Enantioselective addition of diethylzinc to aldehydes catalyzed by fluorous β-aminoalcohols

Article abstract of DOI:10.1016/S0040-4020(01)00483-5

A fluorous aminoalcohol prepared from ephedrine has been used as a catalyst for the enantioselective addition of diethylzinc to aldehydes to afford the corresponding alcohols in up to 84% ee. The fluorous amino alcohol was easily recovered by a simple fil

Full text of DOI:10.1016/S0040-4020(01)00483-5

TETRAHEDRON
Pergamon
Tetrahedron 57 >2001) 5565±5571
Enantioselective addition of diethylzinc to aldehydes catalyzed
by ¯uorous b-aminoalcohols
p
Yutaka Nakamura, Seiji Takeuchi, Kazuo Okumura and Yoshiaki Ohgo
p
Niigata College of Pharmacy, 5-13-2 Kamishin'ei cho, Niigata 950-2081, Japan
Received 16 March 2001;accepted 7 May 2001
AbstractÐA ¯uorous aminoalcohol prepared from ephedrine has been used as a catalyst for the enantioselective addition of diethylzinc to
aldehydes to afford the corresponding alcohols in up to 84% ee. The ¯uorous amino alcohol was easily recovered by a simple ®ltration
through a ¯uorous reverse phase silica gel and was reusable without puri®cation. q 2001 Elsevier Science Ltd. All rights reserved.
1
. Introduction
enantioselective addition of diethylzinc to aldehydes.
We chose the reaction for a catalyst-recycling system to
examine usefulness of the ¯uorous chiral ligands,
5
a,d,f
The recovery and reuse of chiral ligands or catalysts is an
important topic in asymmetric reactions. Thus, the study of
chiral polymer catalysts has attracted extensive attention in
recent years. These catalysts have intrinsic advantages in
that they can be separated from the products by simple
because the reaction brought about a high percentage ee
and yield by a simple procedure and with the use of
commercially available reagents. In addition, we can eval-
uate the ¯uorous chiral ligand by comparing the ¯uorous
ligand system to the catalyst-recycling system using a
polymer-supported chiral b-aminoalcohol which has
®
ltration and reused without loss of catalytic activity or
enantioselectivity. Several asymmetric reactions using
chiral polymer catalysts have been reported in the litera-
ture.
2
e,i±o
already been established by Soai and other researchers.
1
,2
2
. Results and discussion
On the other hand, compounds that have long per¯uorinated
carbon chains are `¯uorous' and are easily separable from
organic compounds by a simple liquid±liquid or solid±
2
.1. Synthesis of ¯uorous chiral b-aminoalcohols
3
liquid extraction techniques. Nowadays an increasing
Curran and co-workers have reported the synthesis and
application of a ¯uorous benzyl protecting reagent 4,
which attaches the readily available tris>per¯uorohexyl-
ethyl)silyl group as a ¯uorous label to p-position of benzyl
bromide. However, the silicon±aryl bond of this ¯uorous
tag is somewhat unstable toward several reaction con-
ditions. Therefore, we have attempted to synthesize a new
number of academic and industrial researchers are working
on the design of ligands containing per¯uoroalkyl groups
and their application to catalysis. To our knowledge,
4
however, only a few reports have been published on asym-
metric reactions using ¯uorous reagents or catalysts. Very
6
5
recently, we have reported the enantioselective protonation
reaction of a samarium enolate prepared from reductive
cleavage of 2-methoxy-2-phenylcyclohexanone with SmI2,
¯uorous benzyl protecting reagent in which the ¯uorous
alkyl group is attached to benzene ring through carbon±
in the presence of ¯uorous C -symmetric chiral diol as a
2
carbon single bond 3.
proton source in THF. The proton source was easily
recovered by liquid±liquid extraction with per¯uoro-
hexanes >FC-72) or solid phase extraction with ¯uorous
reverse phase silica gel >FRP silica gel) and was reusable
without puri®cation.5c
The synthesis of the new ¯uorous benzyl protecting reagent
3 is outlined in Scheme 1. Reaction of the Grignard reagent
prepared from commercially available per¯uoroalkyl iodide
and magnesium powder with dimethyl carbonate in Et O
2
provided tert-alcohol 1 in 40% yield after recrystallization
from CHCl . Friedel±Crafts alkylation of toluene with the
In this paper, we wish to report the synthesis of new ¯uorous
chiral b-aminoalcohols and their application to the catalytic
3
alcohol 1 in the presence of excess tri¯uoromethanesulfonic
acid under re¯ux to yield the corresponding ¯uorous toluene
in 93% yield. The product contained mainly p-substituted
isomer 2a and a small amount of a regioisomer 2b >presum-
ably m-isomer). Since the isomers were not separated by a
Keywords: addition reactions;amino alcohols;asymmetric reactions;¯uor-
ine and compounds;per¯uoroalkyl compounds.
