Highly enantioselective reactions of α-sulfonyl carbanions of trifluoromethyl sulfones

Article abstract of DOI:10.1002/anie.200702185

(Chemical Equation Presented) Making a resolution: The catalytic enantioselective reaction of lithiated benzyl trifluoromethyl sulfone with aldehydes delivers products with excellent diastereoselectivity as well as high enantioselectivity. Fluorination of

Full text of DOI:10.1002/anie.200702185

Communications
DOI: 10.1002/anie.200702185
Homogeneous Catalysis
Highly Enantioselective Reactions of a-Sulfonyl Carbanions of
Trifluoromethyl Sulfones**
Shuichi Nakamura,* Norimune Hirata, Takeshi Kita, Ryusuke Yamada, Daisuke Nakane,
Norio Shibata, and Takeshi Toru*
Table 1: Enantioselective reaction of various a-lithiated sulfones 1a–f with benzaldehyde.
The formation of carbon–carbon
bonds by using readily generated
a-sulfonyl carbanions[1] and their
applications to the synthesis of
natural products[2] have been exten-
sively studied. Sulfones having chir-
ality at the a position are known to
showbiological activity, for exam-
ple, dorzolamide has antiglaucoma
activity,[3] but little attention has
been paid to the enantioselective
reaction of a-sulfonyl carbanions,[4]
probably because of the difficulty in
obtaining high enantioselectivity.
However, there are a few prece-
dents: the enantioselective reaction
of a-lithio sulfones derived from an
allyl sulfone using a chiral amino
alcohol as a chiral ligand[4a] and by
using chiral lithium amides.[4b] How-
Entry
1
Chiral ligand
Product
Yield[a] [%]
d.r.b] syn:anti
e.r.[c] syn
e.r.[c] anti
1[d]
2[d]
3[d]
4[d]
5[d]
6[d]
7[d]
8[d]
9[d]
10[f]
11
1a
1b
1c
1d
1e
1 f
1 f
1 f
1 f
1 f
1 f
1 f
1 f
1 f
1 f
1 f
1 f
3a
3a
3a
3a
3a
3a
3b
3c
4
3a
3a
3d
3e
3 f
3g
3g
3g
2a
2b
2c
2d
2e
2 f
2 f
2 f
2 f
2 f
2 f
2 f
2 f
2 f
2 f
2 f
2 f
19[e]
71[e]
83[e]
72
50:50
64:36
68:32
86:14
61:39
>98:2
>98:2
>98:2
>98:2
95:5
93:7
93:7
92:8
90:10
96:4
55:45
65:35
66:34
62:38
52:48
85:15
71:29
50:50
51:49
94:6
87:13
97:3
97:3
93:7
97:3
51:49
61:39
71:29
57:43
54:46
66[e]
56(56[e])
55
ever,
the
enantioselectivities
reported in these reports are unsat-
isfactory. Herein we report the first
highly and catalytic enantioselec-
tive reaction of a-lithiated sul-
fones.[5]
We first attempted the enantio-
selective reaction of a-carbanions
of various benzyl sulfones, for
example, methyl, tBu, phenyl, pen-
58
31
87
84
74
74
76
87
nd[i]
nd
nd
nd
nd
nd
nd
nd
12
13
14
15
16[g]
17[h]
87
44
96:4
95:5
97:3
95:5
tafluorophenyl,
and
2-pyridyl
benzyl sulfones 1a–e, respectively [a] Conversion yield determined by 19F NMR analysis. [b] Determined by 1H NMR analysis. [c] Deter-
mined by HPLC analysis on a chiral stationary phase. [d] The reaction was carried out at À788C with
125 mol% 3. [e] Yield of isolated product. [f] 3a (125 mol%) was used. [g] 3g (10 mol%) was used.
[h] 3g (2 mol%) was used. [i] Not determined.
(Table 1). The benzyl sulfones were
treated with nBuLi (1.2 equiv)
and
bis(oxazoline)-phenyl
3a
[*] Prof. S. Nakamura, N. Hirata, T. Kita, R. Yamada, D. Nakane,
Prof. N. Shibata, Prof. T. Toru
(1.25 equiv) in toluene and subsequently with benzaldehyde.
Trimethylsilyl chloride (TMSCl) was added for the trimethyl-
silylation of the formed alkoxide, thereby suppressing the
retro-aldol-type reaction. Most of the reactions gave high
yields of a diastereomeric mixture of the syn and anti isomers
of the products 2a–e, with each isomer having low enantio-
selectivity. Trifluoromethyl sulfones are known to have
unusual configurational stability.[6] Indeed, when benzyl
trifluoromethyl sulfone 1 f was allowed to react with a
stoichiometric amount of the bis(oxazoline)s at À788C
under similar reaction conditions, the syn-2 f was formed
exclusively. This syn isomer was obtained in high enantiose-
Department of Applied Chemistry
Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax: (+81)52-735-5442
E-mail: snakamur@nitech.ac.jp
toru@nitech.ac.jp
[**] We thank Dr. Jon Bordner, Shin-ichi Sakemi, and Dr. Masami
Nakane, Pfizer Inc., for X-ray crystallographic analysis. This work
was partly supported by the Asahi Glass Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
7648
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Angew. Chem. Int. Ed. 2007, 46, 7648 –7650

