Threonine-derived thioureas as bifunctional organocatalysts for enantioselective Michael addition

Article abstract of DOI:10.1016/j.tetlet.2019.151382

A series of threonine-derived thioureas were developed through the facile modification of L-threonine chiral scaffold. The enantioselective efficiency were evaluated in the catalytic asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalke

Full text of DOI:10.1016/j.tetlet.2019.151382

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Threonine-derived Thioureas as Bifunctional Organocatalysts for Enantiose-
lective Michael Addition
Zhi Zheng, Jian Lin, Yang Sun, Suoqin Zhang
PII:
S0040-4039(19)31173-6
DOI:
https://doi.org/10.1016/j.tetlet.2019.151382
TETL 151382
Reference:
Tetrahedron Letters
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4 November 2019
7 November 2019
Please cite this article as: Zheng, Z., Lin, J., Sun, Y., Zhang, S., Threonine-derived Thioureas as Bifunctional
Organocatalysts for Enantioselective Michael Addition, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.151382
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Tetrahedron Letters
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Threonine-derived Thioureas as Bifunctional Organocatalysts for Enantioselective
Michael Addition
Zhi Zhenga,b,1,Jian Linb,1, Yang Suna, *, Suoqin Zhangb,
a College of Life Science, Key Laboratory of Straw Biology and Utilization, The Ministry of Education,Jilin Agricultural University, Changchun 130118, P.
R.China
b College of Chemistry, Jilin University, Changchun 130021, P. R. China.
———

ARTICLE INFO
ABSTRACT
Corresponding author: E-mail: suoqin@jlu.edu.cn (Suoqin Zhang), robsuny@163.com. (Yang Sun)
1 These authors contributed equally to this work.
Article history:
Received
Received in revised form
Accepted
A series of threonine-derived thioureas were developed through the facile modification of L-
threonine chiral scaffold. The enantioselective efficiency were evaluated in the catalytic
asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes, which afforded
the chiral nitroalkylated naphthoquinone derivatives in high yields (up to 93%) and enantio-
selectivities (up to 99% ee) under low catalyst loading (3 mol%).
Available online
2019 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Michael addition
Bifunctional thioureas
2-hydroxy-1,4-naphthoquinone
activation through hydrogen bonding interactions in the catalytic
cycle like bifunctional thioureas reported, but also the activities
and stereoselectivities of them could be finely tuned by simply
Introduction
Hydrogen-bonding catalysis and a chiral counterion strategy
have risen recently as a reliable synthetic methodology and much
attention has been paid to the design of new organocatalysts.[1]
Since Jacobsen successfully developed a chiral Schiff base-
thiourea catalyzed asymmetric Strecker reaction, a large number
of bifunctional tertiary amine-thioureas have emerged as efficient
change of the substituent in the chiral scaffold derived from L-
threonine. The Michael addition of 2-hydroxy-1,4-naphtho-
quinones to nitroalkenes is particularly interesting because it
produces chiral nitroalkylated compounds which are precursors
of a variety of other functionalized bioactive compounds. This
reaction has drawn much attentions and became an ideal model
organocatalysts and applied in
a variety of asymmetric
R3
Fine-Tunable Site
transformations.[2] The essential to the great success of these
thiourea-based catalysts is the functionality of the thiourea
moiety as a hydrogen bond donor, which made it to be a general
structural unit in the design of bifunctional catalysts. However,
compared with thioureas conjugated with chiral cyclo-
hexanediamine or Cinchona alkaloid, the success achieved by
low-cost amino acids-derived thioureas was very limited so far.
One of the important reasons is that the stereo-controlled ability
of these thioureas was to a large extent limited by the kinds of
amino acids available to be derived.
O
R2
Tunable
Chiral
S
L-Threonine Scaffold
R3
N
N
Scaffold
H
H
N
R1
R1
N
N
N
S
S
S
O
O
O
Si
Si
N
H
N
H
Si
N
N
N
H
N
H
H
H
1a
1c
1b
N
N
N
S
S
S
Ph
O
O
O
Si
Ph Ph
N
N
Si
Ph Ph
N
N
H
Si
N
H
N
H
H
H
H
Recently, Lu’s group introduced siloxy groups into L-
threonine chiral scaffold to construct tert-phosphine bifunctional
catalysts and succeseful used in asymmetric MBH reaction[3].
Encourgaed by the success of the above strategy, We assumed
that the poor-tunability of amino acids-derived tertiary amine-
thioureas could also be overcome. With our continuing interest in
designing low-cost, fine-tunable and highly efficient
organocatalysts for asymmetric transformations, here, a series of
bifunctional tertiary amine-thioureas derived from L-threonine
were elaborately designed (Figure 1). Besides retained tertiary
amine and thiourea as necessary activated groups, L-threonine
chiral scaffold which was modified through silicon etherification
reaction was introducted into the new structure. We envisioned
that not only designed catalyst candidates could provide dual
1f
1d
1e
CF3
N
N
S
S
O
O
Si
N
N
Si
N
H
N
CF3
H
H
H
1h
1g
Figure 1. Structures of chiral bifunctional catalysts 1a~1h.
for evaluating many bifunctional catalysts.[4] To confirm our
assumption, the bifunctional thioureas bearing
a tunable
threonine-scaffold were synthesized and their catalytic
performance was evaluated in the asymmetric Michael addition
of 2-hydroxy-1,4-naphthoquinone to nitroalkenes.
Results and Discussion

