Catalytic and highly enantioselective reactions of α-sulfonyl carbanions with chiral bis(oxazoline)s

Article abstract of DOI:10.1002/chem.200800221

The enantioselective reactions of lithiated benzyl trifluoromethyl sulfones with a substoichiometric amount of a bis(oxazoline) and various aldehydes is disclosed. The products were formed with excellent diastereo- and enantioselectivities. Fluorination of the sulfone with N- fluorobenzenesulfonimide and a stoichiometric amount of a bis(oxazoline) gave products with extremely high enantioselectivities (up to 99% ee; ee = enantiomeric excess). The enantioselective reaction was confirmed to proceed through a dynamic thermodynamic resolution pathway.

Full text of DOI:10.1002/chem.200800221

FULL PAPER
DOI: 10.1002/chem.200800221
Catalytic and Highly Enantioselective Reactions of a-Sulfonyl Carbanions
with Chiral Bis(oxazoline)s
Shuichi Nakamura,* Norimune Hirata, Ryusuke Yamada, Takeshi Kita,
Norio Shibata, and Takeshi Toru*[a]
Abstract: The enantioselective reactions of lithiated benzyl trifluoromethyl sul-
fones with a substoichiometric amount of a bis(oxazoline) and various aldehydes is
disclosed. The products were formed with excellent diastereo- and enantioselectiv-
Keywords: asymmetric synthesis ·
ities. Fluorination of the sulfone with N-fluorobenzenesulfonimide and a stoichio-
carbanions · catalysis · chirality ·
metric amount of a bis(oxazoline) gave products with extremely high enantioselec-
enantioselectivity
tivities (up to 99% ee; ee=enantiomeric excess). The enantioselective reaction
was confirmed to proceed through a dynamic thermodynamic resolution pathway.
Introduction
the enantioselective reactions of a-sulfonyl carbanions,
which is probably due to the difficulties in obtaining high
enantioselectivities for these reactions.[6,7] Pioneering re-
search on the highly enantioselective reactions of a-sulfonyl
carbanions derived from allyl sulfones by using a chiral di-
amino alcohol and Grignard reagents has been reported by
Akiyama and co-workers (up to 80% ee obtained; ee=ena-
tiomeric excess).[6a] Simpkins has reported the enantioselec-
tive deprotonation of sulfonyl compounds by using cam-
phor-derived chiral lithium amides in an in situ trap reaction
with TMSCl (TMS=trimethylsilyl).[6b] Although these pio-
neering reports anticipated a possible method for improving
the enantioselectivities of these reactions, there have been
no reports that utilise a-lithiated sulfones to challenge these
difficulties. Recently, we communicated the first highly
enantioselective reactions of a-lithiated sulfones with vari-
ous electrophiles by using a stoichiometric or a substoichio-
metric amount of a chiral bis(oxazoline).[8,9] Herein, we
focus on a detailed study of the enantioselective reactions of
a-lithiated sulfones and a systematic study of this type of
asymmetric synthesis.
Carbon–carbon bond formation by using a-sulfonyl carban-
ions has been extensively studied because carbanions can be
easily formed a to sulfonyl groups due to their high acidity.
These a-sulfonyl carbanions can then easily react with vari-
ous electrophiles.[1] Therefore, reactions of a-sulfonyl car-
banions have been applied in the syntheses of a number of
natural products.[2] Furthermore, sulfones with chirality at
the a position are known to show biological activity, for ex-
ample, the antiglaucoma activity of dorzolamide[3] and the g-
secretase inhibitor for Alzheimerꢀs disease.[4] On the other
hand, chiral sulfonyl analogues of carbonyl derivatives are
gaining an increasingly important role in medicinal chemis-
try because the structural and electronic properties of the
chiral sulfonyl group mimic the carbonyl moiety in the tran-
sition state,[5] and thus the catalytic asymmetric preparation
of enantiomerically pure sulfonyl derivatives is in high
demand. However, only a little attention has been paid to
[a] Prof. S. Nakamura, N. Hirata, R. Yamada, T. Kita, Prof. N. Shibata,
Prof. T. Toru
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
Results
Initially, we examined the enantioselective reactions of vari-
ous a-lithiated sulfones 1a–e, such as methyl 1a, tBu 1b,
phenyl 1c, pentafluorophenyl 1d, and 2-pyridyl benzyl 1e
sulfones, with benzaldehyde (Table 1). Sulfones 1a–e were
treated with nBuLi (1.2equiv) and bis(oxazoline)-Ph 3a
Supporting information for this article is available on the WWW
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Table 1. Enantioselective reactions of various a-lithiated sulfones 1a–f
with benzaldehyde
Furthermore, we were pleased to find that the reaction of
1 f proceeded with substoichiometric amount of
a
3
(Table 2). Thus, the reaction of 1 f was performed with
Table 2. Catalyst loading of the bis(oxazoline) ligands for the reaction of
1 f with benzaldehyde.
