Epiandrosterone-derived prolinamide as an efficient asymmetric catalyst for Michael addition reactions of aldehydes to nitroalkenes

Article abstract of DOI:10.1039/c4ra03075c

Epiandrosterone derivatives-organocatalyzed asymmetric Michael addition of aldehydes to nitroalkenes was investigated. Among the various catalysts, a novel type of epiandrosterone-derived l-prolineamide catalyst was synthesized and exhibited better perfor

Full text of DOI:10.1039/c4ra03075c

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Epiandrosterone-derived prolinamide as an
efficient asymmetric catalyst for Michael addition
reactions of aldehydes to nitroalkenes†
Cite this: RSC Adv., 2014, 4, 30850
*
*
Yongchao Wang, Shen Ji, Kun Wei and Jun Lin
Epiandrosterone derivatives-organocatalyzed asymmetric Michael addition of aldehydes to nitroalkenes
was investigated. Among the various catalysts, a novel type of epiandrosterone-derived L-prolineamide
catalyst was synthesized and exhibited better performance in both catalytic activity and stereoselectivity,
providing the products with high yields (up to 98%), excellent enantioselectivities (up to 99% ee) and
diastereoselectivities (up to 99 : 1 dr), and low catalyst loading (5 mol%).
Received 6th April 2014
Accepted 3rd July 2014
DOI: 10.1039/c4ra03075c
www.rsc.org/advances
reactivities and enantioselectivities. Although these organo-
catalysts have provided satisfactory results in asymmetric
Introduction
Michael addition reactions, development of new, effective
catalysts is still desired. In our recent studies directed toward
devising highly enantioselective catalysts for the addition of
aldehydes to nitroalkenes, we planned to design a new class of
bifunctional chiral prolinamide catalysts with an epian-
drosterone-derived primary amine based on the mechanism of
enamine formation and hydrogen bonding. Epiandrosterone
belongs to steroid compounds and could be prepared from
natural product dioscin. Generally, as a weak androgen, it is
widely recognized to inhibit the pentose phosphate pathway
(PPP) and to decrease intracellular NADPH levels.10 To the best
of our knowledge, there is no report to date of epiandrosterone
as organocatalyst except for its analogs used as transition-metal
steroid catalysts.11 It was speculated that the optical activity and
steric effect of epiandrosterone would be benet for enantio-
and diastereoselectivity of the Michael addition ketones or
aldehydes to nitroalkenes. Herein, we describe the ability of the
new bifunctional organocatalyst in performing asymmetric
Michael addition reactions.
Among the numerous asymmetric carbon–carbon bond-form-
ing reactions in organic synthesis, catalytic asymmetric Michael
addition plays a very important role.1 In recent years, this type of
reaction has been an effective strategy for the synthesis of
natural products.2 Among the variants of this reaction, the
Michael addition of ketones or aldehydes to nitroalkenes has
received more and more attention. This is because the nitro
group can be easily transformed into various useful functional
groups, such as amines, nitrile oxides, ketones, and carboxylic
acids, etc.3,4 As one of the most critical factors, organocatalysts
have shown a strong advantage for achieving effective stereo-
control in addition reactions.5 Due to the growing need for an
environmentally-friendly
nonmetal-catalyzed
asymmetric
synthesis, considerable attention has recently been focused on
the development of new, highly effective, relatively non-toxic,
and small-molecule chiral organocatalysts.
As one of the most successfully and widely applicable
modern organocatalyts based on covalent character, proline
and proline derivatives play a dominant role in asymmetric
catalysis.6 Among a variety of different catalysts, diarylprolinol
silyl ethers, introduced as organocatalysts by Jørgensen and
Hayashi independently in 2005,7 have demonstrated excellent
performances in asymmetric enamine organocatalysis.8 More
recently, many proline-derived organocatalysts, such as ami-
nomethyl pyrrolidine,9a–c prolinamide,9d–h peptide,9i,j and diary-
lprolinol silyl ether,9k–m have been developed and exhibited high
Results and discussion
The design and synthesis of highly stereoselective catalysts are
always desirable for asymmetric catalysis. In this direction, we
have developed an efficient synthesis of L-proline-epian-
drosterone organocatalyst. The synthetic route of target
compounds is shown in Scheme 1. Synthesis of amide 6a started
from commercially available epiandrosterꢀone. By treatment
with methanesulfonyl chloride for 3 h at 0 C, the mesylate 2a
was prepared from epiandrosterone (1a). Subsequently,
compound 2a was converted to the azide 3a in dimethyl-
formamide with sodium azide. Then, hydrogenation of 3a with
Pd/C in methanol provided amine 4a. Next, amine 4a was
treated with N-Boc protected proline afford compound 5a.
