A novel method for the preparation of benzylidenecyclohexanes with high optical purity

Article abstract of DOI:10.1016/j.tetlet.2004.01.099

The enantioselective reaction of the α-thio carbanion derived from 1-phenyl-1-(phenylthio)-1-(tributylstannyl)methane with 4-substituted cyclohexanones in the presence of bis(oxazoline)s gave the products as a diastereomeric mixture. Each diastereomer obtained had high optical purity. The reaction of the α-seleno carbanion derived from the bis(phenylseleno) acetal also showed high enantioselectivity. The stereospecific elimination of the isolated diastereomers on treatment with methanesulfonyl chloride and triethylamine afforded axially chiral benzylidenecyclohexanes with high enantioselectivities up to 99% ee.

Full text of DOI:10.1016/j.tetlet.2004.01.099

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2399–2402
A novel method for the preparation of benzylidenecyclohexanes with
high optical purity
Shuichi Nakamura, Takahiro Ogura, Libo Wang and Takeshi Toru*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Received 8 December 2003; revised 8 January 2004; accepted 16 January 2004
Abstract—The enantioselective reaction of the a-thio carbanion derived from 1-phenyl-1-(phenylthio)-1-(tributylstannyl)methane
with 4-substituted cyclohexanones in the presence of bis(oxazoline)s gave the products as a diastereomeric mixture. Each diaste-
reomer obtained had high optical purity. The reaction of the a-seleno carbanion derived from the bis(phenylseleno)acetal also
showed high enantioselectivity. The stereospecific elimination of the isolated diastereomers on treatment with methanesulfonyl
chloride and triethylamine afforded axially chiral benzylidenecyclohexanes with high enantioselectivities up to 99% ee.
Ó 2004 Published by Elsevier Ltd.
The axially chiral cyclohexylidene compound was first
recognized in 1910 by the optical resolution with bru-
cine.1 Recently, the unique chiroptical property of axi-
ally chiral alkylidenecyclohexanes has been studied.2
Stereoselective syntheses of axially chiral olefins hitherto
known are based on diastereoselective reactions using
various chiral auxiliaries,3;4 some of them showing high
diastereoselectivity. For enantioselective reactions, oxi-
dation of b-seleno ketones into optically active cyclo-
hexylidene ketones5 and dehydrohalogenation with
chiral metal alkoxides or amides6 have been reported.
Very recently, enantioselective versions of the Peterson
olefination7 and the Horner–Wadsworth–Emmons8;9
reaction have been reported showing good to moderate
selectivities; one version achieved 90% ee of the product
in the reaction of 4-tert-butylcyclohexanone with lith-
ium phosphonate in the presence of a chiral ligand.8b
Although such stereoselective reactions are known, it
has been still desired to develop a more efficient reaction
for the preparation of enantiomerically pure axially
chiral olefins. We have previously reported highly
enantioselective lithiation–substitution reactions in the
presence of bis(oxazoline)s involving an asymmetric
replacement of prochiral hydrogens adjacent to sul-
fur.10;11 We now report the first synthetic method for
enantiomerically pure axially chiral benzylidenecyclo-
hexanes including the enantioselective reaction of
cyclohexanones with the a-thio and a-seleno carbanions
and subsequent stereospecific formation of a double
bond.