Corresponding authors. Tel.: 181-25-269-3170;fax: 181-25-268-1230;
e-mail: nakamura@niigata-pharm.ac.jp;takeuchi@niigata-pharm.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020>01)00483-5

5566
Y. Nakamura et al. / Tetrahedron 57 )2001ꢀ 5565±5571
Scheme 1.
Scheme 2.
silica gel column chromatography, the mixture was bromi-
nated with N-bromosuccinimide in the presence of AIBN in
we used the mixture as the tag precursor to prepare ¯uouous
b-aminoalcohols.
CCl at 808C to provide the corresponding benzyl bromide 3
4
in 73% yield. In the product, about 20% of the minor regio-
isomer 3b was detected in the H NMR spectra together with
the major p-isomer 3a. Since it was again unsuccessful to
separate the isomers by a silica gel column chromatography,
N-Benzylation of >1R,2S)-ephedrine or >1R,2S)-norephe-
drine with the benzyl bromide mixture >3a and 3b) in the
presence of potassium carbonate in THF at 70±808C
provided ¯uorous chiral b-aminoalcohols I and III in
1
1
moderate yield after column chromatography. In the H
NMR spectra of these products, there was no peak due to
the minor regioisomer of the ¯uorous benzyl group. The
corresponding products containing the minor regioisomer
were not isolated in each case. Therefore, it is considered
that the m-isomer 3b is unreactive under the reaction con-
ditions probably because of a large steric hindrance due to
the long ¯uorous alkyl chains at the m-position. Fluorous
aminoalcohol II was also synthesized from >1R,2S)-ephe-
drine and Curran's ¯uorous benzyl bromide 4 by the same
manner >Scheme 2).
Table 1. Partition coef®cients of ¯uorous aminoalcohol >I)±>III) in organic
solvent and FC-72
Amino alcohol
Organic solvent
Organic solvent/FC-72
I
CH
3
CN
Toluene
12/88
41/59
62/38
CH
2
3
Cl
2
II
CH
CN
18/82
52/48
75/25
Toluene
CH Cl
2
2
III
CH CN
Toluene
CH Cl
3
3/97
3/97
6/94
The approximate partition coef®cients of I±III were deter-
mined by a simple method described in the footnote of
Table 1, and the results are summarized in Table 1. The
aminoalcohol III is a ¯uorous compound and ef®ciently
extracted to FC-72 phase. However, the mono benzylated
aminoalcohols I and II are `less ¯uorous' than the bis
benzylated aminoalcohol III.
2
2
A mixture of 100 mg of >I)±>III) in FC-72 >2 mL) and organic solvent
2 mL) was stirred at room temperature for 10 min. Then the two phases
>
were separated and the solvents were evaporated in vacuo. The contents of
the ¯uorous compound in each phase were determined by weighing the
residue.

Y. Nakamura et al. / Tetrahedron 57 )2001ꢀ 5565±5571
5567
Table 2. The enantioselective addition of diethylzinc to benzaldehyde catalyzed by the ¯uorous aminoalcohols
a
b
c
Entry
Catalyst
Solvent
Reaction temp.
Reaction time >h)
Yield >%)
% ee
Con®g.
1
2
3
4
5
6
7
I
I
I
I
I
II
III
Hexane
rt
rt
rt
08C
08C
rt
18
20
20
20
20
20
20
93
90
87
78
62
91
54
75
83
83
78
85
83
25
R>1)
R>1)
R>1)
R>1)
R>1)
R>1)
R>1)
Toluene/hexane >2:1 v/v)
Toluene
Hexane
Toluene/hexane >2:1 v/v)
Toluene/hexane >2:1 v/v)
BTF/hexane >2:1 v/v)
rt
a
Isolated yield.
