Synthesis of C2-symmetric sulfide and its first application in highly enantioselective synthesis of chiral aziridines

Article abstract of DOI:10.1246/cl.2007.1436

A C₂-symmetric sulfide 6 has been synthesized from cheap L-tartaric acid. It was found that sulfide 6 could perform a tandem reaction with benzyl bromide and tosyl imines to give (2S,3S)-aziridines 9a-9g with good to excellent enantioseletivities (up to 96% ee). Copyright

Full text of DOI:10.1246/cl.2007.1436

1436
Chemistry Letters Vol.36, No.12 (2007)
Synthesis of C2-Symmetric Sulfide and Its First Application in Highly Enantioselective
Synthesis of Chiral Aziridines
Yuan Gui, Sheng Shen, Hai-Yang Wang, Zhi-Yi Li, and Zhi-Zhen HuangÃ
School of Chemisty and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China
(Received September 3, 2007; CL-070946; E-mail: huangzz@nju.edu.cn)
A C2-symmetric sulfide 6 has been synthesized from cheap
mined by single-crystal X-ray diffraction.6 Finally, a one-pot re-
action of chiral diol 5 with methanesulfonyl chloride and then
sodium sulfide afforded the desired C2-symmetrical sulfide 6.7
Metzner et al. prepared a similar C2-symmetrical sulfide with
a locked comformation using D-mannitol instead of L-tartaric
acid as starting material, which has been used successfully in
asymmetric epoxidation with excellent enantioselectivities.7
With the C2-symmetric sulfide 6 in hand, we chose phenyl-
N-tosylmethanimine (8a) as a model substrate to search the reac-
tion conditions for asymmetric aziridination (Scheme 2). We
were pleased to find that the sulfide 6 and benzyl bromide could
react with potassium carbonate in dichloromethane to generate
chiral sulfonium ylide 7 in situ, followed by the reaction with
N-tosyl imine 8a to give the desired aziridines 9a in 52% yield
with 85% ee (Entry 1, Table 1). Encouraged by the result, we ex-
amined other solvents in the tandem aziridination reaction. It
was found that acetonitrile is the best solvent in comparison with
dichloromethane and tert-butanol (Entries 1–3, Table 1). Then,
other bases were also examined in the reaction in acetonitrile.
Experiments showed that sodium hydroxide and sodium hydride
could not lead to the aziridination and cesium carbonate led to
lower yield and enantioselectivity of 8a (Entry 4, Table 1), com-
pared with potassium carbonate. It was further found that, when
0.1 equiv. of tetrabutylammonium iodide (TBAI) relative to
imine 8a was added as a phase-transfer catalyst (PTC), both
the yield and enantioselectivity were improved (Entries 3 and
6, Table 1).8 When the amount of sulfide 6 was increased from
1.0 equiv. to 1.5 equiv. relative to imine 8a, the yield of aziridine
9a was further improved with increasing enantioselectivity
slightly (Entry 7, Table 1). Using 2.0 equiv. of sulfide 6 led to
a little increase in yield with keeping excellent enantioselectivity
(Entries 7 and 8, Table 1). Decreasing the amount of sulfide 6
from 1.0 equiv. to 0.5 equiv. led to the reduction of both yield
and enantioselectivity (Entries 5 and 6, Table 1). Thus, the opti-
mal conditions of the asymmetric aziridination were chosen as
L-tartaric acid. It was found that sulfide 6 could perform a tan-
dem reaction with benzyl bromide and tosyl imines to give
(2S,3S)-aziridines 9a–9g with good to excellent enantioseletivi-
ties (up to 96% ee).
Chiral aziridines are important moieties in many biological-
ly active compounds and versatile building blocks for the syn-
thesis of many biologically important compounds, such as amino
acids, alkaloids, amino sugars, and ꢀ-lactamic antibiotics.1 Re-
cently, the chiral ylide route was envisaged to become possibly
one of the most important methods for the asymmetric synthesis
of aziridines as well as the asymmetric synthesis of epoxides and
cyclopropanes.2 There are some excellent examples on the util-
ities of chiral sulfonium ylides in the synthesis of chiral aziri-
dines.3 However, the development of new methods for highly
enantioselective synthesis of aziridines via chiral ylide is still a
challenging subject. C2-symmetric sulfide or telluride generates
only one diastereomeric sulfonium or telluronium salt as the pre-
cursor of corresponding ylide. The chiral ylides derived from C2-
symmetric sulfides and tellurides have proved very effective in
asymmetric epoxidation and cyclopropanation with high enan-
tioselectivities (up to 99% ee).4 Nevertheless, to our knowledge,
few literatures revealed the application of C2-symmetric chalco-
genide derived chiral ylide in asymmetric aziridination. There-
fore, we started to synthesize C2-symmetric sulfide and explore
its utility in the highly enantioselective synthesis of aziridines
via chiral sulfonium ylide.
