Highly diastereo- and enantioselective tandem reaction toward functionalized pyrrolidines with multiple stereocenters

Article abstract of DOI:10.1021/ol2023196

An efficient asymmetric tandem dual Michael reaction that constructs three contiguous stereocenters in acyclic open-chain systems with very high enantioselectivity and diastereoselectivity has been developed. This protocol provides a reliable and rapid ap

Full text of DOI:10.1021/ol2023196

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5596–5599
Highly Diastereo- and Enantioselective
Tandem Reaction toward Functionalized
Pyrrolidines with Multiple Stereocenters
Shengmei Guo,† Yinjun Xie,† Xinquan Hu,†,‡ and Hanmin Huang*,†
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, P. R. China, and
College of Chemical Engineering and Materials Science, Zhejiang University of
Technology, Hangzhou, 310014, P. R. China
hmhuang@licp.cas.cn
Received August 26, 2011
ABSTRACT
An efficient asymmetric tandem dual Michael reaction that constructs three contiguous stereocenters in acyclic open-chain systems with very
high enantioselectivity and diastereoselectivity has been developed. This protocol provides a reliable and rapid approach for synthesis of chiral
pyrrolidines with multiple stereocenters.
Catalytic asymmetric tandem reactions have proven to
beanefficient and powerful access for synthesisof complex
chiral molecules of interest.1 These reactions are particu-
larly important for synthesis of stereodefined compounds
with multiple stereocenters, which are usually difficult to
achievethroughconventionalstepwiseprocesses. A critical
feature for construction of such an efficient tandem reac-
tion is the identification of a catalyst system capable of
generation of reactive species and that could be compatible
with or activate the subsequent reactants. In this context,
copper-catalyzed asymmetric conjugate addition of di-
alkylzinc to enones has been successfully explored as an
efficient fundamental reaction for constructing a variety of
tandem reactions combined with various electrophiles.2
However, most of these protocols have been inevitably
limited tothe cyclic enones.3 This limitation arises owing to
the difficulty to control the enolate geometry in the acyclic
enolate, which is likely due to the s-cis/s-trans conforma-
tional flexibility inherent to open-chain enoyl systems.4
Over the years, enolates have been a research topic of
great interest to synthetic chemists.5 While a number of
asymmetric reactions with enolates as nucleophiles have
been developed, a practical method for controlling the
† Lanzhou Institute of Chemical Physics.
‡ Zhejiang University of Technology.
(1) For reviews, see: (a) Ho, T.-L. Tandem Organic Reactions; Wiley:
New York, 1992. (b) Bunce, R. A. Tetrahedron 1995, 51, 13103. (c) Tietze,
L. F. Chem. Rev. 1996, 96, 115. (d) Nicolaou, K. C.; Montagnon, T.;
Snyder, S. A. Chem. Commun. 2003, 551. (e) Wasilke, J.-C.; Obrey, S. J.;
ꢀ
Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001. (f) Ramon, D. J.;
Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1628. (g) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (h)
€
Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570.
(2) For a review, see: (a) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int.
Ed. 2006, 45, 354. For selected examples, see:(b) Kitamura, M.; Miki, T.;
Nakano, K.; Noyori, R. Tetrahedron Lett. 1996, 37, 5141. (c) Feringa,
B. L.; Pineschi, M. L.; Arnold, A.; Imbos, R.; de Vries, A. H. M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2620. (d) Keller, E.; Maurer, J.; Nassz, R.;
Schader, T.; Meetsma, A.; Feringa, B. L. Tetrahedron: Asymmetry 1998,
9, 2409. (e) Arnold, L. A.; Nassz, R.; Minnaard, A. J.; Feringa, B. L. J.
Org. Chem. 2002, 67, 7244. (f) Naasz, R.; Arnold, L. A.; Pineschi, M.;
Keller, E.; Feringa, B. L. J. Am. Chem. Soc. 1999, 121, 1104. (g)
Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 779. (h) Rathgeb, X.; March, S.; Alexakis, A. J. Org. Chem. 2006,
71, 5737. (i) Oliver, K.; Alexakis, A. Org. Lett. 2002, 4, 3835. (j) Alexakis,
A.; March, S. J. Org. Chem. 2002, 67, 8753. (k) Agapiou, K.; Cauble,
D. F.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 4528. (l) Li, K.;
Alexakis, A. Tetrahedron Lett. 2005, 46, 5823. (m) Li, K.; Alexakis, A.
Chem.;Eur. J. 2007, 13, 3765. (n) Xu, Y.-J.; Liu, Q.-Z.; Dong, L.
Synlett 2007, 273.
(3) For the control of three stereocenters in an acyclic system, see: (a)
Howell, G. P.; Fletcher, S. P.; Geurts, K.; ter Horst, B.; Feringa, B. L. J.
Am. Chem. Soc. 2006, 128, 14977. (b) Arai, T.; Yokoyama, N. Angew.
Chem., Int. Ed. 2008, 47, 4989. (c) Anderson, J. C.; Stepney, G. J.; Mills,
M. R.; Horsfall, L. R.; Blake, A. J.; Lewis, W. J. Org. Chem. 2011, 76,
1961.
(4) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221.
r
10.1021/ol2023196
Published on Web 09/19/2011
2011 American Chemical Society

