Highly enantioselective reactions of configurationally labile α-thioorganolithiums using chiral bis(oxazoline)s via two different enantiodetermining steps

Article abstract of DOI:10.1021/ja0025191

A cumene solution of α-stannyl benzyl phenyl sulfide was treated with n-BuLi and bis(oxazoline)-(l)Pr at -78 °C and subsequently with benzophenone to give the product with 99% ee. We confirmed that the reaction of α-lithio benzyl phenyl sulfide proceeds t

Full text of DOI:10.1021/ja0025191

11340
J. Am. Chem. Soc. 2000, 122, 11340-11347
Highly Enantioselective Reactions of Configurationally Labile
R-Thioorganolithiums Using Chiral Bis(oxazoline)s via Two Different
Enantiodetermining Steps
Shuichi Nakamura, Ryo Nakagawa, Yoshihiko Watanabe, and Takeshi Toru*
Contribution from the Department of Applied Chemistry, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-8555, Japan
ReceiVed July 11, 2000
Abstract: A cumene solution of R-stannyl benzyl phenyl sulfide was treated with n-BuLi and bis(oxazoline)-
iPr at -78 °C and subsequently with benzophenone to give the product with 99% ee. We confirmed that the
reaction of R-lithio benzyl phenyl sulfide proceeds through a dynamic kinetic resolution pathway. The
enantioselective reactions of R-lithio benzyl 2-pyridyl sulfide gave the products with stereochemistry reverse
to that obtained in the reaction of benzyl phenyl sulfide. We confirmed that this reaction proceeds through a
dynamic thermodynamic resolution pathway in which the reaction with an electrophile proceeds faster than
interconversion between the diastereomeric complexes.
Introduction
often be controlled so as to proceed through an asymmetric
deprotonation pathway. A great number of dipole-stabilized
R-alkoxy1 and R-aminoorganolithium2 species involving the
alkyl carbamates first developed by Hoppe1a and co-workers
have been well designed to proceed through an asymmetric
deprotonation pathway giving high enantioselectivity. A certain
degree of configurational stability of the carbanions may be
required to attain high enantioselectivity through asymmetric
deprotonation. Stereoselectivity derived from the configura-
tional stability of the R-thio-6 and the R-selenoorganolithium
species6d,7 has been observed only in the reactions of in situ
trap with electrophiles and in the intramolecular rearrangement
of allyl sulfides. The enantioselective reaction of the R-sulfenyl
carbanions using tricarbonyl(η6-arene)chromium complexes is
another distinctive example proceeding through an asymmetric
deprotonation process.8 It has been, however, generally accepted
that the R-sulfenyl carbanions are configurationally labile and
Asymmetric induction on the prochiral methylenes through
deprotonation and subsequent reaction with electrophiles is a
most basic and important asymmetric reaction. Enantioinduction
would occur either in the first deprotonation step1-3 or in a post-
deprotonation step4 which Beak has termed an asymmetric
substitution pathway.5 Reactions of the R-hetero carbanions can
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1990, 29, 1422. (b) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl.
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Khourzom, R.; Pancrazi, A.; Robert, P. Synlett 1991, 611. (d) Hense, T.;
Hoppe, D. Synthesis 1997, 1394. (e) Woltering, M. J.; Fro¨hlich, R.; Hoppe,
D. Angew. Chem., Int. Ed. Engl 1997, 36, 1764. (f) Guarnieri, W.; Sendzik,
M.; Fro¨hlich, R.; Hoppe, D. Synthesis 1998, 1274. (g) Oestreich, M.;
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K.; Komine, N.; Sasaki, T.; Shimizu, H.; Nakai, T. Tetrahedron Lett. 1998,
39, 9715. (i) Woltering, M. J.; Fro¨hlich, R.; Wibberling, B.; Hoppe, D.
Synlett 1998, 797. (j) Deiter, A.; Hoppe, D. Angew. Chem., Int. Ed. 1999,
38, 546. (k) Oestreich, M.; Hoppe, D. Tetrahedron Lett. 1999, 40, 1881.
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5, 1905. (m) Oestreich, M.; Fro¨hlich, R.; Hoppe, D. J. Org. Chem. 1999,
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10.1021/ja0025191 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/05/2000

Reactions of Labile R-Thioorganolithiums
J. Am. Chem. Soc., Vol. 122, No. 46, 2000 11341
racemize rapidly even at low temperature.6,7 This presents a
contrast to the configurationally relatively stable R-oxyorgano-
lithium compounds. Thus, the asymmetric reactions of the
dipole-stabilized R-thioorganolithium compounds show moder-
ate enantioselectivities,9 whereas dipole-stabilized R-oxy-
organolithium compounds show high enantioselectivity as
mentioned above.
Scheme 1
Highly enantioselective reaction of nondipole-stabilized
R-oxyorganolithium compounds, which proceeds through a
dynamic thermodynamic resolution pathway, has been recently
reported.10 A good level of enantioselectivity has been achieved
in the reaction of nondipole-stabilized R-seleno carbanions
through a dynamic thermodynamic resolution pathway.11 How-
ever, there have been no reports on the highly enantioselec-
tive reaction of nondipole stabilized R-sulfenyl carbanions.12 It
is important to clarify the reaction pathways of R-sulfenyl
carbanions and to develop highly enantioselective reactions.
Furthermore, R-chiral sulfides have potential to be chiral
templates13 or asymmetric catalysts14 in asymmetric reactions.
