Squaramide-catalysed asymmetric cascade aza-Michael/Michael addition reaction for the synthesis of chiral trisubstituted pyrrolidines

Article abstract of DOI:10.1039/c5ob01749a

A bifunctional squaramide catalysed aza-Michael/Michael cascade reaction between nitroalkenes and tosylaminomethyl enones or enoates has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized chiral pyrrolidines with a broad substrate scope, giving the desired products in good yields (up to 99%) with good diastereoselectivities (up to 91 : 9 dr) and excellent enantioselectivities (up to >99% ee) under mild conditions. This protocol provides a straightforward entry to highly functionalized chiral trisubstituted pyrrolidine derivatives from simple starting materials.

Full text of DOI:10.1039/c5ob01749a

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DOI: 10.1P039A/C5POBE017R49A
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Squaramide-catalysed asymmetric cascade aza-Michael/Michael
addition reaction for synthesis of chiral trisubstituted pyrrolidines†
Bo-Liang Zhao,a Ye Lin,a Hao-Hao Yan,a and Da-Ming Du*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 2015, Accepted Xth XXXXXXXXX 2015
5
DOI: 10.1039/c1ob000000x
A bifunctional squaramide catalysed aza-Michael/Michael cascade reaction between nitroalkenes and
tosylaminomethyl enones or enoates has been developed. This organocatalytic cascade reaction provides
easy access to highly functionalized chiral pyrrolidines with a broad substrate scope, furnishing the
desired products in good yields (up to 99%) with good diastereoselectivities (up to 91:9 dr) and excellent
10 enantioselectivities (up to >99% ee) under mild conditions. This protocol provides a straightforward entry
to highly functionalized chiral trisubstituted prrolidine derivatives from simple starting materials.
In recent years, organocatalytic cascade or domino reactions
Introduction
have attracted considerable attention, and great progress has been
made. Moreover, organocatalysed hetero-Michael cascade
50 reactions, for example aza-Michael,9 oxa-Michael,10 and sulfa-
Michael cascade reactions,11 are considered to be highly efficient
and facile methods for generating chiral functionalized
heterocyclic molecules. As hydrogen-bonding organocatalysts,
squaramides12 have also been successfully used in the
55 organocatalytic cascade reactions.13 Recently, our laboratory has
The optically active pyrrolidines are widely observed in structural
components of numerous naturally occurring alkaloids and
15 biologically active synthetic substances,1 are increasingly present
in pharmaceutical agents,2 and recently has become ubiquitous in
catalysis, finding use as organocatalysts as well as ligands for a
broad range of metal-mediated enantioselective protocols.3 Not
surprisingly, the ‘‘privileged’’ chiral heterocyclic framework has
20 been widely investigated for new reaction invention.4 Among
these, the strategy of efficient catalytic asymmetric [3+2]
cycloaddition reactions,5 such as the reaction of imino esters with
nitroalkenes (scheme 1)6 that is particularly important in the
construction of functionalized pyrrolidinerings, provide a very
25 elegant solution to access stereochemically complex variants.
However, the reported direct asymmetric cycloaddition methods
mostly rely on chiral auxiliary controlled asymmetric synthesis
and transition-metal-catalysed asymmetric dipolar addition
reactions.5,7 In contrast, the methods employing organocatalysed
30 asymmetric processes for the efficient preparation of chiral
pyrrolidines are still limited.8 Recently, we sought to develop a
new strategy for the construction of highly functionalized
pyrrolidine rings. To the best of our knowledge, the asymmetric
synthesis of chiral pyrrolidines via squaramide-catalysed aza-
35 Michael/Michael cascade reactions has rarely been observed.
Herein we describe the successful execution of the ideal and
demonstrate a simple yet powerful pyrrolidine forming reaction.
introduced
a mode of [4 + 2] cyclization to generate
functionalized tetrahydroquinolines with squaramide catalysts
that can enabled the direct cyclization reaction of aromatic 2-
aminoenones with nitroalkenes employing one asymmetric
60 cascade aza-Michael/Michael addition strategy.14 We envisioned
this cascade aza-Michael/Michael addition strategy might be
employed to design
a formal [3 + 2] cyclization for
stereoselectively building chiral pyrrolidine rings. So we try to
synthesize a series of tandem reaction reagents, alphatic
65 aminomethyl enones or enoates, and design new methods for the
synthesis of chiral pyrrolidines. With the aim of expanding our
previous studies on the enantioselective synthesis of biologically
important molecules, we would like to document an efficient
squaramide-catalysed asymmetric cascade aza-Michael/Michael
70 addition reaction for the synthesis of chiral pyrrolidines. As
outlined in scheme 1, this one-pot transformation can produce a
complex molecular architecture formed with three contiguous
stereocenters, which experiences a different process compared
with the previously reported work about the synthesis of chiral
75 pyrrolidines.
aSchool of Chemical Engineering and Environment, Beijing Institute of
40 Technology, Beijing 100081, People’s Republic of China.*Corresponding
author, E-mail: dudm@bit.edu.cn; Tel: +86 10 68914985.
bState key laboratory of Elemento-Organic Chemistry, Nankai University
1
†Electronic Supplementary Information (ESI) available: [Copies of H
and 13C NMR spectra of new compounds, and HPLC chromatograms].
45 See DOI: 10.1039/c1ob000000x/
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Organic & Biomolecular Chemistry
Page 2 of 10
a) Previous work
hydroquinine-derived squaramide VI as the optimal catalyst.
R1
CO2R3
N
CO2R3
O2N
R2
asymmetric 1,3-dipolar
cycloaddition reaction
NO2
+
CO2R3
CO2R3
View Article Online
R1
R2
Table 1. Screening of organocatalysts.a
N
DOI: 10.1039/C5OB01749A
Ph
H
O2N
Ph
O
R2
O
5 mol% I-X
b) This work
O
NO2
TsHN
O2N
R1
+
Ph
Ph
asymmetric aza-Michael
/Michael reaction
Ts
R2
N
CH2Cl2, r.t.
NO2
R1
N
+
H
Ts
3aa
1a
N
2a
O
Ts
Yieldb (%)
drc
eec (%)
Scheme1. Preparation of highly functionalized chiral pyrrolidines.
Catalyst
Entry
1
2
3
4
5
6
7
8
9
65
56
69
66
63
75
71
70
63
66
83:17
82:18
79:21
82:18
77:23
84:16
84:16
76:24
76:24
76:24
99
I
Results and discussion
98
II
At the outset of our investigation, a series of organocatalysts
(Figure 1) were evaluated in the model reaction of nitrostyrene 1a
and N-tosyl aminomethyl enone 2a. In the presence of quinine-
derived squaramide I (5 mol%), the reaction provided the desired
chiral pyrrolidine 3aa in 65% yield in CH2Cl2 (1.0 mL) at room
temprature for 72 h, and with 83:17 dr and 99% ee (Table 1, entry
10 1) according to the chiral HPLC analysis of the crude product.
Encouraged by this important result, we evaluated a small library
of organocatalysts for this cascade reaction. Squaramide II
derived from quinine bearing 4-CF3 group on the aromatic ring
gave a little lower diastereoselectivity and eanantioselectivity
15 (Table 1, entry 2). Squaramide III derived from quinine bearing
4-NO2 group on the aromatic ring afforded the desired adduct
99
III
IV
V
5
99
99
99
VI
VII
VIII
IX
X
97
99
88
10
99
a
Reaction conditions: a mixture of 1a (0.4 mmol), 2a (0.2 mmol),
catalyst (5 mol%) in CH2Cl2 (1.0 mL) was stirred at room temperature
for 72 h. bIsolated yield. c Determined by chiral HPLC analysis.
with
similar
eanantioselectivity,
but
with
lower
diastereoselectivity (Table 1, entry 3).
40
Further optimization was carried out using squaramide VI as
the catalyst. We investigated the effect of solvent, catalyst
loading, temperature and the influence of the ratio of two
reactants for the optimal reaction conditions. The results are
shown in Table 2. The screening of different reaction solvents
O
O
O
O
O
O
O2N
H
H
Ar
N
Ar
N
N
N
H
HN
N
H
HN
N
H
HN
H
OMe
OMe
OMe
N
N
N
45 with 5 mol% catalyst VI show that CH2Cl2 is the optimal solvent
(Table 2, entry 17). Then, other parameters such as reaction
temperature and catalyst loading were further evaluated. When
the model reaction was performed at higher temperature, the
yield, enantioselectivity and diastereoselectivity were reduced
50 (Table 2, entry 8). When increasing the catalyst loading, the
enantioselectivity or diastereoselectivity of the product 3aa
cannot be further improved (Table 2, entries 9 and 10). When the
mol ratio of β-nitrostyrene to N-tosyl aminomethyl enone 2a was
increased to 3:1, the product yield was increased to 85% (Table 2,
55 entry 11). After the above reaction condition evaluation, we
confirmed that the optimum reaction conditions called for the use
of CH2Cl2 as solvent and a 10 mol% catalyst loading at room
temperature with a 3:1 mol ratio of β-nitrostyrene to N-tosyl
aminomethyl enone 2a.
I: Ar = 3,5-(CF3)2C6H3
II: Ar = 4-CF3C6H4
IV: Ar = 3,5-(CF3)2C6H3
V: Ar = 4-CF3C6H4
III
CF3
CF3
O
O
O
O
CF3
O
O
H
H
N
N
F3C
N
H
HN
F3C
OMe
N
H
HN
N
H
N
H
F3C
N
N
N
VI
VII
VIII
CF3
O
O
N
H
N
H
N
CF3
N
H
F3C
N
H
MeO
S
N
CF3
N
IX
X
20
Figure 1. Squaramide and thiourea organocatalysts used in this study.
Squaramides IV and V derived from quinidine afforded the
desired adducts with similar results, but with opposite
60
25 configuration (Table 1, entries 4 and 5). To our surprise, we noted
that a significantly improvement in yield was observed when
squaramide VI derived from hydroquinine was used (Table 1,
entry 6). Squaramides VII derived from hydrocinchonidine
derivative (Table 1, entry 7) was also evaluated, but no