Determined by HPLC analysis using DAICEL CHIRALCEL OD-H.
Determined by comparison of speci®c rotation with literature value.
b
c
2.2. Enantioselective addition of diethylzinc to aldehydes
catalyzed by ¯uorous aminoalcohols
When the reactions were performed at 08C, the enantio-
selectivities were slightly increased compared to those at
room temperature. However, the reactions at 08C were
very slow to give the product alcohol in lower yield after
20 h >entries 1 vs 4 and entries 2 vs 5). The aminoalcohol
II was also effective catalyst for the reaction and the
enantioselectivity of product alcohol reached to 83% ee
>entry 6). Since the aminoalcohol III was insoluble in
toluene, the reaction was carried out in benzotri¯uoride
To ®nd the optimal reaction conditions, we initially
examined the enantioselective addition of diethylzinc to
benzaldehyde catalyzed by the aminoalcohols I±III under
various conditions. All of the reactions are carried out in the
presence of 10 mol% of the catalyst and 2 equiv. of diethyl-
zinc. The results are summarized in Table 2.
>
BTF). The drastic decreases of the enantiomeric excess
As seen from Table 2, when I was used as a catalyst, the
reactions proceeded smoothly at room temperature, and
>R)-1-phenyl-1-propanol was obtained in high enantiomeric
excesses >entries 1±3).
and chemical yield of the product alcohol were observed
>entry 7). This behavior can be explained by a large steric
hindrance around the amino group. Because of the bulki-
ness of the two ¯uorous substituents in III, complexation
of the nitrogen atom with zinc atom may be seriously
inhibited.
Table 3. Enantioselective addition of diethylzinc to aldehydes catalyzed by
¯
uorous aminoalcohol
In these reactions, the product and ¯uorous ligands were
simply and cleanly separated with FRP silica gel by washing
successively with acetonitrile and FC-72. The product alco-
hol from acetonitrile eluate was puri®ed by preparative TLC
and the ¯uorous ligands were recovered from the FC-72
eluate almost quantitatively and in pure form.
a
b
c
Entry
R
Yield >%)
% ee
Con®g.
1
2
3
4
5
6
7
8
9
Ph
90
95
92
93
93
87
95
97
75
83
78
81
83
R>1)
R>1)d
R>1)
R>1)
R>1)
R>1)
R>1)
R>1)
R>2)
Next, several other aldehydes were examined under the
optimal reaction conditions using I and the results were
summarized in Table 3. As seen from the table, I was
generally effective to aromatic aldehydes >entries 1±7).
However, o-substituted benzaldehydes underwent addition
reaction with somewhat lower enantioselectivities com-
pared to their m- and p-analogues >entries 2 vs 3 or 4 and
entries 6 vs 7). In the cases of trans-cinnamaldehyde and
3-phenylpropanal, the reaction provided low enantio-
selectivities of the products >entries 8 and 9).
2-MeO±C
3-MeO±C
4-MeO±C
4-Cl±C
1-Naphthyl
2-Naphthyl
6
6
6
H
H
H
±
4
4
4
±
±
±
e
6
H
4
84
77
82
f
>E)-PhCHvCH
PhCH CH
2
±
70
70
2
2
±
a
Isolated yield.
b
c
d
Determined by HPLC analysis using DAICEL CHIRALCEL OD-H.
Determined by comparison of speci®c rotation with literature value.
Determined by comparison of retention time of HPLC with literature
Finally, we tried to reuse the recovered ¯uorous b-amino-
alcohol I for the next reaction without further puri®cation.
The results for 10 consecutive experiments were summar-
ized in Table 4.
data.
e
f
Determined by capillary GC analysis using SUPELCO b-DEX 120 chiral
column.
Determined by HPLC analysis using DAICEL CHIRALCEL OJ.

5568
Y. Nakamura et al. / Tetrahedron 57 )2001ꢀ 5565±5571
Table 4. Enantioselective addition of diethylzinc to benzaldehyde reusing the recovered catalyst without puri®cation
a
b
c
Run
Yield
% ee
Recovered catalyst >%)
1
2
3
4
5
6
7
8
9
85
90
90
89
88
89
90
91
90
91
82
82
82
83
83
83
84
84
84
84
99
100
98
97
95
98
97
97
97
97
1
0
a
b
c
Isolated yield.
Determined by HPLC analysis using DAICEL CHIRALCEL OD-H.
