Design, synthesis, and application of a C2 symmetric chiral ligand for enantioselective conjugate addition of organolithium to α,β-unsaturated aldimine

Article abstract of DOI:10.1021/jo9813181

A C₂ symmetric chiral diether ligand, (1R,2R)-1,2-dimethoxy-1,2- diphenylethane, was designed and synthesized on the basis of the concept of an asymmetric oxygen atom. Mediated by the chiral diether, high enantioselectivities were achieved in conjugate addition of organolithiums to naphthaldehyde imine and cyclic and acyclic α,β-unsaturated aldimines. The absolute configuration of the product is predictable by the model.

Full text of DOI:10.1021/jo9813181

J . Org. Chem. 1998, 63, 9351-9357
9351
Design , Syn th esis, a n d Ap p lica tion of a C2 Sym m etr ic Ch ir a l
Liga n d for En a n tioselective Con ju ga te Ad d ition of Or ga n olith iu m
to r,â-Un sa tu r a ted Ald im in e
Mitsuru Shindo,† Kenji Koga,‡ and Kiyoshi Tomioka*,§
Institute for Medicinal Resources, University of Tokushima, Sho-machi, Tokushima 770-8505,
Research and Education Center for Materials Science, Nara Institute of Science and Technology,
Takayama-cho, Ikoma-shi, Nara 630-0101, and Graduate School of Pharmaceutical Sciences,
Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, J apan
Received J uly 8, 1998
A C2 symmetric chiral diether ligand, (1R,2R)-1,2-dimethoxy-1,2-diphenylethane, was designed and
synthesized on the basis of the concept of an asymmetric oxygen atom. Mediated by the chiral
diether, high enantioselectivities were achieved in conjugate addition of organolithiums to
naphthaldehyde imine and cyclic and acyclic R,â-unsaturated aldimines. The absolute configuration
of the product is predictable by the model.
In tr od u ction
Rational design of a chiral external ligand is a key for
the success of an enantioselective reaction of organome-
tallics.1 The requirements of the ligand are (1) an
activation of the reactivity of organometallics and sub-
sequently (2) enhancement of the absolute stereochem-
istry control.2 These demands may be satisfied by the
formation of a rigid chelation structure between a chiral
ligand and organometallics.3 Although organometallics
are aggregates in nonpolar solvents, chelation with a
ligand is expected to give rise to a lower aggregate of
higher reactivity.4 Control of the absolute stereochem-
istry is simultaneously enhanced by the formation of the
rigid chelate with a chiral ligand.
F igu r e 1.
oselective conjugate addition of organolithium.7,8 We
describe herein our design, synthesis, and application of
the ligand to the reaction with R,â-unsaturated imine.9
Design of a Ch ir a l Liga n d . It is reasonable to
assume that the chiral chelation structure 1, where Li
is the central lithium of the organometallic reagent and
X is the coordinating atom to the lithium, provides a
chiral environment around the central lithium due to the
configurationally fixed bulk on X. The model has the
advantage that a direct steric effect is operative by the
coordinating chiral atom X just adjacent to the central
lithium, because coordination to lithium by a substrate
is the first step of the reaction.10
On the basis of the scenario described above, we
designed a model (1) for the chiral chelate of organo-
lithium, a powerful reagent5 for a carbon-carbon bond-
forming reaction (Figure 1). The steric control units, two
balloons on heteroatoms X in 1, are placed on the up and
down faces of the chelation plane. Having this concept
in hand,6 we have reported a ligand-controlled enanti-
† University of Tokushima.
‡ Nara Institute of Science and Technology.
§ Kyoto University.
(1) Review for an external chiral ligand, see: (a) Tomioka, K.
Synthesis 1990, 541. (b) Seyden-Penne, J . Chiral Auxiliaries and
Ligands in Asymmetric Synthesis; J ohn Wiley and Sons: New York,
1995.
(2) (a) Tomioka, T.; Sudani, M.; Shinmi, Y.; Koga, K. Chem. Lett.
1985, 329. (b) Nakajima, M.; Tomioka, K.; Koga, K. Tetrahedron 1993,
49, 9751.
The chemical design of model 1 is of primary impor-
tance in our chemistry. It is reasonable to assume that
(3) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J . Am. Chem.
Soc. 1997, 119, 12974.
(7) (a) Shindo, M.; Koga, K.; Tomioka, K. J . Am. Chem. Soc. 1992,
114, 8732. (b) Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron Lett.
1993, 34, 681. (c) Asano, Y.; Iida, A.; Tomioka, K. Tetrahedron Lett.
1997, 38, 8973. (d) Asano, Y.; Iida, A.; Tomioka, K. Chem. Pharm. Bull.
1998, 46, 184. For application of 2 by other groups, see: (e) Amurrio,
D.; Khan, K.; Ku¨ndig, E. P. J . Org. Chem. 1996, 61, 2258. (f) Ishimaru,
K.; Monda, K.; Yamamoto, Y.; Akiba, K. Tetrahedron 1998, 54, 727.
(g) Xu, F.; Tillyer, R. D.; Tschaen, D. M.; Grabowski, E. J . J .; Reider,
P. J . Tetrahedron: Asymmetry 1998, 9, 1651.
(8) For applications of the ligand 2 in enantioselective reactions,
see: (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J .
Am. Chem. Soc. 1997, 119, 2060. (b) Mizuno, M.; Kanai, M.; Iida, A.;
Tomioka, K. Tetrahedron 1997, 53, 10699. (c) Mizuno, M.; Fujii, K.;
Tomioka, K. Angew. Chem., Int. Ed. Engl. 1998, 37, 515.
(4) For pioneering work on chiral ligand promotion of 1,2-addition
reaction of organometallics, see: (a) Seebach, D.; Kalinovski, H.-O.;
Bastani, B.; Crass, G.; Daum, H.; Dorr, H.; Dupreez, N. P.; Ehrig, V.;
Langer, W.; Nussler, C.; Oei, H. A.; Schmidt, M. Helv. Chim. Acta 1977,
60, 302. (b) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K.
J . Am. Chem. Soc. 1979, 101, 1455. (c) Mazaleyrat, J .-P.; Cram, D. J .
J . Am. Chem. Soc. 1981, 103, 4585. (d) Whitesell, J . K.; J aw, B.-R. J .
Org. Chem. 1981, 46, 2798. (e) Colombo, L.; Gennari, C.; Poli, G.;
Scolastico, C. Tetrahedron 1982, 38, 2725. Eleveld, M. B.; Hogeveen,
H. Tetrahedron Lett. 1984, 25, 5187.
(5) Wakefield, B. J . Organolithium Methods; Academic Press: Lon-
don, 1988.
