Enantioselective α-Benzoyloxylation of Malonic Diesters by Phase-Transfer Catalysis

Article abstract of DOI:10.1021/acs.orglett.6b02682

A highly enantioselective α-benzoyloxylation of malonic diester has been achieved by phase-transfer catalysis. The reaction of α-monosubstituted tert-butyl methyl malonate with benzoyl peroxide in the presence of aqueous KOH and N-(9-anthracenylmethyl)cinchoninium chloride afforded the corresponding α,α-disubstituted products in generally excellent chemical yields (up to 99% yield) with high enantioselectivities (up to 96% ee). In addition, the utility of this methodology was exhibited by the synthesis of a mineralocorticoid receptor antagonist.

Full text of DOI:10.1021/acs.orglett.6b02682

Letter
pubs.acs.org/OrgLett
Enantioselective α‑Benzoyloxylation of Malonic Diesters by Phase-
Transfer Catalysis
Takuya Kanemitsu,* Miho Sato, Miyuki Yoshida, Eisuke Ozasa, Michiko Miyazaki, Yuki Odanaka,
Kazuhiro Nagata, and Takashi Itoh*
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
S
* Supporting Information
ABSTRACT: A highly enantioselective α-benzoyloxylation of malonic diester has been achieved by phase-transfer catalysis. The
reaction of α-monosubstituted tert-butyl methyl malonate with benzoyl peroxide in the presence of aqueous KOH and N-(9-
anthracenylmethyl)cinchoninium chloride afforded the corresponding α,α-disubstituted products in generally excellent chemical
yields (up to 99% yield) with high enantioselectivities (up to 96% ee). In addition, the utility of this methodology was exhibited
by the synthesis of a mineralocorticoid receptor antagonist.
symmetric construction of a chiral center at the α-carbon
method in the reaction with tert-butyl methyl α-benzoyloxy
Aof malonic diesters is an important synthetic strategy malonate led to the formation of the α-alkyl α-benzoyloxy
malonate with low enantioselectivity.7 More recently, Shibato-
because chiral malonates are attractive synthetic building blocks
mi and co-workers reported the enantioselective synthesis of α-
aryloxy-β-keto ester through asymmetric α-chlorination of β-
keto esters and SN2 reaction with phenols and ultimately
achieved the enantioselective synthesis of α-aryloxy malonate
through the α-choromalonate.8
due to their readiness to undergo chemoselective trans-
formations.1 However, there have been few reports of
enantioselective catalytic additions at the α-position of malonyl
derivatives.2 In particular, enantioselective synthesis of the
quaternary substituted carbon chiral center is difficult and quite
challenging due to steric repulsion between the substituents. In
this context, Park and co-workers have developed enantiose-
lective catalytic additions at the α-position of malonyl
derivatives.3 Our laboratory has also been interested in the
asymmetric construction of α,α-dialkyl malonic diesters, and we
previously reported a highly enantioselective alkylation of
malonic diester under phase-transfer catalytic conditions.4
Similarly, there have been few reports of the enantioselective
synthesis of α-alkyl α-hydroxy malonyl derivatives, and these
syntheses are even more challenging than the synthesis of chiral
malonates. α-Alkyl α-hydroxy malonyl derivatives are among
the most important classes of compounds for the formation of
tertiary alcohols and versatile intermediates for the synthesis of
natural products and biologically active compounds.5 To our
knowledge, there is only one report of an enantioselective
direct C−O bond-forming reaction at the α-position of
malonates, by Shibata and co-workers,6 who described the
highly enantioselective direct α-hydroxylation of malonate
using oxaziridine as an oxidant and (R,R)-DBFOX/NiII
complex as a transition metal catalyst. Maruoka and co-workers
obtained α-alkyl α-hydroxy β-keto esters with high enantiose-
lectivities by employing the phase-transfer catalyzed asymmetric
alkylation of α-benzoyloxy β-keto esters as a key asymmetric
C−C bond forming step. However, an attempt to extend this
In order to develop a new and convenient method for
synthesizing chiral α-hydroxy malonates, we investigated the
asymmetric α-benzoyloxylation of tert-butyl methyl α-mono-
