Dynamic kinetic asymmetric transformations of β-halo-α-keto esters by N,N′-dioxide/Ni(II)-catalyzed carbonyl-ene reaction

Article abstract of DOI:10.1039/c8cc04993a

Dynamic kinetic asymmetric transformations of racemic β-halo-α-keto esters through carbonyl-ene reaction were realized using a chiral N,N′-dioxide-nickel(ii) complex, giving the corresponding β-halo-α-hydroxy esters containing two vicinal chiral tri- and tetrasubstituted carbon centers in good yields and dr with excellent ee values without the use of extra bases. Meanwhile, a proposed reaction mechanism was presented according to the configuration of the product.

Full text of DOI:10.1039/c8cc04993a

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DOI: 10.1039/C8CC04993A
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Dynamic kinetic asymmetric transformations of -halo--keto
esters by N,N-dioxide/Ni(II)-catalyzed carbonyl-ene reaction
Wen Liu, Weidi Cao,* Haipeng Hu, Lili Lin and Xiaoming Feng*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Dynamic kinetic asymmetric transformations of racemic -halo--
keto esters through carbonyl-ene reaction were realized by using a
chiral N,N-dioxide-nickel(II) complex, giving the corresponding -
halo--hydroxy esters containing two vicinal chiral tri- and
tetrasubstituted carbon centers in good yields and dr with excellent
ee values without the use of extra bases. Meanwhile, a proposed
reaction mechanism was presented according to the configuration
of the product.
Dynamic kinetic asymmetric transformations (DyKATs), which
overcome the drawback of the theoretical maximum 50% yield
in classical resolutions, are potent methods for the synthesis of
enantioenriched molecules from racemic starting materials.1
DyKATs conceptually refer to a process involving a chiral
catalyst-mediated racemization of substrate enantiomers, and
subsequent kinetic resolution leading to an enantioenriched
product. Enantioconversion of racemic
-stereogenic -keto
esters is a prevalent protocol accessing to highly functionalized

-substituted glycolates containing two vicinal stereocenters,2-
generally including asymmetric transfer hydrogenation2 and
5
direct addition to the ketone carbonyl.3-5 Calter’s group
Scheme 1 Background and proposal
reported the “interrupted” Feist-Bénary reactions of racemic
stereogenic -keto esters catalyzed by cinchona alkaloid
catalysts.3 Wang’s group developed
dynamic kinetic
-

initial racemization of
-bromo--keto esters which
a
subsequently occurred direct aldolization with nitromethane or
acetone to give the corresponding products (Scheme 1a).5a
Carbonyl-ene reaction is one of the most powerful tools for
the atom-economical formation of the C−C bond. A lot of
enantioselective carbonyl-ene reactions were documented with
the development of asymmetric catalysis over the past
decades.6 In recent years, our group developed a type of C2
resolution (DKR) of these typological substrates through
cooperative catalysis.4 Johnson’s group made a great progress
by developing diverse asymmetric reactions in this regard, such
5
as annulation, arylation and so on.2, To the best of our
knowledge, most of these cases focused on DKR by introducing
extra bases to assist the racemization of -stereogenic -keto
esters. Only one example through the way of DyKATs was
realized, chiral quinidine derivatives were used to engage in the
symmetric chiral N,N-dioxide ligands, which could combine
with various metal salts,7 and the formed Lewis acid complexes
have been successfully applied in the catalytic asymmetric
carbonyl-ene reactions. The 1,2-dicarbonyl compounds could
be activated by the Lewis acid catalyst in a stable five-
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: wdcao@scu.edu.cn, xmfeng@scu.edu.cn; Fax: +86 28 85418249
†Electronic Supplementary Information (ESI) available. CCDC 1561469. For ESI and
crystallographic data in CIF or other electronic format see DOI:10.1039/x0xx00000x
membered ring fashion, giving the corresponding
-hydroxy
carbonyl compounds (Scheme 1b).8 Therefore, we conceive that
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope of 5-methyleneoxazoline derivativesa
DOI: 10.1039/C8CC04993A
View Article Online
Entry
Ar
3
Yield
(%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
C6H5
3aa
3ab
3ac
3ad
3ae
3af
89
82
77
64
98
81
94
82
93:7
94:6
94:6
94:6
92:8
94:6
93:7
93:7
99
4-BrC6H4
4-MeC6H4
4-PhC6H4
3-ClC6H4
3-MeOC6H4
3,5-Me2C6H3
2-Naphthyl
99
99
99
Entry
Metal salt
Ligand
Yield drc
(%)b
ee
(%)d
99
99
1
2
3
4
5
6
7
8
Fe(ClO4)2·6H2O
Co(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
L-PiPr2
L-PiPr2
L-PiPr2
L-PrPr2
L-RaPr2
L-RaEt2
NR
75
78
69
84
89
-
-
3ag
3ah
99
86:14
87:13
86:14
89:11
93:7
99
99
99
99
99
99
92
99 (S,S)
a Unless otherwise stated, all reactions were performed with 1a (0.1 mmol), 2 (0.2
mmol), and L-RaEt2/Ni(ClO4)2·6H2O (1:1, 10 mol%) in CH2Cl2 (1.0 mL) at 30 °C for 48
h. b Yield of the isolated product. c Determined by 1H NMR of the crude mixture. d
Determined by HPLC analysis on a chiral stationary phase.
L-RaMe2 77
L-RaPh
51
88:12
85:15
the phenyl group had little effect on the diastereo- and
enantioselectivities compared to the model reaction. A lower
yield was observed with the substrate 3d containing a phenyl
substituent at the para-position of the aromatic ring (Table 2,
entry 4). The dimethyl-substituted 2g and naphthyl-substituted
2h could be also tolerated in this reaction and gave good results
(Table 2, entries 7 and 8). The absolute configuration of 3ah was
a Unless otherwise stated, all reactions were performed with 1a (0.1 mmol), 2a (0.2
mmol), and ligand/metal salt (1:1, 10 mol%) in CH2Cl2 (1.0 mL) at 30 °C for 48 h. b
Yield of the isolated product. c Determined by 1H NMR of the crude product.
d
Determined by HPLC analysis on a chiral stationary phase.
the DyKATs of racemic

