Cu(I)/DTBM-BIPHEP-catalyzed exo-selective 1,3-dipolar cycloaddition of azomethine ylides with cis-trifluorocrotonate for asymmetric construction of trifluoromethylated pyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2012.05.021

A direct and facile access to highly substituted exo-pyrrolidines bearing a unique trifluoromethyl group is developed via Cu(I)/DTBM-BIPHEP-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with cis-4,4,4-trifluorocrotonate for the first time.

Full text of DOI:10.1016/j.tetlet.2012.05.021

Tetrahedron Letters 53 (2012) 3650–3653
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cu(I)/DTBM-BIPHEP-catalyzed exo-selective 1,3-dipolar cycloaddition
of azomethine ylides with cis-trifluorocrotonate for asymmetric
construction of trifluoromethylated pyrrolidines
Qing-Hua Li a, Zhi-Yong Xue a, Hai-Yan Tao a, Chun-Jiang Wang a,b,
⇑
a College of Chemistry and Molecular Sciences, Wuhan University, Hubei Province 430072, China
b State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjing 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct and facile access to highly substituted exo-pyrrolidines bearing a unique trifluoromethyl group is
developed via Cu(I)/DTBM-BIPHEP-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides
with cis-4,4,4-trifluorocrotonate for the first time.
Received 10 March 2012
Revised 27 April 2012
Accepted 4 May 2012
Available online 11 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Pyrrolidine
Trifluoromethyl group
1,3-Dipolar cycloaddition
Stereoselectivity
Five-membered nitrogen heterocycles, especially the highly
substituted pyrrolidines are observed widely in pharmaceuticals,
natural alkaloids, organocatalysts, and also useful building blocks
in synthetic chemistry.1 As a consequence, extensive studies have
been conducted on the exploitation of the efficient methods for
the asymmetric synthesis of biologically active pyrrolidines over
the past decade.2 Among these, the catalytic asymmetric 1,3-dipo-
lar cycloaddition of azomethine ylides generated from readily
available imino esters and electron-deficient alkenes has proven
to be one of the most powerful and diversity-oriented synthesis
(DOS)3 for the construction of such compounds.4 Recently, fluori-
nated organic compounds play a unique and significant role in
the pharmaceutical, agrochemical, and material sciences.5 Chiral
trifluoromethylated compounds have attracted considerable atten-
tion, mainly due to the fact that the trifluoromethyl group often
brings remarkably changes in the physical, chemical, and biological
properties of the parent molecules, such as enhanced binding
selectivity, higher lipophilicity, and increased metabolic stability.6
One such example is (3R,4S)-7-(3-aminomethyl-4-trifluoro-
methyl-1-pyrro-lidinyl)-8-ethoxyfluoroquinolone (Fig. 1), in which
the key trifluoromethylated pyrrolidine moiety was achieved
through TFA-mediated 1,3-dipolar cycloaddition of azomethine
ylide with trans-4,4,4-trifluorocrotonate.7 It has been revealed that
the stereogenic carbon center bearing a unique CF3 group on the
pyrrolidine ring plays a significant role in the structure-activity rela-
tionship and exhibits superior activity against quinolone and meth-
icillin-resistant Staphylococcus aureus with low side effect
potential.7 Although various methods have been established for
the synthesis of enantioenriched pyrrolidines, however, for the
trifluoromethylated pyrrolidines, to our knowledge, only limited
racemic examples have been reported employing stoichiometric
amount of catalyst.8 In this topic, we have recently developed a gen-
eral procedure for the asymmetric approach to trifluoromethylated
pyrrolidines with excellent endo-selectivity via Cu(I)/(S)-TF-Bip-
hamPhos-catalyzed 1,3-dipolar cycloaddition of azomethine ylides
with 4,4,4-trifluorocrotonates.9 Because it is important to synthe-
size any of the desired diastereomers of cycloadducts with both high
diastereoselectivity and enantioselectivity, an investigation of con-
struction for the exo-selective trifluoromethylated pyrrolidines is
in a high demand. To further diversify bioactive trifluoromethylated
NH2
CH3
O
N
F
COOH
HCl
N
.
H2N
F3C
⇑
Corresponding author. Tel.: +86 27 68754067; fax: +86 27 65241880.