geometry of acyclic enolate remains elusive. Recently, we
have established an asymmetric tandem reaction based on
the copper-catalyzed conjugate addition reaction, in which
the chiral zinc enolate was involved.6 The excellent diaster-
eoselectivities and enantioselectivities observed there sug-
gested that the geometry of the chiral enolate was
completely controlled by the catalyst system, which guar-
anteed the subsequent trapping reaction to proceed in high
stereoselectivity. To further explore such an approach for
facile control of the geometry of the acyclic enolate, we
therefore selected nitroalkenes aselectrophilesfor trapping
the zinc enolates formed in the copper-catalyzed conjugate
addition of diethylzinc to acyclic enones to examine the
feasibility of this approach. Herein we report a highly
diastereoselective and enantioselective tandem reaction
via copper-catalyzed dual Michael addition reactions that
affords γ-nitro ketones with three contiguous acyclic
stereogenic centers in high stereoselectivities (Scheme 1).
Thanks to the versatility of the nitro group,7 the impor-
tance of the dual Michael addition reaction is demon-
strated in the elaboration of the γ-nitro ketones into chiral
pyrrolidines with multiple stereocenters using a two-step
procedure.
Table 1. Optimized Reaction Conditions for the Tandem Dual
Michael Reactiona
entry
CuXn
solvent yieldb (%)
drc
eed (%)
1
CuBr
Et2O
Et2O
Et2O
Et2O
Et2O
79
78
82
85
72
32
43
85
82
67
21
44
78
95:5
91:9
94
92
2
CuBr2
CuCl
3
>99:1
93:7
97
4
CuCl2
94
5
Cu(OAc)2
90:10
83:17
50:50
95:5
94
6
Cu(CH3CN)4BF4 Et2O
ꢀ30
20
7
Cu(OTf)2
CuCl
Et2O
8
CPME
Bu2O
96
9
CuCl
98:2
96
10
11
12
13e
CuCl
TBME
CH2Cl2
toluene
Et2O
95:5
63
CuCl
97:3
80
CuCl
96:4
96
CuCl
97:3
96
a Reaction conditions: chalcone 1a (0.5 mmol), Et2Zn (0.6 mmol),
nitroalkene 2a (0.6 mmol), CuXn (0.005 mmol), L (0.006 mmol), Et2O
(2.0 mL), ꢀ20 °C, 24 h. b Isolated yield. c Determined by 1H NMR and
HPLC. d Determined by chiral HPLC, and for the major isomer. e With
L1 as ligand.
Scheme 1. Cu-Catalyzed Tandem Conjugate Dual Michael
Reaction
(Table 1, entry 1). As expected, with L2 as chiral ligand, the
less electrophilic neutral copper catalysts with more co-
ordinating counterions, such as CuBr and CuCl, proved to
be more suitable, and among all those tested, CuCl led to
the best results withrespect to bothdiastereoselectivity and
enantioselectivity. In contrast, the copper sources with
fewer coordinating counterions, such as Cu(CH3CN)4BF4
and Cu(OTf)2, gave poor results in this catalytic process
(Table 1, entries 6 and 7). Further screening of solvents
indicated that reactions performed in ether solvents led to
good results, and Et2O was the best choice for this trans-
formation. The chiral ligand L1 could alsobe employed for
this transformation, but with relative lower diastereoselec-
tivity (Table 1, entry 13). Under the optimal reaction
conditions and using CuCl/L2 as the catalyst (Table 1,
entry 3), the desired adduct γ-nitro ketone 3a was obtained
in 82% yield with excellent stereoselectivity.
After having identified the optimal reaction conditions,
we first investigated the substrate scope of nitroalkenes in
this one-pot sequence of reaction. A series of aromatic
nitroalkenes bearing electron-donating or electron-with-
drawing groups in the aryl moiety were first subjected to
the optimal conditions using chalcone 1a and Et2Zn. As
summarized in Table 2, the corresponding adducts were
obtained in good yields (66ꢀ90%) and with excellent
enantioselectivities (94ꢀ97% ee). In each case, the reaction
was highly diastereoselective with almost only one of
four possible diastereomers observed (>20:1 dr, Table 2,
entries 1ꢀ8). Besides the substituted phenyl nitroalkenes, the
naphthyl- and heteroaryl-substituted nitroalkenes2iand 2j
We first investigated the tandem Michael/Michael addi-
tion reaction of Et2Zn to chalcone 1a and β-nitrostyrene 2a
in the presence of copper catalyst with phosphiteꢀpyridine
L2 as chiral ligand and neutral CuBr as copper source.8 A
sequential one-pot procedure was employed in which the
reagents were added step by stepin one pot. After complete
conversion of the chalcone 1a to the zinc enolate in the
presence of the chiral catalyst was confirmed by TLC, the
nitroalkene 2a was added to the reaction mixture to trap
the chiral enolate. To our delight, high yield with excellent
diastereoselectivity and enantioselectivity were observed
(5) For reviews, see: (a) Evans, D. A. In Asymmetric Synthesis;
Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, pp 1ꢀ110.
(b) Heathcock, C. H. Modern Enolate Chemistry: Regio- and Stereo-
selective Formation of Enolates and the Consequence of Enolate Config-
uration on Subsequent Reactions; VCH: Weinheim, 1992. (c) Arya, P.; Qin,
H. Tetrahedron 2000, 56, 917.
(6) Guo, S.; Xie, Y.; Hu, X.; Xia, C.; Huang, H. Angew. Chem., Int.
Ed. 2010, 49, 2728.
(7) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. (b) Larock, R. C. Comprehensive Organic Transforma-
tion; VCH, New York, 1989; p 411.
(8) Hu, Y.; Liang, X.; Wang, J.; Zheng, Z.; Hu, X. J. Org. Chem.
2003, 68, 4542.
Org. Lett., Vol. 13, No. 20, 2011
5597

