Kinetic Resolution of Oxaziridines via Chiral Bifunctional Guanidine-Catalyzed Enantioselective α-Hydroxylation of β-Keto Esters

Article abstract of DOI:10.1021/acs.orglett.6b01614

An efficient kinetic resolution of racemic oxaziridines has been realized via catalytic asymmetric α-hydroxylation of available β-keto esters. In the presence of a chiral bifunctional guanidine catalyst, a variety of optically active oxaziridines and chir

Full text of DOI:10.1021/acs.orglett.6b01614

Letter
pubs.acs.org/OrgLett
Kinetic Resolution of Oxaziridines via Chiral Bifunctional Guanidine-
Catalyzed Enantioselective α‑Hydroxylation of β‑Keto Esters
Xiaobin Lin, Sai Ruan, Qian Yao, Chengkai Yin, Lili Lin, Xiaoming Feng, and Xiaohua Liu*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
S
* Supporting Information
ABSTRACT: An efficient kinetic resolution of racemic oxazir-
idines has been realized via catalytic asymmetric α-hydroxylation of
available β-keto esters. In the presence of a chiral bifunctional
guanidine catalyst, a variety of optically active oxaziridines and
chiral α-hydroxy β-keto esters were generated with excellent results
(ee’s of up to 99% and 97% and yields of up to 44% and 54%,
respectively).
xaziridines, compounds containing O, N, and C atoms in
a three-membered ring, are important synthons, such as
double purpose: asymmetric α-hydroxylation and KR of
oxaziridines (Scheme 1c).
O
oxygen- or nitrogen-transfer reagents1 and 1,3-dipoles.1f
Optically active oxaziridines could directly participate in
stereoselective oxidation1f,2 and cycloaddition reactions.3 In
the past few years, methods related to the asymmetric synthesis
of nonracemic oxaziridines were reported. Asymmetric
oxidation of imines provides direct access to enantiopure
oxaziridines.4 Moreover, kinetic resolution5 (KR) of racemic
oxaziridines provides an alternative approach.3,6 For instance,
our group developed an efficient KR of oxaziridines via
organocatalytic oxyamination of azlactones (Scheme 1a).3
The asymmetric α-hydroxylation reaction of 1,3-dicarbonyl
compounds provides direct access to α-hydroxy dicarbonyl
compounds. A number of chiral metal complex catalysts have
been successfully employed for this purpose using oxaziridines
as the oxidants.7 In addition, Wang, Qu, and co-workers
developed a chiral guanidine featuring a tartaric acid skeleton to
promote the α-hydroxylation reaction.8 Although moderate to
good enantioselectivity of α-hydroxylation was achieved, in
these cases enantiomeric discrimination of oxaziridines was not
studied. Chiral guanidines, which play a prominent role in
organocatalysis,9 have attracted increasing attention during the
past two decades. Our group has developed a class of
bifunctional chiral guanidine catalysts from amino acids.9d
They have been widely applied to various organocatalyzed
asymmetric reactions3,10 because of their strong basicity11 and
capacity to form multiple intermolecular hydrogen bonds12
between the catalyst and substrates.13 Herein we utilized an
acyclic guanidine−amide catalyst to achieve KR of oxaziridines
and asymmetric α-hydroxylation of β-keto esters simulta-
neously. The reactions performed well for a wide range of
oxaziridines and indanone-derived β-keto esters, providing
excellent yields and enantioselection.
Scheme 1. Kinetic Resolution of Oxaziridines
In our initial study, we chose racemic N-sulfonyl oxaziridine
( )-1a and 0.5 equiv of β-keto ester 2a as the starting
substrates. A complete transformation occurred once the two
reactants were mixed at room temperature. Therefore,
evaluation of the chiral organocatalysts for the asymmetric α-
hydroxylation reaction was carried out at −78 °C, and post-
treatment was run until β-keto ester 2a was consumed. Chiral
bisguanidinium hemisalt BGs, which is efficient in oxy-
amination reaction of oxaziridines, provided α-hydroxy β-keto
Subsequently, the Yoon group reported an iron-catalyzed
kinetic resolution of N-sulfonyl oxaziridines via rearrangement
of one enantiomer of the oxaziridine to the corresponding N-
sulfonyl imide (Scheme 1b).6b However, the relative rate (s
factor) should be improved so much more. Our previous study
on KR of oxaziridines via oxyamination was hampered by the
diastereomer differentiation induced by the chiral catalyst and
oxaziridine. Given the extensive use of oxaziridines as
electrophilic oxygen donors,1a−c,e,f we sought to follow a
Received: June 4, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01614
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Letter
ester 3a with 54% ee and the recovered (R,R)-oxaziridine 1a
with 50% ee (Table 1, entry 1). The subunits of the chiral
(entry 8). Moreover, the application of 0.55 equiv of 2b gave
the best results (54% yield with 95% ee for the product 3b and
44% yield with 99% ee for the recovered 1a; entry 9). When the
catalyst loading of G4 was reduced to 5 mol %, the good results
were maintained (entry 10). The enantioselectivity of the
recovered oxaziridine had a slight drop at 2 mol % catalyst
loading (entry 11). Further modification of the amide
substituent with smaller steric hindrance resulted in reduced
enantioselection (entries 12 and 13). Thus, this system of G4
was selected to probe the scope of asymmetric hydroxylation
and KR of oxaziridines.