E-mail address: cjwang@whu.edu.cn (C.-J. Wang).
Figure 1. Fluoroquinolone antibacterial agent bearing the key trifluoromethylated
pyrrolidine moiety: (3R,4S)-S-34109.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.021

Q.-H. Li et al. / Tetrahedron Letters 53 (2012) 3650–3653
3651
showed that AgOAc/(S)–BINAP complex successfully catalyzed this
cycloaddition, and exo-adduct was obtained as the major diaste-
reomer (exo/endo = 67:33) although the corresponding enantiose-
lectivity was unsatisfactory (Table 1, entry 1). Next studies
showed that using Cu(CH3CN)4BF4 as the metal precursor gave bet-
ter results than AgOAc in terms of reactivity and diastereo-/enanti-
oselectivity (entry 2). It is well known that subtle changes in
conformation, steric, and electronic properties of the chiral axially
bisphosphine ligands can often lead to dramatic variation of reac-
tivity and enantioselectivity, hence, further ligand survey was per-
formed with Cu(CH3CN)4BF4 as the metal precursor. A little higher
diastereoselectivity but lower enantioselectivity was observed
when the phenyl group on the phosphorous atom of BINAP was re-
placed by the p-tolyl group (L2) (entry 3). Axially biphenyl ligand
(S)-MeO-BIPHEP (L3) was tested in this transformation leading to
the same diastereoselectivity as (S)-BINAP (L1) but higher enanti-
oselectivity (entry 4). To our delight, the more bulky and
electron-donating biphenyl ligands (R)-DTBM-SEGPHOS (L4) and
(R)-DTBM-BIPHEP (L5) not only exhibited a significant improve-
ment on the diastereo-selectivity (>98:2) but also gave almost per-
fect enantioselectivity11 (98% ee and >99% ee, respectively, entries
5 and 6). A study of reaction with Cu(CH3CN)4BF4/(R)-L5 in various
solvents revealed that CH2Cl2 was the best one in terms of yield
and enantioselectivity. (entries 6–10).
With the optimal reaction conditions in hand, the scope of this
exo-trifluoromethylated pyrrolidine formation was demonstrated
with various imino esters. As summarized in Table 2, a variety of
imino esters 2 derived from aromatic aldehydes, which bear elec-
tron-deficient (Table 2, entries 1–7), electron-neutral (entries 8,
14 and 15), or electron-rich groups (entries 9–12) on the phenyl
ring, reacted smoothly with cis-ethyl 4,4,4-trifluorocrotonate 1 to
afford the desired exo-adducts in high yields (73–87%), excellent
diastereoselectivities (>98:2 dr) and enantioselectivities (92 to
>99% ee). It is noteworthy that comparable results were still
achieved for the sterically hindered ortho-substituted and 1-naph-
thyl-substituted imino esters 2c, 2e, 2f, and 2n in terms of diaste-
reo-/enantioselectivity and reactivity (entries 3, 5, 10 and 14).
Additionally, heteroaromatic 2-furyl imino ester 2m derived from
MeO
MeO
PPh2
PPh2
PPh2
PPh2
PTol2
PTol2
(S)-MeO-BIPHEP (L3)
(S)-BINAP (L1)
(S)-Tol-BINAP (L2)
tBu
tBu
OMe
OMe
O
tBu
MeO
2
tBu
O
O
P
P
P
P
2
tBu
tBu
MeO
O
OMe
OMe
tBu
tBu
2
2
(R)-DTBM-SEGPHOS (L4)
(R)-DTBM-BIPHEP (L5)
Figure 2. Screened chiral ligands.
pyrrolidine derivatives, the screening of some commercially-avail-
able chiral bisphosphine ligands would be desirable and practicable
considering good to excellent exo-selectivity delivered by the
bisphosphine/metal complexes for the cycloaddition of azomethine
ylides with some commonly-used electron-deficient alkenes such as
acrylates, maleates, maleimides, and vinyl sulfones.10 Herein, we re-
ported the asymmetric exo-selective 1,3-dipolar cycloaddition of
azomethine ylides to cis-trifluorocrotonate with high yield and
excellent enantioselectivity catalyzed by Cu(I)/(R)-DTBM-BIPHEP
complex.
