Highly enantioselective reaction of α-selenoorganolithium compounds with chiral bis(oxazoline)s and preparation of enantioenriched benzylidencyclohexanes

Article abstract of DOI:10.1021/jo048505l

The enantioselective reaction of α-seleno carbanions derived from bis(phenylseleno)acetal and bis-(2-pyridylseleno)acetal in the presence of bis(oxazoline)s with various electrophiles gave products with high enantioselectivity. The enantioselective reacti

Full text of DOI:10.1021/jo048505l

Highly Enantioselective Reaction of r-Selenoorganolithium
Compounds with Chiral Bis(oxazoline)s and Preparation of
Enantioenriched Benzylidencyclohexanes
Shuichi Nakamura, Takayuki Aoki, 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
toru@nitech.ac.jp
Received August 26, 2004
The enantioselective reaction of R-seleno carbanions derived from bis(phenylseleno)acetal and bis-
(2-pyridylseleno)acetal in the presence of bis(oxazoline)s with various electrophiles gave products
with high enantioselectivity. The enantioselective reaction of R-lithio benzyl 2-pyridyl selenide gave
the products with stereochemistry reverse to that obtained in the reaction of R-lithio benzyl phenyl
selenide. Mechanistic investigation suggests the enantiodetermination of these reactions at -78
°C depends on dynamic thermodynamic resolution. The enantioselective reaction was applied to
the preparation of enantioenriched olefins and epoxide.
Introduction
derived from benzyl phenyl and pyridyl sulfides, which
were proven to proceed through different resolution
pathways, i.e., dynamic kinetic resolution for the former
carbanion and dynamic thermodynamic resolution for the
latter.6,7 These results showed that pivotal resolution
pathways can be chosen by changing the substituent on
Asymmetric reactions of prochiral compounds having
a sufficiently acidic C-H bond are of great importance
in the access to enantiomerically pure compounds. Enan-
tioselective reactions of dipole-stabilized R-alkoxy-1 and
R-aminoorganolithium2 compounds have been thoroughly
studied and it has been confirmed that these carbanions
are configurationally stable enough to proceed through
an asymmetric deprotonation pathway. However, the
configurational stability of R-seleno carbanion is lower
than that of R-oxy carbanion.3 Configurationally labile
R-thio carbanion4,5 shows lower enantioselectivity than
dipole-stabilized R-oxyorganolithium having a similar
structural arrangement. We have previously reported
highly enantioselective reactions of R-thio carbanions
(3) Hoffmann and co-workers have developed a protocol for survey-
ing the configurational stability of organolithium compounds, showing
that the R-lithio benzyl phenyl selenide is configurationally labile in
THF, see: (a) Hoffmann, R. W.; Ru¨hl, T.; Harbach, J. Liebigs Ann.
Chem. 1992, 725-730. (b) Ruhland, T.; Dress, R.; Hoffmann, R. W.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1467-1468. However, R-lithio
pentyl phenyl selenide is configurationally stable in THF. (c) Hoffmann,
R. W. In Organic Synthesis via Organometallics; Enders, D., Gais, H.-
J., Keim, W., Eds.; Vieweg: Braunschweig, 1993; p 79. (d) Hoffmann,
R. W.; Julius, M.; Chemla, F.; Ruhland, T.; Frenzen, G. Tetrahedron
1994, 50, 6049-6060.
(4) Kaiser, B.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995, 34,
323-325.
* Address correspondence to this author. Phone and Fax: +81-52-
735-5217.
(5) For configurational stability of the R-thio carbanion, see: (a)
McDougal, P. G.; Condon, B. D.; Laffosse, M. D., Jr.; Lauro, A. M.;
VanDerveer, D. Tetrahedron Lett. 1988, 29, 2547-2550. (b) McDougal,
P. G.; Condon, B. D. Tetrahedron Lett. 1989, 30, 789-790. (c) Krief,
A.; Evrard, G.; Badaoui, E.; De Beys, V.; Dieden, R. Tetrahedron Lett.
1989, 30, 5635-5638. (d) Reich, H. J.; Bowe, M. D. J. Am. Chem. Soc.
1990, 112, 8994-8995. (e) Hoffmann, R. W.; Bewersdorf, M. Liebigs
Ann. Chem. 1992, 643-653. (f) Brickmann, K.; Bru¨ckner, R. Chem.
Ber. 1993, 126, 1227-1239. (g) Wang, F.; Tang, J.; Labaudinie´re, L.;
Marek, I.; Normant, J.-F. Synlett 1995, 723-725. For the reaction of
configurationally stable dipole-stabilized R-thiobenzyllithium in THF,
see: (h) Hoppe, D.; Kaiser, B.; Stratmann, O.; Fro¨hlich, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2784-2786. (i) Marr, F.; Fro¨hlich, R.;
Hoppe, D. Org. Lett. 1999, 1, 2081-2083.
(1) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl.
1990, 29, 1422-1424. (b) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2282-2316 and references therein. (c) Fe´re´zou, J. P.;
Julia, M.; Khourzom, R.; Pancrazi, A.; Robert, P. Synlett 1991, 611-
614. (d) Woltering, M. J.; Fro¨hlich, R.; Hoppe, D. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1764-1766. (e) Oestreich, M.; Fro¨hlich, R.; Hoppe,
D. Tetrahedron Lett. 1998, 39, 1745-1748. (f) Tomooka, K.; Komine,
N.; Sasaki, T.; Shimizu, H.; Nakai, T. Tetrahedron Lett. 1998, 39,
9715-9718. (g) Woltering, M. J.; Fro¨hlich, R.; Wibbeling, B.; Hoppe,
D. Synlett 1998, 797-800. (h) Deiters, A.; Hoppe, D. Angew. Chem.,
Int. Ed. 1999, 38, 546-548. (i) Oestreich, M.; Hoppe, D. Tetrahedron
Lett. 1999, 40, 1881-1884. (j) van Bebber, J.; Ahrens, H.; Fro¨hlich,
R.; Hoppe, D. Chem. Eur. J. 1999, 5, 1905-1916. (k) Oestreich, M.;
Fro¨hlich, R.; Hoppe, D. J. Org. Chem. 1999, 64, 8616-8626. (l) Hoppe,
D.; Woltering, M. J.; Oestreich, M.; Fro¨hlich, R. Helv. Chim. Acta 1999,
82, 1860-1877. (m) Kleinfeld, S. H.; Wegelius, E.; Hoppe, D. Helv.
Chim. Acta 1999, 82, 2413-2424.
(6) (a) Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T. Angew.
Chem., Int. Ed. 2000, 39, 353-355. (b) Nakamura, S.; Nakagawa, R.;
Watanabe, Y.; Toru, T. J. Am. Chem. Soc. 2000, 122, 11340-11347.
(c) Nakamura, S.; Furutani, A.; Toru, T. Eur. J. Org. Chem. 2002,
1690-1695. (d) Nakamura, S.; Kato, T.; Nishimura, H.; Toru, T.
