Partially saturated fluorinated heterocycles: Diastereo- and enantioselective synthesis of β-trifluoromethyl-pyrroline carboxylates

Article abstract of DOI:10.1039/c2cc18052a

The first asymmetric synthesis of β-trifluoromethylated pyrroline carboxylates has been achieved by organocatalytic conjugated addition of adamantyl glycine imine to β-trifluoromethylated enones, followed by a deprotection/cyclization/dehydration sequence.

Full text of DOI:10.1039/c2cc18052a

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COMMUNICATION
Partially saturated fluorinated heterocycles: diastereo- and
enantioselective synthesis of b-trifluoromethyl-pyrroline carboxylateswz
Hiroyuki Kawai,a Yutaka Sugita,a Etsuko Tokunaga,a Hiroyasu Sato,b Motoo Shirob and
Norio Shibata*a
Received 23rd December 2011, Accepted 15th February 2012
DOI: 10.1039/c2cc18052a
The first asymmetric synthesis of b-trifluoromethylated pyrroline
carboxylates has been achieved by organocatalytic conjugated
addition of adamantyl glycine imine to b-trifluoromethylated enones,
followed by a deprotection/cyclization/dehydration sequence.
has been recognized as an important class of compounds with
remarkable biological activities and thus a large number of
compounds 2 have been registered in databases.4
We recently reported the catalytic asymmetric synthesis of
biologically important 5-trifluoromethyl-2-isoxazolines 2 (XQO)
using chiral ammonium salts of Cinchona alkaloids.6 An expeditious
synthesis of 2 (XQO) based on the direct introduction of
a trifluoromethyl group into aromatic isoxazoles was also
disclosed.7 As part of our ongoing research programs directed at
the development of efficient methodologies for the construction of
trifluoromethylated heterocycles,8 we targeted b-trifluoromethyl
pyrroline carboxylates 3 (XQCHCO2R0) due to their potential
attractiveness as drug candidates as they have two contiguous
asymmetric centers. We disclose herein the first diastereo- and
enantioselective synthesis of b-trifluoromethylated pyrroline
carboxylates via organocatalytic conjugated addition of a
glycinate Schiff base 5 to b-trifluoromethylated enones 4 by
a phase-transfer catalyst derived from Cinchona alkaloids,
followed by a deprotection/cyclization/dehydration sequence
in excellent yields, excellent diastereoselectivities and high
enantioselectivities (Scheme 1).
Heterocycles constitute a major family of pharmaceuticals and
agrochemicals with a very long history.1 On the other hand,
fluorinated organic compounds have recently emerged as the
leading candidates in the future drug market, since adding
fluorine or a fluorinated group to biologically active compounds
can dramatically alter their metabolic stability, potency, or other
properties of parent compounds.2 In this context, heterocyclic
compounds with fluorine are becoming modern attractive targets
in the field of medicinal chemistry.3 Although the aromatic hetero-
cycles are a well-known group of heterocycles, we are interested in
the partially saturated fluorinated heterocyclic compounds. Fig. 1
shows selected examples of fluorinated aromatic heterocycles 1
(XQO, isoxazole; XQNH, pyrazole; XQCH2, 2H-pyrrole)
and their partially saturated variants 2 (XQO, isoxazoline;
XQNH, pyrazoline; XQCH2, pyrroline).4 The most obvious
aspect that differentiates 2 from 1 is the existence of chirality in
its cyclic framework. The chiral drug industry has soared in
recent years as a result of leading progress in asymmetric
synthesis;5 thus the partially saturated fluorinated heterocycles
containing chiral center(s) are very attractive. Indeed, a series
of partially saturated five-membered fluorinated heterocycles 2
b-Trifluoromethylated a,b-unsaturated carbonyl compounds
4 are used as potential building blocks for construction of a
stereogenic C–CF3 center.9 Billard and co-workers reported the
racemic synthesis of b-trifluoromethylated pyrroline carboxy-
lates 3 in good yields.10 However, the diastereoselectivity was
moderate and the asymmetric synthesis of 3 has not yet been
reported. To achieve the asymmetric variant of Billard’s method-
ology, we initiated our examination of the organocatalytic
asymmetric conjugated addition of glycinate Schiff base 5 onto
b-trifluoromethylated enones 4. In recent years, enantioselective
Fig. 1 While aromatic fluorinated heterocycles 1 do not have chirality,
their partially saturated variants 2 and 3 have chiral center(s).
a Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan. E-mail: nozshiba@nitech.ac.jp;
Fax: +81-52-735-5442
b Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima,
Tokyo 196-8666, Japan
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available. CCDC
866497. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc18052a
Scheme 1 Asymmetric organocatalytic synthesis of b-trifluoromethylated
pyrroline carboxylates 3.
c
3632 Chem. Commun., 2012, 48, 3632–3634
This journal is The Royal Society of Chemistry 2012

1,4-addition of glycinate Schiff base 5 to unsubstituted a,b-
unsaturated carbonyl compounds to construct a single asymmetric
center has been well examined.11 However, the enantioselective
1,4-addition of 5 to b-substituted a,b-unsaturated carbonyl
compounds for construction of two contiguous asymmetric
centers is a challenge.12 Kobayashi and co-workers reported
the catalytic asymmetric 1,4-addition reactions of 5 to
b-substituted a,b-unsaturated acrylates using Ca–Box catalysts
prepared from calcium alkoxides and methylene bridged Box
ligands in 22–82% de with 81–99% ee.12a Very recently, the
catalytic asymmetric 1,4-addition reaction of 5 to chalcones
catalyzed by chiral pentanidium salts to provide adducts with
excellent enantioselectivities and diastereoselectivities was
disclosed by Tan and co-workers.12b We started our investigation
with the reaction of (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one (4a)
with a tert-butyl glycinate-benzophenone Schiff base (5a) in the
presence of 50% KOH aq., and screened a more readily available
catalyst, and chiral quaternary ammonium phase transfer catalysts
(Table 1). We first attempted the reaction in the presence of a
catalytic amount of N-3,5-bis(trifluoromethylbenzyl) cinchoninium
bromide (6a) as a chiral phase transfer catalyst in toluene at 0 1C.
Although the b-trifluoromethylated pyrroline 3a was obtained in
88% yield with a low ee (38%), excellent diastereoselectivity was
observed (entry 1). The quinidine derivative 6b gave a slightly lower
ee value of 36% (entry 2). After screening several phase-transfer
catalysts derived from cinchonine 6c–6f (entries 3–6), catalyst 6e,
having a sterically demanding tBu group, was found to be the most
effective catalyst providing 3a in high yield (90%) with 55% ee
(entry 5). We next attempted the reaction using commercially
available Maruoka catalyst 6g; however, no improvement
was observed (entry 7). We then examined the effect of bases
(entries 8–15), and Cs2CO3 was found to be most effective in
terms of enantioselectivity (71% ee, entry 10). We continued
the survey of reaction conditions (entry 16–20), and a slightly
better result was obtained using cyclopentyl methyl ether,
CPME, as the solvent (entry 20, 96%, 72% ee). We next
turned our attention to the glycinate Schiff base 5. Steric
bulkiness of 5 was necessary for achieving high enantiocontrol,
and ee’s up to 82% of 3b were obtained when 1-adamantyl
glycinate-benzophenone Schiff base (5b) was used (entry 21,
75%, 82% ee). The best result was obtained when the reaction
was carried out at ꢀ20 1C in the presence of 5.0 equiv. of Cs2CO3
(entry 22, 95%, 86% ee). An excellent diastereoselectivity of
>95/5 was observed in all cases.
