Visible Light-Induced Salan-Copper(II)-Catalyzed Enantioselective Aerobic α-Hydroxylation of β-Keto Esters

Article abstract of DOI:10.1002/adsc.201801263

A strategy of visible light-induced salan-copper(II)-catalyzed asymmetric α-hydroxylation of β-keto ester with utilization of sustainable air as the oxidant was developed. This protocol allows convenient access to a number of enantioenriched α-hydroxyl β-keto esters (up to 95% yield, 96% ee), especially for β-keto methyl esters that are valuable architectures in pharmaceuticals, including the key intermediate of the sodium-channel blocker (S)-indoxacarb. Experimental studies suggest that reactive singlet oxygen may participate in this reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.201801263

Title: Visible Light-Induced Salan-Copper(II)-Catalyzed
Enantioselective Aerobic α-Hydroxylation of β-Keto Esters
Authors: Fan Yang, Jingnan Zhao, Xiaofei Tang, yufeng wu, Zongyi
Yu, and Qingwei Meng
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10.1002/adsc.201801263
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Visible Light-Induced Salan-Copper(II)-Catalyzed
Enantioselective Aerobic α-Hydroxylation of β-Keto Esters
Fan Yang, Jingnan Zhao, Xiaofei Tang, Yufeng Wu, Zongyi Yu, Qingwei Meng*
a
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of
Technology, Dalian 116024, P. R. of China.
Fax +86(0411)84986201; e-mail: mengqw@dlut.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A strategy of visible light-induced salan-
copper(II)-catalyzed asymmetric α-hydroxylation of β-keto
ester with utilization of sustainable air as the oxidant was
developed. This protocol allows convenient access to a
number of enantioenriched α-hydroxyl β-keto esters (up to
95% yield, 96% ee), especially for β-keto methyl esters that
are valuable architectures in pharmaceuticals, including the
key intermediate of the sodium-channel blocker (S)-
indoxacarb. Experimental studies suggest that reactive
singlet oxygen may participate in this reaction.
Keywords: asymmetric catalysis; visible light catalysis;
aerobic oxidation; salan-copper(II); α-hydroxylation
Recently, visible light photocatalysis has offered a
technically attractive and energy-saving platform for
aerobic oxidation.[1] In particular, the reactivity of
singlet oxygen (1O2) has been applied to visible light
activated asymmetric catalysis in recent years.[2]
However, the stereoselectivity control of the
enantioselective hydroxylation reaction using
photogenerated 1O2 as the terminal oxidant still
remains a challenge, and work in this field has rarely
been reported.[3] Specifically, our group first reported
on the chiral phase-transfer catalyzed aerobic
transformation using tetraphenylporphyrin (TPP) as
the photosensitizer (Scheme 1b),[3a] while Xiao et al.
Scheme 1. Importance of α-hydroxylation of β-keto esters
reported the asymmetric aerobic oxidation reaction
and approaches for their formation.
by bifunctional photocatalyst-Ni(II) catalysis
(Scheme 1c).[3c] However, current methods are
esters bearing bulky ester groups,[3,9] and an
additional transesterification step is required for
synthesis of the abovementioned biological molecules.
Given these important advances, the direct
enantioselective hydroxylation of valuable β-keto
esters from sustainable, environmentally benign
molecular oxygen remains an important yet elusive
goal. Within this field, we sought to develop a new
approach based on asymmetric photocatalysis to
provide highly enantioselective access toward a broad
limited in application due to their dependence on the
use of either structurally complex catalysts or the
steric induction of substrate itself to generate the
requisite chiral environment.
Enantioenriched α-hydroxy β-keto esters, and
particularly the those containing methyl ester
compounds, are prevalent in a wide range of
bioactive natural products and pharmaceuticals,[4]
including Kjellmanianone,[5] Vindoline,[6] Hamigeran
A,[7] and Indoxacarb (Scheme 1a).[8] However, in
previous studies, consistently high yields and
enantioselectivities were achieved only for the β-keto
1
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10.1002/adsc.201801263
Advanced Synthesis & Catalysis
range of α-hydroxy β-keto ester bearing smaller ester
groups;
such esters are highly valuable architectures but are
challenging and difficult to achieve directly.