30 improvements were observed relative to the squaramide VI. We
then turned our attention to these squaramides VIII and IX
derived from chiral 1,2-diaminocyclohexane (Table 1, entries 8
and 9), but inferior results were observed. For comparison with
the used squaramides, the corresponding quinine-derived thiourea
35 X was also screened (Table1, entry 10). Unfortunately, a decrease
in terms of diastereoselectivity was obtained. At last, we choose
Table 2. Optimization of reaction conditions.a
Ph
O2N
Ph
O
VI
O
NO2
TsHN
+
Ph
Ph
solvent, r.t.
N
1a
2a
Ts
3aa
Loading
(mol%)
Solvent
Yieldb(%) drc
eec (%)
Entry
1
2
3
CH2Cl2
CHCl3
5
5
5
75
72
73
84:16
99
98
98
79:21
83:17
ClCH2CH2Cl
2
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With the optimized conditions in hand, we next examined the
scope of the asymmetric cascade reaction for the synthesis of
highly functionalized chiral trisubstituted DpyOrIr:o10li.d10in3Ve9ise/w.CA5AOrstiBcsl0eh1Oo7nw4l9innAe
in Table 3, a range of electron-poor (entries 2, 3 and 4, 72−84%
yield, 81:19−85:15 dr, 97−99% ee) and electron-rich (entries 5
and 6, 43−82% yield, 73:27−85:15 dr, 98−99% ee) substituents
were appended to the benzene ring of the β-nitrostyrene. The
results show that the electronic nature of the substituents on the
4
PhMe
5
62
51
36
22
62
77
76
85
81:19
82:18
78:22
62:38
81:19
83:17
84:16
84:16
96
96
97
99
96
98
96
99
5
xylene
THF
5
6
5
5
7
8d
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
5
9
10
20
10
10
11e
10 aromatic rings have little influence on the cascade process.
However, the position of the substituent on the aromatic ring of
β-nitrostyrene has an evident effect on enantioselectivity.
a Reaction conditions: a mixture of 1a (0.4 mmol), 2a (0.2 mmol), catalyst
VI in 1.0 mL solvent was stirred at room temperature for 72 h. Isolated
b
c
d
yield.
Determined by chiral HPLC analysis.
The reaction was
performed at 40 C for 48 h. e 0.6 mmol 1a was used.
Table 3. Scope of asymmetric cascade aza-Michael/Michael addition for synthesis of chiral pyrrolidines.a
R2
O2N
O
10 mol% VI
O
NO2
TsHN
+
R1
R2
CH2Cl2, r.t.
R1
N
Ts
3aa-an
Yieldb (%)
1a-f
R2
2a-i
R1
Product
drc
eec (%)
Entry
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
85
79
72
84
43
82
79
81
72
47
69
80
82
85
83
84
83
82
99
99
99
99
84:16
85:15
81:19
85:15
73:27
85:15
80:20
79:21
80:20
88:12
88:12
88:12
89:11
86:14
85:15
86:14
86:14
86:14
91:9
99
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
2
4-ClC6H4
3-BrC6H4
4-BrC6H4
2-MeC6H4
4-MeC6H4
2-furyl
2-thienyl
phenylethyl
cyclohexyl
Ph
98
3
97
4
99
5
98
6
>99
97
7
8
>99
79
9
10
11
12
13
14
15
16
17
18
19d
20d
21e
22d
95
3ja
3ab
3ac
3ad
3ae
3af
3ag
3ah
3dd
3ai
4-FC6H4
>99
>99
97
Ph
4-ClC6H4
4-BrC6H4
4-MeC6H4
Ph
Ph
98
Ph
3-MeOC6H4
4-MeOC6H4
2-naphthyl
4-BrC6H4
Me
98
Ph
99
Ph
98
4-BrC6H4
Ph
98
77
Ph
OEt
53:47
55:45
57:43
92/56
84/56
74/80
3aj
3aj
3ak
Ph
OEt
Ph
OtBu
a Reaction conditions: a mixture of 1 (0.6 mmol), 2 (0.2 mmol), catalyst VI (10 mol%) in CH2Cl2 (1.0 mL) was stirred at room temperature for 6096 h.
b Isolated yield. c Determined by chiral HPLC analysis. d The reaction was performed for 30 h. e The reaction was performed with catalyst X (10 mol%)
in PhMe (1.0 mL) at room temperature for 30 h.
15
products with comparable enantioselectivity and yields, but in
As shown in entry 5, the diastereoselectivity and yield were
both reduced when the o-methylnitrostyrene reacted with N-tosyl
aminomethyl enone 2a, but the enantioselectivity can be
maintained. Additionally, heterocyclic substrates were also
lower diastereoselectivity (entries 7 and 8, 7981% yield,
79:2180:20 dr, 9799% ee). There was a significant decline in
diastereo- and enantioselectivity when phenylethyl substituted β-
25 nitrostyrene was used as the reactant (entry 9, 72% yield, 80:20
dr, 79% ee). Moreover, the diastereo- and enantioselectivity are
20 amenable to this cascade reaction and afforded the corresponding
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Page 4 of 10
Ph
N
NO2
O
maintained for the less reactive cyclohexyl substituted β-
10 mol% VI
NO2
nitrostyrene with large steric hindrance (entry 10, 47% yield,
88:12 dr, 95% ee), but with diminished yield. Then, a variety of
tosylaminomethyl enones or enoates 2 were tested. Among them,
2bg with different substituents on the aromatic ring (entries
1116, 6985% yield, 86:1489:11 dr, 9799% ee), whatever
electron-withdrawing and electron-donating substituents and the
position of the substituents in the benzene ring, all can react
smoothly with β-nitrostyrene 1a to afford the corresponding
Ts
+
TsHN
OEt
Ph
CH2Cl2, r.t.
View Article Online
OEt
DOI: 10.1039/C5OB01749A
O
1a
4a
Scheme 3. An attempt of asymmetric cascade aza-Michael/Michael
5
addition for synthesis of chiral piperidine.
55
Conclusions
10 products 3ab3ag in good diastereoselectivities and yields with
excellent enantioselectivities. Two reactions that 2-naphthyl
substituted enone 2h reacted with β-nitrostyrene 1a (entry 17,
83% yield, 86:14 dr, 98% ee) and 4-bromo substituted N-
tosylaminomethyl enone 2d reacted with 4-bromo substituted β-
15 nitrostyrene 1d (entry 18, 82% yield, 86:14 dr, 98% ee) were also
evaluated, the results both are satisfactory. The alkyl enone 2i
(entry 19, 99% yield, 91:9 dr, 77% ee) dramatically increases the
product yield as compared to aryl enone, which may be due to
smaller sterically hinderance that was advantageous to the
20 nucleophilic addition of nitroalkane to enone. In addition, we also
examined two 4-tosylamino but-2-enoates 2j and 2k (entries 20
and 22, 99% yield, 53:47, 57:43 dr, 92/56, 74/80% ee). These
substrates exhibited much higher reactivity and provided the
In summary, we have developed an efficient highly asymmetric
cascade aza-Michael/Michael reaction catalysed by a chiral
60 bifunctional tertiary amine-squaramide catalyst for the synthesis
of chiral pyrrolidines. The reaction proceeds in good isolated
yield and diastereoselectivity with excellent enantiocontrol.
Salient features of the present protocol include a wide substrates
range (diverse nitroalkenes, tosylaminomethyl enones and
65 enoates), simple starting materials and amenability to gram-scale
synthesis. Further investigations involving the application of this
catalytic approach and catalysts are currently underway in our
group and will be reported in due course.
corresponding products in excellent yields and good 70 Experimental
25 enantioselectivities, but with drastically diminished
diastereoselectivities. In order to determine the absolute
configurations of products 3, entry 21 (99% yield, 55:45 dr,
84/56% ee) was performed with the optimal reaction conditions
reported in the literature.15 Compared with the reported data, the
30 product 3aj has the same NMR data. The absolute configuration
of the major isomer of 3aj was thus determined to be (3’S, 4R,
5’S) according to optical rotation comparision with literature, and
the absolute configurations of other products 3 were assigned by
analogy to major isomer of 3aj.
General Methods
Commercially available compounds were used without further
purification. Solvents were dried according to standard
75 procedures. Column chromatography was performed with silica
gel (200300 mesh). Melting points were determined with an
XT4 melting-point apparatus and are uncorrected. 1H NMR
spectra were measured with a Bruker Avance 400 MHz
spectrometer. Chemical shifts were reported in δ (ppm) units
80 relative to tetramethylsilane (TMS) as the internal standard. 13C
NMR spectra were measured at 100 MHz; chemical shifts were
reported in ppm relative to TMS with the solvent resonance as
internal standard. Infrared spectra were obtained with a Bruker
ALPHA-P spectrometer or a Perkin Elmer Spectrum One
85 spectrometer. High resolution mass spectra (Electron spray
ionization) were measured with a Bruker APEX IV Fourier-
Transform mass spectrometer. Enantiomeric excesses were
determined by chiral HPLC analysis using an Agilent 1200 LC
instrument with a Daicel Chiralpak IB or AD-H column.
90
35
To demonstrate the synthetic potential of this asymmetric
cascade methodology, a gram-scale synthesis of 3aa was
performed (Scheme 2). The reaction proceeded smoothly
affording the corresponding product in moderate yield and with
higher diastereoselectivity and comparable enantioselectivity than
40 0.2 mmol-scale reaction.
Ph
O2N
Ph
O
10 mol% VI
O
NO2
TsHN
+
Ph
Ph
CH2Cl2, r.t.
N
1a
12.0 mmol, 1.79 g
2a
4.0 mmol, 1.26 g
Ts
3aa
Materials
1.33 g, 72% yield
>86:14 dr, 99% ee
Chiral squaramide catalysts I, II, IV, V, VII, VIII and IX,16 III,17
VI,18 and chiral thiourea catalyst X,19 nitroalkenes,20
tosylaminomethyl enones and enoates21 were prepared according
95 to the reported procedures.
Scheme 2. The gram-scale preparation of 3aa.
Because the 4-tosylamino but-2-enoates exhibited so high
45 reactivity, we qustioned if we can develop a aza-Michael/Michael
cascade strategy to synthesize highly functionalized chiral
piperidines. 5-tosylamino pent-2-enoates 4a was synthesized and
reacted with β-nitrostyrene 1a under our optimal reaction
conditions (Scheme 3). Unfortunately, the reaction did not take
50 place as judged by TLC analysis.
Synthesis of (E)-Ethyl 5-(4-methylphenylsulfonamido)pent-2-
enoate (4a)
4
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OEt
OEt
OEt
1) Ts-Cl, Et3N
CDCl3):  196.3, 144.3, 138.7, 135.8, 133.72, 133.66, 129.9,
TsHN
OEt
O
55 129.0, 128.7, 128.4, 127.8, 127.7, 126.2, 96.2, 66.9, 53.2, 39.5,
H2N
2) 1 M HCl, THF
21.6 ppm; IR (ATR): 3063, 3031, 29D6O2,I: 2109.21033,V9ie1/wC725AOr1ti,Bcl0e11O678n4l39in,Ae

v
1597, 1550, 1494, 1449, 1411, 1349, 1305, 1213, 1159, 1090,
1028, 1000, 910, 813, 729, 689, 664, 604, 585, 544 cm1; HRMS
(ESI): m/z calcd. for C25H25N2O5S [M + H]+ 465.14787, found
60 465.14673.
Ph3P
TsHN
O
CH2Cl2, r.t.
O
4a
To a solution of 1-amino-3,3-diethoxyaminopropane (7.36 g,
50.0 mmol) in CH2Cl2 (200 mL) was added Et3N (8.30 mL, 60.0
mmo). The solution was cooled to 0 °C and p-toluenesulfonyl
chloride (10.5 g, 55.0 mmol, 1.0 equiv) in CH2Cl2 (100 mL) was
added over 30 min. The resulting mixture was allowed to warm to
room temperature and treated with saturated aqueous NH4Cl
solution. The layers were separated, the organic layer was
extracted with CH2Cl2, dried over sodium sulfate, and
2-((3S,4R,5S)-5-(4-Chlorophenyl)-4-nitro-1-tosylpyrrolidin-
3-yl)-1-phenylethanone (3ba). The title compound 3ba was
obtained according to the general procedure as a colorless solid
65 (78.4 mg, 79% yield). HPLC (Daicel Chiralpak AD-H, n-
hexane/2-propanol = 60:40, flow rate 1.0 mL/min, detection at
254 nm): major diastereomer: tmajor = 14.2 min, tminor = 18.8 min;
minor diastereomer: tR = 28.2, 51.3 min; 85:15 dr, 98% ee. M.p.
5153 C; H NMR (400 MHz, CDCl3):  7.79 (dd, J1 = 8.2 Hz,
70 J2 = 1.0 Hz, 2H, ArH), 7.70 (d, J = 8.4 Hz, 2H, ArH), 7.597.55
(m, 1H, ArH), 7.43 (t, J = 7.8 Hz, 2H, ArH), 7.377.31 (m, 6H,
ArH), 5.24 (d, J = 5.2 Hz, 1H, CH), 4.75 (dd, J1 = 6.8 Hz, J2 =
5.2 Hz, 1H, CH), 4.16 (dd, J1 = 11.4 Hz, J2 = 7.4 Hz, 1H, CH2),
3.45 (dd, J1 = 11.6 Hz, J2 = 7.6 Hz, 1H, CH2), 3.21 (dd, J1 = 17.8
75 Hz, J2 = 5.0 Hz, 1H, CH2), 3.112.96 (m, 2H, CH + CH2), 2.45 (s,
3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):  196.2, 144.5,
137.2, 135.8, 134.4, 133.8, 133.4, 130.0, 129.2, 128.8, 127.8,
5
o
1
10 concentrated to a yellow oil. The crude sulfonamide was
dissolved in THF (100 mL), treated with 1 M HCl (50 mL), and
stirred at room temperature about
3 h. Upon complete
consumption of the acetal as judged by TLC analysis (petroleum
ether/EtOAc 1:1), EtOAc (100 mL) was added and the layers
15 were separated. The organic layer was washed (H2O, brine), dried
over Na2SO4 and concentrated. Purification by column
chromatography (petroleum ether/EtOAc 3:1 to 2:1) gave the
tosylamino propaldehyde as a pale yellow solid (10.5 g, 77%).
Wittig reagent (5 mmol, 1 equiv) was added to a solution of
20 tosylamino propaldehyde (5 mmol, 1 equiv) in CH2Cl2 (30 mL) in
round bottom flask. The solution was stirred at room temperature
for 30 h. After concentration under reduced pressure, the residue
was purified by flash chromatography on silica gel (petroleum
ether/EtOAc 3:1) to afford 4a (1.37 g, 92%) as a colorless oil. 1H
25 NMR (400 MHz, CDCl3):  7.66 (d, J = 8.4 Hz, 2H, ArH), 7.22
(d, J = 8.4 Hz, 2H, ArH), 6.71 (dt, J1 = 15.6 Hz, J2 = 7.2Hz, 1H,
=CH), 5.71 (d, J = 15.6 Hz, 1H, =CH), 5.24 (t, J = 6.2 Hz, 1H,
NH), 4.07 (q, J = 7.2 Hz, 2H, CH2), 2.98 (q, J = 6.8 Hz, 2H, CH2),
2.34 (s, 3H, CH3), 2.29 (q, J = 6.8 Hz, 2H, CH2), 1.18 (t, J = 7.0
30 Hz, 3H, CH3) ppm.

v
127.7, 95.8, 66.3, 53.1, 39.4, 39.2, 21.6 ppm; IR (ATR): 1682,
1597, 1552, 1491, 1411, 1348, 1305, 1213, 1159, 1089, 1034,
80 1012, 999, 907, 837, 812, 751, 688, 665, 585, 574, 545 cm1;
HRMS (ESI): m/z calcd. for C25H24ClN2O5S [M + H]+ 499.10890,
found 499.10849.
2-((3S,4R,5S)-5-(3-Bromophenyl)-4-nitro-1-tosylpyrrolidin-
85 3-yl)-1-phenylethanone (3ca). The title compound 3ca was
obtained according to the general procedure as a yellow oil (77.8
mg, 72% yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-
propanol = 60:40, flow rate 1.0 mL/min, detection at 254 nm):
major diastereomer: tmajor = 10.9 min, tminor = 13.6 min; minor
1
90 diastereomer: tR = 12.4, 16.8, 19.8 min; 81:19 dr, 97% ee. H
General procedure for asymmetric aza-Michael/Michael
cascade reactions
NMR (400 MHz, CDCl3):  7.71 (d, J = 8.0 Hz, 2H, ArH), 7.60
(d, J = 8.0 Hz, 2H, ArH), 7.47 (t, J = 7.2 Hz, 1H, ArH), 7.43 (s,
1H, ArH), 7.357.32 (m, 3H, ArH), 7.267.22 (m, 3H, ArH),
7.167.10 (m, 1H, ArH), 5.19 (d, J = 5.2 Hz, 1H, CH), 4.68 (t, J
95 = 6.2 Hz, 1H, ArH), 4.12 (dd, J1 = 11.6 Hz, J2 = 7.6 Hz, 1H, CH2),
3.34 (dd, J1 = 11.2 Hz, J2 = 8.0 Hz, 1H, CH2), 3.14 (dd, J1 = 17.6
Hz, J2 = 4.8 Hz, 1H, CH2), 3.032.88 (m, 2H, CH + CH2), 2.35 (s,
3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):  196.2, 144.5,
140.9, 135.7, 133.7, 133.5, 131.6, 130.5, 129.9, 129.2, 128.7,
100 127.8, 127.6, 125.1, 95.7, 66.1, 53.0, 39.5, 39.5, 21.5 ppm; IR
To a dried small bottle were added 2 (0.2 mmol), catalyst I (12.6
35 mg, 0.02 mmol, 10 mol %) in CH2Cl2 (1.0 mL). The mixture was
stirred at room temperature for 15 min, and 1 (0.6 mmol) was
then added. After stirring at room temperature for 6096 h, the
reaction mixture was concentrated and directly purified by silica
gel column chromatography to afford the desired product 3.
40
2-((3S,4R,5S)-4-Nitro-5-phenyl-1-tosylpyrrolidin-3-yl)-1-
phenylethanone (3aa). The title compound 3aa was obtained
according to the general procedure as a colorless solid (78.6 mg,
85% yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol
45 = 65:35, flow rate 1.0 mL/min, detection at 254 nm): major
diastereomer: tmajor = 14.4 min, tminor = 16.9 min; minor
diastereomer: tR = 20.3, 33.3 min; 84:16 dr, 99% ee. M.p. 3335
oC; 1H NMR (400 MHz, CDCl3):  7.837.71 (m, 4H, ArH), 7.57
(t, J = 7.2 Hz, 1H, ArH), 7.457.32 (m, 9H, ArH), 5.33 (d, J = 4.8
50 Hz, 1H, CH), 4.78 (t, J = 5.4 Hz, 1H, CH), 4.18 (dd, J1 = 11.6 Hz,
J2 = 7.2 Hz, 1H, CH2), 3.46 (dd, J1 = 11.6 Hz, J2 = 6.8 Hz, 1H,
CH2), 3.21 (dd, J1 = 21.0 Hz, J2 = 8.6 Hz, 1H, CH2), 3.092.97
(m, 2H, CH2 + CH), 2.45 (s, 3H, CH3) ppm; 13C NMR (100 MHz,

v
(ATR): 1682, 1596, 1551, 1474, 1348, 1305, 1261, 1212, 1158,
1089, 1073, 1015, 997, 884, 811, 787, 752, 688, 665, 578, 544
cm1; HRMS (ESI): m/z calcd. for C25H24BrN2O5S [M + H]+
543.05838, found 543.05829.
105
2-((3S,4R,5S)-5-(4-Bromophenyl)-4-nitro-1-tosylpyrrolidin-
3-yl)-1-phenylethanone (3da). The title compound 3da was
obtained according to the general procedure as a yellow solid
(90.8 mg, 84% yield). HPLC (Daicel Chiralpak AD-H, n-
110 hexane/2-propanol = 60:40, flow rate 1.0 mL/min, detection at
254 nm): major diastereomer: tmajor = 14.6 min, tminor = 21.5 min;
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 00–00 | 5

Organic & Biomolecular Chemistry
Page 6 of 10
1
minor diastereomer: tR = 32.0, 56.1 min; 85:15 dr, 99% ee. H
2-((3S,4R,5R)-5-(Furan-2-yl)-4-nitro-1-tosylpyrrolidin-3-
NMR (400 MHz, CDCl3):  7.79 (d, J = 7.2 Hz, 2H, ArH), 7.69 60 yl)-1-phenylethanone (3ga). The title compound 3ga was
View Article Online
(d, J = 8.4 Hz, 2H, ArH), 7.57 (t, J = 7.4 Hz, 1H, ArH),
7.487.41 (m, 4H, ArH), 7.34 (d, J = 8.0 Hz, 2H, ArH), 7.29 (d, J
= 8.4 Hz, 2H, ArH), 5.22 (d, J = 5.2 Hz, 1H, CH), 4.75 (dd, J1 =
6.8 Hz, J2 = 5.6 Hz, 1H, CH), 4.16 (dd, J1 = 11.4 Hz, J2 = 7.4 Hz,
obtained according to the general procedureDaOs Ia: 1y0e.1l0lo3w9/Co5ilO(B7011.7549A
mg, 79% yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-
propanol = 60:40, flow rate 1.0 mL/min, detection at 254 nm):
5
major diastereomer: tminor = 11.6 min, tmajor = 12.0 min; minor
1
1H, CH2), 3.44 (dd, J1 = 11.6 Hz, J2 = 7.6 Hz, 1H, CH2), 3.21 (dd, 65 diastereomer: tR = 14.2, 17.0, 22.1 min; 80:20 dr, 97% ee. H
J1 = 17.6 Hz, J2 = 4.8 Hz, 1H, CH2), 3.112.96 (m, 2H, CH +
NMR (400 MHz, CDCl3):  7.87 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz,
2H, ArH), 7.65 (d, J = 8.4 Hz, 2H, ArH), 7.58 (t, J = 7.4 Hz, 1H,
ArH), 7.45 (t, J = 7.6 Hz, 2H, ArH), 7.30 (d, J = 8.0 Hz, 2H,
ArH), 7.28 (dd, J1 = 6.0 Hz, J2 = 0.8 Hz, 1H, ArH), 6.50 (d, J =
CH2), 2.45 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): 
10 196.2, 144.5, 137.7, 135.7, 133.8, 133.4, 132.1, 130.0, 128.7,
128.0, 127.8, 127.7, 122.5, 95.7, 66.3, 53.0, 39.4, 39.2, 21.6 ppm;

v
IR (ATR): 2960, 2899, 1682, 1596, 1551, 1487, 1410, 1348, 70 3.2 Hz, 1H, ArH), 6.34 (dd, J1 = 3.2 Hz, J2 = 1.6 Hz, 1H, ArH),
1304, 1264, 1212, 1159, 1089, 1072, 1033, 1009, 907, 855, 834,
811, 751, 688, 665, 586, 573, 544 cm1; HRMS (ESI): m/z calcd.
15 for C25H24BrN2O5S [M + H]+ 543.05838, found 543.05747.
5.39 (d, J = 4.0 Hz, 1H, CH), 5.00 (dd, J1 = 5.6 Hz, J2 = 3.6 Hz,
1H, CH), 4.08 (dd, J1 = 10.8 Hz, J2 = 7.2 Hz, 1H, CH2),
3.433.35 (m, 2H, CH2 ), 3.243.14 (m, 2H, CH + CH2 ), 2.42 (s,
3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):  196.4, 150.0,
75 144.1, 143.1, 135.9, 133.9, 133.7, 129.8, 128.7, 127.9, 127.5,
110.8, 110.0, 92.3, 60.4, 52.6, 39.9, 39.6, 21.5 ppm; IR (ATR):
2-((3S,4R,5S)-4-Nitro-5-(o-tolyl)-1-tosylpyrrolidin-3-yl)-1-
phenylethanone (3ea). The title compound 3ea was obtained
according to the general procedure as a yellow oil (41.2 mg, 43%
20 yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol =
60:40, flow rate 1.0 mL/min, detection at 254 nm): major

v
1681, 1597, 1552, 1449, 1345, 1275, 1214, 1159, 1090, 1011,
1000, 930, 912, 813, 748, 688, 664, 587, 546 cm1; HRMS (ESI):
m/z calcd. for C23H23N2O6S [M + H]+ 455.12713, found
diastereomer: tmajo r= 10.0 min, tminor = 12.8 min; minor 80 455.12686.
1
diastereomer: tR = 14.2, 36.4 min; 73:27 dr, 98% ee. H NMR
(400 MHz, CDCl3):  7.70 (d, J = 7.6 Hz, 2H, ArH), 7.60 (d, J =
25 8.4 Hz, 2H, ArH), 7.47 (t, J = 7.4 Hz, 1H, ArH), 7.407.31 (m,
3H, ArH), 7.24 (d, J = 8.0 Hz, 2H, ArH), 7.177.06 (m, 3H, ArH),
2-((3S,4R,5R)-4-Nitro-5-(thiophen-2-yl)-1-tosylpyrrolidin-3-
yl)-1-phenylethanone (3ha). The title compound 3ha was
obtained according to the general procedure as a yellow oil (75.9
5.45 (d, J = 4.4 Hz, 1H, CH), 4.66 (t, J = 5.0 Hz, 1H, CH), 4.09 85 mg, 81% yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-
(dd, J1 = 11.0 Hz, J2 = 7.4 Hz, 1H, CH2), 3.47 (dd, J1 = 11.0 Hz,
J2 = 6.2 Hz, 1H, CH2), 3.282.89 (m, 3H, CH + CH2 ), 2.35 (s,
30 3H, CH3), 2.25 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
 196.3, 144.1, 136.9, 135.8, 135.1, 133.7, 131.1, 129.7, 128.7,
propanol = 60:40, flow rate 1.0 mL/min, detection at 254 nm):
major diastereomer: tminor = 13.6 min, tmajor = 15.1 min; minor
diastereomer: tR = 17.2, 18.3, 20.4, 37.0 min; 79:21 dr, >99% ee.
1H NMR (400 MHz, CDCl3):  7.82 (d, J = 7.2 Hz, 2H, ArH),
128.3, 127.8, 127.6, 126.5, 95.4, 64.3, 53.2, 40.0, 39.7, 21.5, 19.2 90 7.73 (d, J = 8.0 Hz, 2H, ArH), 7.57 (t, J = 7.4 Hz,1H, ArH), 7.44