We chose readily available L-tartaric acid 1 as the starting
material for the synthesis of C2-symmetric sulfide 6. Initailly,
1 was esterified with ethanol, followed by the condensation with
acetone to give diethyl diester 2 (Scheme 1).5a Diester 2 then
.
reacted with Me(MeO)NH HCl and the Grignard reagent to
generate bis-Weinreb amide 3.5b The reaction of amide 3 with
the ethyl Grignard reagent afforded diethyl diketone 4.5c Dike-
tone 4 could be reducted smoothly by sodium borohydride to af-
ford C2-symmetric diol 55c and the structure of diol 5 was deter-
Ts
N
CH2Br
base/PTC
+
6
RCH NTs
+
R
H
solvent
O
O
H
8a-g
Ph
9a-g
Et
O
O
O
Et
Et
O
O
COOEt
COOEt
N
N
HO
HO
COOEt
COOEt
OCH3
OCH3
O
O
O
S
CH2
7
O
O
1
2
3
4
Et
Et
Et
O
O
O
O
OH
a: R=C6H5,
b: R=p-ClC6H4,
c: R=p-FC6H4,
S
d: R=p-NO2C6H4, e: R=C6H5CH=CH, f: R=p-CH3OC6H4,
g: R=p-CH3C6H4
OH
Et
Et
5
6
Scheme 2. Asymmetric synthesis of (2S,3S)-aziridines 9a–9g
via chiral sulfonium ylide 7.
Scheme 1. Synthetic route for C2-symmetric sulfide 6.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.12 (2007)
1437
Table 1. Optimization of the aziridination in different experi-
mental conditions
diastereoselectivities and enantioselectivities in the asymmetric
aziridination.
In conclusion, we have synthesized C2-symmetric sulfide
6 from cheap L-tartaric acid. Further experiments showed that
the chiral sulfide could conduct the tandem reaction with benzyl
bromide and tosyl imine to give the desired (2S,3S)-aziridines
9a–9g in moderate yields with dominant trans isomers and
good to excellent enantioseletivities (up to 96% ee). Further
investigations on the extension and mechanism of the method
for the highly enantioselective synthesis of aziridines using
the C2-symmetric sulfide 6 and a C2-symmetric telluride are
currently underway.
Reaction
conditionsa
Sulfide Yield Trans/ Trans
/equiv. /%b
Entry
cisc
ee /%d
CH2Cl2/
K2CO3
t-BuOH/
K2CO3
MeCN/
K2CO3
MeCN/
Cs2CO3
MeCN/
K2CO3/TBAI
MeCN/
K2CO3/TBAI
MeCN/
K2CO3/TBAI
MeCN/
K2CO3/TBAI
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
0.5
1.0
1.5
2.0
52
43
58
38
43
62
70
72
76:24
85
72:28
75:25
70:30
75:25
76:24
75:25
75:25
90
92
80
87
95
96
96
We thank the National Natural Science Foundation of China
for its financial support of the project Nos. 20332050 and
20572042.
References and Notes
1
2
3
D. Tanner, Angew. Chem., Int. Ed. Engl. 1994, 33, 599; P.
Muller, C. Friut, Chem. Rev. 2003, 103, 2905; A. K. Yudin,
Aziridines and Epoxides in Organic Synthesis, Wiley, Wein-
heim, 2006.
¨
aReactions were performed at room temperature for 2 days.
bIsolated yields. cDetermined by 1H NMR or HPLC.
dDetermined by chiral HPLC on a chiralcel OD-H column.