Table 1 Optimization of reaction conditions
Entrya
5
6
Base
Solvent
Time/h Yieldb (%) eec (%)
1
2
3
4
5
6
7
5a 6a 50% KOH aq. Toluene
5a 6b 50% KOH aq. Toluene
5a 6c 50% KOH aq. Toluene
5a 6d 50% KOH aq. Toluene
5a 6e 50% KOH aq. Toluene
5a 6f 50% KOH aq. Toluene
5a 6g 50% KOH aq. Toluene
1
1
2
2
2
88
95
97
97
90
95
90
84
76
82
70
59
86
86
83
95
86
90
97
96
75
95
38
36
39
14
55
0
2
2
35
68
69
71
70
27
51
39
60
66
25
66
68
72
82
86
8
9
5a 6e Na2CO3
5a 6e K2CO3
5a 6e Cs2CO3
5a 6e K3PO4
5a 6e tBuOK
5a 6e NaOMe
5a 6e Me4NF
5a 6e CsF
5a 6e Cs2CO3
5a 6e Cs2CO3
5a 6e Cs2CO3
5a 6e Cs2CO3
5a 6e Cs2CO3
5b 6e Cs2CO3
5b 6e Cs2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
62
53
12
12
3
2
2
24
10
11
12
13
14
15
16
17
18
19
20
21
22d
Mesitylene 40
CH2Cl2
THF
Et2O
CPME
CPME
CPME
12
12
4
4
5
9
a
The reaction of 4a with 5 (1.1 equiv.) was carried out in the presence of a
catalyst (10 mol%) and a base in solvent at 0 1C, unless otherwise noted.
Isolated yield. ee’s were determined by chiral HPLC. The reaction
b
c
d
was carried out at ꢀ20 1C in the presence of 5.0 equiv. of Cs2CO3.
With optimal conditions in hand, the scope of the conjugated
addition of glycinate Schiff base 5b to b-trifluoromethylated
enones 4 catalyzed by Cinchona phase-transfer catalyst 6e,
followed by a deprotection/cyclization/dehydration sequence
was explored with a variety of substrates selected in order to
establish the generality of the process, all affording excellent
yields, excellent anti-diastereoselectivities, and high enantio-
selectivities (Table 2). A series of b-trifluoromethylated enone
derivatives 4c–4i with a variety of substituents on their aromatic
rings, such as methyl, methoxy, fluoro, chloro, bromo, and
nitro, were nicely converted to 3c–3i in excellent yields with
excellent diastereoselectivities of >98/2 and high enantio-
selectivities of 77–88% ee (entries 1–8). Sterically demanding
naphthyl substituted enone 4j was also compatible, although
the enantioselectivities were somewhat low, affording product
3j in 97% yield with an ee value of 72% (entry 9). The
heteroaromatic substrate 4k bearing a furanyl group was also
a suitable substrate for this transformation, providing the
desired product 3k in 96% yield with 80% ee (entry 10).
Anti-3 was obtained exclusively in all the cases and the
absolute stereochemistry of anti-3b was determined after
derivatization to its methylester (Fig. S1, ESIz).13 All the other
products 3 were tentatively assigned by analogy.
In summary, we have developed the first asymmetric synthesis of
biologically attractive b-trifluoromethyl pyrroline carboxylates 3
containing two contiguous asymmetric centers in excellent yields
with excellent anti-diastereoselectivities and high enantioselectivities
using the Cinchona alkaloid-catalyzed conjugated addition of a
glycinate Schiff base to b-trifluoromethylated enones, followed by a
deprotection/cyclization/dehydration sequence. It should be noted
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3632–3634 3633

Table 2 Asymmetric synthesis of b-trifluoromethylated pyrroline 3
5 (a) S. C. Stinson, Chem. Eng. News, 2000, 78, 55; (b) S. C. Stinson,
Chem. Eng. News, 2001, 79, 79; (c) L. A. Nguyen, H. He and
C. Pham-Huy, Int. J. Biomed. Sci., 2006, 2, 85.
6 K. Matoba, H. Kawai, T. Furukawa, A. Kusuda, E. Tokunaga,
S. Nakamura, M. Shiro and N. Shibata, Angew. Chem., Int. Ed.,
2010, 49, 5762.
