Aerobic redox deracemization of α-aryl glycine esters

Article abstract of DOI:10.1016/j.tetlet.2020.152107

An effective redox deracemization of α-aryl glycine esters has been described. The one-pot redox process consisted of copper(II) catalysis using molecular oxygen as terminal oxidant and chiral phosphoric acid catalyzed asymmetric transfer hydrogenation wi

Full text of DOI:10.1016/j.tetlet.2020.152107

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Aerobic Redox Deracemization of α-Aryl Glycine Esters
Xiaohan Chen, Lei Yan, Lu Zhang, Changyin Zhao, Guidong Feng, Lei Chen,
Shutao Sun, Qingyun Liu, Lei Liu
PII:
DOI:
Reference:
S0040-4039(20)30558-X
https://doi.org/10.1016/j.tetlet.2020.152107
TETL 152107
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 May 2020
26 May 2020
2 June 2020
Please cite this article as: Chen, X., Yan, L., Zhang, L., Zhao, C., Feng, G., Chen, L., Sun, S., Liu, Q., Liu, L.,
Aerobic Redox Deracemization of α-Aryl Glycine Esters, Tetrahedron Letters (2020), doi: https://doi.org/
10.1016/j.tetlet.2020.152107
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Aerobic Redox Deracemization of α-Aryl Glycine
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Esters
Xiaohan Chen, Lei Yan, Lu Zhang, Changyin Zhao, Guidong Feng, Lei Chen, Shutao Sun*, Qingyun
Liu*, Lei Liu*
aerobic
deracemization
PMP
H
PMP
HN
Ar
HN
Ar
CO2Me
CO2Me
racemate
enantiomer
up to 99% ee
up to 85% yield
14 examples