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University),
Ministry of Education, School of Chemical Science and Technology, Yunnan
University, Kunming 650091, PR China. E-mail: kunwei@ynu.edu.cn; linjun@ynu.
edu.cn; Tel: +86 871 5033715
† Electronic supplementary information (ESI) available: Synthesis of catalysts 6b
and 7–10, 1H and 13C NMR spectra for compounds 2–10, 14a–14o, and spectra
of chiral HPLC for compounds 14a–14o. See DOI: 10.1039/c4ra03075c
30850 | RSC Adv., 2014, 4, 30850–30856
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Scheme 1 Synthetic routes to organocatalyst 6a. Reagents and conditions: (a) MsCl, CH2Cl2, 0 ꢀC, 3 h, 98%; (b) NaN3, DMF, 80 ꢀC, 8 h, 91%; (c)
10% Pd/C, H2, MeOH, 12 h, 95%; (d) EDCI, DMAP, N-Boc protected proline, CH2Cl2, r.t., 20 h, 92%; (e) TFA, CH2Cl2, r.t., 95%.
Finally, N-Boc of 5a was deprotected to afford 6a in TFA. In characterized by 1H NMR, 13C NMR, HRMS, and IR
addition, the epimer (6b) of catalyst 6a and other epian- spectroscopy.
drosterone-derived amides 7–10 were also prepared according
Initially, the model reaction of nitrostyrene (12a) with
to the above-described synthesis method (for the general propanal (13a) was carried out in the presence of 10 mol% of
procedure sees ESI†). All the new compounds synthesized were catalyst and 10 mol% of benzoic acid as an additive in toluene
Table 1 Screening of catalysts and solventsa
Entry
Catalyst (mol%)
Solvent
Time (h)
Yieldb (%)
syn/antic
ee (syn)d (%)
1
2
3
4
5
6
7
8
6a (10)
6b (10)
7 (10)
8 (10)
9 (10)
10 (10)
11 (10)
6a (10)
6a (10)
6a (10)
6a (10)
6a (10)
6a (10)
6a (5)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CHCl3
12
12
36
36
36
36
24
18
18
24
48
48
48
12
45
87
92
81
10
9
72 : 28
68 : 32
88 : 12
74 : 26
—
89
84
90
88
—
—
20
79
81
74
—
—
—
89
86
84
<5
<5
34
82
85
62
<5
<5
<5
90
90
89
—
65 : 35
71 : 29
68 : 32
69 : 31
—
—
—
74 : 26
82 : 18
81 : 19
9
10
11
12
13
14
15
16
Hexane
THF
CH3CN
CH3OH
Toluene
Toluene
Toluene
6a (3)
6a (1)
a
b
All reactions were carried out using 12a (3.0 mmol) and 13a (1.0 mmol) in the presence of catalysts in solvent (1.0 mL). Yield of the isolated
product. Determined by 1H NMR analysis of the products. Determined by chiral HPLC, the absolute conguration was established by
c
d
comparison with literature data.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 30850–30856 | 30851

View Article Online
RSC Advances
Paper
under room temperature (Table 1). As shown in Table 1, cata- were also investigated for this reaction (Table 1, entries 1 and 8–
lysts 6–11 exhibited signicantly different catalytic activity and 11). The excellent yield and enantioselectivity (92% yield, and
enantioselectivity toward the process. Among the organo- 89% ee) could be obtained when the reaction was carried out in
catalysts surveyed, when catalyst 6a was used, the result was toluene (Table 1, entry 1). However, some polar solvents, such as
observed with an excellent yield (92%), diastereoselectivities acetonitrile and methanol, gave rather poor yield and stereo-
(syn/anti ¼ 72 : 28) and enantioselectivity (89% ee) (entry 1). To selectivity (Table 1, entries 12 and 13). Moreover, we examined
further understand the role of epiandrosterone unit of catalyst, the inuence of catalyst loading on the reaction. When the
the epimer (6b) of catalyst 6a was synthesized and its catalytic catalyst 6a was reduced to 5 mol%, the reaction provided the
activity was investigated (entry 2). The experiment result same result as it using 10 mol% of catalyst (Table 1, entry 14).
exhibited a moderate performance on both yield (81%) and However, with lower catalyst loading, a prolonged time was
stereoselectivity (84% ee). It was speculated that epiandroster- required (Table 1, entries 15 and 16). Next, the effect of a series
one or androsterone only acts as a steric hindrance to create a of different organic additives was tested and the results are
chiral environment and their steric effect is very obvious by summarized in Table 2. Apparently, the reaction proceeded very
comparison of the catalytic results of 6a with those of several slowly in the absence of acid additives and provided poor yield
non-chiral prolinamide derivatives in the model Michael reac- and enantioselectivity aer 48 h (Table 2, entries 1–3). When
tion (for the result see ESI†). However, other epiandrosterone- using PhCOOH as an acid additive, the better result was
derived amide catalysts 7–10 gave poor yields. In addition, L- observed with an excellent yield (92%) and enantioselectivity
proline (11) could catalyze this reaction, but rather poor yield (89% ee) (Table 1, entry 1). The other acid additives, such as
and stereoselectivity were observed (entry 7). According to the HCOOH and CH3COOH, were also benet for this reaction,
above result, 3a-N-(pyrrolidine-2-formyl)-5a-androstan-17-one although their yields and enantioselectivities were slightly lower
6a was conrmed to be the most effective catalyst in terms of than the results with PhCOOH (Table 2, entries 5, 6 and 8).
both the yield and enantioselectivity of the reaction.