7 H. Kawai, K. Tachi, E. Tokunaga, M. Shiro and N. Shibata,
Angew. Chem., Int. Ed., 2011, 50, 7803.
8 (a) N. Shibata, H. Fujimoto, S. Mizuta, S. Ogawa, Y. Ishiuchi,
S. Nakamura and T. Toru, Synlett, 2006, 3484; (b) S. Ogawa,
N. Iida, E. Tokunaga, M. Shiro and N. Shibata, Chem.–Eur. J.,
2010, 16, 7090; (c) S. Ogawa, T. Nishimine, E. Tokunaga and
N. Shibata, Synthesis, 2010, 3274; (d) Y. Huang, E. Tokunaga,
S. Suzuki, M. Shiro and N. Shibata, Org. Lett., 2010, 12, 1136.
9 (a) T. Konno, T. Tanaka, T. Miyabe, A. Morigaki and T. Ishihara,
Tetrahedron Lett., 2008, 49, 2106; (b) G. Blay, I. Fernandez,
M. C. Munoz, J. R. Pedro and C. Vila, Chem.–Eur. J., 2010,
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X. Feng, Chem. Commun., 2011, 47, 7821.
Entrya
4
Ar
3
Time/h Yieldb (%) dr
eec (%)
1
2
3
4
5
6
7
8
9
10
4a Ph
4c 3-MeC6H4
4d 4-MeC6H4
4e 3-MeOC6H4 3e 36
4f 4-MeOC6H4 3f 12
4g 4-FC6H4
4h 4-ClC6H4
4i 4-BrC6H4
4j 2-Naphthyl 3j 14
4k 2-Furanyl 3k 16
3b
3c 36
3d 12
9
95
72
95
74
94
94
93
96
81
96
98 : 2 86
99 : 1 84
99 : 1 87
98 : 2 84
99 : 1 88
99 : 1 84
99 : 1 78
99 : 1 77
98 : 2 72
99 : 1 80
3g 15
3h 15
3i 15
10 O. Marrec, C. Christophe, T. Billard, B. Langlois, J.-P. Vors and
S. Pazenok, Adv. Synth. Catal., 2010, 352, 2825.
a
11 Review for the reaction of a glycinate Schiff base under phase-
transfer catalysis, see: (a) M. J. O’Donnell, Acc. Chem. Res., 2004,
37, 506; for selected examples, see:; (b) E. J. Corey, M. C. Noe and
F. Xu, Tetrahedron Lett., 1998, 39, 5347; (c) D. Ma and K. Cheng,
Tetrahedron: Asymmetry, 1999, 10, 713; (d) F.-Y. Zhang and
E. J. Corey, Org. Lett., 2000, 2, 1097; (e) T. Ishikawa, Y. Araki,
T. Kumamoto, H. Seki, K. Fukuda and T. Isobe, Chem. Commun.,
2001, 245; (f) M. J. O’Donnell, F. Delgado, E. Domınguez, J. de
Blas and W. L. Scottc, Tetrahedron: Asymmetry, 2001, 12, 821;
(g) S. Arai, R. Tsuji and A. Nishida, Tetrahedron Lett., 2002,
43, 9535; (h) T. Shibuguchi, Y. Fukuta, Y. Akachi, A. Sekine,
T. Ohshima and M. Shibasaki, Tetrahedron Lett., 2002, 43, 9539;
(i) T. Ohshima, T. Shibuguchi, Y. Fukuta and M. Shibasaki,
Tetrahedron, 2004, 60, 7743; (j) T. Ohshima, V. Gnanadesikan,
T. Shibuguchi, Y. Fukuta, T. Nemoto and M. Shibasaki, J. Am.
Chem. Soc., 2003, 125, 11206; (k) S. Arai, K. Tokumaru and
T. Aoyama, Chem. Pharm. Bull., 2004, 52, 646; (l) T. Akiyama,
M. Hara, K. Fuchibe, S. Sakamoto and K. Yamaguchi, Chem.
Commun., 2003, 1734; (m) B. Lygo, B. Allbutt and E. H. M.