Tetrahedron Letters
journal homepage: www.elsevier.com
Aerobic Redox Deracemization of α-Aryl Glycine Esters
Xiaohan Chena,1, Lei Yanc,1, Lu Zhangb, Changyin Zhaob, Guidong Fengb, Lei Chenb, Shutao Sunb,*,
Qingyun Liua,*, Lei Liub,*
a College of Chemical and Biological Engineering; State Key Laboratory of Mining Disaster Prevention and Control Co-founded by Shandong Province and the
Ministry of Science and Technology, Shandong University of Science and Technology, Qingdao 266590, China
b School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
c Department of Internal Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences,
Jinan 250117, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An effective redox deracemization of α-aryl glycine esters has been described. The one-pot
redox process consisted of copper(II) catalysis using molecular oxygen as terminal oxidant and
chiral phosphoric acid catalyzed asymmetric transfer hydrogenation with benzothiazoline as
hydride donor. The reaction exhibited good functional group tolerance, providing a range of
optically active non-natural α-aryl glycine esters with excellent enantioselectivity.
Available online
2014 Elsevier Ltd. All rights reserved
Keywords:
Deracemization,
Aerobic
Aryl glycine ester
Asymmetric catalysis
Synthetic method
Table 1. Reaction condition optimization.a
Conventional enantioselective approaches involving either
conversion of achiral reactants to chiral products or differential
conversion of stereoisomers of racemic reactants (kinetic
resolutions) have attracted extensive interest.1,2 In contrast, direct
and whole transformation of racemic reactants into a single
enantiomer of the same molecule, namely deracemization, has
remained underexplored, despite conceptual simplicity and
O2, additive
PMP
PMP
H
ClCH2CH2Cl, 35 C
HN
Ph
HN
Ph
2
3
,
then
CO2Me
CO2Me
toluene, 50 C
1a
(S)-
1a
rac-
R
S
2a
2b
2c
, R = 3,5-CF3C6H3
O
O
O
Ph
P
, R = 1-naphthyl
potential
practical
benefits.3,4
To
achieve
such
OH
N
H
i
, R = 2,4,6- Pr3C6H2
3
thermodynamically disfavored process, the stereochemistry is
generally destroyed by oxidation and regenerated by asymmetric
reduction.5 Existing non-enzymatic redox deracemization studies
are limited to alcohol, cyclic amine, and cyclic ether moieties.6-9
Pure chemically catalytic redox deracemization of acyclic amines
has remained elusive.10 In addition, current studies usually
require stoichiometric oxidants like NBS, DDQ, and
oxopiperidinium salt, thus producing undesired waste. More ideal
molecular oxygen as oxidant in terms of economical and
ecological factors with H2O as the only byproduct has not been
applied for the process.11 Given the importance of non-natural α-
aryl glycine derivatives in pharmaceutical science, we herein
reported a redox deracemization of α-aryl glycine derivatives
using molecular oxygen as terminal oxidant.12,13
R
Entry
1
2
3
4
Additive
—
Cu(OTf)2
Cu(OAc)2
CuBr2
CuCl2
CuCl
CuCl2
CuCl2
CuCl2
2
Yieldb (%)
eec (%)
n.d.
n.d.
21
27
31
19
35
67
83
—
—
2a
2a
2a
2a
2a
2b
2c
2c
2c
2c
n.o.
n.o.
10
46
69
16
77
58
82
85
83
86
5
6
7d
8d
9d
10d,e
11d,e,f
12d,e,g
CuCl2
CuCl2
CuCl2
91
88
90
a General conditions: rac-1a (0.1 mmol) and additive (10 mol %) in
ClCH2CH2Cl (2 mL) under 1 atm molecular oxygen at 35 ºC for 18 h,
followed by 2 (5 mol %) and 3 (0.12 mmol) in toluene at 50 ºC for 24 h.
b Yield of isolated product.
Initially, the redox deracemization of α-phenyl glycine ester
rac-1a was chosen for optimization using molecular oxygen as
c Determined by chiral HPLC analysis.
d Oxidation at 50 ºC.
* Corresponding author.
e Asymmetric reduction in mesitylene.
3 Å molecular sieves (20 mg) as additive.
8 mol% 2c as catalyst.
e-mail: qyliu@sdust.edu.cn (Q. Liu); shutaosun@sdu.edu.cn (S.
Sun); leiliu@sdu.edu.cn (L. Liu)
f
g
1 These authors contributed equally to this work.

