Enantioselective synthesis of β-trifluoromethyl-βlactones via NHC-catalyzed ketene - ketone cycloaddition reactions

Article abstract of DOI:10.1021/ol901290z

The highly diastereo- and enantioselective synthesis of β-trifluoromethyl-β-lactones bearing two contiguous stereocenters was realized by chiral N-heterocyclic carbene-catalyzed formal cycloaddition reaction of alkyl(aryl)ketenes and trifluoromethyl ketones.

Full text of DOI:10.1021/ol901290z

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4029-4031
Enantioselective Synthesis of
ꢀ-Trifluoromethyl-ꢀ-lactones via
NHC-Catalyzed Ketene-Ketone
Cycloaddition Reactions
Xiao-Na Wang, Pan-Lin Shao, Hui Lv, and Song Ye*
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China
songye@iccas.ac.cn
Received June 10, 2009
ABSTRACT
The highly diastereo- and enantioselective synthesis of ꢀ-trifluoromethyl-ꢀ-lactones bearing two contiguous stereocenters was realized by
chiral N-heterocyclic carbene-catalyzed formal cycloaddition reaction of alkyl(aryl)ketenes and trifluoromethyl ketones.
Because of their unique properties, fluorinated compounds have
found wide applications in pharmaceuticals, agrochemistry, and
materials.1 Among them, trifluoromethyl-substituted compounds
are especially important and have been developed as several
well-known drugs.2 Thus, the efficient synthesis of these
compounds has been pursued for decades.3 In this context,
commercially available trifluoromethyl ketones are valuable
starting materials, and a wide variety of reactions, including
aldol reaction, Friedal-Crafts reaction, alkynylation, alkeny-
lation, arylation, and reduction, have been developed.4
many natural and unnatural bioactive compounds.5,6 Although
the synthesis of ꢀ-trifluoromethyl-ꢀ-lactones was patented
in 1966,7 to the best of our knowledge, the asymmetric synthesis
of ꢀ-trifluoromethyl-ꢀ-lactones has not been realized.
N-Heterocyclic carbenes (NHCs) have been successfully
demonstrated as catalysts for a variety of reactions,8 including
(4) (a) Ferna´ndez, R.; Mart´ın-Zamora, E.; Pareja, C.; Va´zquez, J.; D´ıez,
E.; Monge, A.; Lassaletta, J. M. Angew. Chem., Int. Ed. 1998, 37, 3428.
(b) Motoki, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 2997. (c)
Martina, S. L. X.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard,
A. J. Chem. Commun. 2006, 4093. (d) Bøgevig, A.; Gothelf, K. V.;
Jørgensen, K. A. Chem.sEur. J. 2002, 8, 5652. (e) Bandini, M.; Sinisi, R.;
Umani-Ronchi, A. Chem. Commun. 2008, 4360. (f) Rueping, M.; Theiss-
mann, T.; Kuenkel, A.; Koenigs, R. M. Angew. Chem., Int. Ed. 2008, 47,
6798. (g) Zhao, J.-L.; Liu, L.; Gu, C.-L.; Wang, D.; Chen, Y.-J. Tetrahedron
Lett. 2008, 49, 1476. (h) Shi, M.; Liu, X.-G.; Guo, Y.-W.; Zhang, W.
Tetrahedron 2007, 63, 12731. (i) Tur, F.; Saa´, J. M. Org. Lett. 2007, 9,
5079. (j) Motoki, R.; Tomita, D.; Kanai, M.; Shibasaki, M. Tetrahedron
ꢀ-Lactones not only are versatile building blocks in organic
synthesis but also represent an important structural motif in
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, 2004. (b) Organofluorine Compounds in Medicinal Chemistry
and Biomedical Applications; Filler, R., Kobayashi, Y., Yagupolskii, L. M.,
Eds.; Elsevier: Amsterdam, 1993.
(2) (a) Asymmetric Fluoroorganic Chemistry; Ramachandran, P. V., Ed.;
ACS Symposium Series; American Chemical Society: Washington, DC,
2000. (b) Abid, M.; Torok, B. AdV. Synth. Catal. 2005, 347, 1797.
(3) (a) Ma, J. A.; Cahard, D. Chem. ReV. 2004, 104, 6119. (b) Uneyama,
K.; Katagiri, T.; Amii, H. Acc. Chem. Res. 2008, 41, 817.
Lett. 2006, 47, 8083.
