N-Pyrrolidine-2-ylmethyl)-2-hydroxy-3-aminopinanes as novel organocatalysts for asymmetric conjugate additions of ketones to α-nitroalkenes

Article abstract of DOI:10.1016/j.tetasy.2013.05.012

Novel stereoisomeric natural pinane-derived bifunctional catalysts 3a-d bearing a pyrrolidine unit have been synthesized and examined in the asymmetric conjugate additions of carbonyl compounds to α-nitroalkenes. Six-membered cyclic ketones react with β-n

Full text of DOI:10.1016/j.tetasy.2013.05.012

Tetrahedron: Asymmetry 24 (2013) 776–779
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Tetrahedron: Asymmetry
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N-Pyrrolidine-2-ylmethyl)-2-hydroxy-3-aminopinanes as novel
organocatalysts for asymmetric conjugate additions of ketones to
a-nitroalkenes
Dmitry E. Siyutkin a, Alexander S. Kucherenko a, Larisa L. Frolova b, Alexander V. Kuchin b, Sergei G. Zlotin a,
⇑
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prosp. 47, 119991 Moscow, Russian Federation
b Institute of Chemistry Komi SC, Ural Department Russian Academy of Sciences, Pervomayskaya St., Komi Rep. 48, 167610 Syktyvkar, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 April 2013
Accepted 22 May 2013
Novel stereoisomeric natural pinane-derived bifunctional catalysts 3a–d bearing a pyrrolidine unit have
been synthesized and examined in the asymmetric conjugate additions of carbonyl compounds to
nitroalkenes. Six-membered cyclic ketones react with b-nitrostyrene derivatives in the presence of
(1R,2R,3R,5R)-2-hydroxy-3-((S)-pyrrolidin-2-ylmethylamino) pinane 3b (10 mol %) with high conversion
to afford with diastereoselectivity (dr (syn/anti) up to 97/3), the corresponding Michael adducts with
enantiomeric purities of up to 88% ee.
a
-
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
fragment of natural origin (Fig. 1) could efficiently catalyze asym-
metric aldol reactions between aldehydes and ketones in aqueous
Asymmetric conjugate additions of C-nucleophiles to electron-
deficient alkenes (the Michael reaction) are a convenient method
for the enantioselective formation of C–C bonds in organic com-
pounds. When performed in the presence of chiral organocatalysts
(commonly chiral amine derivatives), the reactions give complex
products with high enantiomeric purity from simple achiral sub-
strates (ketones, aldehydes, acrylates, nitroalkenes, etc.).1 They
were successfully applied to key stereocontrolling steps in the
enantioselective synthesis of the most active enantiomers of chiral
biologically active compounds and natural products.2 In particular,
precursors of clinically useful medications, such as the antidepres-
sant venlafaxine,3a alkaloid (ꢀ)-pancracine,3b antibiotic (ꢀ)-bot-
media.6 However, prolinamide derivatives, catalysts of choice for
asymmetric aldol reactions, as a rule, exhibit poor activity and a
lower level of stereoinduction in asymmetric Michael reactions.7
On the other hand, camphor-derived b-hydroxyamine 2 efficiently
catalyzed the asymmetric conjugate additions of carbonyl com-
pounds to
a-nitroalkenes, which yielded the corresponding Mi-
chael adducts with excellent high stereocontrol.5 Therefore we
decided to transform compounds 1a–d to their more nucleophilic
pyrrolidine analogues 3a–d and examine their catalytic perfor-
mance in the asymmetric additions of carbonyl compounds to
nitroalkenes.
a-
ryodiplodin3c
,
and others3d–h were synthesized by the
-nitroalkenes.
2. Results and discussion
asymmetric addition of carbonyl compounds to
a
Proline,4a pyrrolidine4b–e, and bipyrrolidine derivatives,4f–h diph-
enyldiaminoethane-4i or 1,2-diaminocyclohexane-derived thio-
ureas4j,k and other chiral amines4l–n are suitable catalysts for
these reactions. The presence of properly positioned hydroxyl
The so far unknown isomeric 2-hydroxy-3-[(2-pyrrolidi-
nyl)methylamino] pinanes 3a–d with a different configuration of
stereocenters at C-2 and C-3 were synthesized by the reduction
of the corresponding hydroxyamides 1a–d with LiAlH4 (Scheme 1).