Entry
1
Chiral ligand
2
Yield[a] [%] dr[b]
syn/anti
er[c] syn er[c] anti
1
2
3
4
5
6
7
8
1a 3a
1b 3a
1c 3a
1d 3a
1e 3a
1 f 3a
1 f 3b
1 f 3c
2a 19[d]
50:50 55:45
64:36 65:35
68:3266:34
51:49
61:39
719:2
Entry Chiral ligand 3 [mol%] Yield[a] [%] dr[b] syn/anti er[c] syn
2b 71[d]
2c 83[d]
1
2
3
4
5
6
7
8
9
3a
3d
3e
3 f
3g
3g
3g
3g
3g
30
30
30
30
30
10
5
84
81
74
76
87
87
81
93:7
93:7
91:9
90:10
96:4
96:4
96:4
87:13
96:4
97:3
93:7
97:3
97:3
95:5
2d :378286:1847:1632
2e 66[d]
61:39 52:48
>98:285:15
>98:2791:2 –
>98:250:50
>98:251:49
>98:270:30
>98:269:31
>98:251:49
54:46
2 f 56(56[d]
2 f 55
2 f 58
2 f 31
2 f 42
2 f 45
2 f 30
2 f 65
2 f 87
)
–
–
–
–
–
–
9
1 f
4
10[e]
11[f]
12[g]
13[h]
14[i]
1 f 3a
1 f 3a
1 f 3a
1 f 3a
1 f 3a
286
1
95:5
96:4
77
96:4
90:10
[a] Conversion yield determined by 19F NMR spectroscopic analysis.
[b] Determined by 1H NMR spectroscopic analysis. [c] Determined by
chiral HPLC analysis.
95:5
95:5
86:14
94:6
nd[j]
nd[j]
[a] Conversion yield determined by 19F NMR analysis. [b] The diastereo-
meric ratio (dr) was determined by 1H NMR spectroscopic analysis.
[c] The enatiomeric ratio (er) was determined by chiral HPLC analysis.
[d] Isolated yield. [e] In cumene. [f] In Et2O. [g] In THF. [h] The reaction
was carried out at À908C. [i] At À308C. [j] nd=not determined
30 mol% of 3a at À308C to give syn-2 f as a major product
in high yield and with slightly lower enantioselectivity than
that obtained by using a stoichiometric amount of 3a
(entry 1). To improve the enantioselectivity, we optimized
the bridging group of the bis(oxazoline) ligand. Several bis-
(1.25 equiv) in toluene for 1 h and subsequently with benzal-
dehyde (1.5 equiv). TMSCl was added to suppress the retro-
aldol-type reaction by trimethylsilylation of the formed alk-
oxides. Most of the reactions gave high yields of a diastereo-
meric mixture of the syn and anti isomers of the products
2a–e, in which each isomer was found to have low enantio-
selectivity (entries 1–5). On the other hand, trifluoromethyl
sulfones,[10] which are known to have unusual configuration-
al stability[11] were allowed to react at À788C under similar
reaction conditions with a stoichiometric amount of a bis-
(oxazoline) and the syn isomer (syn-2 f) was formed exclu-
sively (entry 6). The reaction of lithiated 1 f with bis(oxazo-
line)-tBu 3b afforded syn-2 f with a slightly lower enantiose-
lectivity than that obtained from the reaction with bis(oxa-
zoline)-Ph 3a (entry 7), whereas the reaction with bis(oxazo-
line)-iPr 3c or (À)-sparteine (4) gave racemic 2 f (entries 8
and 9). The reaction of lithiated 1 f with 3a in other solvents,
such as cumene, Et2O, and THF, afforded the product 2 f
with a lower enantioselectivity than that obtained in toluene
(entries 10–12). The best enantioselectivity was obtained
when the reaction was carried out at À308C in toluene with
3a (entry 14).