Chirality 2004, 16, 86-89.
(7) For the enantioselective reaction of the R-carbanion derived from
dithioacetals, see: Nakamura, S.; Ito, Y.; Wang, L.; Toru, T. J. Org.
Chem. 2004, 69, 1581-1589. For enantioselective reaction of the
R-carbanion derived from N,S-acetals with (-)-sparteine, see: Wang,
L.; Nakamura, S.; Toru, T. Org. Biomol. Chem. 2004, 2, 2168-2169.
Wang, L.; Nakamura, S.; Ito, Y.; Toru, T. Tetrahedron: Asymmetry
2004, 15, 3059-3072.
(2) (a) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc.
1994, 116, 3231-3239. (b) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc.
1996, 118, 715-721. (c) Weisenburger, G. A.; Beak, P. J. Am. Chem.
Soc. 1996, 118, 12218-12219. (d) Faibish, N. C.; Park, Y. S.; Lee, S.;
Beak, P. J. Am. Chem. Soc. 1997, 119, 11561-11570. (e) Park, Y. S.;
Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1997, 119, 10537-
10538. (f) Gross, K. M. B.; Jun, Y. M.; Beak, P. J. Org. Chem. 1997,
62, 7679-7689.
10.1021/jo048505l CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/10/2004
8916
J. Org. Chem. 2004, 69, 8916-8923

Reaction of R-Selenoorganolithium Compounds
SCHEME 1
SCHEME 2
the sulfur. Hoffmann and co-workers have reported that
R-seleno carbanions are more configurationally stable
than R-thio carbanions but less stable than R-oxy car-
banions.3,5 Since chiral selenides have the potential to
be asymmetric catalysts8,9 and synthetic intermedi-
ates,10,11 it is important to develop the highly enantio-
selective reaction of R-seleno carbanions and to clarify
the reaction pathways in more detail.12,13 We now report
enantioselective reactions of R-lithio benzyl phenyl se-
lenide and R-lithio benzyl 2-pyridyl selenide with elec-
trophiles in the presence of an external chiral ligand
(Scheme 1), including the reaction mechanism, on the
basis of Beak’s test using a deficient amount of the
electrophile14 and the warm-cool procedure14a-c together
with the analysis of the data obtained by the MO
calculation. We also report a highly enantioselective
olefination involving the enantioselective reaction of the
R-seleno carbanion with 4-substituted cyclohexanones
and the subsequent stereospecific elimination reaction.15
borohydride and subsequently with 1,1-dichlorotoluene
(Scheme 2).
Treatment of a cumene solution of the diselenoacetal
1a or 1b with 1.05 equiv of n-BuLi and 1.1 equiv of a
chiral ligand for 10 min at -78 °C formed the lithiated
species Li-1, which was allowed to react with an electro-
phile to give the products 2.17,18 The yields and enanti-
oselectivities obtained in the reaction of lithiated 1a and
1b with various electrophiles are summarized in Table
1.19
The reaction of Li-1a with benzophenone and (S)-bis-
(oxazoline)s 3a-d gave the product 2a in moderate yields
with moderate to high enantioselectivities (entries 1-5).
Among the bis(oxazoline)s, (S)-bis(oxazoline)-iPr 3a showed
the highest enantioselectivity. Low enantioselectivity was
obtained in the reaction with use of (-)-sparteine 4 (entry
6), which often has been used as a chiral ligand in the
asymmetric reactions of dipole-stabilized R-oxy and R-ami-
no carbanions. The reaction carried out at -50 and -90
°C showed slightly lowered enantioselectivity in com-
parison with that at -78 °C (entries 7, 8, and 9). The
reaction of Li-1a with acetone or cyclohexanone gave the
products 2b and 2c in high yields with high enantio-
selectivities (entries 10-12). It was rather surprising that
acetone and cyclohexanone having acidic protons showed
yields and enantioselectivities as good as those obtained
in the reaction with benzophenone. Methylation and
silylation with (CH3)2SO4 and (CH3)3SiOTf showed mod-
erate enantioselectivity, whereas the reaction with CH3I
and (CH3)3SiCl did not show good enantioselectivity
(entries 13-16). We next studied the enantioselective
reaction of R-lithio benzyl 2-pyridyl selenide Li-1b. When
the reaction was carried out under the same reaction
conditions as in the reaction of Li-1a, the product 2f was
obtained with moderate enantioselectivity (entries 17 and
18). The yield was markedly improved when 2.1 equiv of
n-BuLi and 2.2 equiv of (S)-bis(oxazoline)-tBu 3b were
used, where the seleno alcohol 2f was formed in high
yield but with moderate enantioselectivity (entries 19 and
20). The enantioselectivity in the reaction of Li-1b with
benzophenone varied depending on the temperature of
deprotonation: High enantioselectivity was obtained at
Results
Lithiation-Substitution. We chose bis(arylseleno)-
phenylmethanes 1a,b as the substrates for the formation
of R-seleno carbanions due to the ease of their prepara-
tion and lithiation. Diselenoacetals 1 were prepared on
treatment of selenophenol with benzaldehyde in the
16
presence of TiCl4 or dipyridyl diselenide with sodium
(8) For a review, see: Nishibayashi, Y.; Uemura, S. Organoselenium
Chemistry. In Topics in Current Chemistry; Wirth, T., Ed.; Springer:
New York, 2000; Vol. 208, pp 235-255.
(9) (a) Hiroi, K.; Suzuki, Y.; Abe, I. Tetrahedron: Asymmetry 1999,
10, 1173-1188. (b) Miyake, Y.; Oda, M.; Oyamada, A.; Takada, H.;
Ohe, K.; Uemura, S. J. Organomet. Chem. 2000, 611, 475-487. (c)
Braga, A. L.; Rodrigues, O. E. D.; Paixa˜o, M. W.; Appelt, H. R.; Silveira,
C. C.; Bottega, D. P. Synthesis 2002, 2338-2340.
(10) For a review, see: Wirth, T. Angew. Chem., Int. Ed. 2000, 39,
3740-3749.
(11) (a) Krief, A.; Castillo-Colaux, C. Synlett 2001, 501-504. (b)
Huang, X.; Xu, W. Tetrahedron Lett. 2002, 43, 5495-5497. (c) Tiecco,
M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.;
Temperini, A. Angew. Chem., Int. Ed. 2003, 42, 3131-3133.
(12) For a review, see: Toru, T.; Nakamura, S. Organolithiums in
Enantioselective Synthesis. In Topics in Organometallic Chemistry;
Hodgson, G., Ed.; Springer, New York, 2003; Vol. 5, pp 177-216.
(13) The reaction of nondipole-stabilized R-seleno carbanions pro-
ceeds through a dynamic thermodynamic resolution pathway with good
enantioselectivity, see: (a) 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 Trans. 2 1995,
1721-1726. (c) Hoffmann, R. W.; Klute, W. Chem. Eur. J. 1996, 2,
694-700.