The a-carbanion of benzyl phenyl sulfide was prepared
on treatment of 1-phenyl-1-(phenylthio)-1-(tributyl-
stannyl)methane 1a with n-BuLi and a chiral ligand.10b
Reaction of the sulfide 1a with 1.15 equiv of n-BuLi and
1.2 equiv of a chiral ligand in cumene for 10 min at
)78 °C formed Li-1a, which was then reacted with
4-substituted cyclohexanones (1.3 equiv) to give the
products 4–6.12 The yields and the enantiomeric excesses
obtained in the reactions with 4-tert-butyl-, 4-methyl-,
and 4-phenylcyclohexanones using various chiral
ligands are shown in Table 1.13 The reaction of Li-1a
with 4-tert-butylcyclohexanone in the presence of ())-
sparteine gave the product 4 with good diastereoselec-
tivity but with low enantioselectivity (entry 1). On the
other hand, the reaction using bis(oxazoline)-iPr 3a as a
chiral ligand afforded the product 4 with excellent
enantioselectivity (99% ee for the cis isomer, 99% ee for
the trans isomer, entry 2). Each diastereomer was easily
separated by column chromatography. Bis(oxazoline)-
iPr 3a showed higher enantioselectivity than other
bis(oxazoline)s 3b and 3c (entries 3 and 4). The reaction
of Li-1a with 4-methyl- and 4-phenylcyclohexanones in
the presence of bis(oxazoline)-iPr 3a also afforded the
products 5 and 6 with high enantioselectivity (entries 5
and 6). We next examined the enantioselective reaction
of the a-seleno carbanion generated by treatment of 1,10-
bis(phenylseleno)-1-phenylmethane 1b with n-BuLi in
Keywords: Asymmetric synthesis; Carbanion; Enantioselective substi-
tution; Chiral olefin.
* Corresponding author. Tel./fax: +81-52-735-5217; e-mail: toru@
nitech.ac.jp
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.01.099

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S. Nakamura et al. / Tetrahedron Letters 45 (2004) 2399–2402
Table 1. Enantioselective reaction of lithiated 1 with 4-substituted cyclohexanones
1) n-BuLi
2) chiral ligand
3)
Ph
XPh
OH
O
R1
PhX
Z
PhX
R1
R1
HO
+
cumene, -78 °C
Ph
Ph
1a: X = S, Z = SnBu3
1b: X = Se, Z = SePh
cis
trans
4: X = S, R1 = tBu
5: X = S, R1 = Me
6: X = S, R1 = Ph
7: X = Se, R1 = tBu
8: X = Se, R1 = Me
O
O
N
R2
N
N
N
R2
2: (-)-sparteine
bis(oxazoline)
3a: R2 = iPr
b: R2 = tBu
c: R2 = Ph
Entry
Substrate
Ligand
Electrophile R1
Product
Yield (%)
Ratioa
Ee (%)b
trans
cis:trans
cis
1
1a
1a
1a
1a
1a
1a
1b
1b
2
tBu
tBu
tBu
tBu
Me
Ph
4
4
4
4
5
6
7
8
71
65
68
43
71
53
61
73
74:26
63:37
64:36
76:24
65:35
52:48
65:35
70:30
8
99
92
52
99
99
86
89
0
99
95
32
99
99
90
90
2c
3a
3b
3c
3a
3a
3b
3b
3
4
5
6c
7d
8d
tBu
Me
a The diastereomer ratio was determined by 1H NMR analysis.
b The enantiomeric excess was determined by HPLC analysis using Daicel Chiralpak AD-H (entries 1–4, 6, and 7), Daicel Chiralcel OD-H (entries 5
and 8), and Daicel Chiralcel OJ-H (entry 5).
c The reaction was carried out at )90 °C.
d n-BuLi (1.3 equiv), 3b (1.4 equiv), and 4-methylcyclohexanone (2.0 equiv) were used.