2
A series of chiral thiourea-based catalysts 1a-1h(Figure 1)
were synthesized from commercially available L-threonine via
experimentally conventional protocols[3c,5-8] (see Supplementary
data). The highly modular nature of chiral thioureas and facile
introduction of siloxy groups facilitated the fine-tuning of their
catalytic activities for asymmetric reactions.
enantioselectivity (96% ee) was observed in toluene (Table 2,
entry 4). Moreover, further improvement in enantioselectivity
(97% ee) was achieved by appropriately increasing the amount of
toluene (Table 2, entry 9). Adjusting the catalyst loading
demonstrated that the high enantioselectivities were still
maintained with a reduced catalyst loading from 5 to 2 mol%
(Table 2, entry 10 and 11), and 3 mol% was chosen as the best
catalyst loading because of no remarkable decrease in yields.
When the reaction was performed at 0 oC (Table 2, entry 12), the
Michael addition product with excellent enantioselectivity (>99%
ee) was obtained, although a prolonged time was required (48 h).
The results of detailed evaluation of the catalysts 1a-1h by
the Michael addition of 2-hydroxy-1,4-naphthoquinone 2 to β-
nitrostyrene 3a were presented in Table 1. to investigate the
catalytic effect of the tertiary amino group, catalysts 1a-1d
containing different alkyl group at R1 site were initially prepared
and evaluated (Table 1, entries 1-4). To our delight, cyclic and
acyclic tertiary amines all gave the desired naphthoquinone
derivative in moderate yields (65-75% yields) with high
enantioselectivities (88-94% ee). In tested cases, cyclic
piperidinyl group is the most promising substituent in tertiary
amino structure unit (75% yields, 94% ee) (Table 1, entry 4).
Then, we turned our attention to the R2 site. Catalysts 1e-1g were
easily prepared by the introduction of additional three siloxy
groups in the last synthetic step. When those catalysts were
employed subsequently (Table 1, entries 5-7), highly enantio-
selective Michael addition product was obtained (92-93% ee). It
is noteworthy that the siloxy group has a significant impact on
the yield of Michael addition product. Among the four siloxy
derivatives, sterically small siloxy group seems to be favorable
for chemical yield, and the catalyst 1d containing the tert-
butyldimethylsilyl (TBS) group gave the best results (75% yields,
94% ee) (Table 1, entry 4). Further synthesis and detection of
catalyst with a strong electron-withdrawing group in tunable R3
site were carried out (Table 1, entry 8). Although catalyst 1h
gave the product with high enantioselectivity as the same as
catalyst 1d, the remarkablely decreased yield was observed.
Therefore, bifunctional thiourea 1d was selected as the best
catalyst for further optimization.
Table 2. Optimization of the reaction conditions.
O
O
Ph
NO2
1d
catalyst
NO2
+
Ph
solvent, 25 o
C
OH
OH
O
O
2
3a
4a
Entry[a]
Solvent
CH2Cl2
CH2ClCH2Cl
CHCl3
PhCH3
THF
Loading
[mol%]
5
5
Time
[h]
24
Yield
[%][b]
75
ee
[%][c]
94
1
2
24
24
24
24
24
24
24
24
24
36
48
77
79
73
69
43
65
25
71
67
55
72
93
3
5
5
5
5
5
5
5
3
2
3
93
96
95
63
76
23
97
97
97
>99
4
5
6
EtOH
7
CH3CN
DMF
8