By taking account of the configurationally labile nature of the
R-sulfenyl carbanions that is, indeed, more labile than the
R-seleno carbanions,7a,b a high level of asymmetric induction
would be achievable in a postdeprotonation through an asym-
metric substitution process controlled either by the intermediate
lithium carbanion-chiral ligand complex (dynamic thermody-
namic resolution) or by the complex-electrophile interaction in
the transition state (dynamic kinetic resolution).15 We verified
this working assumption in the highly enantioselective reaction
of the R-sulfenyl carbanion derived from benzyl phenyl sulfide
with carbonyl compounds.16 On continuing the study, we found
the outstanding nature of the R-thioorganolithium compounds;
their reactions proceed through either of the two distinct
enantiodetermining steps, a dynamic kinetic or a dynamic
thermodynamic resolution pathway, depending on the substituent
attached to the sulfur. We now report, in detail, highly stereo-
selective asymmetric substitution reactions of the R-sulfenyl
carbanions derived from benzyl phenyl sulfide and benzyl
2-pyridyl sulfide (Scheme 1) and clarify the stereochemical
course of the enantioselective reactions of these anions. We
analyze the reaction mechanism on the basis of the Hoffmann
test17 as well as Beak’s procedure using the deficient amounts
of the electrophile2d,4b,e,h,5b and his warm-cool procedure4b,h,5b
together with the MO calculations.
Results
Enantioselective Reactions of the Lithiated Benzyl Phenyl
Sulfides. For the study of the reaction of R-lithio benzyl phenyl
sulfides, we used benzyl phenyl sulfide (1a), R-phenylseleno-
sulfide (1b), and R-tributylstannylsulfide (1c) as the precursors,
the latter two of which were prepared from R-lithio benzyl
phenyl sulfide with diphenyldiselenide and tributylstannyl
chloride in THF in high yields. We chose several chiral ligands
to examine (-)-sparteine (3), (1R,2R)-N,N,N′,N′-tetramethyl-
cyclohexane-1,2-diamine (4),18 and 2,2-bis{2-[(4S)-alkyl-1,3-
dioxazolinyl]}propane (5a-c)19,20 [bis(oxazoline)-R]. The ob-
tained yields and the enantiomer ratios for the enantioselective
reactions using these chiral ligands are shown in Table 1.
Reaction of Li-1 with benzophenone using (-)-sparteine 3
in toluene or cumene gave the thio alcohol 2 with low
enantioselectivity (entries 1 and 2). These results are noteworthy
since (-)-sparteine often shows high enantioselectivity in the
reactions of R-hetero carbanions.1c-4 On the other hand, the bis-
(oxazoline)-iPr 5a was found to show excellent asymmetric
induction. The sulfide 1a could be deprotonated on treatment
with n-BuLi without addition of a chiral ligand, when the
reaction was carried out in THF, giving the product 2 in high
yield but with low stereoselectivity (entry 3). The reactions of
1a with n-BuLi in other solvents such as hexane, ether, toluene
or cumene gave 2 in low yields. The yields of 2 in the reactions
using tert-BuLi were low in ether or hexane because 1a
precipitated out at -78 °C (entries 4 and 5). When the reaction
was carried out in toluene using 5a, good yield (77%) and high
enantiomer excess (86% ee) were achieved (entry 6). The above
results show the crucial noncoordinating property of the solvent
to the lithium for exhibiting high enantioselectivity. In addition,
5a and the formed complex are soluble in toluene at -78 °C.
Cumene was found to be an even better solvent than toluene.
The thio alcohol 2 was obtained in cumene with 97-69% ee
(entries 7-9). It is well-known that the lithiated compounds
can be more efficiently obtained by the Sn/Li or Se/Li exchange
than by deprotonation. Lithiation of the R-seleno- and R-stan-
nylbenzyl sulfides 1b and 1c could be achieved with n-BuLi,
(9) Kaiser, B.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 323.
(10) (a) Komine, N.; Wang, L.-F.; Tomooka, K.; Nakai, T. Tetrahedron
Lett. 1999, 40, 6809. (b) Tomooka, K.; Wang, L.-F.; Komine, N.; Nakai,
T. Tetrahedron Lett. 1999, 40, 6813.
(11) (a) Klute, W.; Dress, R.; Hoffmann, R. W. J. Chem. Soc., Perkin
Trans. 2 1993, 1409. (b) Hoffmann, R. W.; Klute, W.; Dress, R. K.; Wenzel,
A. J. Chem. Soc., Perkin Trans. 2 1995, 1721. (c) Hoffmann, R. W.; Klute,
W. Chem. Eur. J. 1996, 2, 694.
(12) The enantioselective reaction of R-sulfenyl carbanions having an
amide group has been reported to afford products with around 40% ee.
Shinozuka, T.; Kikori, Y.; Asaoka, M.; Takei, H. J. Chem. Soc., Perkin
Trans. 1 1995, 119.
(13) (a) Trost, B. M.; Hammen, R. F. J. Am. Chem. Soc. 1973, 95, 962.
(b) Furukawa, N.; Sugihara, Y.; Fujihara, H. J. Org. Chem. 1989, 54, 4222.
(c) Breau, L.; Ogilvie, W. W.; Durst, T. Tetrahedron Lett. 1990, 31, 35.
(d) Breau, L.; Durst, T. Tetrahedron: Asymmetry 1991, 2, 367. (e) Solladie´-
Cavallo, A.; Adib, A.; Schmitt, M.; Fischer, J.; DeCian, A. Tetrahedron:
Asymmetry 1992, 3, 1597. (f) Solladie´-Cavallo, A.; Adib, A. Tetrahedron
1992, 48, 2453. (g) Solladie´-Cavallo, A.; Diep-Vohuule, A.; Sunjic, V.;
Vinkovic, V. Tetrahedron: Asymmetry 1996, 7, 1783. (h) Aggarwal, V.