(16) Clarembeau, M.; Cravador, A.; Dumont, W.; Hevesi, L.; Krief,
A.; Lucchetti, J.; Van Ende, D. Tetrahedron 1985, 41, 4793-4812.
(17) Cumene was found to be a solvent suitable for maximizing the
difference in the reaction rate between the catalyzed and noncatalyzed
reactions: see ref 6. When the reaction was carried out in a coordi-
native solvent such as THF or Et2O, the selenoacetal 1a was spontane-
ously lithiated on treatment with n-BuLi without addition of a chiral
ligand to give the product 2 in high yield but with low enantioselec-
tivity.
(18) When the aging time for lithiation in the presence of a chiral
ligand was longer, the yield was lower.
(19) These results were replicated at least 2 times and they were
reproducible to <3%.
(14) (a) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Tha-
yumanavan, S. Acc. Chem. Res. 1996, 29, 552-560. (b) Thayumanavan,
S.; Basu, A.; Beak, P. J. Am. Chem. Soc. 1997, 119, 8209-8216. (c)
Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J. Am.
Chem. Soc. 1999, 121, 9522-9530. (d) Gallagher, D. J.; Du, H.; Long,
S. A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 11391-11398.
(15) We preliminarily communicated the preparation of optically
pure axially chiral compounds using R-thio and R-seleno carbanions,
see: Nakamura, S.; Ogura, T.; Wang, L.; Toru, T. Tetrahedron Lett.
2004, 45, 2399-2402.
J. Org. Chem, Vol. 69, No. 25, 2004 8917

Nakamura et al.
TABLE 1. Enantioselective Reaction of Li-1a and Li-1b
with Electrophiles in the Presence of Various Chiral
Ligands
SCHEME 3
SCHEME 4
epoxide 5. The epoxide 5 was confirmed to have an
R-configuration by comparison of the value of the specific
rotation with that reported.22 Since a reaction of the
pyridylseleno alcohol 2f similar to the above failed to give
the epoxide, 2f was converted to the selenoxide with
m-CPBA, which was then treated with aqueous NaOH
solution to give the known epoxide (S)-5. Thus, the
absolute configuration of 2f obtained in the reaction of
R-lithio benzyl 2-pyridyl selenide Li-1b with benzophe-
none was determined to be R (Scheme 4).23
Preparation of Axially Chiral Compounds. The
Horner-Wadsworth-Emmons reaction is one of the most
useful methods for making a double bond from carbonyl
compounds. Recently, the asymmetric Horner-Wads-
worth-Emmons reactions using external chiral ligands
have been reported.24 We have reported stereospecific
transformation of R-seleno alcohols into (Z)-olefins R to
a carbonyl group.25 The above stereospecific â-elimination
of â-seleno alcohols allowed us to examine application of
the present reaction to the synthesis of axially chiral
olefins.15 First, Li-1a was allowed to react with 4-tert-
butylcyclohexanone in the presence of chiral ligands
3a-c affording cis- and trans-seleno alcohols 6-8 (Table
2, entries 1-3). The highest enantioselectivity was
obtained when bis(oxazoline)-tBu 3b was used.26 The
reaction with other 4-substituted cyclohexanones and 3b
also afforded the seleno alcohols 7 and 8 with high
enantioselectivity (entries 4 and 5). Each diastereomer
was easily separated by column chromatography.27
seleno- chiral
electro-
phile
temp
(°C) product (%) (%)
yield eea
entry acetal ligand
1
2
3b
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
3a
3b
3b
3c
3d
4
Ph2CO
-78
-78
-78
-78
-78
-78
-90
-50
-90
-78
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2d
2d
2e
2e
2f
60 85
63 70
78 78
62 81
51 67
Ph2CO
Ph2CO
Ph2CO
Ph2CO
Ph2CO
Ph2CO
Ph2CO
Ph2CO
(CH3)2CO
79
5
3a
3a
3b
3a
3a
3b
3a
3a
3a
3a
3a
3b
3a
3b
3b
3b
3a
3c
62 80
56 62
63 72
73 95
71 88
83 95
63 17
62 41
10
11
cyclohexanone -78
cyclohexanone -78
CH3I
12
13
-78
-78
-78
-78
-78
-78
-78
-78
-50
-30
-50
-50
14
(CH3)2SO4
(CH3)3SiCl
(CH3)3SiOTf
Ph2CO
15
80
3
16
59 65
50 56
51 41
99 39
85 46
73 77
64 47
49 73
77 64
17
18
Ph2CO
2f
19c
20c
21c
22c
23c
24c
Ph2CO
2f
Ph2CO
2f
Ph2CO
2f
Ph2CO
2f
Ph2CO
2f
Ph2CO
2f
a Determined by the HPLC analysis with a Chiralcel OD-H. b n-
BuLi (1.3 equiv), 1.4 equiv of 3, and 2.0 equiv of Ph2CO were used.
c n-BuLi (2.10 equiv), 2.2 equiv of 3, and 2.3 equiv of Ph2CO were
used.
(22) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224-11235.
(23) Ceccherelli, P.; Curini, M.; Epifano, F.; Marcotullio, M. C.;
Rosati, O. J. Org. Chem. 1995, 60, 8412-8413.
-50 °C with (S)-bis(oxazoline)-tBu 3b which gave higher
enantioselectivity than other bis(oxazoline)s (entries 21-
24).20
The absolute configuration of 2a was determined to be
S by stereospecific conversion to the epoxide 5 (Scheme
3).21 Thus, treatment of the product 2a with trimethyl-
oxonium tetrafluoroborate gave the selenonium ion,
which was then allowed to react with K2CO3 to give the
(24) For enantioselective Wittig-Horner and Horner-Wadsworth-
Emmons reactions with external chiral ligands, see: (a) Toda, F.; Akai,
H. J. Org. Chem. 1990, 55, 3446-3447. (b) Kumamoto, T.; Koga, K.
Chem. Pharm. Bull. 1997, 45, 753-755. (c) Mizuno, M.; Fujii, K.;
Tomioka, K. Angew. Chem., Int. Ed. 1998, 37, 515-517. (d) Arai, S.;
Hamaguchi, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2997-3000. (e)
Sano, S.; Yokoyama, K.; Teranishi, R.; Shiro, M.; Nagao, Y. Tetrahedron
Lett. 2002, 43, 281-284. For the enantioselective Peterson olefination,
see: Iguchi, M.; Tomioka, K. Org. Lett. 2002, 4, 4329-4331.
(25) (a) Toru, T.; Hayakawa, T.; Nishi, T.; Watanabe, Y.; Ueno, Y.
Phosphorus Sulphur Silicon 1998, 653-658. (b) Nakamura, S.; Hay-
akawa, T.; Nishi, T.; Watanabe, Y.; Toru, T. Tetrahedron 2001, 57,
6703-6711. See also reviews: (c) Clive, D. L. J. Tetrahedron 1978,
34, 1049-1132. (d) Krief, A. Tetrahedron 1980, 36, 2531-2640.