Separation of organic and ¯uorous compounds by solid-phase extraction with FRP silica gel.
As seen from Table 4, the enantioselectivities and yields did
not change throughout the experiments. Therefore, the
3.2. Synthesis of ¯uorous benzyl bromide
¯uorous b-aminoalcohol is recyclable for the reaction by
the simple ®ltration through FRP silica gel.
3.2.1. Tris$3,3,4,4,5,5,6,6,7,7,8,8,8-trideca¯uorooctyl)-
methanol 1. To the Grignard reagent prepared from
1,1,1,2,2,3,3,4,4,5,5,6,6-trideca¯uoro-8-iodooctane >15.0 g,
In conclusion, we have synthesized a series of ¯uorous
aminoalcohols which bear a novel per¯uoroalkylated benzyl
group at amino group of ephedrine or norphedrine.
Aminoalcohols I and II were effective catalysts for the
enantioselective addition of diethylzinc to aldehydes. More-
over, the ¯uorous ligands were easily recovered by solid±
liquid extraction using FRP silica gel and were reusable
without puri®cation.
31.7 mmol) and magnesium powder >984 mg, 40.5 mmol)
in ether >25 mL) was added dimethylcarbonate >570 mg,
6.33 mmol). After re¯uxing for 2 h, the reaction mixture
was stirred for 12 h at room temperature. The reaction
mixture was quenched with saturated NH Cl aqueous
4
solution >20 mL), and then extracted with Et O
2
>20 mL£3). The combined organic layer was washed with
brine >30 mL), dried over anhydrous MgSO , and evapo-
4
rated in vacuo. The residue was puri®ed on a silica gel
column >hexane/EtOAcˆ20:1) to afford alcohol 1 as a
white solid >2.69 g, 40% yield): colorless prisms from
3. Experimental
CHCl , mp 56±578C;IR >KBr) 3510, 2992, 1370, 1240,
3
2
188, 1142, 702 cm ; H NMR d 1.26 >s, 1H, ±OH),
1
1
1
1.75±1.90 >m, 6H, ±CH C±), 2.05±2.15 >m, 6H,
3
.1. General
2
±
CF CH ±);MS >EI)
2
m/z >relative intensity) 1050
2
1
1
The melting point was determined by Yanagimoto micro-
melting point apparatus and was uncorrected. The IR
spectra were recorded on a Perkin±Elmer 1720-X FT-IR
>M 2HF, 28), 1010 >75), 724 >M 1H±CH
100), 673 >34), 375 >97), 327 >52), 77 >30);Anal. Calcd
39O: C, 28.05;H, 1.22;F, 69.23. Found C,
27.76;H, 1.33;F, 69.38.
CH C F ,
2 2 6 13
for C25H F
13
1
spectrometer. The H NMR spectra were obtained on a
JEOL JNM-A400 spectrometer in CDCl with tetramethyl-
3
silane as an internal standard. The optical rotations were
measured with a Perkin±Elmer 241 polarimeter. HPLC
analysis was performed with Hitachi L-7100 ¯ow system
and L-7400 UV detector or JASCO CD-1595 CD detector
using DAICEL CHIRALCEL OD-H or OJ column. GC
analysis was carried out on Shimadzu GC-18APFsc gas
chromatograph with SUPELCO b-DEXe capillary column.
Preparative TLC was run on Wakogel B-5F and column
chromatography was performed using Wakogel C-300.
Hexane and toluene were distilled from sodium. Benzotori-
3.2.2. 3- and 4-[Tris$3,3,4,4,5,5,6,6,7,7,8,8,8-trideca-
¯uorooctyl)methyl]toluene 2. A mixture of alcohol 1
>500 mg, 0.93 mmol) and tri¯uoromethanesulfonic acid
>0.72 g, 6.6 mmol) in toluene >5 mL) was stirred at 1208C
for 15 h. After addition of Et
washed with saturated NaHCO
>20 mL£3). The organic layer was dried over anhydrous
MgSO , and concentrated in vacuo. The crude product
O >30 mL), the solution was
2
aqueous solution
3
4
was passed through a silica gel column >hexane) to afford
¯uorous toluene 2 as a colorless oil >495 mg, 93% yield).
