Asymmetric nucleophilic substitution of acetals

Article abstract of DOI:10.1002/1099-0690(200111)2001:21<4137::AID-EJOC4137>3.0.CO;2-4

Benzaldehyde dimethylacetal (1) and 2-aryl-1,3-dioxolanes 5 react with organolithium reagents 2 in the presence of chiral ligands such as sparteine (3), 1-alkoxy-2-aminoethanes, or 1,2-dialkoxyethanes and BF3 to afford monosubstitution products in high yields and in up to 81% enantiomeric excess. The enantioselectivity is strongly influenced by steric effects in the acetal and in the reagent. The highest ee was achieved with 2-(2-isopropyl)-1,3-dioxolane (5c) on treatment with 2-ethylphenyllithium (2i) in the presence of sparteine. The approach was applied to the synthesis of enantioenriched (S)-(-)-neobenodine (17) with 49% ee.

Full text of DOI:10.1002/1099-0690(200111)2001:21<4137::AID-EJOC4137>3.0.CO;2-4

FULL PAPER
Asymmetric Nucleophilic Substitution of Acetals
[a]
[a]
[a]
´
Paul Müller,* Patrice Nury, and Gerald Bernardinelli
Keywords: Asymmetric synthesis / Chirality / Dioxolanes / Lewis acids / Nucleophilic substitution
Benzaldehyde dimethylacetal (1) and 2-aryl-1,3-dioxolanes 5
react with organolithium reagents 2 in the presence of chiral achieved with 2-(2-isopropyl)-1,3-dioxolane (5c) on treat-
ligands such as sparteine (3), 1-alkoxy-2-aminoethanes, or
ment with 2-ethylphenyllithium (2i) in the presence of spart-
effects in the acetal and in the reagent. The highest ee was
1,2-dialkoxyethanes and BF3 to afford monosubstitution eine. The approach was applied to the synthesis of enantio-
products in high yields and in up to 81% enantiomeric ex- enriched (S)-(−)-neobenodine (17) with 49% ee.
cess. The enantioselectivity is strongly influenced by steric
We have recently reported the desymmetrization of N-
Introduction
sulfonated meso-aziridines by Grignard or organolithium
reagents in the presence of chiral Cu catalysts.[17,18] It ap-
peared feasible that similar conditions might also be applic-
able to acetal cleavage. While such reactions did indeed pro-
ceed in the presence of BF3, the products were invariably
racemic. Extensive screening of reaction conditions was
subsequently carried out in order to find an appropriate
reagent combination for enantioselective acetal cleavage.
Some of the results of this investigation have been reported
in preliminary form.[19] This paper gives a complete account
of the work and includes additional organometallic re-
agents and chiral ligands.
Asymmetric nucleophilic substitutions traditionally in-
volve desymmetrization of meso compounds possessing two
enantiotopic centers, such as epoxides,[1Ϫ5] aziridines,[6Ϫ9]
oxetanes,[10] or cyclopropanes.[11] With these compounds,
the rate of the first substitution step is much greater than
that of the second one, owing to the release of ring strain,
so that double substitution does not occur. In principle,
such reactions may also be accomplished by enantioselec-
tive displacement of one out of two enantiotopic leaving
groups bound to a prochiral, sp3-hybridized carbon atom.
Acetals are suitable candidates for the study of these latter
reactions. They are quite reactive in the presence of elec-
trophiles, and monosubstitution may be controlled through
the stabilization of the developing partial positive charge by
the alkoxy substituent oxygen atom not displaced in the
first step. The Lewis acid catalyzed diastereoselective cleav-
age of chiral cyclic acetals, permitting asymmetric CϪC
bond formation, is well established.[12Ϫ14] More recently,
Harada et al. have described the enantioselective ring open-
ing of 2-substituted 1,3-dioxolanes catalyzed by enantio-
pure arylboron complexes.[15,16]
Results and Discussion
1. Substitution of Benzaldehyde Dimethylacetal (1a)
Preliminary experiments were carried out with benzal-
dehyde dimethylacetal (1a) and nucleophiles such as trime-
thylsilyl cyanide, allyltrimethylsilane, or diethylzinc, in con-
junction with chiral Lewis acid catalysts based on SnII,
ZnII, TiIV, YIII and chiral ligands such as BINOL, TAD-
DOL, bis(oxazolines) or pybox. Although monosubstitu-
tion could be achieved under certain reaction conditions,
only racemic products were formed.[20] In view of these
negative results, it was decided to incorporate the chiral fea-
ture of the reaction into the attacking nucleophile rather
than the electrophile. After much trial and error, we turned
our attention to a combination of an organolithium reagent
with sparteine (3) and BF3, as successfully applied by
Alexakis et al. to the desymmetrization of epoxides
(Scheme 2).[21] Indeed, treatment of 1a with MeLi in the
Scheme 1
[a]
Department of Organic Chemistry, University of Geneva,
30, Quai Ernest Ansermet, 1211 Geneva 4, Switzerland
Fax: (internat.) ϩ 41-22/328-7396
E-mail: paul.muller@chiorg.unige.ch
Scheme 2
Eur. J. Org. Chem. 2001, 4137Ϫ4147
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1121Ϫ4137 $ 17.50ϩ.50/0
4137

P. Müller, P. Nury, G. Bernardinelli
FULL PAPER
presence of sparteine afforded the substitution product 4a 46% on going from 4-methyl- to 2-methyl- and 2-isopropyl-
with significant, although low, enantioselectivity of 11%. phenyllithium (Entries 3, 4, and 6). With the sterically more
The various parameters of the reaction were subsequently demanding 2-tert-butyl (Entry 7) or 2-phenyl[19] groups in
varied so as to optimize yield and enantioselectivity.
the reagent, however, no enantioselectivity was observed.
The reactions were carried out at Ϫ78°, by dropwise ad- Variation of the bulk of the 2-substituent in the acetal 5
dition of BF3·OEt2 (3.0 equiv.) to a solution of the acetal with 2-ethylphenyllithium (2i) showed optimum selectivity
1a (1.0 equiv.), the organolithium compound 2 (4.0 equiv.), with an isopropyl group (Entry 9), while bulkier substitu-
and sparteine (3, 4.0 equiv.) in ether. Representative results ents were less favorable. The mesityl derivative 5g exhibited
are summarized in Table 1, and additional examples are re- only poor enantioselectivity with 2i and 1-naphthyllithium
ported in refs.[19,20] Although the inductions observed in (2e) (Entries 15, 20). Treatment with 1-naphthyllithium was
some of the runs were clearly significant and established the generally less satisfactory than with 2i. The conditions for
feasibility of the approach, no clear trend emerged from the treatment of 5c with 2i were further optimized, and it was
data. Simple alkyllithium compounds gave moderate en- found that reduction of the excess of sparteine to 1.5 equiv.
antioselectivity Ϫ in the 20Ϫ25% range Ϫ with 1a, while resulted in an increase in enantioselectivity from 75 to 81%
aryllithium compounds were somewhat less satisfactory. (Entry 10). However, the ee dropped when a still lower
The introduction of Me or MeO substituents in the p-posi- amount of sparteine was used.[19] Among the various solv-
tions of the acetals resulted in decreased enantioselectivity, ents tried, Et2O was found to be the most efficient, followed
while o-substituents on the aryllithium reagents had only a by Bu2O. Apolar solvents such as pentane and toluene were
minor effect. The best result, with a 40% ee, was obtained inappropriate and so was trifluorotoluene. No enantioselec-
with the o-isopropyl-substituted acetal 1d and o- tivity was observed with THF as solvent,[19] suggesting
ethylphenyllithium (2i) (Entry 17), suggesting that some complexation of the organolithium reagent by the solvent
control over stereoselectivity could be achieved as a result in competition with complexation by sparteine.
of steric crowding near the reacting center.
Table 1. Treatment of benzaldehyde dimethylacetal (1) with organo-
lithium reagents 2 in the presence of sparteine (3)
Run[a] Acetal (1)
No. R ϭ
Reagent (2)
No. RЈ ϭ
Product (4)
No. Yield (%) ee (%)
1
2
3
4
5
6
7
8
a
a
a
a
a
b
b
b
b
c
c
c
c
c
c
c
d
H
H
H
H
a
b
c
d
e
a
b
f
e
a
b
c
d
g
h
e
i
Me
nBu
4-MeC6H4
2-MeC6H4
1-Naphthyl
Me
a
b
c
d
e
f
g
h
i
50
90
85
89
86
53
85
92
89
89
91
91
95
81
69
88
92
11
25
23
9
5
1
11
12
13
0
0
5
7
13
6
4
40
Scheme 3
H
4-Me
4-Me
4-Me
4-Me
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
2-iPr[b]
nBu
4-MeOC6H4
1-Naphthyl
Me
9
10
11
12
13
14
15
16
17
k
l
nBu
4-MeC6H4
2-MeC6H4
2-MeOC6H4
Phenyl
1-Naphthyl
2-EtC6H4
h
m
n
o
p
q
Figure 1. Ligands for asymmetric substitution
[a]
[b]
Conditions: see text and Exp. Sect. Ϫ With 2 equiv. of spart-
eine (3) and 3 equiv. of BF3·OEt2.
Sparteine is a particularly effective chiral ligand for or-
ganolithium compounds, with which it forms tight ion
pairs.[22] Other ligands have been used for desymmetrization
2. Substitution of 2-Aryl-1,3-dioxolanes (5)
In view of the disappointing results with 1a, we turned of epoxides with organolithium compounds in the presence
our attention to 2-aryl-1,3-dioxolanes 5 in the expectation of BF3,[23] and some of these were also examined with 5c
that the restricted conformational mobility of the cyclic sys- and 2-ethylphenyllithium (2i). Isosparteine (11) exhibited
tem should result in enhanced selectivity. This was indeed positive, although moderate induction (38% ee), while the
the case. Table 2 summarizes the more representative re- other ligands tried were ineffective. Surprisingly, however,
sults; for additional data, the reader is referred to refs.[19,20] treatment of phenyllithium (2h) with 5c in the presence of
In the cyclic system the effect of o-substituents in the acetal the dimethyl ether 7 afforded 6f in 82% ee (entry 28), while
and in the reagent is more pronounced. Thus, with the un- 10 (in toluene) provided practically no enantioselectivity for
substituted acetal 5a, the ee increased from 12 to 34 and the same reaction.
4138
Eur. J. Org. Chem. 2001, 4137Ϫ4147

Asymmetric Nucleophilic Substitution of Acetals
FULL PAPER
Table 2. Treatment of 2-aryl-1,3-dioxolanes 5 with organolithium
reagents 2
Run Acetal 5
Reagent 2
RЈ No. RЈЈ
Ligand Product 6
No. Yield ee
No. R
1
2
3
4
5
6
7
8
a
a
a
a
a
a
a
b
c
c
d
e
f
g
h
b
c
e
g
h
c
c
c
c
c
c
c
c
c
H
H
H
H
H
H
H
Me
iPr
iPr
tBu
Ph
H
H
H
H
H
H
H
H
H
H
H
H
a
b
c
d
i
Me
nBu
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
61
94
89
91
90
94
92
76
85
88
87
77
60
59
70
76
84
57
30
66
77
65
85
79
91
57
92
73
82
03
15
12
34
30
46
04
52
75
81
60
69
27
31
12
40
62
56
31
15
13
10
01
00
38
07
65
82
06[b]
4-MeC6H4
2-MeC6H4
2-EtC6H4
2-iPrC6H4
2-tBuC6H4
2-EtC6H4
2-EtC6H4
k
l
i
9
i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
9
i
2-EtC6H4 3[a]
i
k
l
i
2-EtC6H4
2-EtC6H4
2-EtC6H4
2-EtC6H4
2-EtC6H4
1-Naphthyl 3
1-Naphthyl 3
1-Naphthyl 3
1-Naphthyl 3
1-Naphthyl 3
2-EtC6H4
2-EtC6H4
2-EtC6H4
2-EtC6H4 10
2-EtC6H4 11
2-EtC6H4 12
3
3
3
3
3
Figure 2. ORTEP view of the crystal structure of 15
i
2,3-Benzo H
i
m
n
o
p
q
r
s
t
Me3Si
Me
Me
iPr
Phenyl
Me3Si
Me
iPr
iPr
iPr
iPr
iPr
H
Me i
H
H
H
H
i
tion conditions used for 2-aryl-1,3-dioxolanes, and the 1,3-
dioxolane derived from acetophenone afforded only ra-
cemic products. Extension of the approach to other acetals
is in progress.
e
e
e
e
Me e
3. Asymmetric Synthesis of (S)-Neobenodine
H
H
H
H
H
H
H
H
H
i
7
8
9
i
i
i
Chiral diarylmethanols are constituents of biologically
active compounds such as clemastine,[26] neobenodine,[27]
and chloropheniramine.[28Ϫ30] Enantioselective syntheses of
diarylmethanols use either asymmetric catalytic hydrogena-
tion of diarylketones[31,32] or enantioselective addition of
arylzinc reagents to benzaldehydes in the presence of chiral
catalysts.[33] Asymmetric monosubstitution of 1,3-dioxol-
anes provides a simple route to enantioenriched neobenod-
ine (17), although the absence of an o-substituent in the
required acetal precursor 5a is detrimental to the enantiose-
lectivity of the procedure. Nevertheless, treatment of 5a
with p-tolyllithium in the presence of the chiral ligand
(R,R)-7 afforded 6c in 82 yield and 49% ee. Other ligands
such as sparteine (3) or 10 were less satisfactory. The alco-
hol 6c was converted into the iodide 16 with PPh3/I2 in the
presence of imidazole and, subsequently, into neobenodine
(17) by treatment of 16 with dimethylamine (Scheme 5).
