Bifunctional amino sulfonohydrazide catalyzed direct asymmetric mannich reaction of cyclic ketimines with ketones: Highly diastereo-and enantioselective construction of quaternary carbon stereocenters

Article abstract of DOI:10.1021/acs.orglett.5b00196

A bifunctional amino sulfonohydrazide which contains multiple sites for hydrogen bonding with substrates was found to enhance reactivity and enantioselectivity in the direct asymmetric Mannich reaction of N-sulfonyl cyclic ketimines with ketones. In this efficient transformation, not only methyl ketones but also cyclic ketones can be employed to provide a general methodology to construct tetrasubstituted α-amino ester in a stereoselective manner. The synthetic utility of a substituted amino ester product is demonstrated by the synthesis of biologically active spirotetrahydrofuran.

Full text of DOI:10.1021/acs.orglett.5b00196

Letter
pubs.acs.org/OrgLett
Bifunctional Amino Sulfonohydrazide Catalyzed Direct Asymmetric
Mannich Reaction of Cyclic Ketimines with Ketones: Highly
Diastereo- and Enantioselective Construction of Quaternary Carbon
Stereocenters
Sheng Zhang,† Lijun Li,† Yanbin Hu,† Zhenggen Zha,† Zhiyong Wang,*,† and Teck-Peng Loh*,‡
†Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry & Collaborative
Innovation Center of Suzhou Nano Science and Technology, Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, P. R. China
‡Hefei National Laboratory for Physical Science at the Microscale and Department of Chemistry, University of Sciences and
Technology of China, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: A bifunctional amino sulfonohydrazide which
contains multiple sites for hydrogen bonding with substrates
was found to enhance reactivity and enantioselectivity in the
direct asymmetric Mannich reaction of N-sulfonyl cyclic
ketimines with ketones. In this efficient transformation, not
only methyl ketones but also cyclic ketones can be employed
to provide a general methodology to construct tetrasubstituted
α-amino ester in a stereoselective manner. The synthetic utility
of a substituted amino ester product is demonstrated by the
synthesis of biologically active spirotetrahydrofuran.
Scheme 1. Our Strategy to Enhance the Catalytic Activity of
Amino Acid Catalyst (Ns = 2-Nitrobenzene-1-sulfonyl)
mino acids as important organocatalysts have received
Aconsiderable attention since the pioneering work of List and
Barbas, III.1 However, the limitations of amino acids as
organocatalysts have also been recognized gradually. Typically,
high catalyst loadings and low catalytic activity restricted the
applications of amino acids as catalysts for large scale synthesis. It
is well-known that a carboxylic acid proton in the amino acid
plays a critical role in enhancing the reactivity and stereo-
selectivity of the catalyst.2 Accordingly, increasing the acidity of
an amino acid based catalyst became a common approach to
improve catalytic activity.3 In contrast, the effect of increasing the
H-bonding sites of amino acid derived catalysts is less explored.4
Therefore, we envisage that amino sulfonohydrazide (cat.1)
which contains multiple sites for hydrogen bonding with
substrates may enhance the reactivity and enantioselectivity of
reaction. To illustrate, we attempted the direct Mannich reaction
of cyclic N-sulfonyl ketimines with ketones. Here, we found that
the direct Mannich reaction of cyclic N-sulfonyl ketimines with
ketones could indeed be catalyzed by amino sulfonohydrazide
with an increase in catalytic activity and high enantioselectivity
(Scheme 1).
Figure 1. Biologically active sultams.
The asymmetric Mannich reaction of N-sulfonyl ketimines is
an efficient and direct method for enantioselective synthesis of
benzosultams containing quaternary stereocenters,5 which are
widely found in biologically active molecules and serve as useful
chiral auxiliaries in asymmetric transformations (Figure 1).6,7
Recently, transition-metal-catalyzed asymmetric allylation and
arylation of cyclic ketimines have been reported by the Lam, Xu,
Zhang and Hayashi groups,5a−d whereas the enantioselective
Mannich reaction of N-sulfonyl ketimines with aldehydes or
Received: January 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00196
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Organic Letters
Letter
ketones has not been explored yet. In particular, utilizing a
ketone as a nucleophile in the asymmetric Mannich reaction of
cyclic ketimines was scarce in literature.8 In this context, we first
developed the highly diastero- and enantioselective direct
Mannich reaction of cyclic N-sulfonyl ketimines with ketones
by virtue of the efficient amino sulfonohydrazide catalyst.
