)
complexes are due to the single diastereomer after purification by chromatography or crystallization.
General Procedure.
General Procedure for the Synthesis of (Ra)(Sc)-23a. To a suspension of (R)-17 (100 mg, 0.176
mmol, 1 equiv), rac-6-Cl-tryptophan 22a or (R)-6-Cl-tryptophan 22a (46 mg, 0.194 mmol, 1.1
.
equiv), Ni(OAc)2 4H2O (48 mg, 0.194 mmol, 1.1 equiv), K2CO3 (146 mg, 1.06 mmol, 6 equiv) were
refluxed in methanol (6 mL) at 70 oC for 2 hrs. After cooling, the mixture was diluted with icy 2.5%
aqueous acetic acid (25 mL), then extracted three times with dichloromethane. The combined
organic layers were dried with Na2SO4, and concentrated in vacuo. The crude reaction mixture was
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subjected to column chromatography on silica gel. Eluent PE: EA = 4:1 was used to remove the
residual ligand (R)-17, followed by using eluent DCM: MeOH = 20:1 to obtain the mixture of the
two diastereomers (Ra)(Sc)-23a and (Ra)(Rc)-23a (144 mg, yield 97%) for analysis (dr = 99:1). The
mixture was purified again by column chromatography on silica gel (DCM: MeOH = 80:1) to give
the major pure diastereomer (Ra)(Sc)-23a as a red solid.
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Large-scale Preparation of (Sa)(Rc)-23w.
To a suspension of (R)-17 (10.0 g, 17.6 mmol, 1 equiv), rac-cyclohexylalanine 22w (3.3 g, 19.4
.
mmol, 1.1 equiv), Ni(OAc)2 4H2O (4.8 g, 19.4 mmol, 1.1 equiv), K2CO3 (14.6 g, 106 mmol, 6 equiv)
were refluxed in methanol (100 mL) at 70 oC for 12 hrs. After cooling, the mixture was concentrated
in vacuo, then the residue was dissolved in dichloromethane, diluted with icy 2.5% aqueous acetic
acid (500 mL), and extracted three times with dichloromethane. The combined organic layers were
dried with Na2SO4, and concentrated in vacuo, then purified by column chromatography on silica gel
to give the crude products (Ra)(Sc)-23w and (Ra)(Rc)-23w (13.3 g, yield 97%) for analysis (dr > 99:1).
The crude products were purified again by recrystallization in ethanol to give the major pure
diastereomer (Ra)(Sc)-23w as a red solid (12.9g, yield 94%).
General Procedure for the Synthesis of (R)-22j. To a suspension of (Sa)(Rc)-23j (500 mg, 0.621
mmol, 1 equiv) in methanol (15 ml) was added 6 N HCl, and the whole was heated at 40 oC for 6 hrs.
The reaction mixture was concentrated to dryness upon disappearance of the red color of the starting
complex. The residue was added ethyl acetate (20 mL) and water (5 mL), stirred and separated. The
organic phase was extracted sequentially with 1 N HCl (4 mL) and water (4 mL). The resulting
organic phase was washed with saturated sodium hydrogen carbonate solution (5 mL), water (5 mL)
and brine (5 mL), dried with Na2SO4, and concentrated to afford the recovered (S)-17 (341 mg, yield
97%). The combined aqueous phase was evaporated in vacuo to the residue, which was dissolved in
methanol (4 ml) and separated by preparative performance liquid chromatography using Agilent
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1200 Series spectrometer with Eclipse XDB-C18 column (9.4 × 250 mm, 5ꢀm) (MeOH/H2O = 5/95,
λ= 214 nm, 5.0 mL/min) to afford pure (R)-22j as a white solid (118 mg, yield 95%).
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General Procedure for the Synthesis of (R)-22y. To a suspension of (Sa)(Rc)-23y (500 mg, 0.621
mmol, 1 equiv) in methanol (15 ml) was added 6 N HCl, and the whole was heated at 40 oC for 8 hrs.
