A novel method to access chiral nonnatural 2,4-disubstituted pyrrolidines from aldehydes and nitroolefins only with an α-substituent

Article abstract of DOI:10.1039/c3cc40583d

A series of α-substituted nitroolefins were employed in organocatalytic asymmetric Michael reactions with aldehydes. γ-Nitro carbonyl products were achieved in good yields (up to 86%) with good stereoselectivities (up to 96% ee and 24 : 1 dr). Reduction of the nitro group followed by intramolecular reductive amination successfully afforded various novel optically active 2,4-disubstituted pyrrolidine compounds.

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A novel method to access chiral nonnatural
2,4-disubstituted pyrrolidines from aldehydes
Cite this: DOI: 10.1039/c3cc40583d
and nitroolefins only with an a-substituent†
Received 23rd January 2013,
Accepted 26th March 2013
a
b
Bo Zheng,z Hui Wang,z Yong Han,a Changlu Liub and Yungui Peng*a
DOI: 10.1039/c3cc40583d
www.rsc.org/chemcomm
A series of a-substituted nitroolefins were employed in organo-
catalytic asymmetric Michael reactions with aldehydes. c-Nitro
carbonyl products were achieved in good yields (up to 86%) with
good stereoselectivities (up to 96% ee and 24 : 1 dr). Reduction of
the nitro group followed by intramolecular reductive amination
successfully afforded various novel optically active 2,4-disubstituted
pyrrolidine compounds.
Scheme 1 Previous work and this work.
Pyrrolidine, as one of the five-membered heterocycles, is ubiqui-
tous as a core skeleton in many drug candidates and natural
products.1 In addition, a series of chiral organocatalysts containing aldehydes and ketones, and through this approach, optically
a pyrrolidine ring have been developed and successfully employed active 3,4-disubstituted pyrrolidines could be achieved sub-
in many useful asymmetric transformations.2 Because of the sequently (Scheme 1, eqn (1): R2 = alkyl or aryl; R3 = H).5
importance of the chiral pyrrolidine framework, great efforts have Although a,b-disubstituted nitroolefins have also been success-
been devoted towards the development of asymmetric methods for fully applied in the asymmetric Michael reactions with aldehydes
synthesizing novel pyrrolidine derivatives, and thus leading to the (Scheme 1, eqn (1): R2 = aryl; R3 = alkyl),7d,e nitroolefins only with
successful synthesis of chiral 2,3-,3 2,4-,4 3,4-5 or 2,5-6 disubsti- an a-substituent have rarely been used as substrates in asym-
tuted; 2,3,4-,7 2,4,5-8 or 2,3,5-trisubstituted9 and 2,3,4,5-tetrasub- metric catalysis;13 therefore, we were intrigued by the possibility
stituted pyrrolidines.10 Despite the significant advances that have of developing the asymmetric addition of aldehydes to them.
been made in the construction of various chiral substituted The resulting optically active 2,4-disubstituted g-nitro carbonyl
pyrrolidines, the methodology to synthesize chiral pyrrolidines compounds could also be further converted into a wide array of
with nonfunctional 2,4-disubstituents remains rather limited.4a interesting useful synthons such as 1,4-amino alcohols or amino
This challenge stimulated us to develop a novel method for acids, and especially significantly those could be transformed
achieving this target.
Owing to the rich chemistry of the nitro group,11 catalytic eqn (2)). Herein, we wish to report our preliminary results.