However, addition of a strong acid, such as p-TSA or TFA, was
With an optimum catalyst 6a in hand, other reaction not favorable to the reaction (Table 2, entries 4 and 7). In
parameters, including solvents, additives, temperatures, and addition, three chiral acid tartaric acid, N-Boc glycine and
amounts of catalyst were examined in order to further improve mandelic acid was employed (Table 2, entries 8–10), and the
the reactivity and enantioselectivity, and the results are shown yield and stereoselectivity were moderate. It was implied that in
in Tables 1 and 2. A range of typical solvents were rst screened the Michael addition the acid additives only provided the
in the presence of benzoic acid (10 mol%) and catalyst 6a (10 proton. The inuence of acid loading on the reaction was also
mol%) at room temperature. Besides toluene, some nonpolar examined (Table 2, entries 11 and 12). It was observed that 10
and aprotic solvents, such as CH2Cl2, CHCl3, hexane, and THF, mol% of PhCOOH gave the optimal results in terms of both
Table 2 Screening of additive and temperaturea
Entry
Additive
Tem. (ꢀC)
Time (h)
Yieldb (%)
syn/antic
eed (%)
1
2
3
4
5
6
7
8
None
H2O
Et3N
p-TSA
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
48
48
48
48
12
18
18
48
48
48
18
48
6
<5
<5
<5
<5
90
82
<5
62
71
63
51
<5
96
90
88
68
—
—
—
—
—
—
—
—
88
86
—
83
72
78
84
—
80
90
94
95
HCOOH
CH3COOH
CF3COOH
Tartaric acid
N-Boc glycine
Mandelic acid
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
70 : 30
76 : 24
—
70 : 30
62 : 38
68 : 32
65 : 35
—
76 : 24
74 : 26
61 : 39
82 : 18
9
10
11e
12f
13
14
15
16
0
24
24
48
ꢁ20
ꢁ40
a
All reactions were carried out using 12a (3.0 mmol) and 13a (1.0 mmol) in the presence of catalyst 6a (5 mol%) in toluene (1.0 mL). b Yield of the
isolated product. c Determined by 1H NMR analysis of the crude products. d Determined by chiral HPLC. e 5 mol% of PhCOOH was used. f 1 mol%
of PhCOOH was used.
30852 | RSC Adv., 2014, 4, 30850–30856
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
activity and stereoselectivity. Additionally, the effect of reaction excellent diastereoselectivity (98 : 2 dr) (entry 4). Moreover,
temperature was investigated. As revealed in Table 2 (entries aromatic nitroalkenes, regardless of electron-donating and
13–16), temperature has signicant impact on the catalytic electron-withdrawing substituents on the phenyl ring, partici-
effect. It was obvious that good enantioselectivity could be pated in this process in high yield (90–98%) and excellent ee
obtained under low reaction temperature conditions. Based on values (94–99%). The excellent enantioselectivities (93–97% ee)
ꢀ
the overall evaluation, ꢁ20 C was selected to be the optimal was also observed for the Michael addition of aldehydes to
reaction temperature.
nitroalkenes containing heteroaryl groups. Additionally, on the
Under the above optimized conditions, the scope of the basis of the condition, the Michael addition of an alkyl-
asymmetric Michael addition reaction was investigated by substituted nitroalkene has also been investigated (entry 15).
applying different aldehydes and nitroalkenes in the presence The high yield (94%) and excellent enantioselectivities (95%)
of 5 mol% of catalyst 6a and 10 mol% PhCOOH in toluene at were observed for the Michael addition product.
ꢀ
ꢁ20 C. The results are summarized in Table 3. Products were
In order to account for the good enantioselectivity of the
obtained with good yields (88–98%) and excellent enantiose- reaction, a plausible transition-state model is proposed in
lectivities (93–99% ee) (Table 3). The steric hindrance of the R1 Scheme 2. The pyrrolidine functionality activates the aldehyde
group for aliphatic aldehydes was benet for the increase of through the formation of an enamine intermediate, and the
diastereoselectivity to a large degree (entries 1–5). For examples, nitro group of trans-b-nitrostyrene is directed toward the amide
the reaction of propanal gave a moderate diastereoselectivity group by the hydrogen bond between the NH group of the
(61 : 39 dr) (entry 1), while that of 3-methylbutanal provided an amide and the nitro group. The enamine formed in situ attacks
Table 3 Asymmetric Michael additions of aldehydes to nitroalkenes catalyzed by 6aa
Entry
1
Product
Yieldb (%)
88
syn : antic
ee (syn)d (%)
Entry
9
Product
Yieldb (%)
91
syn : antic
ee (syn)d (%)
61 : 39
94
80 : 20
96
2
3
4
94
90
91
83 : 17
94 : 6
98 : 2
98
95
99
10
11
12
90
98
95
87 : 13
84 : 16
82 : 16
98
98
99
5
6
91
96
96 : 4
99 : 1
96
99
13
14
95
92
57 : 43
53 : 47
93
97
7
98
95
68 : 32
92 : 8
98
97
15
94
95 : 5
95
8
a
All reactions were carried out using nitroalkenes (1.0 mmol) and aldehydes (3.0 mmol) in the presence of catalyst 6a (5 mol%) in toluene (1.0 mL)
at ꢁ20 ꢀC. Yield of the isolated product. Determined by 1H NMR analysis of the crude products. Determined by chiral HPLC, the absolute
b
c
d
conguration was established by comparison with literature data.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 30850–30856 | 30853

View Article Online
RSC Advances
Paper
mixture was stirred for 3 h at 0 ꢀC and diluted with cold water.