(26) The reaction of R-thio carbanions with 4-alkylcyclohexanones
showed high enantioselectivity; see ref 15.
(20) Determination of the optical purity of the products obtained in
the reaction of Li-1b with other electrophiles such as acetone, cyclo-
hexanone, CH3I, and (CH3)3SiCl could not be determined because of
their insufficient separation by the HPLC analyses with use of various
chiral columns.
(21) Shanklin, J. R.; Johnson, C. R.; Ollinger, J.; Coates, R. M. J.
Am. Chem. Soc. 1973, 95, 3429-3431.
(27) We also examined the enantioselective reaction of Li-1b with
4-substituted cyclohexanones, but the attempts to separate the ob-
tained diastereomeric isomers by column chromatography failed.
8918 J. Org. Chem., Vol. 69, No. 25, 2004

Reaction of R-Selenoorganolithium Compounds
TABLE 2. Enantioselective Reaction of Li-1a with
4-Substituted Cyclohexanones
SCHEME 5
lithium species Li-1, which was treated with an electro-
phile to give the products 2a-f. It is not likely that the
reaction proceeds through an enantioselective replace-
ment of the prochiral seleno group with lithium, i.e.,
through an enantioselective deselenenylation pathway,
because configurational stability of the R-seleno carban-
ion is assumed to be insufficient. Thus, asymmetric
induction occurs in a postdeselenenylation step through
an asymmetric substitution pathway controlled either by
the stability of lithium carbanion-chiral ligand com-
plexes, i.e., through dynamic thermodynamic resolution,29
or by the complex-electrophile interaction in the transi-
tion state, i.e., dynamic kinetic resolution.30 The reaction
with a different amount of an electrophile enables us to
differentiate these resolution pathways. In the case of
dynamic kinetic resolution, the enantiomer ratio depends
solely upon the difference between the activation energies
in the formation of enantiomers (∆∆Gq) and is indepen-
dent of the amount of electrophile. In the case of dynamic
thermodynamic resolution, the amount of electrophile
affects the enantioenrichment of the product, because the
two diastereomeric complexes would have different ac-
tivation energies for the reaction with the electrophile.
In fact, the reaction of 1a or 1b afforded the products
(S)-2a and (R)-2b in different enantiomer ratios depend-
ing on the reactions with a different amount of benzophe-
none (Scheme 5).
ee (%)
product (%) cis:trans cis transb
electrophile
R
yield ratioa
entry ligand
1
2
3
4
5
3a
3b
3c
3b
3b
tBu
tBu
tBu
Me
Ph
6
6
6
7
8
79
68
58
74
65
60:40 74b
65:35 86b
71:29 73b
69:31 91c
51:49 90d
67
90
39
90
89
a Determined by 1H NMR analysis. b Enantiomeric excess was
determined after conversion to olefins. c Determined by HPLC
analysis with Chiralpak AD-H. d Determined by HPLC analysis
with Chiralcel OJ-H. e Determined by HPLC analysis with Chiral-
cel OD-H.
TABLE 3. Preparation of Axially Chiral Olefins 9-11
from Seleno Alcohols 6-8
These results suggest that the enantioselective reaction
of 1a or 1b proceeds through a dynamic thermodynamic
resolution pathway, i.e., the reaction with a benzophe-
none occurs before the inversion between diastereomeric
complexes of lithiated 1a or 1b with the bis(oxazoline).31
In this case, the enantiomeric excess of the product
formed from the reaction of Li-1 with benzophenone
depends on the difference in the stability between the
two diastereomeric Li-1-bis(oxazoline) complexes (∆∆G
in Figure 4). The decrease in the enantiomer ratios of
2a and 2b in the reaction with a limited amount of
ee
yield
(%)
ee
entry
substrate
(%)
product
(%)a
config.
1
2
3
4
5
6
cis-6
86
91
90
9
89
91
92
91
90
88
86
91
90
90
90
89
(M)
(M)
(M)
(P)
(P)
(P)
cis-7
10
11
9
cis-8
trans-6
trans-7
trans-8
10
11
a Determined by HPLC analysis with Chiralcel OD-H.
(28) (a) Denmark, S. E.; Chen, C.-T. J. Am. Chem. Soc. 1992, 114,
10674-10676. (b) Henessian, S.; Beaudoin, S. Tetrahedron Lett. 1992,
33, 7655-7658.
(29) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel,
D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715-727.
(30) (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc.
Jpn. 1995, 68, 36-56. (b) Ward, R. S. Tetrahedron: Asymmetry 1995,
6, 1475-1490. (c) Caddick, S.; Jenkins, K. Chem. Soc. Rev. 1996, 447-
456. (d) Pellissier, H. Tetrahedron 2003, 59, 8291-8327.
(31) The same range of enantioselectivity should be obtained ir-
respective of the electrophile through a dynamic thermodynamic
resolution process. The reactions with CH3I, (CH3)2SO4, (CH3)3SiCl,
and (CH3)3SiOTf gave the products with lower enantioselectivity than
that obtained in the reaction with benzophenone. The decreased
enantioselectivity in the reaction with alkylating reagents is ascribed
to the activation energy. The alkylation of Li-1a, in which the
alkylating reagent approaches without coordination to lithium, would
have higher activation energy than the reaction with carbonyl com-
pounds and proceed not only through a dynamic thermodynamic
resolution but also through a dynamic kinetic resolution.
The separated diastereomeric seleno alcohols 6-8 were
treated with methanesulfonyl chloride and Et3N in CH2-
Cl2 to give axially chiral olefins 9-11 with high optical
purity (Table 3). The optical purity of the chiral olefins
was determined by the HPLC analysis with Chiralcel
OD-H and the olefination was found to proceed without
loss of optical purity. The absolute stereochemistry of the
chiral olefins 9-11 was assigned by comparison of the
values of the specific rotation with those reported.28
Discussion
Diselenoacetals 1a,b were lithiated by the Se-Li
exchange reaction with n-BuLi to afford the organo-
J. Org. Chem, Vol. 69, No. 25, 2004 8919

Nakamura et al.
FIGURE 1. Geometry optimization of anti- and syn-Li-1a-TMEDA Complexes.
benzophenone also implies that a more stable diastere-
omeric complex has higher activation energy to react with
q
q
benzophenone (∆GR > ∆GS in Figure 4). Interestingly,
the enantioselective reaction of R-lithiated benzyl phenyl
sulfide proceeds through a dynamic kinetic resolution
pathway with high enantioselectivity,6 indicating that the
R-seleno carbanion (Li-1a) has a higher inversion barrier
than that of the R-thio carbanion of benzyl phenyl sulfide.