The reaction mixture was concentrated to dryness upon disappearance of the red color of the starting
complex. The residue was added ethyl acetate (20 mL) and water (5 mL), stirred and separated. The
organic phase was extracted sequentially with 1 N HCl (4 mL) and water (4 mL). The resulting
organic phase was washed with saturated sodium hydrogen carbonate solution (5 mL), water (5 mL)
and brine (5 mL), dried with Na2SO4, and concentrated to afford the recovered (S)-17 (373 mg, yield
97%). The combined aqueous phase was evaporated in vacuo to the residue, which was re-dissolved
in a minimum amount deionized water and loaded on a Dowex 50×2 100 ion-exchange column.
Washed with deionized water until neutral, the column was then washed with 10% aq. NH4OH. The
first fraction (400 mL) was collected and evaporated under vacuum to afford (R)-22y as a white solid
(82mg, yield 93%).
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General Procedure for the Synthesis of (R)-24y. N-benzyloxycarbonyloxysuccinimide (114 mg,
0.457 mmol, 1 equiv) was dissolved in 1 ml acetone at 0 oC, which was added a solution of (R)-22y
(60 mg, 0.457 mmol, 1 equiv), sodium hydrogen carbonate (77 mg, 0.914 mmol, 2 equiv) and
sodium carbonate (49 mg, 0.457 mmol, 1 equiv) in water (3 ml) and acetone (1 ml). The whole was
stirred at room temperature for 12 hrs, then concentrated to remove the acetone. The residual
aqueous phase was acidified with 1 N HCl to pH 4, and then white solid was precipitated out. The
solid was collected by filtration to afford (R)-24y (109 mg, yield 90%, ee > 99%).
Analytical Characterization Data of Products.
Nickel(II)-(R)-17/(S)-6-Chloro-tryptophan Schiff Base Complex 23a: red solid (144 mg, yield
97%). mp 277.8−279.6 °C. [α]25D = +2134 (c 0.058, CHCl3). 1H NMR (400 MHz, CDCl3) δ 9.25 (s,
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The Journal of Organic Chemistry
1H), 8.52 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.3 Hz,
1H), 7.93 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 1.0 Hz, 1H), 7.72 (d, J = 8.5 Hz,
1H), 7.57 (m, 3H), 7.51 – 7.41 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.25 – 7.17 (m,
3H), 7.11 (dd, J = 8.6, 1.4 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 1.5 Hz, 1H), 6.77 (d, J =
2.5 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 4.16 (dd, J = 5.5, 1.5 Hz, 1H), 3.47 (s, 1H), 3.32 (d, J = 14.3
Hz, 1H), 3.26 (d, J = 15.8 Hz, 1H), 2.83 (d, J = 14.0 Hz, 1H), 2.68 (dd, J = 14.5, 6.2 Hz, 1H), 2.50 (d,
J = 15.3 Hz, 1H), 2.40 (d, J = 12.3 Hz, 1H), 1.49 (d, J = 14.4 Hz, 1H). 13C NMR (125 MHz,
DMSO-d6) δ 176.8, 173.5, 168.4, 141.5, 137.3, 135.3, 134.0, 133.4, 133.4, 132.4, 131.5, 131.5,
131.3, 130.6, 130.4, 130.3, 129.4, 129.1, 128.7, 128.6, 128.6, 128.5, 128.5, 128.1, 128.1, 127.9,
127.4, 126.9, 126.7, 126.7, 126.5, 126.3, 126.3, 125.4, 124.0, 121.4, 119.4, 111.4, 108.9, 79.2, 71.0,
64.8, 60.3, 59.8, 55.7, 29.1, 20.8, 14.1. HRMS (ESI) m/z: calcd for C48H34Cl2N4NiO3Na+ [M + Na]+:
865.1254, found: 865.1248. The dr was determined by LC/MS with an Eclipse XDB-C18 column
(4.6 × 150 mm, 5 ꢀm) (MeOH/H2O = 85/15, λ = 254 nm, 1.0 mL/min). tR (major diastereomer) =
15.530 min, tR (minor diastereomer) = 21.123 min, dr = 99:1.