Angewandte
Chemie
lectivity with bis(oxazoline)-Ph 3a (Table 1, entry 6), whereas
bis(oxazoline)-tBu 3b, -iPr 3c, and (À)-sparteine (4) gave
lower enantioselectivity but exclusive formation of syn-2 f
(Table 1, entries 7–9). Other solvents such as cumene, Et2O,
or THF did not improve the enantioselectivity. The best
enantioselectivity was obtained when the reaction was carried
out at À308C in toluene using 3d (Table 1, entry 10).[7]
Furthermore, we were pleased to find that the reaction of
1 f proceeded with a substoichiometric amount of 3a. Thus,
the reaction of 1 f was performed with 30 mol% of 3a at
À308C to give syn-2 f as the major product in high yield and
with high enantioselectivity (Table 1, entry 11). Several
bis(oxazoline) derivatives also showed excellent results
(Table 1, entries 12–15). Even 10 mol% of the dibenzyl
bis(oxazoline) derivative 3g worked well (Table 1, entry 16).
Notably, 2 mol% of 3g was found to show even higher
enantioselectivity (Table 1, entry 17). OꢀBrien and co-work-
ers have reported an asymmetric deprotonation of a methyl-
ene proton a to amino and oxy groups in the presence of a
substoichiometric amount of (À)-sparteine to give products
with high enantioselectivity, with an achiral ligand used to
regenerate the BuLi/(À)-sparteine complex.[8] Interestingly,
our enantioselective reaction proceeded in a catalytic manner
without any additives.[9]
Scheme 1. Enantioselective fluorination of lithiated 1 f.
To define the enantiodetermining step in the enantio-
selective reaction of a-lithiated sulfones, we studied the
reaction of the racemic product syn-6 (rac-syn-6) by treating it
with 1.2 equivalents of nBuLi and a substoichiometric amount
of 3g to cause the retro-aldol-type reaction and then
subsequent reaction with p-chlorobenzaldehyde (Scheme 2).
The reaction of 1 f with various aromatic aldehydes such
as p-tolualdehyde, p-methoxybenzaldehyde, p-chlorobenzal-
dehyde, 2-naphthaldehyde, and 2-furaldehyde in the presence
of 3g gave the products 5–9 with excellent diastereoselectiv-
ities and high enantioselectivities (Table 2, entries 1–6).
Scheme 2. Enantioselective reaction of the racemic carbanion.
It was found that syn-7 was obtained with high enantioselec-
tivity. Furthermore, the reaction of lithiated 1 f with a
deficient amount of benzaldehyde afforded 2 f with complete
enantioselectivity (compare entries 4 and 7 in Table 2). These
results showthat the reaction of 1 f proceeds through a
dynamic thermodynamic resolution pathway.[9,13] The highly
enantio- and diastereoselective reaction of lithiated trifluoro-
methylsulfone can be ascribed to high configurational stabil-
ity of the carbanion as a result of the large n–s* interaction.[14]
In summary, we have disclosed the first highly enantio-
selective reactions of carbanions a to the sulfonyl group using
bis(oxazoline) derivatives. The reaction of lithiated 1 f
proceeds through a dynamic thermodynamic resolution path-
way. Furthermore, the success of the catalytic reaction is
surprising, considering that a stoichiometric amount of
butyllithium is used. To the best of knowledge, this is the
first report for the catalytic enantioselective reaction through
a dynamic thermodynamic resolution. This novel reaction
should provide insight for the development of enantioselec-
tive reactions of carbanions. A detailed study of the reaction
mechanism is currently under investigation and will be
reported in due course.
Table 2: Enantioselective reaction of trifluoromethyl sulfone 1 f with