Compounds 1a and 1b bearing trans-located amido and hydroxyl
groups were refluxed in THF with four equivalents of LiAlH4 for
8 h and afforded the corresponding diamines 3a and 3b in 79–
82% yields. The cis-isomers 1c and 1d were less active in this reac-
tion: a larger excess of the reducing agent (8 equiv) and more pro-
longed heating of the reaction mixtures (56 h) were required for
the reactions to complete. Isolated yields of the corresponding
reduction products 3c and 3d were 65–68% in this case. Presum-
ably, the different activities of cis- and trans-isomeric compounds
1 in these studied reactions could be explained by the formation
and amino groups capable of coordinating with the a-nitroalkene
molecule via hydrogen bonds in the pyrrolidine-derived chiral cat-
alysts may contribute to effective stereocontrol in the enamine
transition state.5
We have recently discovered that bifunctional prolinamide
derivatives 1a-d bearing a rigid bicyclic 2-hydroxy-3-amidopinane
⇑
Corresponding author. Tel.: +7 (499) 1371353; fax: +7 (499) 1355328.
E-mail address: zlotin@ioc.ac.ru (S.G. Zlotin).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.012

D. E. Siyutkin et al. / Tetrahedron: Asymmetry 24 (2013) 776–779
Me
Me
777
Me
Me
Me
Me
Me
Me
Pro
Pro
Pro
Pro
N
N
N
N
H
H
H
H
Me
Me
Me
Me
HO
1c
HO
1d
HO
1a
HO
1b
Me
O
N
1a-d: Pro =
Me
H
NH
NH
HO
2
Figure 1. Known bifunctional organocatalysts of asymmetric aldol and Michael reactions with natural rigid polycyclic skeletons.
5
Me
Me
Me
Me
O
LiAlH4
THF
3
N
H
N
H
1
2
NH
1a-d
NH
Me
Me
HO
3a-d
HO
Me
Me
(R)
(S)
Me
Me
(S)
(R)
Me
Me
Me
Me
(S)
(S)
(R)
(R)
(S)
(R)
(S)
(R)
(R)
(S)
(R)
(S)
N
H
N
H
(S)
N
N
H
(S)
(S)
(S)
Me
Me
H
Me
Me
NH
NH
OH
OH
NH
NH
OH
OH
3c 65%
3b 82%
3a 79%
3d 68%
Scheme 1. Synthesis of isomeric pinane-derived 2-(aminomethyl)pyrrolidine catalysts 3a–d.
of a complex between LiAlH4 and the compounds containing cis-lo-
cated amido- and hydroxy groups, which impeded further
reduction.
At first, we compared the catalytic performance of isomeric pi-
nane-derived 2-(aminomethyl)pyrrolidine catalysts 3a–d in the
model Michael reaction between cyclohexanone 4a and 4-meth-
oxy-b-nitrostyrene 5a (Table 1). The reactions were carried out in
THF at ambient temperature for 24 h and the 4a/5a ratio was
of the HPLC data for compound 6a and the major product of the
corresponding proline-catalyzed reaction 4a. The same stereo-
chemical outcome of the reactions studied may be due to the same
configuration of the key (S)-proline pyrrolidine stereocenters in
diastereomeric catalysts 3a–d.
Next, in order to optimize the reaction conditions, we studied
the 3b-catalyzed reaction between compounds 4a and 5a in var-
ious organic solvents and water (the solvent/ketone ratio was 3:1
v/v) (Table 2). The conversion was poor (<5%) in the presence of
water, presumably because of the heterogeneous nature of
the system where the hydrophilic catalyst and hydrophobic re-
agents are located in different phases. Among organic solvents,
relatively higher ee values were attained in THF, methanol,
and DMF from which the THF medium was chosen as the solvent
5:1. In all cases, the syn-isomer of c-nitroketone 6a was generated
enantioselectively as the main product (1H NMR data) and the
corresponding conversion and diastereoselectivity values were
excellent. The best enantiomeric enrichment of product 6a (81%
ee) was attained in the reaction where (1R,2R,3R,5R)-2-hydroxy-
3-aminopinane 3b was used as the organocatalyst. The absolute
configuration of (S)-2-((R)-1-(4-methoxyphenyl)-2-nitroethyl)
cyclohexanone was assigned to adduct 6a based on the similarity
of choice due to
diastereoselectivity.
a
faster reaction course and higher
Table 1
Asymmetric Michael reaction between 4a and 5a in the presence of isomeric pinane-derived 2-(aminomethyl)pyrrolidine catalysts 3a–da
O
OMe
O
O2N
(S)
(R)
3a-d (10 mol %)
+
THF, RT, 24 h
OMe
NO2
4a
5a
6a
Catalyst
Conversion (%)b
drb (syn/anti)
eec (syn)
3a
3b
3c
3d
95
99
92
90
93/7
94/6
93/7
94/6
60
81
66
68
a
b
c
Reactions were carried out at a molar ratio of 5:1 4a:5a.