3nꢀv with excellent diastereoselectivities and enantioselec-
tivities in the range of 91ꢀ97% ee. Only in the case of 3-(3-
chlorophenyl)-1-phenylprop-2-en-1-one 2s was a slight
decrease in diastereoselectivity and enantioselectivity ob-
served (Table 2, entry 19).
Table 2. Cu-Catalyzed Tandem Dual Michael Reactiona
The absolute configuration of the major stereoisomer
was determined to be 2S,3S,20R by single-crystal X-ray
analysis of the bromo-containing product 3v.10 The as-
signed absolute configuration indicated that the initial
Michael addition takes place from the Re face of the enone
through the control of the catalyst which was identical to
the original 1,4-addition protocol catalyzed by copper
catalyst with the same chiral ligand.8 On the basis of this
information, the absolute configuration of the adduct 3l
which produced by the (Z)-nitroalkene could also be
determined as (2S,3S,4S) by the single-crystal X-ray ana-
lysis, which holds the same relative configuration as that of
3v.11 These results indicated that the geometry of the
nitroalkene did not affect chiral environment in the transi-
tion state and suggested that the (E)-enolate was involved
in the secondMichael reaction. Based onthese results,12 we
propose an eight-membered cyclic ZimmerꢀTraxler-like
transition state (Scheme 2) to account for the observed
stereoselectivity,13 in which the chiral (E)-enolate is in-
volved and the aryl or alkyl group of the nitroalkene
adopts a pseudoequatorial position togivethe antiproduct
during the second Michael reaction. The nitro group of the
nitroalkene might be able to coordinate with the Cu center
and thus make the carbonꢀcarbon double bond more
electrophilic toward the enolate from its Re face to facil-
itate an substrate-induced enantioselective Michael addi-
tion and give the γ-nitro ketone products with high levels
of stereochemical control.
entry 1 (Ar1, Ar2)
2 (R)
yieldb (%)
drc
eed (%)
1
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph
3a, 82
3b, 76
3c, 80
3d, 72
3e, 78
3f, 66
3g, 79
3h, 90
3i, 59
3j, 69
3k, 52
3l, 68
3m, 55
3n, 85
3o, 64
3p, 87
3q, 83
3r, 88
3s, 82
3t, 85
3u, 85
3v, 81
>99:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
17:1
97
96
96
97
96
95
96
94
97
96
96
94
97
96
95
96
95
97
91
96
95
95
2
4-ClPh
3
4-BrPh
4
4-FPh
5
4-CH3Ph
4-MeOPh
3-ClPh
6
7
8
3,4-(MeO)2Ph
1-naphthyl
2-furyl
9
10
11
c-C6H11
12e Ph, Ph
AcNH
13
14
15
16
17
18
19
20
21
22
Ph, Ph
E-PhCHdCH
4-CH3Ph, Ph Ph
4-MeOPh, Ph Ph
4-ClPh, Ph
4-BrPh, Ph
4-FPh, Ph
3-ClPh, Ph
Ph, 4-ClPh
Ph, 4-BrPh
Ph
Ph
Ph
Ph
Ph
Ph
>20:1
>20:1
>20:1
4-MeOPh, Ph 4-BrPh
a Reaction conditions: chalcone 1 (0.5 mmol), Et2Zn (0.6 mmol),
nitroalkene 2 (0.6 mmol), CuCl (0.005 mmol), L2 (0.006 mmol), Et2O
(2.0 mL), ꢀ20 °C, 24 h. b Isolated yield. c Determined by 1H NMR.
d Determined by chiral HPLC. e (Z)-Type nitroalkene was used.
could also react smoothly, generating the corresponding
products 3i and 3j in good yields and excellent stereo-
selectivities. The aliphatic nitroalkene 2k was also shown
to be compatible in this reaction and provided the corre-
sponding adduct 3k with excellent stereoselectivity
(Table 2, entry 11). It is notable that the current reaction
could be extended to some functionalized nitroalkenes.
The (Z)-nitroalkene 2l9 bearing an amide functional group
as well as 2m containing alkenyl moiety reacted with 1a in
good yields with high diastereoselectivities and enantio-
selectivities (Table 2, entries 12 and 13). The formation of
aminated and alkylated adducts are attractive because
those functional groups could be easy convert to some
important chiral compounds.
Scheme 2. Rationalization for the Selective Dual Michael
Reaction
To further demonstrate the general applicability of the
current tandem reaction, a broad spectrum of chalcones were
also tested under the optimal reactions. As Table 2 shows,
changing the electronic properties of the aromatic substi-
tuent in the enone had no major effect on the stereoselec-
tivity of this transformation. Electron-withdrawing as well
as electron-donating groups could be attached to the aro-
matic moiety and afforded the corresponding adducts
The obtained γ-nitro ketone contains the versatile nitro
group and therefore could be readily converted to structu-
rally diverse pyrrolidine derivatives through well-estab-
lished methods. As outlined in Scheme 3, after reductive
cyclization of the 3a and 3l by the known method, the
corresponding dihydropyrroles 4a and 4l were then hydro-
genated under the catalysis of Pd/C to furnish the chiral
pyrrolidines 5a and 5l containing four stereocenters in a
(9) For synthesis of and using this nitroalkene, see: Zhu, S.; Yu, S.;
Wang, Y.; Ma, D. Angew. Chem., Int. Ed. 2010, 49, 4656.
5598
Org. Lett., Vol. 13, No. 20, 2011