We started our study of this topic by investigating
the asymmetric α-hydroxylation of 5-chloro indanone
carboxylic methyl ester 1a that served as the model
reaction. In previous work, we demonstrated that
using cumene hydro peroxide as the oxidant, the
salan-Zr complex[10] can catalyze the α-hydroxylation
of β-keto methyl esters with excellent yields and
enantioselectivities. Inspired by this result, we
became interested in further exploring the potential of
the easily prepared salan-metal complex-catalyzed
asymmetric α-hydroxylation of β-keto esters 1a under
visible light and aerobic conditions (Scheme 1d). We
initially investigated a series of metal salts such as Zr,
Ti, Mn, and Cu chelated with the bionic salan ligand
L1 to catalyze the α-hydroxylation reaction (Table,
entries 1-4) in the presence of accessible TPP as the
Table 1. Screening of Reaction Conditionsa
1
photosensitizer to produce O2 from air under white
compact fluorescent lamp (CFL) irradiation
conditions. Gratifyingly, the desired product 2a was
obtained in 28% yield with 46% ee by using copper
as the central metal. Then, we modified the catalysts
with different copper salts (Table 1, 5-7 entries) and
found that the counterions had a crucial influence in
the reaction. To our delight, the combination of
Cu(OTf)2 with L1 afforded the desired product 2a in
excellent yield and moderate enantioselectivity
(Table 1, entry 7). When the phenyls (L2) were used
instead of tert-butyls (L1), the enantioselectivity
clearly decreased (Table 1, entry 8). The use of the
ligand with C1-symmetry (L3) led to the decreased
yield and enantioselectivity of product 2a (Table 1,
Yieldb eec
Entry Lewis acid
Solvent
L1 toluene
Lig
(%)
72
89
27
28
44
52
92
86
73
93
76
84
92
47
93
92
93
94
92
91
(%)
18
0
1
Zr(acac)4
2
Ti(O-iPr)4 L1 toluene
Mn(OAc)2 L1 toluene
3
7
4
CuCl2
L1 toluene
46
48
34
51
24
42
67
31
49
49
50
20
84
90
96
89
77
84
5
Cu(ClO4)2 L1 toluene
6
Cu(acac)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
L1 toluene
L1 toluene
L2 toluene
L3 toluene
L4 toluene
L5 toluene
L6 toluene
L7 toluene
L8 toluene
L9 toluene
L4 toluene
L4 toluene
L4 toluene
L4 toluene
L4 o-xylene
entry
diphenyldiamine provided the chiral source of the
ligand (L4), excellent yield and good
9).
Nevertheless,
when
(1S,
2S)-
7
8
enantioselectivity were observed (Table 1, entry 10).
The yields and enantioselectivities decreased rapidly
when tert-butyls of L4 were replaced by different
aromatic rings (Table 1, entries 11, 12). Although the
excellent yield can be obtained by the combination of
Cu(OTf)2 and L7, only moderate enantioselectivity
was obtained (Table 1, entry 13). According to the
results of entries 10-13, it was revealed that the tert-
butyls on the both ortho- and para-positions of the
hydroxyl groups in the ligands had a significant
impact on the enantioselectivities of the α-
hydroxylation because of their steric hindrance and
electron donation effect. When different sterically
hindering groups such as trimethylsilyl L8 and
triisopropylsilyl L9 were used instead of tert-butyls,
good to excellent yields and only moderate
enantioselectivities were obtained (Table 1, entries 14,
15). When the Cu(OTf)2 was activated by vacuum
drying, the better enantioselectivity 84% ee can be
observed (Table, entry 16). In order to prevent the
in-situ generation of the salan-copper(II) from being
affected by the water vapor, the air dried by 4 Å
molecular sieves was slowly injected via an air pump
into the reaction flask, the enantioselectivity was
improved to 90% ee (Table 1, entry 17). Lower
reaction temperatures and the loading of TPP were
9
10
11
12
13
14
15
16 d
17d,e
18d-f
19 d,e,g Cu(OTf)2
20 d,e,g Cu(OTf)2
21 d,e,g Cu(OTf)2
L4 mesitylene 90
a)
Unless otherwise noted, reactions are conducted with 1a
(0.2 mmol), 5 mol % photosensitizer under visible light
and air for 15 h. Isolated yields. c) Determined by HPLC
b)
on chiral stationary. d) Activation of Cu(OTf)2 in a vacuum
e)
f)
oven at 110 oC. Dried air by 4 Å MS.
performed at -15 °C, TPP 2.5 mol %.
performed at -20 °C, TPP 2.5 mol %.
Reaction
Reaction
g)
2
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10.1002/adsc.201801263
Advanced Synthesis & Catalysis
beneficial for the ee value of α-hydroxyl-β-keto ester
induced asymmetric α-hydroxylation reactions. As
shown in Table 2, a wide range of β-keto esters can
effectively participate in the reaction to create the
desired products. The unsubstituted indanone
carboxylic methyl ester 2b gave slightly worse results
than those obtained for 2a (89% yield and 89% ee).