The product contained approximately 85% of p-isomer 2a
¯
¯
uoride was distilled from phosphorous pentoxide. The
uorous reverse phase silica gel was prepared by Curran's
1
and 15% of m-isomer 2b >determined by H NMR): IR
>KBr) 3033, 2963, 1515, 1240, 1147, 1122, 848, 813, 732,
7
method.

Y. Nakamura et al. / Tetrahedron 57 )2001ꢀ 5565±5571
5569
21 1
08, 700, 655, 533 cm ; H NMR for the major isomer 2a:
7
d 1.70±1.95 >m, 6H, ±CH C±), 1.95±2.10 >m, 6H,
¯uorooctyl)silyl]benzyl bromide 4 >355 mg, 0.286 mmol)
and >1R,2S)-ephedrine >47.3 mg, 0.286 mmol) were used.
Puri®cation of the crude product on a silica gel column
2
±
CF CH ±), 2.36 >s, 3H, Ar±CH ), 7.15 >d, 2H, Ar±H,
2 2 3
Jˆ8.0 Hz), 7.21 >d, 2H, Ar±H, Jˆ8.0 Hz);the minor isomer
>hexane/Et Oˆ4:1) yielded ephedrine II as a colorless
2
2
5
2
b: 2.39 >s, Ar±CH );MS >EI) m/z >relative intensity) 1144
3
syrup >280 mg, 74% yield): [a] ˆ23.388 >c 1.04, BTF),
D
1
M , 6), 1013 >M 2CF CF , 1), 797 >M 2CH CH C F ),
1
1
25
[a]578 ˆ23.388 >c 1.04, BTF), [a]
25
>
ˆ23.978 >c 1.04,
2
3
2
2
6
13
546
2
5
25
437 >16), 169 >20), 119 >25), 69 >59);Anal. Calcd for
C H F : C, 33.58;H, 1.67. Found C, 33.84;H, 1.78.
BTF), [a]
ˆ27.348 >c 1.04, BTF), [a]
ˆ212.98 >c
4
36
365
1.04, BTF);IR >KBr) 3426, 3069, 3029, 2977, 2977, 2945,
801, 1443, 1426, 1363, 1317, 1240, 1144, 1121, 1069,
1019, 899, 845, 812, 737, 707, 651, 531 cm ; H NMR d
3
2
19 39
2
2
1 1
3.2.3. 3- and 4-[Tris$3,3,4,4,5,5,6,6,7,7,8,8,8-trideca¯u-
orooctyl)methyl]benzyl bromide 3. A mixture of toluene
1.03 >d, 3H, ±C±CH , Jˆ6.7 Hz), 1.10±1.26 >m, 7H, ±
3
2
0
>300 mg, 0.262 mmol), N-bromosuccinimide >47.0 mg,
.262 mmol) and AIBN >4.3 mg, 0.026 mmol) in CCl4
CH Si± and ±OH), 1.95±2.10 >m, 6H, ±CF CH ±), 2.21
2
2
2
>s, 3H, N±CH ), 2.93 >dq, 1H, N±CH±, Jˆ5.1 and
3
>
®
3 mL) was re¯uxed for 1 h. The insoluble material was
ltered off and the ®ltrate was concentrated in vacuo to
give a syrup, which was puri®ed on a silica gel column
hexane) to afford the ¯uorous benzyl bromide 3 as a color-
6.7 Hz), 3.63 >s, 2H, Ar±CH ±), 4.88 >d, 1H, O±CH±,
2
Jˆ5.1 Hz), 7.12±7.36 >m, 9H, Ar±H);MS >EI) m/z >relative
1
1
intensity) 1323 >M , 1), 1305 >M 2H O, 2), 1216 >100),
2
>
169 >13), 105 >17), 69 >37);Anal. Calcd for C H F NOSi:
4
1
32 39
less syrup >235 mg, 73% yield). The product contained
approximately 20% and 80% of m- and p-isomers, respec-
C, 37.20;H, 2.44;N, 1.06. Found C, 37.11;H, 2.36;N, 1.17.