1H NMR data for crude 6a.
Chiral HPLC data.

778
D. E. Siyutkin et al. / Tetrahedron: Asymmetry 24 (2013) 776–779
Table 2
3. Conclusion
3b-Catalyzed asymmetric reaction between 4a and 5a in various solventsa
O
OMe
We have synthesized some novel stereoisomeric natural pi-
nane-derived bifunctional catalysts 3a–d bearing the pyrrolidine
unit for asymmetric Michael reactions. In the presence of
(1R,2R,3R,5R)-2-hydroxy-3-((S)-pyrrolidin-2-ylmethylamino) pi-
O
NO2
3b (10 mol %)
+
solvent,
MeO
RT, 24 h
NO2
4a
5a
6a
nane 3b (10 mol %), six-membered cyclic ketones reacted with a-
nitroalkenes to afford the corresponding chiral adducts with high
diastereoselectivity (dr (syn/anti) up to 97/3) and enantiomeric ex-
cesses of up to 88%.
Solvent
Conversionb (%)
drb (syn/anti)
eec (syn)
THF
>99
43
91
53
64
37
92
<5
95/5
95/5
92/8
97/3
93/7
96/4
90/10
n.d.
81
71
75
79
83
73
82
n.d.
PhMe
MeCN
Hexane
MeOH
CHCl3
DMF
4. Experimental
4.1. General
H2O
a
Reactions were carried out at a molar ratio of 5:1 4a:5a in the corresponding
The NMR spectra were recorded on a Bruker AM300 NMR spec-
trometer (300.13 MHz for 1H, 75.5 MHz for 13C) in CDCl3. Chemical
shifts are given in ppm and referenced to an internal TMS standard
for 1H and CDCl3 for 13C. Elemental analyses were conducted on a
Perkin–Elmer 2400 microanalyzser. The high resolution mass spec-
tra (HRMS) were measured on Bruker microTOF II using electro-
spray ionization (ESI). The measurements were carried out in a
positive ion mode (interface capillary voltage 4500 V); mass range
from m/z 50 to m/z 3000 Da; either external or internal calibration
was done with Electrospray Calibrant Solution (Fluka). A syringe
was used to inject the solution in methanol (flow rate 3 mL/min).
Nitrogen was applied as a dry gas; interface temperature was set
at 180 °C. The IR spectra (KBr pellets) were recorded with Specord
solvent (0.15 mL).
b
1H NMR data for crude 6a.
c
Chiral HPLC data.
Various cyclic ketones 4 and b-nitroalkenes 5 appeared to be
suitable starting compounds for 3b-catalyzed asymmetric Michael
reactions under the optimal conditions (Table 3). b-Nitrostyrene
5b, its analogues 5c–e and 1-thienyl-2-nitroethylene 5f reacted
with cyclohexanone 4a in the presence of pinane-derived 2-(ami-
nomethyl)pyrrolidine catalyst 3b to afford the corresponding chi-
ral adducts 6b–f with high conversion, diastereo- (dr syn/anti 94/
6–97/3), and enantioselectivity (81–87% ee). Under similar condi-
tions, heterocyclic ketones 4b and 4c reacted with b-nitrostyrene
5b stereoselectively (dr syn/anti 94/6–97/3) to yield the enantio-
merically enriched (75–79% ee) derivatives of corresponding het-
erocycles 6h,i. 1,4-Cyclohexanedione monoethylene-acetal 4d
and cyclopentanone 4e appeared to be nearly inactive in the stud-
ied reaction. In the presence of catalyst 3b, acetone 4f added to b-
nitrostyrene 5b and afforded chiral adduct 6k with complete con-
version (98% after 24 h) but with poor enantiomeric purity (40%
ee).
M82. Optical rotations ½a DT
ꢁ
were measured with a Jasco DIP-360
polarimeter at 589 nm. The dr values of the Michael adducts were
evaluated by 1H NMR spectra. Enantiomeric excess values (ee) of
the Michael adducts were determined by HPLC on a Stayer chro-
matograph with the chiral phase Chiralcel OD-H, OJ-H, or Chiralpak
AD-H. Racemic forms of the corresponding Michael adducts were
obtained with pyrrolidine in a THF solution. Silica gels 0.060–
0.200 and 0.035–0.070 nm (Acros) were used for column chroma-
tography. Solvents were purified by standard methods.
