Desymmetrization of meso-aziridines with TMSNCS using metal salts of novel chiral imidazoline-phosphoric acid catalysts

Article abstract of DOI:10.1021/ol501990t

Highly enantioselective desymmetrization of aziridines with TMSNCS has been developed. Good yield and enantioselectivity were observed by using novel chiral imidazoline-phosphoric acid catalysts. The obtained product can be converted to a chiral β-aminothiol and a β-aminosulfonic acid.

Full text of DOI:10.1021/ol501990t

Letter
pubs.acs.org/OrgLett
Desymmetrization of meso-Aziridines with TMSNCS Using Metal Salts
of Novel Chiral Imidazoline−Phosphoric Acid Catalysts
Shuichi Nakamura,*,† Mutsuyo Ohara,† Madoka Koyari,† Masashi Hayashi,† Kengo Hyodo,†
Nadaf Rashid Nabisaheb,† and Yasuhiro Funahashi‡
†Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya
466-8555, Japan
‡Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
S
* Supporting Information
ABSTRACT: Highly enantioselective desymmetrization of
aziridines with TMSNCS has been developed. Good yield
and enantioselectivity were observed by using novel chiral
imidazoline−phosphoric acid catalysts. The obtained product
can be converted to a chiral β-aminothiol and a β-
aminosulfonic acid.
he development of asymmetric catalysts has been
Textensively studied over the past decade. In this context,
chiral phosphoric acid catalysts, developed by Akiyama and
Terada, are among the most powerful chiral catalysts for
asymmetric C−C, C−H, and C−heteroatom bond formation
reactions.1 Despite the impressive progress achieved in various
enantioselective reactions using chiral phosphoric acid catalysts,
the development of novel catalyst designs for chiral phosphoric
acids still remains a major challenge. We recently developed
chiral imidazoline catalysts as Brønsted acid−base catalysts and
Lewis acid−Brønsted base catalysts.2 Herein we would like to
explore novel chiral catalysts having both an imidazoline and a
phosphoric acid moiety. These novel asymmetric catalysts
would control the reactivity and enantioselectivity by intra-
molecular H-bonding or chelation with metal species between
the imidazoline and phosphoric acid moieties (Figure 1).3
For example, β-aminosulfonic acids are known as taurine
derivatives,5 which include biologically active compounds such
as flavocristamide A and B,6 halicylindramides,7 and sulfobacin
B.8 Although there are many reports on the catalytic
desymmetrization of meso-aziridines with various nucleophiles,9
the catalytic desymmetrization of meso-aziridines using sulfur
nucleophiles with high enantioselectivity is rare.10 Efficient
methods for this type of reaction were independently reported
by Antilla and Della Sala, in which an enantioselective
desymmetrization of aziridines with arenethiols or trimethylsilyl
aryl sulfides using a chiral VAPOL phosphoric acid gave
products with high enantioselectivity.11 Although impressive
progress have been achieved in this type of reaction, attempts
to desymmetrize meso-aziridines using alkane- or arenethiols as
sulfur nucleophiles afforded chiral β-aminoalkyl sulfides, which
cannot be easily converted to chiral β-aminothiols or β-
aminosulfonic acids. Recently, Tang et al. reported an
interesting approach for the desymmetrization of aziridines
using CS2 and dibenzylamine in the presence of chiral
guanidine catalysts giving products that could be converted to
β-aminosulfonic acids after a three-step transformation.12 On
the other hand, TMSNCS as a sulfur nucleophile is a very
attractive candidate as a thiol or sulfonic acid equivalent;
however, the desymmetrization of aziridines with TMSNCS is
rare. During the preparation of this manuscript, Della Sala’s11c
and RajanBabu’s13 groups independently reported the
desymmetrization of aziridines with TMSNCS as a sulfur
nucleophile to give a product with moderate enantioselectivity.
Herein, we report the desymmetrization of aziridines with
TMSNCS using novel chiral catalysts.
Figure 1. Design for novel imidazoline−phosphoric acid catalysts.
In order to evaluate the ability of novel catalysts, the
desymmetrization of aziridines with TMSNCS was chosen as a
benchmark reaction. The obtained β-aminothiocyanates are
precursors for the synthesis of β-aminothiols and β-amino-
sulfonic acids, which are very important compounds for use as
stereoselective catalysts4 and biologically active compounds.