1
tively >determined by H NMR): IR >KBr) 3037, 2964,
3.3.3. $1R,2S)-N,N-bis[4-Tris$3,3,4,4,5,5,6,6,7,7,8,8,8-tri-
deca¯uorooctyl)methyl]benzylnorephedrine III. A sus-
pension of the benzyl bromide mixture 3 >405 mg, 0.331
mmol), >1R,2S)-norephedrine >25.0 mg, 0.165 mmol) and
potassium carbonate >91 mg, 0.66 mmol) in THF >2 mL)
was stirred vigorously at 70±808C for 24 h. The suspension
was ®ltered through a celite, the ®ltrate was concentrated in
vacuo. The residue was puri®ed on a silica gel column
1
8
475, 1366, 1351, 1319, 1240, 1146, 1058, 1010, 846,
13, 731, 708, 652, 618, 566, 532 cm ; H NMR for the
2
1 1
major isomer 3a: d 1.75±1.95 >m, 6H, ±CH C±), 1.95±2.10
2
>
m, 6H, ±CF CH ±), 4.495 >s, 2H, ±CH Br), 7.27 >d, 2H,
2 2 2
Ar±H, Jˆ8.1 Hz), 7.45 >d, 2H, Ar±H, Jˆ8.1 Hz);the minor
isomer 3b: 4.504 >s, ±CH Br);MS >EI) m/z >relative
2
1
intensity) 1123 >M 1H, 12), 1144 >M 1H± Br, 100),
1
79
1
75 >M 2CH CH C F , 27), 796 >35), 463 >18), 169
8
>hexane/Et Oˆ10:1) to afford the ¯uorous norephedrine
2
2
6
13
2
>
29), 119 >35), 69 >87);Anal. Calcd for C 32H BrF : C,
19
III as a colorless viscous syrup >223 mg, 55% yield):
ˆ211.48 >c 1.00,
39
2
5
25
3
1.42;H, 1.48. Found C, 30.95;H, 1.25.
[a]D ˆ211.18 >c 1.00, BTF), [a]
578
2
5
25
BTF), [a]
.00, BTF), [a]
365
064, 3033, 2964, 2830, 1474, 1366, 1142, 1061, 1009, 847,
13, 731, 707, 655, 566, 533 cm ; H NMR d 1.20 >d, 3H,
ˆ213.28 >c 1.00, BTF), [a]
ˆ224.68 >c
5
46
436
2
5
1
3
8
ˆ244.28 >c 1.00, BTF);IR >KBr) 3420,
3
3
.3. Synthesis of ¯uorous amino alcohols
2
1 1
.3.1. $1R,2S)-N-[4-Tris$3,3,4,4,5,5,6,6,7,7,8,8,8-trideca-
uorooctyl)methyl]benzylephedrine I. A suspension of
the benzyl bromide mixture 3 >500 mg, 0.409 mmol),
1R,2S)-ephedrine >67.5 mg, 0.409 mmol) and potassium
C±CH , Jˆ6.7 Hz), 1.70±2.10 >m, 25H, ±CF CH CH ±
¯
3
2
2
2
and ±OH), 3.00 >dq, 1H, N±CH±, Jˆ6.1 and 6.7 Hz),
3
.51 >d, 1H, one proton of Ar±CH ±, Jˆ14.2 Hz), 3.70
>
2
>
1
d, 1H, another proton of Ar±CH ±, Jˆ14.2 Hz), 4.77 >d,
carbonate >113 mg, 0.818 mmol) in THF >3 mL) was stirred
vigorously at 70±808C for 8 h. The suspension was ®ltered
through a celite, the ®ltrate was concentrated in vacuo. The
residue was puri®ed on a silica gel column >hexane/
2
H, O±CH±, Jˆ6.1 Hz), 7.11±7.26 >m, 13H, Ar±H);MS
1
EI) m/z >relative intensity) 2417 >M 2H O, 1), 2399 >3),
>
2
2312 >100), 797 >15), 77 >14);Anal. Calcd for
C H F NO: C, 35.99;H, 1.94;N, 0.57. Found C, 35.39;
H, 1.90;N, 0.84.