asymmetric Michael additions of aldehydes and ketones to The Michael addition reaction of isovaleraldehyde 5a to
into the chiral 2,4-disubstituted pyrrolidines also (Scheme 1,
nitroolefins have attracted much attention. A number of organo- a-substituted nitroolefin 6a was selected as the model reaction
catalysts have been employed for these transformations.12 How- (Table 1). Catalyst 1, (Scheme 2) which had shown excellent
ever, the reactions reported to date have been mainly restricted catalytic performance in the asymmetric reactions of aldehydes
to using b-monosubstituted nitroolefins as acceptors with and ketones with b-substituted nitroolefins,5c gave only moderate
yield (50%) and stereoselectivities (60% ee and 83 : 17 dr) in this
reaction (Table 1, entry 1). This may be explained as illustrated by
Wennemers;7d for b-monosubstituted nitroolefins, the stereocontrol
of the reaction is mainly by the catalyst in the C–C bond formation
step. On the basis of the structure of catalyst 1, introducing sterically
hindered groups –OTBS (2a) and –OTBDPS (2b) at the 4-position
with trans-configuration relative to the existing –CH2NHSO2CF3 at
the 2-position increased the performance: 2a led to 80% yield,
90% ee and 94 : 6 dr, and 2b gave the best enantioselectivity (95% ee)
a School of Chemistry and Chemical Engineering, Southwest University,
Chongqing 400715, P. R. China. E-mail: pengyungui@hotmail.com;
Fax: +86 23-68253157; Tel: +86 23-68253157
b Department of Chemistry and Chemical Engineering, Sichuan University of Arts
and Science, Dazhou 635000, P. R. China
† Electronic supplementary information (ESI) available: Catalyst synthesis, partial
results of reaction condition optimization, the proposed transition state model and
spectroscopic data, enantioselectivity measurements. See DOI: 10.1039/c3cc40583d
‡ These authors contributed equally to this work.
c
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Table
1
Catalytic asymmetric Michael reaction of isovaleraldehyde with
were screened in the reaction, with the best result being
achieved in DMF (see ESI†).
a-substituted nitroolefin under various catalysts and conditionsa
In order to improve the efficiency of the catalytic system,
various acids have been investigated for expediting the reaction
by accelerating the formation of the enamine intermediate
between the catalyst and the substrate. The results demon-
strated that the reaction time could be shortened to 4 h from
24 h in the presence of equal amounts of butyric acid and
catalyst 2b, while giving almost the same yield and stereo-
selectivities as those of the reaction catalyzed by 2b alone
(Table 1, entries 3 and 8). Benzoic acid and p-methoxylbenzoic
acid gave similar good results (Table 1, entries 9 and 10). The
best yield was achieved when p-nitrobenzoic acid was used as
the additive and led to 86% yield with 95 : 5 dr and 94% ee
(Table 1, entry 11). The influence of catalyst loading was also
investigated (Table 1, entries 11–14). In the presence of an
equal amount of p-nitrobenzoic acid, 5 mol% catalyst can give
the same good results—84% yield, 96 : 4 dr and 95% ee—if the
reaction time is extended to 26 h. Upon further reducing the
catalyst load to 2 mol% a very long reaction time (84 h) was
required to maintain a good yield (80%) with the same stereo-
selectivities (Table 1, entry 14). The other reaction conditions
were also optimized and the best ratio of p-nitrobenzoic acid to
2b was 1 : 1; 0 1C was selected as the best reaction temperature
and a 5-fold excess of aldehyde was used (see ESI†).
Entry Cat. (x) Additive
Time (h) Yieldb (%) drc
eec (%)
1
2
3
4
1 (20)
—
—
—
—
24
24
24
24
24
24
24
4
50
80
78
Trace
15
22
26
80
76
80
86
86
84
80
83 : 17 60
94 : 6 90
96 : 4 95
n.d
n.d
28 : 72 28
25 : 75 84
96 : 4 95
95 : 5 94
96 : 4 95
95 : 5 94
95 : 5 94
96 : 4 95
95 : 5 95
2a (20)
2b (20)
2c (20)
n.d
n.d
5
6
7
2d (20) —
3 (20)
4 (20)
—
—
8
9
2b (20) CH3(CH2)2CO2H
2b (20) PhCO2H
4
4
4
10
11
12
13
14
2b (20) p-CH3OC6H4CO2H
2b (20) p-NO2C6H4CO2H
2b (10) p-NO2C6H4CO2H 11
2b (5) p-NO2C6H4CO2H 26
2b (2) p-NO2C6H4CO2H 84
a
Unless specified, reactions were conducted on a 0.2 mmol scale of
nitroolefin in solvent (1 mL) with isovaleraldehyde (2.0 mmol) in the
presence of catalyst and equal equivalence of acid was added
b
c
at 0 1C. Isolated yield. Determined by chiral HPLC analysis.