a
Table 1. Optimization of the Reaction Conditions
We next explored the scope of oxaziridines 1 that participate
in the α-hydroxylation of β-keto ester 2b, with a focus on KR of
the oxaziridines (Table 2). Racemic oxaziridines containing C-
a
Table 2. Scope of Oxaziridines
1a (%)
3 (%)
b
c
b
c
entry
cat.
yield ; ee
yield ; ee
1
2
3
4
5
6
7
8
BGs
G1
G2
G3
G4
G5
G6
G4
G4
G4
G4
G7
G8
47; 50 (R,R)
45; 7 (R,R)
47; 21 (S,S)
47; 0
49; 54 (R)
49; 25 (R)
48; 11 (S)
48; 0
47; 75 (S,S)
45; 0
49; 74 (R)
49; 19 (R)
48; 7 (R)
49; 97 (R)
54; 95 (R)
54; 95 (R)
54; 94 (R)
54; 91 (R)
54; 71 (R)
46; 25 (S,S)
47; 90 (S,S)
44; 99 (S,S)
44; 99 (S,S)
42; 96 (S,S)
44; 92 (S,S)
44; 75 (S,S)
d
9
de
,
10
11
12
13
df
,
de
,
de
,
a
Unless otherwise noted, all reactions were carried out with catalyst
(10 mol %), 1a (0.20 mmol), and 2 (0.10 mmol) in THF (1.0 mL) at
b
−78 °C for 72 h (entries 1−7, 2a; entries 8−13, 2b). Isolated yields
c
according to the amount of 1a. The ee values were determined by
HPLC analysis and the absolute configurations by comparison with
d
e
f
refs 3 and 7d. 2 (0.11 mmol). G4 (5 mol %). G4 (2 mol %).
guanidines, including the amide and the amino acid backbone,
are crucial for its basicity and the stereoenvironment.10,13 The
choice of catalyst has a major impact on the selectivity of
hydroxylation (entries 2−7). It was found that chiral
guanidine−amides G1−G3, G5, and G6 derived from L-proline,
L-pipecolic acid, and L-ramipril all failed in terms of
enantioselectivity. To our delight, an obvious increase in
enantioselectivity was observed when chiral guanidine G4
derived from (S)-tetrahydroisoquinoline-3-carboxylic acid was
used, and the reaction performed well with 75% ee for the
recovered (S,S)-oxaziridine 1a and 74% ee for the product 3a
(entry 5). With the purpose of improving the ee value of the
recovered oxaziridine 1a, next we investigated the influence of
the ester group of the β-keto ester.7b−e Steric hindrance of the
β-keto ester turned out to be an important factor. When β-keto
ester 2b bearing an adamantyl group was subjected to the
catalytic system, the corresponding product 3b and the
oxaziridine 1a were given in 97% and 90% ee, respectively
a
Unless otherwise noted, the reactions were performed with G4 (5
mol %), 1 (0.20 mmol) and 2b (0.11 mmol) in THF (1.0 mL) at −78
°C for 72 h. Ad = 1-adamantyl. Isolated yields according to the
amount of 1. Determined by chiral HPLC analysis. With 1a (6.0
mmol) and 2b (3.3 mmol) in THF (30 mL). At −60 °C.
b
c
d
e
aryl substituents with various electronic properties at the para
and meta positions gave the corresponding enantiomerically
enriched isomers in excellent yields (39−44% yield with 92−
99% ee; entries 1−13). Meanwhile, α-hydroxy β-keto ester 3b
was given in 52−54% yield with 90−95% ee. However, the
reaction of oxaziridine 1n bearing a 2-methylphenyl substituent
resulted in decreased enantioselectivity due to the steric
hindrance, and the substrate 1n was recovered with 63% ee
B
DOI: 10.1021/acs.orglett.6b01614
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Letter
(entry 14). 1-Naphthyl-substituted oxaziridine 1o was obtained
with moderate ee in lower yield (entry 15). Oxaziridine 1p with
a C-cyclohexyl substituent underwent the asymmetric α-
hydroxylation smoothly, and the KR process gave the
corresponding oxaziridine with 83% ee at an increased reaction
temperature (−60 °C; entry 16). The resolution of 4-bromo-
substituted N-benzenesulfonyl oxaziridine 1r was more
selective than that of 4-nitro-substituted N-benzenesulfonyl
oxaziridine 1q (entries 17 and 18). Notably, oxaziridines 1e,
1m, 1n, 1o, 1q, and 1r decomposed gradually during the
reaction, which resulted in lower recovered yields (entries 5,
13−15, 17, and 18). We also examined the large-scale
resolution of a racemic oxaziridine and found that this protocol
is readily scalable. The KR of racemic oxaziridine 1a on a gram
scale was as efficient as the model reaction without any
decrease in yield and enantioselectivity, as optically pure
oxaziridine 1a was obtained in 44% yield along with α-hydroxy
β-keto ester 3b with 95% ee in 54% yield (entry 1).