Et Oˆ10:1 then 4:1) to afford the ¯uorous ephedrine I as
73 47 78
2
2
5
a colorless syrup >351 mg, 66% yield): [a] ˆ24.018 >c
D
2
5
25
1
2
[
3
1
1
.12, BTF), [a]578 ˆ24.018 >c 1.12, BTF), [a]
ˆ
546
2
5
4.458 >c 1.12, BTF), [a]
ˆ27.938 >c 1.12, BTF),
3.4. Typical procedure for the enantioselective addition
of diethylzinc to aldehydes catalyzed by ¯uorous
ephedrines
4
36
2
5
a]365 ˆ213.18 >c 1.12, BTF);IR >KBr) 3426, 3065,
032, 2965, 2800, 1474, 1455, 1366, 1350, 1319, 1240,
055, 1009, 812, 731, 702, 655, 532 cm ; H NMR d
2
1
1
.02 >d, 3H, ±C±CH , Jˆ6.8 Hz), 1.70±1.90 >m, 7H,
To a solution of ¯uorous ephedrine I >65.4 mg, 0.050 mmol)
and benzaldehyde >53.0 mg, 0.50 mmol) in toluene >2 mL)
3
±
CH C±, and ±OH), 1.90±2.10 >m, 6H, ±CF CH ±), 2.19
2
2
2
>
3
1
s, 3H, N±CH ), 2.92 >dq, 1H, N±CH±, Jˆ4.9 and 6.8 Hz),
was added 1 M Et Zn hexane solution >1.0 mL, 1.0 mmol)
2
under argon at 08C. After stirring for 20 h at room tempera-
ture, the reaction mixture was quenched with saturated
3
.59 >d, 1H, one proton of Ar±CH ±, Jˆ13.8 Hz), 3.64 >d,
2
H, another proton of Ar±CH ±, Jˆ13.8 Hz), 4.89 >d, 1H,
2
O±CH±, Jˆ4.9 Hz), 7.18±7.33 >m, 9H, Ar±H);MS >EI)
NH
>15 mL£4). The combined organic layer was washed with
brine >15 mL), dried over anhydrous MgSO and concen-
trated in vacuo. The residue was dissolved in Et O >2 mL).
4
Cl aqueous solution >6 mL) and extracted with Et O
2
1
1
m/z >relative intensity) 1307 >M , 1), 1289 >M 2H O, 2),
2
1200 >100), 106 >22), 77 >20);Anal. Calcd for
C H F NO: C, 38.58;H, 2.47;N, 1.07. Found C, 38.30;
H, 2.40;N, 1.23.
4
4
2
32 39
2
To the solution was added >1H,1H,2H,2H)-per¯uorooctyl)-
dimethylsilyl bound silica gel >1 g), then the solvent was
evaporated to dryness. The powder obtained was loaded
on a column of >1H,1H,2H,2H)-per¯uorooctyl)dimethyl-
silyl bound silica gel >5 g) and then eluted successively
with acetonitrile >15 mL) and FC-72 >25 mL). The
3
¯
.3.2. $1R,2S)-N-[4-Tris$3,3,4,4,5,5,6,6,7,7,8,8,8-trideca-
uorooctyl)silyl]benzylephedrine II. Fluorous ephedrine
II was prepared according to the procedure described
above except that 4-[tris>3,3,4,4,5,5,6,6,7,7,8,8,8-trideca-

5570
Y. Nakamura et al. / Tetrahedron 57 )2001ꢀ 5565±5571
1
8
acetonitrile fraction was evaporated in vacuo, and puri®ed
by preparative TLC >hexane/EtOAcˆ4:1) to give 1-phenyl-
3.4.6. 1-$2-Naphthyl)-1-propanol. [a]D ˆ117.48 >c
0.448, benzene) for the product of 82% ee. >lit. [a] ˆ
D
9
1228 >c 3, benzene) for the >R)-enantiomer, 83% ee ).
1
-propanol >61.4 mg, 90% yield) in 83% ee as colorless oil.
1
6
[
CHCl ) for the >S)-enantiomer, 98% ee ). The absolute
a]D ˆ139.78 >c 0.456, CHCl ) >lit. [a] ˆ247.68 >c 6.11,
The absolute con®guration was determined to be R by
comparison of its optical rotation with the reported one.
The ee was determined by HPLC analysis using chiral
column >DAICEL CHIRALCEL OD-H, hexane/2-propa-
3
D
8
3
con®guration was determined to be R by comparison of its
optical rotation with the reported one. The enantioselec-
tivity was determined by HPLC analysis using DAICEL
CHIRALCEL OD-H >hexane/2-propanolˆ98:2, ¯ow rate
nolˆ95:5, ¯ow rateˆ 1.0 mL/min): t ˆ17.8 min for
R
>S)-enantiomer and t ˆ 20.4 min for >R)-enantiomer.