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Nickel(II)-(S)-17/(R)-2-Bromophenylalanine Schiff Base Complex 23b: red solid (142 mg,
1
yield 95%). mp 233.5−235.1 °C. [α]25 = -2230 (c 0.044, CHCl3). H NMR (400 MHz, CDCl3) δ
D
8.59 (d, J = 8.1 Hz, 1H), 8.45 (d, J = 9.1 Hz, 1H), 8.22 – 8.03 (m, 2H), 8.01 – 7.87 (m, 3H), 7.68 –
7.40 (m, 10H), 7.40 – 7.16 (m, 6H), 6.75 (d, J = 2.2 Hz, 1H), 4.57 (d, J = 12.4 Hz, 1H), 4.24 (t, J =
2.7 Hz, 1H), 3.85 (d, J = 15.4 Hz, 1H), 3.19 (dd, J = 14.0, 4.8 Hz, 2H), 3.07 (dd, J = 13.8, 3.5 Hz,
1H), 2.76 (d, J = 15.3 Hz, 1H), 2.69 (d, J = 13.9 Hz, 1H), 2.53 (d, J = 12.5 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 176.4, 173.4, 170.2, 141.1, 136.5, 135.5, 134.8, 133.7, 133.6, 133.2, 133.1, 132.3,
132.2, 132.1, 131.0, 130.7, 130.6, 129.9, 129.1, 128.9, 128.8, 128.8, 128.6, 128.2, 128.2, 128.1,
128.0, 128.0, 127.4, 127.0, 126.9, 126.5, 126.0, 126.0, 125.4, 124.7, 72.0, 65.6, 61.0, 57.2, 38.0.
+
HRMS (ESI) m/z: calcd for C46H34BrClN3NiO3 [M + H]+: 848.0820, found: 848.0811. The dr was
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determined by LC/MS with an Eclipse XDB-C18 column (4.6 × 150 mm, 5 ꢀm) (MeOH/H2O =
80/20, λ = 254 nm, 1.0 mL/min). tR (major diastereomer) = 33.869 min, tR (minor diastereomer) =
54.419 min, dr = 98:2.
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Nickel(II)-(S)-17/(R)-2-Methoxyphenylalanine Schiff Base Complex 23c: red solid (99 mg,
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yield 70%). mp 211.1−212.0 °C. [α]25 = -1223 (c 0.056, CHCl3). H NMR (400 MHz, CDCl3) δ
D
8.71 (d, J = 8.2 Hz, 1H), 8.32 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.99 – 7.89 (m, 3H), 7.79
(t, J = 7.4 Hz, 1H), 7.59 – 7.44 (m, 6H), 7.40 (d, J = 8.3 Hz, 1H), 7.36 – 7.29 (m, 3H), 7.29 – 7.18
(m, 5H), 7.09 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H), 4.52 (d, J = 12.2 Hz, 1H), 4.14 – 4.07 (m,
1H), 3.63 (d, J = 15.3 Hz, 1H), 3.37 (s, 3H), 3.21 (dd, J = 13.7, 6.1 Hz, 2H), 2.85 (d, J = 14.0 Hz,
1H), 2.66 (dd, J = 13.3, 1.9 Hz, 1H), 2.60 (d, J = 15.3 Hz, 1H), 2.38 (d, J = 12.2 Hz, 1H). 13C NMR
(125 MHz, CDCl3) δ 177.8, 174.3, 170.3, 159.0, 141.1, 136.0, 135.2, 134.0, 133.7, 133.7, 133.1,
132.2, 132.2, 131.5, 131.2, 131.1, 130.2, 129.4, 129.4, 129.2, 129.1, 129.0, 128.9, 128.6, 128.5,
128.4, 127.9, 127.7, 127.4, 127.4, 127.1, 126.5, 126.4, 126.3, 125.8, 125.4, 125.1, 121.3, 110.3, 72.6,
65.9, 61.5, 57.6, 54.8, 33.2. HRMS (ESI) m/z: calcd for C47H36ClN3NiO4Na+ [M + Na]+: 822.1640,
found: 822.1630. The dr was determined by LC/MS with an Eclipse XDB-C18 column (4.6 × 150
mm, 5 ꢀm) (MeOH/H2O = 80/20, λ = 254 nm, 1.0 mL/min). tR (major diastereomer) = 37.472 min,
tR (minor diastereomer) = 65.897 min, dr = 96:4.