A.-H. Li, L.-X. Dai, V. K. Aggarwal, Chem. Rev. 1997,
97, 2341. The recent related references are quoted in
Supporting Information, which is available via the Internet
at http://www.csj.jp/journals/chem-lett/.
a) V. K. Aggarwal, E. Alonse, G. Fang, M. Ferrara, G. Hynd,
M. Porcelloni, Angew. Chem., Int. Ed. 2001, 40, 1433. b)
V. K. Aggarwal, A. Thompson, R. V. H. Jones, M. C.
Standen, J. Org. Chem. 1996, 61, 8368. c) A.-H. Li, Y.-G.
Zhou, L.-X. Dai, X.-L. Hou, L.-J. Xia, L. Lin, Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1317. d) T. Saito, M. Sakairi, D.
Table 2. Aziridination of various N-tosyl imines via chiral
ylide 79
Entry
R
Yielda Trans/cisb Trans ee /%c
1
2
3
4
5
6
7
Ph
p-ClC6H4
p-FC6H4
p-NO2C6H4
PhCH=CH
p-OCH3C6H4
p-CH3C6H4
72
62
65
50
75
60
68
75:25
80:20
75:25
65:35
90:10
60:40
80:20
96
87
93
85
90
80
91
´
Akiba, Tetrahedron Lett. 2001, 42, 5451. e) A. Solladie-
Cavallo, M. Roje, R. Welter, V. Sunjic, J. Org. Chem.
ˇ
´
2004, 69, 1409.
4
5
K. Julienne, P. Metzner, V. Henryon, A. Greiner, J. Org.
Chem. 1998, 63, 4532; W.-W. Liao, K. Li, Y. Tang, J. Am.
Chem. Soc. 2003, 125, 13030; J.-C. Zheng, W.-W. Liao,
Y. Tang, X.-L. Sun, L.-X. Dai, J. Am. Chem. Soc. 2005,
127, 12222.
a) G.-C. Xu, J.-T. Sun, B. L. He, Chem. J. Chin. Univ. 1993,
14, 1471. b) J. M. Williams, R. B. Jobson, N. Yasuda, G.
Marchesini, U. Dolling, E. J. J. Grabowski, Tetrahedron Lett.
1995, 36, 5461. c) J. McNulty, V. Grunner, J. Mao, Tetra
hedron Lett. 2001, 42, 5609.
aIsolated yields. bDetermined by 1H NMR or HPLC.
cDetermined by chiral HPLC on a chiralcel OD-H column.
follow: the amount of sulfide 6 was 2.0 equiv., the base was
potssium carbonate, the solvent was acetonitrile and TBAI was
used as a PTC.
Following this optimization, a variety of N-tosyl imines 8a–
8g were examined in the asymmetric aziridination reaction
(Table 2). We found that, in the presence of potassium carbonate
and TBAI, the sulfide 6 and benzyl bromide could react with var-
ious N-tosyl imines 8a–8g via chiral sulfonium ylide 7, giving
the desired chiral aziridines 9a–9g in the yields of 50–75% with
dominant trans isomers. As expected, C2-symmetric sulfide
6 could lead to good to excellent enantioselectivities (80–
96% ee) in the asymmetric aziridination of various tosyl imines.
The absolute configurations of 9a–9g were assigned by compar-
ison of the sign of optical rotation with that of the known com-
pounds and all (2S,3S)-isomers of 9a–9g are levorotatory in
CHCl3.3a Electron-withdrawing or electron-donating groups on
the benzene ring seem to have no significant effects on yields,
6
7
The deposition number: CCDC646590.
M. Davoust, J.-F. Briere, P.-A. Jaffres, P. Metzner, J. Org.
Chem. 2005, 70, 4166.
8
9
J. Zanardi, C. Leriverend, D. Aubert, K. Juliene, P. Metzner,
J. Org. Chem. 2001, 66, 5620.
General procedure for the synthesis of trans-(2S,3S)-aziri-
dines 9a–9g. The mixture of sulfide 6 (1.0 mmol), benzyl
bromide (1.5 mmol), tosyl imines 8 (0.5 mmol), K2CO3
(1.5 mmol), and TBAI (0.05 mmol) in CH3CN (20 mL) was
stirred for 2 days at room temperature. Common workup/
isolation afforded the desired chiral aziridines 9a–9g.
Published on the web (Advance View) November 3, 2007; doi:10.1246/cl.2007.1436