K.; Ford, J. G.; Thompson, A.; Jones, R. V. H.; Standen, M. C. H. J. Am.
Chem. Soc. 1996, 118, 7004. (i) Aggarwal, V. K.; Ford, J. G.; Fonquerna,
S.; Adams, H.; Jones, R. V. H.; Fieldhouse, R. J. Am. Chem. Soc. 1998,
120, 8328. (j) Julienne, K.; Metzner, P.; Henryon, V. J. Chem. Soc., Perkin
Trans. 1 1999, 731.
(17) (a) Hirsch, R.; Hoffmann, R. W. Chem. Ber. 1992, 125, 975. (b)
Hoffmann, R. W.; Bewersdorf, M.; Liebigs Ann. Chem. 1992, 643. (c)
Hoffmann, R. W. In Organic Syntesis Via Organometallics; Enders, D.,
Gais, H.-J., Keim, W., Eds.; F. Vieweg & Sohn Verlagsges: Braunschweig,
1993; p 79.
(18) (a) Whitney, T. A. J. Org. Chem. 1980, 45, 4214. (b) Toftlund, H.;
Pedersen, E. Acta Chem. Scand. 1972, 26, 4019.
(19) For enantioselective reactions using chiral bis(oxazoline)s/RLi: (a)
Denmark, S. E.; Nakajima, N.; Nicaise, O. J.-C. J. Am. Chem. Soc. 1994,
116, 8797. (b) Hodgson, D. M.; Lee, G. P. Tetrahedron: Asymmetry 1997,
8, 2303. (c) Tomooka, K.; Komine, N.; Nakai, T. Tetrahedron Lett. 1998,
39, 5513. (d) Kambara, T.; Tomioka, K. Chem. Pharm. Bull. 1999, 47,
720. (e) Tomooka, T.; Yamamoto, K.; Nakai, T. Angew. Chem., Int. Ed.
1999, 38, 3741 and ref 10.
(14) (a)Yang, T.; Lee, D. Tetrahedron: Asymmetry 1999, 10, 405. (b)
Kataoka, T.; Iwama, T.; Tsujiyama, S.; Kanematsu, K.; Iwamura, T.;
Watanabe, S. Chem. Lett. 1999, 257.
(15) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995,
68, 36.
(16) Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T. Angew. Chem.,
Int. Ed. 2000, 39, 353.
(20) For the preparation of chiral bis(oxazoline)s, see: Evans, D. A.;
Miller, S. K.; Lectka, T. J. Am. Chem. Soc. 1993, 115, 5328.

11342 J. Am. Chem. Soc., Vol. 122, No. 46, 2000
Nakamura et al.
Table 2. Reactions of Li-1 with Various Electrophiles in the
Table 1. Reactions of the Lithiated Benzyl Phenyl Sulfide 1 with
Benzophenone in the Presence of Various Chiral Ligandsa
Presence of the Chiral Ligand 5a
yield
(%)
ratioa
syn:anti syn anti
ee (%)b
entry
electrophile
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CH3COCH3
cyclohexanone
PhCHO
6
7
8
53 (71)c
98 (>99)c
54 (100)c
91 (98)c
100
51
61
100
86e
21e
71e
57
76
41
25
87
60:40 87d >99d
38:62 97 96
EtCHO
9
iPrCHO
10
11
11
11
11
12
12
13
14
15
38:62 94 95
MeI
MeOTf
(MeO)3PO
Me2SO4
(CH3)3SiCl
(CH3)3SiOTf
BuI
64f
81f
1f
17f
77f
77f
1f
CH2dCHCH2Br
CO2
76f
74g
chiral
yield ee
a The diastereomer ratio was determined by the 1H NMR spectrum.
b The enantiomer excess was determined by HPLC using a Chiralcel
OD-H or a Chiralpac AD. c The yield and the enantiomer excess of
the reaction at -95 °C are shown in parentheses. d The enantiomer
excess was determined by HPLC after oxidation with m-CPBA to the
sulfone. e Conversion yield. f The absolute configuration was not
determined. g The enantiomer excess was determined after reduction
with LiAlH4.
entry substrate ligand
base
solvent (%) (%)b config.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1c
3
3
t-BuLi
t-BuLi
n-BuLi THF
t-BuLi
t-BuLi
t-BuLi
t-BuLi
t-BuLi
toluene
cumene
12
5
97
49
3
12
16
1
R
R
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
S
S
S
5a
5a
5a
5a
5a
5ac
5a
5a
5a
5a
5a
5a
5a
5a
3
Et2O
hexane
toluene
57
77
86
97
86
69
93
94
84
96
85
99
92
8
77
cumene 40
cumene 14
Scheme 2
t-BuLid cumene 82
n-BuLi toluene
93
n-BuLi cumene 27
t-BuLi
t-BuLi
n-BuLi toluene
toluene
cumene 67
82
79
n-BuLi cumene 79
n-BuLid cumene 92
n-BuLi cumene 93
4
5b
5c
n-BuLi cumene
8
1
66
59
n-BuLi cumene 60
n-BuLi cumene 17
a The reaction was carried out using a sulfide (1.0 equiv), a base
(1.2 equiv), a chiral ligand (1.25 equiv), and Ph2CO (1.3 equiv). b The
enantiomer excess was determined by HPLC using a Chiralcel OD-H.
c t-BuLi and 5a were mixed prior to the lithiation of 1a. d BuLi (2.0
equiv) was used.