The absolute configuration of 16 was determined by com-
parison of its optical rotation ([α]2D1 ϭ Ϫ5.07 for 49% ee;
i
i
i
i
i
i
iPr
iPr
iPr
iPr
i
i
h
h
h
Ph
Ph
Ph
3
7
10
f
f
k
[a]
[b]
With 2.0 equiv. of sparteine. Ϫ In toluene.
In view of the low optical purity of the reaction products
6, their absolute configurations were not determined, except
in the case of 6i. The alcohol was converted into the iodide
13,[24] which was subjected to elimination with Zn[25] to af-
ford the diarylmethanol 14 (Scheme 4). Treatment of 14
with (Ϫ)-camphanoyl chloride afforded the ester 15 (Fig-
ure 2). After chromatography and recrystallization, the de
of 15 was Ͼ 98%. X-ray crystallography established the ab-
solute configuration at the chiral center of 14 as (R).
Application of the reaction conditions to other acetals
has so far not been successful. Thus, 2-benzyl-1,3-dioxolane
and 2-phenyl-1-3-dioxane were unreactive under the reac-
c ϭ 2.07, EtOH) with that reported in the literature {[α]D20
ϭ
ϩ13.0 (EtOH) for (ϩ)-(R)-neobenodine}. Experiments to-
wards improvement of the enantioselectivity of the substitu-
tion step are currently in progress in our laboratory.
Scheme 4
Scheme 5
Eur. J. Org. Chem. 2001, 4137Ϫ4147
4139

P. Müller, P. Nury, G. Bernardinelli
FULL PAPER
Conclusion
anes were synthesized according to the procedure given for 5c
(see below).
At the present stage of development, the enantioselective
substitution at prochiral sp3-hybridized carbon atoms is far
2-(2-Isopropylphenyl)-1,3-dioxolane
(5c):
2-Isopropylbenzal-
from optimized. The combination of an organolithium dehyde[40] (1.50 g, 10.5 mmol) and ethylene glycol (1.31 g,
21.1 mmol) were subjected to azeotropic distillation in the presence
of p-toluenesulfonic acid (100 mg) for 16 h. After addition of
Na2CO3 (2 g) to the cooled solution, stirring was continued for 15
min, and the solid was filtered and washed with AcOEt (30 mL).
The filtrate was washed, dried, and concentrated, and the crude
product was purified by distillation (118Ϫ120 °C/2 Torr) to give 5c
(1.92 mg, 95%) as a colorless liquid. Ϫ IR (CHCl3): ν˜ ϭ 3009w,
2967s, 2889w, 1710w, 1600w, 1399w, 1100m, 1066s, 1033w, 938m.
Ϫ 1H NMR (CDCl3, 400 MHz): δ ϭ 1.31 (d, J ϭ 7 Hz, 6 H), 3.41
(sept, J ϭ 7 Hz, 1 H), 4.05Ϫ4.13 (m, 2 H), 4.14Ϫ4.23 (m, 2 H),
compound with a chiral base and an achiral Lewis acid, as
presented here, is not yet of general applicability, the enanti-
oselectivity is modest and, above all, the system is not cata-
lytic. However, these problems may eventually be overcome.
While the corresponding enantioselective nucleophilic addi-
tions to carbonyl compounds are admittedly much more
firmly established, these also have limitations in their scope
and are essentially restricted to aldehydes,[34] glyoxylates,
and pyruvates.[35,36] The enantioselective acetal cleavage
could provide an alternative in situations in which carbonyl 6.12 (s, 1 H), 7.22Ϫ7.30 (m, 1 H), 7.36Ϫ7.40 (m, 2 H), 7.60Ϫ7.64
(m, 1 H). Ϫ 13C NMR (CDCl3, 100 MHz): δ ϭ 24.0 (q), 28.3 (d),
additions fail. The mechanism of the acetal substitution is
not yet established. Although an SN2-type reaction invol-
ving nucleophilic attack of the base-associated organoli-
65.2 (t), 101.2 (d), 125.4 (d), 125.6 (d), 125.7 (d), 129.2 (d), 134.0
(s), 147.5 (s). Ϫ MS (EI, 70 eV); m/z: 193 (12), 192 (91) [Mϩ], 191
(38), 149 (37), 148 (16), 147 (62), 133 (24), 132 (10), 131 (25), 130
thium reagent to a BF3-activated acetal appears plausible,
(30), 129 (42), 119 (33), 117 (15), 115 (29), 105 (65), 103 (15), 91
the involvement of chiral ion-pair intermediates cannot be
ϩ
(42), 79 (14), 77 (25), 73 (100),. Ϫ HR MS: 192.1145 (C12H16O2
;
ruled out at present. Further research will deal with the
extension of the approach to other prochiral substrates and
to the use of chiral electrophiles in place of BF3.
calcd. 192.1150).
2-(2-tert-Butylphenyl)-1,3-dioxolane (5d): This compound was pre-
pared from 2-tert-butylbenzaldehyde.[41] Yield 94%. Ϫ IR (CHCl3):
˜
ν ϭ 3023w, 2968s, 2902w, 1713w, 1612w, 1399w, 1111m, 1065s,
1
1038w, 912m. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.49 (s, 9 H),
Experimental Section
4.03Ϫ4.10 (m, 2 H), 4.22Ϫ4.30 (m, 2 H), 6.46 (s, 1 H), 7.27Ϫ7.35
(m, 2 H), 7.40Ϫ7.44 (m, 1 H). Ϫ 13C NMR: (CDCl3, 125 MHz):
δ ϭ 32.5 (q), 35.4 (s), 65.5 (t), 100.8 (d), 125.5 (d), 126.2 (d), 128.5
(d), 129.0 (d), 135.9 (s). Ϫ MS (EI, 70 eV); m/z: 206 (10) [Mϩ], 205
(18), 149 (22), 147 (12), 135 (11), 129 (44), 119 (16), 91 (20), 73
(100). Ϫ HR MS: 206.1323 (C13H18O2ϩ; calcd. 206.1307).
General Remarks: See. ref.[18] NMR spectra were recorded with
Varian XL 200, Varian Gemini 200, Bruker AMX 400, or Bruker
AMX 500 spectrometers. The frequency used is indicated in each
case. Chemical shifts are expressed in δ, relative to TMS.
2-(Naphth-1-yl)-1,3-dioxolane (5e): This compound was prepared
from 1-naphthaldehyde. Yield 68%, colorless liquid, b.p. 128Ϫ130
Synthesis of Acetals
1. Substituted Benzaldehyde Dimethylacetals 1: These acetals are
either commercially available (1a; Fluka) or were synthesized from
the commercially available aldehydes according to reported proced-
ures: 1b,[37] 1c.[38]
˜
°C/0.4 Torr. Ϫ IR (CHCl3): ν ϭ 2889m, 1689w, 1512w, 1339w,
1232m, 1171m, 1111s, 1073m, 1034m, 967m, 943w. Ϫ 1H NMR
(CDCl3, 500 MHz): δ ϭ 4.15Ϫ4.21 (m, 2 H), 4.21Ϫ4.27 (m, 2 H),
6.53 (s, 1 H), 7.50Ϫ7.63 (m, 3 H), 7.83 (d, J ϭ 7.1, 1 H), 7.89Ϫ7.97
(m, 2 H), 8.28 (dd, J ϭ 8.3, 0.5, 1 H). Ϫ 13C NMR (CDCl3, 125
MHz): δ ϭ 65.2 (t), 102.2 (d), 123.5 (d), 123.9 (d), 125.0 (d), 125.7
(d), 126.3 (d), 128.5 (d), 129.6 (d), 130.9 (s), 133.0 (s), 133.8 (s). Ϫ
MS (EI, 70 eV); m/z: 201 (11), 200 (72) [Mϩ], 199 (39), 156 (33),
155 (74), 142 (14), 141 36), 140 (15), 139 (27), 129 (23), 128 (100),
127 (56), 126 (12), 77 (19), 51 (15), 45 (38). Ϫ HR MS: 200.0840
(C13H12O2ϩ; calcd. 200.0.837).
1-Dimethoxymethyl-2-isopropylbenzene (1d): This compound was
prepared by transacetalization of the corresponding dioxolane 5c
(see below): Fuming sulfuric acid (4 drops) was added to 5c
(730 mg, 3.80 mmol) and trimethyl orthoformate (0.84 mL,
7.70 mmol) in dry MeOH (10 mL). The mixture was stirred at room
temp. for 2 h, whereupon Na2CO3 (2.0 g) was added. After stirring
for 15 min, the mixture was filtered, and the residue was washed
with Et2O (10 mL). The filtrate was washed with H2O (10 mL) and
dried (MgSO4), and the solvents were evaporated. The residue was
purified by distillation (124Ϫ126 °C/2 Torr) to give 1d as a colorless
liquid (623 mg, 84%). Ϫ IR (CHCl3): ν˜ ϭ 3010w, 2965s, 2889w,
1713w, 1612w, 1402w, 1101m, 1066s, 1033w, 942m. Ϫ 1H NMR
(CDCl3, 500 MHz): δ ϭ 1.25 (d, J ϭ 7 Hz, 3 H), 3.34 (s, 6 H), 3.36
(sept, J ϭ 7 Hz, 1 H), 5.58 (s, 1 H), 7.17Ϫ7.22 (m, 1 H), 7.31Ϫ7.37
(m, 2 H), 7.54Ϫ7.58 (m, 1 H). Ϫ 13C NMR (CDCl3, 125 MHz):
δ ϭ 24.0 (q), 28.1 (d), 53.1 (q), 101.4 (d), 125.2 (d), 125.6 (d), 126.6
(d), 128.7 (d), 134.1 (s), 147.2 (s). Ϫ MS (EI, 70 eV); m/z: 163 (1)
[Mϩ Ϫ CH3O], 149 (14), 148 (100), 147 (30), 133 (46), 105 (58),
104 (10), 103 (29), 91 (48), 79 (31), 78 (17), 77 (56), 65 (13), 55
(14), 51 (25).
2-(2-Biphenyl)-1,3-dioxolane (5f): This compound was prepared
from 2-phenylbenzaldehyde.[42] Yield 90%, b.p. 170Ϫ180 °C/
˜
0.4 Torr. Ϫ IR (CHCl3): ν ϭ 3026m, 2889m, 1599w, 1481m, 1397m,
1219s, 1120m, 1074s, 946m. Ϫ 1H NMR (CDCl3, 400 MHz): δ ϭ
δ ϭ 3.92Ϫ4.01(m, 2 H), 4.15Ϫ4.24 (m, 2 H), 5.71 (s, 1 H),
7.31Ϫ7.35 (m, 1 H), 7.39Ϫ7.51 (m, 7 H), 7.75Ϫ7.79 (m, 1 H). Ϫ
13C NMR (CDCl3, 100 MHz): δ ϭ 65.4 (t), 101.2 (d), 126.6 (d),
127.1 (d), 127.5 (s), 127.9 (d), 128.9 (d), 129.6 (d), 130.0 (d), 134.5
(s), 139.9 (s), 142.1 (s). Ϫ MS (EI, 70 eV); m/z: 227 (15), 226 (94)
[Mϩ], 225 (91), 198 (19), 197 (15), 182 (17), 181 (100), 166 (15),
165 (52), 154 (50), 153 (47), 152 (63), 151 (18), 148 (50), 104 (11), 77
(11), 76 (14), 73 (58). Ϫ HR MS: 226.0974 (C15H14O2ϩ; 226.0994).
2-(2-Trimethylsilanylphenyl)-1,3-dioxolane (5g): This compound
was prepared from 2-(trimethylsilanyl)benzaldehyde.[43] Yield 88%,
b.p. 110Ϫ112 °C/4 Torr. Ϫ IR (CHCl3): ν˜ ϭ 2956m, 2893m, 1391m,
1251s, 1202m, 1127m, 1094s, 1061m, 944m, 842s. Ϫ 1H NMR
2. 2-Aryl-[1,3]dioxolanes 5: 2-Phenyl-1,3-dioxolane (5a) was pur-
chased from Aldrich. 2-(2-Methylphenyl)-1,3-dioxolane (5b) was
prepared from o-tolualdehyde as described.[39] The other dioxol-
4140
Eur. J. Org. Chem. 2001, 4137Ϫ4147

Asymmetric Nucleophilic Substitution of Acetals
FULL PAPER
(CDCl3, 500 MHz): δ ϭ 0.38 (s, 9 H), 4.03Ϫ4.07 (m, 2 H),
by slow addition of BF3·OEt2 (0.16 mL, 1.2 mmol) in Et2O
4.15Ϫ4.19 (m, 2 H), 6.01 (s, 1 H), 7.33Ϫ7.38 (m, 1 H), 7.40Ϫ7.45 (1.0 mL). After the addition, stirring was continued at Ϫ78°. The
(m, 1 H), 7.56 (d, J ϭ 7.3, 1 H), 7.67 (d, J ϭ 7.6, 1 H). Ϫ 13C reaction mixture was hydrolyzed with saturated NH4Cl (5.0 mL)
NMR: (CDCl3, 125 MHz): δ ϭ 0.00 (q), 64.6 (t), 102.3 (d), 125.7 and extracted with Et2O (3 ϫ 10 mL). The combined organic layers
(d), 127.7 (d), 128.6 (d), 133.7 (d), 138.1 (s), 142.2 (s). Ϫ MS (EI,
were dried (Na2SO4), the solvent was evaporated, and the crude
70 eV); m/z: 222 (1) [Mϩ], 207 (27), 165 (15), 163 (100), 149 (31), product was purified by flash chromatography (SiO2; pentane/Ac-
105 (16), 77 (11), 75 (15), 45 (12).