Received: July 9, 2014
© XXXX American Chemical Society
A
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First we examined the desymmetrization of meso-N-(arene-
sulfonyl)aziridines 1a−e with TMSNCS by using catalytic
amounts of chiral imidazoline−phosphoric acids 3. The results
are shown in Table 1. Recent studies indicated that phosphoric
heteroarenesulfonyl- or heteroarenecarbonyl groups were
effective stereoselective activating groups for the ring-opening
reaction of aziridines.15 Therefore, we next tried the reaction of
heteroarenesulfonylated or heteroarenecarbonylated aziridines
using 3a−Ca(OMe)2. Although the reaction of N-(2-quinoline-
sulfonyl)-, N-(2-thiophenesulfonyl)-, and N-(picolyl)aziridine,
1c,d,e using 3a-Ca(OMe)2 afforded products 2c,d,e with low
enantioselectivities, the reaction of N-(2-pyridinesulfonyl)-
aziridine 1b gave the product 2b in high yield with high
enantioselectivity (Table 1, entries 3−6).16 These results
provide evidence for the clear superiority of the 2-pyridine-
sulfonyl group as a stereocontrolling auxiliary for aziridines.
Optimization experiments for the fine-tuning of the imidazoline
substituent were carried out to improve the enantioselectivity of
(1S,2S)-2b. Changing the substituent on the nitrogen from a
tosyl group to the p-methoxybenzenesulfonyl group showed
slightly higher enantioselectivity (Table 1, entry 7). On the
other hand, the reaction using VAPOL−phosphoric acid 4−
Ca(OMe)2 afforded the product 2b in high yield but with low
enantioselectivity (Table 1, entry 8). We also examined chiral
phosphoric acids 5a,b and bis(imidazoline)−phosphoric acid 6;
however, the reaction gave the product 2b with low
enantioselectivity (Table 1, entries 9−11). Interestingly, the
reaction using either chiral imidazoline−phosphoric acid
catalyst 7 having different stereochemistry on the binaphthyl
group compared to 3a or 3,5-trifluoromethylphenyl-substituted
chiral phosphoric acid catalyst 8 afforded 2b as an almost
racemic product (Table 1, entries 12 and 13). The addition of 4
Å molecular sieves enhanced the reactivity of the reaction
without a loss in enantioselectivity (Table 1, entry 14). When
the reaction was carried out at lower temperature, the
enantioselectivity was improved (Table 1, entry 15). Interest-
ingly, the reaction using 3b with magnesium ethoxide afforded
the product 2b having a stereochemistry opposite that obtained
in the reaction using 3b−Ca(OMe)2 (Table 1, entry 16). The
absolute configuration of product 2b was determined to be
(1S,2S) by X-ray crystallographic analysis.
Table 1. Desymmetrization of Aziridines 1a−e with
TMSNCS in the Presence of Various Chiral Phosphoric Acid
a
Catalysts 3−8
b
entry
1
catalyst
2
time (h)
yield (%)
er (%)
c
1
1a
1a
1b
1c
1d
1e
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
3a
3a
3a
3a
3a
3a
3b
4
2a
2a
2b
2c
2d
2e
2b
2e
2b
2b
2b
2b
2b
2b
2b
2b
120
120
12
72
120
120
4
30
81
95
73
94
87
96
99
95
99
99
83
85
94
99
99
41:59
64:36
88:12
58:42
55:45
59:41
89:11
68:32
49:51
50:50
58:42
50:50
51:49
89:11
94:6
2
3
4
5
6
7
8
120
72
18
48
24
24
2
Having established the reaction conditions, the scope and
limitations of the desymmetrization using TMSNCS with a
variety of aziridines were investigated. The results are
summarized in Table 2. The ring-opening reaction of aziridines
having 5-, 6-, or 7-membered ring structures 1b,f−i also
afforded products 2b,f−i in high yields with good enantiose-
lectivities (Table 2, entries 1−5).17
We also examined the desymmetrization of aziridines with
other nucleophiles using catalyst 3b. The reaction of aziridine
1f with thiobenzoic acid afforded product 9 in high yield with
high enantioselectivity (Scheme 1). To our knowledge, this
result is the first successful example of the desymmetrization of
an aziridine with thiocarboxylic acids.18
9
5a
5b
6
10
11
12
13
7
8
d
14
3b
3b
3b
de
,
15
16
72
12
f
14:86
a
Catalyst (5 mol %) and TMSNCS (1.2 equiv) were used.