Nickel(II)-(S)-17/(R)-2-Hydroxyphenylalanine Schiff Base Complex 23d: red solid (136 mg,
1
yield 98%). mp 246.2−247.9 °C. [α]25 = -2186 (c 0.050, CHCl3). H NMR (400 MHz, CDCl3) δ
D
8.56 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H),
7.92 (d, J = 8.1 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.59 – 7.41 (m, 8H), 7.38 – 7.27 (m, 4H), 7.25 –
7.18 (m, 4H), 6.74 (d, J = 2.5 Hz, 1H), 4.55 (d, J = 12.1 Hz, 1H), 4.19 (dd, J = 5.0, 2.7 Hz, 1H), 3.74
(d, J = 15.7 Hz, 1H), 3.17 (d, J = 14.0 Hz, 1H), 3.10 (dd, J = 13.5, 5.2 Hz, 1H), 2.87 (d, J = 14.1 Hz,
1H), 2.75 – 2.63 (m, 2H), 2.53 (d, J = 12.2 Hz, 1H), 1.99 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ
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The Journal of Organic Chemistry
176.1, 173.6, 169.0, 157.3, 141.6, 135.6, 135.5, 134.1, 134.1, 133.5, 132.7, 132.6, 132.5, 131.7,
131.6, 131.2, 131.1, 130.7, 130.5, 130.4, 130.1, 129.4, 129.1, 128.9, 128.8, 128.8, 128.6, 128.5,
128.4, 128.3, 127.9, 127.4, 126.7, 126.5, 126.3, 126.2, 125.4, 123.8, 122.7, 119.5, 115.3, 71.5, 65.3,
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8
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60.5, 56.4, 32.4. HRMS (ESI) m/z: calcd for C46H35ClN3NiO4 [M + H]+: 786.1664, found: 786.1667.
+
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The dr was determined by LC/MS with an Eclipse XDB-C18 column (4.6 × 150 mm, 5 ꢀm)
(MeOH/H2O = 80/20, λ = 254 nm, 1.0 mL/min). tR (major diastereomer) = 29.411 min, tR (minor
diastereomer) = 51.382 min, dr = 97:3.
Nickel(II)-(S)-17/(R)-2-Cyanophenylalanine Schiff Base Complex 23e: red solid (108 mg,
1
yield 77%). mp 240.8−242.0 °C. [α]25 = -1743 (c 0.044, CHCl3). H NMR (400 MHz, CDCl3) δ
D
8.58 (d, J = 8.3 Hz, 1H), 8.50 (d, J = 9.1 Hz, 1H), 8.13 – 8.07 (m, 2H), 7.94 (t, J = 8.2 Hz, 3H), 7.85
(t, J = 7.5 Hz, 1H), 7.80 (t, J = 7.1 Hz, 1H), 7.61 – 7.39 (m, 9H), 7.34 – 7.19 (m, 5H), 6.75 (d, J =
2.3 Hz, 1H), 4.57 (d, J = 12.1 Hz, 1H), 4.29 (t, J = 4.1 Hz, 1H), 3.68 (d, J = 15.2 Hz, 1H), 3.19 (d, J
= 14.0 Hz, 1H), 3.16 – 3.05 (m, 2H), 2.76 (d, J = 15.3 Hz, 1H), 2.65 (d, J = 13.9 Hz, 1H), 2.50 (d, J
= 12.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 176.1, 173.3, 171.6, 141.1, 140.2, 135.5, 134.9,
133.6, 133.3, 133.2, 132.6, 132.3, 132.2, 131.0, 130.7, 130.5, 130.0, 129.2, 128.9, 128.7, 128.2,
128.1, 128.0, 127.9, 127.8, 127.7, 127.4, 127.0, 126.9, 126.7, 126.5, 126.1, 126.0, 126.0, 125.5,
+
124.4, 117.8, 114.9, 71.4, 65.5, 61.0, 57.5, 37.4. HRMS (ESI) m/z: calcd for C47H34ClN4NiO3 [M +
H]+: 795.1667, found: 795.1686. The dr was determined by LC/MS with an Eclipse XDB-C18
column (4.6 × 150 mm, 5 ꢀm) (MeOH/H2O = 80/20, λ = 254 nm, 1.0 mL/min). tR (major
diastereomer) = 19.638 min, tR (minor diastereomer) = not found, dr > 99:1.