The solution was extracted twice with 100 mL of CH2Cl2. The
organic layer was washed successively with H2O to neutral pH
and with brine. The solution was dried over anhydrous MgSO4,
ltered, and concentrated to afford crude product which was
chromatographed on silica gel using 30% ethyl acetate in n-
hexane to afford 2a in 98% yield as amorphous solid (3.5 g).
[a]2D0 ¼ +67.6 (c 1.0, CDCl3); IR (KBr) 525, 857, 936, 1171, 1350,
1738, 2854, 2932, 3459 cmꢁ1; m.p. 158–159 ꢀC; HRMS (EI) calcd
for C20H32O4S [M + Na]+ 391.1913, found 391.1915. 1H-NMR
(500 MHz, CDCl3) d 4.61 (1H, m), 3.30 (3H, s), 2.43 (1H, dd, J ¼
19, 8.8 Hz), 2.07 (1H, dt, J ¼ 19, 9 Hz), 1.98 (1H, m), 1.93 (1H, m),
1.79 (4H, d), 1.73 (1H, m), 1.62 (3H, m), 1.53 (3H, m), 1.28 (8H,
m), 1.02 (3H, m), 0.86 (6H, s), 0.71 (1H, m); 13C-NMR (125 MHz,
CDCl3) d 221.2, 82.2, 54.6, 51.7, 48.1, 45.2, 39.2, 37.1, 36.2, 35.8,
35.5, 35.4, 31.9, 31.1, 29.0, 28.6, 22.1, 20.9, 14.2, 12.6.
Scheme 2 Possible transition state of the reaction.
the Si face of the nitroalkene to furnish the Michael adduct.
Some literatures12–14 could be taken as a support of the
hypothesis. Additionally, the bulky epiandrosterone group is
considered to be important to the high catalytic activity and
enantio- and diastereo-selectivity of the catalyzed reactions.
Procedure for the synthesis of 3a-azido-5a-androstan-17-one
(3a)16
Conclusions
NaN3 (2 eq., 1.24 g) was added to a solution of mesylate 2a (3.5 g,
9.51 mmol) in DMF (30 mL) and stirred overnight at room
temperature. Water (50 mL) was added and the aqueous phase
was extracted with ethyl acetate (3 ꢂ 30 mL). The combined
organic extracts were washed with saturated aqueous NaCl
solution (2 ꢂ 100 mL) and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure. Silica gel column
chromatography using 10% ethyl acetate in n-hexane to afford
3a in 91% yield as an amorphous solid (2.64 g). [a]2D0 ¼ +55.9 (c
1.0, CDCl3); IR (KBr) 538, 765, 979, 1129, 1310, 1736, 2104, 2932
cmꢁ1; m.p. 113–114 ꢀC; HRMS (EI) calcd for C19H29N3O [M +
Na]+ 338.2202, found 338.2203. 1H-NMR (500 MHz, CDCl3) d
3.81 (1H, m), 2.34 (1H, dd, J ¼ 19, 8.8 Hz), 1.97 (1H, dd, J ¼ 19,
9.4 Hz), 1.86 (1H, m), 1.72 (3H, m), 1.60 (4H, m), 1.44 (8H, m),
1.18 (8H, m), 0.94 (2H, m), 0.78 (3H, s), 0.74 (3H, s); 13C-NMR
(125 MHz, CDCl3) d 221.4, 58.4, 54.6, 51.8, 48.1, 40.4, 36.4, 36.2,
35.3, 33.2, 32.9, 31.9, 31.1, 28.4, 25.9, 22.1, 20.4, 14.2, 11.9.
In summary, we have developed a new prolinamide catalyst 6a
for the asymmetric conjugate addition reactions between alde-
hydes and nitroalkenes. This catalyst exhibited rather high
catalytic efficiency and good to excellent levels of stereo-
selectivity. Since the catalyst 6a is easily prepared from
commercially available Boc-L-proline and epiandrosterone in
several steps, we believe that catalyst 6a is an ideal candidate for
laboratory or large-scale preparations. Further applications of
the catalyst to a wider scope of reactions are being studied in
our laboratory.
Experimental section
General information
Reagents and materials were of the highest commercially
available grade and used without further purication. Solvents
were puried by standard procedures and distilled before use.