The inversion barrier of R-thio- and R-seleno carbanions
can be ascribed to the stabilization energy of the n-σX-C
negative hyperconjugation.32 Thus, we performed the MO
calculation for the Li-1a-TMEDA. The calculations for
these complexes by Gaussian 98 HF/3-21G, HF/6-
31+G*,33 and MOPAC 93/PM334 methods showed a
significant level of difference in energy between anti- and
syn-Li-1a-TMEDA complexes as shown in Figure 2.35
The anti arrangement of the C-Li bond to the Se-
Cips bond of Li-1a was clearly shown to be a preferable
conformation by these calculations. This would be due
to an n-σ*Se-C negative hyperconjugation, where the
unshared electron pair of carbanions can overlap with
the antibonding Se-C bond (σ*Se-C) in the present model
FIGURE 2. Stabilization energy of n-σ* negative hypercon-
jugation.
compounds. We also calculated the n-σ*X-C negative
hyperconjugation energies of R-lithiated benzyl phenyl
selenide and R-lithiated benzyl phenyl sulfide by the
natural bond orbital (NBO) analysis at the HF/6-31+G*
level36,37 (Figure 2). Both compounds were found to have
a significant level of stabilization energy by the n-σ*
negative hyperconjugation. The R-seleno carbanion was
found to be more stabilized by the negative hyperconju-
gation than the R-thio carbanion by 1.3 kcal/mol, showing
the former has a higher inversion barrier than the
latter.38
The stability of diastereomeric complexes of Li-1a with
3a was estimated by the MO calculation with use of HF/
3-21G and the (R)-Li-1a-3a complex was found to be
slightly more stable than the (S)-Li-1a-3a complex as
shown in Figure 3. Thus, it was reasonably inferred that
the reaction of Li-1a with electrophiles such as aldehydes
and ketones proceeded with retention of configuration
through coordination of a carbonyl oxygen to lithium to
afford the (S)-isomer (SE2ret reaction39).40 This reaction
pathway is well-illustrated by the energy diagram of the
enantioselective reaction of Li-1a as shown in Figure 4.
(32) (a) Lehn, J.-M.; Wipff, G.; Demuynck, J. Helv. Chim. Acta 1977,
60, 1239-1246. (b) Ruhland, T.; Dress, R.; Hoffmann, R. W. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1467-1468. (c) Dress, R. K.; Ro¨lle, T.;
Hoffmann, R. W. Chem. Ber. 1995, 128, 673-677. (d) Hoffmann, R.
W.; Dress, R. K.; Ruhland, T.; Wenzel, A. Chem. Ber. 1995, 128, 861-
870.
(33) (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.: Pitts-
burgh, PA, 1998. For the Becke3LYP hybrid method, see: (b) Stephens,
P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem.
1994, 98, 11623-11627.
(36) NBO Version 3.1; Glendening, E. D.; Reed, A. E.; Carpenter,
J. E.; Weinhold, F. See also: (a) Reed, A. E.; Weinstock, R. B.;
Weinhold, F. J. Chem. Phys. 1985, 83, 735-746. (b) Reed, A. E.;
Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899-926.
(37) (a) Salzner, U.; Schleyer, P. R. J. Org. Chem. 1994, 59, 2138-
2155. (b) Cortes, F.; Tenorio, J.; Collera, O.; Cuevas, G. J. Org. Chem.
2001, 66, 2918-2924. (c) Hete´nyi, A.; Martinek, T. A.; La´za´r, L.; Zala´n,
Z.; Fu¨lo¨p, F. J. Org. Chem. 2003, 68, 5707-5705.
(38) By the 1H NMR spectral analysis, Hoffmann and co-workers
have estimated a higher inversion barrier of the R-seleno carbanion
than that of the R-thio carbanion by 1.1 kcal/mol, which accords with
our calculation results, see refs 12 and 31d.
(34) (a) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209-220. (b)
For the lithium parameter for PM3, see: Anders, E.; Koch, R.;
Freunscht, P. J. Comput. Chem. 1993, 14, 1301-1312.
(35) No negative frequency of these optimized structures was
confirmed by the frequency calculation.
(39) Gawley, R. E. Tetrahedron Lett. 1999, 40, 4297-4300.
(40) The inversion/inversion pathway is unlikely, because carbonyl
compounds usually react with organometallic compounds in a retentive
manner through coordination with the metal center.
8920 J. Org. Chem., Vol. 69, No. 25, 2004

Reaction of R-Selenoorganolithium Compounds
FIGURE 3. Geometry optimization of R-lithio benzyl phenyl selenide Li-1a with bis(oxazoline)-iPr 3a.
SCHEME 6
with 3b equilibrate at -50 °C, and the enantiomeric
excess of 2f reflects the ratio of these two diastereomeric
complexes. To gain more quantitative insight into the
reaction mechanism of Li-1b, the diastereomeric com-
plexes with 3b were estimated by the MO calculation by
using the HF/3-21G and MOPAC 93/PM3 methods. The
relative energies of the optimized structures obtained by
these calculations are depicted in Figure 5.
In each optimized structure, a nitrogen of pyridine is
coordinated to the lithium ion together with the two
nitrogens of the bis(oxazoline), giving the fully coordi-
nated lithium complex. Calculations by both methods
showed that the (R)-Li-1b-3b complex is more stable
than the (S)-Li-1b-3b complex. Since the lithium ion is
fully coordinated, the substitution reaction may occur
with inversion of configuration (SE2inv).39,41
FIGURE 4. The assumed energy diagram of the enantio-
selective reaction for the Li-1a under dynamic thermodynamic
resolution.
The enantioselectivity in the reaction of Li-1b with
benzophenone depends on the temperature of the depro-
tonation (Table 1, entries 18, 21, and 22). These results
indicate that the enantioselective reaction of Li-1b
proceeds through a dynamic thermodynamic resolution
pathway. Beak’s “warm-cool procedure”14a-c also con-
firmed this assumption. A cumene solution of 1b was
treated with 2.1 equiv of n-BuLi at -78 °C for 10 min,
and then 2.2 equiv of bis(oxazoline)-tBu 3b was added.
After being stirred for 30 min at -50 °C, the reaction
mixture was cooled to -78 °C, and then 2.3 equiv of
benzophenone was added (Scheme 6). The enantioselec-
tivity in this reaction was substantially the same as that
obtained in the reaction performed at -50 °C (77% ee,
Table 1, entry 21), and was lowered when the reaction
was performed at -78 °C (46% ee, Table 1, entry 20) as
shown in Scheme 6.
Conclusion
In summary, we have demonstrated a highly enantio-
selective reaction of the configurationally labile R-car-
banions derived from benzyl phenyl selenide and benzyl
2-pyridyl selenide in the presence of bis(oxazoline)s as a
chiral ligand. We established the enantiodetermining
step to be a dynamic thermodynamic resolution. Conve-
These results indicate that the diastereomeric com-
plexes derived from Li-1b and bis(oxazoline)-tBu 3b are
configurationally stable at temperatures lower than -50
°C at least on the time scale of the reaction with
electrophiles, i.e., the diastereomeric complexes of Li-1b
(41) This stereochemical pathway is in accord with that in the
reaction of lithiated benzyl 2-pyridyl sulfide, see ref 6.