Nickel(II)-(S)-17/(R)-3-Bromophenylalanine Schiff Base Complex 23f: red solid (145 mg,
1
yield 97%). mp 236.5−238.4 °C. [α]25 = -2000 (c 0.048, CHCl3). H NMR (400 MHz, CDCl3) δ
D
8.65 (d, J = 8.2 Hz, 1H), 8.36 (d, J = 9.1 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.02 – 7.88 (m, 4H), 7.79
(s, 1H), 7.64 – 7.44 (m, 7H), 7.41 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.30 – 7.20 (m, 4H),
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7.18 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 6.69 (d, J = 1.7 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H),
4.22 (dd, J = 5.2, 2.7 Hz, 1H), 3.74 (d, J = 15.3 Hz, 1H), 3.31 (d, J = 14.0 Hz, 1H), 3.03 (d, J = 14.2
Hz, 1H), 2.99 (dd, J = 13.8, 2.2 Hz, 1H), 2.69 (d, J = 15.4 Hz, 1H), 2.53 (dd, J = 13.6, 5.7 Hz, 1H),
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2.49 (d, J = 12.4 Hz, 1H). C NMR (125 MHz, CDCl3) δ 176.8, 173.7, 169.7, 141.0, 138.5, 135.7,
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134.8, 133.7, 133.6, 133.2, 132.5, 132.3, 132.0, 131.1, 130.7, 130.7, 130.5, 130.1, 130.1, 129.9,
129.0, 129.0, 128.8, 128.7, 128.4, 128.1, 128.0, 127.6, 127.4, 127.1, 127.0, 126.9, 126.8, 126.6,
126.1, 126.0, 125.9, 125.9, 125.7, 124.7, 123.0, 71.1, 65.5, 61.2, 57.5, 38.0. HRMS (ESI) m/z: calcd
for C46H34BrClN3NiO3 [M + H]+: 848.0820, found: 848.0819. The dr was determined by LC/MS
+
with an Eclipse XDB-C18 column (4.6 × 150 mm, 5 ꢀm) (MeOH/H2O = 80/20, λ = 254 nm, 1.0
mL/min). tR (major diastereomer) = 32.911 min, tR (minor diastereomer) = 58.600 min, dr = 94:6.
Nickel(II)-(S)-17/(R)-3-Hydroxyphenylalanine Schiff Base Complex 23g: red solid (136 mg,
yield 98%). mp 242.1−243.0 °C. [α]25D = -2352 (c 0.048, CHCl3). 1H NMR (400 MHz, DMSO-d6) δ
9.78 (s, 1H), 9.23 (s, 1H), 8.37 (d, J = 9.1 Hz, 1H), 8.18 (d, J = 7.5 Hz, 2H), 8.11 (t, J = 9.7 Hz, 2H),
7.70 – 7.49 (m, 5H), 7.45 – 7.12 (m, 9H), 6.91 (s, 1H), 6.74 (d, J = 6.5 Hz, 2H), 6.23 (s, 1H), 4.55 (d,
J = 12.0 Hz, 1H), 3.89 (d, J = 15.0 Hz, 1H), 3.83 (s, 1H), 3.17 (d, J = 13.3 Hz, 1H), 3.03 (d, J = 13.9
13
Hz, 1H), 2.71 (d, J = 13.3 Hz, 1H), 2.46 – 2.31 (m, 2H), 2.08 (d, J = 10.8 Hz, 1H). C NMR (125
MHz, DMSO-d6) δ 176.1, 174.2, 169.1, 158.4, 142.1, 137.8, 136.0, 134.5, 134.0, 133.9, 132.8, 132.0,
131.7, 131.2, 130.9, 130.8, 130.2, 129.9, 129.6, 129.3, 129.2, 129.1, 129.1, 128.8, 128.4, 128.3,
127.8, 127.2, 127.1, 126.9, 126.9, 126.8, 126.7, 125.9, 124.5, 122.5, 118.4, 115.3, 71.7, 65.9, 61.0,
+
56.8, 38.7. HRMS (ESI) m/z: calcd for C46H35ClN3NiO4 [M + H]+: 786.1664, found: 786.1666. The
dr was determined by LC/MS with an Eclipse XDB-C18 column (4.6 × 150 mm, 5 ꢀm) (MeOH/H2O
= 85/15, λ = 254 nm, 1.0 mL/min). tR (major diastereomer) = 23.764 min, tR (minor diastereomer) =
32.856 min, dr = 94:6.
