Enantioselective synthesis of 2-substituted pyrrolidines via domino cross metathesis/intramolecular aza-Michael addition

Article abstract of DOI:10.1039/c2ra22374k

A highly enantioselective intramolecular aza-Michael addition with enone carbamates catalyzed by chiral Bronsted acids was developed. A domino cross metathesis/aza-Michael addition for the preparation of 2-substituted pyrrolidines or benzopyrrolidines was also explored. The reactions described here provide an efficient asymmetric protocol for enantio-enriched heterocycles, especially 2-substituted pyrrolidines.

Full text of DOI:10.1039/c2ra22374k

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Enantioselective synthesis of 2-substituted pyrrolidines
via domino cross metathesis/intramolecular aza-
Michael addition3
Cite this: RSC Advances, 2013, 3, 1666
Received 2nd October 2012,
Accepted 29th November 2012
Hanbin Liu, Chuanqi Zeng, Jiajia Guo, Mengyao Zhang and Shouyun Yu*
DOI: 10.1039/c2ra22374k
www.rsc.org/advances
aromatic enone carbamates were even worse and only one of this
kind of substrates did not give the desired Michael adduct in both
papers.6
A highly enantioselective intramolecular aza-Michael addition
with enone carbamates catalyzed by chiral Brønsted acids was
developed. A domino cross metathesis/aza-Michael addition for
the preparation of 2-substituted pyrrolidines or benzopyrrolidines
was also explored. The reactions described here provide an
efficient asymmetric protocol for enantio-enriched heterocycles,
especially 2-substituted pyrrolidines.
Recently, we have engaged in the synthesis of the phenan-
throindolizidine and phenanthroquinolizidine alkaloids via orga-
nocatalytic intramolecular aza-Michael addition. We have
synthesized several phenanthroquinolizidine alkaloids using a
modified version of Fan and Fustero’s methodology.8 However we
failed to synthesize phenanthroindolizidine alkaloids enantiose-
lectively by using a similar strategy (Table 1). The intramolecular
aza-Michael addition of 1a catalyzed by the TFA salt of quinine
derived primary amine 3a could give the desired product 2a in
good yield but in almost a racemic form (entry 1). An improved er
Michael addition represents one of the most important methods
for the formation of carbon–carbon bonds in organic synthesis.1
Aza-Michael addition has been intensely investigated as a powerful
carbon–nitrogen bond formation reaction in the preparation of
amines and nitrogen heterocyclic compounds.2 Due to the strong
Lewis basicity of nitrogen, organometallic catalyzed aza-Michael
addition remains a challenging task. This inherent problem could
be addressed by organocatalysis. Since being pioneered by
MacMillan and co-workers,3 organocatalytic aza-Michael addition
received intense attention.2a–c Its intramolecular variants, which
are efficient strategies for the preparation of chiral nitrogen
heterocycles, were firstly reported by Takasu and Ihara, but with
moderate enantioselectivity (up to 53% ee).4 The highly enatiose-
lective intramolecular aza-Michael addition of enal carbamates
catalyzed by TMS-prolinol derivatives was elaborated by Fustero
and Carter independently.5 In 2011, the Fan6a and Fustero6b
groups independently described intramolecular aza-Michael addi-
tion of enone carbamates catalyzed by quinine derived primary
amines. Great success has been achieved in the preparation of
2-substituted piperidines with unsaturated aliphatic ketones while
reactions with unsaturated aromatic ketones were less efficient
giving lower yields and ee values. Limited success has been
achieved in the preparation of 2-substituted pyrrolidines7 via this
protocol (less than 80% ee). The reactions with electron-rich
Table 1 Reaction optimizationa
Entry
Cat.
Solvent
Temp./uC
Time/h
Yield/%b
erc
1
2
3
4
5
6
7
8
9
3a
3a
3b
3c
3c
3c
3c
3d
3d
THF
rt
rt
rt
rt
rt
0
220
0
220
30
24
24
0.5
1
0.5
0.5
3
80
85
83
95
89
92
94
95
93
44/56
38/62
42/58
8/92
9/91
8/92
9/91
91/9
94/6
CH2Cl2
PhCH3
PhCH3
THF
PhCH3
PhCH3
PhCH3
PhCH3
State Key Laboratory of Analytical Chemistry for Life Science, Institute of Chemical
Biology and Drug Innovation, School of Chemistry and Chemical Engineering,
Nanjing University, 22 Hankou Road, Nanjing 210093, China.