(6) A similar design has appeared in the formation of chiral boron
enolate. Corey, E. J .; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J . Am.
Chem. Soc. 1989, 111, 5493.
(9) Preliminary results have appeared in the following: Tomioka,
K.; Shindo, M.; Koga, K. J . Am. Chem. Soc. 1989, 111, 8266.
(10) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 29, 356.
10.1021/jo9813181 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/20/1998

9352 J . Org. Chem., Vol. 63, No. 25, 1998
Shindo et al.
developed by Meyers and is an established method for
regioselective introduction of a carbonucleophile to naph-
thalene nucleus.15 Extension to the diastereoselective
asymmetric reaction and application to natural product
synthesis16 have been also developed using chiral oxazo-
line derivatives17 or chiral imines.18 Computational
rationale for regioselective addition to unsaturated al-
dimines has been proposed by us.19 Application of our
chiral diether ligand was examined in the enantioselec-
tive addition reaction of organolithium to achiral imine
11.20
With a stoichiometric amount of the simplest chiral
diether ligand 5, the enantioselective conjugate addition
reaction of phenyllithium to the cyclohexyl aldimine 11a 21
was examined. Toluene was used as a solvent because
organolithiums are supposed to be much less reactive due
to their high aggregation in less polar solvents.22 In the
presence of 1.1 equiv (to phenyllithium) of 5, the reaction
proceeded at -45 °C, and the reaction mixture showed a
deep-red color that would indicate the formation of
lithium azaenolate.15 The reaction was quenched and
hydrolyzed with acetate buffer (pH 4.5). The usual
workup afforded 2-phenyl-1,2-dihydronaphthalene-1-car-
baldehyde 12a , which was immediately reduced with
NaBH4 in methanol to the corresponding trans alcohol
13a in 68% overall yield after column chromatography.
The enantiomeric excess was determined by HPLC
analysis using a chiral stationary phase column to be as
high as 90%. The absolute configuration was determined
to be 1S,2R by optical rotation of 13a 17 (Table 1, entry
1).
The reaction of butyllithium with the ligand 5 at -78
°C for 2 h gave (1R,2S)-13b in 92% yield and 53% ee
(entry 2). In the absence of the ligand, the conjugate
addition of butyllithium was sluggish in toluene to afford
racemic 13b in only 22% yield after 3 h (entry 15). Thus,
the chiral diether 5 not only controls the absolute
stereochemistry but also promotes the conjugate addition.
Encouraged by these results, tuning of the chiral diethers
was examined to improve the enantioselectivity.
F igu r e 2.
a C2 symmetric chiral diether 2 forms a five-membered
chelation, 3, with organolithium. The four substituents,
two R1 on the ethylene bridge and two R2 on the ether
oxygen atoms, take an all-trans arrangement due to
steric factors. The arrangement of the two R2 groups on
the oxygen atoms, which represent the steric bulk shown
in 1, is important.
Generally, an oxygen atom is not an asymmetric center
in itself. However, due to the steric effect of a neighbor-
ing asymmetric carbon of the ethylene bridge, the ether
oxygen becomes an asymmetric center. Herein, we
propose the concept of stereocontrol by formation of an
asymmetric oxygen atom. Our proposal of chiral ether
oxygen is supported by X-ray diffraction of the complex
of dimethoxyethane and lithium enolate,11 in which
oxygen atoms of dimethoxyethane chelating to lithium
appear to be tetrahedral. Formation of the chelate 3
enhances the reactivity of organometallics due to a lower
aggregation.
Syn th esis of Ch ir a l Dieth er s. The C2 symmetric
chiral diethers in both enantiomeric forms are easily
synthesized via dialkylation of the corresponding com-
mercially or synthetically available chiral diols 4 (Figure
2). Chiral diethers 5,12 6,13 and 7 were synthesized by
dialkylation of sodium alkoxides of commercial chiral 2,3-
butanediol 4a in THF. A variety of C2 symmetric chiral
diols are also available in the necessary quantity and in
high optical purity by the asymmetric dihydroxylation
of olefins.14 The chiral diether 8 was synthesized by
dimethylation of optically pure hydrobenzoin 4b and is
a stable, nonhygroscopic, colorless, crystalline solid. The
dimethyl ether 9 and bisdimethylamine 10 were prepared
as reference ligands.
Ster ic Requ ir em en ts of th e Liga n d . Higher enan-
tioselectivity would be achieved when the all-trans ar-
rangement of the substituents on the five-membered
chelate of 3 is more efficiently fixed. Therefore, bulkier
substituents on the oxygen atoms of diether 3 were
introduced at first. Contrary to our expectation, chiral
diether 6 having an ethyl group on the oxygen atom
Con ju ga te Ad d ition of Or ga n olith iu m to 1-Na p h -
th a ld eh yd e Im in e. The conjugate addition of an orga-
nolithium to an imine of 1-naphthaldehyde 11 has been
(15) (a) Meyers, A. I.; Brown, J . D.; Laucher, D. Tetrahedron Lett.
1987, 28, 5279. (b) Meyers, A. I.; Lutomski, K. A.; Laucher, D.
Tetrahedron 1988, 44, 3107.
(11) (a) Williard, P. G.; Hinze, M. J . J . Am. Chem. Soc. 1990, 112,
8602. For other reports on ether oxygen in lithium-ether complexes,
see: (b) Becker, G.; Birkhahn, M.; Massa, W.; Uhl, W. Angew. Chem.,
Int. Ed. Engl. 1980, 19, 741. (c) Amstutz, R.; Schweizer, W. B.; Seebach,
D.; Dunitz, J . D. Helv. Chim. Acta 1981, 64, 2617. (d) Hope, H.; Power,
P. P. J . Am. Chem. Soc. 1983, 105, 5320. (e) Wanat, R. A.; Collum, D.
B.; Van Cuyne, G.; Clardy, J .; Depue, R. T. J . Am. Chem. Soc. 1986,
108, 3415. (f) Williard, P. G.; Hintze, M. J . J . Am. Chem. Soc. 1987,
109, 5539. (g) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.
(h) Nichols, M. A.; Williard, P. G. J . Am. Chem. Soc. 1993, 115, 1568.
(12) Cohen, H. L.; Wright, G. F. J . Org. Chem. 1952, 17, 432.
(13) (a) Helmkamp, G. K.; Lucas, H. J . J . Am. Chem. Soc. 1952, 74,
951. (b) Moritani, I.; Nagai, T.; Shirota, Y. Kogyo Kagaku Zasshi 1965,
68, 40.
(14) (a) Tomioka, K.; Nakajima, M.; Koga, K. J . Am. Chem. Soc.
1987, 109, 6213. (b) Nakajima, M.; Tomioka, K.; Iitaka, Y.; Koga, K.
Tetrahedron 1993, 49, 10793. (c) Lohray, B. B.; Kalantar, T. H.; Kim,
B. M.; Park, C. Y.; Shibata, T.; Wai, J . S. M.; Sharpless, K. B.
Tetrahedron Lett. 1989, 30, 2041. (d) Mckee, B. H.; Gilheany, D. G.;
Sharpless, K. B. Org. Synth. 1991, 70, 47.
(16) (a) Robichaud, A. J .; Meyers, A. I. J . Org. Chem. 1991, 56, 2607.
(b) Meyers, A. I.; Higashiyama, K. J . Org. Chem. 1987, 52, 4592. (c)
Andrews, R. C.; Teague, S. J .; Meyers, A. I. J . Am. Chem. Soc. 1988,
110, 7854.
(17) (a) Barner, B. A.; Meyers, A. I. J . Am. Chem. Soc. 1984, 106,
1865. (b) Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.; Laucher,
D. J . Am. Chem. Soc. 1988, 110, 4611. (c) Rawson, D. J .; Meyers, A. I.
J . Org. Chem. 1991, 56, 2292.
(18) Meyers, A. I.; Brown, J . D.; Laucher, D. Tetrahedron Lett. 1987,
28, 5283.
(19) Tomioka, K.; Okamoto, T.; Kanai, M.; Yamataka, H. Tetrahe-
dron Lett. 1994, 35, 1891.
(20) For the recent brilliant example of a chiral ligand controlled
conjugate addition of organolithium, see: Park, Y. S.; Weisenburger,
G. A.; Beak, P. J . Am. Chem. Soc. 1997, 119, 10537.
(21) Comins, D. L.; Brown, J . D. J . Org. Chem. 1984, 49, 1078.
(22) In THF, the reaction proceeds smoothly even without any
ligands. THF is suspected to compete with the chiral ligand to form a
complex with organolithiums. Actually, with
ligand, no asymmetric induction occurred.
a chiral aminoether

C2 Symmetric Chiral Ligand
J . Org. Chem., Vol. 63, No. 25, 1998 9353
Ta ble 1. En a n tioselective Con ju ga te Ad d ition of Or ga n olith iu m to 1-Na p h th a ld eh yd e Im in e 11 Con tr olled by Ch ir a l
Liga n d s 5-10
entry
aldimine
R4
Ph
chiral ligand
temp/°C
time/h
product 13a
ee/%b
yield/%c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11b
11b
11a
11a
11a
(S,S)-5
(R,R)-5
(S,S)-6
(S,S)-6
(S,S)-7
(S,S)-7
(R,R)-8
(R,R)-8
(S)-9
-45
-78
-45
-78
-45
-78
-45
-78
-78
-78
-45
-45
-23
-78
-78
13
2
15
5
12
2
13
6
7
4
16
22
20
1
(1S,2R)-13a
(1R,2S)-13b
(1S,2R)-13a
(1S,2R)-13b
(1S,2R)-13a
(1R,2S)-13b
(1R,2S)-13a
(1R,2S)-13b
(1R,2S)-13b
(1S,2R)-13b
(1S,2R)-13a
(1R,2S)-13a
(1R,2R)-13c
(1R,2S)-13d
racemic-13b
90
53
33
28
20
15
94
91
6
11
92
95
64
59
68
92
64
83
26
89
82
80
46
26
80
76
19e
79
22
Bu
Ph
Bu
Ph
Bu
Ph
Bu
Bu
Bu
Ph
Ph
Me
t-Bu
Bu
(S,S)-10d
(S,S)-5
(R,R)-8
(R,R)-8
(R,R)-8
none
3
a
b
Determined by optical rotation.17 Determined by HPLC analysis using a chiral column. c Overall yield purified by silica gel column
chromatography. In ether. e The 1,2-adduct was obtained in 49% yield.
d
lower coordinating ability of the phenolic oxygen atoms
(entry 9). It is also important to note that diamine 1024
induced only 11% ee in ether, although it has a diphe-
nylethane unit as in 8 (entry 10). This suggests that the
direct stereocontrol factor is not the bulky groups on the
asymmetric carbons but the “asymmetric oxygen” coor-
F igu r e 3.
dinated to the central lithium.
Other organolithiums, methyl- and tert-butyllithiums,
afforded only 33% ee for 13a and 28% ee for 13b (entry
reacted with 11a to afford 13c,d in 64% and 59% ee’s
3, 4). The chiral diether 7 bearing a benzyl group on the
(entries 13 and 14). The reaction of methyllithium gave
oxygen gave 13a and 13b in poorer ee’s of 20% and 15%
(entries 5 and 6).
the 1,2-adduct as the major product in 49% yield.25
The reaction of vinyllithium, prepared in situ from
Unfavorable interactions between the bulky substitu-
tetravinyltin and methyllithium in toluene, gave, after
methylation in situ, 16 in 83% ee. On the other hand,
crystallized vinyllithium reacted with 11a in the presence
of 8 in toluene at -35 °C for 16 h to afford, after
methylation, the N-methylated 1,2-adduct in 22% yield,
without production of 16 (Figure 4).
Con ju ga t e Ad d it ion t o Cyclic r,â-Un sa t u r a t ed
Ald im in e. The present asymmetric reaction of organo-
lithiums is applicable to other unsaturated aldimines.
The reaction of phenyllithium with cyclic R,â-unsaturated
aldimines 17a,b proceeded smoothly. The initially formed
cis aldehyde 18 was isomerized to trans-19 by treating
18 with concentrated hydrochloric acid in THF.26 Then
ent R2 on oxygen and the alkyl group R of the organo-
lithium (14) would be greater than that with the methyl
group on the chiral carbon and R2 and would force the
all-trans conformation 14 to take the conformation 15,
which would give rise to lower selectivity (Figure 3).
Therefore, the chiral diether 8 having phenyl groups on
the asymmetric carbons was expected to be more efficient
than 5.
In fact, the chiral diether 8 exerted better enantiose-
lectivity 94% ee in the reaction of phenyllithium (entry
7). Furthermore, the reaction with butyllithium gave
13b in dramatically improved 91% ee (entry 8). The
chiral diether 8 was recovered quantitatively for reuse
without any loss of optical purity.
(24) (a) Gulloti, M.; Pasini, A.; Fantucc, P.; Ugo, R.; Gilland, R. D.
Gazz. Chim. Ital. 1972, 102, 855. (b) Lifshits, I.; Bas, J . G. Recl. Trav.
Chim. Pays-Bas 1940, 59, 173.
The solvent effect on the ee was marginal. The
reaction of 11a with butyllithium in the presence of 8 in
ether for 9 h at -78 °C gave (1R,2S)-13b in 89% ee and
61% yield.
(25) Chiral external ligand controlled 1,2-addition of organolithium
to imines has been another interesting kind of chemistry, see: (a)
Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett. 1990,
31, 6681. (b) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahe-
dron: Asymmetry 1993, 4, 1603. (c) Inoue, I.; Shindo, M.; Koga, K.;
Tomioka, K. Tetrahedron 1994, 50, 4429. (d) Inoue, I.; Shindo, M.;
Koga, K.; Kanai, M.; Tomioka, K. Tetrahedron: Asymmetry 1995, 6,
2527. (e) Taniyama, D.; Kanai, M.; Iida, A.; Tomioka, K. Chem. Pharm.
Bull. 1997, 45, 1705. (f) Taniyama, D.; Kanai, M.; Iida, A.; Tomioka,
K. Heterocycles 1997, 46, 165. (g) Tomioka, K.; Satoh, M.; Taniyama,
D.; Kanai, M.; Iida, A. Heterocycles 1998, 47, 77. For review, see:
Denmark, S. E.; Nicaise, O. J .-C. J . Chem. Soc., Chem. Commun. 1996,
999.
The reaction of the adamantylimine of 1-naphthalde-
hyde 11b with phenyllithium in the presence of 5 and 8
also gave conjugate adduct 13a in 92% and 95% ee,
respectively (entries 11 and 12).
It was disappointing that 923 with a binaphthyl unit
only induced a miserable ee of 6%, probably due to the
(23) Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J . J . Org. Chem.
1981, 46, 393.
(26) Corey, E. J .; Boger, D. L. Tetrahedron Lett. 1978, 9.

9354 J . Org. Chem., Vol. 63, No. 25, 1998
Shindo et al.
initial event leads to two model structures, 24 and 25,
for the reactive complexes involving 8, R-Li, and cyclo-
hexylimine of crotonaldehyde (21a ), where the migrating
C-Li bond is almost parallel to the p orbital of the imine
(Figure 5). Obviously, there are less unfavorable steric
interactions in 24 than in 25.30 The absolute configura-
tion predicted from 24 is identical with the experimental
results.
F igu r e 4.
Ta ble 2. En a n tioselective Con ju ga te Ad d ition of
P h en yllith iu m to Cyclic r,â-Un sa tu r a ted Ald im in e 17
Med ia ted by Ch ir a l Dieth er s 5 a n d 8
Con clu sion
The chiral C2 symmetric ligands 5 and 8 show the
powerful effect on the activation of the addition of
organolithium to R,â-unsaturated imines as well as on
the enantioselectivity of the reaction.31 The methyl group
on the ether oxygen seems to be critical to the enanti-
oselectivity of the addition. This principle is very simple
for designing chiral ligands and is applicable in a variety
of asymmetric reactions.
chiral temp/ time/
ee/ yield/
b
c
entry aldimine ligand
°C
h
producta
%
%
1
2
3
4
17a
17a
17b
17b
(R,R)-8 -45
(S,S)-5 -45
(R,R)-8 -45
(S,S)-5 -45
3
4
7
1
(1S,2S)-20a 91
(1R,2R)-20a 82
(1S,2S)-20b 96
(1R,2R)-20b 80
59
76
61
69
Exp er im en ta l Section
a
Absolute configuration was determined by optical rotation.27
Gen er a l. 1H and 13C NMR were recorded in CDCl3, unless
otherwise noted. Chemical shift values are presented in parts
per million downfield from tetramethylsilane. Data are
reported as follows: integration, multiplicity (br ) broad, s )
singlet, d ) doublet, t ) triplet, q ) quartet, m ) multiplet),
coupling constant (hertz), and assignment where relevant.
Mass spectra were recorded under electron impact (EI) condi-
tions. Analytical HPLC was performed using Waters Optipak-
TA, XC, PC, TC, Daicel Chiralcel AD. Reactions were moni-
tored by thin-layer chromatography carried out on 0.25 mm
E. Merck silica gel plates (60F-254), with UV light, ethanolic
phosphomolybdic acid, or p-anisaldehyde solution and heat as
the developing agent. Melting points are uncorrected. Boiling
points are uncorrected. THF, Et2O, DME, and toluene were
distilled from sodium benzophenone ketyl.
Determined by HPLC analysis using a chiral column. c Purified
yield of 20.
b
the trans-19 was reduced with NaBH4 to the correspond-
ing alcohol 20. As shown in Table 2, 20a ,b were obtained
in over 90% ee with use of 8 from both of five- and six-
membered imines 17a and 17b. The chiral diether 8
exhibited higher enantioselectivity than 5 (entry 1 vs
entry 2 and entry 3 vs entry 4). The sense of asymmetric
induction was the same as that of the naphthalene imines
described above.27
Con ju ga t e Ad d it ion t o Acyclic r,â-Un sa t u r a t ed
Ald im in e. Acyclic unsaturated imines were also good
substrates for the asymmetric conjugate addition reac-
tion. The reactivity was so high that the reaction
proceeded at -78 °C even when phenyllithium was used.
High enantioselectivity was achieved as shown in Table
3. Especially with phenyllithium as the nucleophile,
nearly optically pure products 23 were obtained by the
use of chiral diether ligand 8 (entries 1 and 3). Chemical
yields were modest in some cases, since the 1,2-adducts
were also obtained in 10-25% yield. The sense of
asymmetric induction was the same as that of the
naphthalene imines 11.28
The reaction of phenylmagnesium bromide with 21a
in the presence of 8 in toluene at -23 °C for 3 h gave
racemic 22 (R5 ) Me, R4 ) Ph). This result indicates
that lithium is the essential metal in the reaction
promoted by the diether ligand 8.
Ster eoch em ica l Asp ects of th e Rea ction . The
sense of asymmetric induction exhibited by the chiral
diether ligand 8 is the same regardless of whether
1-naphthyl-, cyclic, or acyclic imines are used as the
substrates. Organolithium attacks from the top face of
imines 11, 17, and 21. The assumption that coordination
of nitrogen of the imine to tetravalent lithium10,29 is the
(2S,3S)-2,3-Dim eth oxybu ta n e, 5.12 5 was prepared from
(2S,3S)-2,3-butanediol. [R]20 -3.65 (neat). 1H NMR: 1.10
D
(6H, d, J ) 6 Hz), 3.10-3.70 (8 H, m). IR (neat): 3000, 2960,
2900, 2840 cm-1
.
(2S,3S)-2,3-Dieth oxybu ta n e, 6.13 Prepared from (2S,3S)-
2,3-butanediol. [R]25 +4.86 (neat), [R]25 +10.7 (c 5.45, CH2-
D
D
Cl2). 1H NMR: 1.09 (6H, d, J ) 6 Hz), 1.18 (6H, t, J ) 7 Hz),
3.30-3.80 (6H, m). 13C NMR: 15.0 (q), 15.6 (q). 64.7 (t), 77.3
(d). IR (neat): 2900, 1120 cm-1
.
(2S,3S)-2,3-Diben zyloxybu ta n e, 7. (2S,3S)-2,3-Butane-
diol (2.00 g, 22.2 mmol) in THF (10 mL) was added dropwise
over 10 min to a suspension of 2.22 g (55.5 mmol) of sodium
hydride (60% in mineral oil, washed 3 times with hexane (5
mL)) in THF (40 mL). After being stirred at room temperature
for 30 min, the viscous mass was refluxed for 30 min until
hydrogen evolution ceased. Then, 9.49 g (55.5 mmol) of benzyl
bromide in THF (10 mL) was added dropwise during 10 min.
After being stirred at room temperature for 13 h, the reaction
mixture was refluxed for 1 h, poured into saturated NH4Cl
(50 mL), and extracted with Et2O (50 mL). The extract was
washed with brine and dried over MgSO4. Concentration
provided a yellow oil, which was chromatographed over silica
gel (hexane/Et2O ) 10:7) to yield 7 (5.19 g, 86%) as a pale-
yellow oil of bp 130-132 °C at 0.4 mmHg. [R]25D +20.3 (c 1.48,
CHCl3). 1H NMR: 1.17 (6H, d, J ) 6 Hz), 3.4 (2H, m), 4.57
(2H, d, J ) 12 Hz), 4.59 (2H, d, J ) 12 Hz), 7.1-7.4 (10H, m).
13C NMR: 15.0 (q), 71.3 (t), 77.1 (d), 127.4 (d), 127.6 (d), 128.3
(d), 139.0 (s). IR (neat): 1615, 1590 cm-1. MS m/z: 270 (M+).
Anal. Calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 79.68;
H, 8.26.
(27) Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron
1981, 37, 3951.
(28) Hashimoto, S.; Yamada, S.; Koga, K. Chem. Pharm. Bull. 1979,
27, 771.
(29) (a) For a review, see: Olsher, U.; Izatt, R. M.; Bradshaw, J . S.;
Dalley, N. K. Chem. Rev. 1991, 91, 137. (b) Seebach, D. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 1624. (c) Setzer, W. N.; Schleyer, P. v. R. Adv.
Organomet. Chem. 1985, 24, 353. (d) Beno, M. A.; Hope, H.; Olmstead,
M. M.; Power, P. P. Organometallics 1985, 4, 2117.
(30) Cache calculation indicates the stability of 24 is higher than
that for 25 by a factor of around 2 kcal/mol.
(31) Unfortunately, the attempted catalytic reaction of phenyl-
lithium with 11a using 0.2 equiv of 5 or 8 gave 12a in at most 10%
yield.

C2 Symmetric Chiral Ligand
J . Org. Chem., Vol. 63, No. 25, 1998 9355
Ta ble 3. En a n tioselective Con ju ga te Ad d ition of Or ga n olith iu m to Acyclic r,â-Un sa tu r a ted Ald im in e 21 Med ia ted by
Ch ir a l Dieth er s 5 a n d 8
entry
R5
R4
chiral ligand
temp/°C
time/h
producta
ee/%b
yield/%
1
2
3
4
5
Me
Me
Bu
Bu
Ph
Ph
Ph
Ph
Ph
Bu
(R,R)-8
(S,S)-5
(R,R)-8
(S,S)-5
(R,R)-8
-78
-78
-78
-78
-78
3
1
4
3
1
(S)-23a
(R)-23a
(S)-23b
(R)-23b
(R)-23c
>99
94
>99
93
48
42
58
45
40
82
a
Absolute configuration was determined by optical rotation of 23, which was obtained from the corresponding ester with the established
absolute configuration.28 Determined by HPLC analysis using a chiral column.
b
mmol) in benzene (100 mL) was refluxed for 3 h with a Dean-
Stark trap. The mixture was washed with cold saturated
NaHCO3 and cold brine and dried over K2CO3. Concentration
gave a yellow solid, which was recrystallized from EtOH (20
mL) to yield 11b (2.43 g, 80%) as colorless needles of mp 119-
120.5 °C. 1H NMR: 1.7-2.1 (12H, m), 2.1-2.4 (3H, m), 7.4-
7.7 (3H, m), 7.7-8.1 (3H, m), 8.7-8.9 (1H, m), 8.97 (1H, s).
13C NMR: 29.6 (d), 36.6 (t), 43.3 (t), 58.3 (s), 124.1 (d), 125.3
(d), 125.8 (d), 126.7 (d), 127.5 (d), 128.6 (d), 130.3 (d), 131.4
(s), 132.8 (s), 133.8 (s), 154.3 (d). IR (KBr): 1630, 1615, 1510
cm-1. MS m/z: 289 (M+). Anal. Calcd for C21H23N: C, 87.15;
H, 8.01; N, 4.84. Found: C, 87.09; H, 8.11; N, 4.68.
(1R,2S)-(2-P h en yl-1,2-d ih yd r on a p h t h yl)m et h a n -1-ol,
13a 17 (Ta ble 1, en tr y 7). To a suspension of the naphth-
ylimine 11a (237 mg, 1.00 mmol)21 and (R,R)-8 (582 mg, 2.40
mmol) in 10 mL of toluene at -78 °C was added dropwise a
solution of phenyllithium (0.97 mL, 2.2 mmol). The solution
was stirred for 13 h at -45 °C, and then 20 mL of 10% HCl
was added to the red mixture. After being stirred for 4 h at
room temperature, the mixture was extracted with Et2O (3 ×
20 mL). The combined organic layer was washed with 10%
HCl (20 mL), saturated NaHCO3, and brine and then dried
over MgSO4. Concentration gave an oily solid. The crude
aldehyde was reduced with NaBH4 (0.12 g) in MeOH (6 mL)
at 0 °C for 10 min and quenched with 20% NH4Cl (3 mL). After
concentration, 20% NH4Cl (20 mL) was added and the mixture
was extracted with Et2O (20 mL). The extract was washed
with brine and dried over MgSO4. Concentration and subse-
quent purification by column chromatography on silica gel
(hexanes-Et2O ) 3:1) gave (1R,2S)-13a (193 mg, 82%) as a
colorless oil of [R]26D +519.7 (c 1.09, CHCl3). The spectral data
were identical with those reported. The ee was determined
to be 94% by HPLC analysis (Waters Optipak-TA; hexane/2-
propanol ) 9:1; 0.5 mL/min; major peak, 26 min; minor peak,
21 min). The ligand 8 (0.59 g) was recovered quantitatively.
(1R,2S)-(2-Bu tyl-1,2-dih ydr on aph th yl)m eth an -1-ol, 13b17
(Ta ble 1, en tr y 8). To a solution of the naphthylimine 11a
(237 mg, 1.00 mmol) and (R,R)-8 (339 mg, 1.40 mmol) in 10
mL of toluene at -78 °C was added dropwise a solution of
butyllithium (0.82 mL, 1.30 mmol). The mixture was stirred
for 6 h at -78 °C, and then 20 mL of 10% HCl was added.
After the mixture was stirred for 15 h at room temperature,
workup as above gave an oil (0.67 g), which was reduced with
NaBH4 (0.12 g) in MeOH (5 mL) at 0 °C. After 10 min, workup
as above and purification by chromatography on silica gel
(hexane/AcOEt ) 15/1) gave (1R,2S)-13b (172 mg, 80%) as a
colorless oil of [R]20D +403.8 (c 2.43, CHCl3). The spectral data
were identical with those reported. The ee was determined
to be 91% by HPLC analysis (Waters Optipak-TA; hexane/2-
propanol ) 9:1; 0.5 mL/min; major peak, 13.0 min; minor peak,
14.5 min).
F igu r e 5.
(1R,2R)-1,2-Dim eth oxy-1,2-d ip h en yleth a n e, 8. (R,R)-
(+)-Hydrobenzoin (10.0 g, 46.7 mmol) in THF (50 mL) was
added dropwise during 10 min to a suspension of sodium
hydride (4.67 g, 117 mmol, 60% in mineral oil, washed 3 times
with hexane) in THF (100 mL). After the mixture was refluxed
for 30 min, dimethyl sulfate (12.4 g, 98.1 mmol) was added
dropwise under ice bath cooling. The hard viscous mass was
stirred for 15 h at room temperature. The mixture was
quenched with saturated NH4Cl (10 mL) and extracted with
Et2O (200 mL). The combined organic layers were washed
with saturated NaHCO3 and brine and then dried over MgSO4.
Concentration afforded a colorless solid (11.1 g), which was
recrystallized from hexane to give 8 as colorless prisms (9.33
g, 82%) of mp 99-100 °C. [R]25 -15.2 (c 1.22, CHCl3). 1H
D
NMR: 3.27 (6H, s), 4.31 (2H, s), 6.85-7.25 (10H, m). 13C
NMR: 57.1 (q), 87.7 (d), 127.6 (d), 127.8 (d), 138.2 (s). IR
(KBr): 1490, 1450 cm-1. MS m/z: 241 (M+ - 1). Anal. Calcd
for C16H18O2: C, 79.31; H, 7.49. Found: C, 79.41; H, 7.52.
(S,S)-N,N,N′,N′-Tet r a m et h yl-1,2-d ip h en ylet h ylen ed i-
a m in e, 10. To a solution of (1S,2S)-1,2-diphenylethylenedi-
amine (1.90 g, 8.9 mmol, 98.7% ee) in formic acid (90%, 4.1
mL, 214 mmol) and H2O under reflux was added formalin
(37%, 5.2 mL, 138 mmol) dropwise. After the mixture refluxed
for 3 days, formic acid (4.1 mL) and formalin (5.2 mL) were
added, and reflux was continued for 3 days. To the mixture,
10% HCl (150 mL) was added, and then the aqueous layer was
washed with Et2O (50 mL). After addition of 50% NaOH (pH
11), it was extracted with AcOEt (200 mL) and the organic
layer was washed with brine and then dried over K2CO3.
Concentration gave 2.86 g of a colorless solid, which was
chromatographed over silica gel (AcOEt/hex ) 1:4) to yield 10
(2.11 g, 88%) as colorless needles of mp 88.0-89.5 °C (hexane).
[R]20D +57.2 (c 1.09, CHCl3). 1H NMR: 2.25 (12H, s), 4.25 (2H,
s), 6.9-7.4 (10H, m). IR (KBr): 1450, 1035 cm-1
. MS m/z:
269 (M+ + 1), 268 (M+). Anal. Calcd for C18H24N2: C, 80.55;
H, 9.01; N, 10.44. Found: C, 80.79; H, 9.11; N, 10.68.
N-(1-Na p h th ylm eth ylid en e)-1-a d a m a n ta n a m in e, 11b.
A solution of 1-naphthaldehyde (1.67 g, 10.7 mmol), 1-ada-
mantanamine (2.00 g, 12.8 mmol), and BF3OEt2 (0.06 mL, 0.5
(1R,2R)-(2-Met h yl-1,2-d ih yd r on a p h t h yl)m et h a n -1-ol,
13c17 (Ta ble 1, en tr y 13). To a solution of 11a (237 mg, 1.0
mmol) and (R,R)-8 (800 mg, 3.3 mmol) in 20 mL of toluene at

9356 J . Org. Chem., Vol. 63, No. 25, 1998
Shindo et al.
-78 °C was added dropwise a solution of methyllithium (2.2
mL, 3.0 mmol, 1.36 M in Et2O, low halide). After 20 h at -23
°C, acetate buffer (20 mL) was added. After the mixture was
stirred for 3 h at room temperature, the usual workup gave
an oil, which was reduced with NaBH4 (0.12 g) in MeOH (3
mL) at 0 °C. After 10 min, the usual workup and purification
by column chromatography over silica gel (hexane/Et2O ) 5:1)
gave (1R,2R)-13c (36 mg, 19%) of [R]24D +274.3 (c 0.63, CHCl3)
in 64% ee. The spectral data were identical with those
reported.
(t), 26.0 (t), 34.4 (t), 69.8 (d), 137.8 (d), 138.1 (s), 161.9 (d). IR
(neat): 1650, 1630, 1450 cm-1. MS m/z: 191 (M+). HRMS:
calcd for C13H21N, 191.1674; found, 191.1663.
(1S,2S)-tr a n s-2-P h en ylcyclop en t a n em et h a n ol, 20a 27
(Ta ble 2, en tr y 1). To a solution of 17a (177 mg, 1.0 mmol)
and (R,R)-8 (339 mg, 1.4 mmol) in toluene (10 mL) at -78 °C
was added dropwise a solution of phenyllithium (0.57 mL, 1.3
mmol, 2.27 M). The yellow solution was stirred for 3 h at -45
°C, and then 20 mL of acetate buffer was added. After being
stirred for 1.5 h at room temperature, the mixture was
extracted with Et2O (3 × 25 mL). The combined organic layer
was washed with saturated NaHCO3 and brine and then dried
over MgSO4. Concentration gave a yellow oil (18a trans/cis
) 4:3 by NMR; CHO trans 9.55 ppm, cis 9.20 ppm), which was
dissolved in THF (4 mL) and concentrated HCl (2 drops) and
stirred for 2 h at room temperature. The mixture was
neutralized with saturated NaHCO3 and extracted 3 times
with Et2O (15 mL). The extract was washed with brine and
dried over MgSO4. Concentration and purification by column
chromatography on silica gel (hexane/AcOEt ) 2:1) afforded
(1R,2S)-(2-ter t-Bu t yl-1,2-d ih yd r on a p h t h yl)m et h a n -1-
ol, 13d 17 (Ta ble 1, en tr y 14). To a solution of 11a (237 mg,
1.00 mmol) and (R,R)-8 (339 mg, 1.40 mmol) in 20 mL of
toluene at -78 °C was added dropwise a solution of tert-
butyllithium (0.78 mL, 1.3 mmol, 1.67 M in pentane). After 1
h, acetate buffer (20 mL) was added to the deep-red reaction
mixture. After the mixture was stirred for 3 h at room
temperature, the usual workup gave an oil, which was reduced
with NaBH4 (0.12 g) in MeOH (3 mL) at 0 °C. After 10 min,
the usual workup and purification by column chromatography
over silica gel (hexane/Et2O ) 5:1) gave (1R,2S)-13d (171 mg,
trans-19a of [R]20 +87.2 (c 1.20, PhH), which was reduced
D
79%) of [R]20 +253.8 (c 3.0, CHCl3). The spectral data were
with NaBH4 (0.12 g) in MeOH (3 mL) at 0 °C. After 10 min,
20% NH4Cl (3 mL) was added. The usual workup, concentra-
tion, and purification by column chromatography over silica
gel (hexane/Et2O ) 2:1) gave 20a (104 mg, 59% from 17a ) as
a colorless oil. The spectral data were identical with those
reported. The ee was determined to be 91% by HPLC analysis
(Waters Optipak-XC; hexane/2-propanol ) 9:1; 0.5 mL/min;
major, 15 min; minor, 12 min).
D
identical with those reported. The ee was determined to be
59% by HPLC analysis (Waters Optipak-TA; hexane/2-pro-
panol ) 9:1; 0.5 mL/min; major peak, 20 min; minor peak, 11
min).
(1S,2S)-(1-Meth yl-2-vin yl-1,2-dih ydr on aph th yl)m eth an -
1-ol 16.17 To a solution of tetravinyltin (81.9 mg, 0.36 mmol)
in 10 mL of toluene was added dropwise a solution of
methyllithium (0.96 mL, 1.3 mmol, 1.36 M in Et2O, low halide)
at room temperature. The resulting slightly white suspension
was stirred for 1 h at room temperature. The vinyllithium
solution was added to a solution of naphthylimine 11a (237
mg, 1.0 mmol) and (R,R)-8 (339 mg, 1.4 mmol) via cannula at
-78 °C. The mixture was stirred for 36 h at -78 °C, for 24 h
at -40 °C, and finally for 5 h at -30 °C. Then, HMPA (0.87
mL, 5 mmol) and THF (15 mL) were added to the resulting
deep-red mixture at -78 °C. After 10 min, methyl iodide (0.25
mL, 4 mmol) was added and the mixture was allowed to warm
gradually to room temperature for 1.5 h. Acetate buffer (20
mL) was added to the pale-yellow solution. After being stirred
for 3 h at room temperature, the mixture was extracted with
Et2O (20 mL), and the combined organic layer was washed
with 10% HCl (20 mL), saturated NaHCO3, and brine and then
dried over MgSO4. Concentration and subsequent purification
by chromatography on silica gel (hexane/Et2O ) 50:1) gave
(1S,2S)-16 (27 mg, 14%) as an oil of [R]22D +71.3 (c 2.54, CHCl3)
in 83% ee and the starting aldehyde (64.8 mg, 65%). 1H
NMR: 1.40 (3H, s), 3.15 (1H, ddd, J ) 2, 4, 9 Hz), 4.95-5.40
(2H, m), 5.6-6.1 (2H, m), 6.55 (1H, dd, J ) 2, 9 Hz), 6.9-7.6
(1S,2S)-tr a n s-2-P h en ylcycloh exa n em et h a n ol, 20b 27
(Ta ble 2, en tr y 3). A solution of 17b (191 mg, 1.0 mmol),
(R,R)-8 (339 mg, 1.4 mmol), and phenyllithium (0.57 mL, 1.3
mmol, 2.27 M) in 10 mL of toluene was stirred for 7.5 h at
-45 °C. A workup as above and chromatography over silica
gel (hexane/AcOEt ) 20:1) gave a colorless oil (116 mg, 61%)
of 19b. The trans aldehyde (77.0 mg) was reduced with NaBH4
(0.12 g) in MeOH (1 mL) at 0 °C. A workup as above and
chromatography over silica gel (hexane/Et2O ) 5:1) afforded
20b (66.5 mg) as colorless needles of mp 71.5-73.5 °C. [R]27
D
+34.8 (c 0.09, MeOH). [R]25 +33.3 (c 1.04, CHCl3). The ee
D
was determined to be 80% by HPLC analysis (Waters Optipak-
XC; hexane/2-propanol ) 9:1; 0.5 mL/min; UV, 254 nm; major,
11.7 min; minor, 10.7 min).
The alcohol 20b was recrystallized twice from hexane to
afford colorless needles of mp 76-77 °C. [R]25 +35.3 (c 0.93,
D
CHCl3). 1H NMR: 1.00-2.50 (11H, m), 3.20 (1H, dd, J ) 6,
11 Hz), 3.39 (1H, dd, J ) 4, 11 Hz), 7.0-7.4 (5H, m). IR
(KBr): 3260, 1600, 1490 cm-1
.
MS m/z: 190 (M+). Anal.
Calcd for C13H18O: C, 82.06; H, 9.53. Found: C, 82.08; H, 9.57.