The reactions were monitored by thin layer chromatography
(TLC) using silica gel GF254. Column chromatography was per-
formed on silica gel (200–300 mesh). Compounds were visual-
ized by UV and spraying with H2SO4 (10%) in ethanol and
followed by heating. The NMR spectra were recorded on a
Bruker DRX400 (1H: 400 MHz, 13C: 100 MHz) and DRX500 (1H:
500 MHz, 13C: 125 MHz) with TMS as the internal standard,
chemical shis (d) are expressed in ppm, and J values are given
in Hz, and deuterated CDCl3 and was used as solvent. IR spectra
were recorded on a FT-IR Thermo Nicolet Avatar 360 using KBr
pellet. The mass spectroscopic data were obtained at the Agilent
1100 LC/MSD Trap LC-mass spectrometer. HPLC analysis was
performed with a Shimadzu LC-10A instrument equipped with
Daicel HPLC columns.
Procedure for the synthesis of 3a-amino-5a-androstan-17-one
(4a)17
A mixture of 3a (2.64 g, 8.38 mmol), 5% Pd–C (177 mg, 5 mol%)
in 100 mL methanol was hydrogenated under stirring overnight
by using hydrogen balloon. Aer hydrogenation, the reaction
mixture was ltered. The solvent was evaporated under reduced
pressure. The crude product was puried by column chroma-
tography over silica gel using 2% MeOH in CH2Cl2 to get the
amine 4a in 95% yield as an amorphous solid (1.94 g). [a]D20
+95.5 (c 1.0, CDCl3); IR (KBr) 837, 1008, 1049, 1368, 1446, 1593,
¼
1736, 2835, 3371 cmꢁ1; m.p. 124–126 C; HRMS (EI) calcd for
ꢀ
C
19H31NO [M + H]+ 290.2478, found 290.2479. 1H-NMR (500
MHz, CD3OD) d 3.34 (1H, m), 2.85 (1H, m), 2.62 (2H, q, J ¼ 7.1
Hz), 2.42 (1H, dd, J ¼ 19, 8.8 Hz), 2.05 (1H, dt, J ¼ 19, 9 Hz), 1.94
(1H, m), 1.81 (2H, m), 1.72 (2H, m), 1.67 (4H, m), 1.57 (3H, m),
1.50 (2H, m), 1.44 (4H, m), 1.18 (8H, m), 0.94 (2H, m), 0.85 (6H,
Procedure for the synthesis of 3b-mesyloxy-5a-androstan-17-
one (2a)15
To a 10 mmol solution of 1a in 100 mL of CH2Cl2 at 0 C was s), 0.76 (1H, s); 13C-NMR (125 MHz, CD3OD) d 223.0, 54.8, 52.4
added 20 mmol (2 eq., 2.8 mL) of Et3N followed by slow addition 51.9, 47.5, 39.8, 36.4, 35.7, 35.4, 32.6, 32.3, 31.9, 31.0, 28.6, 25.2,
of 12 mmol (1.2 eq., 929 mL) of methanesulfonyl chloride. The 21.7, 20.2, 13.2, 10.9.
ꢀ
30854 | RSC Adv., 2014, 4, 30850–30856
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
equiv.) was added. The resulting solution was stirred at the
same temperature until complete consumption of nitroalkene
(monitored by TLC). The solvent was quenched with ice water (2
mL), and extracted with ethyl acetate (3 ꢂ 2 mL). The combined
organic phase was dried over Na2SO4, aer removing the
solvent, the crude product was puried by ash chromatog-
raphy to afford the corresponding Michael adducts. Enantio-
meric excess was determined by chiral HPLC analysis.
Procedure for the synthesis of 3a-N-(Boc-pyrrolidine-2-
formyl)-5a-androstan-17-one (5a)
To a stirred solution of N-Boc-L-proline (1.075 g, 5 mmol) in dry
dichloromethane (15 mL), was added DMAP (210 mg, 1.5
mmol). The mixture was allowed to stir for 15 min and then
cooled to 0 ꢀC and then EDCI (1.22 g, 5.5 mmol) was added.
Aer 20 min, a solution of 4a (1.16 g, 4 mmol) in dichloro-
methane (15 mL) was added to the above reaction mixture. The
resulting solution was stirred at room temperature until
complete consumption of nitroalkene (monitored by TLC). The
reaction was quenched with water and extracted with
dichloromethane (3 ꢂ 50 mL). The combined organic layers
were washed with saturated brine solution (20 mL), followed by
drying over Na2SO4 and evaporating in vacuo. The crude product
was puried by column chromatography to give the pure the
prolineamide 5a in 92% yield as an amorphous solid (1.75 g).
[a]2D0 ¼ +14.1 (c 1.0, CHCl3); IR (KBr) 768, 918, 1168, 1254, 1409,
Acknowledgements
This work was supported by Program for Changjiang Scholars
and Innovative Research Team in University (IRT13095) and
Training Plan for Young Teachers of Yunnan University.