18
a
E-mail: yushouyun@nju.edu.cn http://hysz.nju.edu.cn/yusy
Reaction conditions: a mixture of 1a (0.5 mmol) and catalyst 3
Electronic supplementary information (ESI) available: Experimental procedures
(0.05 mmol) in solvent (2 mL) was stirred for the indicated time at
the indicated temperature. Isolated yield. The er value was
determined by HPLC on a chiral stationary phase.
3
b
c
and characterization and copies of NMR for all new compounds.. See DOI: 10.1039/
c2ra22374k
1666 | RSC Adv., 2013, 3, 1666–1668
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value (38/62) could be achieved when the solvent was changed
from THF to CH2Cl2, but it was still not synthetically useful (entry
2). So we had to find a more efficient catalyst for this
transformation. During the previous investigations, we found that
TFA itself could catalyze this reaction, which suggested that chiral
Brønsted acids may be the solution to this problem.9 We next
tested BINOL-derived phosphoric acid 3b. To our delight, the
desired product could be isolated in good yield although with a
low er value (42/58) (entry 3). When (R)-TRIP (3c)10 was employed,
the reaction completed in 0.5 h with high enantioselectivity (8/92
er) and excellent yield (95%) (entry 4). Further screening of
temperature and solvent did not give improved results (entries 5–
7). The best result could be achieved (93% yield and 94/6 er) when
the reaction was catalyzed by (S)-phosphoric acid 3d11 in toluene at
220 uC (entry 9).
With the optimized conditions in hand, the reaction was next
applied to a variety of enone carbamates as shown in Table 2. All
the substrates we tested worked quite well to give 2-substituted
pyrrolidines in good yield and high enantioselectivity. The Cbz-
protected carbamates were proved to be more suitable for this
transformation than their Boc-protected counterparts (2a vs. 2b, 2i
vs. 2j). a,b-Unsaturated aliphatic ketones turned out to be more
efficient (up to 98/2 er) in this reaction than aromatic ketones.
Different substituents on the aromatic ring did not affect this
reaction significantly. Electron-rich, poor or neutral aromatic
ketones gave comparable result (2b–2h).
The precursors of Michael addition were prepared through
cross metathesis and the yields for these precursors were not
always satisfactory (see ESI ). So we next tried to improve the
3
overall efficiency of the preparation of 2-substituted pyrrolidines
via domino reactions.12 Recently, Fustero and co-workers reported
diastereoselective domino cross metathesis/aza-Michael additions
catalyzed by ruthenium complexes and Lewis acids to provide
heterocyclic compounds.13 Additionally You’s group also described
an elegant enantioselective domino cross metathesis/aza-Michael
addition of indoles promoted by the cooperation of a chiral
phosphoric acid and a ruthenium complex.14 Inspired by these
works, we conducted domino cross metathesis/aza-Michael
addition of enecarbamate 4b and methyl vinyl ketone 5a
(Table 3). After a quick screening, we were pleased to find that
the domino reaction could be catalyzed by chiral phosphoric acid
3d and Grubbs II catalyst to give pyrrolidine 2j in 80% yield and
93/7 er (entry 1). Phosphoric acid 3c was proved to be more active
but less selective (entry 2). Lowering the temperature to 0 uC could
improve the enantioselectivity but at the sacrifice of the chemical
yield (entry 3). When Hoveyda–Grubbs II catalyst was employed
instead of Grubbs II catalyst, the yield could reach 74% with a
comparable er value (entry 4). With the optimized conditions in
hand, we extended this transformation to a variety of vinyl
ketones. Aliphatic vinyl ketones were suitable substrates for this
domino reaction to give the enantio-enriched 2-substituted
pyrrolidines in acceptable yield and good er value (entries 5–6).
Electron-neutral or rich aromatic vinyl ketones could also undergo
this transformation smoothly (entries 7–8 and 11–12).