(5) For the highlights and reviews, see: (a) Schneider, C. Angew. Chem.,
Int. Ed. 2002, 41, 744. (b) Yang, H. W.; Romo, D. Tetrahedron 1999, 55,
6403. (c) Wang, Y.; Tennyson, R. L.; Romo, D. Heterocycles 2004, 64,
605
.
10.1021/ol901290z CCC: $40.75
Published on Web 08/14/2009
 2009 American Chemical Society

a1-d1 umpolung of aldehydes,9 a3-d3 umpolung of R,ꢀ-
unsaturated aldehydes,10 umpolung of Michael acceptors,11
aza-Mortia-Baylis-Hillman reaction,12 and addition of
silylated nucleophiles.13 The synthesis of γ-trifuoromethyl
γ-butyrolactones via NHC-catalyzed annulation of enals and
ketones was reported by Glorius et al. and You et al.14
Interestingly, Glorius et al. obsevered that, under certain
reaction conditions, the corresponding ꢀ-lactones could be
formed albeit in quite low yields and diastereoselectivities.15
Table 1. Optimization of Conditions for the NHC-Catalyzed
Ketene-Ketone Cycloaddition Reactiona
yield
ee
Recently, the NHC-catalyzed enantioselective cycloaddition
of ketenes and imines, 2-oxoaldehydes, enones, and N-ben-
zoyldiazenes to give ꢀ-lactams, ꢀ-lactones, δ-lactones, and
oxadiazinones, respectively, have been accomplished by Smith’s
and our group.16 These findings prompted us to explore the
asymmetric synthesis of ꢀ-trifluoromethyl-ꢀ-lactones via NHC-
catalyzed ketene-ketone cycloaddition reactions.
entry catalyst
conditions
toluene, rt
(%)b trans:cisc (%)d
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
16
47
42
57
5:1
5:1
5:1
5:1
77
86
86
89
toluene, rt
toluene, rt
toluene, rt
toluene, rt
toluene, rt
toluene, rt
toluene, rt
toluene, rt
toluene, rt
benzene, rt
ether, rt
THF, rt
CH2Cl2, rt
toluene/ether (1:1), rt 50
toluene, 0 °C
toluene, -20 °C
toluene, -40 °C
toluene, -78 °C
toluene, -40 °C
toluene, -40 °C
trace
10
1:1
73
7
8
9
4g
4h
5
trace
trace
trace
trace
52
43
42
41
Initially, a series of NHC precurors 4a-h (Figure 1), derived
from L-pyroglutamic acid,16a were tested for the [2 + 2]
10
11
12
13
14
15
16
17
18
19
20
21
6
4d
4d
4d
4d
4d
4d
4d
4d
4d
4de
4df
5:1
4:1
3:1
2:1
4:1
5:1
6:1
6:1
89
88
88
85
87
92
96
97
64
65
81
NR
71
17
6:1
6:1
97
97
a NHCs were prepared freshly from precursors 4-6 (12 mol %) in the
presence of Cs2CO3 (10 mol %) at rt for 1 h. b Isolated yields. c Determined
by H NMR (300 MHz) and/or GC. d ee of trans-3a, determined by GC.
1
e 4d (6 mol %) and Cs2CO3 (5 mol %) were employed. f 4d (1.2 mol %)
Figure 1. Structure of NHC precursors.
and Cs2CO3 (1 mol %) were employed.
yl-ꢀ-lactone 3a bearing two contiguous stereocenters with good
diastereoselectivity and enantioselectivity albeit in only 16%
yield (entry 1). Better yield and enantioselectivity were observed
when precatalyst 4b, bearing a bulkier tert-butyldimethylsilyl
group, was employed (entry 2). Further optimizations were
carried out by installing an electron-donating group in the N-aryl
group of the NHCs in order to increase the nucleophilicity of
cycloaddition reaction of ethyl(phenyl)ketene (1a) and triflu-
oromethyl ketone 2a (Table 1). It was found that NHC4a′,17
generated freshly from its precursor 4a and Cs2CO3,18 could
catalyze the reaction to give the corresponding ꢀ-trifluorometh-
(6) For the enantioselective synthesis of ꢀ-lactones via [2 + 2]
cycloaddition of ketenes and aldehydes, see: (a) Wynberg, H.; Staring,
E. G. J. J. Am. Chem. Soc. 1982, 104, 166. (b) Nelson, S. G.; Peelen, T. J.;
Wan, Z. J. Am. Chem. Soc. 1999, 121, 9742. (c) Cortez, G. S.; Tennyson,
R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945. (d) Evans, D. A.;
Janey, J. M. Org. Lett. 2001, 3, 2125. (e) Calter, M. A.; Tretyak, O. A.;
Flaschenriem, C. Org. Lett. 2005, 7, 1809. (f) Wilson, J. E.; Fu, G. C. Angew.