Notes and references
1 P. Perlmutter, Conjugate Addition Reactions in Organic
Synthesis, ed. J. E. Baldwin and P. D. Magnus, Pergamon
Press, Oxford, 1992.
1540, 1740, 2864, 2953, 3338 cmꢁ1; HRMS (EI) calcd for
1
C
29H46N2O4 [M + Na]+ 509.3385, found 509.3387. H-NMR (500
MHz, CDCl3) d 4.12 (1H, m), 3.36 (1H, m), 2.62 (1H, m), 2.44 (1H,
dd, J ¼ 19, 8.8 Hz), 2.08 (1H, dt, J ¼ 19, 9.6 Hz), 1.92 (3H, m),
1.80 (2H, m), 1.66 (2H, m), 1.57 (3H, m), 1.49 (9H, s), 1.28 (10H,
m), 0.86 (3H, s), 0.77 (3H, s); 13C-NMR (125 MHz, CDCl3) d 221.4,
170.7, 156.3, 59.9, 54.4, 51.6, 48.0, 47.3, 44.6, 36.3, 35.8, 35.0,
34.0, 32.9, 31.5, 30.8, 28.6, 28.2, 26.7, 26.1, 25.0, 21.9, 20.0, 13.9,
11.5.
2 For some recent references in this area, see: (a) S. I. Lee,
J. H. Jang, G.-S. Hwang and D. H. Ryu, J. Org. Chem., 2013,
78, 770; (b) M. Charpentier, M. Hans and J. Jauch, Eur. J.
Org. Chem., 2013, 4078l; (c) Z.-Y. Lu, Y. Li, J. Deng and
A. Li, Nat. Chem., 2013, 5, 679; (d) J. S. Wzorek,
T. F. Knopfel, I. Sapountzis and D. A. Evans, Org. Lett.,
2012, 14, 5840; (e) P. Ghosal, D. Sharma, B. Kumar,
S. Meena, S. Sinha and A. K. Shaw, Org. Biomol. Chem.,
2011, 9, 7372; (f) H. Yang and R. G. Carter, J. Org. Chem.,
2010, 75, 4929.
Procedure for the synthesis of 3a-N-(pyrrolidine-2-formyl)-5a-
androstan-17-one (6a)
3 (a) N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH,
New York, 2001; (b) V. V. Perekalin, E. S. Lipina,
V. M. Berestovitskaya and D. A. Efremov, Nitroalkenes:
Conjugated Nitro Compounds, Wiley-VCH, New York, 1994.
4 (a) A. G. M. Barrett and G. G. Grabowski, Chem. Rev., 1986,
86, 751; (b) R. Somanathan, D. Chavez, F. A. Servin,
J. A. Romero, A. Navarrete, M. Parra-Hake, G. Aguirre,
C. Anaya de Parrodi and J. Gonzalez, Curr. Org. Chem.,
2012, 16, 2440; (c) O. M. Berner, L. Tedeschi and
D. Enders, Eur. J. Org. Chem., 2002, 1877; (d) T. Ikariya and
I. D. Gridnev, Top. Catal., 2010, 53, 894.
5 For some selected references in this area, see: (a)
R. Somanathan, D. Chavez, F. A. Servin, J. A. Romero,
A. Navarrete, M. Parra-Hake, G. Aguirre, C. Anaya de
Parrodi and J. Gonzalez, Curr. Org. Chem., 2012, 16, 2440;
(b) P. Chauhan, J. Kaur and S. S. Chimni, Chem. – Asian J.,
2013, 8, 328; (c) J. Wang, P.-F. Li, P. Y. Choy, A. S. C. Chan
and F. Y. Kwong, ChemCatChem, 2012, 4, 917; (d) R. Miyaji,
K. Asano and S. Matsubara, Org. Biomol. Chem., 2014, 12,
119; (e) C. G. Kokotos, Org. Lett., 2013, 15, 2406; (f)
W. Wang, J.-F. Wang, S. Zhou, Q. Sun, Z.-M. Ge, X. Wang
and R.-T. Li, Chem. Commun., 2013, 49, 1333; (g)
R. Chowdhury and S. K. Ghosh, Eur. J. Org. Chem., 2013,
6167; (h) R. Miyaji, K. Asano and S. Matsubara, Org. Lett.,
2013, 15, 3658; (i) L.-L. Wen, L. Yin, Q.-L. Shen and L. Lu,
ACS Catal., 2013, 3, 502; (j) K. Dudzinski, A. M. Pakulska
and P. Kwiatkowski, Org. Lett., 2012, 14, 4222; (k)
To a solution of 5a (1.75 g, 3.6 mmol) in CH2Cl2 (10 mL) was
added TFA (3 mL). Aer stirring at 0 ꢀC for 2.5 hour, the solution
was concentrated under vacuum to leave a glutinous phase. The
pH of the mixture was brought into the range of ꢃ12 by the
addition of 2 M NaOH. The aqueous phase was extracted with
ethyl acetate. The ethyl acetate extracts were pooled, washed
with brine, dried over anhydrous Na2SO4, ltered off and the
solvent was evaporated at low pressure to give a crude residue
that was puried by column chromatography to give the pure 6a
in 95% yield as amorphous solid (1.32 g). [a]2D0 ¼ +40.5 (c 1.0,
CHCl3); IR (KBr) 768, 918, 1168, 1254, 1409, 1540, 1740, 2864,
2953, 3338 cmꢁ1; HRMS (EI) calcd C24H38N2O2, [M + H]+
387.3006, found for 387.3008. 1H NMR (400 MHz, CDCl3) d 7.92
(1H, d, J ¼ 7.0 Hz), 3.99 (1H, br s), 3.65–3.62 (1H, m), 2.98–2.94
(1H, m), 2.88–2.82 (1H, m), 2.08–2.06 (1H, m), 2.05–2.1.85 (7H,
m), 1.83–1.82 (2H, m), 1.75–1.41 (11H, m), 1.40–1.20 (9H, m),
1.02–0.98 (2H, m), 0.80 (3H, s), 0.77 (3H, s); 13C NMR (100 MHz,
CDCl3) d 221.2, 174.0, 60.8, 54.7, 51.5, 47.8, 47.3, 43.8, 41.2, 36.2,
35.8, 35.0, 33.3, 33.0, 31.5, 30.9, 30.8, 28.2, 26.2, 26.0, 21.7, 20.1,
13.8, 11.5.