We initially investigated the reaction between acetone and 1a
in the presence of 10 mol % of cat.1 in various solvents at rt
(Table 1). Nonpolar solvent toluene was found to be the optimal
Table 2. Direct Mannich Reaction of Cyclic N-Sulfonyl
Ketimines with Methyl Ketones Catalyzed by Amino
a
Sulfonohydrazide
b
c
entry
1
3
R1
5-Me
R2
R3
yield (%)
ee (%)
3aa
3ba
3ca
3da
3ea
3fa
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
99
95
d
a
2
5-Me
−
−
Me
Et
98(87)
90
99(96)
94
Table 1. Optimization of the Direct Mannich Reaction
3
d
4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
99(82)
99
96(92)
91
5
5-F
e
6
4-F
70
90
d
7
3ga
3ha
3ia
5-OMe
5-t-Bu
5-Cl
89(87)
99(97)
95
94(92)
96(93)
95
d
8
9
e
b
c
10
3ja
7-Cl
60
90
entry
solvent
x
yield (%)
ee (%)
11
12
13
3ka
3la
5-CF3
5-OCF3
6-Me
5,6-(CH)4
5-Me
81
90
1
2
3
MTBE
CHCl3
toluene
toluene
toluene
toluene
toluene
toluene
10
10
10
10
5
86
80
90
94
93
97
90
92
3ma
3na
3bb
99
95
99
e
d
14
15 ,
87
97
4
71
fg
e
90(72)
80(98)
5
f
73(99)
57(85)
34
93(94)
84(87)
70
a
The reaction of 1 (0.3 mmol) with 2 (3.0 mmol) was performed in
6
2.5
1
the presence of cat.1 (0.015 mmol) and TFA (0.015 mol) in toluene
7
b
g
(1.5 mL) at rt for 30 h. The product was isolated by flash
8
5
99
95
c
chromatography. The ee value of the product was determined by
a
The reaction of 1a (0.1 mmol) with 2a (1 mmol) was performed in
the presence of cat.1 (x mol %) and TFA (x mol %) in solvent (0.5
d
HPLC on a chiral stationary phase. The numbers in paretheses were
obtained when the catalyst loading was lowered to 2.5 mol % (see
b
c
mL) at rt for 8 h. Yield of isolated product. The ee value of the
product 3a was determined by HPLC on a chiral stationary phase.
e
details in Supporting Information). The numbers in paretheses were
f
obtained when chloroform (1.5 mL) was used as solvent. MTBE (1.5
d
e
The reaction was carried out without TFA as additive. The numbers
g
mL) was used as solvent. The numbers in paretheses were obtained
in paretheses were obtained when the reaction was carried out in 0.5
when the product was treated with ethanol.
f
mL of toluene for 15 h. The numbers in paretheses were obtained
g
when the reaction was carried out in 0.2 mL of toluene for 72 h. The
entry 6). The exchange of the methyl ester group for ethyl group
in 1 had little influence on both yield and enantioselectivity.
Remarkably, high levels of asymmetric induction continued to be
observed when reactions were performed with only 2.5 mol % of
the catalyst (Table 2, 3ba, 3da, 3ga, and 3ha). Replacing acetone
with less reactive acetophenone as a nucleophile still furnished
the adduct 3bb with moderate ee (80%) and excellent yield
(90%) (Table 2, entry 15). Moreover, the enantioselectivity
could be further improved by washing the product with EtOH,
giving a white solid with 98% ee after concentrating the filtrate.
To the best of our knowledge, this is the first example utilizing
acetophenone as a direct nucleophile to construct a chiral
quaternary carbon center.
After demonstrating the direct Mannich reaction of N-sulfonyl
ketimines with methyl ketones, we applied our catalytic system to
more challenging substrates, such as cyclohexanone and
cyclopentanone. Pleasingly, the high levels of enantioselectivity
and excellent yields were maintained in both cases (Table 3). In
addition, most products were obtained with high control of the
diastereoselectivity (up to >99:1). For electron-rich ketimines,
the desired products can be obtained with lower diastereose-
lectivity. When the reactions were carried out at 0 °C the
satisfactory diastereoselectivity can be obtained for these
ketimines (Table 3, entries 7, 8, 12, 14).
reaction was performed on 0.3 mmol scale under standard conditions
(see details in Supporting Information) (MTBE = methyl tert-butyl
ether).
solvent for this reaction with respect to both catalytic activity and
asymmetric induction (Table 1, entries 1−3). On the other hand,
acid additive had a great influence on catalytic activity. In the
absence of trifluoroacetic acid, the yield was decreased from 99%
to 71% (Table 1, entry 4). The catalyst loading had a great effect
on the yield of this reaction, since the byproduct of this process
was increased when lowering the catalyst loading. But a higher
concentration and prolonged reaction time provided the product
with a good yield and excellent enantioselectivity (Table 1,
entries 5−7). After different reaction conditions were screened,
the best result was obtained when 5 mol % catalyst was
employed. To our delight, upon scaling up to 0.3 mmol, the
enantioselectivity and yield of the reaction were maintained
(Table 1, entry 8).