(C12H18O2Siϩ; calcd. 222.1076).
Ϫ
HR MS: 222.1029
OEt) to afford the pure product. For yields: see Tables 1 and 2.
Substitution of Acetals 1
2-(2,4,6-Trimethylphenyl)-1,3-dioxolane (5h): This compound was
prepared from mesitaldehyde in 79% yield. Colorless crystals, m.p.
(1-Methoxyethyl)benzene (4a): B.p. 172Ϫ174 °C (ref.[48] 71Ϫ72 °C/
23 Torr). 11% ee (Lipodex E, 40 °C, T1 ϭ 17.3, T2 ϭ 20.8 min). Ϫ
˜
65Ϫ67 °C. Ϫ IR (CHCl3): ν ϭ 3029m, 2928m, 1734m, 1680s, 1608s,
˜
IR (CHCl3): ν ϭ 2935w, 2824w, 1698w, 1452w, 1372w, 1111s, 992w.
1379w, 1208s, 1149m, 1077m, 1032m, 854w, 758s. Ϫ 1H NMR
(CDCl3, 500 MHz): δ ϭ 2.27 (s, 3 H), 2.41 (s, 6 H), 4.01Ϫ4.04 (m,
2 H), 4.18Ϫ4.22 (m, 2 H), 6.08 (s, 1 H), 6.83 (s, 2 H). Ϫ 13C NMR
(CDCl3, 125 MHz): δ ϭ 19.9 (q), 20.9 (q), 65.0 (t), 102.2 (d), 128.3
(s), 130.0 (d), 138.0 (s), 138.6 (s). Ϫ MS (EI, 70eV); m/z: 192 (9)
[Mϩ], 148 (74), 147 (100),120 (100), 120 (11), 119 (48), 105 (14), 91
(18), 77 (14), 62 (11). Ϫ HR MS; 192.1145 (C12H16O2ϩ; 192.1151).
1
Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.37 (d, J ϭ 6.3, 3 H), 3.15
(s, 3 H), 4.22 (q, J ϭ 6.3, 1 H), 7.18Ϫ7.25 (m, 5 H). Ϫ 13C NMR
(CDCl3, 125 MHz): δ ϭ δ ϭ 23.9 (q), 56.4 (q), 79.6 (d), 125.1 (d),
126.4 (d), 127.4 (d), 143.5 (s).
(1-Methoxypentyl)benzene (4b): B.p. 144Ϫ145 °C (ref.[49] 145Ϫ150
°C). Ϫ [α]2D1 ϭ ϩ10.3 (c ϭ 1.01, EtOH) for 25% ee (Lipodex E, 45
˜
°C, T1 ϭ 95.6, T2 ϭ 100.9 min). Ϫ IR (CHCl3): ν ϭ 3619w, 3032s,
Chiral Ligands
2933w, 2399s, 1521s, 1424m, 1228s, 1202s, 1091m, 1045m, 928m,
Sparteine (3): (Ϫ)-Sparteine·H2SO4·5H2O (Fluka) was treated with 802s, 703s. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 0.88 (t, J ϭ 7.1,
1
aq. NaOH, the mixture extracted with Et2O, the extract distilled,
3 H), 1.19Ϫ1.43 (m, 4 H), 1.60Ϫ1.68 (m, 1 H), 1.79Ϫ1.88 (m, 1
and the product stored under Ar at Ϫ78°. (R,R)-1,2-Diphenyl-1,2- H), 3.22 (s, 3 H), 4.09 (dd, J ϭ 6.3, 7.1, 1 H), 7.27Ϫ7.31 (m, 3 H),
dimethoxyethane (7) and (R,R)-2,3-dimethoxybutane (12) were
7.34Ϫ7.38 (m, 2 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 14.0 (q),
prepared from the appropriate diols according to Kündig et al.,[44] 22.6 (t), 28.0 (t), 37.9 (t), 56.6 (q), 84.1 (d), 126.7 (d), 127.4 (d),
(1R,2S)-2-dimethylamino-1-methoxy-1,2-diphenylethane (8) from 128.3 (d), 142.5 (s). Ϫ MS (EI, 70 eV); m/z: 178 (1) [Mϩ·], 122 (9),
(Ϫ)-(1R,2S)-2-amino-1,2-diphenylethanol according to ref.[45] and
(1R,2S)-2-dimethylamino-1-methoxy-1-phenylpropane (9) from
(Ϫ)-(1R,2S)-N-methylephedrine according to ref.[46]
121 (100), 105 (4), 91 (12), 77 (10), 51 (3). Ϫ HR MS: 178.13258
(C12H18Oϩ·; calcd. 178.13577).
1-[Methoxy(phenyl)methyl]-4-methylbenzene (4c): B.p. 286Ϫ288 °C
(ref.[50] 160Ϫ162 °C/10 Torr.). Ϫ [α]2D1 ϭ ϩ7.5 (c ϭ 2.10, EtOH) for
(؊)-(1R,2S)-2-Dimethylamino-1-methoxymethoxy-1-phenylpropane
(10): (Ϫ)-(1R,2S)-N-methylephedrine (3.00 g, 16.7 mmol) and NaH 23% ee (HPLC, Chiracel OD-H, hexane/2-propanol, 25:1, 0.5 mL/
˜
(80%; 747 mg, 25.1 mmol) in anhydrous DMF (50 mL) were stirred min, T1 ϭ 14.2 min, T2 ϭ 15.2 min. Ϫ IR (CHCl3): ν ϭ 3001s,
at room temp. for 1.5 h. MeOCH2Cl (MOMCl, 1.72 mg,
2928w, 2359w, 1513w, 1453w, 1208s, 1088s, 738s. Ϫ 1H NMR
21.4 mmol) in DMF (15 mL) was added at 0 °C and the mixture (CDCl3, 400 MHz): δ ϭ 2.36 (s, 3 H), 3.41 (s, 3 H), 5.25 (s, 1 H),
was stirred for 1.5 h at room temp. The solution was poured into
7.15Ϫ7.20 (m, 2 H), 7.25Ϫ7.30 (m, 3 H), 7.33Ϫ7.40 (m, 4 H). Ϫ
ice/water (80 mL) and extracted with EtOAc (2 ϫ 150 mL). The 13C NMR (CDCl3, 100 MHz): δ ϭ 21.0 (q), 56.9 (q), 85.2 (d), 126.7
organic layers were washed with satd. NaCl (100 mL) and dried (d), 126.8 (d), 127.3 (d), 128.3 (d), 129.0 (d), 137.0 (s), 139.0 (s). Ϫ
(Na2SO4), and the solvents were evaporated. The residue was puri-
fied by distillation (150Ϫ155 °C/0.3 Torr) to afford 10 (2.95 g, 79%)
as a colorless oil. Ϫ [α]2D1 ϭ Ϫ107.3 (c ϭ 1.0, CHCl3). Ϫ IR
SM (EI, 70 eV, m/z): 212 (32) [Mϩ·], 213 (6), 211 (8), 197 (10), 182
(9), 181 (49), 178 (8), 166 (12), 165 (14), 136 (5), 135 (42), 122 (6),
121 (67), 119 (15), 105 (21), 91 (20), 89 (6), 88 (6), 86 (38), 84 (60),
(CHCl3): ν˜ ϭ 3020w, 1890w, 1670m, 1410w, 1170m, 1080w, 980m. 77 (18), 65 (7), 51 (41), 50 (7), 49 (100), 48 (8), 47 (15). Ϫ HR MS:
1
Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.14 (d, J ϭ 6. 6, 3 H), 2.33 212.12322 (C15H16Oϩ·; calcd. 212.12012).
(s, 6 H), 2.82 (dq, J ϭ 6.6, 5.6, 1 H), 3.43 (s, 3 H), 4.59 (q, J ϭ
1-[Methoxy(phenyl)methyl]-2-methylbenzene (4d): B.p. 298Ϫ300 °C
6.6, 2 H), 4.81 (d, J ϭ 5.6, 1 H), 7.28Ϫ7.39 (m, 5 H). Ϫ 13C NMR
(ref.[51] 94Ϫ97 °C/0.1 Torr). 9% ee (HPLC, Chiracel OJ, n-hexane/
(CDCl3, 125 MHz): δ ϭ 8.6 (q), 41.4 (q), 56.0 (d), 64.4 (d), 79.3
˜
2-propanol, 99:1, T1 ϭ 12.6, T2 ϭ 14.5 min). Ϫ IR (CHCl3): ν ϭ
(q), 94.5 (t), 127.2 (d), 128.0 (d), 141.1 (s). Ϫ MS (EI, 70 eV); m/z:
162 (9), 147 (5), 117 (7), 105 (13), 91 (7), 77 (11), 73 (12), 72 (100),
56 (7), 51 (6), 45 (55).
1
3010s, 1620m, 1513m, 1250w, 1205s, 1180w, 1081m, 1042w. Ϫ H
NMR (CDCl3, 500 MHz): δ ϭ 2.30 (s, 3 H), 3.41 (s, 3 H), 5.55 (s,
1 H), 7.04Ϫ7.19 (m, 4 H), 7.21Ϫ7.25 (m, 4 H), 7.34 (dd, J ϭ 7.6,
1.3, 1 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 19.4 (q), 57.0 (q),
82.6 (d), 126.0 (d), 126.8 (d), 127.4 (d), 127.45 (d), 127.5 (d), 128.3
(R,R)-Isosparteine (11): This compound was prepared by isomeriz-
ation of sparteine (3) with AlCl3.[47] Ϫ M.p. 101Ϫ103 °C. Ϫ [α]2D1
ϭ
˜
Ϫ29.1 (c ϭ 1.0, EtOH). Ϫ IR (CHCl3): ν ϭ 2936w, 1203w, 786m, (d), 130.5 (s), 135.9 (s), 139.5 (s), 140.9 (s).
738s. Ϫ 1H NMR (CDCl3, 500 MHz): δ ϭ 1.25Ϫ1.40 (m, 2 H),
1-[Methoxy(4-methylphenyl)methyl]naphthalene (4e): Colorless oil,
4% ee (HPLC, Chiracel OD-H, hexane/2-propanol, 25:1, 0.5 mL/
1.53Ϫ1.62 (m, 2 H), 1.65Ϫ1.85 (m, 4 H), 1.86Ϫ2.00 (m, 1 H),
2.10Ϫ2.30 (m, 1 H), 2.83Ϫ2.96 (m, 1 H), 3.00Ϫ3.10 (m, 1 H), 3.46
(s, large, 1 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 24.6 (t), 25.1
(t), 29.8 (t), 35.1 (d), 56.0 (t), 57.1 (t), 66.4 (d).
˜
min, T1 ϭ 16.8, T2 ϭ 18.4 min). Ϫ IR (CHCl3): ν ϭ 3023w, 2359m,
1230m, 1202m, 1090m, 802m, 747m. Ϫ 1H NMR (CDCl3,
500 MHz): δ ϭ 3.49 (s, 3 H), 5.96 (s, 1 H), 7.25Ϫ7.30 (m, 1 H),
Substitution of Acetals 1 and Dioxolanes 5. ؊ General Procedure: 7.32Ϫ7.37 (m, 2 H), 7.41Ϫ7.54 (m, 5 H), 7.62 (d, J ϭ 6.9, 1 H),
BuLi (1.0 mL, 1.6 ) was slowly added at Ϫ30° to the appropriate
bromide or iodide (1.60 mmol) and sparteine (3; 375 mg,
1.60 mmol) in Et2O (2.0 mL). After stirring for 1 h, the mixture
7.84 (d, J ϭ 8.2, 1 H), 7.88Ϫ7.91 (m, 1 H), 8.07Ϫ8.12 (m, 1 H). Ϫ
13C NMR (CDCl3, 125 MHz): δ ϭ 57.3 (q), 83.2 (d), 124.1 (d),
125.2 (d), 125.4 (d), 125.5 (d), 126.0 (d), 127.3 (d), 127.5 (d), 128.3
was cooled to Ϫ78° and the acetal (0.40 mmol) was added, followed (d), 128.4 (d), 128.7 (d), 131.1 (s), 134.0 (s), 136.8 (s), 141.3 (s).
Eur. J. Org. Chem. 2001, 4137Ϫ4147 4141

P. Müller, P. Nury, G. Bernardinelli
FULL PAPER
1
(1-Methoxyethyl)]-4-methylbenzene (4f): Colorless liquid, b.p.
198Ϫ200 °C (ref.[52] 71Ϫ74 °C/10 Torr. 1% ee (Lipodex E, 40 °C,
1202s, 1035m, 928m, 802s, 708s. Ϫ H NMR (CDCl3, 400 MHz):
δ ϭ 0.88 (t, J ϭ 7, 3 H), 1.15Ϫ1.25 (m, 1 H), 1.25Ϫ1.41 (m, 3 H),
˜
T1 ϭ 15.2, T2 ϭ 17.6 min). Ϫ IR (CHCl3): ν ϭ 2929w, 2826w, 1.58Ϫ1.68 (m, 1 H), 1.78Ϫ1.88 (m, 1 H), 3.19 (s, 3 H), 3.83 (s, 3
1703w, 1455w, 1367w, 1117s, 994w, 883w. Ϫ 1H NMR (CDCl3, H), 4.05 (t, J ϭ 6.9, 1 H), 6.91 (d, J ϭ 8.3, 2 H), 7.23 (d, J ϭ 8.3,
500 MHz): δ ϭ 1.41 (d, J ϭ 6.4, 3 H), 3.18 (s, 3 H), 3.63 (s, 3 H), 2 H). Ϫ 13C NMR (CDCl3, 100 MHz): δ ϭ 13.9 (q), 22.5 (t), 37.7
4.22 (q, J ϭ 6.3, 1 H), 7.16 (d, J ϭ 7.9, 2 H), 7.35 (d, J ϭ 7.9, 2
(t), 55.1 (q), 56.2 (q), 83.6 (d), 113.7 (d), 127.8 (d), 134.4 (s),
H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 21.2 (q), 23.9 (q), 52.6 158.9 (s).
(q), 79.6 (d), 125.1 (d), 126.4 (d), 127.4 (d), 138.1 (s), 143.5 (s).
1-[Methoxy(4-methoxyphenyl)methyl]-2-methylbenzene (4m): Color-
4-(1-Methoxypentyl)-1-methylbenzene (4g): B.p. 256Ϫ258 °C
less oil. 7% ee (HPLC, Chiracel OD-H, hexane/2-propanol, 25:1,
(ref.:[53] 125 °C/10 Torr). 11% ee (HPLC. Chiracel OJ, hexane/2- 0.5 mL/min, T1 ϭ 15.7, T2 ϭ 16.4 min). Ϫ IR (CHCl3): ν ϭ 3010s,
˜
1
propanol, 25:1, 1 mL/min; T1 ϭ 3.5, T2 ϭ 4.1 min). Ϫ IR (CHCl3):
1610w, 1511m, 1250m, 1205s, 1172w, 1082m, 1031w. Ϫ H NMR
˜
ν ϭ 3629w, 3012s, 2935w, 2399s, 1525s, 1434m, 1228s, 1202s, (CDCl3, 500 MHz): δ ϭ 2.26 (s, 3 H), 3.39 (s, 3 H), 3.80 (s, 3 H),
1
1093m, 1044m, 928m, 802s. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 5.38 (s, 1 H), 6.87 (d, J ϭ 8.5, 2 H), 7.15 (d, J ϭ 7.3, 2 H),
0.89 (t, J ϭ 7.2, 3 H), 1.21Ϫ1.41 (m, 4 H), 1.59Ϫ1.67 (m, 1 H), 7.19Ϫ7.26 (m, 2 H), 7.23 (d, J ϭ 8.5, 2 H), 7.48 (dd, J ϭ 7.3, 1.3,
1.77Ϫ1.89 (m, 1 H), 3.26 (s, 3 H), 4.13 (dd, J ϭ 6.5, 7.2, 1 H), 7.17
1 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 19.3 (q), 55.2 (q), 56.9
(d, J ϭ 7.8, 2 H), 7.36 (d, J ϭ 7.8, 2 H). Ϫ 13C NMR (CDCl3, (q), 82.1 (d), 113.6 (d), 125.9 (d), 126.4 (d), 127.2 (d), 129.1 (d),
125 MHz): δ ϭ 14.0 (q), 21.2 (q), 22.5 (t), 28.2 (t), 37.8 (t), 56.7 130.4 (d), 132.9 (s), 135.7 (s), 139.7 (s), 158.9 (s). Ϫ MS (EI, 70
(q), 84.1 (d), 126.8 (d), 127.5 (d), 128.2 (d), 142.5 (s). Ϫ MS: (EI,
eV); m/z: 242 (23) [Mϩ·], 243 (6), 212 (21), 211 (100), 155 (12), 152
70 eV); m/z: 192 (1) [Mϩ·], 136 (25), 135 (100), 119 (15), 105 (14), 91 (9), 150 (31), 135 (32), 119 (16), 92 (14). Ϫ HR MS: 242.13003
(28), 65 (7). Ϫ HR MS: 192.15104 (C13H20Oϩ·; calcd.: 192.15141).
(C16H18O2ϩ·; calcd. 242.13069).
1-[Methoxy(phenyl)methyl]-4-methylbenzene (4h): Colorless oil.
4-Methoxy-1-[methoxy(2-methoxyphenyl)methyl]benzene (4n): Col-
12% ee (HPLC, Chiracel OJ, hexane/2-propanol, 25:1, 0.5 mL/min, orless oil. 13% ee (Chiracel OB-H, hexane/2-propanol, 9:1, 0.5 mL/
˜
˜
T1 ϭ 23.3, T2 ϭ 27.2 min). Ϫ IR (CHCl3): ν ϭ 3001m, 2929w, min, T1 ϭ 28.6, T2 ϭ 32.9 min). Ϫ IR (CHCl3): ν ϭ 2998s, 1601w,
1
2363w, 1501w, 1455w, 1201s, 1101s, 725s. Ϫ 1H NMR (CDCl3, 1512s, 1251m, 1210s, 1181m, 1081w, 1032w. Ϫ H NMR (CDCl3,
500 MHz): δ ϭ 2.34 (s, 3 H), 3.38 (s, 3 H), 3.80 (s, 3 H), 5.15 (s, 1
500 MHz): δ ϭ 3.38 (s, 3 H), 3.78 (s, 3 H), 3.80 (s, 3 H), 5.65 (s, 1
H), 6.87 (d, J ϭ 8.8, 2 H), 7.15 (d, J ϭ 7.9, 2 H), 7.24 (d, J ϭ 7.9, H), 6.82Ϫ6.87 (m, 3 H), 6.99 (ddd, J ϭ 8.2, 7.3, 0.7, 1 H), 7.23
2 H), 7.27 (d, J ϭ 8.8, 2 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ
(ddd, J ϭ 9.1, 7.9, 1.6, 1 H), 7.30 (d, J ϭ 8.5, 2 H), 7.49 (dd, J ϭ
21.1 (q), 55.2 (q), 56.8 (q), 84.7 (d), 113.7 (d), 126.7 (d), 128.1 (d), 7.9, 1.6, 1 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 55.2 (q), 55.4
129.0 (d), 134.5 (s), 136.9 (s), 139.3 (s), 158.8 (s). SM (EI, 70 eV); (q), 55.9 (q), 78.4 (d), 110.5 (d), 113.5 (d), 120.7 (d), 126.5 (d),
m/z: 243 (11), 242 [Mϩ·, 41), 243 (16), 212 (31), 211 (100), 155 (22),
128.2 (d), 130.7 (s), 134.2 (s), 156.5 (s), 158.7 (s). Ϫ MS (EI, 70
152 (19), 151 (31), 135 (42), 119 (14), 92 (18). Ϫ HR MS: 242.13102 eV); m/z: 259 (10), 258 (54) [Mϩ·], 257 (10), 243 (16), 228 (14), 227
(C16H18O2ϩ·; calcd. 242.13143).
(74), 226 (35), 225 (6), 211 (16), 197 (5), 195 (7), 181 (7), 168 (5),
153 (6), 152 (15), 151 (69), 141 (5), 139 (5), 136 (6), 135 (48), 122
(9), 121 (100), 115 (8), 92 (8), 91 (8), 78 (6), 77 (15), 76 (5), 65
(6), 65 (11), 63 (8), 51 (7), 50 (5), 45 (14). Ϫ HR MS: 258.12370
(C16H18O3ϩ·; calcd. 258.12558).
1-[Methoxy(4-methylphenyl)methyl]naphthalene (4i): Colorless oil.
13% ee (HPLC, Chiracel OD-H, hexane/2-propanol, 25:1, 0.5 mL/
˜
min, T1 ϭ 10.0, T2 ϭ 10.7 min). Ϫ IR (CHCl3): ν ϭ 3010s, 2932w,
2361w, 1515w, 1453w, 1208s, 1089s, 741m. Ϫ 1H NMR (CDCl3,
500 MHz): δ ϭ δ ϭ 2.35 (s, 3 H), 3.50 (s, 3 H), 5.94 (s, 1 H), 7.15 4-Methoxy-1-[methoxy(phenyl)methyl]benzene (4o): Colorless solid,
(d, J ϭ 7.9, 2 H), 7.32 (d, J ϭ 7.9, 2 H), 7.45Ϫ7.62 (m, 4 H), m.p. 61Ϫ63 °C (ref.[55] 64Ϫ66 °C), b.p. Ͼ 300 °C (ref.[56] 135 °C/
7.80Ϫ7.91 (m, 2 H), 8.10Ϫ8.16 (m, 1 H). Ϫ 13C NMR (CDCl3,
1 Torr). 6% ee (Chiracel OJ, hexane/2-propanol, 99:1, 1 mL/min,
125 MHz): δ ϭ 21.1 (q), 57.2 (q), 83.0 (d), 124.1 (d), 125.1 (d), T1 ϭ 60.7, T2 ϭ 69.8 min). Ϫ IR (CHCl3): ν˜ ϭ 3619w, 3026s,
125.3 (d), 125.4 (d), 125.9 (d), 127.3 (d), 128.3 (d), 128.7 (d), 129.0
2399m, 1511m, 1423w, 1228s, 1202s, 1032w, 928m, 802s, 710s. Ϫ
(d), 131.1 (s), 132.1 (s), 133.9 (s), 136.9 (s), 137.1 (s), 137.4 (s), 1H NMR (CDCl3, 500 MHz): δ ϭ 3.38 (s, 3 H), 3.80 (s, 3 H), 5.23
138.3 (d). Ϫ MS (EI, 70 eV); m/z: 263 (20), 262 (96) [Mϩ·], 261 (s, 1 H), 6.88 (d, J ϭ 8.8, 2 H), 7.27 (d, J ϭ 8.8, 2 H), 7.34Ϫ7.36
(10), 255 (8), 254 (79), 247 (13), 232 (23), 231 (100), 230 (6), 229
(m, 5 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 55.2 (q), 56.9 (q),
(11), 217 (6), 216 (28), 215 (36), 202 (8), 172 (5), 171 (36), 156 (9), 84.9 (d), 113.7 (d), 126.7 (d), 127.3 (d), 128.2 (d), 128.3 (d), 134.2
155 (38), 136 (5), 135 (50), 129 (7), 128 (60), 127 (75), 126 (15), 120 (s), 142.3 (s), 159.0 (s).
(6), 119 (56), 115 (7), 114 (7), 108 (18), 101 (14), 91 (18), 77 (10),
1-[Methoxy(4-methoxyphenyl)methyl]naphthalene (4p): M.p. 46Ϫ48
76 (5), 75 (9), 74 (8), 65 (13), 63 (9), 51 (10). 50 (7). Ϫ SM-HR:
°C (ref.[57] 50 °C). 4% ee (HPLC, Chiracel OD-H, hexane/2-pro-
262.13833 (C19H18Oϩ·; calcd. 262.13577).
panol, 25:1, 0.5 mL/min, T1 ϭ 21.2, T2 ϭ 22.7 min). Ϫ IR (CHCl3):
4-Methoxy-(1-methoxyethyl)benzene (4k): B.p. 182Ϫ184 °C (ref.[54] ν˜ ϭ 3023m, 2365m, 1235s, 1205m, 1100s, 805m. Ϫ 1H NMR
72 °C/10 Torr). 0% ee (γ-Dex, 80 °C, T1 ϭ 60.8, T2 ϭ 61.4 min).
(CDCl3, 500 MHz): δ ϭ 3.47 (s, 3 H), 3.78 (s, 3 H), 5.91 (s, 1 H),
˜
Ϫ IR (CHCl3): ν ϭ 3619w, 3025s, 2399s, 1611w, 1513s, 1475w, 6.86 (d, J ϭ 8.8, 2 H), 7.32 (d, J ϭ 8.8, 2 H), 7.36Ϫ7.55 (m, 3 H),
1
1244s, 1202s, 1103w, 1082w, 1035s, 928m, 803s, 708s. Ϫ H NMR
7.63 (d, J ϭ 6.9, 1 H), 7.82 (d, J ϭ 8.2, 1 H), 7.80Ϫ7.98 (m, 1 H),
(CDCl3, 400 MHz): δ ϭ 1.45 (d, J ϭ 6.5, 3 H), 3.22 (s, 3 H), 3.83 8.05Ϫ8.11 (m, 1 H). Ϫ 13C NMR (CDCl3,125 MHz): δ ϭ 55.2 (q),
(s, 3 H), 4.27 (q, J ϭ 6.5, 1 H), 6.91 (d, J ϭ 8.5, 2 H), 7.26 (d, J ϭ
57.2 (q), 82.7 (d), 113.7 (d), 124.3 (d), 125.2 (d), 125.3 (d), 125.5
8.5, 2 H). Ϫ 13C NMR (CDCl3, 100 MHz): δ ϭ 23.7 (q), 55.2 (q), (d), 126.1 (d), 127.2 (d), 127.6 (d), 128.2 (d), 128.4 (d), 128.6 (d),
56.1 (q), 79.0 (d), 113.7 (d), 127.3 (d), 127.4 (d), 135.4 (s), 158.9 (s). 131.2 (s), 134.2 (s), 136.5 (s), 141.4 (s), 158.9 (s).
1-Methoxy-4-(1-methoxypentyl)benzene (4l): Colorless liquid, b.p. 1-Ethyl-2-[(2-isopropylphenyl)(methoxy)methyl]benzene (4q): Color-
262Ϫ263 °C (ref.[53] 95 °C/1 Torr). 0% ee (γ-Dex, 80 °C, 60 min,
less oil, [α]2D1 ϭ 6.5 (c ϭ 1.08, EtOH) for 40% ee (HPLC, Chiracel
rate 1 °C/min to 120 °C, T1 ϭ 95.1, T2 ϭ 95.5 min. Ϫ IR (CHCl3): OJ, hexane/2-propanol, 99:1, 0.5 mL/min, T1 ϭ 7.8, T2 ϭ 9.9 min).
˜
˜
ν ϭ 3620w, 3022s, 2960m, 2400m, 1611w, 1511s, 1423m, 1231s, Ϫ IR (CHCl3): ν ϭ 3005s, 2934w, 2359w, 1511w, 1453w, 1203s,
4142 Eur. J. Org. Chem. 2001, 4137Ϫ4147

Asymmetric Nucleophilic Substitution of Acetals
FULL PAPER
1
1088s, 744s. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.10 (d, J ϭ 7, 180 (65), 179 (38), 178 (13), 166 (31), 165 (46), 151 (14), 121 (16),
3 H), 1.21 (t, J ϭ 7, 3 H), 1.30 (d, J ϭ 7, 3 H), 2.58Ϫ2.74 (m, 2 119 (12), 107 (21), 105 (16), 91 (14), 77 (18), 45 (14). HR MS:
H), 3.12 (sept, J ϭ 7, 1 H), 3.43 (s, 3 H), 5.78 (s, 1 H), 7.14Ϫ7.20 242.1310 (C16H18O2ϩ; calcd. 242.1307).
(m, 4 H), 7.24Ϫ7.31 (m, 3 H), 7.35 (dd, J ϭ 7.6, 1.3, 1 H). Ϫ 13C
2-[(2-Ethylphenyl)(phenyl)methoxy]ethanol (6e): Colorless oil,
NMR (CDCl3, 125 MHz): δ ϭ 14.9 (q), 23.5 (q), 24.2 (q), 25.2 (t),
28.5 (d), 57.5 (q), 78.5 (d), 125.5 (d), 125.6 (d), 125.7 (d), 127.4 (d),
127.5 (d), 127.7 (d), 127.9 (d), 128.6 (d), 137.1 (s), 138.2 (s), 142.4
[α]2D1 ϭ Ϫ5.90 (c ϭ 0.96, EtOH). 30% ee (HPLC, Chiracel AD;
hexane/2-propanol, 99:1; 1 mL/min, T1 ϭ 13.7, T2 ϭ 16.3 min). Ϫ
˜
IR (CHCl3): ν ϭ 3620m, 2975m, 2894w, 1390w, 1240w, 1048s,
(s), 147.5 (s). Ϫ MS (EI, 70 eV); m/z: 268 (1) [Mϩ·], 237 (6), 236
(24), 225 (6), 222 (5), 221 (27), 208 (19), 207 (100), 194 (12), 193
(65), 192 (23), 191 (5), 182 (5), 179 (11), 178 (19), 165 (7), 163 (14),
149 (39), 147 (5), 133 (8), 132 (8), 131 (59), 130 (5), 129 (11), 119
(8), 117 (21), 116 (8), 115 (13), 105 (7), 103 (10), 91 (28), 89 (8), 77
(10), 51 (5). 237.1653 (C18H21ϩ; calcd. 237.1638).
1
877m. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.16 (t, J ϭ 7.6, 3 H),
2.01 (s large, 1 H), 2.58Ϫ2.67 (m, 1 H), 2.67Ϫ2.76 (m, 1 H),
3.60Ϫ3.64 (m, 2 H), 3.79 (dd, J ϭ 6, 4.5, 2 H), 5.67 (s, 1 H),
7.21Ϫ7.30 (m, 4 H), 7.31Ϫ7.36 (m, 4 H), 7.44 (dd, J ϭ 7.3, 1.3, 1
H). Ϫ 13CNMR (CDCl3, 125 MHz): δ ϭ 15.1 (q), 25.1 (t), 63.6 (t),
70.5 (t), 80.9 (d), 126.0 (d), 127.2 (d), 127.51 (d), 127.55 (d), 127.8
(d), 128.3 (d), 128.6 (d), 138.5 (s), 141.2 (s), 141.9 (s). Ϫ MS (EI,
70 eV); m/z: 256 (6) [Mϩ·], 195 (45), 194 (60), 180 (20), 179 (100),
178 (14), 165 (14), 151 (11), 135 (10), 117 (57), 115 (12), 107 (21),
105 (17), 91 (23), 89 (12), 79 (18), 77 (18), 45 (15). Ϫ HR MS:
256.14676 (C17H20O2ϩ·; calcd. 256.14633).
Substitution of 2-Aryl-1,3-dioxolanes 5
2-(1-Phenylethoxy)ethanol (6a): Colorless liquid, b.p. 145Ϫ147 °C
(ref.[58] 64Ϫ65 °C/16 Torr). 3% ee (HPLC, Chiralcel OD-H, hexane/
2-propanol, 9:1, 0.5 mL/min, T1 ϭ 12.6, T2 ϭ 13.9 min). Ϫ IR
(CHCl3): ν˜ ϭ 3430brs, 3014s, 1231w, 1205s, 801m, 783s, 745w. Ϫ
1H NMR (CDCl3, 500 MHz,):1.47 (d, J ϭ 6.5, 3 H), 1.85 (s large,
1 H), 3.41Ϫ3.46 (m, 2 H), 3.70Ϫ3.74 (m, 2 H), 4.46 (q, J ϭ 6.5, 1
H), 7.26Ϫ7.38 (m, 5 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ
24.0 (q), 62.0 (t), 69.6 (t), 78.5 (d), 126.1 (d), 127.6 (d), 128.5 (d),
143.5 (s).
2-[(2-Isopropylphenyl)(phenyl)methoxy]ethanol (6f): Colorless solid,
m.p. 40Ϫ42 °C, [α]2D1 ϭ ϩ1.50 (c ϭ 1.36, EtOH) for 46% ee (HPLC,
Chiracel OD-H, hexane/2-propanol, 25:1, 0.5 mL/min, T1 ϭ 19.8,
˜
T2 ϭ 20.9 min). Ϫ IR (CHCl3): ν ϭ 3620m, 2973m, 2891w, 1402w,
1
1242w, 1054s, 867m. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.08 (d,
J ϭ 6.7, 3 H), 1.21 (d, J ϭ 6.7, 3 H), 2.01 (s large, 1 H), 3.24 (sept,
J ϭ 6.7, 1 H), 3.62Ϫ3.66 (m, 2 H), 3.80Ϫ3.85 (m, 2 H), 5.74 (s, 1
H), 7.21Ϫ7.44 (m, 9 H). Ϫ 13C NMR (125 MHz, CDCl3): 23.7 (q),
24.1 (q), 28.4 (d), 62.1 (t), 70.5 (t), 90.0 (d), 125.7 (d), 125.80 (d),
127.4 (d), 127.5 (d), 128.0 (d), 128.3 (d), 137.6 (s), 141.6 (s), 146.9
(s). Ϫ MS (EI, 70 eV); m/z: 270 (3) [Mϩ·], 209 (20), 208 (49), 194
(18), 193 (100), 179 (15), 178 (15), 165 (8), 151 (10), 132 (7), 131
(62), 129 (6), 117 (5), 116 (5), 115 (8), 107 (18), 105 (11), 91 (30),
89 (6), 79 (8), 77 (10), 51 (5), 45 (11). Ϫ HR MS: 270.16205
(C18H22O2ϩ·; calcd. 270.16199).
2-[(1-Phenylpentyl)oxy]ethanol (6b): Colorless oil, 15% ee (HPLC,
Chiracel OB-H, hexane/2-propanol, 9:1, 0.5 mL/min, T1 ϭ 10.4,
˜
T2 ϭ 11.8 min). Ϫ IR (CHCl3): ν ϭ 3443sbr, 3007w, 2933m, 2862w,
2341s, 1453w, 1203s, 1102m, 1050m, 889w. Ϫ 1H NMR (CDCl3,
500 MHz): δ ϭ 0.88 (t, J ϭ 7, 3 H), 1.19Ϫ1.45 (m, 4 H), 1.61Ϫ1.70
(m, 1 H), 1.79Ϫ1.90 (m, 1 H), 2.07 (s, 1 H), 3.38Ϫ3.45 (m, 2 H),
3.68Ϫ3.72 (m, 2 H), 4.24 (dd, J ϭ 7.2, 6.6, 1 H), 7.28Ϫ7.31 (m, 3
H), 7.35Ϫ7.39 (m, 2 H). Ϫ 13C NMR: (CDCl3, 125 MHz): δ ϭ
14.1 (q), 22.7 (t), 28.0 (t), 37.9 (t), 62.0 (t), 69.9 (t), 82.9 (d), 126.5
(d), 127.6 (d), 128.6 (d), 142.5 (s). Ϫ MS (EI, 70 eV); m/z: 208 (1)
[Mϩ·], 152 (16), 151 (100), 147 (8), 108 (11), 107 (93), 105 (9), 104
(8), 92 (7), 91 (71), 79 (33), 78 (5), 77 (14), 51 (6), 45 (32). Ϫ HR
MS: 208.14475 (C13H20O2ϩ·; calcd. 208.14633).
2-[(2-tert-Butylphenyl)(phenyl)methoxy]ethanol (6g): 4% ee (HPLC,
Chiracel OD-H, hexane/2-propanol, 25:1, 0.5 mL/min, T1 ϭ 23.7,
˜
T2 ϭ 31.2 min). Ϫ IR (CHCl3): ν ϭ 3630m, 2965m, 2891w, 1400w,
1
1250w, 1049s, 857m. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.35(s,
2-[(4-Methylphenyl)(phenyl)methoxy]ethanol (6c): Colorless oil, 12%
ee (HPLC, Chiracel OD-H, hexane/2-propanol, 9:1, 0.5 mL/min,
9 H), 1.93 (s large, 1 H), 3.46Ϫ3.51 (m, 1 H), 3.63Ϫ3.72 (m, 3 H),
6.17 (s, 1 H), 7.14Ϫ7.26 (m, 7 H), 7.37Ϫ7.43 (m, 2 H). Ϫ 13C NMR
(CDCl3, 125 MHz): δ ϭ 32.4 (q), 35.6 (s), 62.2 (t), 70.2 (t), 79.6
(d), 125.9 (d), 126.4 (d), 127.4 (d), 127.7 (d), 128.1 (d), 128.2 (d),
130.3 (d), 139.1 (s), 142.3 (s), 148.2 (s). Ϫ MS (EI, 70 eV); m/z: 285
(9), 284 (42) [Mϩ·], 239 (17), 224 (11), 223 (50), 222 (7), 208 (13),
207 (66), 193 (10), 181 (6), 179 (10), 178 (16), 167 (14), 166 (5), 165
(14), 163 (8), 161 (11), 152 (14), 151 (100), 146 (8), 145 (61), 131
(7), 130 (6) 129 (20), 128 (7), 117 (10), 115 (11), 108 (5), 107 (68),
˜
T1 ϭ 16.5, T2 ϭ 24.4 min). Ϫ IR (CHCl3): ν ϭ 3610brw, 2932w,
2360m, 1481w, 1451w, 1091s, 1032s, 1029w, 912w. Ϫ 1H NMR
(CDCl3, 500 MHz): δ ϭ 2.02 (s large, 1 H), 2.34 (s, 3 H), 3.60(dd,
J ϭ 4.8, 4.4, 2 H), 3.79 (dd, J ϭ 4.8, 4.4, 2 H), 5.39 (s, 1 H),
7.14Ϫ7.17 (m, 2 H), 7.24Ϫ7.29 (m, 3 H), 7.31Ϫ7.38 (m, 4 H). Ϫ
13C NMR (CDCl3, 125 MHz): δ ϭ 21.1 (q), 62.0 (t), 70.2 (t), 83.9
(d), 126.8 (d), 126.9 (d), 127.4 (d), 128.4 (d), 129.1 (d), 137.3 (s),
138.9 (s), 142.0 (s). Ϫ MS (EI, 70 ev); m/z: 242 (19) [Mϩ·], 198 (5),
197 (28), 182 (17), 181 (100), 180 (16), 179 (6), 167 (5), 166 (19),
105 (24), 104 (5), 103 (7), 91 (52), 89 (12), 79 (16), 77 (18), 76
ϩ·
(5), 57 (30), 51 (8), 45 (23). Ϫ HR MS: 284.17813 (C19H24O2
;
165 (31), 152 (5), 121 (13), 119 (15), 107 (7), 105 (17), 91 (9), 89
ϩ·
calcd. 284.17764).
(6), 77 (12), 51 (5), 45 (7). Ϫ HR MS: 242.13003 (C16H18O2
;
calcd. 248.13068).
2-[(2-Ethylphenyl)(2-methylphenyl)methoxy]ethanol (6h): Colorless
oil, [α]2D1 ϭ ϩ2.51 (c ϭ 0.93, EtOH) for 52% ee (HPLC, Chiracel
OD-H, hexane/2-propanol, 25:1, 0.5 mL/min, T1 ϭ 21.4, T2 ϭ 23.2
2-[(2-Methylphenyl)(phenyl)methoxy]ethanol (6d): Colorless oil,
[α]2D1 ϭ ϩ3.60 (c ϭ 1.25, EtOH), for 34% ee (HPLC, hexane/2-
˜
propanol, 9:1, 0.5 mL/min, T1 ϭ 16.5, T2 ϭ 24.4 min). Ϫ IR min). Ϫ IR (CHCl3): ν ϭ 3619m, 2956m, 2887w, 1447w, 1391w,
1
(CHCl3): ν˜ ϭ 3600brw, 2930w, 2359w, 1493w, 1452w, 1094s, 1035s,
1248w, 1049s, 877m. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.21 (t,
1
1029w, 899w. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.80 (s large, 1 J ϭ 7.6, 3 H), 2.09 (s large, 1 H), 2.34 (s, 3 H), 2.58Ϫ2.73 (m, 2
H), 2.28 (s, 3 H), 3.60Ϫ3.62 (m, 2 H), 3.79Ϫ3.81 (m, 2 H), 5.59 (s, H), 3.65 (dd, J ϭ 4.8, 4.4, 2 H), 3.80 (dd, J ϭ 4.4, 5.1, 3 H), 5.83
1 H), 7.15Ϫ7.17 (m, 2 H), 7.19Ϫ7.31 (m, 3 H), 7.31Ϫ7.35 (m, 4 (s, 1 H), 7.18Ϫ7.31 (m, 8 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ
H), 7.42Ϫ7.45 (m, 1 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 19.4 14.9 (q), 19.3 (q), 25.1 (t), 62.1 (t), 71.1 (t), 77.9 (d), 125.8 (d), 125.9
(q), 62.1 (t), 70.4 (t), 81.3 (d), 126.0 (d), 126.9 (d), 127.55 (d), 127.57
(d), 127.4 (d), 127.7 (d), 127.9 (d), 128.6 (d), 130.5 (d), 136.6 (s),
(d), 127.59 (d), 128.4 (d), 130.6 (d), 135.9 (s), 139.4 (s), 140.7 (s). 137.4 (s), 138.6 (s), 142.5 (s). Ϫ MS (EI, 70 eV); m/z: 270 (1) [Mϩ·],
Ϫ MS (EI, 70 eV); m/z: 242(34) [Mϩ·], 197 (24), 182 (19), 181 (100),
210 (7), 209 (40), 208 (50), 194 (19), 193 (100), 181 (7), 180 (10),
4143
Eur. J. Org. Chem. 2001, 4137Ϫ4147

P. Müller, P. Nury, G. Bernardinelli
FULL PAPER
179 (48), 178 (20), 166 (5), 165 (24), 135 (13), 133 (12), 131 (5), 121 2.14 (s large, 1 H), 2.58Ϫ2.80 (m, 2 H), 3.65Ϫ3.85 (m, 4 H), 6.42
(18), 119 (14), 118 (6), 117 (43), 115 (10), 105 (12), 103 (5), 96 (8), (s, 1 H), 7.20Ϫ7.48 (m, 6 H), 7.50Ϫ7.61 (m, 2 H), 7.85 (d, J ϭ 8.1,
93 (7), 91 (20), 89 (9), 79 (9), 77 (11), 65 (6), 51 (5), 45 (14). Ϫ HR 1 H), 7.93 (dd, J ϭ 8.4, 1.8, 1 H), 8.08 (d, J ϭ 8.1, 1 H). Ϫ 13C
MS: 270.16372 (C18H22O2ϩ·; calcd. 270.16199).
NMR (CDCl3, 125 MHz): δ ϭ 14.9 (q), 25.0 (t), 62.1 (t), 71.2 (t),
77.8 (d), 123.5 (d), 125.2 (d), 125.6 (d), 125.7 (d), 126.3 (d), 127.6
(d), 128.0 (d), 128.6 (d), 128.8 (d), 131.8 (s), 133.9 (s), 136.1 (s),
137.4 (s), 142.5 (s). Ϫ MS (EI, 70 eV); m/z: 307 (11), 306 (50) [Mϩ·],
246 (16), 245 (61), 244 (21), 230 (23), 229 (100), 228 (14), 217 (17),
216 (23), 215 (31), 202 (10), 201 (26), 179 (10), 157 (21), 155 (11),
135 (11), 133 (58), 129 (18), 128 (11), 127 (12), 118 (10), 117 (40),
115 (38), 114 (15), 91 (10), 45 (14). Ϫ HR MS: 306.16316
(C21H22O2ϩ·; calcd. 306.16199).
2-[(2-Ethylphenyl)(2-isopropylphenyl)methoxy]ethanol (6i): Colorless
oil, [α]2D1 ϭ 10.0 (c ϭ 1.33, EtOH) for 75% ee (HPLC, Chiracel
OD-H, hexane/2-propanol, 25:1, 0.5 mL/min, T1 ϭ 14.0, T2 ϭ 14.9
˜
min). Ϫ IR (CHCl3): ν ϭ 3623m, 2956m, 2892w, 1447w, 1394w,
1
1245w, 1052s, 877m. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.11 (d,
J ϭ 7, 3 H), 1.15 (t, J ϭ 7.6, 3 H), 1.31 (d, J ϭ 7, 3 H), 1.89 (s
large, 1 H), 2.57Ϫ2.72 (m, 2 H), 3.15 (sept, J ϭ 7, 1 H), 3.63Ϫ3.67
(m, 2 H), 3.78Ϫ3.82 (m, 2 H), 5.95 (s, 1 H), 7.12Ϫ7.39 (m, 8 H).
13C NMR (CDCl3, 125 MHz): δ ϭ 14.9 (q), 23.7 (q), 24.3 (q),
2-[(2-Ethylphenyl)(2-trimethylsilanylphenyl)methoxy]ethanol (6n):
Colorless oil. Ϫ [α]2D1 ϭ Ϫ4.90 (c ϭ 2.17, EtOH) for 31% ee (HPLC,
Chiracel OD-H, hexane/2-propanol, 9:1, 0.5 mL/min, T1 ϭ 8.6,
T2 ϭ 9.5 min). Ϫ IR (CHCl3): ν˜ ϭ 3682w, 3603w, 3028m, 2965w,
2360w, 1601w, 1228s, 1048m, 839m, 795m, 676m. Ϫ 1H NMR
(CDCl3, 500 MHz): δ ϭ 0.22 (s, 9 H), 1.34 (t, J ϭ 7.6, 3 H), 2.06
(s large, 1 H), 2.75Ϫ2.90 (m, 2 H), 3.57Ϫ3.67 (m, 2 H), 3.75Ϫ3.79
(m, 2 H), 5.94 (s, 1 H), 6.80 (dd, J ϭ 7.9, 1, 1 H), 7.07 (ddd, J ϭ
8.8, 7.6, 1.3, 1 H), 7.24Ϫ7.29 (m, 1 H), 7.30Ϫ7.33 (m, 1 H), 7.35
(ddd, J ϭ 8.8, 7.6, 1.3, 1 H), 7.46 (ddd, J ϭ 8.8, 7.6, 1.3, 1 H),
7.55 (dd, J ϭ 7.6, 1, 1 H), 7.61 (dd, J ϭ 7.6, 1.3, 1 H). Ϫ 13C NMR
(CDCl3, 125 MHz): δ ϭ 0.47 (q), 14.9 (q), 24.8 (t), 62.1 (t), 70.2
(t), 80.1 (d), 125.4 (d), 127.1 (d), 128.0 (d), 128.1 (d), 128.3 (d),
128.5 (d), 129.3 (d), 134.9 (d), 138.6 (s), 139.2 (s), 142.3 (s), 145.2
(s). Ϫ MS (EI, 70 eV); m/z: 328 (1) [Mϩ·], 267 (8), 266 (6), 255 (5),
254 (14), 253 (56), 251 (8), 223 (9), 195 (15), 194 (17), 193 (27), 192
(34), 180 (8), 179 (51), 178 (15), 167 (8), 165 (11), 163 (10), 135
Ϫ
25.2 (t), 28.5 (d), 62.2 (t), 71.1 (t), 77.2 (d), 125.68 (d), 125.7 (d),
125.9 (d), 126.6 (d), 126.7 (d), 127.9 (d), 128.2 (d), 128.7 (d), 136.9
(s), 137.9 (s), 142.4 (s), 147.5 (s). Ϫ MS (EI, 70 eV); m/z: 237 (8)
[Mϩ· Ϫ C2H6O2] 236 (17), 222 (5), 221 (25), 208 (18), 207 (100),
195 (8), 194 (14), 193 (78), 192 (17), 179 (22), 178 (19), 165 (6), 135
(13), 133 (10), 132 (10), 131 (65), 129 (8), 119 (5), 117 (14), 116 (6),
115 (9), 105 (9), 103 (7), 91 (25), 89 (5), 79 (10), 77 (8), 45 (13). Ϫ
HR MS: 236.1574 (C18H20ϩ, calcd. 236.1565). Ϫ C20H26O2: calcd.
C 80.49, H 8.78; found C 80.19, H 8.86.
2-[(2-tert-Butylphenyl)(2-ethylphenyl)methoxy]ethanol (6k): Color-
less oil, [α]2D1 ϭ Ϫ15.3 (c ϭ 0.85, EtOH) for 60% ee (HPLC, Chira-
cel OD-H, hexane/2-propanol, 25:1, 0.5 mL/min, T1 ϭ 10.6 min,
T2 ϭ 13.2 min). Ϫ IR (CHCl3): ν˜ ϭ 3620m, 2959m, 2921w, 1448w,
1
1398w, 1239w, 1064s, 887m. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ
1.35 (s, 9 H), 1.93 (s br, 1 H), 3.46Ϫ3.51 (m, 1 H), 3.63Ϫ3.72 (m,
3 H), 6.17 (s, 1 H), 7.14Ϫ7.26 (m, 7 H), 7.37Ϫ7.43 (m, 2 H). Ϫ 13C
NMR (CDCl3, 125 MHz): δ ϭ 32.4 (q), 35.6 (s), 62.2 (t), 70.2 (t),
79.6 (d), 125.9 (d), 126.4 (d), 127.4 (d), 127.7 (d), 128.1 (d), 128.2
(d), 130.3 (d), 139.1 (s), 142.3 (s), 148.2 (s). Ϫ MS (EI, 70 eV); m/
z: 285 (6), 286 (42) [Mϩ·], 239 (17), 224 (11), 223 (50), 222 (7), 208
(13), 207 (66), 193 (10), 181 (6), 179 (10), 178 (16), 167 (14), 166
(5), 165 (14), 163 (8), 161 (11), 152 (14), 151 (100), 146 (8), 145
(61), 131 (7), 130 (6), 129 (20), 128 (7), 117 (10), 115 (11), 108 (5),
(11), 119 (9), 117 (8), 105 (5), 77 (6), 75 (54), 74 (12), 73 (100), 59
ϩ·
(11), 45 (15).
328.18630).
Ϫ HR MS: 328.18961 (C20H28SiO2 ; calcd.
2-[(2-Ethylphenyl)(2,4,6-trimethylphenyl)methoxy]ethanol (6o): Col-
orless oil, 12% ee, (HPLC, Chiracel OD-H, hexane/2-propanol, 9:1,
˜
0.5 mL/min, T1 ϭ 9.3, T2 ϭ 10.1 min). Ϫ IR (CHCl3): ν ϭ 3688w,
3607w, 2965w,1224m, 1208w, 794s, 743s, 717w. Ϫ 1H NMR
(CDCl3, 400 MHz): δ ϭ 1.33 (t, J ϭ 7.6, 3 H), 2.08 (s large, 1 H),
2.30 (s, 6 H), 2.34 (s, 3 H), 2.84 (dq, J ϭ 7.6, 2.8, 2 H), 3.51Ϫ3.64
(m, 2 H), 3.76Ϫ3.82 (m, 2 H), 6.01 (s, 1 H), 6.92 (s, 2 H), 6.97 (d,
J ϭ 7.6, 1 H), 7.07 (ddd, J ϭ 9.1, 7.8, 1.5, 1 H), 7.25Ϫ7.34 (m, 2
H). Ϫ 13C NMR (CDCl3, 100 MHz): δ ϭ 15.2 (q), 20.8 (q), 20.9
(q), 25.2 (t), 62.2 (t), 70.4 (t), 78.8 (d), 125.3 (d), 127.8 (d), 128.0
(d), 128.8 (d), 130.1 (d), 132.2 (s), 136.6 (s), 136.9 (s), 137.4 (s),
143.9 (s). Ϫ MS (EI, 70 eV); m/z: 298 (2) [Mϩ·], 238 (6), 237 (33),
236 (42), 222 (18), 221 (90), 209 (5), 208 (20), 207 (100), 206 (15),
205 (8), 194 (8), 193 (47), 192 (20), 191 (8), 179 (22), 178 (25), 149
(30), 147 (25), 135 (16), 134 (6), 133 (35), 121 (6), 119 (11), 118
(10), 117 (44), 115 (13), 105 (21), 103 (12), 91 (15), 79 (12), 77 (11),
45 (25). Ϫ HR MS: 298.19079 (C20H26O2ϩ·; calcd. 298.19327).
107 (68), 105 (24), 104 (5),103 (7), 91 (52), 89 (12), 79 (16), 77 (18),
76 (5), 57 (30), 51 (8), 45 (23). Ϫ HR MS: 284.1711 (C19H24O2
calcd. 284.1776).
ϩ·
;
2-[(1,1Ј-Biphenyl-2-yl)(2-ethylphenyl)methoxy]ethanol (6l): Colorless
oil. Ϫ [α]2D1 ϭ ϩ28.4 (c ϭ 0.94, EtOH) for 69% ee (HPLC, Chiracel
OD-H, hexane/2-propanol, 9:1, 0.5 mL/min, T1 ϭ 9.7, T2 ϭ 10.6
min). Ϫ IR (CHCl3): ν˜ ϭ 3610w, 3503w, 2983w, 1609w, 1227s,
1047m, 757w. Ϫ 1H NMR (CDCl3, 500 MHz): δ ϭ 0.89 (t, J ϭ
7.6, 3 H), 1.87 (s large, 1 H), 2.18Ϫ2.36 (m, 2 H), 3.28Ϫ3.34 (m, 1
H), 3.46Ϫ3.51 (m, 1 H), 3.65Ϫ3.76 (m, 2 H), 5.63 (s, 1 H),
7.14Ϫ7.48 (m, 13 H). Ϫ 13C NMR (CDCl3, 100 MHz): δ ϭ 14.5
(q), 24.9 (t), 62.0 (t), 70.4 (t), 77.4 (d), 125.7 (d), 127.0 (d), 127.2
(d), 127.4 (d), 127.5 (d), 127.6 (d), 128.1 (d), 128.2 (d), 128.7 (d),
129.0 (d), 130.0 (d), 137.95 (s), 137.97 (s), 141.0 (s), 142.3 (s), 142.5
(s). Ϫ MS (EI, 70 eV); m/z: 332 (7) [Mϩ·], 287 (17), 271 (19), 270
(73), 269 (5), 256 (11), 255 (47), 254 (5), 253 (6), 252 (5), 242 (5),
241 (17), 239 (6), 181 (14), 179 (10), 178 (5), 166 (15), 165 (100),
153 (5), 152 (7), 135 (11), 133 (7), 128 (6), 126 (5), 117 (7), 115 (6),
105 (7), 91 (9), 79 (6), 77 (6), 45 (8). Ϫ HR MS: 332.17765
(C23H24O2ϩ·; calcd. 332.17764).
2-[(2-Methylphenyl)(1-naphthyl)methoxy]ethanol (6p): Colorless oil.
Ϫ [α]2D1 ϭ Ϫ1.1 (c ϭ 1.24, EtOH) for 40% ee (HPLC, Chiracel OD-
H, hexane/2-propanol, 9:1, 0.5 mL/min, T1 ϭ 23.7, T2 ϭ 26.3 min).
˜
Ϫ IR (CHCl3): ν ϭ 3611w, 3499w, 2975m, 1601w, 1227s, 1049m,
756w. Ϫ 1H NMR (CDCl3, 500 MHz): δ ϭ 1.96 (s large, 1 H), 2.34
(s, 3 H), 3.75Ϫ7.85 (m, 4 H), 6.32 (s, 1 H), 7.17Ϫ7.33 (m, 5 H),
7.43 (dd, J ϭ 7.55, 7.6, 1 H), 7.49Ϫ7.56 (m, 2 H), 7.83 (d, J ϭ 8.2,
1 H), 7.89Ϫ7.92 (m, 1 H), 8.02 (d, J ϭ 7.9, 1 H). Ϫ 13C NMR
(CDCl3, 125 MHz): δ ϭ 19.3 (q), 62.2 (t), 71.6 (t), 78.5 (d), 123.5
(d), 125.3 (d), 125.6 (d), 125.62 (d), 126.1 (d), 126.3 (d), 127.4 (d),
2-[(2-Ethylphenyl)(1-naphthyl)methoxy]ethanol (6m): Colorless oil,
[α]2D1 ϭ ϩ2.41 (c ϭ 1.08, EtOH) for 27% ee (HPLC, Chiracel OD-
H, hexane/2-propanol, 9:1, 0.5 mL/min, T1 ϭ 17.2, T2 ϭ 20.5 min). 127.8 (d), 128.7 (d), 128.9 (d), 130.7 (d), 131.8 (s), 133.9 (s), 135.7
Ϫ IR (CHCl3): ν˜ ϭ 3611w, 3503w, 2975m, 1601w, 1232s, 1045m, (s), 136.6 (s), 138.3 (s). Ϫ MS (EI, 70 eV); m/z: 293 (14), 292 (65)
1
764w. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.24 (t, J ϭ 7.6, 3 H), [Mϩ·], 232 (24), 231 (100), 230 (36), 229 (26), 228 (10), 216 (34),
4144
Eur. J. Org. Chem. 2001, 4137Ϫ4147

Asymmetric Nucleophilic Substitution of Acetals
FULL PAPER
215 (43), 202 (11), 201 (23), 165 (12), 157 (17), 155 (11), 129 (16), 2.38 (s, 3 H), 3.61Ϫ3.68 (m, 1 H), 3.76Ϫ3.87 (m, 3 H), 6.52 (s, 1
127 (12), 121 (14), 119 (65), 115 (14), 114 (11), 108 (27), 91 (16), H), 6.97 (s, 2 H), 7.05Ϫ7.08 (m, 1 H), 7.33 (dd, J ϭ 8.1, 7.4, 1 H),
45 (13). Ϫ HR MS: 292.14628 (C20H20O2ϩ·; calcd. 292.14633).
7.53Ϫ7.58 (m, 1 H), 7.61Ϫ7.66 (m, 1 H), 7.82 (d, J ϭ 8.1, 1 H),
7.92 (d, J ϭ 8.1, 1 H), 8.25 (d, J ϭ 8.3, 1 H). Ϫ 13C NMR (CDCl3,
100 MHz): δ ϭ 20.8 (q), 20.9 (q), 62.3 (t), 70.5 (t), 78.8 (d), 124.3
(d), 124.9 (d), 125.5 (d), 125.6 (d), 126.3 (d), 128.8 (d), 128.9 (d),
130.1 (d), 131.7 (s), 132.4 (s), 134.2 (s), 134.6 (s), 137.1 (s), 137.6
(s). Ϫ MS (EI, 70 eV); m/z: 231 (15), 320 (63) [Mϩ·], 260 (13), 259
(45), 258 (34), 257 (16), 244 (21), 243 (62), 242 (10), 230 (9), 229
(28), 228 (13), 215 (8), 208 (6), 202 (7), 201 (19), 193 (21), 157 (19),
156 (6), 155 (25), 149 (25), 148 (13), 147 (100), 132 (5), 129 (26),
128 (15), 127 (19), 122 (22), 121 (20), 120 (7), 119 (17), 115 (24),
2-[2-Isopropylphenyl)(1-naphthyl)methoxy]ethanol (6q): Colorless
oil. Ϫ [α]2D1 ϭ ϩ3.5 (c ϭ1.1, EtOH) for 62% ee (HPLC: Chiracel
OD-H, hexane/2-propanol, 25:1, 0.5 mL/min, T1 ϭ 23.7, T2 ϭ 31.2
˜
min). Ϫ IR (CHCl3): ν ϭ 3625m, 2958m, 2901w, 1441w, 1398w,
1
1242w, 1052s, 875m. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.10 (d,
J ϭ 7, 3 H), 1.32 (d, J ϭ 7, 3 H), 2.08 (s large, 1 H), 3.14 (sept,
J ϭ 7, 1 H), 3.75Ϫ3.81 (m, 2 H), 3.81Ϫ3.86 (m, 2 H), 6.46 (s, 1
H), 7.20 (ddd, J ϭ 7.6, 7.6, 1.3, 1 H), 7.25 (d, J ϭ 7.6, 1 H),
7.31Ϫ7.38 (m, 2 H), 7.39Ϫ7.45 (m, 2 H), 7.48Ϫ7.58 (m, 2 H), 7.83
(d, J ϭ 8.2, 1 H), 7.92 (dd, J ϭ 7.6, 1.6, 1 H), 8.07 (d, J ϭ 8.2, 1
H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 23.5 (q), 24.5 (q), 28.5
(q), 62.2 (t), 71.2 (t), 77.8 (d), 123.6 (d), 125.2 (d), 125.6 (d), 125.8
(d), 125.9 (d), 126.4 (d), 127.6 (d), 128.2 (d), 128.7 (d), 128.9 (d),
131.8 (s), 133.9 (s), 136.3 (s), 136.4 (s), 147.5 (s). Ϫ MS (EI, 70
eV); m/z: 321 (7), 320 (27) [Mϩ·], 259 (14), 258 (14), 244 (22), 243
(100), 229 (11), 228 (16), 217 (9), 216 (6), 215 (16), 202 (7), 201
(18), 193 (5), 157 (15), 155 (7), 147 (22), 141 (8), 132 (12), 131 (82),
130 (11), 129 (30), 128 (14), 127 (11), 122 (5), 117 (5), 116 (8), 115
(21), 114 (11), 105 (5), 91 (22), 77 (6), 45 (11). Ϫ HR MS: 320.17574
(C22H24O2ϩ·; calcd. 320.17764).
114 (18), 113 (6), 108 (14), 105 (7), 101 (7), 91 (10), 86 (9), 84 (11),
ϩ·
73 (6), 57 (7), 55 (5), 45 (17). Ϫ HR MS: 320.17970 (C22H24O2
;
calcd. 320.17764).
Absolute Configuration of 2-[(2-Ethylphenyl)(2-isopropylphenyl)-
methoxy]ethanol (6i)
2-Ethyl-1-[(2-iodoethoxy)(2-isopropylphenyl)methyl]benzene
(13):
PPh3 (1.526 g, 5.82 mmol), imidazole (396 mg, 5.82 mmol), and I2
(1.107 g, 4.36 mmol) were stirred in dry Et2O (5.0 mL) and MeCN
(2.0 mL) at room temp. for 30 min. Compound 6i (434 mg,
1.45 mmol) in Et2O (2.0 mL) was added dropwise. The mixture was
stirred at room temp. for 3 h, and was then diluted with petroleum
ether (25 mL). The precipitate was removed by filtration, the filtrate
2-[(1,1Ј-Biphenyl-2-yl)(1-naphthyl)methoxy]ethanol (6r): Colorless
oil. Ϫ [α]2D1 ϭ ϩ14.3 (c ϭ 1.01, EtOH) for 56% ee (HPLC, Chiracel was concentrated to 75% and filtered again, and the solvents were
OD-H, hexane/2-propanol, 9:1, 0.5 mL/min; T1 ϭ 12.6, T2 ϭ 17.4
evaporated. The residue was purified by column chromatography
˜
min). Ϫ IR (CHCl3): ν ϭ 3620w, 3504w, 2986m, 1609w, 1227s, (SiO2; pentane/EtOAc, 25:1) to give 13 (525 mg, 89%). Ϫ IR
1
1048m, 765w. Ϫ H NMR (CDCl3, 400 MHz): δ ϭ 1.63 (s large, 1 (CHCl3): ν ϭ 3602m, 1602m, 1479w, 1227s, 908w, 740s. Ϫ 1H
˜
H), 3.36Ϫ3.42 (m, 1 H), 3.56Ϫ3.62 (m, 1 H), 3.71Ϫ3.78 (m, 2 H), NMR (CDCl3, 500 MHz): δ ϭ 1.10 (d, J ϭ 6.9, 3 H), 1.19 (t, J ϭ
5.32 (s, 1 H), 7.33Ϫ7.53 (m, 12 H), 7.57Ϫ7.63 (m, 2 H), 7.82 (d, 7.4, 3 H), 1.31 (d, J ϭ 6.9, 3 H), 2.56Ϫ2.73 (m, 2 H), 3.15 (sept,
J ϭ 8.3, 1 H), 7.85 (d, J ϭ 7.8, 1 H). Ϫ 13C NMR (CDCl3,
J ϭ 6.9, 1 H), 3.31 (t, J ϭ 7.1, 2 H), 3.75Ϫ3.83 (m, 2 H), 5.97 (s,
100 MHz): δ ϭ 62.1 (t), 70.5 (t), 77.9 (d), 123.5 (d), 125.0 (d), 125.1 1 H), 7.12Ϫ7.22 (m, 3 H), 7.23Ϫ7.32 (m, 4 H), 7.34Ϫ7.37 (m, 1
(d), 125.4 (d), 125.9 (d), 127.2 (d), 127.5 (d), 127.7 (d), 128.2 (d),
H). Ϫ 13C NMR: (CDCl3, 125 MHz): δ ϭ 2.3 (t), 14.8 (q), 23.6
128.3 (d), 128.6 (d), 129.1 (d), 130.2 (d), 131.2 (s), 133.8 (s), 136.3 (q), 24.3 (q), 25.2 (t), 28.5 (d), 70.7 (t), 77.3 (d), 125.62 (d), 125.65
(s), 137.8 (s), 141.0 (s), 142.3 (s). Ϫ MS (EI, 70 eV); m/z: 355 (12), (d), 125.8 (d), 127.71 (d), 127.77 (d), 127.9 (d), 128.2 (d), 128.6 (d),
(45) 354 [Mϩ·], 309 (12), 294 (6), 293 (14), 292 (49), 291 (27), 290 136.7 (s), 137.8 (s), 142.3 (s), 147.5 (s).
(9), 289 (12), 276 (5), 201 (7), 181 (27), 166 (16), 165 (100), 157 (6),
(2-Ethylphenyl)(2-isopropylphenyl)methanol (14): A mixture of 13
155 (6), 153 (6), 152 (6), 145 (10), 128 (7), 127 (8). Ϫ HR MS:
(450 mg, 1.10 mmol) and Zn (previously dried at 100 °C/0.4 Torr,
401 mg, 6.13 mmol) in dry DME (3.0 mL) was heated to reflux for
12 h. The suspension was filtered, the filtrate concentrated and the
residue purified by flash chromatography (SiO2; pentane/AcOEt,
4:1) to give 14 (273 mg, 98%) as a colorless oil. Ϫ [α]2D1 ϭ ϩ7.37
354.16245 (C25H22O2ϩ·; calcd. 354.16244).
2-[(1-Naphthyl)(2-trimethylsilanylphenyl)methoxy]ethanol (6s): Col-
orless oil. Ϫ [α]2D1 ϭ Ϫ33.8 (c ϭ 1.01, EtOH) for 31% ee (HPLC,
Chiracel OD-H, hexane/2-propanol, 9:1, 0.5 mL/min, T1 ϭ 10.1,
T2 ϭ 18.2 min). Ϫ IR (CHCl3): ν˜ ϭ 3682w, 3604w, 3032m, 2965w, (c ϭ 0.99, CHCl3) for 79% ee (HPLC, Chiracel OD-H, hexane/2-
2360w, 1623w, 1224s, 1054m, 839m, 791m. Ϫ 1H NMR (CDCl3, propanol, 9:1, 0.5 mL/min; T1 ϭ 9.9, T2 ϭ 11.3 min). Ϫ IR
˜
(CHCl3): ν ϭ 3597m, 2967s, 2361w, 1731w, 1602w, 1485m, 1450m,
500 MHz,): 0.13 (s, 9 H), 1.95 (s large, 1 H), 3.70Ϫ3.86 (m, 4 H),
1
6.43 (s, 1 H), 6.83 (d, J ϭ 7.3, 1 H), 7.28 (dd, J ϭ 7.9, 7.3, 1 H), 1230s, 1201s, 1006s. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.07 (d,
7.40 (ddd, J ϭ 8.9, 7.6, 1.3, 1 H), 7.51Ϫ7.56 (m, 2 H), 7.61Ϫ7.66 J ϭ 6.9, 3 H), 1.19 (t, J ϭ 7.6, 3 H), 1.30 (d, J ϭ 6.9, 3 H), 1.93
(m, 2 H), 7.70 (d, J ϭ 7.3, 1 H), 7.79 (d, J ϭ 8.2, 1 H), 7.90 (d, (s large, 1 H), 2.59Ϫ2.75 (m, 2 H), 3.23 (sept, J ϭ 6.9, 1 H), 6.38
J ϭ 7.9, 1 H), 8.19 (d, J ϭ 8.2, 1 H). Ϫ 13C NMR (CDCl3, (s, 1 H), 7.15Ϫ7.36 (m, 8 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ
125 MHz): δ ϭ 0.41 (q), 62.2 (t), 70.7 (t), 80.3 (d), 123.8 (d), 124.9
14.9 (q), 23.5 (q), 24.3 (q), 25.1 (t), 28.3 (d), 69.2 (d), 125.6 (d),
(d), 125.7 (d), 126.6 (d), 126.8 (d), 127.3 (d), 127.9 (d), 128.8 (d), 125.7 (d), 125.8 (d), 126.7 (d), 126.8 (d), 127.8 (d), 128.0 (d), 128.6
128.9 (d), 129.4 (d), 132.2 (s), 134.0 (s), 134.9 (s), 137.3 (s), 139.2 (d), 139.6 (s), 140.8 (s), 141.5 (s), 146.7 (s). Ϫ MS (EI, 70 eV); m/
(s), 144.7 (s). Ϫ MS (EI, 70 eV); m/z: 350 (10) [Mϩ·], 289 (12), 275 z: 253 (1) [Mϩ·], 236 (17), 225 (5), 222 (5), 221 (27), 211 (7), 208
(17), 218 (6), 217 (33), 216 (39), 215 (52), 201 (15), 177 (12), 129
(18), 207 (100), 194 (11), 193 (57), 192 (27), 182 (5), 179 (11), 178
(17), 119 (15), 75 (60), 73 (100), 45 (10). Ϫ HR MS 350.16926 (17), 165 (6), 149 (6), 148 (6), 147 (20), 135 (13), 134 (10), 133 (43),
(C22H26SiO2ϩ·; calcd. 350.17020).
131 (22), 129 (12), 119 (9), 117 (10), 116 (5), 115 (11), 106 (9), 105
(46), 103 (11), 91 (35), 89 (7), 79 (24), 78 (6), 77 (21), 65 (5), 51 (8).
Ϫ HR MS: 236.1574 (C18H20ϩ, calcd. 236.1565).
2-[(1-Naphthyl)(2,4,6-trimethylphenyl)methoxy]ethanol (6t): Color-
less oil, 15% ee (HPLC, Chiracel OD-H, hexane/2-propanol, 9:1,
˜
0.5 mL/min, T1 ϭ 10.7, T2 ϭ 15.7 min). Ϫ IR (CHCl3): ν ϭ 3689w,
(1R)-(2-Ethylphenyl)(2-isopropylphenyl)methyl (1S,4R)-4,7,7-Trime-
1
3610w, 2965w,1224m, 1208w, 795s, 753s, 733m, 717w cmϪ1. Ϫ H thyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (15): (Ϫ)-(1S)-
NMR (CDCl3, 400 MHz): δ ϭ 2.17 (s large, 1 H), 2.31 (s, 6 H), Camphanoyl chloride (222 mg, 1.02 mmol) was added at 0 °C to
Eur. J. Org. Chem. 2001, 4137Ϫ4147
4145

P. Müller, P. Nury, G. Bernardinelli
14 (200 mg, 0.79 mmol) in dry pyridine (6.0 mL). The mixture was 13C NMR (CDCl3, 125 MHz): δ ϭ 21.1 (q), 43.6 (q), 43.7 (q), 57.0
FULL PAPER
stirred at room temp. for 2 h, then 2  HCl (20 mL) was added,
followed by CH2Cl2 (40 mL). The organic layer was washed with
saturated NaHCO3 (20 mL) and H2O (20 mL) and then dried
(Na2SO4), and the solvents were evaporated. The residue was puri-
fied by flash chromatography (SiO2; pentane/AcOEt, 4:1) to afford
(t), 63.4 (t), 84.5 (d), 126.7 (d), 126.8 (d), 127.8 (d), 128.6 (d), 129.3
(d), 137.8 (s), 141.0 (s).
X-ray Crystallographic Study of 15: C28H34O4, Mr ϭ 434.6; µ ϭ
0.08mmϪ1, dX ϭ 1.147 g·cmϪ3, orthorhombic, P212121, Z ϭ 4, a ϭ
3
˚
˚
9.0595(4), b ϭ 13.7776(8), c ϭ 20.1637(13) A, V ϭ 2516.8(2) A ,
colorless prism 0.11 ϫ 0.16 ϫ 0.21 mm. Cell dimensions and in-
tensities were measured at 200 K with a Stoe IPDS diffractometer
15 (321 mg, 93%) as a colorless solid, m.p. 110Ϫ114°. Ϫ [α]2D1
ϭ
ϩ7.77 (c ϭ 1.03, CHCl3) for Ͼ 98% de (HPLC, Chiracel OD-H,
hexane/2-propanol, 9:1, 0.5 mL/min; T1 ϭ 9.2, T2 ϭ 9.9 min). Ϫ IR
(CHCl3): ν˜ ϭ 3021m, 2969m, 1784s, 1727s, 1450w, 1272w, 1226m,
1100m, 1058m, 929w. Ϫ 1H NMR (CDCl3, 500 MHz): δ ϭ 0.92 (s,
3 H), 1.04 (s, 3 H), 1.10 (s, 3 H), 1.10 (d, J ϭ 6.7, 3 H), 1.19 (t,
J ϭ 7.5, 3 H), 1.29 (d, J ϭ 6.7, 3 H), 1.66Ϫ1.73 (m, 1 H), 1.88Ϫ1.95
(m, 1 H), 2.03Ϫ2.12 (m, 1 H), 2.40Ϫ2.47 (m, 1 H), 2.55Ϫ2.72 (m,
2 H), 3.12 (sept, J ϭ 6.7, 1 H), 7.12Ϫ7.36 (m, 8 H), 7.56 (s, 1 H).
˚
with graphite-monochromated Mo-Kα radiation (λ ϭ 0.71069 A).
Ϫ11 Ͻ h Ͻ 11; Ϫ16 Ͻ k Ͻ 16; Ϫ24 Ͻ l Ͻ 24; 31768 measured
reflections, 4930 unique reflections of which 2435 were observables
(|Fo| Ͼ 4 σ (Fo)]. Full-matrix, least-squares refinement based on F
using weighting of 1/[σ2(Fo) ϩ 0.0003(F2o)] gave final values of R ϭ
0.039, wR ϭ 0.041, and S ϭ 1.90(4) for 289 variables and 2435
contributing reflections. The absolute configuration of the (Ϫ)-
camphor moiety being known, the Flack parameter was fixed to 0.
Hydrogen atoms were placed in calculated positions. The final ∆ρ
Ϫ
13C NMR (CDCl3, 125 MHz): δ ϭ 9.6 (q), 14.7 (q), 16.7 (q),
16.8 (q), 23.6 (q), 24.0 (q), 25.3 (t), 28.7 (d), 28.9 (t), 30.9 (t), 54.3
(s), 54.8 (s), 71.9 (d), 90.9 (s), 125.7 (d), 125.8 (d), 125.9 (d), 127.7
(d), 127.8 (d), 128.5 (d), 128.7 (d), 128.7 (d), 135.0 (s), 136.3 (s),
141.8 (s), 146.8 (s), 166.8 (s), 178.3 (s). Ϫ MS (EI, 70 eV); m/z: 434
(1) [Mϩ·], 392 (5), 391 (16), 237 (17), 236 (29), 222 (5), 221 (28),
209 (5), 208 (19), 207 (100), 195 (12), 194 (17), 193 (94), 192 (11),
179 (11), 178 (15), 165 (5), 132 (13), 131 (83), 130 (31), 129 (6), 119
(8), 118 (8), 117 (12), 116 (8), 115 (7), 91 (24), 83 (20), 77 (5), 55
(12). Ϫ HR MS: 434.24665 (C28H34O4ϩ·; calcd. 434.24570).
Ϫ3
˚
showed a maximum of ϩ0.20 and a minimum of Ϫ0.70 eA
.
Crystallographic data (excluding structure factors) for the structure
of 15 reported in this paper have been deposited at the Cambridge
Crystallographic Data Centre (deposition no. CCDC-160245).
Copies of the data can be obtained free of charge on application
to the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
(internat.) ϩ 44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
Synthesis of (S)-Neobenodine (17)
Acknowledgments
1-[(2-Iodoethoxy)(phenyl)methyl]-4-methylbenzene (16): This com-
pound was prepared as described for 13. Ϫ IR (CHCl3): ν ϭ
This work was supported by the Swiss National Science Founda-
tion (grants nos. 20-52581.97 and 2027-048156). The authors thank
Mrs. A. Pinto and J.-P. Saulnier for the NMR spectra, and Ms. D.
Klink for the mass spectra.
˜
3620m, 1580w, 1450w, 1213s, 880w, 760s. Ϫ 1H NMR (CDCl3,
500 MHz): δ ϭ 2.34 (s, 3 H), 3.32 (dd, J ϭ 6.6, 6.6, 2 H), 3.73 (dd,
J ϭ 6.6, 6.6, 2 H), 5.42 (s, 1 H), 7.16 (d, J ϭ 7.9, 2 H), 7.24Ϫ7.29
(m, 3 H), 7.32Ϫ7.40 (m, 4 H). Ϫ 13C NMR (CDCl3, 125 MHz):
δ ϭ 3.3 (t), 21.2 (q), 69.5 (t), 83.6 (d), 126.9 (d), 127.0 (d), 128.4
(d), 129.1 (d), 137.3 (s), 138.7 (s), 141.9 (s).
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(S)-Dimethyl{2-[(4-methylphenyl)(phenyl)methoxy]ethyl}amine (17):
The iodide 16 (280 mg, 0.79 mmol) was stirred in Me2NH (2.0 mL,
40% in H2O) and EtOH (5.0 mL) for 72 h at room temp. The solv-
ent was evaporated and 5% KOH (10 mL) was added. The mixture
was extracted with AcOEt (3 ϫ 50 mL) and washed with H2O (2
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1
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oil. Ϫ IR (CHCl3): ν ϭ 2905m, 1453w, 1224s, 1102m, 705w. Ϫ H
52, 7817Ϫ7832.
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NMR (CDCl3, 500 MHz): δ ϭ 2.32 (s, 9 H), 2.66 (dd, J ϭ 6.0, 6.0,
2 H), 3.59 (dd, J ϭ 6.0, 6.0, 2 H), 5.34 (s, 1 H), 7.16 (d, J ϭ 7.9, 2
H), 7.22Ϫ7.26 (m, 3 H), 7.29Ϫ7.36 (m, 4 H). Ϫ 13C NMR (CDCl3,
125 MHz): δ ϭ 21.1 (q), 45.8 (q), 58.8 (t), 67.1 (t), 83.9 (d), 126.8
(d), 126.9 (d), 127.2 (d), 128.3 (d), 129.0 (d), 137.0 (s), 139.1 (s),
142.3 (s). Ϫ MS (EI, 70 eV); m/z: 269 (1) [Mϩ], 165 (5), 73 (17), 59
(5), 58 (100), 45 (10). Ϫ HR MS: 269.1814 (C18H23ONϩ, calcd.
269.1780).
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´
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°C). Ϫ [α]2D0 ϭ Ϫ5.07 for 49% ee (c ϭ 2.07, EtOH) {ref.[59] [α]20
ϭ
1
ϩ13.0 for (R) isomer}. Ϫ H NMR (CDCl3, 500 MHz): δ ϭ 1.80
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3 H), 3.26Ϫ3.30 (m, 2 H), 3.90Ϫ3.93 (m, 3 H), 5.39 (s, 1 H), 7.14
(d, J ϭ 7.9, 2 H), 7.19 (d, J ϭ 7.9, 2 H), 7.24Ϫ7.35 (m, 5 H). Ϫ
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4146
Eur. J. Org. Chem. 2001, 4137Ϫ4147

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4147