A
(entries 2–5). Even 10 or 5 mol% of dibenzyl bis(oxazoline)
derivative 3g worked well and produced a good yield and
excellent enantiomeric ratio (entries 6 and 7). Notably,
2mol% of 3g was found to show even higher enantioselec-
tivity, although the reaction by using 1 mol% of 3g gave 2 f
with slightly lower enantioselectivity (entries 8 and 9). In
general, enantioselective reactions of carbanions a to hetero-
atoms prepared from a substoichiometric amount of a chiral
ligand and a stoichiometric amount of alkyllithium species
afforded adducts derived from the reaction of aldehydes
with alkyllithium species as major products. Recently,
OꢀBrien and co-workers have overcome this difficulty by
using a substoichiometric amount of (À)-4 and a stoichio-
metric amount of an achiral ligand; however, an achiral
ligand is inevitably used to regenerate the chiral ligand.[12a,b]
It should be noted that our enantioselective reaction pro-
ceeds in a catalytic manner without any additives.
Table 3 shows the results of the reaction of sulfone 1 f
with various aldehydes in the presence of a substoichiomet-
ric amount of 3g. The reaction of 1 f with various aromatic
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Enantioselective Reactions of a-Sulfonyl Carbanions
FULL PAPER
Table 3. Enantioselective reaction of trifluoromethyl sulfone 1 f with var-
ious aldehydes in the presence of 3g.
fones. Although the reaction of lithiated 1 f and bis(oxazo-
line)-Ph 2a with Selectfluor as a fluorination reagent afford-
ed a trace amount of the product 21, the reaction with NFSI
(N-fluorobenzenesulfonimide) afforded 21 in moderate
yield with excellent enantioselectivity (99% ee; Scheme 1).
Entry
R
Product Yield[a] [%] dr[b] syn/anti er[c] syn
1[d]
2
3
4
5
6
7
8
9
Ph
2 f
5
6
7
8
87
84
88
71
91
85
87
96
80
80
58
95
94
96: 4
97: 3
97: 3
98: 299: 1
97: 3
90:10
84:16
91: 9
98: 298: 2
94: 6
97: 3
97: 3
98: 2
p-CH3C6H4
o-CH3C6H4
2,4-(CH3)2C6H3
p-MeOC6H4
p-ClC6H4
o-ClC6H4
p-FC6H4
1-Naphthyl
2-Naphthyl
2-Furyl
99: 1
92: 8
91: 9
96: 4
9
Scheme 1. Enantioselective fluorination of lithiated 1 f.
10
11
12
13
14
15
16
10[d]
11
-Th1i2e2nyl
13
98: 2
95: 5
96: 4
99: 1
The absolute configuration of 21 was determined to be R by
X-ray crystallographic analysis. These results are the first ex-
amples of highly enantioselective reactions of a-lithiated
sulfones with various electrophiles.
93: 7
97: 3
86:16
À
PhCH=CH
[a] Conversion yield. [b] Determined by 1H NMR spectroscopic analysis.
[c] Determined by chiral HPLC analysis. [d] Bis(oxazoline) 3g
(10 mol%) was used.
Discussion
aldehydes gave products 5–16 with excellent diastereo- and
enantioselectivities (entries 1–13).
Table 4 shows the results of the reaction of various fluo-
roalkyl sulfones 1 f–j with benzaldehyde in the presence of a
Kinetic test for the reaction and proposed reaction mecha-
nism: To understand the enantioselective reactions of a-
lithiated sulfones, the enantiodetermining step was studied
by the use of a kinetic test for the reaction. First, rac-syn-8
was treated with 1.2equivalents of nBuLi to give the race-
mic a-sulfonyl carbanion of 1 f through the retroaldol-type
reaction. Carbanion 1 f was then allowed to react with p-
chlorobenzaldehyde after the addition of 30 mol% of 3g
(Scheme 2). The reaction afforded syn-9 with high enantio-
Table 4. Enantioselective reaction of various trifluoromethyl sulfones
1 f–j with benzaldehyde in the presence of 3g.
Entry
Sulfone
Product
Yield[a,b] [%]
dr[c] syn/anti
er[d] syn
1
2
3
4
5
1 f
1g
1h
1i
2 f
17
18
19
20
87 (74)
75 (60)
73 (55)
90 (64)
94 (38)
96:4
94:6
93:7
97:3
>98:298:2
97:3
97:3
82:18
98:2
Scheme 2. Enantioselective reaction of the racemic carbanion of 1 f.
