Cu-catalyzed asymmetric [3+2] cycloaddition of α-iminoamides with activated olefins

Article abstract of DOI:10.1039/c2cc17149j

A variety of 2-amido pyrrolidines, including Weinreb-type amides, have been prepared with very high exo diastereoselectivity and enantioselectivitiy in the reaction of α-iminoamides with activated alkenes catalyzed by Cu ^I-Segphos ligands.

Full text of DOI:10.1039/c2cc17149j

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COMMUNICATION
Cu-catalyzed asymmetric [3+2] cycloaddition of a-iminoamides with
activated olefinswz
Marıa Gonzalez-Esguevillas, Javier Adrio* and Juan C. Carretero*
´
´
Received 17th November 2011, Accepted 23rd December 2011
DOI: 10.1039/c2cc17149j
A variety of 2-amido pyrrolidines, including Weinreb-type amides,
have been prepared with very high exo diastereoselectivity and
enantioselectivitiy in the reaction of a-iminoamides with activated
alkenes catalyzed by CuI–Segphos ligands.
a highly exo-diastereoselective and enantioselective catalytic
asymmetric procedure for the 1,3-dipolar cycloaddition of
a-iminoamides by using CuI/Segphos complexes as catalyst
system. Some aspects of the chemical versatility of the resulting
adducts are also presented.
As model reaction we chose the [3+2] cycloaddition
of 2-(benzylidenamino)-N,N-dimethylacetamide (1a) with
N-methylmalemide (2) in the presence of catalytic amounts
of Cu(CH3CN)PF6,12 a chiral ligand, and Et3N as base, in
THF at room temperature. Among the tested chiral ligands13
Segphos family afforded the best outcome14 (Table 1).
Gratifyingly, Segphos ligand 3a led to the pyrrolidine 4a in
excellent yield, and nearly complete exo-selectivity (>98 : o2)
and enantioselectivity ( Z 99% ee) (entry 1). Under these
conditions, the catalyst loading could be reduced to 5 mol%
with similar diastereo- and enantioselectivity (entry 2). However
a further reduction to 3 mol% resulted in a much lower
enantioselectivity (Table 1, entry 3). A very similar behaviour
was observed from DM-Segphos ligand 3b (entries 4 and 5).
Interestingly, the use of the bulkier and electron rich
DTBM-Segphos ligand 3c allowed us to reduce the catalyst
loading to 1 mol% maintaining the excellent levels of enantio-
selectivity and exo-selectivity, albeit an excess of a-iminoamide
(1.5 equiv.) and longer reaction times were required (entry 7).
With these optimal reaction conditions in hand, the scope of
Pyrrolidine derivatives have attracted great attention in recent
years owing to both their abundance in bioactive natural and
unnatural products,1 as well as their applications as chiral
ligands and organocatalysts in asymmetric synthesis.2 Their
importance has prompted the development of different efficient
approaches for their enantioselective synthesis.3 Among them,
the 1,3-dipolar cycloaddition of azomethine ylides with activated
alkenes has emerged as one of the most powerful and atom
economy strategies. Since the first catalytic asymmetric protocols
reported in 2002,4 a wide variety of procedures based on the
combination of a metal salt and a chiral ligand as catalyst system
have been developed.5 In addition, several organocatalytic
asymmetric methods have been recently reported.6 Despite these
impressive achievements, there are still significant limitations,
especially regarding the structural variety of the dipole precursor.
Thus, the majority of procedures deal with the use of a-iminoesters,
providing pyrrolidines with 2-carboxylate substitution. As notable
exceptions to this trend azlactones,7 a-iminophosphonates,8
a-iminonitriles,9 and N-(2-pyridylmethyl)imines10 have been very
recently incorporated into the arsenal of suitable azomethine ylide
precursors for this reaction.
In this context, surprisingly, a-iminoamides have remained
unexplored as azomethine precursors, in spite of the fact that
the expected strong metal coordination ability of the carbonyl
amide group would render this type of species very suitable
bidentate substrates in the formation of the key chiral metallo-
dipole. In addition, the resulting prolineamides are biologically
relevant compounds11 and the chemical versatility of the amide
moiety could offer novel possibilities for further transformations
on the enantioenriched pyrrolidine moiety. Herein we describe
Table 1 Optimization studies
Entrya
Ligand
X
t/h
Yield 4ab (%)
ee 4ac (%)
1
2
3
4
3a
3a
3a
3b
3b
3c
3c
10
5
3
5
3
10
10
10
30
30
48
48
91
86
88
86
84
87
85
Z 99
Z 99
52
Z 99
70
Z 99
Z 99
´
Departamento de Quımica Organica, Facultad de Ciencias,
Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid,
´
´
5
Spain. E-mail: javier.adrio@uam.es, juancarlos.carretero@uam.es;
Fax: +34914973966
6d
7d
3
1
w This article is part of the ChemComm ‘Chirality’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data and NMR spectra. CCDC 846895. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2cc17149j
a
b
Only the exo adduct was detected by 1H-NMR. In pure adduct 4a
c
after column chromatography. By HPLC, see ESI for details.
