O-Monoacyltartaric Acid/(Thio)urea Cooperative Organocatalysis for Enantioselective Conjugate Addition of Boronic Acid

Article abstract of DOI:10.1021/acs.orglett.0c00981

(Thio)urea cocatalyst accelerates O-monoacyltartaric acid (MAT)-catalyzed enantioselective conjugate addition of boronic acid to unsaturated ketone. Kinetic studies of this reaction revealed first-order dependence of each substrate and catalyst and second

Full text of DOI:10.1021/acs.orglett.0c00981

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Letter
O‑Monoacyltartaric Acid/(Thio)urea Cooperative Organocatalysis for
Enantioselective Conjugate Addition of Boronic Acid
Takuto Yoshimitsu,# Yukinobu Kuboyama,# Sari Nishiguchi,# Makoto Nakajima, and Masaharu Sugiura*
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ABSTRACT: (Thio)urea cocatalyst accelerates O-monoacyltartaric acid (MAT)-catalyzed enantioselective conjugate addition of
boronic acid to unsaturated ketone. Kinetic studies of this reaction revealed first-order dependence of each substrate and catalyst and
second-order dependence of (thio)urea, leading to reduction of the catalyst loading and development of more active and
enantioselective MAT monoaryl ester catalyst.
acid (2a)6d under previously optimized reaction conditions6a
rganocatalysts offer several advantages such as desig-
Onability, reusability, and low toxicity. Despite these provided adduct 5aa in a high yield with 88% ee (Table 1,
entry 1). When the amount of catalyst 2a was reduced from 10
to 3 mol %, the yield was decreased by half, and the
enantioselectivity was also reduced (entry 2). Therefore,
Schreiner’s thiourea 1a (9 mol %) was examined as cocatalyst
and was found to recover both the yield and selectivity (entry
3). However, reproducibility was impeded: yields were
sometimes in the 90% range and sometimes reduced to the
60% range. It was therefore rationalized that unknown
amounts of water which may have been present in the boronic
acid due to dehydrative formation of the corresponding
boroxine might have suppressed the reaction progress. It has
already been confirmed that appropriate amounts of methanol
or water prevented uncatalyzed background reactions, but
excess amounts suppressed even the desired catalytic reactions.
To control the amount of water in the reaction medium,
anhydrous MgSO4, which was effective for conjugate addition
of diborons,6d was used and assessed as a drying agent.
Reproducible results were obtained (entry 4).
benefits, their low catalytic activity is often a major limitation
in their use.1 Cooperative use of a hydrogen bond donor may
greatly improve their catalytic activity.2 Although the examples
are still limited, combination of carboxylic acids and thioureas
is one of the key strategies for cooperative Brønsted acid
catalysis (Scheme 1).3 For instance, Schreiner’s thiourea 1a4,5
accelerates mandelic acid-catalyzed alcoholysis of styrene
epoxides (Scheme 1a)3a and proline-catalyzed asymmetric
aldol reactions (Scheme 1b).3b−d,h Combination of a chiral
thiourea and benzoic acid catalyzes cyanosilylation of
aldehydes (Scheme 1c).3e Thiourea/carboxylic acid-combined
chiral catalysts effectively mediate asymmetric Povarov,
Pictet−Spengler, and related reactions (Scheme 1d).3f−o
Hydrogen bonding between thioureas and carboxylic acids
(or their conjugate bases) enhances their acidities and creates
an effective chiral environment. O-Monoacyltartaric acids
(MAT) 2 (Scheme 1e) have been proven in our previous
work as a class of asymmetric organocatalysts for 1,4-addition
of boron compounds to α,β-unsaturated ketones.6−8 Among
the acyl groups tested, bulky benzoyl groups (R = tert-butyl or
1-adamantyl, R′ = H) gave optimal results. However, using 10
mol % of MAT catalyst is usually required to attain sufficient
catalytic activity. Therefore, the use of thiourea 1a and urea 1b
as cocatalysts was attempted, and kinetic studies were
conducted to elucidate their effects. Here, we report MAT/
(thio)urea cooperative catalysis leading to further improve-
ment in catalytic activity and development of more active
MAT monoaryl ester catalysts (R′ = aryl).