Kirton, Tetrahedron Lett., 2005, 46, 4461; (n) S. Arai,
F. Takahashi, R. Tsuji and A. Nishida, Heterocycles, 2006,
67, 495; (o) T. Shibuguchi, H. Mihara, A. Kuramochi,
S. Sakuraba, T. Ohshima and M. Shibasaki, Angew. Chem., Int.
Ed., 2006, 45, 4635; (p) H. Mihara, T. Shibuguchi, A. Kuramochi,
T. Ohshima and M. Shibasaki, Heterocycles, 2007, 72, 421;
(q) S. Saito, T. Tsubogo and S. Kobayashi, J. Am. Chem. Soc.,
2007, 129, 5364; (r) T. Tsubogo, S. Saito, K. Seki, Y. Yamashita and
S. Kobayashi, J. Am. Chem. Soc., 2008, 130, 13321; (s) L. Bernardi,
J. Lopez-Cantarero, B. Niess and K. A. Jørgensen, J. Am. Chem.
Soc., 2007, 129, 5772; (t) A. Ryoda, N. Yajima, T. Haga,
T. Kumamoto, W. Nakanishi, M. Kawahata, K. Yamaguchi and
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G. D. Salla, J. Overgaard and K. A. Jørgensen, J. Am. Chem. Soc.,
2008, 130, 4897; (v) T. Kano, T. Kumano and K. Maruoka, Org.
Lett., 2009, 11, 2023; (w) G. Zhang, T. Kumamoto, T. Heima and
T. Ishikawa, Tetrahedron Lett., 2010, 51, 3927; (x) M. Strohmeier,
K. Leach and M. A. Zajac, Angew. Chem., Int. Ed., 2011, 50, 12335.
12 (a) S. Kobayashi, T. Tsubogo, S. Saito and Y. Yamashita, Org.
Lett., 2008, 10, 807; (b) T. Ma, X. Fu, C. W. Kee, L. Zong, Y. Pan,
K.-W. Huang and C.-H. Tan, J. Am. Chem. Soc., 2011, 133, 2828.
13 3b was converted into methylester [TfOH (1.0 equiv.), MeOH,
reflux, 48 h, 92%], and the absolute stereochemistry of (2R, 3R)-3
was determined by X-ray analysis (CCDC 866497, Fig. S1, ESIz).
14 I. Kin, G. Ohta, K. Teraishi and K. Watanabe, US 2005065060,
2005.
The reaction of 4 with 5b (1.1 equiv.) was carried out in the presence
of 6e (10 mol%) and Cs2CO3 (5.0 equiv.) in CPME at ꢀ20 1C.
b
c
Isolated yield. ee’s were determined by chiral HPLC.
that the combination of the new bulky adamantyl glycinate
and CPME14 solvent introduced asymmetry into the Billard
chemistry,10 with especially good diastereocontrol. The
adamantyl ester would provide an attractive alternative to
the analogous methyl, tert-butyl, or cumyl esters.15 The use of
CPME should be advantageous for industrial use due to the
high stability, wide liquidity range, low heat of vaporization,
resistance to peroxide formation and narrow explosion area.14
This study was financially supported in part by Grants-in-
Aid for Scientific Research (21390030, 22106515, 23915014,
Project No. 2105: Organic Synthesis Based on Reaction
Integration). We also thank the Asahi Glass Foundation for
support in part.
Notes and references
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Soc., 2011, 133, 11757.
4 More than 29 000 compounds 2 (XQO), 15 000 compounds 2
(XQN), 12 000 compounds 2 (XQCH2) have been registered in
the SciFinder database on December, 2011.
c
3634 Chem. Commun., 2012, 48, 3632–3634
This journal is The Royal Society of Chemistry 2012