Asymmetric Synthesis of (2S,3S)-α-(1-Oxoisoindolin-3-yl)glycines under Low-Basicity "kinetic" Control

Article abstract of DOI:10.1021/acs.joc.5b01730

The previously illusive (2S,3S)-configured α-(1-oxoisoindolin-3-yl)glycines can be prepared under mild DBU-catalyzed, low-basicity conditions. The overall process includes a cascade of aldol addition, cyclization, rearrangement, and conjugate addition reactions, leading to the target products with moderate to good chemical yields and diastereoselectivity.

Full text of DOI:10.1021/acs.joc.5b01730

Article
pubs.acs.org/joc
Asymmetric Synthesis of (2S,3S)‑α-(1-Oxoisoindolin-3-yl)glycines
under Low-Basicity “Kinetic” Control
†
,‡,⊥
†,⊥
†
§
,∥
Tingting Li, ,†S,‡hengbin Zhou, Jiang Wang, Jose
́
̃
Luis Acena, Vadim A. Soloshonok,*
and Hong Liu*
†Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road,
Shanghai 201203, China
‡
School of Pharmacy, China Pharmaceutical University, Jiangsu, Nanjing 210009, China
§
Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab
, 20018 San Sebastian, Spain
IKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza Bizkaia, 48011 Bilbao, Spain
́
al
3
∥
́
*
S Supporting Information
ABSTRACT: The previously illusive (2S,3S)-configured α-(1-oxoisoindolin-3-yl)glycines can be prepared under mild DBU-
catalyzed, low-basicity conditions. The overall process includes a cascade of aldol addition, cyclization, rearrangement, and
conjugate addition reactions, leading to the target products with moderate to good chemical yields and diastereoselectivity.
INTRODUCTION
Scheme 1. Synthesis of Diastereomers (2R,3S)-1 and
2S,3S)-4 under the Conditions of Thermodynamic and
Kinetic Control, Respectively
■
(
Due to the paramount role of α-amino acids in the
development of life, biological evolution, and sustenance of
human health, synthesis of this class of organic compounds
continues to attract considerable attention. In fact, interest in
development of new methods for preparation of tailor-made α-
1
2
amino acids (α-AAs) in enantiomerically pure form is at an all-
3
time high because of the rapidly growing number of
pharmaceutical products incorporating α-AAs in the their
4
5,6
structures. For quite some time, the research in our groups
has been focused on the development of general asymmetric
methodology for asymmetric synthesis of α- and β-amino acids
7
via homologation of chiral equivalents of glycine and β-
8
alanine. In particular, drawing inspiration from the recent work
9
by Massa et al., we reported synthesis of (2R,3S)-α-(1-
oxoisoindolin-3-yl)glycines 1 (Scheme 1) via addition reactions
between chiral Ni(II) glycine complex 2 and 2-cyanobenzalde-
successive transformations and multiple intermediates. On the
other hand, these α-amino acids are of very significant
pharmacological interest, allowing for an efficient control of
peptide-space side conformations. Consequently, building on
our earlier success in the synthesis of (2R,3S)-1, we were highly
motivated to accomplish synthesis of yet another diastereomer
1
0
hydes 3. Amino acids of type 1 embody the least studied
structural class of sterically constrained α-amino acids as their
synthesis, especially in enantiomerically pure form, still remains
quite a challenging undertaking. The major synthetic hurtle
associated with the preparation of amino acids of type 1, is not
only the two consecutive stereogenic centers and the sensitive
polyfunctional nature, but rather the fact that this structure
cannot be assembled in one reaction step, requiring a cascade of
11
Received: July 8, 2015
Published: November 2, 2015
©
2015 American Chemical Society
11275
DOI: 10.1021/acs.joc.5b01730
J. Org. Chem. 2015, 80, 11275−11280

The Journal of Organic Chemistry
Article
Scheme 2. Four Diastereomeric Products in the Reaction of Ni(II) Complex (S)-2 with Aldehyde 3a
a
Table 1. Optimization of the Reaction Conditions for Preparation of Diastereomer (2S,3S)-5a
b
c
entry
bases
solvents
DCM
time (h)
temp (°C)
yield (%)
A/B/C/D dr
1
2
3
4
5
6
7
8
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
20
20
20
20
20
20
20
14
rt
rt
56.9
48
50/18/5/27
52/17/3/28
47/18/3/32
52/22/5/22
34/28/13/25
71/9/2/18
88/6/2/4
CH CN
3
acetone
THF
THF
THF
THF
THF
rt
43
rt
62.8
51.2
69.5
50.9
0
40
60
80
29.5
61/29/5/5
a
b
Reactions conditions: (S)-2 (0.2 mmol), 3a (0.22 mmol) and base (0.24 mmol) were run in solvent (2 mL). Combined yield of isolated crude
c
products. Determined by LC/MS analysis of the crude products.