4.2. General procedure for the synthesis of catalysts 3a–d
Table 3
The corresponding amide 1a–d (1a: 0.64 g/2.40 mmol; 1b:
1.20 g/4.51 mmol; 1c: 1.035 g/3.89 mmol; 1d: 1.03 g/3.87 mmol)
was gradually added for 5 min to an LiAlH4 suspension (1a:
0.366 g/9.60 mmol; 1b: 0.686 g/18.05 mmol; 1c: 1.183 g/
31.12 mmol; 1d: 1.176 g/30.96 mmol) in dry THF (25/45/40/
40 mL) and the reaction mixture was refluxed for 8 h (3a,b) or
56 h (3c,d) (1H NMR control). After completion of the reaction,
10% aq. NaOH solution was gradually added to the reaction mix-
ture until the exothermic reaction subsided. The resulting mixture
was further refluxed for 10–20 min (it turned from graey to white)
and cooled to ambient temperature. Solid materials were filtered
off and washed with THF (2 ꢂ 20 mL). The combined filtrates were
rotary-evaporated and the residue was dried in vacuo (0.15 Torr)
for 5 h to afford compounds 3a–d in 79%, 82%, 65%, and 68% yields
respectively.
Scope of the 3b-catalyzed asymmetric Michael reactiona
O
O
R3
NO2
3b (10 mol %)
NO2
R3
+
THF, RT, 24 h
R1
4a-f
R2
R1
R2
6a-k
5a-f
Entry R1, R2
4
R3
5
6
Conversionb drb
eec
(%)
(syn/ (syn)
anti)
7
1
8
9
10
11
3d
4d
5d
2d
6
–(CH2)3– a
–(CH2)3– a
–(CH2)3– a
–(CH2)3– a
–(CH2)3– a
–(CH2)3– a
–CH2OCH2– b
–CH2SCH2– c
4-MeOC6H4
Ph b
a
a
b
c
d
e
f
99
96
92
98
92
95
82
89
94/6 81
92/8 78
95/5 87
97/3 88
94/6 85
96/4 84
94/6 75
97/3 79
n.d. n.d.
n.d. n.d.
4-ClC6H4
c
2-NO2C6H4
2,4-Cl2C6H3
2-thienyl f
Ph b
d
e
h
i
Ph b
–CH2C(O(CH2)2O)CH2– d Ph b
j
<10
<10
98
4.2.1. (1S,2S,3S,5S)-2,6,6-Trimethyl-3-((S)-pyrrolidin-2-
–(CH2)2– e
H, H f
Ph b
Ph b
g
k
ylmethylamino)bicyclo[3.1.1]heptan-2-ol 3a
—
40
Pale-yellow oil. ½a D25
ꢁ
¼ þ20:7 (c 1.0, CHCl3). 1H NMR (CDCl3): d
a
Reactions were carried out with 4 (0.5 mmol), 5 (0.1 mmol), and catalyst 3b
0.89 (s, 3H), 1.25 (s, 3H), 1.33 (s, 3H), 1.15–1.45 (m, 2H), 1.60 (d,
J = 10.3 Hz, 1H), 1.66–1.78 (m, 2H), 1.82–1.95 (m, 2H), 2.03–2.19
(m, 2H), 2.21–2.37 (m, 1H), 2.60–2.79 (m, 2H), 2.82–3.00 (m,
2H), 3.11 (t, J = 9.0 Hz, 1H), 3.19–3.29 (m, 1H) ppm. 13C NMR
(0.01 mmol) in THF (0.15 mL).
b
1H NMR data for crude 6a.
Chiral HPLC data (Chiralcel OD-H, OJ-H, or Chiralpak AD-H).
Reactions were carried out for 48 h.
c
d

D. E. Siyutkin et al. / Tetrahedron: Asymmetry 24 (2013) 776–779
779
(CDCl3): d 23.1, 24.7, 24.8, 25.5, 27.7, 29.6, 32.9, 40.2, 46.2, 52.9,
55.4, 58.1, 60.3, 62.0, 73.5 ppm. Anal. calcd for C15H28N2O: C,
71.38; H, 11.18; N, 11.10, found: C, 71.47; H, 11.22; N, 11.07. IR
mixture was stirred for 24 h unless other conditions were specified
(Table 3). The solvent was evaporated and EtOAc (8 mL) was added
to the residue. The resulting solution was filtered through a silica
gel pad (ꢃ1 g) and rotary-evaporated to afford crude adducts 6,
which were purified by column chromatography (Silica Gel,
0.035–0.070 nm, eluent: hexane/EtOAc 4:1–3:1).
(m
, cmꢀ1): 902, 1071, 1367, 2921, 3266.