alkylated malonate under phase-transfer conditions using
cinchona alkaloid derivatives.9 tert-Butyl and methyl ester are
simple protecting groups that are readily cleaved chemo-
selectively under acidic or alkaline conditions. Phase-transfer
catalytic reactions are among the most efficient synthetic
methods, both from the viewpoints of low cost and being
environmentally benign.10 α-Benzoyloxylation is a useful
synthetic strategy for introducing an oxygen atom at the α-
position of ketone or ester groups. Although catalytic α-
benzoyloxylation reactions have been accomplished by metal,11
enamine,12 and Bu4NI catalysis,13 there has been no report of
this reaction using phase-transfer catalysis. In this paper, we
report the highly efficient enantioselective α-benzoyloxylation
of tert-butyl methyl α-monoalkylated malonate using cinchona
alkaloid derivatives as inexpensive phase-transfer catalysts
(PTCs). The present reaction is the first example of an
organocatalyzed asymmetric direct α-benzoyloxylation of
malonic diesters. In addition, the utility of this method is
Received: September 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02682
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Organic Letters
Letter
demonstrated by the synthesis of a mineralocorticoid receptor
antagonist being developed by a group at Merck.14
The effects of an N-anthracenylmethyl group on the catalysts
were examined next. N-(9-Anthracenylmethyl)cinchoninium
catalyst V afforded the product 3a in moderate yield (63%)
with good enantioselectivity (81% ee, Table 1, entry 5). N-
Anthracenylmethylquinine catalyst VI gave both a low yield and
low enantioselectivity (Table 1, entry 6). N-Anthracenylmethyl-
cinchonidinium VII and N-anthracenylmethylquininium VIII
gave poor enantioselectivities (Table 1, entries 7 and 8).
Consequently, catalyst V, which provided the highest
enantioselectivity, was selected for further studies.
To further improve the enantioselectivity, we focused our
attention on reaction conditions using N-(9-anthracenyl-
methyl)cinchoninium chloride (V) as the catalyst. The results
of the optimization studies are summarized in Table 2. We first
To initiate our study, we screened various cinchona alkaloid
derivatives as PTCs for the benzoyloxylation reaction. α-Benzyl
tert-butyl methyl malonate (1a) was adopted as the substrate
for benzoyloxylation with benzoyl peroxide (BPO, 2) in the
presence of a PTC. Addition of PTCs I−VIII to the reaction
mixture accelerated the reaction rate considerably in each case.
The enantiomeric excess of the purified α-benzoyloxy malonate
3a was measured by chiral HPLC, and the absolute
configuration was determined by comparison with specific
rotation values reported in the literature.7 The results are
summarized in Table 1.
Table 1. Catalyst Screening for the α-Benzoyloxylation of
tert-Butyl Methyl Malonate 1a
Table 2. Optimization Studies of the α-Benzoyloxylation
b
c
temp
(°C)
time
(h)
yield
ee
(%)
a
entry
solvent
base
(%)
1
CH2Cl2 50% KOH
rt
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
48
48
96
48
48
48
59
91
44
73
99
4
7
2
Et2O
50% KOH
50% KOH
50% KOH
50% NaOH
50% CsOH
75% CsOH
LiOH
rt
49
18
81
36
65
84
13
32
38
42
ND
83
ND
83
89
91
91
93
90
95
91
92
3
hexane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
rt
4
rt
5
rt
6
rt
7
rt
49
98
98
>99
>99
8
rt
9
NaOH
rt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
KOH
rt
CsOH
rt
d
e
e
Na2CO3
rt
NR
18
a
b
c
K2CO3
rt
entry
PTC
yield (%)
ee (%)
config
d
CaCO3
rt
NR
94
1
2
3
4
5
6
7
8
I
37
36
44
45
63
47
39
64
56
52
5
(S)
(S)
(R)
(R)
(S)
(S)
(R)
(R)
Cs2CO3
rt
II
50% KOH
75% CsOH
Cs2CO3
0
>99
62
III
IV
V
0
11
81
36
7
0
73
50% KOH
Cs2CO3
−20
−20
−40
−50
−60
>99
6
VI
VII
VIII
50% KOH
50% KOH
50% KOH
>99
81
2
a
The reactions were performed with 1a (0.1 mmol), 2 (0.1 mmol),
68
catalyst (0.01 mmol), and 50% KOH/H2O (100 μL) in toluene (1
a
b
mL) at room temperature for 24 h. Determined by 1H NMR analysis
The reactions were performed with 1a (0.1 mmol), 2 (0.2 mmol),
b
catalyst (0.01 mmol), and base in toluene (1 mL). Determined by 1H
NMR analysis using 1,3,5-trimethylbenzene as an internal standard.