With the more-reproducible reaction conditions (MeOH
and MgSO4 additives), kinetic studies were conducted using
3,5-di(tert-butyl)benzoyltartaric acid (2b),6a which has been
extensively studied in our work. The reaction of 3a and 4a (0.3
mmol each) in toluene was performed in the presence of 1,4-
Received: March 18, 2020
The reaction of chalcone (3a) and (E)-styrylboronic acid
(4a) with 10 mol % of 3,5-di(1-adamantyl)benzoyl tartaric
https://dx.doi.org/10.1021/acs.orglett.0c00981
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Scheme 1. Carboxylic Acid/(Thio)urea Cooperative
Catalysis
Table 2. Kinetic Study Using an Internal Standard
entry
2b (mol %)
k′ (M−1 h−1
)
ee (%)
1
2
3
4
10
7
5
0.307
0.204
0.140
0.058
86
86
86
81
3
a
Performed using MAT 2b, chalcone (0.3 mmol), styrylboronic acid
(0.3 mmol), 1,4-methoxybenzene (0.075 mmol), methanol (0.6
mmol), and MgSO4 (90 mg) in toluene (1 mL) at 50 °C.
a
Table 3. Effect of Cocatalyst 1
entry
cocatalyst
mol %
k′ (M−1 h−1
)
ee (%)
1
2
3
4
5
6
7
0
3
6
9
3
6
9
0.058
0.072
0.106
0.188
0.093
0.143
0.259
81
85
85
84
84
83
82
1a
1a
1a
1b
1b
1b
a
With MAT 2b (3 mol %), cocatalyst 1 (0, 3, 6, or 9 mol %), 3a (0.3
mmol), 4a (0.3 mmol), 1,4-dimethoxybenzene (0.075 mmol),
methanol (0.6 mmol), and anhydrous MgSO4 (90 mg) in toluene
(1 mL) at 50 °C.
Table 1. Effect of Thiourea 1a on MAT-Catalyzed
Conjugate Addition
a
entry
2a (mol %)
1a (mol %)
yield (%)
98
ee (%)
88
85
1
2
3
10
3
3
0
0
9
9
46
c
c
92, 66, 62
88, 85, 85
b
d
d
4
3
88, 91
87, 87
a
Performed using MAT 2a, chalcone (0.3 mmol), styrylboronic acid
(0.36 mmol), and methanol (0.72 mmol) in toluene (1 mL) at 50 °C.
b
c
d
With anhydrous MgSO4 (90 mg). Results of three trials. Results of
Figure 1. Plot of rate constant k′ vs [1]2.
two trials.
constant k′ exhibited a second-order dependence on the
concentration of 1a or 1b (Figure 1). Urea 1b was slightly
more active than thiourea 1a.11,12 Close to no acceleration was
observed with only 1a or 1b in the absence of catalyst 2b. The
enantioselectivity was also improved, although it tended to
decrease as the amount of 1a or 1b increased. These results
suggest that two molecules of 1a or 1b are associated in the
rate-determining transition state.
Figure 2 shows a possible reaction mechanism. The MAT
catalyst 2 reacts with boronic acid 4a or the corresponding
boroxine or methyl ester to generate dioxaborolanone 6a, to
which enone 3a coordinates to form ternary complex 7aa.
Formation of 6a was previously confirmed by 1H NMR
analysis.6c Because the reaction rate showed the first-order
dependences on concentration of each substrate and catalyst as
described above, generation of 7aa is supposed to be
dimethoxybenzene as an internal standard and monitored by
1H NMR analysis by taking aliquots of the reaction mixtures
every hour until 5 h.9 The presence of 1,4-dimethoxybenzene
did not affect the reaction outcome. It turned out that the
reaction rate followed first-order dependence of each substrate
and catalyst concentration (Table 2 and eqs 1−3).9,10
d[5aa]/dt = k′[3a][4a] = k′[3a]2
1/[3a] − 1/[3a]0 = 2k′t
k′ = k[2b]
(1)
(2)
(3)
Next, the kinetic effect of thiourea 1a and urea 1b as the
cocatalyst was investigated for the reaction using 3 mol % of
MAT catalyst 2b (Table 3). It was interesting that the rate
B
https://dx.doi.org/10.1021/acs.orglett.0c00981
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Letter
Figure 2. Assumed reaction mechanism.