R
ˆ
1.0 mL/min). Fluorous aminoalcohol I was recovered
almost quantitatively from FC-72 fraction without a loss
of optical purity.
1
D
8
3.4.7. 1-Phenylpent-1-en-3-ol. [a] ˆ14.98 >c 0.45,
CHCl ) for the product of 70% ee. >lit. [a] ˆ26.68 >c
.18, CHCl ) for the >S)-enantiomer, 75% ee ). The
2
3
3
D
1
1
3
3
1
5
3
>
[
.4.1. 1-$2-Methoxyphenyl)-1-propanol. [a]D ˆ144.68
absolute con®guration was determined to be R by compar-
ison of its optical rotation with the reported one. The ee was
determined by HPLC analysis using chiral column
>DAICEL CHIRALCEL OJ, hexane/2-propanolˆ98:2,
c 0.451, toluene) for the product of 78% ee >lit.
a] ˆ127.38 >c 2, toluene) for the >R)-enantiomer, 62%
D
9
ee ). The absolute con®guration was determined to be R
by comparison of its optical rotation with the reported
one. The enantiomeric excess >ee) was determined by
HPLC analysis using chiral column >DAICEL CHIRAL-
CEL OD-H, hexane/2-propanolˆ100:1, ¯ow rateˆ0.5 mL/
min): t ˆ38.5 min for >S)-enantiomer and t ˆ40.6 min for
¯ow rateˆ1.0 mL/min): t ˆ24.5 min for >S)-enantiomer
R
and t
ˆ27.3 min for >R)-enantiomer.
R
1
8
3.4.8. 1-Phenyl-3-pentanol. [a]
ˆ217.78 >c 0.327,
D
D
2
2
EtOH) for the product of 70% ee. >lit. [a]
ˆ123.98 >c
1.44, CHCl ) for the >S)-enantiomer, 90% ee ). The absolute
3
R
R
8
>
R)-enantiomer.
con®guration was determined to be R by comparison of its
optical rotation with the reported one. HPLC analysis using
chiral column >DAICEL CHIRALCEL OD-H, hexane/
1
5
3
.4.2. 1-$3-Methoxyphenyl)-1-propanol. [a]D ˆ123.38
>c 0.498, benzene) for the product of 81% ee. The absolute
con®guration was determined to be R by comparison of its
retention time of chiral HPLC with the reported one . The
ee was determined by HPLC analysis using chiral column
2-propanolˆ98:2, ¯ow rateˆ1.0 mL/min): t
ˆ23.8 min
R
1
0
for >R)-enantiomer and t
ˆ42.7 min for >S)-enantiomer.
R
>
¯
DAICEL CHIRALCEL OD-H, hexane/2-propanolˆ98:2,
ow rateˆ1.0 mL/min): t ˆ27.2 min for >R)-enantiomer
Acknowledgements
R
and t ˆ32.2 min for >S)-enantiomer.
R
The authors are grateful to Professor Dennis P. Curran,
University of Pittsburgh, for his helpful advice on this
work. They also wish to express their thanks to Professor
Akira Kato, Niigata College of Pharmacy, for the measure-
ments of MS spectra, and to the Laboratory for Organic
Elemental Microanalysis, Faculty of Pharmaceutical
Sciences, Kyoto University, for the elemental analysis.
This work was partially supported by Grant-in-Aid for
Scienti®c Research from the Ministry of Education,
Science, Sports and Culture, Japan.
1
5
3
>
2
.4.3. 1-$4-Methoxyphenyl)-1-propanol. [a]D ˆ128.58
c 0.534, benzene) for the product of 83% ee >lit. [a] ˆ
D
8
32.18 >c 1.25, benzene) for the >S)-enantiomer, 93% ee ).
The absolute con®guration was determined to be R by
comparison of its optical rotation with the reported one.
The ee was determined by HPLC analysis using chiral
column >DAICEL CHIRALCEL OD-H, hexane/2-propa-
nolˆ98:2, ¯ow rateˆ1.0 mL/min): t ˆ24.0 min for
R
>
R)-enantiomer and t ˆ27.5 min for >S)-enantiomer.
R
2
0
3
>
[
.4.4. 1-$4-Chlorophenyl)-1-propanol. [a]D ˆ119.88
c 0.479, benzene) for the product of 82% ee >lit.
a] ˆ223.58 >c 0.82, benzene) for the >S)-enantiomer,
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>