2
Tetrahedron Letters
PMP = 4-Methoxyphenyl, n.o. = no oxidation, n.d. = not determined
demonstrated by the formation of enantiopure 1m and 1n
with excellent enantiocontrol. No oxidation was observed
for substrate 1o bearing a Boc (tert-butyloxycarbonyl)
moiety and 1q with an α-alkyl substituent. Substrate 1p
containing an ethyl ester afforded an incomplete oxidation
under the standard condition.
Control experiments were conducted to understand the
preliminary reaction mechanism (Scheme 2). In the presence
of catalytic amount of CuCl2 under molecular oxygen
atmosphere, α-amino ester rac-1a was converted to an
intermediate detected by TLC analysis, which was identified
as α-imino ester 4 (Scheme 2a). Subjecting 4 to standard
conditions in the absence of oxidation elements furnished
expected (S)-1a with comparable ee to that of
deracemization process, indicating the intermediacy of α-
imino ester 4 (Scheme 2b). The reaction can be scaled up
without obvious loss of efficiency and ee, as demonstrated
by the effective deracemization of 1a in 1.0 mmol scale
(Scheme 2c).
terminal oxidant (Table 1). Chiral phosphoric acid 2a and
benzothiazoline were used for asymmetric transfer
3
hydrogenation.13d,14,15 Oxidation and asymmetric reduction were
conducted in a two-step, one-pot manner to avoid reagent
quenching. No oxidation was observed in the presence of sole
molecular oxygen (entry 1, Table 1). An extensive investigation
of copper additives suggested that efficient aerobic oxidation was
achieved in the presence of 10 mol % of CuCl2 at 50 ºC,
furnishing desired (S)-1a in 77% yield with 35% ee (entries 2-7,
Table 1). Further optimization of chiral phosphoric acids
identified 2c to be optimal (entries 7-9, Table 1). Performing the
asymmetric transfer hydrogen in mesitylene provided (S)-1a in
85% yield with 91% ee (entry 10, Table 1). The reaction was not
sensitive to moisture, and molecular sieves as additive did not
afford improvement on ee (entry 11, Table 1). Increasing the
loading of phosphoric acid 2c did not give superior ee (entry 12,
Table 1).
The scope of aerobic one-pot deracemization of α-aryl
glycine esters was next investigated (Scheme 1). In general,
substrates bearing electronically varied aryl groups at α-
position with diverse substituent patterns were effectively
deracemized, affording respective 1a-1l with excellent ee
(90%-99%). Higher efficiency was observed for substrates
bearing an electron-rich α-aryl group. Polyarene substituted
glycine esters were also suitable components, as
CuCl2, O2
ClCH2CH2Cl, 50 C
PMP
H
PMP
HN
Ph
N
(a)
CO2Me
Ph
CO2Me
1a
4
, 93%
rac-
PMP
PMP
N
2c
3
HN
Ph
,
(b)
mesitylene, 50 C
Ph
CO2Me
CO2Me
4
1a
(S)-
O2, CuCl2
ClCH2CH2Cl, 50 C
PMP
PMP
H
94%, 92% ee
HN
Ar
HN
Ar
2c
3
,
then
CO2R
CO2R
O2, CuCl2
ClCH2CH2Cl, 50 C
mesitylene, 50 C
PMP
HN
PMP
H
HN
Ph
1
(S)-
1
rac-
(c)
PMP = 4-MeOC6H4
2c 3
,
then
Ph
CO2Me
1a
CO2Me
mesitylene, 50 C
1a
(S)-
77%, 88% ee
rac-
1.0 mmol
PMP
HN
PMP
PMP
HN
HN
CO2Me
CO2Me
CO2Me
1a
Scheme 2. Control experiments
1b
1c
MeO
Me
81%, 91% ee
79%, 96% ee
85%, 91% ee
In conclusion, an effective redox deracemization of α-
aryl glycine esters has been described. The one-pot redox
process consisted of CuCl2 catalysis using molecular oxygen
as terminal oxidant and chiral phosphoric acid catalyzed
asymmetric transfer hydrogenation with benzothiazoline as
hydrogen donor. The reaction exhibited good functional
group tolerance, providing a range of optically active non-
natural α-aryl glycine esters with excellent enantioselectivity.
PMP
HN
PMP
HN
PMP
HN
CO2Me
CO2Me
CO2Me
1e
1f
1d
Cl
F
Ph
77%, 90% ee
80%, 94% ee
83%, 95% ee
PMP
HN
PMP
HN
PMP
HN
MeO
Cl
CO2Me
CO2Me
CO2Me
1h
1i
1g
F3C
78%, 96% ee
76%, 91% ee
72%, 94% ee
Acknowledgments
PMP
HN
PMP
HN
PMP
HN
MeO
F3C
F
CO2Me
CO2Me
CO2Me
This work was financial supported by the Natural Science
Foundation of China (21722204, 21971148).
1j
1l
1k
74%, 97% ee
70%, 96% ee
81%, 99% ee
OMe
CF3
Boc
HN
PMP
HN
PMP
HN
H
Supplementary Material
CO2Me
CO2Me
CO2Me
1o
1m
1n
no oxidation
The spectra of the products associated with this manuscript
can be found in the supporting information.
83%, 99% ee
79%, 97% ee
PMP
PMP
HN
H
HN
H
References and notes
C5H11
CO2Me
CO2Et
1p
1q
1.
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Scheme 1. Scope of α-aryl glycine esters.

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• Redox deracemization of α-aryl glycine esters
• Molecular oxygen as terminal oxidant