J. Org. Chem, Vol. 69, No. 25, 2004 8921

Nakamura et al.
FIGURE 5. Geometry optimization of (R)- and (S)-Li-1b-3b complexes.
1
127-128 °C; [R]20 +38.8 (c 0.40, CHCl3); H NMR δ 3.55 (s,
nient removal of the seleno group from the products
provides an efficient method for the preparation of axially
chiral olefins or a chiral epoxide.
D
1H), 5.46 (s, 1H), 6.95-7.30 (m, 18H), 7.59-7.65 (m, 2H); 13
C
NMR δ 60.6, 80.6, 125.8, 126.0, 126.3, 126.6, 127.1, 127.6,
128.1, 128.6, 130.2, 135.6, 138.9, 144.2, 146.2; IR (KBr) 3450,
3020, 1492, 1448, 1332, 1171 cm-1; MS (EI) m/z 255 (M+
-
Experimental Section
PhSeOH). Anal. Calcd for C26H22OSe: C, 72.71; H, 5.16.
Found: C, 72.63; H, 5.06. HPLC (Daicel Chiralcel OD-H,
hexane/iPrOH 97/3, 0.5 mL/min) tR 13.8 (R) and 40.2 (S) min
(82% ee).
Preparation of Diselenoacetals: Bis(2-pyridylseleno)-
phenylmethane (1b). To a solution of di(2-pyridyl) diselenide
(1.0 g, 3.18 mmol) in ethanol (10 mL) was added NaBH4 (263
mg, 6.94 mmol) at room temperature, and the solution was
stirred for 30 min. Benzal chloride (0.37 mL, 2.88 mmol) was
then added and the solution was heated to reflux for an
additional 24 h. The reaction was quenched with a 1 mol/L
HCl solution and extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure to give a crude oil
that was purified by column chromatography (silica gel 20 g,
hexane/CH2Cl2 80/20) to afford 1b (818 mg, 70%). Rf 0.20
2-Methyl-1-phenyl-1-(phenylseleno)-2-propanol (2b): Rf
0.21 (hexane/ethyl acetate 90/10); [R]20D +307.9 (c 0.42, CHCl3);
1H NMR δ 1.30 (s, 3H), 1.32 (s, 3H), 4.27 (s, 1H), 5.29 (s, 1H),
7.13-7.45 (m, 10H); 13C NMR δ 27.8, 65.0, 73.5, 126.9, 127.2,
127.8, 128.7, 129.2, 130.2, 133.8, 140.5; IR (neat) 3450, 3057,
2971, 1578, 1476, 1369, 1332 cm-1; MS (EI) m/z 289 (M+
-
H2O). Anal. Calcd for C16H18OSe: C, 62.95; H, 5.94. Found:
C, 62.95; H, 6.28. HPLC (Daicel Chiralcel OD-H, hexane/iPrOH
95/5, 0.5 mL/min) tR 12.3 (R) and 15.5 (S) min (95% ee).
1
1-[1-Phenyl-1-(phenylseleno)methyl]-1-cyclohexanol
(2c): Rf 0.30 (hexane/ethyl acetate 90/10); [R]25D +242.2 (c 0.72,
CHCl3); 1H NMR δ 1.40-1.65 (m, 8H), 1.84-2.00 (m, 2H), 2.10
(s, 1H), 4.25 (s, 1H), 7.09-7.43 (m, 10H); 13C NMR δ 22.1, 22.3,
25.6, 35.5, 37.3, 64.6, 74.0, 126.8, 127.2, 127.8, 128.7, 128.9,
129.4, 134.0, 140.3; IR (KBr) 3483, 2936, 2852, 1578, 1477
cm-1; MS m/z 329 (M+ - H2O). Anal. Calcd for C19H22OSe: C,
66.08; H, 6.42. Found: C, 66.13; H, 6.72. HPLC (Daicel
Chiralcel OD-H, hexane/2-propanol 98/2, 0.5 mL/min) tR 14.0
(R) and 18.0 (S) min (95% ee).
(hexane/ethyl acetate 80/20); H NMR(CDCl3) δ 6.74 (s, 1H),
6.98-7.66 (m, 10H), 7.76-7.84 (m, 2H), 8.40-8.48 (m, 2H);
13C NMR (CDCl3) δ 39.2, 120.7, 125.5, 127.4, 128.0, 128.2,
136.0, 141.1, 149.7, 156.1; IR (KBr) 1570, 1442, 1411, 1273,
1108, 1052 cm-1; MS (EI) m/z 403 (M+). Anal. Calcd for
C17H14N2Se2: C, 50.51; H, 3.49; N, 6.93. Found: C, 50.49; H,
3.52; N, 6.91.
Enantioselective Reaction of Lithiated Benzyl Phenyl
Selenide (Li-1a) with an Electrophile in the Presence
of a Chiral Ligand: 1,1,2-Triphenyl-2-(phenylseleno)-
ethanol (2a). To a solution of bis(phenylseleno)phenyl-
methane (1a) (27 mg, 0.068 mmol) in cumene (0.45 mL) was
added n-BuLi (0.050 mL, 1.43 mol/L solution in hexane, 0.072
mmol) at -78 °C, and the solution was stirred for 10 min. Bis-
(oxazoline)-iPr (20 mg, 0.075 mmol) was then added and the
solution was stirred for an additional 10 min. A solution of
benzophenone (15 mg, 0.082 mmol) in cumene (0.20 mL) was
then added. After the mixture was stirred for 5 min, the
reaction was quenched with saturated aqueous NH4Cl and the
aqueous solution was extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure to give a
crude oil that was purified by column chromatography (silica
gel 10 g, hexane/ethyl acetate 95/5) affording 2a (18 mg, 62%)
as a colorless solid. Rf 0.36 (hexane/ethyl acetate 90/10); mp
1-Phenyl-1-(phenylseleno)ethane (2d):42 Rf 0.22 (hex-
ane); 1H NMR δ 1.74 (d, J ) 7.2 Hz, 3H), 4.44 (q, J ) 7.2 Hz,
1H), 7.12-7.48 (m, 10H). HPLC (Daicel Chiralcel OD-H,
hexane, 0.5 mL/min) tR 20.9 and 22.9 min (41% ee).