Chem., Int. Ed. 2004, 43, 6358. (g) Gnandesikan, V.; Corey, E. J. Org.
Lett. 2006, 8, 4943.
(11) Fischer, C.; Smith, S. W.; Powell, D. A.; Fu, G. C. J. Am. Chem.
Soc. 2006, 128, 1472.
(12) He, L.; Jian, T.-Y.; Ye, S. J. Org. Chem. 2007, 72, 7466.
(13) (a) Song, J. J.; Tan, Z.; Reeves, J. T.; Gallou, F.; Yee, N. K.;
Senanayake, C. H. Org. Lett. 2005, 7, 2193. (b) Wu, J.; Sun, X.; Ye, S.;
Sun, W. Tetrahedron Lett. 2006, 47, 4813.
(7) Linn, W. J. U.S. Patent 3,271,419, Sept. 6, 1966.
(14) (a) Hirano, K.; Piel, I.; Glorius, F. AdV. Synth. Catal. 2008, 350,
984. (b) Li, Y.; Zhao, Z.-A.; He, H.; You, S.-L. AdV. Synth. Catal. 2008,
350, 1885. (c) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43,
6205.
(8) For reviews of NHC-catalyzed reactions, see: (a) Enders, D.;
Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606. (b) Marion, N.;
D´ıez-Gonza´lez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988.
(c) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506. (d) Enders, D.;
Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
(15) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006, 2418.
(16) (a) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett.
2008, 10, 277. (b) Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith,
A. D. Org. Biomol. Chem. 2008, 6, 1108. (c) He, L.; Lv, H.; Zhang, Y.-R.;
Ye, S. J. Org. Chem. 2008, 73, 8101. (d) Zhang, Y.-R.; Lv, H.; Zhou, D.;
Ye, S. Chem.sEur. J. 2008, 14, 8473. (e) Huang, X.-L.; He, L.; Shao,
P.-L.; Ye, S. Angew. Chem., Int. Ed. 2009, 48, 192.
(9) (a) Sheehan, J.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666.
(b) Enders, D.; Breuer, K.; Teles, J. H. HelV. Chim. Acta 1996, 79, 1217.
(c) Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.;
Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696. (d) Li, G.-Q.; Dai, L.-X.;
You, S.-L. Chem. Commun. 2007, 852. (d) Stetter, H. Angew. Chem., Int.
Ed. 1976, 15, 639. (e) Enders, D.; Han, J.; Henseler, A. Chem. Commun.
2008, 3989.
(17) For convenience, the corresponding NHCs prepared from the
precursors 4a-h were denoted as NHCs 4a′-h′.
(18) It was found that Cs2CO3 alone could promote the reaction. Thus
a little excess of NHC precursor was used to make the full consumption of
the base of Cs2CO3.
(10) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205.
(b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370. (c) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905.
4030
Org. Lett., Vol. 11, No. 18, 2009

the corresponding NHCs.19 Interestingly, although no notable
difference was found for the reaction catalyzed by NHC4c′ (Ar2
) 4-MeOC6H4), NHC 4d′ (Ar2 ) 2-i-PrC6H4) resulted in better
yield and enantioselectivity (entries 3 and 4). The NHCs 4e-g
bearing a free hydroxyl group showed very little activities for
this reaction (entries 5-7).20 NHC 4h, which switched the
enantioselectivities for the [4 + 2] cycloaddition reaction of
ketenes with N-benzoydiazene in our previous report,9e did not
work for this reaction (entry 8). Both the tetracyclic precatalyst
5 and thiazolium precatalyst 6 failed to catalyze the reaction
under current reaction conditions (entries 9 and 10). Experiments
revealed that toluene is the solvent of choice (entries 11-15)
and -40 °C is the optimal reaction temperature (entries 16-19).
Decreasing the loading of the NHC catalyst led to low yields
but without notable change of diastereo- and enantioselectivities
(entries 20 and 21).
cycloaddition reaction with 2-oxoaldehydes,9c gave no ꢀ-lac-
tones (entries 17 and 18). The reaction of benzyl(ethyl)ketene
afforded the corresponding ꢀ-lactone in quantitative yield with
1:1 diastereoselectivity but excellent enantioselectivities for both
diastereomers (entry 19).