1j
selectivity. Considering the apparent formation of the race-
mic a-sulfonyl carbanion in the reaction, the result shows
that the enantiodetermining step is not at the deprotonation
stage.
[a] Conversion yield. [b] Yield in parenthesis is the isolated yield. [c] De-
termined by 1H NMR spectroscopic analysis. [d] Determined by chiral
HPLC analysis.
We also studied the temperature dependence of the enan-
tioselectivity in the reaction of a-lithiated 1 f with benzalde-
hyde (Table 5). The reaction with benzaldehyde at À958C
showed slightly lower enantioselectivity relative to the reac-
tion performed at À788C. A solution of the a-carbanion of
1 f, prepared at À958C, was warmed to À788C. The reaction
mixture was stirred for 1 h at that temperature, and was
then recooled to À958C before the addition of benzalde-
substoichiometric amount of 3g. These reactions also gave
the products 2 f and 17–20 with excellent diastereo- and
enantioselectivities (entries 1–5).
a-Fluorinated sulfur compounds can also serve as useful
synthetic intermediates for the synthesis of fluorinated mol-
ecules[13] and precursors of bioactive compounds.[14] There-
fore, we tried to prepare optically active a-fluorobenzyl sul-
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T. Toru, S. Nakamura et al.
Table 5. Temperature dependence of the enantioselective reaction of 1f
with benzaldehyde.
T1 [8C]
T2 [8C]
T3 [8C]
Yield [%]
syn/anti
er syn
À95
À78
À95
À30
À30
À95
À78
À78
À78
À30
À95
À78
À95
À78
À30
65
67
60
4297:3
87
95:5
97:3
95:5
96:4
96:4
86:14
93:7
92:8
97:3
Scheme 4. Enantioselective reaction of lithiated 1 f with a mixture of
electrophiles.
hyde. The product 2 f was found to have an enantiomeric
ratio similar to that obtained in the reaction at À788C, but
higher than that at À958C. When the first deprotonation
step was carried out at À308C and the subsequent reaction
with benzaldehyde at À788C, syn-2 f was obtained with high
enantioselectivity.
Furthermore, we carried out the modified Hoffman test
by using a deficient amount of an electrophile. The reaction
of lithiated 1 f with a deficient amount of p-chlorobenzalde-
hyde afforded 9 with almost complete enantioselectivity,
which is even higher than the 92:8 enantiomeric ratio ob-
tained in the reaction with a stoichiometric amount of p-
chlorobenzaldehyde (Scheme 3).
tained with a stoichiometric amount of an electrophile if the
reaction proceeds through a dynamic kinetic resolution
pathway.
All these results show that the reaction of 1 f in the pres-
ence of a substoichiometric amount of 3g proceeds through
a dynamic thermodynamic resolution pathway.[15] To the
best of our knowledge, this is the first report of a catalytic
enantioselective reaction of a carbanion a to a heteroatom
that proceeds by dynamic thermodynamic resolution. The
highly enantio- and diastereoselective reactions of lithiated
trifluoromethyl sulfones can be ascribed to the high configu-
rational stability of the carbanion, which is caused by the
large n–s* interaction. Gais and co-workers have reported
that the racemization barrier of lithiated trifluoromethyl sul-
fone (16.0–17.3 kcalmolÀ1) is larger than that of a-lithio
phenyl or tert-butyl sulfones (9.6–13.0 kcalmolÀ1), that is,
that an electron withdrawing group, such as a trifluorometh-
yl group, in a-sulfonyl carbanions enhances their configura-
tional stability.[11,16] Based on the configurational stability of
a-sulfonyl carbanions, the plausible catalytic reaction path-
way is as follows (Scheme 5): Bis(oxazoline) and nBuLi
form a chiral organolithium species, which reacts with sul-
fone 1 f to afford a mixture of the diastereomeric complexes
(M)-Li–1 f–3 and (P)-Li–1 f–3. The thermodynamically more
stable a-lithiated sulfone–bis(oxazoline) complex (M)-Li–
1 f–3 is transformed into enantioenriched dimers or oligo-
mers of the a-lithiated sulfone with simultaneous regenera-
tion of bis(oxazoline) 3. The dimer or oligomers react with
an aldehyde to yield the enantioenriched product.