the presence of bis(oxazoline) 3a or 3b. There are a few
preceding reports of reactions of a-seleno carbanions,
which show a good level of enantioselectivity.14;15 The
enantioselective reaction of the a-seleno carbanion with
4-tert-butyl- or 4-methylcyclohaxanone in the presence
of bis(oxazoline)-iPr 3a showed high enantioselectivity
(entries 7 and 8),16 which was the highest ever reported
in reactions using a-seleno carbanions.17
benzylidenecyclohexanes (M)-9–11 and trans-sulfides
trans-4–6 afforded (P)-9–11. Thus, both enantiomers
were obtained in highly optically active forms. This
procedure is the first example for the preparation of
enantiomerically pure chiral benzylidenecyclohexanes
from the corresponding cyclohexanones through an
enantioselective reaction and the subsequent anti-elimi-
nation. The absolute stereochemistry of 9–11 was
assigned by comparison of the values of the specific
rotation with those reported.3c;d
The obtained products 4–8 were converted to chiral
benzylidenecyclohexanes by the modified reaction
reported in the literature,18;19 in which a-arylthio- or a-
arylseleno-b-hydroxy compounds can be transformed to
alkenes through the stereospecific anti-elimination of the
arylthio or the arylseleno group together with the
methanesulfonyloxy group. Thus, the separated diaste-
reomeric alcohols 4–8 were reacted with methanesulfo-
nyl chloride in the presence of Et3N in CH2Cl2 at room
temperature to give the axially chiral benzylidenecyclo-
hexanes 9–11 (Table 2).20 Optical purity of 9–11 was
determined by HPLC analyses using Chiralcel OD-H.
No loss of optical purity was observed during the
b-elimination. The b-elimination proceeded in an anti
fashion to give 9–11 stereospecifically. Especially,
enantiomerically pure cis-sulfides cis-4–6 gave (M)-
In summary, we have demonstrated the first highly
enantioselective preparation of axially chiral benzylid-
enecyclohexanes through an enantioselective reaction of
a-thio- and a-seleno carbanions of benzyl phenyl sulfide
and benzyl phenyl selenide in the presence of bis(oxaz-
oline)s and subsequent stereospecific elimination.
Acknowledgements
This work was supported by a Grant-in Aid for Scien-
tific Research (no. 11650890) from the Ministry of

S. Nakamura et al. / Tetrahedron Letters 45 (2004) 2399–2402
2401
Table 2. Preparation of axially chiral benzylidenecyclohexanes 9–11 from cis- and trans-4–8
OH
MsCl, Et3N
PhX
R
R
Ph
Ph
CH2Cl2, 0 °C
cis-4: X = S, R = tBu
cis-5: X = S, R = Me
cis-6: X = S, R = Ph
cis-7: X = Se, R = tBu
cis-8: X = Se, R = Me
(M)-9-11
Ph
XPh
MsCl, Et3N
R
HO
R
Ph
CH2Cl2, 0 °C
trans-4: X = S, R = tBu
trans-5: X = S, R = Me
trans-6: X = S, R = Ph
trans-7: X = Se, R = tBu
trans-8: X = Se, R = Me
(P)-9-11
Entry
Substrate
Product
Yield (%)
Ee (%)a
Config.
Ee (%)
1
2
cis-4
cis-5
99
99
99
86
89
99
99
99
90
90
9
10
11
9
51
64
57
88
80
55
50
52
89
90
99
99
99
86
89
99
99
99
90
90
(M)
(M)
(M)
(M)
(M)
(P)
3
cis-6
cis-7
4
5
cis-8
10
9
6
trans-4
trans-5
trans-6
trans-7
trans-8
7
10
11
9
(P)
(P)
8
9
10
(P)
(P)
10
a The enantiomeric excess was determined by HPLC analysis using Daicel Chiralcel OD-H.
Tetrahedron: Asymmetry 2002, 13, 2187–2191, and refer-
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Education, Science, Sports and Culture of Japan and a
NIT research promotion program.
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12. When the reaction was carried out in a coordinative
solvent such as THF or Et2O, 1a could be lithiated on
treatment with n-BuLi without addition of a chiral ligand,
giving 4 in high yield but with low enantioselectivity after
addition of 3a and 4-tert-butylcyclohexanone.