After the optimal reaction conditions had been established, we
turned our attention to the reaction scope (Table 2). The results
have shown that the asymmetric Michael addition of a variety of
acyclic aldehydes to a-nitroolefin proceeded smoothly to give the
desired products in good yields (60%–80%) with good stereo-
selectivities (91 : 9–96 : 4 dr and 90%–95% ee) (Table 2, entries 1–8).
Table 2 Catalytic asymmetric Michael reaction of aldehydes with a-substituent
nitroolefinsa
Scheme 2 Pyrrolidine-based chiral organocatalysts.
and diastereoselectivity (96 : 4 dr) with 78% yield after 24 h. Replace-
ment of the trifluoromethanesulfonyl (2b) subunit with methane-
sulfonyl (2c) and 4-methylbenzenesulfonyl (2d), respectively, caused
the reactivity to decrease dramatically, with only trace amounts
or 15% yield being obtained (Table 1, entries 4 and 5). This
inferior catalytic performance can be correlated to the decrease
in the hydrogen bond donating ability of the sulfonamide
hydrogen, which is closely linked to acidity and governed by
the electronic nature of the R5 group. In catalyst 2b, with
stronger electron-withdrawing groups (–CF3), both the hydrogen
bond donating ability and the acidity were stronger than those
in 2c and 2d. When the strongly hydrogen bond donating
thiourea (4) was introduced instead of trifluoromethanesulfonyl,
only 26% yield, 84% ee and 25 : 75 dr were achieved (Table 1,
entry 7). When catalyst 3, in which the functional groups of 2b
are exchanged, was employed to promote the reaction, the
Entry R1
R6
Time (h) Yieldb (%)
drc
eec (%)
1
i-Pr
n-C2H5 Ph
n-Pr
Ph
28
20
13
36
20
36
36
36
80 (7aa)
66 (7ba)
62 (7ca)
64 (7da)
62 (7ea)
60 (7fa)
64 (7ga)
64 (7ha)
86 (7ab)
70 (7ac)
86 (7ad)
82 (7ae)
56 (7af)
85 (7ag)
85 (7cg)
96 : 4
93 : 7
95 : 5
91 : 9
92 : 8
94 : 6
91 : 9
91 : 9
94 : 6
94 : 6
99 : 1
93 : 7
95 : 5
89 : 11
80 : 20
95
93
95
90
90
91
90
90
94
92
93
91
98
91
84
2d
3d
4d
5d
6d
7d
8d
9
Ph
n-C4H9 Ph
n-C5H11 Ph
n-C6H13 Ph
n-C7H15 Ph
n-C8H17 Ph
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
n-Pr
n-Pr
Bn
4-CH3OPh 36
10
11
12
13
14e
15e
16f
17e
2-ClPh
3-ClPh
2-BrPh
H
OTBS
OTBS
OTBS
OTBS
30
35
29
60
15
12
12
48
86 (ent-7cg) 79 : 21 ꢀ84
63 (7ig) 86 : 14 70
a
Unless specified, reactions were conducted on a 0.2 mmol scale
reactivity decreased dramatically and only gave 22% yield with nitroolefin in solvent (1 mL) with isovaleraldehyde (1.0 mmol) in the
b
presence of catalyst 2b (5%) and p-nitrobenzoic acid (5%). Isolated
28% ee and 28 : 72 dr (Table 1, entry 6). With the best catalyst
2b in hand, a series of solvents, including hexane, toluene,
c
d
yield. Determined by chiral HPLC analysis. p-Nitrobenzoic acid
e
(50%) was added. Catalyst 2b (10%) and p-nitrobenzoic acid (10%)
f
t-BuOCH3, THF, CH2Cl2, CHCl3, CH3CN, DMF, i-PrOH and CH3OH, were added. ent-2b (10%) was used as catalyst.
c
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reported in the literature.4f To account for the stereochemical
outcome, a catalytic cycle and transition state model was
proposed (see ESI†).
In conclusion, we have developed an asymmetric catalytic
Michael reaction involving aldehydes and a-substituted nitro-
olefins. A variety of g-nitro carbonyl products were afforded in
good yields with good stereoselectivities. To the best of
our knowledge, this is the first report of using a-substituted
nitroolefins in the catalytic asymmetric Michael reaction with
aldehydes for synthesizing optically active 2,4-disubstituted
pyrrolidine compounds.