Scheme 3. Enantioselective reaction of lithiated 1 f with
amount of p-chlorobenzaldehyde.
a deficient
In addition, we also examined a novel kinetic test for the
enantioselective reaction of lithiated 1 f by using a substoi-
chiometric amount of 3g with a mixture of p-chlorobenzal-
dehyde and p-methoxybenzaldehyde to give two products
syn-8 and syn-9 (Scheme 4). As described in Scheme 2, p-
chlorobenzaldehyde is more reactive towards lithiated 1 f
than p-methoxybenzaldehyde, and thus, syn-8 was produced
in higher yield than syn-9. It should be noted that syn-8 was
formed with a higher enantioselectivity than that obtained
in the reaction with 1.2equivalents of chlorobenzaldehyde
(Table 3, entry 6; er=92:8). On the other hand, the reaction
with p-methoxybenzaldehyde gave syn-9 with a lower enan-
tioselectivity than that obtained in the reaction with
1.2equivalents of p-methoxybenzaldehyde (Table 3, entry 5;
er=99:1). All these results support the dynamic thermody-
namic resolution pathway, because the enantioselectivity for
both syn-8 and syn-9 should not be different from that ob-
Confirmation of formation of the dimer species: In the pro-
posed reaction mechanism in Scheme 5, the key step of the
catalytic cycle is the transformation of the (M)-Li–1 f–3
complex into a homochiral dimer with regeneration of bis-
(oxazoline) 3. In fact, we observed precipitation of the com-
plex in the reaction mixture prior to the addition of the al-
dehyde, the precipitates being redissolved in the reaction
mixture on the addition of the aldehyde, and the formation
of the dimer of lithiated 1 f was confirmed by ESIMS of the
reaction mixture (calcd for C16H12F6O4S2Li2: 460; found:
460, Figure 1).[17]
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Enantioselective Reactions of a-Sulfonyl Carbanions
FULL PAPER
the sulfone 1 f by examination
of the spectra of the reaction
mixture mixed with 1 f (Fig-
ure 2b,c). Although we were
not able to clearly assign the
two other minor signals at
around d=À80 ppm, which are
possibly due to the 1 f–3g com-
plex, it was definitely shown
that non-lithiated 1 f was not
observed as a major species
after lithiation with an even less
than stoichiometric amount of
3g, and almost only one species
A
signal at d=À73.9 ppm, was
formed in the reaction mixture
before the addition of the alde-
hyde. When combining these
NMR spectral and ESIMS data,
it is reasonable to conclude that
1 f is transformed into the enan-
tioenriched dimeric lithiated 1 f
through the sulfone–bis(oxazo-
line) complex (M)-Li–1 f–3.
Scheme 5. Catalytic cycle for the enantioselective reaction for 1 f when using a substoichiometric amount of 3.
Origin of the enantioselectivity: To elucidate the origin of
the enantioselectivity, we next estimated the activation
energy for the deprotonation of both prochiral methylene
protons and the stability of diastereomeric complexes be-
tween a-sulfonyl carbanion 1 f and bis(oxazoline) 3 by MO
calculations by using Gaussian 03 HF/3-21+G* or 6-31+
G* methods.[18] Structures were first optimized by using a
semiempirical method (MOPAC93/PM3) and then fully op-
timized at the HF/3-21+G* or 6-31+G* level of theory.[19]
The relative energies of the transition-state structures are
depicted in Figure 3a. To simplify the calculation, bis(oxazo-
line)-Ph 1a and MeLi were used for the optimization of the
Figure 1. ESIMS of the reaction mixture.
Furthermore, in the 19F NMR spectrum of the reaction
mixture, prepared from 1 f, 0.3 equivalents of 3g, and
1.2equivalents of nBuLi in [D8]toluene at À308C, one
major signal and three minor signals are shown (Figure 2a).