9[d]
10[d]
11[d]
12[d,e]
PhCH3
PhCH3
PhCH3
PhCH3
[a] Unless noted otherwise, reactions were carried out with: 2-hydroxy-1,4-
naphthoquinone 2 (0.2 mmol), β-nitrostyrene 3a (0.24 mmol) and catalyst
1d (0.01 mmol) in solvent (2 mL) at 25 oC for 24 h.
[b] Isolated yields after column chromatography purification.
[c] Determined by HPLC using a Daicel Chiralcel OJ-H column.
[d] 4 ml of PhCH3 was used.
Table 1. Evaluation of the catalysts 1a-1h.
O
O
Ph
NO2
1
5 mol% catalyst
NO2
+
Ph
CH2Cl2, 25 o
C
OH
OH
[e] Reaction was carried out at 0 oC.
O
O
2
3a
4a
Entry[a]
Catalyst
Yield [%][b]
ee [%][c,d]
Further investigations into the scope and limitations of this
asymmetric Michael addition was performed, and the results are
summarized in Table 3. Various aromatic and aliphatic
nitroalkenes were tested under the optimized catalytic conditions
(Table 2, entry 12). Aromatic nitroalkenes bearing various
substituents (CN, CF3, F, Cl, Br, CH3, OCH3) at the para position
on the phenyl ring reacted smoothly with 2-hydroxy-1,4-
naphthoquinone to afford corresponding Michael addition
products in moderate to good yields (71-91% yields) with high
enantioselectivities (98- >99% ee) (Table 3, entries 2-8). When
ortho or meta- substituted aromatic nitroalkenes (Table 3, entries
9-11) was used as an acceptor, desired products were obtained
with very high enantioselectivities (99% ee), although a longer
time was required to achieve moderate yields. Heteroaromatic
nitroalkene (Table 3, entry 12) can also be applied in this
Michael addition reaction, 96% ee was observed. In addition,
aliphatic nitroalkenes were also suitable substrates (Table 3,
entries 13-17). Linear and branched alkyl nitroalkenes all worked
faster than aromatic nitroalkenes, and good yields (84-93%
yields) and high ee values (97-99% ee) were attained. It is worth
noting that compared to previous results, not only our catalyst
loading can be reduced to lower amounts (3 mol%), but also
aliphatic nitroalkenes (Table 3, entries13-17) provided the
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
65
67
76
75
63
52
70
65
88
90
92
94
93
92
93
94
1g
1h
[a] Unless noted otherwise, reactions were carried out with: 2-hydroxy-1,4-
naphthoquinone 2 (0.2 mmol), β-nitrostyrene 3a (0.24 mmol) and catalyst
1 (0.01 mmol) in CH2Cl2 (2 mL) at 25 oC for 24 h.
[b] Isolated yields after column chromatography purification.
[c] Determined by HPLC using a Daicel Chiralcel OJ-H column.
[d] The absolute configuration of the addition product(R-enantiomer) was
assigned by comparison to the literature value of optical rotation in
ref.10a.
The solvent employed in asymmetric transformations can have
a dramatic influence on enantioselectivities and yields of product.
Firstly, the common solvents (Table 2, entries 1-8) were
examined in the 1d catalyzed asymmetric Michael addition of 2-
hydroxy-1,4-naphthoquinones 2 to β-nitrostyrene 3a. Obviously,
high enantioselective Michael addition products (93-96% ee)
were obtained in the moderate polar solvent (Table 2, entries 1-
5), while strong polar solvent (Table 2, entries 6-8) gave more
poor
yields
and
enantioselectivities.
The
highest