To explore the feasibility of the diastereoselectivity control for
this 1,3-dipoar cycloaddition process, reaction of cis-ethyl triflu-
orocrotonate (1) with N-(4-chlorobenzyli-dene)-glycine methyl
ester (2a) was carried out in dichloromethane at room temperature
in the presence of silver or copper salts with several commercially-
available chiral bisphosphine ligands ( Fig. 2). Our initial study
Table 1
Screening studies of the catalytic asymmetric 1,3-dipolar cycloaddition of imino ester 2a with cis-ethyl trifluorocrotonate 1a
EtO C
2
CF
3
CO Me
p-Cl-C H
CO Me
6
4
2
2
N
H
+
F C
3
[M]/L (3 mol %)
Et N (15 mol %), rt
endo-4a
+
N
3
EtO C
CF
EtO C
2
3
2
p-Cl-C H
6
4
1
2a
CO Me
exo-3a
p-Cl-C H
2
6
4
N
H
Entry
L
(M)
Solvent
t (h)
3a/4a
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
L1
L1
L2
L3
L4
L5
L5
L5
L5
L5
AgOAc
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
DCM
DCM
DCM
DCM
DCM
DCM
Et2O
THF
CH3CN
PhMe
5
3
3
3
3
3
3
5
8
6
67:33
86:14
92:8
90:10
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
53
65
70
72
79
82
88
64
38
78
À15
À27
À20
À40
98
>99
95
95
94
95
10
a
b
c
All reactions were carried out with 0.23 mmol of 1 and 0.35 mmol of 2a in 2 mL solvent. CuBF4 = Cu(CH3CN)4BF4.
Isolated yield.
Ee was determined by chiral HPLC analysis.

3652
Q.-H. Li et al. / Tetrahedron Letters 53 (2012) 3650–3653
Table 2
Substrate scope of CuBF4/L5-catalyzed exo-selective 1,3-DC of various imino esters 2 with cis-ethyl trifluorocrotonate 1a
EtO C
CF
3
2
CF
EtO C
3
2
CuBF /(R)-L5 (3 mol%)
4
1
+
CO Me
R
2
Et N (15 mol%),
N
H
3
DCM
CO Me
N
2
R
2
exo-3 (dr >98:2)
Entry
R
3
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
p-Cl-Ph (2a)
m-Cl-Ph (2b)
o-Cl-Ph (2c)
p-F-Ph (2d)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
82
83
82
80
80
85
78
81
85
86
78
73
81
87
83
68
>99
95
99
98
92
99
97
96
97
92
95
98
95
98
94
>99
o-F-Ph (2e)
p-CF3-Ph (2f)
p-Br-Ph (2g)
Ph (2h)
p-Me-Ph (2i)
o-Me-Ph (2j)
m-Me-Ph (2k)
p-MeO-Ph (2l)
2-furyl (2m)
1-Naphthyl (2n)
2-Naphthyl (2o)
PhCH@CH (2p)
a
b
c
All reactions were carried out with 0.23 mmol of 1 and 0.35 mmol of 2 in 2 mL DCM.
Isolated yield.
Ee was determined by chiral HPLC analysis.
2-furylaldehyde also works in this transformation leading to 81%
yield and 95% ee (entry 13). Noticeably, ,b-unsaturated imino
a
Ar
Ar
ester 2p derived from cinammyl aldehyde also proved to be viable
substrates in this process, producing the desired exo-3p with excel-
lent diastereoselectivity and >99% ee (entry 16). However, no
cycloaddition was observed when alkyl substituted imino ester
was tested under the same reaction conditions.
Ar
Ar
P
P
OMe
OMe
F3C
O
O
Cu
Cu
CF3
P
P
Ar
Ar
N
N
Ar
Ar
O
The relative and absolute configuration of exo-3a achieved by
Cu(CH3CN)4BF4/(R)-DTBM-BIPHEP (L5) was unequivocally deter-
RO
disfavored
R
R
O
favored
RO
EtO C
CF
EtO C
CF
3
2
3
2
TsCl/NEt
3
DCM, rt
CO Me
CO Me
2
2
RO2C
CF3
RO2C
CF3
CO2Me
N
H
N
Ts
Cl
Cl
R
N
CO2Me
R
(2R,3R,4S,5S)-exo-5
exo-3a
99%ee
N
H
H
98%ee
endo-adduct
exo-adduct
Figure 4. Proposed transition states leading to exo-cycloadduct.
mined by X-ray analysis of its corresponding N-tosylated deriva-
tive 5, and it was assigned as (2R,3R,4S,5S)12 (Fig. 3). Those of
other cycloadducts were tentatively proposed on the basis of these
results.