One of the minor signals at d=À72.0 ppm was assigned to
transition-states TS-1
A
2
ACHTREUNG
increased by the n–s* interaction, it is preferably deproton-
ated and one of the sulfonyl oxygen atoms, pro-S sulfonyl
oxygen, is preferably coordinated to lithium together with
two bis(oxazoline) nitrogen atoms and a methyl group in
TS-1 and TS-2.[20] As a result, the pro-S proton was found to
be slightly more reactive towards deprotonation by the Box
3a/MeLi complex than the pro-R proton; this is probably
due to destabilization of transition-state TS-2 by steric re-
pulsion of the two phenyl groups. Therefore, the (M)-Li–1 f–
3a complex is formed kinetically through TS-2; however,
the energy difference between TS-1 and TS-2 is not very
large. This calculated result is in good agreement with the
reaction of 1 f at À958C, in which syn-2 f is kinetically
formed with a slightly lower enantioselectivity (Scheme 3;
er=86:14) than that obtained in the reaction at À78 and
À308C. We next estimated the optimized structures of lithi-
ated diastereomeric complex (Li–1 f–3a), which is closely re-
Figure 2. 19F NMR spectra for the lithiated 1 f when using a substoichio-
metric amount of 3g. a) reaction mixture; b) reaction mixture and
CF3SO2CH2Ph; c) CF3SO2CH2Ph
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T. Toru, S. Nakamura et al.
ceeds through dynamic axial
chirality.[11,22]
Calculation of the racemiza-
tion barrier of the carbanion–
diamine complexes confirmed
the configurational stability of
(M)-Li–1 f–3a. It is known that
the racemization rate of the a-
sulfonyl carbanion is in accord
with the rotational barrier
[11]
À
around the C S bond.
The
ground state of the (M)-Li–1 f–
3a complex and the transition-
state TS-Li–1 f–3a for rotation
À
around the C S bond were cal-
culated (Figure 4). The activa-
tion energy for the rotational
À
barrier around the C S bond
was estimated to be 16.8 and
17.5 kcalmolÀ1 by the HF/3-
21+G*
and
HF/6-31+G*
methods, respectively. The half-
À
life of rotation around the S Ca
bond in Li–1 f–3a was calculat-
ed as 1000 h at À788C from the
activation energy of 17.5 kcal
Figure 3. a) Structures in the transition state for deprotonation and b) the optimized structures of Li–1 f–3a.
lated to the determination of enantioselectivity in the dy-
namic thermodynamic resolution pathway (Figure 3b). Cal-
culation of the stability of Li–1 f–3a showed that the (M)-
Li–1 f–3a complex is more stable than the (P)-Li–1 f–3a
complex because of steric repulsion between the two phenyl
groups. The results of the calculations show that the lithium
atoms are coordinated to two nitrogen atoms of bis(oxazo-
line) 3a and two oxygen atoms
molÀ1. The high activation energy of the rotational barrier
À
around the S CCF3 bond in the trifluoromethylsulfonyl carb-
anion was attributed to an increase of the n–s* overlap
caused by the lower energy s* orbital of the S CCF3 bond.[11]
À
À
The (M)-Li–1 f–3a complex shows that the S CCF3 bond is
conformationally arranged at the position parallel to the
lone pair orbital of the carbanion (the dihedral angle of the
of the sulfonyl group, but not
with the anionic carbon atom.
These calculated structures are
in good agreement with the
findings with regard to the
structural aspects of a-lithiated
sulfones.[21] Since the sum of
bond angles of the carbanionic
carbon atom is about 3608, the
carbanionic carbon atom nearly
attains sp2 hybridization, in
which the molecule may lose
the stereogenic center. Howev-
er, this is not the case: the ste-
reochemistry induced on re-
moval of one of the prochiral
protons is maintained by the
À
axial chirality around the S C
bond in the a-sulfonyl carban-
ion, which indicates that the
enantioselective reaction of the
a-sulfonyl carbanion of 1 f pro-
Figure 4. Structures and relative energies of optimized structure and transition state of Li–1 f with bis(oxazo-
line)-Ph 2a.
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Chem. Eur. J. 2008, 14, 5519 – 5527

Enantioselective Reactions of a-Sulfonyl Carbanions
FULL PAPER
À
CCF3-S-Ca H bond in the (M)-Li–1 f–3a complex is 91.58)
Conclusion
due to stabilization by the n–s* negative hyperconjugation
[11]
À
between the lone pair and s* orbital of the CCF3 S bond,
We have disclosed the first highly enantioselective reactions
of configurationally stable a-sulfonyl carbanions derived
from trifluoromethyl sulfone 1 f by using bis(oxazoline)s as
chiral ligands. The reaction of lithiated 1 f proceeded
through a dynamic thermodynamic resolution pathway. It
should be noted that a highly enantioselective reaction can
be achieved with a substoichiometric amount of a chiral
ligand and a stoichiometric amount of butyllithium. To the
best of our knowledge, this is the first report of a catalytic
version of an enantioselective reaction that was found to
proceed through dynamic thermodynamic resolution. A de-
tailed survey of the catalytic pathway on the basis of stereo-
scopic features and MO calculations elucidated a novel cata-
lytic reaction mechanism involving a dimeric or a less likely
oligomeric lithiated species as an intermediate, which ena-
bles the enantioselective catalytic cycle. The dimerization
mechanism of lithiated species opens the door for a catalytic
enantioselective dynamic thermodynamic resolution path-
way. The present novel reaction may provide insight into
the development of enantioselective reactions for carban-
ions.