and the anti isomers, and each isomer has high enantiomer
excess (entries 3-5). However, the alkylation or silylation of
Li-1 gave the product 11 or 12 with moderate to low enantio-
selectivity. When Li-1 was reacted with various methylating
reagents having various leaving groups, the reaction proceeded
with different enantioselectivity (entries 6-9). These results
suggest that the reaction proceeds through an asymmetric
substitution pathway for alkylation.4e In all reactions, the chiral
ligand 5a was quantitatively recovered without any loss of the
enantiomer purity.
and both sulfides showed high yields and high enantioselec-
tivities (entries 10-16). The R-stannylbenzyl sulfide 1c in the
presence of 5a gave the product 2 with 99% ee (entry 15),
although other ligands 3, 4, 5b and 5c did not afford high
enantioselectivity (entries 17-20). Thus, 5a was found to be
the ligand of choice. On using excess amounts of bases,
particularly when t-BuLi was used, enantioselectivities decreased
(entries 7 vs 9 and 15 vs 16). Table 2 shows the results obtained
in the reaction of Li-1 with various electrophiles in the presence
of 5a.
The absolute configurations of the products 6 and 15 were
determined as follows (Scheme 2).
Reduction of the carboxylic acid 15 with LiAlH4 in Et2O at
0 °C gave the â-thio alcohol 16 with 73% ee determined by
the HPLC analysis using a Chiralcel OD-H. The absolute
stereochemistry of 16 was assigned to be (S) in comparison with
the specific rotation reported in the literature,21 showing the
configuration of the carboxylic acid 15 to be (S). Esterification
of (S)-15 with diazomethane gave (S)-17 with 74% ee. The ester
The obtained enantioselectivity in the reaction with carbonyl
compounds was also high (entries 1-5). In the reactions of Li-1
with acetone and cyclohexanone, undesired deprotonation of
the protons R to the carbonyl occurred at -78 °C, lowering the
yields of the products together with recovery of a certain amount
of benzyl phenyl sulfide. Both the enantioselectivity and the
yield increased as the reaction temperature was lowered (entries
1 and 2 in parentheses). The reaction of Li-1 with benzaldehyde,
propionaldehyde or isobutyraldehyde gave a mixture of the syn
(21) Toshimitsu, A.; Hirosawa, C.; Tamao, K. Tetrahedron 1994, 50,
8997.

Reactions of Labile R-Thioorganolithiums
J. Am. Chem. Soc., Vol. 122, No. 46, 2000 11343
Table 3. Enantioselective Reaction of R-Lithio Benzyl 2-Pyridyl
Sulfides
Figure 1. Absolute configurations of the major isomers of 8 and 18.
reaction
temp
(°C) product (%)
(S)-17 was treated with MeMgI in the presence of CeCl3 to
give the product (S)-6 without racemization (44%, 74% ee),22
which had the same stereochemistry by the HPLC analysis as
that of the product predominantly obtained in the enantioselec-
tive reaction of Li-1 using 5a. The reaction of (S)-17 with MeLi
or MeMgI in place of MeMgI-CeCl3 was not accomplished
without partial racemization. Treatment of (S)-17 with PhLi also
gave the product having the same stereochemistry as that of
the predominantly formed thio alcohol 2. The relative configu-
rations of the products obtained in the reactions with aldehydes
were determined by the larger vicinal coupling constant for the
syn-8 (8.5 Hz) in comparison with anti-8 (5.8 Hz).23 The
yield
ee
(%)
entry
X
ligand electrophile
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
H
3
4
Ph2CO
Ph2CO
-78
-78
-78
-78
-78
-78
-78
0
-30
-50
-95
-95
-50
20
20
20
20
20
20
20
20
20
20
20
20
21
22
23
79
70
89
49
13
86
80
79
87
91
74
42
67
71
9
21
64
51
58
90
64
28
49
78
43
53
54
42
5a Ph2CO
5b Ph2CO
5c
Ph2CO
5d Ph2CO
SnBu3 5a Ph2CO
H
H
H
H
H
H
H
H
5a Ph2CO
5a Ph2CO
5a Ph2CO
5a Ph2CO
5d Ph2CO
5a CH3COCH3
1
absolute configuration of 8 was determined by the H NMR
analysis of the (S)-MTPA ester of the corresponding sulfone
5a cyclohexanone -50
18 (Figure 1).24
5a PhCHO
-50
94a syn: 79
anti: 81
60
72
97
91
The stereochemistry of the carbon R to the phenylthio group
of the other products obtained in the reaction with cyclohex-
anone, propionaldehyde and isobutyraldehyde was tentatively
assigned to be S. The absolute stereochemistry of the alkylation
products has not yet been determined.
Enantioselective Reactions of Lithiated Benzyl 2-Pyridyl
Sulfides. We next studied the enantioselective reaction of the
R-sulfenyl carbanion Li-19 of benzyl 2-pyridyl sulfides 19a and
19b (Table 3).
16
17
18
19
H
H
H
H
5a CO2
5d CH3I
5d (CH3)3SiCl
5d (CH3)3SiOTf
-78
-78
-78
-78
24
25
26
26
70b
89
71
93
a syn:anti)37:63. b The enantiomer excess was determined after
reduction with LiAlH4.
Scheme 3
The reactions of 19a using the bis(oxazoline)s 5a and 5d gave
high yields of 20 with high stereoselectivity. The bis(oxazoline)-
tBu 5d showed higher asymmetric induction than any other
chiral ligand (entries 1-6). The Sn/Li exchange reaction of 19b
also smoothly proceeded (entry 7). Notably, the enantioselec-
tivity varies depending on the reaction temperature (entries 3,
8, 9, 10 and 11 or 6 and 12). The highest enantioselectivity
(90% ee) was obtained in the reaction using 5d at -78 °C (entry
6). The reaction of Li-19 with acetone and cyclohexanone
having acidic protons gave the products with moderate stereo-
selectivity (entries 13 and 14). The reaction with other electro-
philes, such as PhCHO, CO2, CH3I, TMSCl, and TMSOTf gave
the products with high stereoselectivity (entries 15-19).