-halo-

-keto esters can be achieved by determined to be (S,S) by X-ray diffraction crystal analysis.9
Subsequently, we turned our attention to broadening the
substrate scope of the -halo- -keto esters (Table 3). The effect
-keto ester 1a of the ester groups was evaluated firstly. The yields and dr
an N,N -dioxide/metal salt-catalyzed carbonyl-ene reaction

(Scheme 1c).
In our preliminary investigation, -bromo-


and 5-methylene-2-phenyl-4,5-dihydrooxazole 2a were decreased slightly when more sterically hindered ester groups
selected as the model substrates to explore the DyKATs. Initially, were applied to this carbonyl-ene reaction. Chlorine-
various metal salts were screened to coordinate with (S)- substituted
-keto ester 2e could also transform into the
pipecolic acid-derived chiral N,N -dioxide L-PiPr2 in CH2Cl2 at corresponding product 3ea in moderate yield and dr. It was

30 °C (Table 1, entries 1−3). No desired product was observed noteworthy that the products could be formed with 99% ee in
when L-PiPr2/Fe(ClO4)2·6H2O was applied in the reaction. To our
delight, the carbonyl-ene product -bromo--hydroxy ester 3aa
Table 3 Effects of the ester group and halogen substituentsa
could be smoothly obtained in high yields and dr with uniformly
excellent ee values by the use of Co(ClO4)2·6H2O and
Ni(ClO4)2·6H2O, which demonstrated that our hypothesis of the
DyKATs of racemic
the presence of Lewis acid catalyst. The chiral backbone of the
N,N -dioxide ligands had a slight effect on the reaction.
ramipril derived L-RaPr2 is more competent than L-PrPr2 derived
from -proline and L-PiPr2 in terms of dr and yield (Table 1, entry
-stereogenic -keto esters was feasible in

L-
L
5 vs entries 3 and 4). The investigation of the steric hindrance
of the amide moiety showed that L-RaEt2/Ni(ClO4)2·6H2O gave
the best result (entries 5−8).
a Unless otherwise stated, all reactions were performed with 1 (0.1 mmol), 2a (0.2
mmol), and L-RaEt2/Ni(ClO4)2·6H2O (1:1, 10 mol%) in CH2Cl2 (1.0 mL) at 30 °C for 48
h. Yield of the isolated product. Dr was determined by 1H NMR of the crude mixture.
Ee was determined by HPLC analysis on a chiral stationary phase.
With the optimized reaction conditions in hand, a series of 5-
methyleneoxazoline derivatives were probed to react with 1a
,
giving the corresponding -bromo- -hydroxy esters in high yields