which was estimated to be 56.2kcalmol À1 by NBO analy-
sis.[23,24] On the other hand, the dihedral angle of the CCF3-S-
À
Ca H bond in the TS-Li–1 f–3a complex was 174.18. The
strong n–s* negative hyperconjugation in (M)-Li–1 f–3a
À
À
causes a longer S CCF3 bond and a shorter S Ca bond in the
(M)-Li–1 f–3a complex than that in the TS-Li–1 f–3a.
Therefore, the high configurational stability of the a-sulfo-
nyl carbanion derived from trifluoromethyl sulfone is
enough to transfer the chirality of the carbanion to the axial
À
chirality around the S Ca bond in the a-sulfonyl carbanion
complex. Thus, finally, the dimer or the oligomer of Li–1 f
complexes is formed from the (M)-Li–1 f–2a complex.[25]
Origin of the diastereoselectivity: In the reaction of the
dimer or the oligomer of lithiated 1 f with an electrophile
such as an aldehyde, the electrophile approaches the carba-
nionic center, avoiding any steric interaction with the CF3
group to form the expected products with retention of con-
figuration in a SE2Ret reaction manner[26] (Scheme 6). The
Experimental Section
General methods: All reactions were performed in oven-dried glassware
under a positive pressure of nitrogen. Solvents were transferred by sy-
ringe and were introduced into the reaction vessels through a rubber
septum. All of the reactions were monitored by TLC carried out on
0.25 mm Merck silica gel (60-F254). The TLC plates were visualized with
UV light and 7% phosphomolybdic acid or panisaldehyde in ethanol/
heat. Column chromatography was carried out on a column packed with
silica gel 60N spherical neutral size 63–210mm. The 1H (200 MHz), 19F
(188 MHz), and 13C NMR (50.3 MHz) spectra for solutions in CDCl3
were recorded on a Varian Gemini-200. Chemical shifts (d) are expressed
in ppm downfield from internal TMS or CHCl3. HPLC analyses were
performed on a JASCO PU-2080 Plus or Shimadzu LC-2010A HT by
using a 4.6”250 mm CHIRALPAK AD-H or OJ-H, CHIRALCEL OD-
H, or CHIRALPAK AS-H column. Mass spectra were recorded on a Shi-
madzu GCMS-QP5050A. Optical rotations were measured on
a
HORIBA SEPA-300. IR spectra were recorded on a JASCO FTIR 200
spectrometer.
Scheme 6. Proposed transition state for the reaction of [(S)-Li–1 f]2 with
benzaldehyde.
General procedure for the enantioselective reaction of a-sulfonyl carban-
ions with bis(oxazoline)s: 1,2-Diphenyl-2-(trifluoromethylsulfonyl)etha-
nol (2 f): nBuLi (0.11 mL, 0.142mmol) was added to a solution of bis(ox-
azoline) 3g (17.3 mg, 0.035 mmol) and sulfone 1 f (26.5 mg, 0.118 mmol)
in toluene (1.5 mL) at À308C and the solution was stirred for 1 h at this
temperature. Benzaldehyde (0.018 mL, 0.177 mmol) was then added.
After stirring for 5 min, TMSCl (0.017 mL, 0.13 mmol) was added and
the mixture was stirred for an additional 12h. Aqueous NH 4Cl was
added to the reaction mixture and the aqueous layer was extracted with
Et2O. The combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure to give silylat-
ed 2 f. Silylated 2 f was treated with aqueous HCl (6 molLÀ1) to give the
crude, which was purified by column chromatography (silica gel 15 g,
hexane/ethyl acetate 90:10) to give syn-2 f (28.4 mg, 74%; 94% ee). The
enantiomeric ratio was determined by HPLC analysis by using chiralpak
AD-H.
syn isomer is formed exclusively through the boat form of
the six-membered transition-state TS-3 from the dimer of
the a-sulfonyl carbanion, which is more stable than TS-4
due to the 1,3-diaxial steric repulsion between the aldehyde
substituent and the sulfonyl oxygen atom. It should be
noted that the reaction afforded the products with high syn
selectivity, in contrast to the low diastereoselectivities
(50:50–86:14)[27] generally obtained in the reactions of vari-
ous a-sulfonyl carbanions with aldehydes, which is probably
due to the lower stabilization energy arising from n–s* neg-
ative hyperconjugation.