(
2S,3S)-4 (Scheme 1), which we failed to prepare in the
eomers (S)(2S,3S)-5a (A), (S)(2S,3R)-B, (S)(2R,3R)-C, and
(S)(2R,3S)-D are usually observed in the reaction mixture.
1
0
12
previous work. The diastereomer(2S,3S)-4 is thermodynami-
cally unfavorable and, therefore, stereochemically more
challenging.
RESULTS AND DISCUSSION
■
One may agree that the development of a procedure for
All four reactions involved in the formation of products are
base-catalyzed and can be accelerated at an elevated temper-
preparation of diastereomer (2S,3S)-4, along with the previous
1
0
work, will provide access to all four possible enantiomers
2R,3S)-/(2S,3R)-4 and (2S,3S)-/(2R,3R)-4, starting corre-
10
ature. As established previously, application of strong bases,
(
such as NaOMe in MeOH, at 80 °C led to relatively rapid (∼10
h) thermodynamic control (relative ratios of the diastereomers
ceased to change) strongly favoring (2R,3S)-diastereomers D.
Taking into account the cascade of various transformations
taking place in the reaction of (S)-2 with 3a, one might agree
that the sense of kinetic control in such processes is somewhat
ambiguous. Nevertheless, diastereomer (2S,3S)-5a repetitively
appeared as a prevailing isomer in the early reaction stages,
rendering it rather “kinetic” as compared with the thermody-
namically favored (2R,3S)-D. Numerous experiments designed
to screen various bases and solvents revealed that strong
inorganic bases (NaH, KOH, NaOH, t-BuONa, t-BuOK),
needed to catalyze the chain of the consecutive reactions, led to
spondingly from (S)- or (R)-2, affording a stereochemically
complete study of biological properties of these amino acids.
Thus, owing both to practical importance and scientific
curiosity, we sought to develop the method for preparation
of diastereomer (2S,3S)-4. Herein, we describe the results of
this study.
As demonstrated previously by Massa et al. and us, the
formation of target structure 5a (Scheme 2), from staring
Ni(II) complex (S)-2 and aldehyde 3a, proceeds via the
consecutive sequence of at least four reactions: aldol addition,
cyclization, rearrangement, and conjugate addition. Due to such
reaction complexity, all four theoretically possible diaster-
9
10
1
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DOI: 10.1021/acs.joc.5b01730
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a
Table 2. Scope of the Reaction between Schiff Base Ni(II) Complex (S)-2 and Aldehydes 3a−d
b
c
entry
R
time (h)
5a−d
yield (%)
dr (A/B/C/D)
1
2
3
4
H
20
8
5a
5b
5c
5d
50.9
47.9
70.6
72.6
88/6/2/4
4-F
80/13/2/5
73/15/1/11
85/12/1/2
4-MeO
4-Me
22
30
a
b
Reactions conditions: (S)-2 (0.2 mmol), 3a−d (0.22 mmol), and DBU (0.24 mmol) were run in THF (2 mL). Combined yield of isolated crude
c
products. Determined by LC/MS analysis of the crude products.
Scheme 3. Mechanistic Considerations Accounting for the Formation of (S)(2S,3S)-5a
thermodynamic control and rapid disappearance of the target
diastereomer (2S,3S)-5a. On the other hand, relatively weak
organic bases (TEA, DABCO, DBN) were generally ineffective
as the catalysts. Eventually, we found that application of DBU
might be promising to realize a synthetic opportunity for
preparation of (2S,3S)-5a. Some key and selected results are
presented in Table 1.