A possible catalytic cycle is depicted in Figure 2. The
stereochemical outcome of the cycloaddition reaction of
A wide variety of aryl(alkyl)ketenes were then tested for the
NHC-catalyzed reaction (Table 2). Both electron-donating and
Table 2. Enantioselective Synthesis of
ꢀ-Trifluoromethyl-ꢀ-lactones Catalyzed by NHC 4d′
Figure 2. Proposed catalytic cycle.
ketenes and ketones catalyzed by NHC 4a′-d′ is the same
as other reported [2 + 2] and [4 + 2] cycloaddition reactions
of ketenes and imines, enones, and N-benzoyldiazenes
catalyzed by NHC 4b′. However, this stereochemical out-
come is different from the formal cycloaddition of ketenes
bearing bulkyl substituents and 2-oxoaldehydes.16c,21
In conclusion, chiral triazolium NHCs, derived from
L-pyroglutamic acid, are found to be efficient catalysts for
the enantioselective [2 + 2] cycloaddition reaction of
aryl(alkyl)ketenes and trifluoromethyl ketones to give the
corresponding ꢀ-trifluoromethyl-ꢀ-lactones bearing two con-
tiguous stereocenters in high yields with good diastereose-
lectivities and excellent enantioselectivities.22
yield
ee
entry
1 (Ar1, R)
Ph, Et
4-MeC6H4, Et
4-MeOC6H4, Et Ph
4-ClC6H4, Et
Ph, Me
4-MeC6H4, Me Ph
Ph, Et,
4-MeC6H4, Et
4-MeOC6H4, Et 4-ClC6H4
4-ClC6H4, Et
4-BrC6H4, Et
4-MeC6H4, Me 4-ClC6H4
Ph, n-Pr
2 (Ar2)
Ph
3
(%)a trans:cisb (%)c
1
2
3
4
5
6
7
8
3a 81
3b 86
3c 90
3d 50
3e 76
3f 84
3g 89
3h 93
3i 95
6:1
7:1
7:1
97
95
Ph
93
Ph
Ph
14:1
23:1
17:1
9:1
11:1
11:1
16:1
16:1
12:1
4:1
FDd
99
99
98
99
97
93
93
99
FD
FD
96
4-ClC6H4
4-ClC6H4
9
10
11
12
13
4-ClC6H4
4-ClC6H4
3j
90
Acknowledgment. This paper is dedicated to Professor
Li-Xin Dai on the occasion of his 85th birthday. Financial
support from National Natural Science Foundation of China
(Nos. 20602036, 20872143), the Ministry of Science and
Technology of China (2009ZX09501-018), and the Chinese
Academy of Sciences are greatly acknowledged.
3k 83
3le 96
3m 99
3n 81
3o 56
3p 60
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
Ph
14f, g Ph, n-Bu
6:1
7:1
7:1
15f
16f
17
18
19
Ph, Et
4-MeC6H4, Et
2-ClC6H4, Et
4-ClC6H4, i-Pr Ph
Bn, Et
FD
NRh
NR
4-MeOC6H4 3q 99
Supporting Information Available: Experimental pro-
cedures, compound characteriations, CD spectra, and crystal
structure data of lactone 3l in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
1:1
91
a Isolated yields. Determined by H NMR (300 MHz). c ee of trans-
isomer, determined by GC (3a) and HPLC (3b-q). d FD ) failed to
determine the ee because the two enantiomers could not be separated on
the Daicel chiralpak columns. e The absolution configurations of lactone 3l
was determined to be (3S,4S) by X-ray. f The ketenes were added in three
portions every 3 h. g The reaction was carried out at room temperature.
h NR ) no reaction.
b
1
OL901290Z
(19) Lv, H.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. AdV. Synth. Catal. 2008,
350, 2715.
(20) He, L.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Synthesis 2008, 2825.
(21) The different stereochemical outcome of bulky ketenes is also
observed in the [4 + 2] cycloaddition reaction of ketenes with N-
benzoyldiazenes (ref 16e).
electron-withdrawing groups in aryl substituent of ketenes or
in trifluoromethyl ketones are tolerable. Ketenes with methyl,
ethyl, n-propyl, and n-butyl substituents all worked well.
However, ketenes with a sterically bulky subsituent, such as
2-chlorophenyl and isopropyl, which worked well in the
(22) Attempts for the chemical transformations of ꢀ-lactone 3a revealed
that (1) compound 3a was stable and did not decarboxylate upon heating
in acidic conditions; (2) no reaction occurred under the saponification
condition; and (3) reductive opening with LiAlH4 led to a complex instead
of the corresponding diol. See Supporting Information for details.
Org. Lett., Vol. 11, No. 18, 2009
4031