Compound syn-2 f: [a]2D6 =+1.03 (c=0.59 in CHCl3, 90% ee); 1H NMR
(200 MHz, CDCl3): d=2.90 (brs, 1H), 4.75 (d, J=9.8 Hz, 1H), 5.59 (d,
J=9.8 Hz, 1H), 7.11–7.26 ppm (m, 10H); 13C NMR (50.3 MHz, CDCl3):
Chem. Eur. J. 2008, 14, 5519 – 5527
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T. Toru, S. Nakamura et al.
d=74.0, 75.1, 116.4, 122.9, 126.7, 126.9, 128.0, 128.2, 128.5, 129.5, 130.0,
138.5 ppm; 19F NMR (188 MHz, CDCl3): d=À73.3 ppm; IR (KBr) n˜ =
3538, 3067, 3035, 2924, 2853, 2359, 1716, 1493, 1455, 1346, 1296, 1203,
1105, 1053, 1034, 917, 857, 802, 763, 698, 651, 632, 620 cmÀ1; EIMS m/z
(%) 330 (12) [M+], 197 (14), 165 (22), 107, (100), 91 (77), 79 (83); HPLC
(CHIRALPAK AD-H hexane/iPrOH 95:5, flow rate=1.0 mLminÀ1), tR
15.7 (minor) and 17.8 (major) min. anti-2 f; 1H NMR (200 MHz, CDCl3):
d=2.80 (brs, 1H), 4.46 (d, J=7.2Hz, 1H), 5.99 (s, 1H), 6.99–7.43 ppm
(m, 10H); 19F NMR (188 MHz, CDCl3): d=À74.4 ppm (s).
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Acknowledgements
We thank Dr. J. Bordner, S.-i. Sakemi and Dr. M. Nakane, Pfizer Inc.,
for the X-ray crystallographic analysis. This work was supported by the
Asahi Glass Foundation. We also thank Prof. H.-J. Gais, Prof. P. OꢀBrien,
and Prof. I. Coldham for valuable discussions.
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Enantioselective Reactions of a-Sulfonyl Carbanions
FULL PAPER
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[24] Anders and co-worker (see reference [21i]) have reported that the
estimated negative hyperconjugation energy of the a-carbanion of
dimethyl sulfone is 33.9 kcalmolÀ1 by NBO analysis.
[25] We also calculated the transition state for the racemization barrier
of dimeric lithiated 1 f to be 18.0 kcalmolÀ1 by the HF/6-31+G*
method.
[19] All optimized structures were confirmed to have no negative fre-
quency by frequency calculations. All transition structures were
found to have only one negative eigenvalue, with the corresponding
À
eigenvector involving the formation of the newly created C C
bonds. The transition states reported were shown to belong to the
studied reaction by an intrinsic reaction coordinate (IRC).
[26] R. E. Gawley, Tetrahedron Lett. 1999, 40, 4297–4300.
[27] a) P. J. Kocienski, B. Lythgoe, S. Ruston, J. Chem. Soc. Perkin Trans.
1 1978, 829–834; b) A. Solladiꢅ-Cavallo, D. Roche, J. Fischer, A. D.
Cian, J. Org. Chem. 1996, 61, 2690–2694, and references therein.
[20] We recently reported the selective coordination of metal salts to a
sulfonyl oxygen atom. a) Y. Watanabe, N. Mase, R. Furue, T. Toru,
Tetrahedron Lett. 2001, 42, 2981–2984; b) H. Sugimoto, S. Naka-
mura, Y. Watanabe, T. Toru, Tetrahedron: Asymmetry 2003, 14,
3045–3055; c) H. Sugimoto, K. Kobayashi, S. Nakamura, T. Toru,
Received: February 4, 2008
Published online: May 6, 2008
Chem. Eur. J. 2008, 14, 5519 – 5527
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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