The absolute configuration of the product 21 was determined
as follows (Scheme 3).
analysis. The configuration of 27 was confirmed by the derived
chiral styrene oxide 28.25 The carboxylic acid 24 was converted
to the methyl ester 29 which was treated with MeLi at 0 °C to
give 18% yield of the thio alcohol (R)-21 with 36% ee;26
although partial epimerization inevitably occurred during the
reaction, the stereochemistry of 21 still reflects that of 29. The
HPLC analyses using a chiral column showed that this major
product (R)-21 was identical with the product, shown in Table
3, entry 13. These results unequivocally indicate that the product
21 obtained in the enantioselective reaction of benzyl 2-pyridyl
sulfide 19a with acetone using 5a has stereochemistry opposite
that of the products predominantly formed in the enantioselective
The carboxylic acid 24 was reduced with LiAlH4 to give the
alcohol 27 with 70% ee, which was determined by the HPLC
(22) (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (b) Takada, N.; Imamoto,
T. Org. Synth. 1999, 76, 228. We thank Professor Tsuneo Imamoto at Chiba
University for helpful suggestions.
(23) Shimagaki, M.; Maeda, T.; Matsuzaki, Y.; Hori, I.; Oishi, T.
Tetrahedron Lett. 1984, 25, 4775.
(24) The stereochemistries of 18 were assigned on the basis of the upfield
shift of the methoxy proton signal for the (1R)-isomers due to the phenyl
anisotropic effect relative to that for the (1S) isomers. For the NMR spectral
analysis of MTPA esters, see: (a) Dale, J. A.; Dull, D. L.; Mosher, H. S.;
J. Org. Chem. 1969, 34, 2543. (b) Dale, J. A.; Mosher, S. H.; J. Am. Chem.
Soc. 1973, 95, 512. (c) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal,
P. G.; Balkovek, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.;
Varga, S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370.
(25) Preparation of styrene oxide from the thio alcohol: (a) Shanklin, J.
R.; Johnson, C. R.; Ollinger, J.; Coates, R. M. J. Am. Chem. Soc. 1973, 95,
3429. (b) Berti, G.; Bottari, F.; Ferrarini, P. L.; Macchia, B. J. Org. Chem.
1965, 30, 4091.
(26) The reaction using CeCl3 did not provide the desired methylated
product.

11344 J. Am. Chem. Soc., Vol. 122, No. 46, 2000
Table 4. Configurational Instability of Li-1
Nakamura et al.
aldehyde (S)-30 at -78 °C gave the product 31 in a ratio of
61:39, which was experimentally identical to the ratio (58:42)
obtained in the reaction of a racemic aldehyde with TMEDA.
The diastereomer ratio was 80:20 when the bis(oxazoline)-iPr
5a and the chiral aldehyde (S)-30 were used. If the enantio-
selective reaction of 1 using 5a proceeds through a dynamic
thermodynamic resolution pathway, the reaction of 1 with (S)-
30 in the presence of 5a should give the product having the de
of approximately 99% as in the reaction of 1 with benzophenone
in the presence of 5a. These results show that the complex of
the lithium carbanion with a ligand such as TMEDA or 5a is
configurationally labile at -78 °C. Thus, we have concluded
that enantioinduction in the reaction of Li-1 occurs through
dynamic kinetic resolution, in which high enantioselectivity is
derived from the difference in energy of the transition state
(∆∆Gq) at the substitution step. This enantiodetermining
sequence is also supported by the fact that higher enantio-
selectivity was obtained in the reaction at lower reaction
temperature (Table 2, entries 1 and 2).30 It is important to know
the exact geometry of the R-sulfenyl carbanion, which would
significantly affect the structure of the transition state. Wiberg
and co-workers have recently shown by ab initio calculation
(MP2/6-311++G**) that the R-sulfenyl carbanion of dimethyl
sulfide is stabilized by an n-σ*S-C negative hyperconjugation.31
Hoffmann and co-workers have elucidated the stereoselective
cyclization by this hyperconjugation.32 To understand the
preferred conformation for the R-sulfenyl carbanion in our case,
we performed the calculation of energies of the complexes
formed from R-lithio benzyl phenyl sulfide with TMEDA as a
simple model of the diamine ligand.33 The calculations for the
complexes by Gaussian 98 Becke3LYP/3-21+G*, HF/3-
21+G*,34 and MOPAC 93/PM335 methods showed a signifi-
cantly large difference in energy between the anti-TMEDA-
complex and syn-TMEDA-complex as shown in Figure 2.
ligand
TMEDA
aldehyde
yield (%)
ratio
(dl)-30
(S)-30
(S)-30
90
88
90
58:42
61:39
80:20
TMEDA
bis(oxazoline)-iPr
reaction of 1. The stereochemistry of the methylated product
25 was assigned to be S by comparison of the value of the
specific rotation with the reported one.27 The stereochemistry
of the other products was tentatively assigned to be the same
as that of 21. The relative configurations of the products 23
were determined by the vicinal coupling constant as in the case
of 8.23
Discussion
Reaction Mechanism of r-Lithio Benzyl Phenyl Sulfide.