d
1.5 equiv. of iminoamide 1a was used.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2149–2151 2149

Table
2
Cu(CH3CN)4PF6/DTBM-Segphos catalyzed 1,3-dipolar
yields (entries 7–9). The procedure can be also applied to
heteroaryl substituted glycine derivatives (entry 10) and a,b-
unsaturated imines (entry 11) with complete diastereoselectivity
and similar levels of enantioselectivity. The stereochemical and
configurational assignment of 4c was unequivocally established
by X-ray diffraction analysis.15 To further explore other struc-
tural possibilities of this methodology, the influence of the
substitution at the amide on the reactivity and selectivity was
also studied. The procedure tolerates the presence of aromatic
substitution without erosion in the reactivity or selectivity (entry
12). Moreover, we found that the appealing glycine-derived
Weinreb amides16 1n and 1o afforded, under similar conditions,
the corresponding pyrrolidines with excellent yields and enantio-
selectivities (entries 13 and 14).
cycloaddition of a-iminoamides 1 with N-methylmaleimide
Entrya R1
R2
Product Yieldb (%) eec (%)
1
2
3
4
5
6
p-CF3C6H4
p-BrC6H4
p-ClC6H4
p-MeOC6H4
p-NO2C6H4
m-MeC6H4
o-MeC6H4
2-Naphtyl
3-Thienyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
4b
4c
4d
4e
4f
4g
4h
4i
98
92
94
67
86
86
83
76
95
82
60
83
71
79
98
99
Z 99
96
Z 99
96
98
Z 99
Z 99
Z 99
98
We next studied other dipolarophiles in this asymmetric
7d
8d
9d
10d
11
12
13
14
[3+2] cycloaddition of a-iminoamides
1 catalyzed by
CuI–Segphos chiral ligands (Table 3). Monosubstituted
activated alkenes, such as acrylates 5 and 6 and phenylvinyl-
sulfone 7, proved to be excellent dipolarophiles for this
cycloadditon furnishing the corresponding pyrrolidines with
excellent exo-selectivities17 and asymmetric inductions, with
both the N,N-dimethylamide 1a (entries 1 and 4) and the
Weinreb-type amide 1n (entries 2, 3 and 5). In addition, the
enantiopurity of 13n can be enhanced to Z 99% ee by simple
recrystallization with isopropanol (entry 5). On the contrary,
we did not observe reaction under similar conditions, when
(E)-b-nitrostyrene (8) or trans-chalcone (9) were used as
dipolarophiles (entries 6 and 9). Interestingly, this drawback
was overcome using the less sterically hindered Segphos ligand
3a, which afforded the desired pyrrolidines 14a, 14n and 15 in
high yield and enantioselectivity (entries 7, 8 and 10), albeit a
non-complete exo-selectivity was observed when nitrostyrene
was used as dipolarophile (entries 7 and 8).
4j
4k
4l
5-Br-2-thienyl Me
CHQCHPh
Ph
Ph
Me
p-FC6H4 4m
OMe
OMe
Z 99
98
96
4n
4o
p-BrC6H4
a
b
Only the exo aduct was detected by 1H-NMR. In pure product
c
after column chromatography. By HPLC, see ESI for details.
d
5 mol% of catalyst was used.