There were some slight fluctuations in the
enantioselectivities of the 5- or 6-position halogen-
substituted substrates (84%-93% ee, 2d-2g). However,
a much lower ee value was obtained by the 4-bromo-
substituted substrate (58% ee, 2c). When electron-
donating methoxyl groups were introduced to the
meta-positions of the carbonyl in the aromatic ring,
good yields and ee values were observed (up to 96%
ee, 2h, 2i, and 2k). Unexpectedly, the
enantioselectivity declined to 73% ee when the
methoxyl group was on the para-position of the
carbonyl (2j). The substrates with more hindered
substituents replacing methoxyl of 1k were also
examined and were successfully transformed into α-
hydroxylation products with satisfactory yields and
enantioselectivities (71%-90% yields, 78%-86% ee,
2l-2n). In addition to investigating the effects of the
substituents of the aromatic ring, various ester groups
were also examined. To our delight, most ester
groups were tolerated in this transformation.
Interestingly, the yields and ee values of the
corresponding products decreased for more hindered
substituents on the ester side of the substrates (83%-
90% yields, 58%-93% ee, 2o-2s). Better results were
obtained for the substrates with smaller ester groups
than for the substrates with the larger ester groups,
which is very different from the results of the
previous studies.[3,9]
product (Table 1, entries 18, 19), and the
Table 2. Enantioselective α-Hydroxylation of β-Keto
estersa
To highlight the utility of this enantioselective α-
hydroxylation, we carried out further transformations
of the obtained α-hydroxyl products (Scheme 2). The
enantioenriched 2a was improved to >99% ee (S)
after the recrystallization. The product 2a was
smoothly converted into chiral pinacol 3a by NaBH4
reduction, providing a useful method for the synthesis
of highly substituted α,β-dihydroxyl esters. Moreover,
the catalytic product 2a can be easily protected by
acylation to afford 4a without a decrease in the
enantioselectivity. Significantly, the triethylamine
catalyzed ketone-hydrazine condensation reaction
was used to transform product 2a into α-hydroxyl
hydrazone 5a with high yield and 99% ee, and then
5a could be further modified to afford the sodium-
channel blocker pesticide (S)-indoxacarb.[8]
a)
Unless otherwise noted, the reactions were performed
under the optimal conditions as indicated in Table 1, entry
15. All yields are isolated yields, and ee values were
determined by chiral HPLC. b) The reaction was performed
for 24 h.
enantioselectivity increased to 96% ee. The
enantioselectivities decreased dramatically when
other aromatic solvents were used (entries 20, 21).
Control experiments indicated that visible light,
copper salt, chiral ligand, photosensitizer, and air
were essential for this transformation (Table S3).
After further screening of additional solvents,
temperatures, and photosensitizers, the best
conditions for α-hydroxylation were as follows: L4
with Cu(OTf)2 as the catalyst and TPP as the
photosensitizer in toluene at -15 °C under white CFL
irradiation.
Experiments were conducted under the optimized
conditions to probe the substrates of this visible light-
3
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10.1002/adsc.201801263
Advanced Synthesis & Catalysis
Variation of standard
conditions
Entry
yielda (%)
ee b (%)
1
2
3
4
1,1-diphenylethylene
TEMPO
DABCO
93
94
34
97
93
96
N.D.
N.D.
D8-toluene
100%
80%
60%
40%
20%
0%
Toluene
D8-Toluene
Scheme 2. Further transformations of the α-hydroxyl-β-
keto ester compounds.
0h 2h 4h 6h 8h 10h 12h 14h
a)
b)
isolated yields.
Determined by chiral HPLC
analysis. N.D., not determined.
To gain an understanding of the mechanism of the
reaction, we performed some control experiments.
The reaction proceeded well in the presence of the
1,1-diphenylethylene or the radical trap 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) to produce
the desired chiral product 2a in 93% yield and 93%
ee or 94% yield and 96% ee, respectively (Table 3,
entries 1, 2).[11] Thus, the visible light-induced
reactions indicated that a radical process may not be
involved in the present transformation. By contrast,
hydroperoxide 12a is a strong oxidant with high
reactivity.