First, we confirmed that no retroaldol reaction of the products
2 and 20 would occur during the deprotonation and the
subsequent electrophilic reaction. Thus, to a cumene solution
of 2 (99% ee) or 20 (49% ee) was added 1.2 equiv of n-BuLi
and TMEDA at -78 °C. After the mixture was stirred for 1 h,
benzaldehyde was added. The thio alcohols 2 and 20 were found
to remain unreacted without loss of the enantiomeric purity,
indicating that the stereoselective outcome in the reactions of
Li-1 and Li-19 should be a kinetically controlled one. Although
the Sn/Li exchange is known to occur with complete retention28
of configuration at the sp3 carbanion,29 the reactions starting
with the racemic stannyl sulfides 1c and 19b proceed with high
enantioselectivity (Table 1, entry 15, Table 3, entry 7). This
clearly shows that induction of enantioselectivity is independent
of the method of generation of the organolithium species, and
thus, these asymmetric lithiation-substitution reactions proceed
through an asymmetric substitution pathway, involving the
enantiodetermining step via either a dynamic kinetic or a
dynamic thermodynamic resolution. Hoffmann and co-workers
have developed a protocol for surveying the configurational
stability of organolithium compounds,17 showing that the R-lithio
benzyl phenyl sulfide is configurationally labile in THF.7a In
the present reaction, the product was obtained with no stereo-
selectivity in THF (Table 1, entry 3). We tried to confirm
whether the lithiated 1-ligand complex is also labile in cumene
by using dl- and (S)-2-(N,N-dibenzylamino)-3-phenylpropanals
(30) according to their protocol (Table 4).
These calculations indicate that the C-Li bond of the
R-lithiated benzyl phenyl sulfide prefers the anti conformation
for the S-Cips bond probably by an n-σ*S-C negative hyper-
conjugation. The plausible reaction mechanism is shown in
Figure 3.
We have confirmed by performing the Hoffmann test that
the (R)-Li complex is rapidly equilibrated with the (S)-Li
complex (Table 4). According to the frontier orbital theory, both
(30) The reaction using 0.2 equiv of cyclohexanone gave the product 7
in 13% yield, but the enantiomer excess of 7 was still 91%. This result
also shows that the reactions using stoichiometric amounts of carbonyl
compounds proceed through a dynamic kinetic resolution.
(31) Wiberg, K. B.; Castejon, J. Am. Chem. Soc. 1994, 116, 10497.
(32) (a) Hoffmann, R. W.; Koberstein, R.; Harms, K. J. Chem. Soc.,
Perkin Trans. 2 1999, 183. (b) Hoffmann, R. W.; Koberstein, R.; Remacle,
B.; Krief, A. Chem. Commun. 1997, 2189.
(33) The R-sulfenyl carbanion forms a dimeric complex such as the four-
membered and the six-membered cyclic dimers with TMEDA, Amstutz,
R.; Laube, T.; Schweiser, W. B.; Seebach. D.; Dunitz, J. D. HelV. Chim.
Acta 1984, 67, 224. However, formation of these dimeric complexes seems
to be difficult due to significant steric repulsion between the isopropyl groups
of each bis(oxazoline). The complex of some transition metals with bis-
(oxazoline)s is known to show nonlinear effects, but we observed a linear
relationship between the enantiomer excesses of 2 and 5a. On the basis of
these results, it would be reasonable to assume that the dimer is not formed.
For the general nonlinear effect, see: (a) Guillaneux, D.; Zhao, S.; Samuel,
O.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994, 116, 9430. (b)
Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2923. For the
nonlinear effect using bis(oxazoline) complexes, see: (c) Evans, D. A.;
Lectka, T.; Miller, S. J. Tetrahedron Lett. 1993, 34, 7027. (d) Kanemasa,
S.; Oderaotoshi, Y.; Sakaguchi, S.; Yamamoto, H.; Tanaka, J.; Wada. E.;
Curran, D. P. J. Am. Chem. Soc. 1998, 120, 3070. (e) Evans, D. A.;
Kozlowski, M. C. Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B.
T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669. (f) Crosignani, S.;
Desimoni, G.; Faita, G.; Filippone, S.; Mortoni, A.; Righetti, P.; Zema, M.
Tetrahedron Lett. 1999, 40, 7007.
Provided that the complex of an organolithium and a ligand
is configurationally stable, the reaction of the racemic carbanion
with a chiral aldehyde should afford the product in a diastere-
omer ratio of 50:50. However, the reaction with the chiral
(27) Oae, S.; Takeda, T.; Wakabayashi, S.; Iwasaki, F.; Yamazaki, N.;
Katsube, Y. J. Chem. Soc., Perkin Trans. 2 1990, 273.
(28) (a) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201.
(b) Sawyer, J. S.; Kucerovy, A.; Macdonald, T. L.; McGarvey, G. J. J. Am.
Chem. Soc. 1988, 110, 842. For reaction with partial inversion, see: (c)
Clayden, J.; Pink, J. H. Tetrahedron Lett. 1997, 38, 2565.
(29) The R-lithiated benzyl phenyl sulfide is known to have an sp3
character, Zarges, W.; Marsch, M.; Harms, K.; Koch, W.; Frenking, G.;
Boche, G. Chem. Ber. 1991, 124, 543.

Reactions of Labile R-Thioorganolithiums
J. Am. Chem. Soc., Vol. 122, No. 46, 2000 11345
Figure 4. Assumed energy diagram of the enantioselective reaction
for Li-1 under dynamic kinetic resolution
coordinating electrophiles may take the retention pathway.37 It
is reasonable that the reaction of Li-1 with the electrophiles
such as the lithium-coordinating carbonyl compounds proceeds
with retention. Thus, we assumed that the reaction proceeds
via a four-membered cyclic transition state38 stabilized by the
negative hyperconjugation. The S isomer is formed via TS-1,
which would be assumed to be much more stable than TS-2
involving a steric interaction between the methyl and phenyl
groups. The assumed energy diagram of the enantioselective
reaction for Li-1 is shown in Figure 4.