c
using 1,3,5-trimethylbenzene as an internal standard. Determined by
chiral HPLC.
c
d
e
Determined by chiral HPLC. No reaction. Not detected.
We first attempted to use cinchoninium derivatives I-IV
containing an N-benzyl group as a catalyst for benzoyloxylation.
Treatment of malonate 1a with BPO (2) in the presence of
50% (w/w) KOH/H2O and 10 mol % of PTC I in toluene at
room temperature gave the corresponding α-benzoyloxy
malonate 3a in low yield with moderate enantioselectivity
(Table 1, entry 1). The reaction with N-benzylquinidinium
chloride (II) also afforded malonate 3a in low yield with
moderate enantioselectivity (Table 1, entry 2). In contrast, N-
benzylcinchonidinium III and N-benzylquininium IV provided
poor enantioselectivities (Table 1, entries 3 and 4).
investigated the α-benzoyloxylation of malonate 1a in various
solvents. A survey of solvents revealed that the reaction
medium had a significant effect on the α-benzoyloxylation
reaction rate. Using CH2Cl2 as the solvent resulted in moderate
yields and poor enantioselectivity (Table 2, entry 1). Reactions
carried out in Et2O gave a high yield but low enantioselectivity
(Table 2, entry 2), whereas hexane as a solvent resulted in a
moderate yield and poor enantioselectivity (Table 2, entry 3).
However, performing the reaction in toluene provided the
highest enantioselectivity (81% ee) (Table 2, entry 4).
B
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Letter
a
We next screened several bases in toluene in the presence of
catalyst V (Table 2, entries 5−15). Although the use of 50%
NaOH aqueous solution provided a higher yield, the
enantioselectivity was low (Table 2, entry 5). The use of 50%
CsOH aq provided a poor yield and moderate enantioselec-
tivity, but 75% CsOH aq provided both a higher yield and high
enantioselectivity (Table 2, entries 6 and 7). The solid bases
LiOH, NaOH, KOH, and CsOH all resulted in excellent yields
of α-benzoyloxy product 3a, but the enantioselectivities were
unsatisfactory (Table 2, entries 8−11). Solid Na2CO3 and
CaCO3 were completely ineffective (Table 2, entries 12 and
14), whereas K2CO3 provided a low yield and high selectivity
(Table 2, entry 13) and Cs2CO3 provided both a high yield and
high selectivity (Table 2, entry 15).
Scheme 1. Substrate Scope of the α-Benzoyloxylation
We next investigated the reaction temperature, using 50%
KOH aq, 75% CsOH aq, or Cs2CO3 as the base; with all bases,
enantioselectivity increased when the reaction temperature was
decreased to 0 °C (Table 2, entries 16−18). With Cs2CO3, a
further decrease in the reaction temperature led to a decrease in
yield without a decrease in enantioselectivity (Table 2, entries
18 and 20). In contrast, 50% KOH aq resulted in an increase in
enantioselectivity as the reaction temperature was gradually
decreased to −40 °C (Table 2, entries 16, 19, and 21), although
further cooling to −50 °C and −60 °C decreased significantly
both the chemical yield and enantioselectivity (Table 2, entries
22 and 23). Accordingly, conducting the reaction in toluene
and 50% KOH at −40 °C using PTC V was considered optimal
with respect to ee and chemical yield of the product.