corresponding Michael addition products in high yields and
enantioselectivities (up to 98%).
evaluated in the catalytic asymmetric Michael addition of 2-
hydroxy-1,4-naphthoquinone to nitroalkenes, which afforded the
chiral nitroalkylated naphthoquinone derivatives in high yields
(up to 93%) and enantio-selectivities (up to 99% ee) . Because of
the highly enantioselective efficiency and fine tunability of these
bifunctional thioureas, further application in asymmetric
organocatalysis has great potential, which is currently under
investigation.
Based on the experimental results described above, a plausible
transition state was proposed in Figure 2. We envisioned that
catalyst 1d provide dual activation through hydrogen bonding
interactions like similar bifunctional thiourea catalysts.[10] The 2-
hydroxy-1,4-naphthoquinone is deprotonated by the basic
nitrogen atom of the tertiary amine, while the nitroalkene is
activited by the thiourea moiety through double hydrogen
bonding between the NH groups and the nitro group. There are
two type of transition states formed in this stage (as showed in
Figure 2.), but TS-1 is favorable, The nucleophile attacks the
fixed nitroalkene from the Si-face to afford the R-enantiomer as
the major product.
Acknowledgments
The authors are grateful for financial support from the National
Natural Science Foundation of China (21372098) and the Jilin
Province Science & Technology Development Program (nos.
20150203006GX and 20140307004GX).
Table 3. Scope of the Michael addition of 2-hydroxy-1,4-
Appendix A. Supplementary data
naphthoquinone to nitroalkenes
O
O
O
R
Supplementary data to this article can be found online at
NO2
1d
3 mol% catalyst
PhCH3, 0 o
NO2
+
R
C
OH
OH
References and notes
O
2
3
4
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Entry[a]
R (4)
Time
[h]
48
72
72
72
72
72
48
48
96
96
96
96
24
24
24
24
24
Yield
[%][b]
72
71
75
75
78
80
86
91
56
54
73
62
93
84
89
ee
[%][c]
>99
>99
98
1
2
3
4
5
6
7
8
Ph (4a)
4-CNC6H4 (4b)
4-CF3C6H4 (4c)
4-FC6H4 (4d)
4-ClC6H4 (4e)
4-BrC6H4 (4f)
4-CH3C6H4 (4g)
4-CH3OC6H4 (4h)
2-BrC6H4 (4i)
3-BrC6H4 (4j)
3-CH3C6H4 (4k)
2-Furyl (4l)
n-Propyl (4m)
i-Propyl (4n)
i-Butyl (4o)
Phenylethyl (4p)
Cyclohexyl (4q)
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9
10
11
12
13
14
15
16
17
88
90
98
[a] Unless noted otherwise, reactions were carried out with: 2-hydroxy-1,4-
naphthoquinone 2 (0.2 mmol), β-nitroalkenes 3 (0.24 mmol) and catalyst
1d (0.006 mmol) in toluene (4 mL) at 0 oC.
[b] Isolated yields after column chromatography purification.
[c] Determined by HPLC using a Daicel Chiralcel OJ-H, AD-H or OD-H
column.
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naphthoquinone, see:
O TBS
O TBS
S
S
N
H
N
H
N
H
N
H
N
N
H
O
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O
O
H
O
O
O
N
N
O
O
O
O
TS-1 (favorable)
TS-2 (unfacorable)
Figure 2. Proposed transition state.
Conclusions
In summary, chiral bifunctional thioureas 1a-1h derived from
threonine were designed, synthesized and verified as highly
efficient organocatalysts in the asymmetric Michael addition of
2-hydroxy-1,4-naphthoquinone to nitroalkenes. The facile
introduction of siloxy groups into the chiral scaffold makes these
thioureas very flexible. The enantioselective efficiency were
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4
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Chiralcel OJ-H column (n-hexane : 2-propanol : CF3COOH = 50 : 50 :
0.05, flow rate 1.0 mL/min, 254 nm). minor enantiomer tr=14.7 min,
major enantiomer t =44.0 min, >99% ee; [α]2D0: -36.1 (c 0.8, CH OCH );
r
3
3
[9] General Procedure for the Enantioselective Michael Addition Reaction:
1H NMR (300 MHz, CDCl3): δ = 8.10 (dd, J1 = 13.8 Hz, J2 = 7.5 Hz,
2H), 7.74 (dt, J1 = 24.6 Hz, J2 = 7.5 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H),
7.41-7.21 (m, 3H), 5.49 (dd, J1 = 12.9 Hz, J2 = 9.0 Hz, 1H), 5.42-5.27 (m,
1H), 5.15 (dd, J1 = 12.9 Hz, J2 = 6.6 Hz, 1H).
o
To a cooled solution (0 C) of β-nitroalkenes 3 (0.24 mmol) and catalyst
1d (0.006 mmol) in anhydrous toluene (4 mL) was added 2-hydroxy-1,4-
o
naphthoquinone 2 (0.2 mmol). The reaction mixture was stirred at 0 C
for the requisite times as indicated in Table 3. Then the mixture was
purified by silica gel column chromatography (CH2Cl2) to afford the
desired products 4. Compound 4a was obtained according to the general
procedure as yellow solid; reaction time 48 h; 46.5 mg (72%); m.p. 149-
150 oC. The enantiomeric excess was determined by HPLC with a Daicel
[10] (a) Yang W, Du DM. Adv Synth Catal. 2011, 353,1241–1246.
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13151–13160.
Graphical Abstract
Threonine-derived Thioureas as Bifunctional
Organocatalysts for Enantioselective
Michael Addition
Leave this area blank for abstract info.
Zhi Zheng, Jian Lin, Yang Sun*, Suoqin Zhang*
N
S
O
O
R
O
O
N
N
Si
NO2
H
H
NO2
+
R
OH
OH
O
up to 93% yields, 99% ee

Highlights
1. A series of fine-tunable threonine-derived thioureas were developed as efficient organocatalysts.
2. A new approach to high-efficiency asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes.
3. The catalytic system can tolerate various substrates.
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential
competing interests: