Sulfonamides of homoproline and dipeptides as organocatalysts for Michael and aldol reactions

Article abstract of DOI:10.1016/j.tet.2008.12.008

Sulfonamides of the non-natural amino acid homoproline and the dipeptide Pro-Phe were synthesised and evaluated for their catalytic activity in Michael and aldol reactions. Sulfonamides of homoproline outperform proline and Pro-Phe in the Michael reaction

Full text of DOI:10.1016/j.tet.2008.12.008

Tetrahedron 65 (2009) 1444–1449
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Sulfonamides of homoproline and dipeptides as organocatalysts for Michael
and aldol reactions
*
Evaggelia Tsandi, Christoforos G. Kokotos, Sofia Kousidou, Valentine Ragoussis, George Kokotos
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2008
Received in revised form 17 November 2008
Accepted 4 December 2008
Available online 9 December 2008
Sulfonamides of the non-natural amino acid homoproline and the dipeptide Pro–Phe were synthesised
and evaluated for their catalytic activity in Michael and aldol reactions. Sulfonamides of homoproline
outperform proline and Pro–Phe in the Michael reaction, whereas sulfonamides of Pro–Phe lead to better
results in the aldol reaction. The results of the present study show that the conversion of the carboxylic
group of either homoproline or dipeptide Pro–Phe to the bioisosteric acyl sulfonamide group lead to
improved organocatalysts.
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Aldol reaction
Homoproline
Michael reaction
Organocatalysis
Sulfonamides
1. Introduction
was to synthesise sulfonamide derivatives of homoproline and
sulfonamide derivatives of the dipeptide Pro–Phe–OH and evaluate
During the last few years organocatalysis has emerged as
a powerful tool in modern organic synthesis.1 Since the pioneering
work of List et al. on the application of the amino acid proline as
a catalyst for the aldol reaction (1, Fig. 1),2 a number of organo-
catalysts have been synthesised and employed in various organic
transformations.3 Recently, we and others have shown that acyl
sulfonamides of proline (2a, b) and 4-substituted proline (2c) are
excellent organocatalysts for the asymmetric aldol reaction.4–7 The
tetrazolyl derivative of proline (3a) was also studied as an orga-
nocatalyst for the aldol reaction.7,8 In addition, homoproline9 and
homoproline tetrazole10 (3b) have been reported to give improved
results as catalysts for the Michael reaction.
their ability to catalyse Michael and aldol reactions.
2. Results and discussion
The synthesis of homoproline sulfonamides is depicted in
Scheme 1. tert-Butoxycarbonyl-L-homoproline (4), prepared according
to a literature procedure,16 was coupled with methanesulfonamide
and p-toluenesulfonamide using N,N0-dicyclohexylcarbodiimide
(DCC) as a coupling reagent in the presence of 4-(dimethylamine)-
pyridine (DMAP)4 in dichloromethane to produce derivatives 5a, b.
Apart from amino acids and amino acid derivatives, peptides
have also been employed successfully as organocatalysts in
a number of reactions.11 The reaction that peptides are most com-
monly used as catalysts is the aldol reaction.12 In particular, di-
peptide Pro–Phe was used in the aldol reaction of acetone with
4-nitrobenzaldehyde leading to high yield but moderate enantio-
selectivity.12d Furthermore, in the same reaction, the dipeptide Pro–
Phe–OMe led to high yield but with lower enantioselectivity.13
Continuing our work on acyl sulfonamide derivatives4 and
4-substituted proline derivatives,14,15 the aim of the present work
R2
O
O
OH
NHSO2R1
N
H
N
H
2a, R1= CH3, R2= H
1
2b, R1= pCH3C6H4, R2= H
2c, R1= CH3 or pCH3C6H4, R2= OH or OBn
( )n
N
N
N
H
HN
N
3a, n= 0
3b, n= 1
* Corresponding author. Tel.: þ30 210 727 4462; fax: þ30 210 727 4761.
E-mail address: gkokotos@chem.uoa.gr (G. Kokotos).
Figure 1. Structures of proline and related organocatalysts.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.008

E. Tsandi et al. / Tetrahedron 65 (2009) 1444–1449
1445
Table 1
Removal of the Boc protecting group by treatment with HCl in
Michael reaction of cyclohexanone with
organocatalysts
b
-nitrostyrene using sulfonamide
MeOH afforded homoprolyl sulfonamides 6a, b in almost quanti-
tative yield.
O
O
NO2
catalyst, Et3N
NHSO2R
OH
NO2
+
a
i-PrOH-EtOH (1:1)
18 h, r.t.
N
Boc
N
Boc
O
O
5a, 79%
5b, 80%
4
Entry
Catalyst
)-Prod,e
Catalyst
loading (%)
Yielda
(%)
drb
15:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
eec
(%)
b
5, 6
R
1
2
3
(
L
15
20
10
5
10
20
10
10
89
70
64
16
33
21
19
33
25
83
90
84
92
79
81
13
NHSO2R
a
b
CH3
pCH3C6H4
6a
6a
6a
6a
6b
6b
11a
N
O
H.HCl
4f
5g
6
6a, 93%
6b, 90%
Scheme 1. Reagents and conditions: (a) methanesulfonamide or p-toluenesulfona-
mide, DCC, DMAP, DCM, rt, 48 h; (b) 5 N HCl/MeOH, rt, 30 min.
7
8
a
Isolated yield after column chromatography.
Boc-Proline (7) was coupled with the methyl ester of L-phenyl-
b
c
d
e
f
The dr was measured from the 1H NMR spectrum of the crude mixture.
The ee was determined by HPLC on a Daicel Chiralpak AD-H column.
In the absence of Et3N.
alanine in good yield using 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide (WSCI) as a condensing agent in the presence of
1-hydroxybenzotriazole (HOBt) (Scheme 2). After saponification,
dipeptide 8 was coupled with methanesulfonamide in the presence
of DCC and DMAP to afford sulfonamide 9a or with p-toluene-
sulfonamide to afford sulfonamide 9b in respectable yields.
Dipeptide 10 was prepared by treatment of 8 with a methanolic
solution of HCl and was used in our study as a test organocatalyst in
the aldol reaction of acetone with 4-nitrobenzaldehyde. Sulfon-
amides 9a and 9b were also deprotected with a methanolic solution
of HCl to afford organocatalysts 11a and 11b in almost quantitative
yields. To study the role of the chiral centre of the dipeptide in the
asymmetric transformations, we also synthesised dipeptides 12a
Using DMSO as solvent.
The reaction time was 48 h.
The reaction was carried out at ꢁ20 ꢀC for 48 h.
g
studied and the results are summarised in Table 1. L-Proline is
known to catalyse this reaction in high yields but low selectivities.18
Indeed, in our hands the product was isolated in 89% yield with
a 15:1 dr and low ee (entry 1, Table 1). In all cases where sulfon-
amides of homoproline or dipeptide Pro–Phe were utilised, the
diastereoselectivity of the reaction was extremely high >19:1
(entries 2–8, Table 1). The methanesulfonamide of homoproline
(6a) gave the best results among the catalysts used in this study. As
we observed, the loading of the catalyst was crucial for the reaction
yield and enantioselectivity (entries 2–4, Table 1). After identifying
10% catalyst loading as the optimal for the reaction, the effect of the
temperature was studied leading to similar results as far as selec-
tivities are concerned but a lower yield was obtained (entry 5, Table
1). Sulfonamide 6b afforded the product in high diastereo- and
enantioselectivities but in low yields in all cases (entries 6 and 7,
Table 1). Finally, dipeptide methanesulfonamide 11a was also
tested, leading to low yield and enantioselectivity (entry 8, Table 1).
Thus, using methanesulfonamide 6a at 10% catalyst loading and at
room temperature, the product of the reaction between cyclohex-
and 12b containing
D-phenylalanine by similar procedures.
Ph
O
O
a, b
c
OH
OH
N
H
N
Boc
7
N
Boc
O
8, 72%
d
Ph
Ph
O
N
O
NHSO2R
OH
N
H
anone with b-nitrostyrene was obtained in good yield, excellent
N
H
N
O
O
H
.HCl
diastereoselectivity and high enantioselectivity. The enantiose-
lectivity is far higher than that observed with proline and compa-
rable to that using tetrazolyl homoproline as a catalyst.10 It should
be noticed that homoproline by itself cannot catalyse this particular
Michael reaction.10
Boc
9a, 62%
9b, 40%
10, 88%
d
Ph
Ph
O
The reaction of acetone with b-nitrostyrene using sulfonamides
O
NHSO2R
of homoproline as catalysts was also studied (Table 2). Under the
reaction conditions used (see Table 2), the addition product was
obtained in very low ee, when proline was used at 20% catalyst
loading in accordance with the literature data18 (entry 1, Table 2).
However, at the same catalyst loading sulfonamides 6a and 6b gave
the products in high yields and outperformed proline in the context
of enantioselectivity (entries 2 and 6, Table 2). The effect of the
catalyst loading on the conversion and enantioselectivity for this
Michael reaction was also studied (entries 2–5, Table 2). The use of
methanesulfonamide of homoproline (6a) led to the formation of
the product in 87% yield and 48% ee, when 5% catalyst loading was
employed (entry 4, Table 2). At an even lower catalyst loading both
yield and enantioselectivity dropped (entry 5, Table 2). Catalyst 6b
in lower loadings led to significant decreased yields (entries 7 and
8, Table 2).
NHSO2R
N
H
N
H
N
N
.HCl
O
.HCl
O
H
H
12a,b
11a, 100%
11b, 93%
9, 11, 12
R
a
b
CH3
pCH3C6H4
Scheme 2. Reagents and conditions: (a) (L)-Phe–OMe, WSCI, HOBt, Et3N, CH2Cl2, 0 ꢀC,
1 h, then rt for 18 h; (b) 1 N NaOH, MeOH, rt, 18 h; (c) methanesulfonamide or p-tol-
uenesulfonamide, DCC, DMAP, CH2Cl2, rt, 18 h; (d) 5 N HCl/MeOH, rt, 1 h.
The asymmetric Michael addition of carbonyl compounds to
nitro-olefins is a useful synthetic transformation.17 First, the Mi-
chael reaction between cyclohexanone and
b-nitrostyrene was

1446
E. Tsandi et al. / Tetrahedron 65 (2009) 1444–1449
Table 2
Table 3
Michael reaction of acetone with
catalysts
b-nitrostyrene using derivatives of homoproline as
Direct asymmetric aldol reaction of acetone with 4-nitrobenzaldehyde using sul-
fonamide catalysts
O
O
OH
O
catalyst 20%
Et3N
H
+
O
NO2
O
catalyst, Et3N
NO2
+
NO2
i-PrOH-EtOH (1:1)
24h, r.t.
NO2
Entry
Catalyst
Solvent
Reaction
time (h)
Temperature
Yielda
(%)
eeb
(%)
Entry
Catalyst
)-Proc
6a
6a
6a
6a
6b
6b
6b
Catalyst
loading (%)
Yielda
(%)
eeb
(%)
1
2
3
4
5
6
7
8
(
L
)-Proc
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH2Cl2
CH2Cl2
DMSO
CH2Cl2
DMSO
CH2Cl2
CH2Cl2
Acetone
Toluene
MeOH
H2O
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Acetone
Acetone
CH2Cl2
18
18
18
18
18
48
18
18
48
18
18
18
18
18
18
18
18
48
48
48
48
48
48
48
48
48
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
73
68
47
62
61
64
67
74
40
72
29
62
47
65
57
56
81
10
79
82
48
49
13
35
16
60
73
44
35
27
54
54
34
77
79
61
84
31
37
77
48
38
10
80
84
82
77
87
74
75
73
75
1
2
3
4
5
6
7
8
(
L
20
20
10
5
63
88
84
87
68
70
15
8
7
13
30
48
29
16
42
38
6a
6b
10
10d
10d
10
2
20
10
5
11a
11a
11b
11b
12a
12b
11a
11a
11a
11a
11a
11a
11ad
11ae
11af
11a
11a
11a
11b
9
a
Isolated yield after column chromatography.
The ee was determined by HPLC on a Daicel Chiralpak AD-H column.
In the absence of Et3N.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
b
c
As described in the literature, under the same conditions the
Michael product of the reaction between acetone and -nitro-
b
styrene was obtained in 68% yield and 42% ee, when the tetrazole
analogue of homoproline 3b was used as a catalyst.10 Using
homoproline as a catalyst in different solvents, the product was
isolated in 5–88% yield and 13–42% ee.9 Homoprolyl meth-
anesulfonamide 6a leads to better yield and enantioselectivity in
comparison to tetrazolyl catalyst 3b, clearly indicating that the
conversion of the carboxyl group into sulfonamide functionality
provides results at least comparable or even better than those
obtained by the tetrazole functionality. However, according to re-
cent findings a chiral thiourea may catalyse the reaction between
0
ꢀC
ꢁ20 ꢀ
ꢁ20 ꢀ
ꢁ20 ꢀ
ꢁ20 ꢀ
ꢁ78 ꢀ
C
C
C
C
C
ꢁ20 ꢀC
ꢁ78 ꢀ
ꢁ20 ꢀ
C
C
a
Isolated yield after column chromatography.
b
c
d
e
f
The ee was determined by HPLC on a Daicel Chiralpak AD-RH column.
In the absence of Et3N.
In the presence of NMM instead of Et3N.
Catalyst loading: 10%.
acetone and b-nitrostyrene giving the product in both high yield
and enantioselectivity.19
Two possible transition states have been proposed to explain the
enantioselectivity observed in Michael additions catalysed by
proline derivatives.10,20,21 In accordance with those literature data,
two similar frameworks may be proposed for homoprolyl sulfon-
amides (Fig. 2). In both models, an electrostatic interaction between
the nitro group and the nitrogen of the enamine is involved. The
first model (A) suggests that it may be an extended hydrogen-
bonded transition state. The second model (B) proposes that the
selectivity is determined by the steric hindrance of the pyrrolidine
ring substituent.
Catalyst loading: 5% .
results obtained in the present study for the homoproline sulfon-
amides 6a and 6b indicate that increase of the distance between the
sulfonamide group and the pyrrolidine scaffold by one carbon atom
leads to a substantial decrease in both yield and enantioselectivity
in this particular aldol reaction. Probably the formation of the hy-
drogen bond network is disfavoured. This is in plain contrast to the
beneficial effect of the longer distance between the sulfonamide
group and the pyrrolidine scaffold observed in this study for the
Michael reaction.
The reaction of acetone with 4-nitrobenzaldehyde is a usual
model reaction to study the efficacy of dipeptide sulfonamides
organocatalysts.
L-Proline is known to catalyse this reaction in good
Although dipeptide 10 is known to catalyse this reaction in high
yield but with moderate enantioselectivity,12d our attempts failed
to reproduce this result in DMSO and the product was obtained in
moderate yield (62%) and low enantiomeric excess (entry 4, Table
3). When N-methyl morpholine (NMM) was used as a base, the
yield did not improve but the enantiomeric excess increased, in
accordance with the literature12d (entry 5, Table 3). The reaction
time as well as the change of solvent did not improve either the
yield or the selectivity (entries 6 and 7, Table 3). When the novel
organocatalysts 11a and 11b were used, the yield was highly de-
pendent on the solvent of the reaction. Using methanesulfonamide
11a in dichloromethane for 18 h at room temperature, the product
was obtained in 74% yield and 77% ee, while when DMSO was used
as a solvent and even at prolonged reaction times, the yield drop-
ped to 40% with an enantiomeric excess of 79% (entries 8 and 9,
Table 3). When sulfonamide 11b was used in dichloromethane the
product was produced in 72% yield and 61% ee, while in DMSO the
yield was far lower (29%) and the enantiomeric excess was
yield and enantioselectivity. In our hands, when
L
-proline was used
as a catalyst in DMSO for 18 h, the product was obtained in 73%
yield and 73% ee (entry 1, Table 3). Both sulfonamides of homo-
proline 6a and 6b led to decreased yields and enantioselectivities
(entries 2 and 3, Table 3). We and others have previously shown
that proline sulfonamides 2a and 2b outperform proline in the al-
dol reaction between acetone and p-nitrobenzaldehyde.4,7 The
O
O
RO2SHN
N
O
N
N
NO2
NSO2R
O
H
A
B
Figure 2. Transition state models for the reaction of acetone with b-nitrostyrene.

E. Tsandi et al. / Tetrahedron 65 (2009) 1444–1449
1447
increased (84%, entries 10 and 11, Table 3). When the di-
astereomeric sulfonamides 12a and 12b were used, both yield and
enantiomeric excess dropped significantly (entries 12 and 13, Table
the Michael addition product of cyclohexanone to
was obtained in high chemical yield, high diastereoselectivity and
enantioselectivity, whereas the product of the reaction between
b
-nitrostyrene
3). Methanesulfonamide 12a containing
D
-phenylalanine afforded
acetone and b-nitrostyrene was produced in high yield and mod-
the product in 62% yield and in 31% ee, while sulfonamide 12b gave
similar results (47% yield, 37% ee). It is quite clear that the asym-
metric efficacy of the catalyst also depends on the chirality of the
second amino acid of the catalyst and the (S)-configuration leads to
better results. Since sulfonamide 11a afforded the best results as far
as both yield and enantioselectivity are concerned, we decided to
study the effect of the solvent in the catalytic efficiency of 11a
(entries 14–17, Table 3). When acetone was used, the yield dropped
slightly (65%) but the enantiomeric excess was the same (77%, entry
14, Table 3). Toluene as well as methanol proved to give lower
yields and ees (entries 15 and 16, Table 3), while water afforded the
product in good yield (81%) but in very low ee (entry 17, Table 3).
The effect of the temperature was also studied (entries 18–26, Table
3). When DMSO was used with sulfonamide 11a at 0 ꢀC, the yield
was decreased (10%) but the enantiomeric excess was almost the
same (80%, entry 18 vs entry 9, Table 3). Sulfonamide 11a in
dichloromethane afforded the best results, so it was decided to
drop the temperature and extend the reaction time. At ꢁ20 ꢀC the
product was obtained in higher yield (79%) and improved enan-
tiomeric excess (84%, entry 19, Table 1). Earlier, we had observed
that in the case of dipeptide 10 when N-methyl morpholine was
used instead of triethylamine as a base, an increase in the enan-
tioselectivity was observed (entry 5 vs entry 4, Table 3). Thus, we
decided to explore whether the change of the base had any sig-
nificant implication with sulfonamide 11a (entry 20, Table 3);
however, similar results were obtained. When the catalyst loading
was decreased, the yield dropped, while the enantioselectivity was
maintained at the same levels (entries 21 and 22, Table 3). When
the temperature was dropped down to ꢁ78 ꢀC, the yield was sig-
nificantly decreased, while the ee was maintained at the same
levels (entry 23, Table 3). In acetone, low temperatures led to de-
creased yield, while the enantiomeric excess was left intact (entries
24 and 25, Table 3). Finally, sulfonamide 11b was also used in
dichloromethane at ꢁ20 ꢀC leading to decreased yield (60%) and
increased selectivity (entry 26 vs entry 10, Table 1).
erate enantioselectivity. However, even in this case, the sulfon-
amide of homoproline outperformed proline itself as a catalyst.
Methanesulfonamide of the dipeptide Pro–Phe was also proved
better catalyst in comparison to either proline or the dipeptide Pro–
Phe in the aldol reaction between acetone and p-
nitrobenzaldehyde.
3. Experimental
3.1. General
All chemicals were purchased from Aldrich, Fluka or Alfa. An-
hydrous solvents were prepared according to the literature known
procedures. Flash chromatography was performed on silica gel
(Merck Kieselgel 60 F254 230–400 mesh). TLC was performed on
aluminium backed silica plates (0.2 mm, 60 F254), which were de-
veloped using standard visualising agents: UV fluorescence (254
and 366 nm), phosphomolybdic acid/D, anisaldehyde/D. Melting
points were determined on a Buchi 530 hot stage apparatus. 1H
NMR spectra were recorded at 200 MHz Varian Mercury in-
strument. Chemical shifts (dH) are quoted in parts per million
(ppm), referenced to CDCl3. 13C NMR spectra were recorded at
50 MHz Varian Mercury instrument. Chemical shifts (dC) are quoted
in parts per million (ppm), referenced to the appropriate solvent
peak. Where rotamers are apparent and resolved, peaks for major
and minor rotamers are reported. IR spectra were recorded on
a Nicolet IR6700 FT-IR spectrometer. Only selected absorbencies
(
nmax) are reported. Mass spectra were recorded on a Finnigan
Surveyor MSQ Plus, with only molecular ions (Mþ or MHþ) and
major peaks being reported with intensities quoted as percentages
of the base peak.
3.2. General procedure for the coupling of a carboxylic acid
with methanesulfonamide or p-toluenesulfonamide
From the results of Table 3 and in accordance with the results
observed for the Michael reaction, the conversion of the carboxylic
group of Pro–Phe into the methanesulfonamide functionality has
a profound effect in the enantioselectivity in the aldol reaction
between acetone and p-nitrobenzaldehyde. Fine tuning of solvent
and temperature showed that CH2Cl2 and ꢁ20 ꢀC are optimal for
this reaction. Similarly as in the Michael reaction, the higher se-
lectivities obtained in the aldol reaction using sulfonamides of di-
peptide Pro–Phe can be attributed to the extended hydrogen
bonding between the carbonyl group of 4-nitrobenzaldehyde and
the NHs of dipeptide sulfonamides (Fig. 3). To the best of our
knowledge, this is the first example of dipeptide sulfonamides used
as organocatalysts.
To a stirring solution of carboxylic acid (1 mmol) in CH2Cl2
(10 mL), DCC (206 mg, 1 mmol), the corresponding sulfonamide
(1 mmol) and DMAP (122 mg, 1 mmol) were added consecutively.
The reaction mixture was left stirring for 18 h at room temperature.
After filtration, the solvent was removed and the residue was pu-
rified by column chromatography eluting with the appropriate
CH2Cl2/MeOH mixture to give the product.
3.2.1. (S)-tert-Butyl-2-[2-(methylsulfonamido)-2-oxoethyl]-
pyrrolidine-1-carboxylate (5a)
25
White solid (242 mg, 79%); mp 49–50 ꢀC; [
a
]
þ43.9 (c 1,
D
CHCl3); IR (KBr, cmꢁ1) 1720, 1332, 1167; 1H NMR (200 MHz, CDCl3)
d
10.84–10.67 (br s, 1H, NH), 4.17–4.06 (m, 1H, CH), 3.33 (t, J¼6.0 Hz,
In conclusion, the results of the present study show that the
conversion of the carboxyl group of either homoproline or di-
peptide Pro–Phe to the bioisosteric acyl sulfonamide group lead to
improved organocatalysts. Using methanesulfonamide of homoproline,
2H, NCH2), 3.25 (s, 3H, CH3), 2.79 (dd, J¼14.0 and 4.0 Hz, 1H,
COCHH), 2.39 (dd, J¼14.0 and 8.0 Hz, 1H, COCHH), 2.12–1.97 (m, 1H,
CHH), 1.96–1.73 (m, 3H, 3ꢂCHH), 1.45 [br s, 9H, C(CH3)3]; 13C NMR
(50 MHz, CDCl3) d 171.0 (CONH), 155.7 (OCONH), 80.8 [C(CH3)], 54.4
(CH), 46.9 (NCH2), 42.9 (CH2CO), 41.5 (SO2CH3), 31.7 (CH2CH2CH),
28.7 [C(CH3)], 23.6 (CH2CH2CH); MS (ESI): m/z (%) 305 (100)
[MꢁH]ꢁ. Anal. Calcd for C12H22N2O5S: C, 47.04; H, 7.24; N, 9.14.
Found: C, 46.85; H, 7.33; N, 9.03.
O
Bn
N
H
N
O
H
H
N
O
3.2.2. (S)-tert-Butyl-2-[2-(4-methylphenylsulfonamido)-2-
SO2R
oxoethyl]pyrrolidine-1-carboxylate (5b)
Ar
25
White solid (306 mg, 80%); mp 52–54 ꢀC; [
a
]
þ27.9 (c 1,
D
CHCl3); IR (KBr, cmꢁ1) 1726, 1337, 1174; 1H NMR (200 MHz,
CDCl3)
10.73–10.47 (br s, 1H, NH), 7.90 (d, J¼8.2 Hz, 2H, Ar),
Figure 3. Proposed transition state model for the reaction of acetone with
b-
nitrostyrene.
d

1448
E. Tsandi et al. / Tetrahedron 65 (2009) 1444–1449
7.28 (d, J¼8.2 Hz, 2H, Ar), 4.07–3.95 (m, 1H, CH), 3.35–3.16 (m,
2H, NCH2), 2.72 (dd, J¼15.8 and 4.2 Hz, 1H, COCHH), 2.39 (s, 3H,
CH3), 2.34 (dd, J¼15.8 and 7.8 Hz, 1H, COCHH), 2.03–1.87 (m, 1H,
CHH), 1.84–1.62 (m, 3H, 3ꢂCHH), 1.42 [br s, 9H, C(CH3)3]; 13C
[MþH]þ. Anal. Calcd for C7H15N2O3SCl: C, 34.64; H, 6.23; N, 11.54.
Found: C, 34.42; H, 6.48; N, 11.37.
3.3.2. (S)-N-(4-Methylphenylsulfonyl)-2-(pyrrolidin-2-yl)-
NMR (50 MHz, CDCl3)
d
169.7 (CONH), 155.9 (OCONH), 144.9 (Ar),
acetamide hydrochloride (6b)
25
136.3 (Ar), 129.6 (Ar), 128.5 (Ar), 80.6 [C(CH3)], 54.2 (CH), 46.8
(NCH2), 42.4 (CH2CO), 31.6 (CH2CH2CH), 28.7 [C(CH3)], 23.5
(CH2CH2CH), 21.8 (CH3); MS (ESI): m/z (%) 381 (100) [MꢁH]ꢁ.
Anal. Calcd for C18H26N2O5S: C, 56.52; H, 6.85; N, 7.32. Found: C,
56.21; H, 6.98; N, 7.21.
White solid (229 mg, 90%); mp 192–194 ꢀC; [
a
]
þ41.0 (c 1,
D
CH3OH); IR (KBr, cmꢁ1) 1724, 1339, 1174; 1H NMR (200 MHz,
CD3OD)
d
7.86 (d, J¼8.2 Hz, 2H, Ar), 7.35 (d, J¼8.2 Hz, 2H, Ar), 3.79–
3.62 (m, 1H, CH), 3.48–3.11 (m, 2H, NCH2), 2.81 (dd, J¼17.4 and
3.8 Hz, 1H, COCHH), 2.64 (dd, J¼17.4 and 9.4 Hz, 1H, COCHH), 2.39
(s, 3H, CH3), 2.03–1.49 (m, 4H, 4ꢂCHH); 13C NMR (50 MHz, CD3OD)
3.2.3. (S)-tert-Butyl-2-[(S)-1-(methylsulfonamido)-1-oxo-3-
d 169.5 (CONH), 145.0 (Ar), 136.8 (Ar), 129.3 (Ar), 128.1 (Ar), 55.9
phenylpropan-2-ylcarbamoyl]pyrrolidine-1-carboxylate (9a)
(CH), 45.4 (NCH2), 37.4 (CH2CO), 29.9 (CH2CH2CH), 23.2
(CH2CH2CH), 20.3 (CH3); MS (ESI): m/z (%) 283 (100) [MþH]þ. Anal.
Calcd for C13H19N2O3SCl: C, 48.97; H, 6.01; N, 8.79. Found: C, 48.67;
H, 6.28; N, 8.62.
25
White solid (272 mg, 62%); mp 78–79 ꢀC; [
a]
ꢁ45.9 (c 1,
D
CH2Cl2); IR (KBr, cmꢁ1
)
1719, 1679, 1339, 1142; 1H NMR
(200 MHz, CDCl3) 10.44–10.11 (br s, 1H, NH), 7.36–7.03 (m, 5H,
d
Ar), 6.91 (br d, J¼8.0 Hz, 1H, NHCO), 4.87–4.69 (m, 1H, CH), 4.29–
4.02 (m, 1H, CH), 3.38–3.21 (m, 3H, NCH2 and CHH), 3.16–2.96
(m, 4H, CH3 and CHH), 2.13–1.52 (m, 4H, 4ꢂCHH), 1.37 [br s, 9H,
3.3.3. (S)-N-[(S)-1-(Methylsulfonamido)-1-oxo-3-phenylpropan-2-
yl]pyrrolidine-2-carboxamide hydrochloride (11a)
25
C(CH3)3]; 13C NMR (50 MHz, CDCl3)
d
173.6 (CONH), 173.0
White solid (300 mg, 100%); mp 135–136 ꢀC; [
a
]
ꢁ17.6 (c 1,
D
(CONH), 155.4 (155.3) (OCONH), (136.0) 135.8 (Ar), 129.5 (Ar),
128.9 (Ar), 127.5 (127.4) (Ar), 81.5 (81.0) [C(CH3)], 60.9 (60.5)
(CH), (54.9) 54.4 (CH), 47.3 (NCH2), 41.3 (SO2CH3), 37.4 (CH2Ph),
29.8 (29.7) (CH2CH2CH), 28.5 (28.4) [C(CH3)], 24.6 (CH2CH2CH);
MS (ESI): m/z (%) 438 (100) [MꢁH]ꢁ. Anal. Calcd for
C20H29N3O6S: C, 54.65; H, 6.65; N, 9.56. Found: C, 54.33; H, 6.84;
N, 9.46.
CH3OH); IR (KBr, cmꢁ1) 1718, 1677, 1337, 1140; 1H NMR (200 MHz,
CD3OD) 7.36–7.12 (m, 5H, Ar), 4.79–4.59 (m,1H, CH), 4.29–4.14 (m,
d
1H, CH), 3.74–2.87 (m, 7H, CH3 and 4ꢂCHH), 2.28–1.42 (m, 4H,
4ꢂCHH); 13C NMR (50 MHz, CD3OD)
d (172.9) 172.6 (CONH), 169.9
(169.5) (CONH), (137.9) 137.3 (Ar), 130.4 (130.3) (Ar), 129.6 (129.5)
(Ar),128.2 (128.0) (Ar), 60.9 (60.8) (CH), 56.9 (55.0) (CH), 48.2 (47.5)
(NCH2), 43.3 (41.4) (SO2CH3), 38.5 (38.0) (CH2Ph), 31.2 (31.1)
(CH2CH2CH), 25.0 (24.7) (CH2CH2CH); MS (ESI): m/z (%) 340 (100)
[MþH]þ. Anal. Calcd for C15H22N3O4SCl: C, 47.93; H, 5.90; N, 11.18.
Found: C, 47.64; H, 6.18; N, 11.03.
3.2.4. (S)-tert-Butyl-2-[(S)-1-(4-methylphenylsulfonamido)-1-oxo-
3-phenylpropan-2-ylcarbamoyl]pyrrolidine-1-carboxylate (9b)
25
White solid (206 mg, 40%); mp 83–84 ꢀC; [
a
]
D
ꢁ43.0 (c 1,
CH2Cl2); IR (KBr, cmꢁ1
)
1726, 1680, 1344, 1162; 1H NMR
10.49–10.00 (br s, 1H, NH), 7.89 (d, J¼8.0 Hz,
3.3.4. (S)-N-[(S)-1-(4-Methylphenylsulfonamido)-1-oxo-3-
phenylpropan-2-yl]pyrrolidine-2-carboxamide hydrochloride (11b)
(200 MHz, CDCl3)
d
25
2H, Ar), 7.27 (d, J¼8.0 Hz, 2H, Ar), 7.22–7.08 (m, 3H, Ar), 7.02–
6.89 (m, 2H, Ar), 6.73 (br d, J¼8.0 Hz, 1H, NHCO), 4.92–4.67 (m,
1H, CH), 4.28–4.09 (m, 1H, CH), 3.42–3.19 (m, 2H, 2ꢂCHH), 3.08–
2.89 (m, 2H, 2ꢂCHH), 2.40 (s, 3H, CH3), 2.07–1.63 (m, 4H,
4ꢂCHH), 1.39 [br s, 9H, C(CH3)3]; 13C NMR (50 MHz, CDCl3)
White solid (336 mg, 93%); mp 110–113 ꢀC; [
a]
ꢁ18.6 (c 1,
D
CH3OH); IR (KBr, cmꢁ1) 1724, 1677, 1343, 1159; 1H NMR (200 MHz,
CD3OD)
d
7.83 (d, J¼8.2 Hz, 2H, Ar), 7.37 (d, J¼8.2 Hz, 2H, Ar), 7.27–
7.05 (m, 5H, Ar), 4.73–4.51 (m, 1H, CH), 4.21–4.11 (m, 1H, CH), 3.75–
3.67 (m, 1H, CHH), 3.32–3.19 (m, 1H, CHH), 3.01 (dd, J¼14.0 and
5.8 Hz, 1H, PhCHH), 2.80 (dd, J¼14.0 and 8.2 Hz,1H, PhCHH), 2.41 (s,
3H, CH3), 2.08–1.79 (m, 4H, 4ꢂCHH); 13C NMR (50 MHz, CD3OD)
d
172.5 (CONH), 169.9 (CONH), 155.5 (OCONH), 144.9 (Ar), 136.1
(Ar), 135.6 (Ar), 129.6 (Ar), 129.4 (Ar), 128.9 (Ar), 128.8 (Ar), 127.4
(Ar), 81.6 (81.1) [C(CH3)], 60.9 (60.7) (CH), (54.3) 53.7 (CH), 47.3
(NCH2), 37.3 (CH2Ph), 29.9 (29.6) (CH2CH2CH), 28.5 [C(CH3)], 24.8
(CH2CH2CH), 21.8 (CH3); MS (ESI): m/z (%) 538 (100) [MþNa]þ.
Anal. Calcd for C26H33N3O6S: C, 60.56; H, 6.45; N, 8.15. Found: C,
60.38; H, 6.52; N, 8.04.
d
170.5 (170.4) (CONH), 168.6 (168.4) (CONH), 145.1 (Ar), 136.5 (Ar),
136.1 (135.9) (Ar), 129.5 (Ar), 129.2 (Ar), 128.4 (Ar), 128.1 (Ar), 126.9
(Ar), 59.8 (59.6) (CH), 55.7 (54.9) (CH), 46.4 (46.3) (NCH2), (37.4)
36.9 (CH2Ph), (30.1) 29.9 (CH2CH2CH), 23.7 (23.7) (CH2CH2CH), 20.6
(CH3); MS (ESI): m/z (%) 416 (100) [MþH]þ. Anal. Calcd for
C21H26N3O4SCl: C, 55.81; H, 5.80; N, 9.30. Found: C, 55.57; H, 5.98;
N, 9.13.
3.3. General procedure for the deprotection of Boc group
To a stirring solution of Boc protected compound (0.80 mmol) in
MeOH (2 mL), a methanolic solution of HCl 6 N (6.7 mL) was added.
The reaction mixture was left stirring for 1 h at room temperature.
The solvent was removed in vacuo, methanol (5ꢂ10 mL) was added
and the solvent was removed in vacuo. The residue was recrystal-
lised from MeOH/cold Et2O to afford the product.
3.4. General procedure for the Michael reaction of
cyclohexanone with b-nitrostyrene catalysed by
methanesulfonamides or p-toluenesulfonamides
To a suspension of catalyst (depending on the catalyst loading)
in a mixture of isopropanol and ethanol (1:1) (1 mL) was added
triethylamine (equimolar amount with the catalyst). trans-b-
3.3.1. (S)-N-(Methylsulfonyl)-2-(pyrrolidin-2-yl)acetamide
Nitrostyrene (37.3 mg, 0.25 mmol) was added followed by cyclo-
hexanone (0.04 mL, 0.38 mmol). The resulting mixture was allowed
to stir at room temperature for 18 h and the solvents were evapo-
rated in vacuo. EtOAc (10 mL) was added and the organic layer was
washed with a saturated solution of NH4Cl (2ꢂ10 mL). The com-
bined aqueous layers were extracted with EtOAc (5ꢂ10 mL). The
combined organic layers were dried (Na2SO4), and the solvent was
removed in vacuo. The residue was purified by column chroma-
tography eluting with a mixture of petroleum ether 40–60/EtOAc
80:20 affording the product as a white solid.
hydrochloride (6a)
25
White solid (180 mg, 93%); mp 246–247 ꢀC; [
a]
þ39.2 (c 1,
D
CH3OH); IR (KBr, cmꢁ1) 1718, 1330, 1169; 1H NMR (200 MHz,
CD3OD) 3.96–3.80 (m, 1H, CH), 3.34–3.27 (m, 2H, NCH2), 3.26 (s,
d
3H, CH3), 2.95 (dd, J¼17.2 and 4.2 Hz, 1H, COCHH), 2.77 (dd, J¼17.2
and 8.6 Hz, 1H, COCHH), 2.34–2.18 (m, 1H, CHH), 2.12–1.88 (m, 2H,
2ꢂCHH), 1.80–1.62 (m, 1H, CHH); 13C NMR (50 MHz, CD3OD)
d 171.2
(CONH), 55.9 (CH), 45.4 (NCH2), 40.3 (SO2CH3), 37.4 (CH2CO), 29.9
(CH2CH2CH), 23.4 (CH2CH2CH); MS (ESI): m/z (%) 207 (100)

E. Tsandi et al. / Tetrahedron 65 (2009) 1444–1449
1449
3.4.1. (S)-2-[(R)-3-Nitro-1-phenylethyl]cyclohexanone18
1H NMR (200 MHz, CDCl3)
7.38–7.05 (m, 5H, Ar), 4.93 (dd,
3.6.1. (R)-4-Hydroxy-4-(4-nitrophenyl)butan-2-one22
1H NMR (200 MHz, CDCl3)
8.20 (d, J¼7.0 Hz, 2H, Ar), 7.52 (d,
J¼7.0 Hz, 2H, Ar), 5.25 (m, 1H, CH), 3.56 (br s, 1H, OH), 2.83 (m, 2H,
CH2CO), 2.21 (s, 3H, CH3CO); 13C NMR (50 MHz, CDCl3)
208.6 (CO),
149.9 (Ar), 147.4 (Ar), 126.4 (Ar), 123.8 (Ar), 68.9 (CH), 51.5 (CH2),
30.7 (CH3); HPLC analysis: Daicel Chiralpak AD-RH, MeCN/H2O
30:70, flow rate 0.5 mL/min, retention time: 17.45 (major) and
20.75 (minor).
d
d
J¼12.5 and 4.5 Hz, 1H, CHHNO2), 4.59 (dd, J¼12.5 and 9.9 Hz, 1H,
CHHNO2), 3.76 (m, 1H, CHPh), 2.69 (m, 1H, CHCO), 2.50–2.35 (m,
2H, CHH), 2.16–2.05 (m, 1H, CHH), 1.81–1.52 (m, 4H, 4ꢂCHH), 1.32–
d
1.16 (m, 1H, CHH); 13C NMR (50 MHz, CDCl3)
d 212.2 (CO),138.0 (Ar),
129.1 (Ar), 128.4 (Ar), 127.9 (Ar), 79.1 (CH2NO2), 52.7 (CHCO), 44.2
(CH2CO), 42.9 (CHPh), 33.4 (CH2), 28.8 (CH2), 25.2 (CH2); HPLC
analysis: Daicel Chiralpak AD-H, hexane/i-PrOH 95:5, flow rate
1 mL/min, retention time: 14.06 (minor) and 17.7 (major).
Acknowledgements
The project is co-funded by the European Social Fund and Na-
tional Resources (EPEAEK II).
3.5. General procedure for the Michael reaction of acetone
with b-nitrostyrene catalysed by methanesulfonamides or p-
toluenesulfonamides
References and notes
1. For books, see: (a) Berkessel, A.; Groger, H. Asymmetric OrganocatalysisdFrom
Biomimetic Concepts to Powerful Methods for Asymmetric Synthesis; Wiley-VCH:
Weinheim, 2005; (b) Dalko, P. I. Enantioselective Organocatalysis: Reactions and
Experimental Procedures; Wiley-VCH: Weinheim, 2007.
To a suspension of catalyst (depending on the catalyst loading)
in a mixture of isopropanol and ethanol (1:1) (1.6 mL) was added
triethylamine (equimolar amount with the catalyst). trans-b-
2. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395–2396.
3. For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–
5175; (b) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–
1543; (c) List, B. Chem. Commun. 2006, 819–824; (d) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713–5743; (e) Pellissier, H. Tetrahedron 2007, 63, 9267–
9331; (f) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18,
2249–2293; (g) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471–5569; (h) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun. 2007,
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Wascholowski, V.; Ley, S. V. Aldrichimica Acta 2008, 41, 3–11.
4. Bellis, E.; Vasilatou, K.; Kokotos, G. Synthesis 2005, 2407–2413.
5. Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831–1834.
6. Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004, 346, 1141–1146.
7. Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol.
Chem. 2005, 3, 84–96.
Nitrostyrene (30.0 mg, 0.20 mmol) was added followed by acetone
(0.4 mL, 5.45 mmol). The resulting mixture was allowed to stir at
room temperature for 18 h and the solvents were evaporated in
vacuo. EtOAc (10 mL) was added and the organic layer was washed
with a saturated solution of NH4Cl (2ꢂ10 mL). The combined
aqueous layers were extracted with EtOAc (5ꢂ10 mL). The com-
bined organic layers were dried (Na2SO4), and the solvent was re-
moved in vacuo. The residue was purified by column
chromatography eluting with a mixture of petroleum ether 40–60/
EtOAc 80:20 affording the product as a white solid.
3.5.1. (R)-5-Nitro-4-phenylpentan-2-one18
8. (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int.
Ed. 2004, 43, 1983–1986; (b) Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am.
Chem. Soc. 2004, 126, 5962–5963.
1H NMR (200 MHz, CDCl3)
d 7.38–7.07 (m, 5H, Ar), 4.69 (dd,
J¼12.2 and 7.0 Hz, 1H, CHHNO2), 4.57 (dd, J¼12.2 and 7.8 Hz, 1H,
9. Terakado, D.; Takano, M.; Oriyama, T. Chem. Lett. 2005, 34, 962–963.
10. Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett 2005, 611–614.
11. For reviews, see: (a) Miller, S. J. Acc. Chem. Res. 2004, 37, 601–610; (b) Revell,
J. D.; Wennemers, H. Curr. Opin. Chem. Biol. 2007, 11, 269–278; (c) Colby Davie,
E. A.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. Rev. 2007, 107, 5759–5812.
12. (a) Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445–
2447; (b) Martin, H. J.; List, B. Synlett 2003, 1901–1902; (c) Tang, Z.; Yang, Z.-H.;
Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285–2287; (d)
Shi, L.-X.; Sun, Q.; Ge, Z.-M.; Zhu, Y.-Q.; Cheng, T.-M.; Li, R.-T. Synlett 2004,
2215–2217; (e) Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.;
Tomasini, C. J. Org. Chem. 2005, 70, 7418–7421; (f) Krattiger, P.; Kovasy, R.;
Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101–1103; (g) Zou, W.;
Ibrahem, I.; Dziedzic, P.; Sunden, H.; Cordova, A. Chem. Commun. 2005, 4946–
4948; (h) Akagawa, K.; Sakamoto, S.; Kudo, K. Tetrahedron Lett. 2005, 46, 8185–
8187; (i) Tsogoeva, S. B.; Wei, S. Tetrahedron: Asymmetry 2005, 16, 1947–1951;
(j) Zheng, J.-F.; Li, Y.-X.; Zhang, S.-Q.; Yang, S.-T.; Wang, X.-M.; Wang, Y.-Z.; Bai,
J.; Liu, F.-A. Tetrahedron Lett. 2006, 47, 7793–7796; (k) Dziedzic, P.; Zou, W.;
Hafren, J.; Cordova, A. Org. Biomol. Chem. 2006, 4, 38–40; (l) Lei, M.; Shi, L.; Li,
G.; Chen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li, R. Tetrahedron 2007, 63, 7892–7898.
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Sci. U.S.A. 2004, 101, 5755–5760.
CHHNO2), 3.99 (m, 1H, CHPh), 2.89 (d, J¼7.4 Hz, 2H, CH2CO), 2.09 (s,
3H, CH3); 13C NMR (50 MHz, CDCl3)
d 205.6 (CO), 139.1 (Ar), 129.3
(Ar), 128.1 (Ar), 127.6 (Ar), 79.7 (CH2NO2), 46.3 (CH2CO), 39.3 (CH),
30.6 (CH3); HPLC analysis: Daicel Chiralpak AD-H, hexane/i-PrOH
94:6, flow rate 1 mL/min, retention time: 12.82 (minor) and 14.07
(major).
3.6. General procedure for the aldol reaction of acetone with
4-nitrobenzaldehyde catalysed by methanesulfonamides or p-
toluenesulfonamides
To a suspension of catalyst (depending on the catalyst loading) in
dichloromethane (8 mL) was added triethylamine (equimolar
amount with the catalyst) followed by acetone (2.0 mL, 27.2 mmol).
4-Nitrobenzaldehyde (151.1 mg, 1 mmol) was added to the reaction
mixture and left stirring for 18 h at room temperature and the sol-
vents were evaporated in vacuo. EtOAc (10 mL) was added and the
organic layer was washed with a saturated solution of NH4Cl
(2ꢂ10 mL). The combined aqueous layers wereextracted with EtOAc
(5ꢂ10 mL). The combined organic layers were dried (Na2SO4), and
the solvent was removed in vacuo. The residue was purified by
column chromatography eluting with a mixture of petroleum ether
40–60/EtOAc 50:50 affording the product as a yellow oil.
14. Bellis, E.; Kokotos, G. Tetrahedron 2005, 61, 8669–8676.
15. Bellis, E.; Kokotos, G. J. Mol. Catal. A: Chem. 2005, 241, 166–174.
16. Cassal, J.-M.; Furst, A.; Meier, W. Helv. Chim. Acta 1976, 59, 1917–1924.
17. For recent reviews, see: (a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716; (b)
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19. Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170–7171.
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4212–4215.
22. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260–
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