v
ppm; IR (ATR): 1683, 1597, 1550, 1449, 1349, 1305, 1262,
(t, J = 7.8 Hz, 2H, ArH), 7.33 (d, J = 8.4 Hz, 2H, ArH), 7.26 (dd,
J1 = 5.8 Hz, J2 = 1.2Hz, 1H, ArH), 7.10 (d, J = 3.6 Hz, 1H, ArH),
6.96 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H, ArH), 5.61 (d, J = 4.4 Hz,
1H, CH), 4.88 (dd, J1 = 6.6 Hz, J2 = 4.6 Hz, 1H, CH), 4.14 (dd, J1
95 = 11.6 Hz, J2 = 7.6 Hz, 1H, CH2), 3.41 (dd, J1 = 11.6 Hz, J2 = 7.6
Hz, 1H, CH2), 3.30 (dd, J1 = 17.6 Hz, J2 = 5.2 Hz, 1H, CH2),
3.172.99 (m, 2H, CH + CH2 ), 2.44 (s, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3):  196.3, 144.4, 142.6, 135.8, 133.74, 133.68,
129.9, 128.7, 127.9, 127.7, 127.3, 126.0, 125.9, 96.0, 63.2, 52.8,
1211, 1159, 1090, 1000, 909, 813, 755, 731, 688, 664, 586, 546
35 cm1; HRMS (ESI): m/z calcd. for C26H27N2O5S [M + H]+
479.16352, found 479.16224.
2-((3S,4R,5S)-4-Nitro-5-(p-tolyl)-1-tosylpyrrolidin-3-yl)-1-
phenylethanone (3fa). The title compound 3fa was obtained
40 according to the general procedure as a colorless solid (88.7 mg,
82% yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol

v
= 60:40, flow rate 1.0 mL/min, detection at 254 nm): major 100 39.7, 39.6, 21.6 ppm; IR (ATR): 1681, 1596, 1551, 1492, 1447,
diastereomer: tmajor = 14.1 min; minor diastereomer: tR = 19.0,
61.0 min; 85:15 dr, >99% ee. M.p. 4345oC; 1H NMR (400 MHz,
45 CDCl3):  7.78 (d, J = 8.0 Hz, 2H, ArH), 7.71 (d, J = 8.0 Hz, 2H,
ArH), 7.56 (t, J = 7.0 Hz, 1H, ArH), 7.42 (t, J = 7.6 Hz, 2H, ArH),
1349, 1305, 1275, 1213, 1158, 1089, 1032, 989, 907, 838, 813,
751, 706, 689, 665, 583, 544 cm1; HRMS (ESI): m/z calcd. for
C23H23N2O5S2 [M + H]+ 471.10429, found 471.10490.
7.34 (d, J = 8.4 Hz, 2H, ArH), 7.30 (d, J = 7.6 Hz, 2H, ArH), 7.16 105 2-((3S,4R,5S)-4-nitro-5-phenethyl-1-tosylpyrrolidin-3-yl)-1-
(d, J = 7.6 Hz, 2H, ArH), 5.24 (d, J = 5.2 Hz, 1H, CH), 4.76 (t, J
= 5.6 Hz,1H, CH), 4.15 (dd, J1 = 11.6 Hz, J2 = 7.2 Hz, 1H, CH2),
50 3.45 (dd, J1 = 11.2 Hz, J2 = 6.8 Hz, 1H, CH2), 3.222.96 (m, 3H,
CH + CH2 ), 2.44 (s, 3H, CH3), 2.34 (s, 3H, CH3) ppm; 13C NMR
phenylethanone (3ia). The title compound 3ia was obtained
according to the general procedure as a yellow oil (70.9 mg, 72%
yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol =
70:30, flow rate 1.0 mL/min, detection at 254 nm): major
(100 MHz, CDCl3):  196.3, 144.3, 138.3, 135.8, 135.7, 133.7, 110 diastereomer: tmajor = 11.4 min, tminor = 13.5 min; minor
133.6, 129.9, 129.6, 128.7, 127.9, 127.7, 126.1, 96.3, 66.9, 53.2,
diastereomer: tR = 14.7, 19.3, 20.6, 21.4 min; 80:20 dr, 79% ee.
1H NMR (400 MHz, CDCl3):  7.87 (d, J = 7.2 Hz, 2H, ArH),
7.62 (d, J = 8.4 Hz, 2H, ArH), 7.46 (d, J = 8.0 Hz, 2H, ArH),
7.317.28 (m, 4H, ArH), 7.257.20 (m, 4H, ArH), 4.60 (dd, J1 =
115 6.4 Hz, J2 = 4.4 Hz, 1H, CH2), 4.30 (t, J = 6.6 Hz, 1H, CH),
4.134.09 (m, 1H, CH), 3.95 (dd, J1 = 11.8 Hz, J2 = 7.4 Hz, 1H,

v
39.6, 39.4, 21.6, 21.1 ppm; IR (ATR): 2920, 1682, 1597, 1551,
55 1514, 1411, 1348, 1305, 1271, 1212, 1159, 1090, 1034, 999, 908,
832, 811, 752, 706, 689, 664, 581, 542 cm1; HRMS (ESI): m/z
calcd. for C26H27N2O5S [M + H]+ 479.16352, found 479.16287.
6
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CH2), 3.293.22 (m, 2H, CH2), 3.10 (dd, J1 = 18.0 Hz, J2 = 8.4
hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at
Hz, 1H, CH2), 2.892.81 (m, 1H, CH2), 2.772.68 (m, 2H, CH2), 60 254 nm): major diastereomer: tmajor
= 24.8 min; minor
View Article Online
2.41 (s, 3H, CH3), 2.152.06 (m, 1H, CH) ppm; 13C NMR (100
MHz, CDCl3):  196.4, 144.2, 140.1, 135.8, 133.8, 129.9, 128.8,
128.7, 128.6, 128.5, 127.9, 127.7, 126.2, 93.2, 63.5, 52.7, 39.5,
39.3, 36.9, 31.5, 21.5 ppm; IR (KBr): 3028, 2959, 2929, 2872,
diastereomer: tR = 17.5, 20.5 min; 88:12 dr, >99% ee. M.p. 3435
DOI: 10.1039/C5OB01749A
oC; 1H NMR (400 MHz, CDCl3):  7.70 (d, J = 8.4 Hz, 4H, ArH),
7.417.30 (m, 9H, ArH), 5.31 (d, J = 5.2 Hz, 1H, CH), 4.77 (t, J
= 5.6 Hz, 1H, CH), 4.15 (dd, J1 = 11.4 Hz, J2 = 7.4 Hz, 1H, CH2),
5
1727, 1688, 1598, 1581, 1552, 1496, 1471, 1450, 1349, 1288, 65 3.43 (dd, J1 = 11.6 Hz, J2 = 7.2 Hz, 1H, CH2), 3.15 (dd, J1 = 21.0
1278, 1219, 1163, 1123, 1093, 1075, 1013, 1001, 815, 749, 700,
Hz, J2 = 8.2 Hz, 1H, CH2), 3.052.92 (m, 2H, CH + CH2), 2.44 (s,
3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):  195.1, 144.3,
140.2, 138.6, 134.1, 133.6, 129.9, 129.2, 129.02, 128.97, 128.5,
127.7, 126.2, 96.0, 66.9, 53.0, 39.4, 39.3, 21.6 ppm; IR (ATR):
691, 665, 631, 590, 550 cm1; HRMS (ESI): m/z calcd. for
10 C27H29N2O5S [M + H]+ 493.17917, found 493.18017.

v
1683, 1589, 1551, 1492, 1452, 1400, 1349, 1306, 1273, 1212,
2-((3S,4R,5S)-5-Cyclohexyl-4-nitro-1-tosylpyrrolidin-3-yl)-
1-phenylethanone (3ja). The title compound 3ja was obtained
according to the general procedure as a colorless oil (44.2 mg,
15 47% yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol
= 60:40, flow rate 1.0 mL/min, detection at 254 nm): major
70
1159, 1090, 1031, 990, 909, 812, 766, 731, 698, 662, 571, 544,
529 cm1; HRMS (ESI): m/z calcd. for C25H24ClN2O5S [M + H]+
499.10890, found 499.10862.
diastereomer: tmajor = 8.0 min, tminor = 8.8 min; minor diastereomer: 75 1-(4-Bromophenyl)-2-((3S,4R,5S)-4-nitro-5-phenyl-1-
tR = 11.7, 20.6 min; 88:12 dr, 95% ee. 1H NMR (400 MHz,
CDCl3):  7.797.76 (m, 4H, ArH), 7.51 (t, J = 6.8 Hz, 1H, ArH),
20 7.38 (t, J = 7.0 Hz, 2H, ArH), 7.27 (d, J = 8.0 Hz, 2H, ArH), 4.56
(t, J = 6.2 Hz, 1H, CH), 4.22 (br s, 1H, CH), 4.10 (dd, J1 = 12.6
tosylpyrrolidin-3-yl)ethanone (3ad). The title compound 3ad
was obtained according to the general procedure as a colorless
solid (88.9 mg, 82% yield). HPLC (Daicel Chiralpak AD-H, n-
hexane/2-propanol = 60:40, flow rate 1.0 mL/min, detection at
Hz, J2 = 7.8 Hz, 1H, CH2), 3.22 (dd, J1 = 18.0 Hz, J2 = 2.0 Hz, 80 254 nm): major diastereomer: tmajor = 21.6 min, tminor = 24.0 min;
1H, CH2), 2.972.87 (m, 2H, CH + CH2), 2.35 (s, 3H, CH3),
1.781.72 (m, 4H, CH2), 1.661.53 (m, 2H, CH2), 1.191.08 (m,
25 4H, CH2), 1.030.94 (m, 2H, CH2) ppm; 13C NMR (100 MHz,
CDCl3):  196.3, 144.2, 135.9, 134.7, 133.7, 130.0, 128.8, 127.9,
minor diastereomer: tR = 34.3, 68.8 min; 89:11 dr, 97% ee. M.p.
5152 oC; 1H NMR (400 MHz, CDCl3):  7.71 (d, J = 8.4 Hz, 2H,
ArH), 7.62 (d, J = 8.8 Hz, 2H, ArH), 7.55 (d, J = 8.8 Hz, 2H,
ArH), 7.427.31 (m, 7H, ArH), 5.31 (d, J = 4.8 Hz, 1H, CH),
127.8, 91.4, 68.3, 53.1, 42.7, 41.0, 39.0, 29.3, 27.8, 26.1, 25.9, 85 4.76 (dd, J1 = 6.0 Hz, J2 = 5.2 Hz, 1H, CH2), 4.15 (dd, J1 = 11.6

v
25.8, 21.6 ppm; IR (ATR):
1683, 1597, 1550, 1448, 1344,
Hz, J2 = 7.2 Hz, 1H, CH2), 3.44 (dd, J1 = 11.6 Hz, J2 = 7.2 Hz,
1H, CH2), 3.15 (dd, J1 = 21.0 Hz, J2 = 8.2 Hz, 1H, CH2),
3.052.92 (m, 2H, CH + CH2), 2.45 (s, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3):  195.3, 144.4, 138.6, 134.5, 133.6, 132.1,
90 129.9, 129.3, 129.0, 128.5, 127.7, 126.2, 96.1, 66.9, 53.1, 39.5,
1304, 1262, 1231, 1214, 1158, 1089, 1019, 989, 810, 751, 689,
30 664, 588, 543 cm1; HRMS (ESI): m/z calcd. for C25H31N2O5S
[M + H]+ 471.19482, found 471.19456.

v
1682, 1584, 1551, 1493, 1348,
1-(4-Fluorophenyl)-2-((3S,4R,5S)-4-nitro-5-phenyl-1-
tosylpyrrolidin-3-yl)ethanone (3ab). The title compound 3ab
35 was obtained according to the general procedure as a colorless
solid (66.6 mg, 69% yield). HPLC (Daicel Chiralpak IB, n-
hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection at
39.3, 21.6 ppm; IR (ATR):
1305, 1275, 1262, 1159, 1089, 1070, 1031, 988, 811, 750, 698,
665, 571, 543 cm1; HRMS (ESI): m/z calcd. for C25H24BrN2O5S
[M + H]+ 543.05838, found 543.05814.
95
254 nm): major diastereomer: tmajor
=
31.0 min; minor
2-((3S,4R,5S)-4-Nitro-5-phenyl-1-tosylpyrrolidin-3-yl)-1-(p-
tolyl)ethanone (3ae). The title compound 3ae was obtained
according to the general procedure as a colorless solid (81.2 mg,
85% yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol
diastereomer: tR = 22.7, 25.7 min; 88:12 dr, >99% ee. M.p. 3537
40 oC; 1H NMR (400 MHz, CDCl3):  7.71 (dd, J1 = 8.8 Hz, J2 = 5.4
Hz, 2H, ArH), 7.63 (d, J = 8.0 Hz, 2H, ArH), 7.357.22 (m, 7H,
ArH), 6.99 (t, J = 8.6 Hz, 2H, ArH), 5.23 (d, J = 5.2 Hz, 1H, CH), 100 = 60:40, flow rate 1.0 mL/min, detection at 254 nm): major
4.69 (t, J = 5.6 Hz,1H, CH), 4.07 (dd, J1 = 11.6 Hz, J2 = 7.2 Hz,
1H, CH2), 3.36 (dd, J1 = 11.8 Hz, J2 = 7.0 Hz, 1H, CH2), 3.08 (dd,
45 J1 = 20.8 Hz, J2 = 8.4 Hz, 1H, CH2), 3.092.98 (m, 2H, CH +
CH2 ), 2.47 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): 
diastereomer: tmajor = 15.1 min, tminor = 16.9 min; minor
diastereomer: tR = 21.9, 35.9 min; 86:14 dr, 98% ee. M.p. 4142
oC; 1H NMR (400 MHz, CDCl3):  7.72 (d, J = 8.4 Hz, 2H, ArH),
7.67 (d, J = 8.4 Hz, 2H, ArH), 7.447.31 (m, 7H, ArH), 7.21 (d, J
194.7, 166.0 (d, 1JCF = 254.5 Hz), 144.3, 138.6, 133.6, 130.5 (d, 105 = 8.0 Hz, 2H, ArH), 5.32 (d, J = 4.8 Hz, 1H, CH), 4.78 (d, J = 5.6
3JCF = 9.3 Hz), 129.9, 129.0, 128.4, 127.7, 126.2, 115.8 (d, 2JCF
= 21.8 Hz), 96.1, 66.9, 53.1, 39.40, 39.36, 21.5 ppm; IR (ATR):
Hz, 1H, CH), 4.17 (dd, J1 = 11.4 Hz, J2 = 7.0 Hz, 1H, CH2), 3.45
(dd, J1 = 11.6 Hz, J2 = 7.2 Hz, 1H, CH2), 3.17 (dd, J1 = 20.8 Hz,
J2 = 8.4 Hz, 1H, CH2), 3.062.93 (m, 2H, CH + CH2), 2.44 (s, 3H,
CH3), 2.39 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): 

v
50
1683, 1596, 1551, 1506, 1452, 1410, 1349, 1305, 1261, 1229,
1156, 1089, 1013, 992, 910, 832, 811, 763, 732, 698, 662, 604,
580, 543 cm1; HRMS (ESI): m/z calcd. for C25H24FN2O5S [M + 110 195.9, 144.7, 144.3, 138.7, 133.7, 133.4, 129.9, 129.4, 129.0,
H]+ 483.13845, found 483.13708.
128.4, 128.0, 127.7, 126.2, 96.2, 67.0, 53.2, 39.6, 39.4, 21.63,

v
21.59 ppm; IR (ATR): 2921, 1678, 1605, 1551, 1494, 1451,
55
1-(4-Chlorophenyl)-2-((3S,4R,5S)-4-nitro-5-phenyl-1-
1408, 1349, 1305, 1271, 1232, 1182, 1159, 1119, 1090, 1030,
998, 912, 809, 762, 737, 699, 662, 605, 581, 543 cm1; HRMS
tosylpyrrolidin-3-yl)ethanone (3ac). The title compound 3ac
was obtained according to the general procedure as a colorless 115 (ESI): m/z calcd. for C26H27N2O5S [M + H]+ 479.16352, found
solid (79.5 mg, 80% yield). HPLC (Daicel Chiralpak IB, n-
479.16349.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem., 2015, 13, 00–00 | 7

Organic & Biomolecular Chemistry
Page 8 of 10
(dd, J1 = 17.6 Hz, J2 = 5.2 Hz, 1H, CH2), 3.17 (dd, J1 = 17.6 Hz,
1-(3-Methoxyphenyl)-2-((3S,4R,5S)-4-nitro-5-phenyl-1-
tosylpyrrolidin-3-yl)ethanone (3af). The title compound 3af
was obtained according to the general procedure as a colorless
solid (82.0 mg, 83% yield). HPLC (Daicel Chiralpak AD-H, n-
hexane/2-propanol = 55:45, flow rate 1.0 mL/min, detection at
60 J2 = 8.4 Hz, 1H, CH2), 3.113.05 (m, 1H, CH), 2.42 (s, 3H, CH3)
View Article Online
ppm; 13C NMR (100 MHz, CDCl3):  196.3, 144.3, 138.7, 135.7,
DOI: 10.1039/C5OB01749A
133.7, 133.1, 132.3, 129.9, 129.8, 129.5, 129.0, 128.8, 128.7,
128.5, 127.8, 127.7, 127.0, 126.2, 123.3, 96.2, 67.0, 53.2, 39.6,
5

v
39.5, 21.6 ppm; IR (ATR):
1676, 1627, 1597, 1550, 1494,
254 nm): major diastereomer: tmajor = 13.3 min, tminor = 15.1 min; 65 1470, 1349, 1305, 1276, 1185, 1159, 1123, 1090, 1027, 992, 909,
minor diastereomer: tR = 21.7, 56.3 min; 85:15 dr, 98% ee. M.p.
856, 812, 749, 698, 662, 583, 544 cm1; HRMS (ESI): m/z calcd.
3840 oC; 1H NMR (400 MHz, CDCl3):  7.72 (d, J = 8.4 Hz, 2H,
for C29H27N2O5S [M + H]+ 515.16352, found 515.16356.
10 ArH), 7.437.31 (m, 10H, ArH), 7.127.09 (m, 1H, ArH), 5.32 (d,
J = 4.8 Hz, 1H, CH), 4.78 (dd, J1 = 6.2 Hz, J2 = 5.0 Hz, 1H, CH),
1-(4-Bromophenyl)-2-((3S,4R,5S)-5-(4-bromophenyl)-4-
4.17 (dd, J1 = 11.6 Hz, J2 = 7.6 Hz, 1H, CH2), 3.82 (s, 3H, OCH3), 70 nitro-1-tosylpyrrolidin-3-yl)ethanone
(3dd).
The
title
3.45 (dd, J1 = 11.6 Hz, J2 = 7.2 Hz, 1H, CH2), 3.18 (dd, J1 = 20.6
Hz, J2 = 8.2 Hz, 1H, CH2), 3.082.95 (m, 2H, CH + CH2), 2.45 (s,
15 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):  196.1, 159.9,
144.3, 138.7, 137.1, 133.7, 129.9, 129.7, 129.0, 128.5, 127.7,
compound 3dd was obtained according to the general procedure
as a colorless solid (101.3 mg, 82% yield). HPLC (Daicel
Chiralpak AD-H, n-hexane/2-propanol = 60:40, flow rate 1.0
mL/min, detection at 254 nm): major diastereomer: tmajor = 22.3
126.2, 120.4, 120.3, 112.1, 96.2, 66.9, 55.4, 53.1, 39.6, 39.5, 21.6 75 min, tminor = 27.8 min; minor diastereomer: tR = 37.3, 131.6 min;
86:14 dr, 98% ee. M.p. 5557 oC; 1H NMR (400 MHz, CDCl3): 
7.58 (d, J = 7.6 Hz, 2H, ArH), 7.55 (d, J = 8.4 Hz, 2H, ArH), 7.46
(d, J = 8.0 Hz, 2H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.25 (d, J
= 8.0 Hz, 2H, ArH), 7.19 (d, J = 8.8 Hz, 2H, ArH), 5.12 (d, J =
80 5.2 Hz, 1H, CH), 4.65 (t, J = 6.2 Hz, 1H, CH), 4.04 (dd, J1 = 11.4
Hz, J2 = 7.4 Hz, 1H, CH2), 3.34 (dd, J1 = 11.4 Hz, J2 = 7.8 Hz,
1H, CH2), 3.08 (dd, J1 = 17.6 Hz, J2 = 4.8 Hz, 1H, CH2),
2.992.83 (m, 2H, CH + CH2), 2.36 (s, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3):  195.3, 144.6, 137.6, 134.4, 133.3, 132.05,

v
ppm; IR (ATR): 1682, 1597, 1583, 1551, 1487, 1452, 1430,
1348, 1305, 1288, 1257, 1199, 1158, 1120, 1090, 1031, 993, 860,
20 813, 787, 760, 737, 699, 685, 664, 571, 543 cm1; HRMS (ESI):
m/z calcd. for C26H27N2O6S [M + H]+ 495.15843, found
495.15864.
1-(4-Methoxyphenyl)-2-((3S,4R,5S)-4-nitro-5-phenyl-1-
25 tosylpyrrolidin-3-yl)ethanone (3ag). The title compound 3ag
was obtained according to the general procedure as a colorless
solid (82.9 mg, 84% yield). HPLC (Daicel Chiralpak AD-H, n- 85 132.01, 129.9, 129.3, 129.0, 128.0, 127.6, 122.5, 95.5, 66.3, 52.9,

v
hexane/2-propanol = 55:45, flow rate 1.0 mL/min, detection at
254 nm): major diastereomer: tmajor = 18.8 min, tminor = 23.8 min;
30 minor diastereomer: tR = 25.5, 49.0 min; 86:14 dr, 99% ee. M.p.
3941 oC; 1H NMR (400 MHz, CDCl3):  7.75 (d, J = 9.2 Hz, 2H,
ArH), 7.72 (d, J = 8.0 Hz, 2H, ArH), 7.437.31 (m, 7H, ArH),
6.88 (d, J = 9.2 Hz, 2H, ArH), 5.31 (d, J = 4.8 Hz, 1H, CH), 4.78
(dd, J1 = 6.2 Hz, J2 = 5.0 Hz, 1H, CH), 4.16 (dd, J1 = 11.4 Hz, J2
35 = 7.4 Hz, 1H, CH2), 3.84 (s, 3H, OCH3), 3.45 (dd, J1 = 11.4 Hz,
J2 = 7.0 Hz, 1H, CH2), 3.13 (dd, J1 = 20.8 Hz, J2 = 8.4 Hz, 1H,
39.2, 39.1, 21.6 ppm; IR (ATR): 1682, 1585, 1551, 1486, 1398,
1347, 1304, 1275, 1211, 1159, 1090, 1070, 1034, 1008, 988, 907,
810, 750, 706, 665, 586, 572, 544 cm1; HRMS (ESI): m/z calcd.
for C25H23Br2N2O5S [M + H]+620.96889, found 620.96729.
90
1-((3S,4R,5S)-4-Nitro-5-phenyl-1-tosylpyrrolidin-3-
yl)propan-2-one (3ai). The title compound 3ai was obtained
according to the general procedure as a colorless solid (79.3 mg,
99% yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol
95 = 60:40, flow rate 1.0 mL/min, detection at 254 nm): major
diastereomer: tmajor = 19.7 min, tminor = 23.2 min; minor
diastereomer: tR = 10.5, 13.2 min; 91:9 dr, 77% ee. M.p. 4647
oC; 1H NMR (400 MHz, CDCl3):  7.61 (d, J = 8.0 Hz, 2H, ArH),
7.297.23 (m, 7H, ArH), 5.17 (br s, 1H, CH), 4.79 (d, J = 5.2 Hz,
CH2), 3.052.91 (m, 2H, CH + CH2), 2.44 (s, 3H, CH3) ppm; 13
C
NMR (100 MHz, CDCl3):  194.7, 163.9, 144.3, 138.7, 133.7,
130.2, 129.9, 129.0, 128.9, 128.4, 127.7, 126.2, 113.9, 96.3, 67.0,

v
40 55.5, 53.2, 39.6, 39.1, 21.6 ppm; IR (ATR): 1672, 1598, 1550,
1510, 1455, 1420, 1348, 1306, 1260, 1236, 1158, 1112, 1089,
1026, 1009, 988, 910, 830, 812, 763, 699, 662, 605, 574, 543 100 1H, CH), 3.92 (t, J = 6.6 Hz, 1H, CH), 3.113.01 (m, 2H, CH2),
cm1; HRMS (ESI): m/z calcd. for C26H27N2O6S [M + H]+
495.15843, found 495.15828.
2.412.29 (m, 5H, CH2 + CH3), 1.97 (s, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3):  204.3, 143.9, 138.7, 133.7, 129.6, 128.9,
128.4, 127.7, 126.1, 93.6, 67.1, 51.0, 40.3, 35.5, 29.8, 21.5 ppm;
45

v
IR (ATR): 1716, 1550, 1495, 1476, 1347, 1161, 1120, 1091,
1-(Naphthalen-2-yl)-2-((3S,4R,5S)-4-nitro-5-phenyl-1-
tosylpyrrolidin-3-yl)ethanone (3ah). The title compound 3ah 105 1011, 815, 763, 703, 683, 662, 604, 569, 547 cm1; HRMS (ESI):
was obtained according to the general procedure as a colorless
m/z calcd. For C20H23N2O5S [M + H]+ 403.13222, found
solid (85.3 mg, 83% yield). HPLC (Daicel Chiralpak AD-H, n-
403.13279.
50 hexane/2-propanol = 60:40, flow rate 1.0 mL/min, detection at
254 nm): major diastereomer: tmajor = 20.9 min, tminor = 23.9 min;
Ethyl 2-((3S,4R,5S)-4-nitro-5-phenyl-1-tosylpyrrolidin-3-
minor diastereomer: tR = 30.9, 73.7 min; 86:14 dr, 98% ee. M.p. 110 yl)acetate (3aj). The title compound 3aj was obtained according
o
1
4547 C; H NMR (400 MHz, CDCl3):  8.24 (s, 1H, ArH),
7.907.83 (m, 4H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH),
55 7.627.52 (m, 2H, ArH), 7.44 (d, J = 7.2 Hz, 2H, ArH),
7.397.31 (m, 5H, ArH), 5.35 (d, J = 4.8 Hz, 1H, CH), 4.83 (dd,
to the general procedure as a yellow oil (85.2 mg, 99% yield).
HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 60:40,
flow rate 1.0 mL/min, detection at 254 nm): for major
diastereomer: 92% ee, tmajor = 9.1 min, tminor = 11.2 min; minor
J1 = 6.8 Hz, J2 = 5.2Hz, 1H, CH), 4.20 (dd, J1 = 11.4 Hz, J2 = 7.8 115 diastereomer: 56% ee, tminor = 13.8 min, tmajor = 18.1 min; 53:47
1
Hz, 1H, CH2), 3.49 (dd, J1 = 11.6 Hz, J2 = 7.6 Hz, 1H, CH2), 3.33
dr. For major diastereomer: H NMR (400 MHz, CDCl3):  7.62
8
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alkaloids, see: (e) T. J. Donohoe, C. J. R. Bataille and G. W.
Churchill, Annu. Rep. Prog. Chem., Sect. B, 2006, 102, 98; (f) A. A.
(d, J = 8.0 Hz,1H, ArH), 7.58 (d, J = 8.0 Hz, 1H, ArH),
7.307.23 (m, 7H, ArH), 5.22 (d, J = 5.2 Hz, 1H, CH), 4.68 (t, J
= 6.0 Hz, 1H, CH), 4.023.94 (m, 3H, CH2), 3.38 (dd, J1 = 11.4
Hz, J2 = 8.2 Hz, 1H, CH2), 2.802.73 (m, 1H, CH), 2.432.30 (m,
4H, CH2 + CH3), 2.22 (dd, J1 = 8.0 Hz, J2 = 5.6 Hz, 1H, CH2),
1.12 (t, J = 7.2 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
 170.0, 144.3, 138.4, 133.8, 129.8, 128.9, 128.4, 127.6, 126.2
95.8, 67.0, 61.1, 52.7, 39.8, 34.9, 21.5, 14.0 ppm. For minor
diastereomer: 1H NMR (400 MHz, CDCl3):  7.62 (d, J = 8.0 Hz,
10 1H, ArH), 7.58 (d, J = 8.0 Hz, 1H, ArH), 7.307.23 (m, 7H, ArH),
5.20 (s, 1H, CH), 4.82 (d, J = 5.6 Hz, 1H, CH), 4.023.94 (m, 3H,
CH2), 3.15 (t, J = 10.0 Hz, 1H, CH2), 3.073.01 (m, 1H, CH),
2.432.30 (m, 4H, CH2 + CH3), 2.22 (dd, J1 = 8.0 Hz, J2 = 5.6
Hz, 1H, CH2), 1.12 (t, J = 7.2 Hz, 3H, CH3) ppm; 13C NMR (100
15 MHz, CDCl3):  170.0, 144.0, 138.7, 133.6, 129.6, 128.9, 128.4,
127.7, 126.0, 93.7, 67.3, 61.1, 51.1, 36.5, 31.5, 21.5, 14.0 ppm.
Agbodjan, B. E. Cooley, R. C. B. Copley, J. A. Corfield, R. C.
View Article Online
DOI: 10.1039/C5OB01749A
Flanagan, B. N. Glover, R. Guidetti, D. Haigh, P. D. Howes, M. M.
60
65
70
75
80
Jackson, R. T. Matsuoka, K. J. Medhurst, A. Millar, M. J. Sharp, M.
J. Slater, J. F. Toczko and S. Xie, J. Org. Chem., 2008, 73, 3094; (g)
C. Nájera, J. M. Sansano, Org. Biomol. Chem., 2009, 7, 4567.
For some recent examples of biologically active pyrrolidines, see: (a)
M. E. Hensler, G. Bernstein, V. Nizet and A. Nefzi, Bioorg. Med.
Chem. Lett., 2006, 16, 5073; (b) X. Li and J. Li, Mini-Rev. Med.
Chem., 2010, 10, 794; (c) K. W. Lexa, Proteins, 2011, 79, 2282. For
recent studies of pyrrolidines as peptidomimetics, see: (d) L. R.
Whitby, Y. Ando, V. Setola, P. K. Vogt, B. L. Roth and D. L. Boger,
J. Am. Chem.Soc., 2011, 133, 10184; (e) A. Raghuraman, E. Ko, L.
M. Perez, T. R. Ioerger and K.Burgess, J. Am. Chem. Soc., 2011, 133,
12350.
For a recent survey of chiral amine organocatalysis, see (a) S. Zhang
and W. Wang, Privileged Chiral Ligands and Catalysts; Q.-L. Zhou,
Ed., Wiley-VCH: Weinheim, Germany, 2011; pp 409-439. For
selected examples, see: (b) S. Karlsson and H.-E. Hogberg,
Tetrahedron: Asymmetry, 2002, 13, 923; (c) S. S. Chow, M.
Nevalainen, C. A. Evans and C. W. Johannes, Tetrahedron Lett. 2007,
48, 277; (d) J. Vesely, R. Rios, I. Ibrahem, G.-L. Zhao, L. Eriksson
and A. Córdova, Chem.Eur. J., 2008, 14, 2693; (e) X. Cai, C. Wang
and J. Sun, Adv. Synth. Catal., 2012, 354, 359; (f) J. Alemán, A.
Fraile, L.Marzo, J. L. G. Ruano, C. Izquierdo and S. Díaz-Tendero,
Adv. Synth. Catal., 2012, 354, 1665; (g) C. Izquierdo, F. Esteban, A.
Parra, R. Alfaro, J. Alemán, A. Fraile and J. L. G. Ruano, J. Org.
Chem., 2014, 79, 10417; (h) S. Reboredo, E. Reyes, J. L. Vicario, D.
Badía, L. Carrillo, A. Cózar and F. P. Cossío, Chem. Eur. J., 2012,
18, 7179; (i) S. Reboredo, J. L. Vicario, L. Carrillo, E. Reyes and U.
Uria, Synthesis, 2013, 2669. For a review with examples of chiral
amine ligands, see: (j) C. A. Caputo and N. D. Jones, Dalton Trans.,
2007, 4627.
5
2
3
tert-Butyl 2-((3S,4R,5S)-4-nitro-5-phenyl-1-tosylpyrrolidin-
3-yl)acetate (3ak). The title compound 3ak was obtained
20 according to the general procedure as a colorless solid (90.8 mg,
99% yield). HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol
= 80:20, flow rate 1.0 mL/min, detection at 254 nm): for major
diastereomer: 74% ee, tmajor = 11.6 min, tminor = 13.3 min; minor
diastereomer: 80% ee, tmajor = 10.2 min, tminor = 14.2 min; 57:43 dr. 85
25 M.p. 2830 oC; For major diastereomer: 1H NMR (400 MHz,
CDCl3):  7.71 (d, J = 8.4 Hz, 1H, ArH), 7.67 (d, J = 8.4 Hz, 1H,
ArH), 7.387.31 (m, 7H, ArH), 5.24 (s, 1H, CH), 4.90 (d,J = 5.6
Hz, 1H, CH), 4.074.00 (m, 1H, CH2), 3.20 (dd, J1 = 11.2 Hz, J2
= 8.8 Hz, 1H, CH2), 3.153.05 (m, 1H, CH), 2.44 (s, 3H, CH3),
30 2.412.34 (m, 1H, CH2), 2.29 (dd, J1 = 17.2 Hz, J2 = 6.8 Hz, 1H,
CH2), 1.38 (s, 9H, CH3) ppm; 13C NMR (100 MHz, CDCl3): 
169.2, 144.0, 138.7, 133.6, 129.6, 128.9, 128.4, 127.7, 126.0,
93.7, 81.8, 67.3, 51.1, 36.6, 32.5, 27.8, 21.5 ppm. For minor
diastereomer: 1H NMR (400 MHz, CDCl3):  7.71 (d, J = 8.4 Hz,
35 1H, ArH), 7.67 (d, J = 8.4 Hz, 1H, ArH), 7.387.31 (m, 7H, ArH),
5.28 (d, J = 5.2 Hz, 1H, CH), 4.74 (dd, J1 = 6.8 Hz, J2 = 5.2 Hz,
1H, CH), 4.074.00 (m, 1H, CH2), 3.45 (dd, J1 = 11.6 Hz, J2 =
8.0 Hz, 1H, CH2), 2.862.77 (m, 1H, CH), 2.44 (s, 3H, CH3),
2.412.34 (m, 1H, CH2), 2.18 (dd, J1 = 17.4 Hz, J2 = 7.8 Hz, 1H,
40 CH2), 1.38 (s, 9H, CH3) ppm; 13C NMR (100 MHz, CDCl3): 
169.1, 144.2, 138.4, 133.8, 129.8, 128.9, 128.4, 127.6, 126.1,
95.9, 81.8, 67.0, 52.7, 40.0, 36.3, 27.8, 21.5 ppm. IR (ATR):
90
4
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95
100
105
110
115
120
5

v
1725, 1552, 1454, 1350, 1278, 1258, 1152, 1091, 1029, 1009,
946, 842, 814, 765, 751, 699, 644, 582, 545 cm1; HRMS (ESI):
45 m/z calcd. For C23H29N2O6S [M + H]+ 461.17408, found
461.17460.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21272024).
50 Notes and references
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10 | Org. Biomol. Chem., 2015, 13, 00–00
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