Figure 2. Geometry optimization of the lithiated 1 coordinated with
TMEDA.
The stereochemical outcome in the reaction of Li-1 is
noteworthy as compared with the Tomooka and Nakai results
of the preferential formation of the (R)-isomer in the reaction
of benzyl methyl ether with the bis(oxazoline).10 They have
disclosed that the reaction proceeds through a dynamic ther-
modynamic resolution pathway. In addition, Wiberg and co-
workers31 have shown very suggestive results that the repulsive
effect of a lone pair of the R-oxy carbanion onto a lone pair of
the oxygen arranges these lone pairs anti, that is, syn between
the carbanion lobe and the substituent on the oxygen. We have
confirmed, as described before, the anti configuration of the
R-sulfenyl carbanion, which is completely different from that
of the R-oxy carbanion.
Reaction Mechanism of R-Lithio Benzyl 2-Pyridyl Sulfide.
The lithiated benzyl 2-pyridyl sulfide (Li-19) showed some
peculiar aspects in the reactions with carbonyl compounds: (1)
the (R)-preference of the product stereochemistry is different
from the preferential formation of the (S)-isomer in the reaction
of Li-1; (2) higher enantioselectivity is not always obtained in
the reactions performed at lower temperature and there may be
a certain temperature for the maximal enantioinduction (Table
3, entries 6-12). These features of Li-19 may suggest the
reaction pathway through dynamic thermodynamic resolution.
To confirm the enantiodetermining step, we collected further
information on the chemical behavior of Li-19. The enantio-
selectivity in the reaction with a deficient amount of benzo-
phenone turned out to be different from that obtained in the
reactions using stoichiometric amounts of the electrophile (Table
3, entries 3, 6, and 11, and Scheme 4). This is a notable aspect
of the reaction of Li-19 as compared with the reaction30 of Li-1
Figure 3. Reaction mechanism of R-lithio benzyl phenyl sulfide.
retention and inversion of the lithium stereochemistry are an
allowed pathway in the SE2 reaction.36 Indeed, the stereochem-
ical course depends on the electrophiles; the reactions with
highly reactive or non-lithium coordinating electrophiles may
proceed with inversion and those with less reactive or lithium
(34) (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels,
A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.6;
Gaussian, Inc.: Pittsburgh, PA, 1998. For the Becke3LYP hybrid method,
see: (b) P. J. Stephens, F. J. Devlin, C. F. Chabalowski, M. J. Frisch, J.
Phys. Chem. 1994, 98, 11623.
(37) (a) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6097. (b)
Tomooka, K.; Igarashi, T.; Komine, N.; Takeshi, N. J. Synth. Org. Chem.
Jpn. 1995, 53, 480.
(38) The alkyllithium addition to the carbonyl group has been suggested
to proceed through a four-memberd cyclic transition state. For example,
see: (a) Kaufmann, E.; Schleyer, P. R. Houk, K. N.; Wu, Y.-D. J. Am.
Chem. Soc. 1985, 107, 5560. (b) Kaufmann, E.; Sieber, S.; Schleyer, P. R.
J. Am. Chem. Soc. 1989, 111, 4005. (c) Ando, K.; Houk, K. N.; Busch, J.;
Menasse´, A.; Se´quin, U. J. Org. Chem. 1998, 63, 1761. (d) Bra¨uer, M.;
Weston, J.; Anders, E. J. Org. Chem. 2000, 65, 1193.
(35) (a) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209 (b) For the
lithium parameter for PM3, see: Anders, E.; Koch, R.; Freunscht, P.; J.
Comput. Chem. 1993, 14, 1301.
(36) Fleming, I. Frontier Orbital and Organic Chemical Reactions; John
Wiley & Sons: New York, 1976.

11346 J. Am. Chem. Soc., Vol. 122, No. 46, 2000
Nakamura et al.
Scheme 4
Scheme 5
Figure 5. Geometry optimization of diastereomeric complexes of Li-
19 with 5a and 5d.
To gain more quantitative insight to clarify the reaction
mechanism of 19, the diastereomeric complexes with 5a and
5d were estimated by the MO calculation using the HF/3-
21+G*, and MOPAC 93/PM3 methods. The relative energies
of the optimized structures obtained by these calculations are
depicted in Figure 5.
which was reasonably verified to proceed through a dynamic
kinetic resolution.
These results show that the diastereomeric complexes derived
from Li-19 and the bis(oxazoline) are configurationally stable
at low temperature at least on the time scale of the reaction
with electrophiles, and each diastereomeric complex may react
with electrophiles at a different rate.2d,4b,e,h,5b Consequently, the
reaction of Li-19 proceeds through a dynamic thermodynamic
resolution pathway. In addition, the minor diastereomeric
complex can be reasonably assumed to have a lower activation
energy in the reaction with an electrophile, since the enantio-
selectivity in the reaction with a deficient amount of the
electrophile is lower than that of the reactions using stoichio-
metric amounts of the electrophile. We also examined Beak’s
excellent “warm-cool procedure”4b,h,5b for further confirmation
of the above reaction pathway. A solution of the R-sulfenyl
carbanion prepared from 19a in the presence of 5a at -78 °C,
was warmed to -50 °C and stirred for 1 h at that temperature.
The reaction mixture was divided into two parts which were
subjected to separate parallel reactions, followed by recooling
one reaction to -78 °C and the other to -95 °C. Each reaction
mixture was stirred for 30 min and subsequently benzophenone
was added. One afforded 70% ee of 20 at -78 °C and the other
gave 76% ee of 20 at -95 °C (Scheme 5).