Based on the relative and absolute configuration of the
cycloadducts 3, the high exo-selectivity observed in the Cu(I)/(R)-
DTBM-BIPHEP (L5) catalyzed asymmetric 1,3-dipolar cycloaddition
reaction of azomethine ylide with cis-ethyl 4,4,4-trifluorocrotonate
can be rationalized by the proposed transition states in Figure 4. The
active species is a copper(I) complex having bulky and electron-
donating bisphosphine (R)-DTBM-BIPHEP and an in situ-formed
azomethine ylide in tetrahedral configuration.10f An exo approach
of cis-ethyl 4,4,4-trifluorocrotonate to the copper(I) complex
occurred predominantly because of the disfavored steric repulsion
between the substituents of cis-ethyl 4,4,4- trifluorocrotonate and
Figure 3. X-ray structure of exo-(2R,3R,4S,5S)-5.

Q.-H. Li et al. / Tetrahedron Letters 53 (2012) 3650–3653
3653
3. Schreiber, S. L. Science 1964, 2000, 287.
the large bulky aryl group on the phosphorus atom of the chiral
ligand corresponding to the endo approach.
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In conclusion, we have successfully developed a facile and prac-
tical approach to the catalytic asymmetric synthesis of the exo-pyr-
rolidines bearing a unique trifluoromethyl group for the first time.
An appropriate combination of a bulky and electron-donating bis-
phosphine ligand DTBM-BIPHEP with copper(I) salt led to excellent
diastereoselectivity and high enantioselectivity control. The ready
availability of the starting materials and the great importance of
the chiral trifluoromethylated pyrrolidines make the current meth-
odology particularly interesting in synthetic chemistry. Efforts are
currently underway to elucidate the mechanistic details and the
scope and limitations of this reaction, and the results will be
reported in due course.
Acknowledgments
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11. The Cu(I)/DTBM-BIPHEP(L5)-catalyzed reaction of trans-ethyl 4,4,4-
trifluorocrotonate with imino ester 2a delivered racemic endo-adduct in
moderate yield.
This work is supported by the NSFC (20972117, 21172176),
NCET-10-0649, IRT1030, 973 program (2011CB808600), the Fun-
damental Research Funds for the Central Universities, and Large-
scale Instrument And Equipment Sharing Foundation of Wuhan
University. We thank Prof. Hua Li in Wuhan University for solv-
ing the crystal structure and Prof. Jun-Liang Zhang in East China
Normal University for his generous support and helpful
discussion.
Supplementary data
Supplementary data (experimental procedures and character-
isation data) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.021.
References and notes
1. (a) Harwood, L. M.; Vickers, R. J. In Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, W., Eds.; Wiley & Sons: New York, 2002; (b) Michael, J. P. Nat. Prod.
Rep. 2008, 25, 139.
12. Crystal data for (2R,3R,4S,5S)-5:
C23H23ClF3NO6S, Mr = 533.94, T = 293 K,
2. For recent reviews about 1,3-dipolar cycloaddition reactions of azomethine
ylides, see: (a) Engels, B.; Christl, M. Angew. Chem., Int. Ed. 2009, 48, 7968; (b)
Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887; (c) Alvarez-Corral, M.;
Munoz-Dorado, M.; Rodrıguez-Garcıa, I. Chem. Rev. 2008, 108, 3174; (d)
Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132; (e) Bonin, M.;
Chauveau, A.; Micouin, L. Synlett 2006, 2349; (f) Nájera, C.; Sansano, J. M.
Angew. Chem., Int. Ed. 2005, 44, 6272; (g) Nair, V.; Suja, T. D. Tetrahedron 2007,
63, 12247; (h) Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784.
Orthorhombic, space group P212121, a = 10.1514(18), b = 12.640(2),
c = 20.255(4) Å, V = 2599.0(8) Å3, Z = 4. CCDC 847014 contains the
supplementary crystallographic data for this Letter. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/re-trieving.html (or
from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge
CB21EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).