Figure 1. Proposed asymmetric induction models.
2b is blocked by the amidine backbone, and the oxygen-transfer
reagent has to approach from the less hindered Re face,
generating (R)-3b. The enantiomeric recognition of the
oxaziridine is controlled by the amide subunit of the catalyst.
An intermolecular hydrogen bond between the Ts group of
oxaziridine 1a and the amide of the catalyst occurs. (R,R)-1a
gets close more easily than its enantiomer and is consumed in
the α-hydroxylation reaction. Nevertheless, steric hindrance
between the catalyst and the oxidant is generated when the
(S,S) isomer is used, between the C-aryl substituent of 1a and
the tetrahydroisoquinoline backbone of G4 and also between
the Ts group of 1a and the triphenylmethanamine substituent
of G4. Therefore, (S,S)-1a is inactive and can be recovered
enantioselectively.
To summarize, we have developed a chiral bifunctional
guanidine-catalyzed synchronous α-hydroxylation of β-keto
esters and kinetic resolution of oxaziridines. A variety of
oxaziridines and β-keto esters are well-tolerated, affording the
corresponding oxaziridines and α-hydroxy β-keto esters in
excellent yields and enantioselectivities. The resolution could
easily be performed on a gram-scale preparation without loss of
selectivity or yield. The performance of this type of bifunctional
organocatalyst in asymmetric transformations will stimulate
further efforts to explore new applications.
Next, the scope of β-keto esters 2 was probed through α-
hydroxylation with oxaziridine 1a (Table 3). A representative
a
Table 3. Substrate Scope of β-Keto Esters
1a (%)
3 (%)
b
c
b
c
entry
1
R3
yield
ee
yield
ee
6-Cl
43
43
43
43
40
44
96
93
95
94
99
90
50 (3c)
54 (3d)
54 (3e)
52 (3f)
54 (3g)
49 (3h)
96
93
93
96
95
97
d
2
6-Me
6-MeO
5-Cl
3
4
5
6
5-F
4-Br
a
Unless otherwise noted, the reactions were performed with G4 (5
mol %), 1a (0.20 mmol), and 2 (0.11 mmol) in THF (1.0 mL) at −78
b
°C for 72 h. Ad = 1-adamantyl. Isolated yields according to the
c
d
amount of 1a. Determined by chiral HPLC analysis. At −60 °C.
selection of inden-1-one-derived β-keto esters with different
substituent at C4, C5, and C6 (2c−h) were used in the
reaction. The related α-hydroxylation products 3c−h were
obtained in 49−54% yield with excellent enantioselectivity
(93−97% ee), and the unreacted (−)-oxaziridine 1a was
recovered in reasonable yields (40−44%) with 90−99% ee. The
reaction of β-keto ester 2d bearing a 6-methyl substituent had
to be conducted at −60 °C (entry 2). Comparatively, the 4-
bromo substituent of substrate 2h had an effect on the
resolution of the oxaziridine, although the highly enantiose-
lective product 3h was generated (49% yield with 97% ee; entry
6). Unfortunately, a tetralone-derived β-keto ester underwent
the reaction without enantioselection at 35 °C (see the
Supporting Information for details).
The absolute configurations of the recovered oxaziridine 1a
and the α-hydroxylation product 3b were determined to be
(S,S) and (R), respectively, by comparison of the optical
rotations with those reported in the literature.3,7d On the basis
of previous studies employing guanidine−amides as bifunc-
tional organocatalysts,10a a possible catalytic model was
proposed. As depicted in Figure 1, the guanidine subunit of
catalyst G4 acts as a base, on which strong zwitterionic
hydrogen bonds with β-keto ester 2b can be tied. The Si face of
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01614.
■
S
Experimental details and analytical data (NMR, HPLC,
and ESI-HRMS) (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: liuxh@scu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21222206, 21332003, and 21321061), the Fok Ying Tung
Education Foundation (141115), and the National Program for
Support of Top-Notch Young Professionals for financial
support.
C
DOI: 10.1021/acs.orglett.6b01614
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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