These enantiomer excess values are quite close to that
obtained in the reaction performed at -50 °C (78% ee, Table
3, entry 10), but higher than those performed at -78 °C and
-95 °C throughout the reaction. These results suggest that the
interconversion of (R)-Li-19 and (S)-Li-19 is quite slow at below
-78 °C, and it is necessary to warm the reaction mixture up to
-50 °C to equilibrate the diastereomeric complexes. Similar
results were obtained in the reaction using 5d in which the
equilibration may complete at -78 °C (90% ee, Table 3, entry
6). This evidence of the configurational stability of the carbanion
unequivocally indicates that the reaction proceeds through a
dynamic thermodynamic resolution pathway; that is, the reaction
with an electrophile occurs before the interconversion of the
diastereomeric complexes, and, therefore, the enantiomer excess
of the reaction of Li-19 reflects the ratio of the two diastereo-
meric complexes.39
Calculations by both methods showed that the (R)-Li-19
complex is more stable than the (S)-Li-19 complex. The
differences in energy of the (R)-Li-19 and the (S)-Li-19
complexes with 5a and 5d giving 78% ee at -50 °C and 90%
ee at -78 °C correspond to 0.93 and 1.14 kcal/mol, respectively,
under dynamic thermodynamic conditions, both of which are
in good agreement with the calculated energy differences. In
the optimized structure, the third pyridyl nitrogen in addition
to the two nitrogens of the bis(oxazoline) is incorporated to the
lithium ion. Since the lithium ion is fully coordinated, an
electrophile can hardly approach the reaction site while coor-
dinating to the lithium ion with retention of configuration of
the carbanionic center, and thus the substitution reaction may
occur with inversion of configuration.40 The stereochemical
course with inversion of configuration was also supported by
the HOMO of Li-19-5a complex which obviously showed the
lobe of the carbanionic center considerably expanding in the
direction opposite the C-Li bond (Figure 6).
Reactions of carbanions with carbonyl compounds generally
proceed with retention of stereochemistry. Indeed, the reaction
of the R-sulfenyl carbanion of 1 proceeds with retention of
configuration as described before. The reaction of 19 very
exceptionally proceeds with inversion. Obviously, the pyridyl
nitrogen plays an important role in determining the way of
approach of an electrophile. The lithium ion is fully coordinated
by the additional nitrogen coordination and the electrophilic
carbonyl attacks the carbanion without coordination to the
(39) We also examined the configurational lability of Li-19 using the
chiral aldehyde (S)-30 (the Hoffmann test). The reaction of Li-19 with the
chiral aldehyde (S)-30 gave the product in a ratio of 54:46, whereas the
diastereoselectivity of the reaction with the racemic aldehyde (dl)-30 was
58:42. These results may support the reaction pathway.
(40) Recently, Hoppe and co-workers suggested that the SE2 reaction
on the sp2-like hybridized carbanion proceeds with inversion of the
stereochemistry. Derwing, C.; Frank, H.; Hoppe, D. Eur. J. Org. Chem.
1999, 3519. The carbanionic center of the geometry-optimized structure
(R)-Li-19 is close to the sp2 carbon. The sum of the three angles at the
lithium-bearing carbon atom was found to be 338.8°.

Reactions of Labile R-Thioorganolithiums
J. Am. Chem. Soc., Vol. 122, No. 46, 2000 11347
Figure 7. Assumed energy diagram of the enantioselective reaction
for the Li-19 under dynamic thermodynamic resolution
Figure 6. HOMO of the complex of the lithiated 19 with 5a.
In summary, we have disclosed the first excellent enantio-
selective reactions of the configurationally labile R-sulfenyl
carbanions by using bis(oxazoline)s as the chiral ligand. We
have shown two distinct reaction pathways of the asymmetric
substitution of the R-sulfenyl carbanions. Reaction of the
lithiated benzyl phenyl sulfide with carbonyl compounds
proceeds through a dynamic kinetic resolution pathway with
retention of configuration of the carbanion center to give the
(S)-isomer, whereas that of the lithiated benzyl pyridyl sulfide
proceeds through a dynamic thermodynamic resolution pathway
with inversion of configuration to give the (R)-isomer.
lithium ion. To the best of our knowledge, there is only one
precedent of the SE2 reaction with a carbonyl compound
proceeding with inversion,41 that is, the reaction of the lithium
carbanion derived from N-pivaloyl o-ethylaniline which also
has a nitrogen to coordinate with a lithium ion. For better
understanding, the energy diagram of the enantioselective
reaction of Li-19 is shown in Figure 7.
According to the dynamic thermodynamic resolution process,
the enantioselectivity should be independent of the electrophiles.
The reactions with benzaldehyde, CO2, CH3I and TMSOTf gave
the products with enantioselectivity similar to those with
benzophenone (Table 3, entries 10 vs 15, 3 vs 16 and 6 vs 17
and 19). On the other hand, the reactions with acetone and
cyclohexanone gave the products with slightly lower stereo-
selectivity (Table 3, entries 13 and 14). Deprotonation from the
carbonyl compounds would occur during the reaction and reduce
the yields of 21 and 22 together with the formation of the aldol
product. These results show that deprotonation by (R)-Li-19
would occur faster than that by (S)-Li-19.
Acknowledgment. This work was supported by a Grant-in
Aid for Scientific Research (no. 11650890) from the Ministry
of Education, Science, Sports and Culture of Japan and the
Sasakawa Scientific Research Grant from The Japan Science
Society.
Supporting Information Available: Spectroscopic charac-
terization of the products 1b,1c,2,6-18,20-23,25-27,29 (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(41) Basu, A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 1575.
JA0025191