General procedure for the Michael addition
To a stirred mixture of corresponding nitroolen (1 mmol, 1.0
equiv.) in 2 mL indicated solvent were added catalyst and ben-
zoic acid. The mixture was stirred at the indicated temperature
for 30 min, and then freshly distilled aldehyde (3 mmol, 3.0
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 30850–30856 | 30855

View Article Online
RSC Advances
Paper
M. Joerres, I. Schiffers, I. Atodiresei and C. Bolm, Org. Lett., 10 (a) E. Hemann, Androgens. In: Steroid Biochemistry,
2012, 14, 4518; (l) Z.-X. Jia, Y.-C. Luo, Y. Wang, L. Chen,
P.-F. Xu and B.-H. Wang, Chem.–Eur. J., 2012, 18, 12958;
(m) J. Xiao, Y.-P. Lu, Y.-L. Liu, P.-S. Wong and T.-P. Loh,
Academic Press, London, 1970; (b) G. Gordon,
M. C. Mackow and H. R. Levy, Arch. Biochem. Biophys.,
1995, 318, 25.
Org. Lett., 2011, 13, 876; (n) L. Lykke, D. Monge, M. Nielsen 11 F. L. Bideau and S. Dagorne, Chem. Rev., 2013, 113, 7793.
and K. A. Jørgensen, Chem.–Eur. J., 2010, 16, 13330; (o) 12 For some selected references of empirical discoveries in this
D. Enders, C. Wang and A. Greb, Adv. Synth. Catal., 2010,
352, 987.
area, see: (a) C. M. R. Volla, I. Atodiresei and M. Rueping,
Chem. Rev., 2014, 114, 2390; (b) A. Moyano and R. Rios,
ˇ
Chem. Rev., 2011, 111, 473; (c) A. Tsybizova, M. Remes,
6 (a) S. Indumathi, J. C. Menendez and S. Perumal, Curr. Org.
Chem., 2013, 17, 2038; (b) S. K. Panday, Tetrahedron:
Asymmetry, 2011, 22, 1817; (c) L.-W. Xu and Y.-X. Lu, Org.
Biomol. Chem., 2008, 6, 2047; (d) H. Kotsuki, H. Ikishima
and A. Okuyama, Heterocycles, 2008, 75, 757.
7 (a) M. Marigo, T. C. Wabnitz, D. Fielenbach and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 794; (b)
Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew.
Chem., Int. Ed., 2005, 44, 4212.
´
´
J. Vesel´y, S. Hybelbauerova and J. Roithova, J. Org. Chem.,
2014, 79, 1563; (d) K. Xu, S. Zhang, Y.-B. Hu, Z.-G. Zha and
Z.-Y. Wang, Eur. J. Org. Chem., 2013, 19, 3573; (e) Z. Tang,
F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang
and Y.-D. Wu, J. Am. Chem. Soc., 2013, 125, 5262; (f)
R. J. Reddy, H. H. Kuan, T. Y. Chou and K. Chen, Chem.–
Eur. J., 2009, 15, 9294; (g) S. Mukherjee, J. W. Yang,
S. Huffman and B. List, Chem. Rev., 2007, 107, 5471; (h)
S. Pedatella, M. D. Nisco, D. Mastroianni, D. Naviglio,
A. Nucci and R. Caputo, Adv. Synth. Catal., 2011, 353, 1443.
8 For selected reviews, see: (a) K. L. Jensen, G. Dickmeiss,
H. Jiang, L. K. Albrecht and K. A. Jørgensen, Acc. Chem.
Res., 2012, 45, 248; (b) L.-W. Xu, L. Li and Z. H. Shi, Adv. 13 For some selected references of computational insights in
Synth. Catal., 2010, 352, 243; (c) A. Mielgo and C. Palomo,
Chem. – Asian J., 2008, 3, 922; (d) C. Palomo and A. Mielgo,
Angew. Chem., Int. Ed., 2006, 45, 7876; (e) Y. He, T.-R. Kang,
Q.-Z. Liu, L.-M. Chen, Y.-L. Tu, Y.-J. Liu, T.-B. Chen,
Z.-Q. Wang, J. Liu., Y.-M. Xie, J.-L. Yang and L. He, Org.