Nickel(II)-(S)-17/(R)-3-Methoxyphenylalanine Schiff Base Complex 23h: red solid (140 mg,
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The Journal of Organic Chemistry
1
yield 99%). mp 234.2−235.7 °C. [α]25 = -2142 (c 0.048, CHCl3). H NMR (400 MHz, CDCl3) δ
D
1
2
3
4
5
6
7
8
9
8.68 (d, J = 8.3 Hz, 1H), 8.37 (d, J = 9.1 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.99 – 7.92 (m, 3H), 7.62
– 7.44 (m, 6H), 7.43 – 7.30 (m, 4H), 7.28 – 7.21 (m, 3H), 7.18 (d, J = 7.4 Hz, 1H), 7.10 – 7.05 (m,
2H), 6.96 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H), 4.21 (dd, J = 5.3,
3.0 Hz, 1H), 3.84 (s, 3H), 3.78 (d, J = 15.3 Hz, 1H), 3.25 (d, J = 13.9 Hz, 1H), 3.00 (dd, J = 13.4, 2.7
Hz, 1H), 2.90 (d, J = 13.8 Hz, 1H), 2.63 (d, J = 15.2 Hz, 1H), 2.56 (dd, J = 13.5, 5.4 Hz, 1H), 2.45 (d,
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J = 12.3 Hz, 1H). C NMR (125 MHz, CDCl3) δ 177.1, 173.8, 169.3, 159.9, 140.9, 137.5, 135.6,
134.8, 133.6, 133.2, 132.4, 132.3, 131.9, 131.0, 130.7, 130.6, 130.0, 129.5, 129.0, 128.9, 128.8,
128.6, 128.4, 128.2, 128.0, 127.8, 127.5, 127.1, 127.0, 126.9, 126.6, 126.1, 125.9, 125.9, 125.6,
124.8, 123.5, 115.6, 113.9, 71.5, 65.5, 61.1, 57.1, 55.0, 38.6. HRMS (ESI) m/z: calcd for
+
C47H37ClN3NiO4 [M + H]+: 800.1821, found: 800.1827. The dr was determined by LC/MS with an
Eclipse XDB-C18 column (4.6 × 150 mm, 5 ꢀm) (MeOH/H2O = 85/15, λ = 254 nm, 1.0 mL/min). tR
(major diastereomer) = 30.174 min, tR (minor diastereomer) = 48.851 min, dr = 91:9.
Nickel(II)-(S)-17/(R)-4-Bromophenylalanine Schiff Base Complex 23i: red solid (148 mg,
1
yield 99%). mp 250.0−250.9 °C. [α]25 = -1896 (c 0.056, CHCl3). H NMR (400 MHz, CDCl3) δ
D
8.66 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H),
7.94 (t, J = 9.4 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.66 – 7.27 (m, 11H), 7.26 – 7.12 (m, 3H), 7.05 (d,
J = 7.2 Hz, 1H), 6.68 (d, J = 2.6 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H), 4.20 (t, J = 4.0 Hz, 1H), 3.76 (d,
J = 15.6 Hz, 1H), 3.19 (d, J = 13.8 Hz, 1H), 2.92 (dd, J = 13.5, 3.3 Hz, 1H), 2.73 (dd, J = 14.7, 9.0
13
Hz, 2H), 2.55 (dd, J = 13.6, 4.8 Hz, 1H), 2.47 (d, J = 12.1 Hz, 1H). C NMR (125 MHz, CDCl3) δ
176.6, 173.9, 169.8, 140.9, 135.6, 134.8, 134.7, 133.5, 133.2, 132.9, 132.3, 131.9, 131.5, 130.9,
130.6, 130.4, 130.0, 129.0, 128.7, 128.1, 128.0, 127.7, 127.3, 127.0, 127.0, 126.9, 126.5, 126.0,
125.9, 125.8, 125.7, 124.8, 121.5, 71.3, 65.5, 61.2, 57.5, 38.1. HRMS (ESI) m/z: calcd for
C46H33BrClN3NiO3Na+ [M + Na]+: 870.0640, found: 870.0635. The dr was determined by LC/MS
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with an Eclipse XDB-C18 column (4.6 × 150 mm, 5 ꢀm) (MeOH/H2O = 80/20, λ = 254 nm, 1.0
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3
4
mL/min). tR (major diastereomer) = 46.207 min, tR (minor diastereomer) = not found, dr > 99:1.