Enantiomer ratio was determined by HPLC analysis using chiral
b
c
d
e
columns. Without Ca(OMe)2. MS 4 Å was added. At −20 °C.
f
Magnesium salt of 3b was prepared using Mg(OEt)2.
We next examined the transformation of the product 2b into
β-aminothiol and β-aminosulfonic acid. The thiocyano group
can be reduced to a thiol using LiAlH4 to give the β-aminothiol
(Scheme 2). Since the obtained β-aminothiol dimerized to form
a disulfide, the reaction was performed with benzyl bromide in
situ to afford benzyl thioether 10 without loss of enantiopurity.
We also attempted the oxidation of product 2b to the β-
aminosulfonic acid. The 2-pyridinesulfonyl group can be
removed by magnesium in MeOH to give the β-amino-
thiocyanate. Oxidation of the thiocyano group in the β-
aminothiocyanate to a sulfonic acid using H2O2 gave the chiral
β-aminosulfonic acid 11 in high yield (Scheme 2). Based on the
acids obtained after purification using column chromatography
may contain metallic phosphate impurities.14 Therefore,
catalysts were used after purification by column chromatog-
raphy and washing by aqueous HCl. The reaction of N-(p-
toluenesulfonyl)aziridine 1a with TMSNCS using chiral
imidazoline−phosphoric acid catalyst 3a afforded product 2a
with 18% ee (Table 1, entry 1). In order to improve the
stereoselectivity of the reaction, we used the calcium phosphate
salt of 3a, which was prepared by the reaction of 3a with
calcium methoxide, to give product 2a with slightly better
enantioselectivity (Table 1, entry 2). Recently, we reported that
B
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Table 2. Desymmetrization of N-
(Heteroarenesulfonyl)aziridines 1b,f−i with TMSNCS in the
Presence of 3b
a
3b (10 mol %) and Ca(OMe)2 (10 mol %) were used.
Scheme 1. Desymmetrization of N-(2-
Pyridinesulfonyl)aziridine 1f with Thiobenzoic Acid in the
Presence of 3b−Mg(OEt)2
Figure 2. Proposed catalytic cycle for the desymmetrization of
aziridines with TMSNCS using 3.
pyridinesulfonyl)aziridines with TMSNCS in the presence of
these new chiral imidazoline−phosphoric acid catalysts 3 gives
chiral β-aminothiocyanates with good enantioselectivities. Both
enantiomers of the product can be obtained by changing the
metal salt. A range of aziridines are tolerated in the process.
The 2-pyridinesulfonyl group works as an efficient stereo-
controlling group for the ring-opening reaction of aziridine.
These results present a novel method to synthesize optically
active β-aminothiols and β-aminosulfonic acids. Further
experiments are in progress to study the scope of this process
and the potential applications of imidazoline−phosphoric acid
catalysts to other reactions.
Scheme 2. Reduction of Thiocyano Group in 2b to β-
Aminothiol 10 and Preparation of β-Aminosulfonic Acid 11
from 2b
ASSOCIATED CONTENT
* Supporting Information
value of the specific rotation reported in the literature,12 the
product can be obtained without loss of enantiopurity.
On the basis of the obtained results, we envisioned that
catalyst 3 could act in a bifunctional fashion. We also checked
the reaction using various ratios of 3 and Ca(OMe)2 (1:2 to
2:1). The best enantioselectivity was obtained from the reaction
using a 1:1 ratio of 3 and Ca(OMe)2. Therefore, the reaction
must be activated by a 1:1 complex of 3 and Ca(OMe)2. The
proposed catalytic cycle is shown in Figure 2. The catalyst 3
reacts with calcium methoxide to give the calcium salt (complex
A) by coordination of the imidazoline nitrogen with the
calcium cation. TMSNCS then reacts with complex A to give
complex B. Coordination of the N-(2-pyridinesulfonyl)aziridine
to the calcium cation in complex B affords complex C, which
includes an octahedral Ca(II) cation. The SCN group in
complex C reacts with the aziridine to give complex D. Finally,
the reaction of complex D with TMSNCS affords the product
and regenerates complex B.19
■
S
1H and 13C NMR spectra and experimental procedures for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: snakamur@nitech.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by Grants-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from MEXT (26105727), A-
Step (AS251Z00922M) from JST, the Kurata Memorial Hitachi
Science and Technology Foundation, and The Naito
Foundation.
In conclusion, we have developed novel imidazoline−
phosphoric acid catalysts. The desymmetrization of N-(2-
C
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