the 1,3-dipolar cycloaddition with regard to the substitution at
the azomethine ylide was investigated (Table 2). All aryl
substituted dipole precursors afforded a single diastereomer
with excellent enantiocontrol regardless of the electronic
nature of the substituent (entries 1–6). However, bulkier
aromatic substrates showed lower reactivity, a higher catalyst
loading (5 mol%) being required to obtain good chemical
Table 3 1,3-dipolar cycloaddition of a-iminoamides 1 with other dipolarophiles
Entrya
Amide
Dipolarophile
R1
R2
R3
R4
Ligand
Product
exo/endo
Yieldb (%)
eec (%)
94
Z 99
98
t
1
2
3
4
5
6
7
8
1a
1n
1n
1a
1n
1a
1a
1n
1a
1a
1a
1a
1a
1m
1a
1a
1a
5
5
6
7
7
8
8
8
CO2tBu
CO2 Bu
CO2Me
SO2Ph
SO2Ph
NO2
NO2
NO2
COPh
COPh
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
CO2Me
CO2Me
CO2Me
CO2Me
H
Me
3c
3c
3c
3c
3c
3c
3a
3a
3c
3a
3c
3a
3b
3a
3c
3a
3b
11a
11n
12
13a
13n
—
14a
14n
—
15
—
16a
16a
16m
—
17a
17a
>98/o2
>98/o2
>98/o2
>98/o2
>98/o2
—
82
50
60
85
95
—
80
87
—
58
—
78
50
73
—
70
68
OMe
OMe
Me
OMe
Me
Me
OMe
Me
Me
Me
Me
Z 99
90 ( Z 99)d
—
91
89
—
89
—
61
70
71
—
41
94
85/15
88/12
9
9
9
—
>98/o2
10
11
12
13
14
15
16
17
10
10
10
10
11
11
11
—
80/20
Me
85/15
80/20
p-FC6H4
Me
Me
—
>98/o2
H
H
Me
90/10
a
b
c
d
By 1H-NMR from the crude reaction mixtures. In pure product after column chromatography. By HPLC, see ESI for details. ee after
recrystallization.
c
2150 Chem. Commun., 2012, 48, 2149–2151
This journal is The Royal Society of Chemistry 2012

Notes and references
1 Five membered nitrogen heterocycles are present in about 9000
natural products: W. Hess and J. W. Burton, Chem.–Eur. J., 2010,
16, 12306.
2 For reviews, see: (a) C. Grondal, M. Jeanty and D. Enders, Nat.
Chem., 2010, 2, 167; (b) special feature issue on organocatalysis,
Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 20618.
3 For recent selected references, see: (a) A. Z. Gonzalez, D. Benitez,
E. Tkatchouk, W. A. Goddard III and F. D. Toste, J. Am. Chem. Soc.,
2011, 133, 5500; (b) K. X.-K. Liu, S. Qiu, Y.-G. Xiang, Y.-P. Ruan,
X. Zheng and P.-Q. Huang, J. Org. Chem., 2011, 76, 4952.
4 (a) J. M. Longmire, B. Wang and X. Zhang, J. Am. Chem. Soc.,
2002, 124, 13400; (b) A. S. Gothelf, K. V. Gothelf, R. J. Hazell and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2002, 41, 4236.
5 For recent reviews, see: (a) J. Adrio and J. C. Carretero, Chem.
Commun., 2011, 47, 6784; (b) C. Najera and J. M. Sansano, Top.
Heterocycl. Chem., 2008, 12, 117; (c) L. M. Stanley and M. P. Sibi,
Chem. Rev., 2008, 108, 2887; (d) H. Pellisier, Tetrahedron, 2007,
63, 3235. For a very recent reference, see: (e) M. Wang, Z. Wang,
Y.-H. Shi, X.-X. Shi, J. S. Fossey and W.-P. Deng, Angew. Chem.,
Int. Ed., 2011, 50, 4897 and references therein.
6 For a very recent reference see: J.-F. Bai, L.-L. Wang, L. Peng,
Y.-L. Guo, J.-N. Ming, F.-Y. Wang, X.-Y. Xu and L.-X. Wang,
Eur. J. Org. Chem., 2011, 4472.
7 A. D. Melhado, M. Luparia and F. D. Toste, J. Am. Chem. Soc.,
2007, 129, 12638.
8 Y. Yamashita, X.-X. Guo, R. Takashita and S. Kobayashi, J. Am.
Chem. Soc., 2010, 132, 3262.
9 R. Robles-Machın, I. Alonso, J. Adrio and J. C. Carretero,
Chem.–Eur. J., 2010, 16, 5286.
Scheme 1 Application to enantioselective pyrrolizidine synthesis.
The cycloadditions of 1 with acyclic diactivated alkenes,
such as dimethyl fumarate (9) and dimethyl maleate (10), were
also conducted. Only traces of adduct were formed in the
reaction with 9 or 10 using CuI/DTBM-Segphos as catalyst
system (entries 11 and 15). Again, in these cases we found a
strong beneficial effect on the reactivity when the less bulkier
Segphos ligand 3a was used. Under these conditions the
reaction with fumarate 9 took place with good yield and
reasonable exo-selectivity but moderate enantioselectivity
(61% ee, entry 12). The enantioselectivity could be slightly
enhanced to 70% ee using DM-Segphos as ligand (entry 13) or
the iminoamide 1m as dipole precursor (entry 14). On the
other hand, in the reaction with dimethyl maleate Segphos
ligand 3a provided the pyrrolidine 17a with complete exo-
selectivity but low enantioselectivity (41% ee, entry 16).