reversible.13 The complex 7aa next goes through the rate- and
stereodetermining transition state TS, giving boron enolate
8aa, which is immediately protonated by methanol or water to
give product 5aa along with regeneration of catalyst 2. One
might think that the boron byproduct B(OR′)3 is attached to
MAT catalyst 2 and suppresses the catalyst turnover. This
possibility was ruled out because the reaction proceeded at a
similar rate in the presence of B(OMe)3 (1.0 equiv) instead of
methanol (2.4 equiv).9 The computational studies6c on the
most favored transition state TS have revealed that both the
classical and nonclassical hydrogen bonding make TS the most
stable, leading to product (S)-5aa. Considering the second-
order dependence of thiourea 1a or urea 1b, two cocatalyst
molecules could be associated in the rate-determining TS. It
can be speculated that both the dioxaborolanone ring and the
carboxy group are activated by hydrogen bond formation, as
depicted in the dashed rectangle in Figure 2. The activation of
the dioxaborolanone seems reasonable because the mandelic
acid-catalyzed reaction was also accelerated by thiourea 1a.9
It was thus envisaged that certain bis(thiourea)s should
promote the reaction effectively. Screening several bis-
(thiourea)s revealed that 3 mol % of cocatalyst 1c14 was as
effective as 6 mol % of thiourea 1a (eq 4).
(entries 1−3) and exhibited the first-order dependence of
cocatalyst 1b as expected.9
a
Table 4. Catalysis by MAT Monoaryl Ester 9
entry
1b (mol %)
k′ (M−1 h−1
)
ee (%)
1
2
3
0
3
6
0.204
0.306
0.426
90
90
89
a
Performed using catalyst 9 (3 mol %), cocatalyst 1b (0, 3, or 6 mol
%), 3a (0.3 mmol), 4a (0.3 mmol), methanol (0.6 mmol), and
anhydrous MgSO4 (90 mg) in toluene (1 mL) at 50 °C.
Finally, MAT monoester 9/urea 1b cooperative catalysis was
applied to the reactions of other substrates (Table 5). The
reaction of an electron-rich, heterocyclic boronic acid 4b
instead of (E)-styrylboronic acid (4a) proceeded smoothly to
give good enantioselectivity (entry 2). The o-methoxy-
substituted chalcone 3c provided superior enantioselectivity,
compared to p-methoxy- or o-bromo-substituted chalcone 3b
and 3d (entries 3−5). This indicates that high enantioselec-
tivity can be obtained when the enone has an electron-rich,
sterically congested aromatic ring at the β-position. In fact, 1-
naphthyl-substituted enone 3e also provided high selectivity
(entry 6). In the reaction of dienone 3f, monostyrylated adduct
5fa, which still has the enone function, was obtained with high
selectivity (entry 7). In all cases, higher enantioselectivities
were obtained with 3 mol % each of catalyst 9 and cocatalyst
1b than when using 10 mol % of MAT 2b.16
A question was raised as to how much catalytic activity
would be expected if the carboxy group of the MAT 2b bound
to the cocatalyst was protected as an ester group. After
screening of several MAT monoesters, 3,5-di(1-adamantyl)-
phenyl ester 915 was found to promote the reaction even more
effectively than MAT 2b (Table 4, entry 1 vs Table 2, entry 4).
The reaction with catalyst 9 was also accelerated by urea 1b
C
https://dx.doi.org/10.1021/acs.orglett.0c00981
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Letter
Author Contributions
#T.Y., Y.K., and S.N. contributed equally.
Table 5. Cooperative Catalysis for Conjugate Addition of
Other Substrates.
a
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Alex Boateng (Sojo University) for the
English editing. This work was partially supported by JSPS
KAKENHI (grants 16KT0164 and 19K06986).
yield
(%)
ee
entry
3 (R1, R2)
3a (Ph, Ph)
3a (Ph, Ph)
3b (Ph, p-MeOC6H4) 4a
3c (Ph, o-MeOC6H4) 4a
3d (Ph, o-BrC6H4)
3e (Ph, 1-naphthyl)
3f ((E)-styryl, Ph)
4 (R3)
5
(%)
1
2
3
4a [(E)-styryl]
5aa
5ab
5ba
5ca
5da
5ea
5fa
97
89
86
96
91
93
81
90
83
90
96
88
94
92
b
4b (Ar )
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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■
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Corresponding Author
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Authors
Takuto Yoshimitsu − Faculty of Pharmaceutical Sciences, Sojo
University, Kumamoto 860-0082, Japan; Graduate School of
Pharmaceutical Sciences, Kumamoto University, Kumamoto
862-0973, Japan
Yukinobu Kuboyama − Graduate School of Pharmaceutical
Sciences, Kumamoto University, Kumamoto 862-0973, Japan
Sari Nishiguchi − Graduate School of Pharmaceutical Sciences,
Kumamoto University, Kumamoto 862-0973, Japan
Makoto Nakajima − Graduate School of Pharmaceutical
Sciences, Kumamoto University, Kumamoto 862-0973, Japan
Complete contact information is available at:
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D
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