1-Phenyl-1-(phenylseleno)-1-trimethylsilylmethane (2e):
42b,43 Rf 0.29 (hexane); [R]21D +202.9 (c 0.44, CH2Cl2); 1H NMR
δ 0.14 (s, 9H), 3.74 (s, 1H), 7.10-7.36 (m, 10H); 13C NMR δ
-1.8, 38.0, 125.1, 126.4, 127.9, 128.1, 128.5, 131.7, 131.9, 142.0;
IR (neat) 3057, 3020, 2955, 2895, 1578, 1476, 1248 cm-1; MS
(42) (a) Lapkin, I. I.; Bogoslovskii, N. I. Zh. Obsh. Khim. 1972, 49,
1972-1974. (b) Reich, H.-J.; Shah, S. K. J. Am. Chem. Soc. 1975, 97,
3250-3252. (c) Reich, H. J.; Wollowitz, S.; Trend, J. E.; Chow, F.;
Wendelborn, D. F. J. Org. Chem. 1978, 43, 1697-1705.
(43) Reich, H. J.; Shah, S. K. J. Org. Chem. 1977, 42, 1773-1776.
8922 J. Org. Chem., Vol. 69, No. 25, 2004

Reaction of R-Selenoorganolithium Compounds
m/z 320 (M+, 40), 163 (80), 135 (100). Anal. Calcd for C16H20-
SiSe: C, 60.17; H, 6.31. Found: C, 60.32; H, 6.38. HPLC
(Daicel Chiralpak AD-H, hexane, 0.5 mL/min) tR 8.1 (S) and
8.9 (R) min (66% ee).
1H NMR δ 0.87 (d, 3H, J ) 6.4 Hz), 1.00-1.75 (m, 8H), 2.13
(s, 1H), 2.23-2.30 (m, 1H), 4.45 (s, 1H), 7.13-7.40 (m, 10H);
13C NMR δ 20.8, 30.7, 31.1, 34.9, 37.2, 59.2, 74.5, 126.7, 127.3,
127.8, 128.6, 129.2, 130.1, 134.7, 140.4; IR (neat) 3446, 3059,
2925, 2855, 1455, 1375; 1156, 1045, 989, 737, 700 cm-1; MS
(FAB) m/z 385 (M+ - OH). Anal. Calcd for C20H24OSe: C,
66.84; H, 6.73. Found: C, 66.71; H, 6.93.
1,1,2-Triphenyl-2-(2-pyridylseleno)ethanol (2f): Rf 0.34
(hexane/ethyl acetate 80/20); mp 141 °C; [R]23 +32.8 (c 0.67,
D
1
CH2Cl2); H NMR δ 5.93 (s, 1H), 5.97 (s, 1H), 6.95-7.45 (m,
16H), 7.65-7.75 (m, 2H), 8.45-8.50 (m, 1H); 13C NMR δ 58.6,
81.0, 121.1, 125.7, 126.0, 126.4, 125.4, 127.3, 127.5, 127.8,
129.9, 136.7, 139.6, 144.7, 147.8, 148.3, 152.8; IR (KBr) 3200,
1577, 1451, 1413, 1109, 1049 cm-1; MS (EI) m/z 255 (PhCHd
CPh2+). Anal. Calcd for C25H21NOSe: C, 69.76; H, 4.92; N, 3.25.
Found: C, 69.73; H, 4.70; N, 3.32. HPLC (Daicel Chiralcel OD-
H, hexane/2-propanol 80/20, 0.5 mL/min) tR 14.8 (R) and 19.5
(S) min (77% ee).
(S)-1-[1-Phenyl-1-(phenylseleno)methyl]-4-phenylcy-
clohexan-1-ol (cis- and trans-8): cis-8: Rf 0.25 (hexane/ethyl
acetate 90/10); mp 132-133 °C; [R]25D +199.1 (c 0.53, CHCl3);
1H NMR δ 1.12-2.42 (m, 8H), 2.01-2.10 (m, 2H), 4.26 (s, 1H),
7.10-7.40 (m, 15H); 13C NMR δ 29.4, 29.6, 35.4, 37.0, 43.7,
65.8, 73.2, 125.8, 126.6, 126.9, 127.3, 127.9, 128.1, 128.7, 129.5,
130.3, 133.9, 140.1, 146.6; IR (KBr) 3577, 3066, 3023, 2928,
1492, 1474, 1438, 1136, 977, 756, 737, 701, 669 cm-1; MS (FAB)
m/z 405 (M+ - OH). Anal. Calcd for C25H26OSe: C, 71.25; H,
6.22. Found: C, 70.96; H, 6.51. HPLC (Daicel Chiralpak AD-
H, hexane/iPrOH 95/5, 0.75 mL/min) tR 19.5 (R) and 25.6 (S)
Conversion of 2a to (R)-5. To a solution of the seleno
alcohol 2a (128 mg, 0.298 mmol) in nitromethane (2 mL) was
added trimethyloxonium tetrafluoroborate (88 mg, 0.596 mmol)
at room temperature and the mixture was stirred for 45 min.
Then the mixture was added to a methanol (1 mL) solution of
potassium carbonate (82 mg, 0.596 mmol). After 1 h, a
saturated aqueous NaCl solution was added and the mixture
was extracted with CH2Cl2. The combined organic extracts
were dried over Na2SO4, filtered, and concentrated under
reduced pressure to give a crude oil that was purified by
column chromatography (silica gel 10 g, hexane/ethyl acetate
95/5) affording (R)-5 (38 mg, 47%). Rf 0.39 (hexane/ethyl
min (90% ee). trans-8: Rf 0.16 (hexane/ethyl acetate 90/10);
1
[R]25 +154.3 (c 0.37, CHCl3); H NMR δ 1.45-1.90 (m, 7H),
D
2.26 (s, 1H), 2.56-2.63 (m, 2H), 4.63 (s, 1H), 7.14-7.40 (m,
15H); 13C NMR δ 30.3, 30.8, 36.3, 38.8, 42.8, 57.7, 74.4, 125.9,
126.5, 126.8, 127.5, 128.0, 128.2, 128.7, 128.9, 129.1, 134.9,
140.2, 145.6; IR (neat) 3446, 3058, 3025, 2928, 2858, 1578,
1493, 1475, 1451, 1437, 1074, 1046, 738, 698 cm-1; MS (FAB)
m/z 405 (M+ - OH). Anal. Calcd for C25H26OSe: C, 71.25; H,
6.22. Found: C, 71.05; H, 6.42.
Typical Procedure for the Preparation of Chiral
Benzylidenecyclohexanes: (M)-1-Benzylidene-4-tert-bu-
tylcyclohexane [(M)-9].28 To a solution of cis-6 (77 mg, 0.19
mmol) in CH2Cl2 (1.9 mL) was added methanesulfonyl chloride
(0.31 mL, 3.9 mmol) at 0 °C and the solution was stirred for
30 min. Triethylamine (1.3 mL, 9.3 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. The reaction was quenched with saturated
aqueous NH4Cl and extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure to give a
crude oil that was purified by column chromatography (silica
gel 25 g, hexane) to afford (M)-9 (39 mg, 89%). [R]25D -37.4 (c
acetate 90/10); [R]D25 -36.0 (83% ee, c 0.76, EtOH) [lit.21 [R]D
25
1
-43.2 (c 0.82, EtOH)]; H NMR δ 4.33 (s, 1H), 7.00-7.40 (m,
15H).