4.2.2. (1R,2R,3R,5R)-2,6,6-Trimethyl-3-((S)-pyrrolidin-2-ylmeth-
ylamino)bicyclo[3.1.1]heptan-2-ol 3b
Pale-yellow oil. ½a D25
ꢁ
¼ ꢀ24:9 (c 1.0, CHCl3). 1H NMR (CDCl3): d
Acknowledgements
0.89 (s, 3H), 1.26 (s, 3H), 1.33 (s, 3H), 1.19–1.45 (m, 2H), 1.59 (d,
J = 10.3 Hz, 1H), 1.64–1.80 (m, 2H), 1.80–2.04 (m, 3H), 2.05–2.17
(m, 1H), 2.22–2.36 (m, 1H), 2.49–2.60 (m, 1H), 2.80 (dd,
J1 = 11.7 Hz, J2 = 4.0 Hz, 1H), 2.85–3.00 (m, 2H), 3.07 (t, J = 9.0 Hz,
1H), 3.16–3.27 (m, 1H) ppm. 13C NMR (CDCl3): d 23.1, 24.7, 25.0,
25.5, 27.7, 29.7, 33.3, 38.9, 40.2, 46.2, 54.0, 55.4, 59.2, 61.6,
77.3 ppm. Anal. calcd for C15H28N2O: C, 71.38; H, 11.18; N, 11.10,
This work was supported by the Russian Foundation of Basic
Research (Grant No. 12-03-31805), the Ural Branch of Russian
Academy of Sciences (Grant No. 12-U-3-1015), and the President
of the Russian Federation (Grant for young Ph.D. No. 3551.2012.3).
References
found: C, 71.43; H, 11.20; N, 11.08. IR (
2921, 3266.
m
, cmꢀ1): 902, 1071, 1367,
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0.96 (s, 3H), 1.26 (s, 3H), 1.44 (s, 3H), 1.15–1.54 (m, 2H), 1.61–
2.00 (m, 6H), 2.08–2.31 (m, 2H), 2.41–2.53 (m, 1H), 2.59–2.72
(m, 1H), 2.76–3.03 (m, 3H), 3.11–3.27 (m, 1H) ppm. 13C NMR
(CDCl3): d 24.0, 25.4, 27.9, 29.4, 30.0, 31.3, 37.8, 40.4, 46.3, 54.1,
55.0, 57.6, 58.3, 62.1, 71.9 ppm. Anal. calcd for C15H28N2O: C,
71.38; H, 11.18; N, 11.10, found: C, 71.52; H, 11.24; N, 11.03. IR
(m
, cmꢀ1): 902, 1071, 1367, 2921, 3266.
4.2.4. (1R,2R,3S,5R)-2,6,6-Trimethyl-3-((S)-pyrrolidin-2-ylmeth-
ylamino)bicyclo[3.1.1]heptan-2-ol 3d
Pale-yellow oil. ½a D25
ꢁ
¼ þ25:0 (c 1.0, CHCl3). 1H NMR (CDCl3): d
0.95 (s, 3H), 1.26 (s, 3H), 1.42 (s, 3H), 1.13–1.50 (m, 2H), 1.62–
2.00 (m, 6H), 2.07–2.32 (m, 2H), 2.40–2.72 (m, 3H), 2.80–2.89
(m, 1H), 2.89–2.96 (m/d, 1H), 3.19–3.22 (m, 1H) ppm. 13C NMR
(CDCl3): d 24.0, 25.8, 27.9, 28.0, 30.0, 31.3, 37.6, 40.4, 46.4, 54.2,
55.6, 57.8, 58.5, 62.1, 71.5 ppm. Anal. calcd for C15H28N2O: C,
71.38; H, 11.18; N, 11.10, found: C, 71.50; H, 11.25; N, 11.03. IR
(m
, cmꢀ1): 902, 1071, 1367, 2921, 3266.
4.3. General procedure for the asymmetric Michael reaction
Ketone 4 (0.5 mmol) and -nitroalkene 5 (0.1 mmol) were
6. Siyutkin, D. E.; Kucherenko, A. S.; Kuchin, A. V.; Frolova, L. L.; Zlotin, S. G.
Tetrahedron: Asymmetry 2011, 22, 1320–1324.
7. (a) Rodriguez-Llansola, F.; Miravet, J. F.; Escuder, B. Chem. Eur. J. 2010, 16, 8480–
8486; (b) Clarke, M. L.; Fuentes, J. A. Angew. Chem., Int. Ed. 2007, 46, 930–933.
a
added to the solution or suspension of catalyst 3a–d (2.5 mg, 0.
01 mmol) in the corresponding solvent (0.15 mL). The reaction