5
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Nickel(II)-(S)-17/(R)-4-Chlorophenylalanine Schiff Base Complex 23j: red solid (702 mg,
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9
1
yield 99%). mp 256.5−257.9 °C. [α]25 = -2067 (c 0.052, CHCl3). H NMR (400 MHz, CDCl3) δ
D
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8.69 (d, J = 8.2 Hz, 1H), 8.39 (d, J = 9.2 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H),
7.95 (t, J = 8.7 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.63 – 7.30 (m, 11H), 7.25 – 7.19 (m, 2H), 7.14 (d,
J = 7.7 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.20 (t,
J = 3.2 Hz, 1H), 3.75 (d, J = 15.6 Hz, 1H), 3.19 (d, J = 13.7 Hz, 1H), 2.95 (dd, J = 13.4, 2.7 Hz, 1H),
2.71 (dd, J = 14.6, 4.6 Hz, 2H), 2.57 (dd, J = 13.2, 4.7 Hz, 1H), 2.45 (d, J = 12.4 Hz, 1H). 13C NMR
(125 MHz, CDCl3) δ 177.0, 174.4, 170.2, 141.4, 136.1, 135.2, 134.9, 134.0, 133.9, 133.7, 133.0,
132.8, 132.4, 131.5, 131.1, 130.9, 130.5, 129.5, 129.5, 129.3, 129.1, 128.6, 128.5, 128.5, 128.2,
127.8, 127.5, 127.4, 127.0, 126.5, 126.4, 126.3, 126.2, 125.3, 71.9, 66.0, 61.7, 58.0, 38.5. HRMS
+
(ESI) m/z: calcd for C46H34Cl2N3NiO3 [M + H]+: 804.1325, found: 804.1303. The dr was
determined by LC/MS with an Eclipse XDB-C18 column (4.6 × 150 mm, 5 ꢀm) (MeOH/H2O =
85/15, λ = 254 nm, 1.0 mL/min). tR (major diastereomer) = 17.230 min, tR (minor diastereomer) =
20.807 min, dr = 99:1.
Nickel(II)-(S)-17/(R)-4-Fluorophenylalanine Schiff Base Complex 23k: red solid (138 mg,
1
yield 99%). mp 210.5−212.0 °C. [α]25 = -2385 (c 0.052, CHCl3). H NMR (400 MHz, CDCl3) δ
D
8.65 (d, J = 8.3 Hz, 1H), 8.38 (d, J = 9.2 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.03 – 7.87 (m, 3H), 7.66
– 7.26 (m, 14H), 7.24 – 7.15 (m, 2H), 7.05 (d, J = 7.1 Hz, 1H), 6.68 (s, 1H), 4.60 (d, J = 12.2 Hz,
1H), 4.20 (t, J = 3.9 Hz, 1H), 3.75 (d, J = 15.5 Hz, 1H), 3.22 (d, J = 13.9 Hz, 1H), 2.96 (d, J = 13.0
13
Hz, 1H), 2.73 (t, J = 14.5 Hz, 2H), 2.58 (dd, J = 14.0, 4.6 Hz, 1H), 2.48 (d, J = 12.3 Hz, 1H). C
NMR (125 MHz, CDCl3) δ 176.7, 173.8, 169.7, 162.4 (d, J = 246.0 Hz), 140.8, 135.6, 134.7, 133.5,
133.2, 132.6 (d, J = 7.0 Hz), 132.3, 131.9, 131.6, 131.0, 130.6, 130.4, 130.0, 129.0, 128.8, 128.8,
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128.1, 128.0, 127.8, 127.3, 126.9, 126.9, 126.7, 126.6, 126.0, 125.9, 125.7, 124.7, 115.3 (d, J = 21.2
Hz), 71.5, 65.6, 61.2, 57.5, 37.9. HRMS (ESI) m/z: calcd for C46H33ClFN3NiO3Na+ [M + Na]+:
810.1440, found: 810.1429. The dr was determined by LC/MS with an Eclipse XDB-C18 column
(4.6 × 150 mm, 5 ꢀm) (MeOH/H2O = 85/15, λ = 254 nm, 1.0 mL/min). tR (major diastereomer) =
23.932 min, tR (minor diastereomer) = 40.639 min, dr = 99:1.
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Nickel(II)-(S)-17/(R)-4-Trifluoromethylphenylalani-ne Schiff Base Complex 23l: red solid
1
(136 mg, yield 92%). mp 242.0−243.9 °C. [α]25 = -2121 (c 0.072, CHCl3). H NMR (400 MHz,
D
CDCl3) δ 8.66 (d, J = 8.3 Hz, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.00 – 7.91 (m,
5H), 7.65 – 7.53 (m, 5H), 7.52 – 7.44 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.35 – 7.19 (m, 6H), 7.08 (d,
J = 7.4 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.27 – 4.24 (m, 1H), 3.56 (d, J =
15.6 Hz, 1H), 3.20 (d, J = 14.3 Hz, 1H), 3.02 (dd, J = 13.4, 3.4 Hz, 1H), 2.72 (d, J = 15.5 Hz, 1H),
2.65 (dd, J = 13.5, 5.0 Hz, 1H), 2.58 (d, J = 14.0 Hz, 1H), 2.48 (d, J = 12.2 Hz, 1H). 13C NMR (125
MHz, CDCl3) δ 176.9, 174.2, 170.5, 141.5, 140.6, 136.1, 135.2, 134.0, 133.7, 133.0, 132.8, 132.5,
131.9, 131.4, 131.1, 130.8, 130.6, 130.3 (q, J = 32.4 Hz), 129.5, 129.3, 129.3, 128.6, 128.5, 128.4,
128.1, 127.8, 127.5, 127.4, 127.3, 127.1, 126.9, 126.5, 126.4, 126.4, 126.3, 126.2, 125.7 (q, J = 3.3
Hz), 125.2, 124.5 (q, J = 272.1 Hz), 71.6, 65.7, 61.5, 58.0, 38.8. HRMS (ESI) m/z: calcd for
+
C47H34ClF3N3NiO3 [M + H]+: 838.1589, found: 838.1569. The dr was determined by LC/MS with
an Eclipse XDB-C18 column (4.6 × 150 mm, 5 ꢀm) (MeOH/H2O = 80/20, λ = 254 nm, 1.0 mL/min).
tR (major diastereomer) = 37.403 min, tR (minor diastereomer) = 63.798 min, dr = 94:6.
Nickel(II)-(S)-17/(R)-4-Acetylphenylalanine Schiff Base Complex 23m: red solid (112 mg,
1
yield 78%). mp 236.8−238.7 °C. [α]25 = -2145 (c 0.040, CHCl3). H NMR (400 MHz, CDCl3) δ
D
8.57 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.26 (d, J = 7.8 Hz, 2H), 8.08 (d, J = 8.6 Hz, 1H),
7.99 (d, J = 8.1 Hz, 1H), 7.94 (dd, J = 11.1, 8.4 Hz, 2H), 7.65 – 7.53 (m, 5H), 7.48 (q, J = 8.3 Hz,
2H), 7.40 (d, J = 8.5 Hz, 1H), 7.35 – 7.18 (m, 6H), 7.10 (d, J = 6.7 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H),
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