Conversion 2f to (S)-5. To a solution of the seleno alcohol
2f (66% ee, 60 mg, 0.139 mg) in CH2Cl2 (1 mL) was added
m-chloroperbenzoic acid (172 mg, 70% purity, 0.697 mmol) and
the solution was stirred for 5 min at room temperature. A 1
mol/L aqueous NaOH solution (3 mL) was added and the
mixture was stirred for 12 h. Workup and purification as above
gave (S)-5 (4 mg, 10%). HPLC (Daicel Chiralcel OD-H, hexane/
2-propanol 95/5, 1.0 mL/min) tR 5.1 (S) and 10.2 (R) min (58%
ee).
(S)-1-[1-Phenyl-1-(phenylseleno)methyl]-4-tert-butyl-
cyclohexan-1-ol (cis- and trans-6): cis-6: Rf 0.34 (hexane/
0.59, CH3OH) [lit. (P-isomer): [R]rt +43.3 (c 1.23, CH3OH)];
D
ethyl acetate 90/10); mp 94-95 °C; [R]25 +208.3 (c 1.62,
1H NMR δ 0.86 (s, 9H), 0.95-1.27 (m, 3H), 1.80-1.97 (m, 3H),
2.12-2.27 (m, 1H), 2.35-2.43 (m, 1H), 2.93-3.02 (m, 1H), 6.21
(s, 1H), 7.16-7.33 (m, 5H). HPLC (Daicel Chiralcel OD-H,
hexane, 0.2 mL/min) tR 27.8 (R) and 33.5 (S) min (86% ee).
D
CHCl3); 1H NMR δ 0.82 (s, 9H), 1.25-1.58 (m, 8H), 1.99-2.10
(m, 1H), 2.11 (s, 1H), 4.19 (s, 1H), 7.15-7.40 (m, 10H, Ar); 13
C
NMR δ 22.7, 22.9, 27.7, 32.4, 35.6, 37.4, 47.5, 65.7, 73.5, 126.8,
127.2, 127.7, 128.7, 129.4, 130.4, 133.8, 140.3; IR (KBr) 3449,
3056, 2956, 2865, 1578, 1479, 1435, 1364, 1262, 1245, 1074,
963, 729, 700, 688 cm-1; MS (FAB) m/z 385 (M+ - OH). Anal.
Calcd for C23H30OSe: C, 68.81; H, 7.53. Found: C, 68.59; H,
7.75. HPLC (Daicel Chiralpak AD-H, hexane/iPrOH 96/4, 0.5
mL/min) tR 15.2 (R) and 19.9 (S) min (86% ee). trans-6: Rf 0.23
(hexane/ethyl acetate 90/10); [R]25D +183.4 (c 0.97, CHCl3); 1H
NMR δ 0.75 (s, 9H), 0.96-1.52 (m, 8H), 2.01 (s, 1H), 2.45-
2.54 (m, 1H), 4.45 (s, 1H), 7.06-7.33 (m, 10H); 13C NMR δ
23.9, 24.4, 27.7, 32.4, 36.7, 39.4, 47.1, 57.1, 74.7, 126.7, 127.3,
127.9, 128.6, 129.1, 130.1, 134.8, 140.3; IR (neat) 3446, 3058,
3024, 2945, 2867, 1475, 1453, 1437, 1365, 1074, 1053, 736, 692
cm-1; MS (FAB) m/z 385 (M+ - OH). Anal. Calcd for C23H30-
OSe: C, 68.81; H, 7.53. Found: C, 68.53; H, 7.81.
(M)-1-Benzylidene-4-methylcyclohexane [(M)-10]:28 [R]25
D
-36.5 (c 0.84, CH3OH) [lit. (P-isomer): [R]rt +40.2 (c 0.33,
D
1
CH3OH)]; H NMR δ 0.92 (d, 3H, J ) 6.4 Hz), 0.88-1.19 (m,
2H), 1.54-1.70 (m, 1H), 1.73-2.00 (m, 3H), 2.15-2.40 (m, 2H),
2.82-2.90 (m, 1H), 6.22 (s, 1H), 7.16-7.29 (m, 5H). HPLC
(Daicel Chiralcel OD-H, hexane, 0.2 mL/min) tR 29.0 (R) and
40.1 (S) min (91% ee).
(M)-1-Benzylidene-4-phenylcyclohexane [(M)-11]:28 [R]25
D
-36.5 (c 0.84, CH3OH) [lit. (P-isomer): [R]rt +110.2 (c 0.67,
D
1
CH3OH)]; H NMR δ 1.49-1.76 (m, 2H), 1.94-2.12 (m, 3H),
2.31-2.53 (m, 2H), 2.68-2.83 (m, 1H), 3.00-3.07 (m, 1H), 6.30
(s, 1H), 7.17-7.32 (m, 10H). HPLC (Daicel Chiralcel OD-H,
hexane, 0.5 mL/min) tR 31.0 (R) and 41.1 (S) min (90% ee).
(S)-1-[1-Phenyl-1-(phenylseleno)methyl]-4-methylcy-
clohexan-1-ol (cis- and trans-7): cis-7: Rf 0.35 (hexane/ethyl
acetate 85/15); mp 73.5-74.5 °C; [R]25D +272.4 (c 1.65, CHCl3);
1H NMR δ 0.87 (d, 3H, J ) 5.6 Hz), 1.20-1.60 (m, 8H), 1.97-
2.05 (m, 1H), 2.08 (s, 1H), 4.19 (s, 1H), 7.12-7.38 (m, 10H);
13C NMR δ 22.3, 30.4, 30.5, 32.0, 35.2, 36.9, 65.6, 73.5, 126.8,
127.2, 127.7, 128.7, 129.4, 130.3, 133.9, 140.3; IR (KBr) 3481,
3057, 3025, 2921, 2852, 1578, 1491, 1476, 1438, 1371, 1158,
1022, 987, 737, 700, 662 cm-1; MS (FAB) m/z 343 (M+ - OH).
Anal. Calcd for C20H24OSe: C, 66.84; H, 6.73. Found: C, 66.65;
H, 6.95. HPLC (Daicel Chiralcel OD-H, hexane/iPrOH 99/1,
0.5 mL/min) tR 16.8 (R) and 24.6 (S) min (91% ee). trans-7: Rf
0.24 (hexane/ethyl acetate 85/15); [R]25D +267.0 (c 1.25, CHCl3);
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 NIT research promotion program. We
thank Dr. Shinya Kusuda, Ono Pharmaceutical Co.,
Ltd., for the mass spectra measurements.
Supporting Information Available: Calculation results
of anti-Li-1a-TMEDA, syn-Li-1a-TMEDA, (R)-Li-1a-3a, (S)-
Li-1a-3a, (R)-Li-1b-3b, and (S)-Li-1b-3b. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO048505L
J. Org. Chem, Vol. 69, No. 25, 2004 8923