and dr with excellent ee values (Table 2). The substituents on
2 | J. Name., 2012, 00, 1-3
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Table 4 Substrate scope of the -halo--keto estersa
View Article Online
DOI: 10.1039/C8CC04993A
Entry
R
3
Yield
(%)b
drc
ee
(%)d
1
2-MeC6H4
2-MeOC6H4
2-ClC6H4
3-MeOC6H4
3-BnOC6H4
3-FC6H4
3fg
84
77
78
89
93
83
96
95
90
84
91
81
96
91
92
76
90:10
94:6
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
2
3gg
3hg
3ig
3
90:10
>95:5
94:6
4
5
3jg
Scheme 2 (a) The gram-scale reaction (b) synthetic utility
6
3kg
3lg
94:6
7
4-MeC6H4
4-iPrC6H4
4-F3CC6H4
4-FC6H4
94:6
dr by using a L-PiPr2/Mg(OTf)2 complex as the catalyst (Table 4,
entry 16).
8
3mg
3ng
3og
3pg
3qg
3rg
3sg
3tg
93:7
To show the synthetic utility of this reaction, a gram-scale
version was conducted as shown in Scheme 2. 1a (4.0 mmol)
reacted with 2a (8.0 mmol) under the optimized reaction
conditions, providing the corresponding carbonyl-ene reaction
product 3aa in 75% yield (1.26 g), 93:7 dr and 99% ee.
9
82:18
89:11
89:11
88:12
>95:5
>95:5
86:14
67:33
10
11
12
13
14
15
16e
4-ClC6H4
4-BrC6H4
3,4-Me2C6H3
2-Naphthyl
1-Naphthyl
Bn
Intramolecular SN2 substitution reaction of
a straightforward way to achieve epoxides. After screening the
reaction conditions, we found that the desired epoxide could
-bromo alcohols is
4
be obtained in high yield by manipulating 3aa with NaBH4 in
MeOH. The C-Br bond of 3aa routinely broke and a new C-N
3ug
bond formed in the presence of NaN3, affording the
-azido--
hydroxy ester without any erosion of the stereoselectivity.
5
a Unless otherwise stated, all reactions were performed with 1 (0.1 mmol), 2g (0.2
mmol), and L-RaEt2/Ni(ClO4)2·6H2O (1:1, 10 mol%) in CH2Cl2 (1.0 mL) at 30 °C for 48
h. b Yield of the isolated product. c Determined by 1H NMR of the crude mixture. d
Determined by HPLC analysis on a chiral stationary phase. e Using L-PiPr2/Mg(OTf)2
(1:1, 10 mol%) as the catalyst.
According to the absolute configuration of product 3ah,9 a
postulated reaction mechanism for this reaction was briefly
illustrated in Scheme 3. The electron withdrawing carbonyl
group and bromine atom allowed the rapid transformation
between two configurationally labile
the presence of the chiral L-RaEt2/Ni(ClO4)2·6H2O complex. The
S-configuration at -position of 3ah (S,S) indicated that the S-
-bromo--keto ester in
all the cases (3ba
Next, the influence of R group of the
was investigated. The carbonyl-ene reaction between the
structurally diverse and 5-methyleneoxazoline derivative 2g
−3ea).

-

-bromo--keto esters
1
1
could smoothly proceed under the optimized reaction
conditions (Table 4). Generally, the electronic nature and
position of substituents on the phenyl group had no effect on
the enantioselectivity of the carbonyl-ene reaction, and the
desired products could be obtained in high yields and dr (Table
3, entries 1
observed with the electron withdrawing substituents installing
on the para-position of the phenyl group (Table 3, entries 9 12).
Disubstituted and 2-naphthyl-substituted -halo- -keto esters 1r
− 12). Decreased diastereoselectivities were
−


and 1s worked well to provide the corresponding products in 96%
and 91% yields with excellent dr and ee values (Table 4, entries
13 and 14, >95:5 dr, 99% ee). The replacement of 2-naphthyl by
1-naphthyl (3tg) led to a decrease of dr without loss of yield and
ee value (Table 4, entry 15). Moreover, the
-bromo--keto
ester 1u bearing a benzyl group at the -position was suitable

to provide the product 3ug in 76% yield with 99% ee and 67:33
Scheme 3 Proposed reaction mechanism and the absolute configuration of 3ah
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Chem. Soc., 2014, 136, 14698; (c) C. G. Goodman, M. M.
bromo-
2h much faster than its enantiomer in the carbonyl-ene reaction.
In addition, based on X-ray crystal structure of the N,N
dioxide/Ni(II) complex,10 a possible activation model was
proposed. The two carbonyl groups of -bromo- -keto ester
-keto ester reacts with 5-methyleneoxazoline derivative
View Article Online
Walker and J. S. Johnson, J. Am. ChemD.OSI:o1c0.,.1203091/5C,81C3C70,4919232A;
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-


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face was masked by the neighboring 2,6-diethylphenyl group of
the ligand. The nucleophile 2h attacked from the Re face
predominantly to give 3ah with S,S-configuration.
In summary, we have developed an N,N
catalytic system to promote the dynamic kinetic asymmetric
transformations of racemic -halo- -keto esters by an
enantioselective carbonyl-ene reaction. series of
corresponding -halo- -hydroxy esters with two vicinal chiral
-dioxide/Ni(II)


A


Kuenkel and R. M. Koenigs, Angew. Chem., Int. Ed., 2008, 47
,
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tri- and tetrasubstituted carbon centers could be smoothly
obtained in good to high dr and excellent ee values under very
mild reaction conditions without the use of bases. A possible
Tan, Z.-L. Shen and T.-P. Loh, J. Am. Chem. Soc., 2010, 132
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catalyst accelerated the racemization of -halo-

-keto esters
and subsequently catalyzed the carbonyl-ene in a resolution
fashion.
We appreciate the National Natural Science Foundation of
China (No. 21432006, and 21772127) for financial support.
7
8
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Conflicts of interest
There are no conflicts to declare.
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