4-Chlorophenyl vinyl ketone also worked quite well with 94/6 er
Table 2 Substrate scope for the aza-Michael additiona,b,c
Table 3 Substrate scope for the domino cross metathesis/aza-Michael additiona
Entry
R
Product
Time/h
Yield/%b
erc
1d,e
2d,f
3e
4
5
6
7
8
9
10
11
Me (5j)
Me (5j)
Me (5j)
Me (5j)
Et (5k)
PhCH2CH2 (5l)
Ph (5c)
4-MeOPh (5d)
4-NO2Ph (5e)
4-ClPh (5f)
2j
2j
2j
2j
2k
2l
2c
2d
2e
2f
2g
12
4
80
84
62
74
76
61
76
59
52
60
62
93/7
20/80
96/4
95/5
97/3
96/4
94/6
97/3
87/13
94/6
97/3
12
14
18
20
11
18
36
24
12
12
2h
15
52
92/8
a
Reaction conditions: a mixture of 4b (1.5 mmol), 5 (0.5 mol), 3d
(0.05 mmol) and Hoveyda–Grubbs II (0.025 mmol) in CH2Cl2 (2 mL)
b
c
was stirred for the indicated time at 0 uC Isolated yield. The er
a
d
Reaction conditions: a mixture of 1 (0.5 mmol) and catalyst 3d
value was determined by HPLC on chiral stationary phase. The
e
(0.05 mmol) in toluene (2 mL) was stirred for the indicated time at
reaction carried out at room temperature. Grubbs II catalyst was
b
c
f
220 uC. Isolated yield. The er value was determined by HPLC on
used instead of Hoveyda-Grubbs II catalyst. 3c was used instead of
chiral stationary phase.
3d.
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2 For selected reviews on asymmetric aza-Michael addition, see:
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Scheme 1 Preparation of benzopyrrolidines via the domino cross metathesis/aza-
Michael addition.
3 Y. K. Chen, M. Yoshida and D. W. C. MacMillan, J. Am. Chem.
Soc., 2006, 128, 9328.
4 K. Takasu, S. Maiti and M. Ihara, Heterocycles, 2003, 59, 51.
´
´
´
5 (a) S. Fustero, D. Jimenez, J. Moscardo, S. Catalan and C. del
Pozo, Org. Lett., 2007, 9, 5283; (b) E. C. Carlon, L. K. Rathbone,
H. Yang, N. D. Collett and R. G. Carter, J. Org. Chem., 2008, 73,
value (entry 10). An electron-deficient aromatic ketone was a less
effective substrate in this reaction with lower er value (entries 9).
The procedure could also be used to prepare enantio-enriched
benzopyrrolidine derivatives (Scheme 1). Benzoenecarbamate 6 or
7 could go through this domino transformation with 5j smoothly
to give benzopyrrolidines 2m and 2n respectively with good yield
and er value.
Furthermore, the absolute configuration of 2j, 2i, 2m and 2n
was assigned as R by a comparison of their specific optical
rotations with the literature values of known enantiomers (for
´
´
´
5155; (c) S. Fustero, J. Moscardo, D. Jimenez, M. D. Perez-
Carrion, M. Sanchez-Rosello and C. del Pozo, Chem.–Eur. J.,
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6 (a) J.-D. Liu, Y.-C. Chen, G.-B. Zhang, Z.-Q. Li, P. Chen, J.-Y. Du,
Y.-Q. Tu and C.-A. Fan, Adv. Synth. Catal., 2011, 353, 2721; (b)
S. Fustero, C. del Pozo, C. Mulet, R. Lazaro and M. Sanchez-
´
´
´
´
´
Rosello, Chem.–Eur. J., 2011, 17, 14267.
7 For selected reviews about pyrrolidine-containing alkaloids, see:
(a) F.-X. Felpin and J. Lebreton, Eur. J. Org. Chem., 2003, 3693;
(b) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed.,
2007, 46, 8748.
details, see ESI ). The rest of the adducts could also be assigned as
3
having an R-configuration based on the assumption that all the
reactions went through a similar pathway.
8 C. Zeng, H. Liu, M. Zhang, J. Guo, S. Jiang and S. Yu, Synlett,
2012, 23, 2251.
In conclusion, we have described here the preparation of
enantio-enriched 2-substituted pyrrolidines via highly enantiose-
lective intramolecular aza-Michael addition catalyzed by chiral
phosphoric acid 3d or via domino cross metathesis/intramolecular
aza-Michael addition promoted by the cooperation of chiral
phosphoric acid 3d and the Hoveyda–Grubbs II catalyst.
Benzopyrrolidines could also be prepared by this domino reaction.
Synthesis of pyrrolidine alkaloids and other enantio-enriched
heterocycles using this protocol is currently under study in our
laboratory and will be reported in due course.
9 For selected reviews on chiral Brønsted acid-catalyzed reactions,
see: (a) M. Terada, Synthesis, 2010, 1929; (b) X. H. Yu and
W. Wang, Chem.–Asian J., 2008, 3, 516; (c) M. Terada, Chem.
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10 G. Adair, S. Mukherjee and B. List, Aldrichimica Acta, 2008, 41,
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This work was supported by the National Natural Science
Foundation of China (21142001, 21102072 and 21272113) and the
Research Fund for the Doctoral Program of Higher Education of
China (20110091120008).
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1668 | RSC Adv., 2013, 3, 1666–1668
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