(S)-3-P h en ylbu ta n ol, 23a 28 (Ta ble 3, en tr y 1). A mixture
of 21a 34 (151 mg, 1.0 mmol), (R,R)-8 (582 mg, 2.4 mmol), and
phenyllithium (0.97 mL, 2.2 mmol) in toluene (20 mL) was
stirred for 3 h at -78 °C. A workup as above and purification
by column chromatography over silica gel (hexane/Et2O ) 5:1-
1:1) gave, after distillation (100-150 °C, 5 mmHg), 23a (71.9
(4H, m), 9.75 (1H, s). IR (neat): 1730 cm-1
. MS m/z: 198
(M+). HRMS: calcd for C14H14O, 198.1045; found, 198.1047.
N-(1-Cyclopen ten ylm eth yliden e)cycloh exylam in e, 17a.
To 1-cyclopentenecarbaldehyde32 (1.79 g) in hexane (20 mL)
was added cyclohexylamine (2.03 g, 20.5 mmol) and molecular
sieves (4 Å). After being stirred for 14 h, the reaction mixture
was filtered and concentrated. Distillation (bp 115 °C/12
mmHg) gave 17a (2.36 g, 72%) as a yellow oil. 1H NMR: 0.8-
1.7 (16H, m), 1.7-2.2 (1H, m), 6.00-6.20 (1H, m), 8.13 (1H,
s). 13C NMR: 23.0 (t), 24.9 (t), 25.5 (t), 30.6 (t), 33.0 (t), 34.2
(t), 70.1 (d), 139.6 (d), 144.7 (s), 156.4 (d). IR (neat): 1645,
1610, 1450 cm-1. HRMS: calcd for C12H19N, 177.1517; found,
177.1512.
N-(1-Cycloh exen ylm eth ylid en e)cycloh exyla m in e, 17b.
To 1-cyclohexenecarbaldehyde33 (1.95 g) in hexane (30 mL) was
added cyclohexylamine (1.93 g, 19.5 mmol) and molecular
sieves (4 Å). After being stirred for 2 days, the reaction
mixture was filtered and concentrated. Distillation (bp 111
°C/6 mmHg) provided 17b (2.09 g, 70%) as a pale-yellow oil.
1H NMR: 0.8-2.2 (18H, m), 2.75-3.12 (1H, m), 6.12 (1H, m),
7.81 (1H, s). 13C NMR: 22.0 (t), 22.4 (t), 23.9 (t), 24.9 (t), 25.6
mg, 48%) as a colorless oil of [R]25 +25.5 (c 1.52, CHCl3). The
D
spectral data were identical with those reported. The ee was
determined to be >99% by HPLC analysis (Waters Optipak-
PC; hexane/2-propanol ) 9:1; 0.2 mL/min; major, 20 min;
minor, 22 min).
N-(2-Hep ten ylid en e)cycloh exyla m in e, 21b. To 2-hep-
tenal (8.48 g, 75.6 mmol) was added cyclohexylamine (8.25 g,
83.2 mmol) dropwise at 0 °C. After the mixture was stirred
for 10 min, Na2SO4 (20 g) was added. The mixture was stirred
for 1.5 h and then filtered. The residue was washed with Et2O,
and the combined organic layer was concentrated to afford 15.5
g of a pale-yellow oil, which was distilled (bp 125 °C/10 mmHg)
to give labile 21b as a yellow oil (8.23 g, 60%). 1H NMR: 0.70-
3.40 (20H, m), 6.08-6.32 (2H, m, CHdCH), 7.75-8.00 (1H,
m, CHdN). 13C NMR: 13.6 (q), 22.0 (t), 24.6 (t), 25.4 (t), 30.4
(t), 32.0 (t), 34.2 (t), 69.2 (d), 130.7 (d), 144.8 (d), 150.3 (d). IR
(neat): 1660, 1650, 1625 cm-1
193.1832; found, 193.1780.
. HRMS: calcd for C13H23N,
(32) Smith, A. B.; Agosta, W. C. J . Am. Chem. Soc. 1973, 95, 1961.
(33) Ho, T. L.; Wong, C. M. Synthesis 1974, 196.
(34) Brun, P.; Tenaglia, A.; Waegell, B. Tetrahedron 1985, 41, 5019.

C2 Symmetric Chiral Ligand
J . Org. Chem., Vol. 63, No. 25, 1998 9357
(S)-3-P h en ylh ep ta n ol, 23b35 (Ta ble 3, en tr y 3). A solu-
tion of 21b (193 mg, 1.0 mmol), (R,R)-8 (582 mg, 2.4 mmol),
and phenyllithium (0.97 mL, 2.2 mmol, 2.27 M) in toluene (10
mL) was stirred for 4 h at -78 °C. A workup as above and
purification by column chromatography over silica gel (hexane/
Et2O ) 5:1) gave 23b (112 mg, 58%) as a colorless oil (200 °C,
solution was stirred for 1 h at -78 °C, and then 20 mL of
acetate buffer was added. After being stirred for 3 h at room
temperature, the mixture was extracted with Et2O. The
combined organic layer was washed with saturated NaHCO3
and brine and then dried over MgSO4. Concentration gave
an oil (0.82 g), which was reduced with NaBH4 (0.10 g) in
MeOH (3 mL) at 0 °C. After 10 min, 20% NH4Cl (3 mL) was
added. The usual workup and purification through column
chromatography over silica gel (hexane/Et2O ) 5:1) gave 23c
3 mmHg) of [R]25 -12.1 (c 0.98, CHCl3). 1H NMR: 0.50-
365
2.0 (12H, m), 2.55 (1H, m), 3.50 (2H, t, J ) 6), 6.9-7.6 (5H,
m). IR (neat): 3380, 1610 cm-1. MS m/z: 193 (M+). HRMS:
calcd for C13H20O, 192.1515; found, 192.1518. The ee was
determined to be 99% by HPLC analysis (Waters Optipak TA;
hexane/2-propanol ) 9:1; 0.20 mL/min; major, 21 min; minor,
23 min).
(77.7 mg, 40%) as a colorless oil (200 °C, 3 mmHg) of [R]25
365
+9.80 (c 1.22, CHCl3). The ee was determined to be 82% by
HPLC analysis.
(R)-3-P h en ylh ep ta n ol, 23c (Ta ble 3, en tr y 4). To a
solution of 21c (213 mg, 1.0 mmol)36 and (R,R)-8 (582 mg, 2.4
mmol) in 15 mL of toluene at -78 °C was added dropwise a
solution of butyllithium (1.38 mL, 2.2 mmol). The violet
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from J apan Society for Promotion of
Science (RFTF-96P00302), the Ministry of Education,
Science, Sports and Culture, and the Science and
Technology Agency, J apan.
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