With the optimal reaction conditions in hand, we then
examined malonates 1a−o to demonstrate the general utility of
the cinchona catalyst V in asymmetric α-benzoyloxylation
reactions. The results are summarized in Scheme 1. The α-
benzoyloxylation of malonate 1 (0.2 mmol) with BPO (2, 0.4
mmol) was carried out in toluene (2.0 mL) using PTC V (0.02
mmol) at −40 °C for 48 h. Significantly, the majority of the
reactions using malonates 1 afforded the corresponding α-
benzoyl products 3 with excellent yields and enantioselectiv-
ities. Benzyl-type substituted substrates 1a−i yielded enan-
tioenriched α-benzoyl products 3a−i containing a quaternary
stereocenter in good to excellent yields and enantiopurities. 4-
Nitrobenzyl substrate 1g provided moderate enantioselectivity.
The reason is not clear, but presumably, hydrogen bond, which
formed between the nitro group and the catalyst V, affected the
enantioselectivity. Ortho-substituted benzyl substrate 1i
provided moderate yield and enantioselectivity. In the case of
pyridin-3-ylmethy 1j, and pyridin-4-ylmethyl substituted
malonates 1k, both reactions afforded good yields and
enantioselectivities. Similarly, substitution of the benzyl group
with other groups such as methyl 1l, homobenzyl 1m, and allyl
1n provided the corresponding α-adducts 3l−n in excellent
yields and enantiopurities. However, use of the α-acetate group
substrate 1o afforded 3o in good yield but with unsatisfactory
enantioselectivity.
a
The reactions were performed with 1 (0.2 mmol), 2 (0.4 mmol),
catalyst V (0.02 mmol), and 50% KOH/H2O (0.2 mL) in toluene (2
mL). Yields of isolated product. The enantiomeric excess values were
determined by chiral HPLC.
Scheme 2. Synthesis of Mireralocorticoid Receptor
Antagonist 9
The synthesis of a biologically active compound was
investigated to demonstrate the utility of the present method-
ology for α-benzoylation reactions. The synthesis of miner-
alocorticoid receptor antagonist 9 from α,α-disubstituted
malonate 3a is depicted in Scheme 2. Removal of the tert-
butyl group from 3a with TFA afforded the carboxylic acid 4 in
quantitative yield. The acid 4 was coupled with 3,5-dimethoxy-
benzylamine (5) to afford amide 6 in 89% yield. Removal of the
benzoyl group of α,α-disubstituted malonate 6 by treatment
with NaOMe in MeOH furnished tertiary alcohol 7.
Subsequent conversion to the final target oxazolidinedione 9
was achieved by condensation with commercially available
isocyanate 8 in the presence of sodium hydroxide. The
stereochemistry of 9 was confirmed by comparison of the
measured spectra data with the literature value.14a
C
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Letter
(d) Rong, J.; Pellegrini, T.; Harutyunyan, S. R. Chem. - Eur. J. 2016, 22,
3558−3570.
In conclusion, we have described the first enantioselective α-
benzoyloxylation of malonic diesters promoted by a phase-
transfer catalyst. The reaction of the α-monosubstituted
malonate with benzoyl peroxide in the presence of N-(9-
anthracenylmethyl)cinchoninium chloride afforded the corre-
sponding α,α-disubstituted products in excellent yields with
high enantioselectivities. The utility of this method was
demonstrated by the successful synthesis of a mineralocorticoid
receptor antagonist. We are currently investigating the synthesis
of other useful compounds via the enantioselective α-
benzoyloxylation of other malonic diesters in addition to tert-
butyl methyl malonate. The results will be reported in due
course.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02682.
Experimental procedures, characterization data, and
1
copies of H and 13C NMR spectra and HPLC traces
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: kanemitsu@pharm.showa-u.ac.jp.
*E-mail: itoh-t@pharm.showa-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a “High-Tech Research Center”
Project for Private Universities: matching fund subsidy from
MEXT (Ministry of Education, Culture, Sports, Science and
Technology), and a Grant-in-Aid for Scientific Research (C)
from the Japan Society for the Promotion of Science.
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