Notes and references
1 (a) D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435; (b) G. Pandey,
P. Banerjee and S. R. Gadre, Chem. Rev., 2006, 106, 4484.
2 For reviews, see: (a) S. Mukherjee, J. W. Yang, S. Hoffmann and
B. List, Chem. Rev., 2007, 107, 5471; (b) F. Giacalone, M. Gruttadauria,
P. Agrigento and R. Noto, Chem. Soc. Rev., 2012, 41, 2406.
3 (a) M.-Y. Han, Y. Zhang, H.-Z. Wang, W.-K. An, B.-C. Ma, Y. Zhang
and W. Wang, Adv. Synth. Catal., 2012, 354, 2635; (b) A. Feula,
L. Male and J. S. Fossey, Org. Lett., 2010, 12, 5044; (c) S.-S. Jin and
M.-H. Xu, Adv. Synth. Catal., 2010, 352, 3136.
Scheme 3 Synthesis of 2,4-disubstituted pyrrolidines.
4 (a) X.-Q. Shen and S. L. Buchwald, Angew. Chem., Int. Ed., 2010,
49, 564; (b) K. Manna, S.-C. Xu and A. D. Sadow, Angew. Chem., Int.
Ed., 2011, 50, 1865; (c) D. N. Mai and J. P. Wolfe, J. Am. Chem. Soc.,
2010, 132, 12157; (d) H. Ma, K. Liu, F.-G. Zhang, C.-L. Zhu, J. Nie and
J.-A. Ma, J. Org. Chem., 2010, 75, 1402; (e) B. D. Zlatopolskiy, K. Loscha,
P. Alvermann, S. I. Kozhushkov, S. V. Nikolaev, A. Zeeck and
A. De Meijere, Chem.–Eur. J., 2004, 10, 4708; ( f ) J. R. Del Valle and
M. Goodman, J. Org. Chem., 2003, 68, 3923; (g) M. Nevalainen,
P. M. Kauppinen and A. M. P. Koskinen, J. Org. Chem., 2001, 66, 2061.
5 (a) J. M. Betancort and C. F. Barbas III, Org. Lett., 2001, 3, 3737;
a-Nitroolefins with various electron donating and withdrawing
substituents on the phenyl ring were also tested, and were
suitable for the asymmetric Michael addition with isovaler-
aldehyde (Table 2, entries 9–12). The position of the substituent
has some influence on the reactivity, since 2-ClPh gave only
70% yield but 3-ClPh gave 86% yield with almost the same level
of stereoselectivities (94 : 6 dr vs. 99: 1 dr and 92% ee vs. 93% ee)
(Table 2, entries 10 and 11). 2-Nitropropene gave excellent
stereoselectivities (98% ee and 95 : 5 dr), but only a moderate
yield (56%) was achieved (Table 2, entry 13). The nitropropene
tethered functional –OTBS at the 3-position worked well in the
reactions and led to good yields (63%–85%), enantioselectivities
(70%–91% ee) and diastereoselectivities (80 : 20–89 : 11 dr) (Table 2,
entries 14, 15 and 17).
´
(b) N. Ruiz, E. Reyes, J. L. Vicario, D. Badıa, L. Carrillo and U. Uria,
Chem.–Eur. J., 2008, 14, 9357; (c) J. Wang, H. Li, B. Lou, L. Zu, H. Guo
and W. Wang, Chem.–Eur. J., 2006, 12, 4321.
6 G. S. Lemen and J. P. Wolfe, Org. Lett., 2010, 12, 2322.
7 (a) A. Nakamura, S. Lectard, D. Hashizume, Y. Hamashima and
M. Sodeoka, J. Am. Chem. Soc., 2010, 132, 4036; (b) S.-M. Guo,
Y.-J. Xie, X.-Q. Hu and H.-M. Huang, Org. Lett., 2011, 13, 5596;
(c) Y.-J. Xu, S. Matsunaga and M. Shibasaki, Org. Lett., 2010, 12, 3246;
´
(d) J. Duschmale and H. Wennemers, Chem.–Eur. J., 2012, 18,
1111; (e) L.-L. Wang, X.-J. Zhang and D.-W. Ma, Tetrahedron, 2012,
68, 7675.