various aldehydes in the presence of 3g.
Entry
R
Product Yield[a,b] [%] d.r.[c] syn:anti e.r.[d] syn
1[e]
2
3
Ph
2 f
5
6
7
8
74 (87)
70 (84)
57 (91)
66 (85)
54 (80)
35 (58)
16 (18)[g]
96:4
97:3
97:3
90:10
94:6
93:7
90:10
97:3
97:3
99:1
92:8
98:2
95:5
99:1
p-CH3C6H4
p-MeOC6H4
p-ClC6H4
2-naphthyl
2-furyl
4
5[e]
6
9
7
7[f]
p-ClC6H4
[a] Yield of isolated product. [b] Yield in parenthesis is the conversion
yield. [c] Determined by 1H NMR analysis. [d] Determined by HPLC
analysis on a chiral stationary phase. [e] 3g (10 mol%) was used. [f] p-
ClC6H4CHO (0.2 equiv) was used. [g] Based on 1 f.
Received: May 17, 2007
Published online: August 31, 2007
a-Fluorinated sulfur compounds can also serve as syn-
thetic intermediates or precursors for the synthesis of
fluorinated molecules[10] and bioactive compounds.[11] We
further studied the preparation of optically active a-fluoro-
benzyl sulfones. Fluorination of 1 f with N-fluorobenzensul-
fonimide (NFSI) with 1.25 equivalents of 3a afforded (R)-10
exclusively in moderate yield (Scheme 1).[12]
Keywords: asymmetric synthesis · carbanions ·
enantioselectivity · homogeneous catalysis · sulfones
.
[1] For reviews, see a) J. C. Stowell, Carbanion in Organic Synthesis,
Wiley, NewYork, 1979; b) N. S. Simpkins, Sulphones in Organic
Angew. Chem. Int. Ed. 2007, 46, 7648 –7650
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Communications
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OꢀBrien, J. Am. Chem. Soc. 2005, 127, 16378 – 16379; for the
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[9] We assume the catalytic pathway is as follows: The first-formed
dynamic thermodynamic-controlled a-lithiated sulfone-bis(ox-
azoline) complexes are transformed, together with regeneration
of bis(oxazoline), to an enantioenriched dimer or oligomer of
the a-lithiated sulfone which reacts with an aldehyde to yield the
enantioenriched product. In fact, we observed the precipitation
of the complex out of the reaction mixture before the addition of
an aldehyde, and confirmed that the precipitates mainly consist
of the dimer of the sulfonyl carbanions by ESI mass spectrom-
etry. The dimeric structure has been reported by Gais and co-
workers, see Ref. [6a]; see also the Supporting Information.
[10] a) J. R. McCarthy, D. P. Matthews, D. M. Stemerick, E. W.
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[12] The absolute configuration of 10 was determined by X-ray
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[13] For dynamic thermodynamic resolution, see P. Beak, D. R.
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[5] We have previously reported highly enantioselective lithiation-
substitution reactions of sulfides or selenides in the presence of
bis(oxazoline)s through asymmetric substitution, see a) S. Naka-
mura, R. Nakagawa, Y. Watanabe, T. Toru, Angew. Chem. 2000,
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[7] We also used NaOH, K2CO3, sBuLi, tBuLi, and EtMgBr as bases
in place of nBuLi, but lower enantioselectivity was obtained.
[8] A substoichiometric amount of (À)-sparteine and a stoichio-
metric amount of achiral ligand are used, see M. J. McGrath, P.
[14] It is well known that the configurational stability of a-sulfonyl
carbanions depends upon the magnitude of the n–s*(CCF3-S)
interaction, which is enhanced by the electron-withdrawing
group attached to the sulfonyl group, see Refs. [6a,d].
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