Based on these results and the results obtained in
previous studies,[10,15] a plausible induction model is
proposed in Scheme 3 . It is assumed that the
aromatic ring of 1a was located away from the chiral
ligand to avoid possible stereo-selection. The Re-face
of the enolate intermediate was effectively shielded
1
when the O2 inhibitor 1,4-diazabicyclo-[2,2,2]octane
1
(DABCO)[12] was added to the model reaction, a
greatly reduced product yield was observed (Table 3,
entry 3, 15 h, 34% yield). Furthermore, replacing
toluene with D8-toluene resulted in an accelerated
reaction (toluene, 15 h, 97% yield; D8-toluene, 10 h,
by the back t-Bu group. Thus, the oxidants, O2 or α-
hydroperoxide 12a, could only attack the enolate
from the Si-face, resulting in the α-hydroxylation
product 2a with the S-configuration. We proposed
that a methyl group in this process is more conducive
to approach the chiral catalyst center, which
explained the reason why methyl-substituted group in
this work can achieve better results in opposite to
previous works, in which only substrates with large
steric hindrance group, such as adamantyl group,
gave good results.
1
97% yield, see SI 6.2). The lifetimes of O2 were
found to be strongly dependent on the solvents; for
example, comparison of D8-toluene (τΔ = 280 μs) and
1
toluene (τΔ = 29 μs) showed that the rate of O2
reactions was higher in deuterated solvents.[13] These
1
results suggested the presence of photoexcited O2 in
this reaction system. Therefore, the detection of the
intermediate formed by reactive 1O2 with substrate 1a
was carried out, and the intermediate α-
hydroperoxide β-keto ester 12a was observed though
HRMS. Notably, a-hydroperoxide 12a was the major
product when the photooxygenation reaction was
carried out under 10 bar of O2 in a flow photoreactor.
Then, substrate 1a was added into the reaction
mixture, and the intermediate 12a smoothly reacted
with the substrate resulting in the formation of the α-
hydroxylation product 2a under dark and airtight
conditions (see SI 6.3).[14] This suggests that the α-
Table 3. Control Experiments
Scheme 3. Plausible salan-copper(II)-catalyzed route of α-
hydroxylation.
4
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10.1002/adsc.201801263
Advanced Synthesis & Catalysis
In conclusion, using the easily prepared salan
Niu, H. Yi, A. W. Lei, Asian J. Org. Chem. 2017, 6,
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ligand as a stereoselective controller and green
sustainable air as the oxidant, we have developed a
practical, efficient, and safe protocol for visible light-
induced salan-copper(II)-catalyzed asymmetric α-
hydroxylation of β-keto esters. Cyclic substrates were
converted to the corresponding α-hydroxyl products
with good to excellent yields and enantioselectivities
(up to 95% yield, 96% ee), particularly for the
substrates with smaller ester groups which until now
were difficult to achieve. Tetraphenylporphyrin was
introduced as the photosensitizer to produce singlet
oxygen from unreactive triplet oxygen under visible
light irradiation to participate in the reactions. The
importance of this transformation was highlighted
through the synthesis of the key intermediate of (S)-
indoxacarb. Further investigations of the synthetic
application of this transformation and the exploration
of the scope of α-hydroxylation are underway in our
laboratory.
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A dried 10 mL Schlenk tube equipped with a magnetic stir
bar was charged with Cu(OTf)2 (7.2 mg, 0.02 mmol), salan
ligand L4 (14.24 mg, 0.022 mmol) and toluene 2 mL. The
mixture was stirred at 50 °C for 30 min in the dark and N2
atmosphere. Then, the mixture was cooled to -15 °C. Then,
the methyl 5-chloro-1-oxo-2,3-dihyhydro-1H-indene-2-
carboxylate (44.9 mg, 0.2 mmol), and TPP (3.1 mg, 0.005
mmol) were added while air (dried by 4 Å MS) was slowly
injected via air pump into the reaction flask and the
reaction mixture was stirred under irradiation of a 25 W
white compact fluorescent lamp (distance 3 cm). The
resulting solution was stirred at -15 °C for 15 h. After the
reaction was completed the solution of the crude product
was concentrated in vacuo, and the residue was purified by
column chromatography on a silica gel (petroleum
ether/ethyl acetate = 5/1) to afford the product 2a (45.2 mg,
94% yield, 96% ee) as a white solid.
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Acknowledgements
We would like to thank the National Natural Science Foundation
of China (Nos. 21476041, U1608224, 61633006) and the State
Key Laboratory of Fine Chemicals for their support.
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5
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10.1002/adsc.201801263
Advanced Synthesis & Catalysis
UPDATE
Visible Light-Induced Salan-Copper(II)-Catalyzed
Enantioselective Aerobic α-Hydroxylation of β-
Keto Esters
Adv. Synth. Catal. Year, Volume, Page – Page
Fan Yang, Jingnan Zhao, Xiaofei Tang, Yufeng
Wu, Zongyi Yu, Qingwei Meng*
6
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