single isomer. The relative configuration of the newly
formed chiral center was determined by 2D NMR (see the
group, which should find applications in the design of
new catalysts14 and biologically active molecules.15 In
addition, the adduct 3a was also successfully transformed
into the chiral acids 6a and 7a in high yields. The structure
of 7a was confirmed by single-crystal X-ray analysis.10
In summary, we have successfully established an
efficient method for assembling of two distinct electro-
philes into one molecule through the copper-catalyzed
dual Michael addition reaction. The reaction is applic-
able to a wide array of R,β-unsaturated ketones as well
as nitroalkenes and proceeds with excellent diastereo-
selectivity and enantioselectivity for obtaining γ-nitro
ketones with three contiguous stereocenters. In addi-
tion, the dramatic effect of neutral copper in the
tandem reactions has been disclosed, which provided
evidence that the electrophilic of catalyst precursor
plays a crucial role in the control of stereoselectivity.
These finds may suggest an efficient strategy for con-
trolling geometry of acyclic enolate.
Scheme 3. Synthesis of Chiral Pyrrolidine Derivatives
Supporting Information). Both dihydropyrrole 4l and
pyrrolidine 5l contain the useful acetamide functional
(10) CCDC 834880 (3v), 834881 (3l), and 834882 (7a) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/conts/datarequest/cif.
(11) The difference of absolute configuration of 3v and 3l resulted
from the sequence difference of the Ar group and AcNH group accord-
ing to the sequence rule.
Acknowledgment. Financial support provided by the
National Natural Science Foundation of China (21172226,
21133011) and the Chinese Academy of Sciences is grate-
fully acknowledged.
(12) A control experiment was carried out: the conjugate addition
product 8a with 92% ee was reacted with LDA at ꢀ78 °C for generation
of the enolate, which was then subjected to react with the nitroalkene in
the absence of copper catalyst. The desired dual Michael adduct 3a was
obtained in lower yield with high enantioselectivity (92% ee for major
isomer) but relative lower diastereoselectivity. These results indicated
that the absolute configuration of the final adduct was determined by the
chiral enolate and the Cu catalyst could accelerate the second Michael
reaction but may not exert chiral induction in this step.
Supporting Information Available. Experimental de-
tails and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1. (b) Heathcock, C. H. In Comprehensive Carbanion Chem-
istry, Part B; Elsevier: Amsterdam, 1984; p 177.
(14) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471.
(15) Pearson, W. H. In Studies in Natural Product Chemistry;
Rahman, A. U., Ed.; Elsevier: New York, 1998; Vol. 1, p 323.
Org. Lett., Vol. 13, No. 20, 2011
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