Interestingly, a great enhancement in the enantioselectivity
was achieved in the presence of DM-Segphos ligand (94% ee,
entry 17).
10 S. Padilla, R. Tejero, J. Adrio and J. C. Carretero, Org. Lett., 2010,
12, 5608.
11 For applications in medicinal chemistry, see for example:
K. K.-C. Liu, B. A. Lefker, M. A. Dombroski, P. Chiang,
P. Cornelius, T. A. Patterson, Y. Zeng, S. Santucci, E. Tomlinson,
C. P. Gibbons, R. Marala, J. A. Brown, J. X. Kong, E. Lee,
W. Werner, Z. Wenzel, C. Giragossian, H. Chen and S. B. Coffey,
Bioorg. Med. Chem. Lett., 2010, 20, 2365.
The synthetic usefulness of this methodology to the
preparation of substituted pyrrolizidines was next demon-
strated.18 The reaction of the enantiopure Weinreb amide
pyrrolidine 13n with acetyl chloride gave rise to the N-acetyl
pyrrolidine 18 in 97% yield. Subsequent treatment
with LiHMDS led to the straightforward formation of the
pyrrolizidine 1,3-dione19 which was in situ reduced to the
alcohol 19 (NaBH4, EtOH) due to its instability. Finally,
the reductive elimination of the sulfonyl group provided the
hydroxypyrrolizidine 20 in 70% yield20 (Scheme 1).
12 The use of other metal complexes such as AgOAc, Zn(OAc)2 or
Cu(OAC)2 afforded poorer results than Cu(CH3CN)4PF4.
13 For the use of Segphos ligands in catalytic asymmetric 1,3-dipolar
cycloadditions of azomethine ylides, see: (a) Y. Yamashita,
T. Imaizumi and S. Kobayashi, Angew. Chem., Int. Ed., 2011,
50, 4893; (b) R. Robles-Machın, M. Gonzalez-Esguevillas, J. Adrio
and J. C. Carretero, J. Org. Chem., 2010, 75, 233; (c) A. Lopez-Perez,
J. Adrio and J. C. Carretero, Angew. Chem., Int. Ed., 2009, 48, 340;
(d) Y. Oderaotoshi, W. Cheng, S. Fujitomi, Y. Kasano, S. Minakata
and M. Komatsu, Org. Lett., 2003, 5, 5043. See also ref. 8.
14 A variety of structurally diverse chiral ligands were tested in this
cycloaddition, see ESIz for details.
In summary, we have developed an efficient protocol for the
catalytic asymmetric [3+2] cycloaddition of a-iminoamides,
including Weinreb-type amides. This procedure relies on
the use of CuI/Segphos as catalyst system, providing
2-amidopyrrolidines usually with excellent levels of exo
diastereoselectivity and enantiocontrol (up to Z 99% ee) in
15 CCDC 846895z.
16 For a review on the synthetic utility of Weinreb amides, see:
J. S. Balasubramaniam and I. S. Aidhen, Synthesis, 2008, 3707.
17 The exo configuration of the 2-amidopyrrolidines 13n and 14n was
established by chemical correlations to known pyrrolidines-
2-carboxylate esters, see ESIz.
18 The pyrrolizidine structural motif is present in a wide variety of
polyhydroxylated alkaloids with important biological activities
and potential therapeutic use, such as anti-HIV or anticancer
agents. J. P. Michael, Nat. Prod. Rep., 2007, 24, 191.
the reaction with
a variety of activated alkenes. This
methodology offers a new entry to the enantioselective
construction of pyrrolidine containing structures, such as
pyrrolizidines.
19 It has been reported that this kind of cyclization cannot be achieved
from methyl N-acetylprolinate. The competitive deprotonation at the
a position of the ester is the main process, resulting in racemization of
the starting material, see: A. Murray, G. R. Proctor and P. J. Murray,
Tetrahedron, 1996, 52, 3757.
20 A nOe experiment was used to establish the stereochemistry at the
carbinol center in 20, see ESIz for details. A similar diastereofacial
selectivity has been previously described in the reduction of related
pyrrolizin-1,3-diones: N. Galeotti, J. Poncet, L. Chiche and
P. Jouin, J. Org. Chem., 1993, 58, 5370. See also ref. 19.
Financial support of this work by the Ministerio de Ciencia
e Innovacion of Spain (MICINN, CTQ2009-07791), CAM
(project AVANCAT; S2009/PPQ-1634) and CAM-UAM
(CCG-10-UAM/PPQ-5853) is gratefully acknowledged.
M.G.-E. thanks the MICINN for a predoctoral fellowship.
We thank Takasago Company (Dr Taichiro Touge) for generous
loans of Segphos chiral ligands.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2149–2151 2151