For example, the reaction of (S)-2 and 3a, conducted in
DCM and catalyzed by DBU (entry 1), took place at an
ambient temperature with fairly slow rate. The best ratio of the
diastereomers, with respect to the relative amount of
diastereomer (2S,3S)-A, was observed at about 20 h of the
reaction time. A similar stereochemical outcome, but with
slightly lower yields, was recorded for the DBU-catalyzed
reactions conducted in acetonitrile (entry 2) and acetone
results in terms of the diastereoselectivity, albeit the yield was
lower. Finally, an attempt to conduct the reaction at even
higher temperature (80 °C) was rather disappointing (entry 8),
leading to decreased yield and stereoselectivity. According to
these results, application of DBU as a base and use of THF as a
solvent at 60 °C were considered as the optimized conditions
providing for synthetically meaningful yield and stereochemical
control. With the aim of understanding reaction progress and
stereochemical outcome under optimized conditions, we
monitored the reaction using HPLC analysis. The main
product (2S,3S)-5a (A) was afforded as a kinetically favored
isomer. Over time, the relative amounts of the diastereomer
(
2S,3S)-5a (A) steadily increased, reached a peak at 20 h, and
decreased when the reaction time was prolonged to 27 h (see
Table S1 in the Supporting Information).
(
entry 3). In contrast, the use of THF, as a reaction solvent,
With the optimized reaction conditions thus established, we
decided to evaluate briefly the scope of this procedure for
preparation of several analogues containing various substituents
on the phenyl ring of the oxoisoindolinyl moiety. The results
are presented in Table 2. In general, the presence of electron-
withdrawing/donating substituents on the starting benzalde-
hydes 3a−d has no effect on the kinetic stereochemical
preferences, favoring in these reactions the (S)(2S,3S)
configured products 5a−d (A) as major diastereomers (Table
2, entries 1−4).
gave noticeably better results furnishing the diastereomeric
mixture (entry 4) in 62.8% yield with (2S,3S)-A as a major
product. Quite unexpectedly, lowering the reaction temperature
to 0 °C (entry 5) decreased both the reaction yield and relative
ratio of (2S,3S)-A. Following this trend we conducted the
reaction at elevated (40 °C; entry 6) temperature. To our
delight, the yield and stereochemical outcome were both
markedly improved, clearly rendering the target diastereomer
(
2S,3S)-A as a major reaction product. Further increase of the
reaction temperature to 60 °C (entry 7) gave even better
1
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Scheme 4. Disassembly of Product (2S,3S)-5a, Isolation of Target Free Amino Acid (2S,3S)-4a, and Recycling of the Chiral
Ligand 11
On the other hand, a clear tendency for higher yields and
stereochemical outcome could be noticed for the reactions of
aldehydes bearing electron-donating substituents (entries 3, 4
vs 1, 2). Thus, the best yield and relative ratio of major product
and conjugate addition reactions. Regardless the chemical
complexities of this procedure, the yields and diastereoselec-
tivity are generally moderate to good allowing preparation of
target amino acids of high pharmaceutical potential.
(
S)(2S,3S)-5d was observed in the reaction of p-Me-substituted
derivative.
On the basis of the mechanism suggested by Massa et al. as
EXPERIMENTAL SECTION
General Information. The chemicals were purchased from
commercial sources and used without further purification. Analytical
thin-layer chromatography (TLC) was performed on HSGF 254
■
9
10
well as our previous work, we can assume that the initial
reaction step results in the formation of expected aldol product
6
(
0.15−0.2 mm thickness). All products were characterized by NMR
(Scheme 3).
1 13
and MS spectra. H and C NMR spectra were recorded in
Next, the ionized form of 6 might undergo cyclization with
deuterochloroform (CDCl ), dimethyl sulfoxide-d6 (DMSO-d ), or
3
6
the o-CN group to produce intermediate cyclic compound 7,
rearrangement of which, via an E1cb mechanism, gives rise to
ionized amide 8/9. Intramolecular conjugate addition of 9 was
realized through acetamide anion attacked from the Si-face of
the Michael acceptor with smaller steric hindrance and faster
kinetic rate, which would lead to recyclization with the
formation of (3S)-enolate 10 as major products. The final
step in this reaction cascade would be the protonation of
enolate 10 furnishing neutral product (S)(2S,3S)-5a, which has
preferred (2S)-configuration avoiding mutual repulsion with
chiral ligand residue.
deuterium oxide (D O) on a 400 or 500 MHz instrument. Chemical
shifts are reported in parts per million (ppm, δ) downfield from
tetramethylsilane. Proton-coupling patterns were described as singlet
2
(
s), doublet (d), triplet (t), quartet (q), quintet (p), doublet of triplets
(dt), and multiplet (m). High-resolution mass spectra (HRMS) were
measured on a Q-TOF spectrometer. The determination of dr was
performed via LC/MS analysis. The determination of ee was
performed via HPLC analysis. Optical rotations were measured
using a 1 mL cell with a 10 mm path length on matic polarimeter and
were reported as follows: [α] 25 (c: g/100 mL, in solvent). Melting
D
points 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.
General Procedure. General Procedure for the Synthesis
of(S)(2S,3S)-5a. (S)-2 (100 mg, 0.20 mmol) was dissolved in THF
Aldol addition reactions of glycine Schiff base Ni(II) complex
(
S)- or (R)-2 were previously studied, however, only on simple
1b
examples, not like in the present case where we have the
chain of subsequent transformations. However, the mechanistic
rational and the stereochemical outcome giving preference for
(
(
2 mL) at ambient conditions followed by 2-cyano benzaldehyde 3a
28.9 mg, 0.22 mmol) and DBU (36.0 mmL, 0.24 mmol). The
solution was stirred at 60 °C. After 20 h, the reaction was cooled and
quenched by pouring it into 5 mL of aq satd NH Cl. The suspension
(S)(2S,3S) stereochemistry is consistent with general mode of
4
the stereocontrol of chiral Ni(II) complex, strongly favoring
was extracted with CH Cl . The combined organic layer was washed
1
,10,13
2
2
(S)-configuration of an amino acid residue.
with brine, dried over Na SO , concentrated, and purified by column
2
4
It should be noted that considering the fact that this
chromatography on silica gel (CH Cl /acetone = 1/5, v/v) to give
2
2
developed one-pot procedure actually includes a consecutive
chain of aldol addition, cyclization, rearrangement, and
conjugate addition reactions, the obtained yields (Table 1
and 2) are rather good allowing synthetically attractive
preparation of the target products.
(S)(2S, 3S)-5a as a red solid (64.3 mg, yield 50.9%).
Disassembly of Ni(II) Complex (S)(2S,3S)-5a. To a stirring solution
of (S)(2S,3S)-5a (385 mg, 0.6 mmol) in 1,4-dioxane (10 mL) was
added 1 N HCl (20 mL) at 70 °C for 20 min, the solution was
evaporated, and the solid residue was dissolved in water. Then the
precipitate ((S)-11) was filtered, and the filtrate was extracted with
CH Cl to recover extra (S)-11. The aqueous phase was concentrated.
As a final goal of this study, diastereomerically pure Ni(II)
complex (S)(2S,3S)-5a was disassembled (Scheme 4) under
2
2
Water (5 mL) was added to the residue, which was purified by
reversed-phase preparative chromatography (MeOH/water = 5/95, v/
v) resulting in optically pure product (2S,3S)-4a·HCl as a white solid
(109 mg, 86.5%).
1b
the standard conditions using 1 N HCl to furnish free amino
acid (2S,3S)-4a (Scheme 1) in 82.5% yield with 97.7% ee. At
the same time, chiral ligand (S)-11 was recycled with 86% yield
and used again for preparation of starting glycine Schiff base
Ni(II) complex (S)-2.