13. Representative procedure: To a solution of 1a (46.4 mg,
0.0948 mmol) in cumene (0.4 mL) was added n-BuLi
(0.109 mmol) at )78 °C under argon and the solution
was stirred for 10 min. Then a solution of 3a (30.1 mg,
0.114 mmol) in cumene (0.3 mL) was added and the
solution was stirred for 1 h. The reaction mixture was
cooled to )90 °C and was added dropwise a solution of 4-
tert-butylcyclohexanone (19.0 mg, 0.123 mmol) in cumene
(0.3 mL). The solution was stirred for 1 h at this temper-
ature and then saturated aqueous NH4Cl was added. The
aqueous layer was extracted with diethyl ether and
combined extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure to leave
a residue, which was purified by silica gel column
chromatography (hexane/ethyl acetate 97:3), giving cis-4
(13.7 mg, 41%), and trans-4 (8.2 mg, 24%). The diastereo-
mer ratio was determined by 1H NMR spectral analysis of
15. We have demonstrated that the enantioselective reaction
of the a-thio carbanion derived from benzyl phenyl sulfide
proceeds through a dynamic kinetic resolution pathway;
see Ref. 10. The reaction of the a-seleno carbanion derived
from benzyl phenyl selenide was confirmed to proceed
through a dynamic thermodynamic resolution pathway,
showing that the a-seleno carbanion is configurationally
more stable than the a-thio carbanion. The results will be
published in due course.
16. The reaction of 1b taking a longer time for lithiation
resulted in lower yield of the product.
17. We also examined the enantioselective reaction of
2-pyridyl selenide with 4-substituted cyclohexanone, but
the obtained diastereomeric mixture could not be sepa-
rated by column chromatography.
18. (a) Toru, T.; Hayakawa, T.; Nishi, T.; Watanabe, Y.;
Ueno, Y. Phosphorus Sulphur Silicon 1998, 653–658; (b)
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Toru, T. Tetrahedron 2001, 57, 6703–6711.
19. For conversion of b-selenoalcohols to alkenes, see: (a)
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2640.
the crude product. cis-4: Rf 0.34 (hexane/ethyl acetate
25
D
90:10); mp 93–94 °C; ½aꢀ +192.0° (c 1.41, CHCl3); 1H
NMR d 0.82 (s, 9H), 1.25–1.58 (m, 8H), 1.95–2.15 (m,
2H), 4.13 (s, 1H), 7.11–7.40 (m, 10H); HPLC (Daicel
Chiralpak AD-H, hexane/iPrOH 95/5, 0.5 mL/min) tR 16.4
20. Representative procedure: To a solution of cis-4 (11.1 mg,
0.0313 mmol) in CH2Cl2 was added methanesulfonyl
chloride (0.050 mL, 0.626 mmol) at 0 °C and the solution
was stirred for 30 min. Triethylamine (0.22 mL,
1.57 mmol) was then added and the reaction mixture was
stirred for 1 h. The cooling bath was removed and the
mixture was stirred for an additional 1 h at room
temperature. Usual work-up afforded an oil, which was
[(R)], and 23.9 [(S), 99% ee] min. trans-4: Rf 0.23 (hexane/
25
D
ethyl acetate 90:10); ½aꢀ +186.4° (c 1.15, CHCl3); 1H
NMR d 0.86 (s, 9H), 1.11–1.80 (m, 8H), 2.05 (m, 1H),
2.67–2.73 (m, 1H), 4.42 (s, 1H), 7.11–7.38 (m, 10H);
HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 95/5,
0.5 mL/min) tR 16.9 [(R)], and 19.0 [(S), 99% ee] min.
14. (a) A good level of enantioselectivity has been reported in
the reaction of non-dipole-stabilized a-seleno carbanions
through a dynamic thermodynamic resolution pathway,
see: Klute, W.; Dress, R.; Hoffmann, R. W. J. Chem. Soc.,
Perkin Trans. 2 1993, 1409–1411; (b) Hoffmann, R. W.;
Klute, W.; Dress, R. K.; Wenzel, A. J. Chem. Soc., Perkin
purified by silica gel column chromatography (hexane),
25
giving (M)-9 (3.6 mg, 51%): ½aꢀ )43.0° (c 0.70, CH3OH)
D
[lit.3c )43.25 (c 1.23, CH3OH)]; HPLC (Daicel Chiralcel
OD-H, hexane, 0.2 mL/min) tR 28.7 [(M)-9, 99% ee], and
33.4 [(P)-9] min.