Lett., 2013, 15, 4054.
this area, see: (a) P. H. Y. Cheong, C. Y. Legault, J. M. Um,
¨
¨
N. Çelebi-Olçum and K. N. Houk, Chem. Rev., 2011, 111,
´
5042; (b) C. Palomo, S. Vera, A. Mielgo and E. Gomez-
Bengoa, Angew. Chem., Int. Ed., 2006, 45, 5984; (c)
M. Wiesner, J. D. Revell and H. Wennemers, Angew. Chem.,
Int. Ed., 2008, 47, 1874.
9 For some selected reports in this area, see: (a) Y.-R. Zhou, 14 For some selected references including similar N-protected
¨
chiral catalysts in this area, see: (a) F. Bachle,
J.-F. Dong, F.-L. Zhang and Y.-F. Gong, J. Org. Chem., 2011,
76, 588; (b) Y.-R. Zhou, Y.-Q. Zhu, S.-B. Yan and Y.-F. Gong,
Angew. Chem., Int. Ed., 2013, 52, 10265; (c) L. Wang, J. Liu,
T. Miao, W. P. Zhou, H. Li, K. Ren and X. L. Zhang, Adv.
Synth. Catal., 2010, 352, 2571; (d) S. Pedatella, M. D. Nisco,
D. Mastroianni, D. Naviglio, A. Nucci and R. Caputoa, Adv.
´
J. Duschmale, C. Ebner, A. Pfaltz and H. Wennemers,
Angew. Chem., Int. Ed., 2013, 52, 12619; (b) Y. Arakawa,
M. Wiesner and H. Wennemers, Adv. Synth. Catal., 2011,
353, 1201; (c) R.-S. Luo, J. Weng, H.-B. Ai, G. Lu and
A. S. C. Chan, Adv. Synth. Catal., 2009, 351, 2449; (d)
˜´
Synth. Catal., 2011, 353, 1443; (e) A. Banon-Caballero,
´
J. Duschmale, J. Wiest, M. Wiesner and H. Wennermers,
´
G. Guillena and C. Najera, J. Org. Chem., 2013, 78, 5349; (f)
Chem. Sci., 2013, 4, 1312; (e) L. Zhao, J.-F. Shen, D.-L. Liu,
Y.-G. Liu and W.-B. Zhang, Org.Biomol. Chem., 2012, 10,
2840; (f) Y.-Q. Cheng, Z. Bian, Y.-B. He, F.-S. Han,
C.-Q. Kang, Z.-L. Ning and L.-X. Gao, Tetrahedron:
Asymmetry, 2009, 20, 1753; (g) M. Wiesner and
H. Wennemers, Synthesis, 2010, 9, 1568.
C. G. Kokotos, J. Org. Chem., 2012, 77, 1131; (g) N. Hara,
R. Tamura, Y. Funahashi and S. Nakamura, Org. Lett.,
2011, 13, 1662; (h) R. J. Reddy, H.-H. Kuan, T.-Y. Chou and
K. Chen, Chem.–Eur. J., 2009, 15, 9294; (i) A. F. Torre,
D. G. Rivera, M. A. B. Ferreira, A. G. Correa and
M. W. Paixao, J. Org. Chem., 2013, 78, 10221; (j) K. Akagawa 15 S. Kamijo, S. Matsumura and M. Inoue, Org. Lett., 2010, 12,
and K. Kudo, Angew. Chem., Int. Ed., 2012, 51, 12786; (k) 4195.
C. A. Wang, Z. K. Zhang, T. Yue, Y. L. Sun, L. Wang, 16 W. G. Kerr and J. D. Chisholm, WO2011/127465 A2, 2011.
W. D. Wang, Y. Zhang, C. Liu and W. Wang, Chem.–Eur. J., 17 N. Hamilton, M. Dawson, E. E. Fairweather, N. S. Hamilton,
2012, 18, 6718; (l) S. K. Ghosh, Z. L. Zheng and B. Ni, Adv.
Synth. Catal., 2010, 352, 2378; (m) B. G. Wang, B. C. Ma,
Q. Wang and W. Wang, Adv. Synth. Catal., 2010, 352, 2923.
J. R. Hitchin, D. I. James, S. D. Jones, A. M. Jordan,
A. J. Lyons, H. F. Small, G. J. Thomson, I. D. Waddell and
D. J. Ogilvie, J. Med. Chem., 2012, 55, 4431.
30856 | RSC Adv., 2014, 4, 30850–30856
This journal is © The Royal Society of Chemistry 2014