´
´
´
8 C. Najera, M. de G. Retamosa, M. Martın-Rodrıguez, J. M. Sansano,
In order to demonstrate the synthetic utility of the resultant
Michael addition products, the 2,4-disubstituted g-nitro carbonyl
compound 7aa was treated with Zn/AcOH, and the corresponding
optically active 2,4-disubstituted pyrrolidine 8 was achieved suc-
cessfully by intramolecular reductive amination. Then, we pro-
´
´
A. de Cozar and F. P. Cossıo, Eur. J. Org. Chem, 2009, 5622.
9 (a) M. Weber, S. Jautze, W. Frey and R. Peters, J. Am. Chem. Soc.,
2010, 132, 12222; (b) A. T. Parsons, A. G. Smith, A. J. Neel and
J. S. Johnson, J. Am. Chem. Soc., 2010, 132, 9688; (c) S. Hanessian,
´
´
S. Guesne and E. Chenard, Org. Lett., 2010, 12, 1816; (d) C. Liu and
Y.-X. Lu, Org. Lett., 2010, 12, 2278.
tected the amine by a one-pot reaction with tosyl chloride to afford 10 (a) H. Y. Kim, J.-Y. Li, S. K. Kim and K. S. Oh, J. Am. Chem. Soc., 2011,
133, 20750; (b) T. Arai, A. Mishiro, N. Yokoyama, K. Suzuki and
H. Sato, J. Am. Chem. Soc., 2010, 132, 5338; (c) I. Oura, K. Shimizu,
K. Ogata and S. Fukuzawa, Org. Lett., 2010, 12, 1752; (d) C. Zhang,
the N-tosyl derivative 8 in good overall yields (Scheme 3). Almost
no epimerization and racemization occurred during the proce-
dure of reductive amination. We further carried out the same
reductive amination process with 7cg, ent-7cg and 7ig, followed by
Boc-protection and deprotection of TBS to give 9, ent-9 and 10.
The structure and relative configuration of compound ent-9
were identified using 1H NMR and 13C NMR, its absolute
configuration could be determined by comparison of the
optical rotation data and was found to be in agreement with
that reported in the literature.4f Correlating the ee values of 7cg
with those of ent-7cg and specific rotation data of 9 with those
of ent-9, we concluded that the absolute configurations of 7cg
and 9 were both (2R, 4R). Other product configurations were
deduced based on analogy, which were further verified by
correlating the specific rotation data of 10 with those of ent-10
S.-B. Yu, X.-P. Hu, D.-Y. Wang and Z. Zheng, Org. Lett., 2010,
´
12, 5542; (e) R. Robles-Machın, I. Alonso, J. Adrio and J. C.
Carretero, Chem.–Eur. J., 2010, 16, 5286.
11 N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, Weinheim,
Germany, 2001.
12 (a) H. Pellissier, Recent Developments in Asymmetric Organocatalysis,
Royal Society of Chemistry, 2010; (b) A. Dondoni and A. Massi,
´
Angew. Chem., Int. Ed., 2008, 47, 4638; (c) J. L. Vicario, D. Badıa and
L. Carrillo, Synthesis, 2007, 2065; (d) C. Palomo and A. Mielgo,
Angew. Chem., Int. Ed., 2006, 45, 7876; (e) Z.-W. Sun, F.-Z. Peng,
Z.-Q. Li, L.-W. Zou, S.-X. Zhang, X. Li and Z.-H. Shao, J. Org. Chem.,
2012, 77, 4103; ( f ) Z.-L. Zheng, B. L. Perkins and B. Ni, J. Am. Chem.
Soc., 2010, 132, 50; (g) R. Imashiro, H. Uehara and C. F. Barbas III,
Org. Lett., 2010, 12, 5250.
13 (a) K. L. Kimmel, J. D. Weaver, M. Lee and J. A. Ellman, J. Am. Chem.
Soc., 2012, 134, 9058; (b) B. D. Chandler, J. T. Roland, Y.-K. Li and
E. J. Sorensen, Org. Lett., 2010, 12, 2746.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.