With the optimized conditions in hand, a wide variety of cyclic
N-sulfonyl ketimines 1 were tested to examine the reaction scope
(Table 2). Good to excellent enantioselectivities were obtained
with aromatic sulfamide-derived imines bearing either electron-
withdrawing or -donating substituents (up to 99% yield, up to
99% ee; Table 2). Variation of the substituent position on
aromatic rings of cyclic ketimines 1 resulted in no significant
change in the enantioselectivity of this process, but led to a
decrease in the product yield. Notably, when the 4-position of 1,
close to the reaction site, was substituted by a fluorine atom, the
adduct 3fa was still obtained with 90% ee and 70% yield (Table 2,
The performance of our amino sulfonohydrazide catalyst cat.1
for enantioselective catalysis on a preparative scale was explored
next. Using 5 mol % cat.1, 2.4 g of ketimine 1b was reacted with
10 equiv of acetone at rt over 24 h to afford the product in 81%
yield and 99% ee (Scheme 2). To demonstrate the synthetic
B
DOI: 10.1021/acs.orglett.5b00196
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Organic Letters
Letter
NMR experiments.11 Initially, interaction between catalyst cat.1
and 1b/N15-1b was observed in the 13C NMR spectra, where H-
bonding induced a downfield shift of 0.041/0.035 ppm of the
ester group in 1b (Figure 2). In addition, when the ester group
Table 3. Direct Mannich Reaction of Cyclic N-Sulfonyl
Ketimines with Cyclic Ketones Catalyzed by Amino
a
Sulfonohydrazide
b
c
d
entry
3
R1
5-Me
R2
n
yield (%) ee (%) dr (3:4)
1
2
3
4
5
6
3ac
3bc
3cc
3dc
3ec
3fc
Et
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
99
98
86
99
99
75
88
99
95
73
93
99
99
99
88
82
99
98
98
98
96
97
99
99
97
95
97
98
96
99
98
97
19:1
16:1
14:1
19:1
18:1
33:1
10:1
25:1
18:1
36:1
15:1
39:1
14:1
17:1
>99:1
43:1
5-Me
Me
Et
−
−
5-F
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-F
e
7
e
3gc
3hc
3ic
5-OMe
5-t-Bu
5-Cl
Figure 2. Interaction between cat.1 and 1b, and the proposed transition-
state model.
8
9
f
10
3jc
7-Cl
11
3kc
3lc
5-CF3
5-OCF3
6-Me
5,6-(CH)4
5-Me
−
e
12
was removed in the control experiments, the reaction did not
work and no desired products were obtained.11 This implied that
the ester group was involved in the formation of the hydrogen
bond. On the other hand, variation in the 15N NMR spectra of
N15-1b provided further proof of the H-bonding interaction
between cat.1 and 1b. Based on these results, other control
experiments, the absolute configuration of the product 3fc, and
the previously reported mechanism,12,13 a possible transition-
state model was proposed as shown in Figure 2.
In conclusion, we have developed bifunctional chiral amino
sulfonohydrazide organocatalyst cat.1, which showed excellent
catalytic activity and high stereoselectivity in the direct
asymmetric Mannich reaction of N-sulfonyl cyclic ketimines
with ketones. This method provides a general access to the
optically active tetrasubstituted α-amino esters. With these
densely functionalized products, biologically active spirotetrahy-
drofuran was synthesized in three steps. More importantly,
increasing the hydrogen bonding sites for maximum coordina-
tion with substrates proved to be an effective strategy to improve
the activity of the catalyst in this process. Further application of
the chiral amino sulfonohydrazide catalyst is presently under
active investigation in our laboratory.
13
3mc
3nc
3bd
3dd
ef
,
14
15
16
a
The reaction of 1 (0.3 mmol) with 2 (3.0 mmol) was performed in
the presence of cat.1 (0.015 mmol) and TFA (0.015 mol) in toluene
(1.5 mL) at room temperature for 30 h. The product was isolated by
flash chromatography. The ee value of the product was determined by
b
c
d
HPLC on a chiral stationary phase. The dr (dr = 3:4) value was
e
determined by 1H NMR. The reaction was conducted at 0 °C for 40
f
h. Chloroform (1.5 mL) was used as solvent.
Scheme 2. Synthetic Utility of the Direct Mannich Reaction
and the Biological Activity of the Products
ASSOCIATED CONTENT
■
S
* Supporting Information
Typical experimental procedure and characterization for all
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
utility of the product 3ba, we transformed 3ba to biologically
active spirotetrahydrofuran 6a via a three-step sequence, which
involved sodium borohydride reduction followed by N-benzyl
protection and then dehydrated etherification. The product 6a
contains a spiro structure, which is an important moiety in a large
number of natural products with potent pharmacological
properties.6,9 Furthermore, a biological activity assay indicated
that the products 3ka and 3gc had potential activity as an HIV-1
inhibitor.10
*E-mail: zwang3@ustc.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Nature Science
Foundation of China (2127222, 91213303, 21172205,
J1030412).
To shed light on the reaction mechanism, we synthesized N15
isotope labeled substrate N15-1b and performed 13C and 15N
C
DOI: 10.1021/acs.orglett.5b00196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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D
DOI: 10.1021/acs.orglett.5b00196
Org. Lett. XXXX, XXX, XXX−XXX