Analytical Characterization Data of Products. Ni(II)−(S)-BPB/
(
S)-2-Amino-2-((S)-1-oxoisoindolin-3-yl)acetic Acid Schiff Base
Complex (5a). Red solid (64.3 mg, yield 50.9%). Mp: 264.5−266.5
°
C. [α]25 = +2810 (c 0.05 g/100 mL, CHCl ). H NMR (400 MHz,
1
D
3
CONCLUSIONS
CDCl ) δ 8.32 (dd, J = 8.7, 1.1 Hz, 1H), 8.10−8.02 (m, 2H), 7.86−
■
3
7
7
6
.79 (m, 1H), 7.56 (td, J = 7.6, 1.4 Hz, 1H), 7.52−7.27 (m, 7H),
.25−7.20 (m, 1H), 7.19−7.12 (m, 2H), 6.86−6.82 (m, 1H), 6.72−
.63 (m, 2H), 6.31 (d, J = 7.7 Hz, 1H), 4.99 (d, J = 5.0 Hz, 1H), 4.42
In summary, we demonstrate that previously illusive α-(1-
oxoisoindolin-3-yl)glycines of (2S,3S) absolute configuration
can be prepared under specially designed DBU-catalyzed, low-
basicity protocol, favoring “kinetic” stereochemical outcome.
The developed one-pot procedure actually includes a
consecutive chain of aldol addition, cyclization, rearrangement
(
d, J = 12.7 Hz, 1H), 4.17 (d, J = 5.2 Hz, 1H), 3.67−3.44 (m, 4H),
2
.88−2.75 (m, 1H), 2.64−2.50 (m, 1H), 2.29−2.17 (m, 1H), 2.15−
13
2.05 (m, 1H). CNMR (100 MHz, CDCl ) δ 180.2, 174.4, 172.3,
3
170.9, 142.8, 142.6, 133.4, 132.8, 132.2, 131.6, 131.3, 131.2, 129.5,
1
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1
7
28.8, 128.7, 128.4, 127.4, 127.0, 125.7, 123.7, 123.0, 122.7, 120.2,
= 37.772 min, t (minor diastereomers) = 38.638 min, 41.103 min,
47.841 min, respectively. dr = 85/12/1/2.
R
+
2.4, 69.8, 62.7, 59.2, 56.8, 30.5, 23.1. LRMS (ESI) [M + Na] found
+
+
m/z 651.1. HRMS (ESI) calcd for C H N NiO [M + H]
6
(S)-2-Amino-2-((S)-1-oxoisoindolin-3-yl)acetic Acid 4a·HCl. White
3
5
31
4
4
2
5
29.1693, found 629.1690. The dr was determined by LC/MS with
solid (109 mg, yield 86.5%). Mp: 295.3−297.1 °C. [α] = −26 (c
D
1
an Eclipse XDB-C18 column (5 μm, 4.6 × 150 mm) (MeOH/H O
0.10 g/100 mL, H O). H NMR (500 MHz, D O + CF COOH) δ
2
2
3
2
50/50 for 20 min, rise to 60/40 in 10 min, then 60/40 sustained 20
7.57 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz,
1H), 7.25 (d, J = 7.7 Hz, 1H), 5.16 (d, J = 3.4 Hz, 1H), 4.57 (d, J = 3.3
min, λ = 254 nm, 1.0 mL/min). t (major diastereomer) = 34.266 min,
tR (minor diastereomers) = 35.255 min, 37.036 min, 40.754 min,
respectively. dr = 88:6:2:4.
R
Hz, 1H). 13C NMR (125 MHz, D
O + CF
COOH) δ 172.1, 167.9,
2
3
139.6, 132.9, 130.7, 129.6, 123.4, 123.0, 55.1, 53.7. LRMS (ESI) [M-
−
+
[M + H]+
Ni(II)−(S)-BPB/(S)-2-Amino-2-((S)-6-fluoro-1-oxoisoindolin-3-yl)-
H] found m/z 205.1. HRMS (ESI): calcd for C10H N O
11 2 3
acetic Acid Schiff Base Complex 5b. Red solid (62.2 mg, yield
4
CHCl ). H NMR (500 MHz, CDCl ) δ 8.34 (s, 1H), 8.30 (d, J = 8.7
207.0764, found 207.0770. The ee was determined through its
corresponding methyl 2-amino-2-(3-oxoisoindolin-1-yl)acetic acid by
HPLC with a Chiralpak AD-H column (n-hexane/i-PrOH = 90/10, λ
= 254 nm, 1.0 mL/min). tR (major enantiomer) = 29.491 min, tR
(minor enantiomer) = 37.558 min, 97.7% ee.
2
5
7.9%). Mp: 299.4−300.3 °C. [α]
= +2759 (c 0.05 g/100 mL,
D
1
3
3
Hz, 1H), 8.04 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.57−7.45
m, 3H), 7.40−7.28 (m, 3H), 7.22−7.08 (m, 2H), 6.95 (td, J = 8.6, 2.5
Hz, 1H), 6.79−6.66 (m, 2H), 6.57 (d, J = 7.6 Hz, 1H), 6.31 (dd, J =
(
8
.4, 4.2 Hz, 1H), 4.67−4.57 (m, 1H), 4.50 (d, J = 12.8 Hz, 1H), 4.23
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01730.
■
(
2
d, J = 3.9 Hz, 1H), 3.61−3.38 (m, 4H),, 2.84 (p, J = 7.3 Hz, 1H),
*
S
13
.53−2.40 (m, 1H), 2.15−2.05 (m, 1H), 2.04−1.96 (m, 1H).
C
NMR (125 MHz, CDCl ) δ 180.0, 174.0, 172.2, 169.6, 162.4 (d, J =
3
2
1
48.9 Hz), 142.6, 138.2, 133.3, 132.5, 132.1, 131.2, 129.6, 128.7, 128.6,
28.3, 127.2, 127.0, 125.8, 124.1, 124.1, 122.9, 120.1, 119.1 (d, J = 23.5
Stereochemical outcome over time, HPLC spectra for dr
determination, and NMR spectra (PDF)
Hz), 110.2 (d, J = 23.5 Hz), 71.9, 69.5, 62.5, 58.4, 56.5, 30.5, 22.9.
LRMS (ESI) [M + Na] found m/z 669.0. HRMS (ESI): calcd for
C H FN NiO [M + H] 647.1599, found 647.1595. The dr was
+
+
+
35
30
4
4
AUTHOR INFORMATION
Corresponding Authors
*E-mail: vadym.soloshonok@ehu.es.
E-mail: hliu@simm.ac.cn.
determined by LC/MS with an Eclipse XDB-C18 column (5 μm, 4.6
150 mm) (MeOH/H O 50/50 for 20 min, rise to 60/40 in 10 min,
■
×
2
then 60/40 sustained 20 min, λ = 254 nm, 1.0 mL/min), t (major
R
diastereomer) = 36.461 min, t (minor diastereomers) = 38.326 min,
R
*
40.367 min, 44.662 min, respectively. dr = 80/13/2/5.
Author Contributions
Ni(II)−(S)-BPB/(S)-2-Amino-2-((S)-6-methoxy-1-oxoisoindolin-3-
⊥
yl)acetic Acid Schiff Base Complex 5c. Red solid (93.5 mg, yield
7
CHCl ). H NMR (500 MHz, CDCl ) δ 8.24 (d, J = 8.7 Hz, 1H), 7.98
T.L. and S.Z. contributed equally.
2
5
0.6%). Mp: 305.1−306.5 °C. [α]
= +2404 (c 0.05 g/100 mL,
D
Notes
1
3
3
The authors declare no competing financial interest.
(
7
(
6
(
1
d, J = 7.4 Hz, 2H), 7.69 (s, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.44 (t, J =
.5 Hz, 1H), 7.32−7.21 (m, 5H), 7.08 (t, J = 7.5 Hz, 1H), 7.04−6.99
m, 1H), 6.85 (dd, J = 8.3, 2.4 Hz, 1H), 6.66−6.58 (m, 2H), 6.55−
.47 (m, 2H), 4.75 (d, J = 4.7 Hz, 1H), 4.35 (d, J = 12.8 Hz, 1H), 4.11
d, J = 4.7 Hz, 1H), 3.76 (s, 3H), 3.53−3.34 (m, 4H), 2.71−2.58 (m,
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grant Nos. 21021063,
■
13
H), 2.46−2.33 (m, 1H), 2.13−2.04 (m, 1H), 2.01−1.93 (m, 1H). C
9
1229204, and 81025017) and the National S&T Major
NMR (125 MHz, CDCl ) δ 180.1, 174.5, 172.2, 170.2, 160.0, 142.5,
3
Projects (Nos. 2012ZX09103101-072, 2012ZX09301001-005,
1
1
5
34.7, 133.4, 133.3, 132.8, 132.7, 132.3, 131.0, 129.5, 128.6, 128.4,
27.2, 126.8, 123.7, 122.9, 120.3, 120.1, 106.3, 72.6, 69.9, 62.7, 59.0,
6.8, 55.2, 30.5, 23.1. LRMS (ESI) [M + Na] found m/z 681.0.
2
013ZX09507-001, and 2014ZX09507002001).
+
+
+
REFERENCES
HRMS (ESI) calcd for C H N NiO [M + H] 659.1799, found
■
36
33
4
5
659.1787. The dr was determined by LC/MS with an Eclipse XDB-
̃
(1) For review articles, see: (a) Acena, J. L.; Sorochinsky, A. E.;
C18 column (5 μm, 4.6 × 150 mm) (MeOH/H O 50/50 for 20 min,
Soloshonok, V. A. Amino Acids 2014, 46, 2047−2073. (b) Sorochinsky,
A. E.; Acena, J. L.; Moriwaki, H.; Sato, T.; Soloshonok, V. A. Amino
Acids 2013, 45, 1017−33.
2
rise to 60/40 in 10 min, then 60/40 sustained 20 min, λ = 254 nm, 1.0
mL/min). tR (major diastereomer) = 36.345 min, tR (minor
diastereomers) = 37.891 min, 39.412 min, 46.171 min, respectively.
dr =73/15/1/11.
(2) For definition of “tailor-made amino acids”, see: Soloshonok, V.
A.; Cai, C.; Hruby, V. J.; Van Meervelt, L. Tetrahedron 1999, 55,
12045−12058.
Ni(II)−(S)-BPB/(S)-2-Amino-2-((S)-6-methyl-1-oxoisoindolin-3-yl)-
acetic Acid Schiff Base Complex 5d. Red solid (93.7 mg, yield
7
CHCl ). H NMR (400 MHz, CDCl ) δ 8.31 (d, J = 8.7 Hz, 1H),
(3) (a) Zhang, F.; Sun, H.; Song, Z.; Zhou, S.; Wen, X.; Xu, Q.-L.;
Sun, H. J. Org. Chem. 2015, 80, 4459. (b) Fanelli, R.; Jeanne-Julien, L.;
25
2.6%). Mp: 295.2−296.7 °C. [α]
= +2625 (c 0.05 g/100 mL,
D
1
́
Rene, A.; Martinez, J.; Cavelier, F. Amino Acids 2015, 47, 1107−1115.
(c) Drouet, F.; Noisier, A. F.; Harris, C. S.; Furkert, D. P.; Brimble, M.
A. Eur. J. Org. Chem. 2014, 2014, 1195−1201.
(4) (a) Augeri, D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D. R.;
Khanna, A.; Robertson, J. G.; Wang, A.; Simpkins, L. M.; Taunk, P.;
Huang, Q. J. Med. Chem. 2005, 48, 5025−5037. (b) Barrett, Y. C.;
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2004, 22, 304−311.
(5) (a) Ellis, T. K.; Ueki, H.; Yamada, T.; Ohfune, Y.; Soloshonok, V.
A. J. Org. Chem. 2006, 71, 8572−8578. (b) Yamada, T.; Okada, T.;
Sakaguchi, K.; Ohfune, Y.; Ueki, H.; Soloshonok, V. A. Org. Lett. 2006,
8, 5625−5628.
(6) (a) Wang, J.; Zhou, S. B.; Lin, D. Z.; Ding, X.; Jiang, H. L.; Liu,
H. Chem. Commun. 2011, 47 (29), 8355−8357. (b) Lin, D. Z.; Wang,
J.; Zhang, X.; Zhou, S. B.; Lian, J.; Jiang, H. L.; Liu, H. Chem. Commun.
3
3
8
(
7
(
.11−8.03 (m, 2H), 7.63 (s, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.52−7.45
m, 1H), 7.33 (t, J = 7.7 Hz, 2H), 7.29 (s, 1H), 7.25−7.20 (m, 3H),
.19−7.12 (m, 2H), 6.76 (d, J = 7.8 Hz, 1H), 6.71−6.63 (m, 2H), 6.33
d, J = 7.7 Hz), 4.96 (d, J = 5.2 Hz, 1H), 4.42 (d, J = 12.7 Hz, 1H),
4
2
(
.15 (d, J = 5.2 Hz, 1H), 3.64−3.43 (m, 4H), 2.87−2.77 (m, 1H),
.64−2.52 (m, 1H), 2.40 (s, 3H, CH ), 2.28−2.17 (m, 1H), 2.15−2.03
3
m, 1H). 13C NMR (125 MHz, CDCl ) δ 180.2, 174.5, 172.2, 170.9,
3
1
1
1
42.5, 140.0, 138.5, 133.4, 133.4, 132.8, 132.7, 132.2, 131.4, 131.1,
29.5, 128.8, 128.7, 128.4, 128.4, 127.3, 127.0, 125.6, 123.9, 123.0,
22.4, 120.3, 72.6, 69.9, 62.7, 59.1, 56.8, 30.5, 23.1, 21.0. LRMS (ESI)
+
+
[
[
M + Na] found m/z 665.1. HRMS (ESI): calcd for C H N NiO
M + H] 643.1850, found 643.1867. The dr was determined by LC/
36 33 4 4
+
MS with an Eclipse XDB-C18 column (5 μm, 4.6 × 150 mm)
(
MeOH/H O 50/50 for 20 min, rise to 60/40 in 10 min, then 60/40
2
sustained 20 min, λ = 254 nm, 1.0 mL/min). t (major diastereomer)
R
1
1279
DOI: 10.1021/acs.joc.5b01730
J. Org. Chem. 2015, 80, 11275−11280

The Journal of Organic Chemistry
Article
2
013, 49 (25), 2575−2577. (c) Zhou, S.; Wang, J.; Chen, X.; Acen
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7) (a) Ueki, H.; Ellis, T. K.; Martin, C. H.; Bolene, S. B.; Boettiger,
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Angew. Chem., Int. Ed. 2014, 53, 12214−12217.
8) (a) Deng, G.; Wang, J.; Zhou, Y.; Jiang, H.; Liu, H. J. Org. Chem.
007, 72, 8932−8934. (b) Lin, D.; Lv, L.; Wang, J.; Ding, X.; Jiang, H.;
Liu, H. J. Org. Chem. 2011, 76, 6649−6656.
9) Perillo, M.; Di Mola, A.; Filosa, R.; Palombi, L.; Massa, A. RSC
Adv. 2014, 4, 4239−4246.
10) Li, T.; Zhou, S.; Wang, J.; Acen
H. Chem. Commun. 2015, 51, 1624−1626.
11) (a) Hruby, V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich, M.
̃
a, J.
7
(
(
̃
(
2
(
(
̃
a, J. L.; Soloshonok, V. A.; Liu,
(
Biopolymers 1997, 43, 219−266. (b) Hruby, V. J.; Balse, P. M. Curr.
Med. Chem. 2000, 7, 945−970.
(
12) All four diastereomers, and their chemical composition (mass),
10
were unambiguously detected by LC−MS and labeled A−D
according to the increasing retention times.
(
13) (a) Soloshonok, V. A.; Avilov, D. V.; Kukhar, V. P.; Tararov, V.
I.; Saveleva, T. F.; Churkina, T. D.; Ikonnikov, N. S.; Kochetkov, K. A.;
Orlova, S. A.; Pysarevsky, A. P.; Struchkov, Y. T.; Raevsky, N. I.;
Belokon, Y. N. Tetrahedron: Asymmetry 1995, 6, 1741−1756.
(
b) Soloshonok, V. A.; Avilov, D. V.; Kukhar, V. P. Tetrahedron:
Asymmetry 1996, 7, 1547−1550.
1
1280
DOI: 10.1021/acs.joc.5b01730
J. Org. Chem. 2015, 80, 11275−11280