Catalytic enantioselective reactions. Part 18: Preparation of 3-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-D-altritol derivatives from D-mannitol and their applications for catalytic enantioselective addition of dialkylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(00)00183-X

A series of new chiral β-aminoalcohols, 3-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-D-altritol derivatives 2-4 possessing a variety of amine substituents at the 3-position and thiol or acetylthio group at the 4-position was prepared from D-mannitol and enantioselective additions of diethylzinc to aldehydes using them as chiral catalysts were examined. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00183-X

Tetrahedron: Asymmetry 11 (2000) 2149±2157
1
Catalytic enantioselective reactions. Part 18: Preparation of
-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-d-
3
altritol derivatives from d-mannitol and their applications for
catalytic enantioselective addition of dialkylzinc to aldehydes
Byung Tae Cho,* Yu Sung Chun and Weon Ki Yang
Department of Chemistry, Hallym University, Chunchon 200-702, South Korea
Received 27 March 2000; accepted 8 May 2000
Abstract
A series of new chiral b-aminoalcohols, 3-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-d-
altritol derivatives 2±4 possessing a variety of amine substituents at the 3-position and thiol or acetylthio
group at the 4-position was prepared from d-mannitol and enantioselective additions of diethylzinc to
aldehydes using them as chiral catalysts were examined. # 2000 Elsevier Science Ltd. All rights reserved.
1
. Introduction
Enantioselective carbon±carbon bond formation is one of the most interesting challenges in
organic synthesis. In recent years the catalytic enantioselective addition of dialkylzinc to aldehydes
has attracted much attention because of its potential in the preparation of optically active sec-
2
ondary alcohols. Although several kinds of chiral alcohols, amines and aminoalcohols have been
developed as chiral catalysts for the enantioselective addition of dialkylzinc to aldehydes, it was
found that most of the successful results to exhibit high enantioselectivity were achieved by the
3
4
5
6
use of sterically constrained b-aminoalcohols, amino sulfur compounds, diamines and diols.
In the course of developing new chiral catalysts for the reaction from inexpensive chiral pool,
7
8
9
compounds such as a-d-xylose, a-d-glucose and l-tartaric acid, we found that 3-deoxy-3-N,N-
di-n-octylamino-1,2;5,6-di-O-isopropylidene-d-altritol 2b obtained from d-mannitol served as
highly e€ective chiral catalysts for the ethylation to both aromatic and unhindered aliphatic
aldehydes to a€ord high enantioselectivity. In order to gain a better understanding of the catalytic
e€ect and with the hope of developing improved chiral catalysts for the enantioselective alkylation
10
*
Corresponding author. E-mail: btcho@sun.hallym.ac.kr
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00183-X

2
150
B. T. Cho et al. / Tetrahedron: Asymmetry 11 (2000) 2149±2157
of aldehydes, we prepared a series of new 3-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-
d-altritol derivatives 2±4 possessing a variety of amine substituents at the 3-position and a thiol
or acetylthio group at the 4-position and compared their enantioselectivities as the catalysts for
such reactions. In this paper, we describe details of our preliminary reports and the scope and
limitations of these reactions.
2
. Results and discussion
2
.1. Synthesis of chiral ligands 2±4
In order to investigate their structure±selectivity relationships, we ®rst prepared a series of new
-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-d-altritols 2 in 42±54% yield by re¯uxing
-amino-3-deoxy-1,2;5,6-di-O-isopropylidene-d-altritol 1 with 2.2 mol equiv. of alkyl bromide
3
3
11
(or 1.1 mol equiv. of a,o-dibromoalkane) in the presence of excess potassium carbonate in acetonitrile.
Next, we synthesized the b-amino thioacetate 3 and thiol 4 from the corresponding b-amino-
alcohol 2b. Thus, 2b was treated with 1.2 mol equiv. of methanesulfonyl chloride in the presence
ꢀ
of 1.2 mol equiv. of triethylamine in dichloromethane at ^78 C. The resulting mesyloxy compound
was directly reacted with 3 mol equiv. of potassium thioacetate in water at room temperature to give
the corresponding thioacetate 3 with retention of con®guration in 62% yield.4a Subsequent
treatment of 3 with lithium aluminum hydride provided the b-amino thiol 4 in a 65% yield
(Scheme 1).
Scheme 1.
2
.2. E€ect of the structure of the chiral catalysts 2±4
To examine e€ect of the structure of the chiral catalysts 2±4 on asymmetric induction, we
compared the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal

B. T. Cho et al. / Tetrahedron: Asymmetry 11 (2000) 2149±2157
2151
chosen as a representative aromatic and aliphatic aldehyde, respectively. Thus, the reaction was
carried out by addition of 2 mol equiv. of diethylzinc in toluene to the aldehydes in the presence
ꢀ
of 0.1 mol equiv. of the catalyst at 0 C. As shown in Table 1, all the reactions except the cases
with 3 and 4 proceeded smoothly to give the corresponding alcohols in good yields. The reaction
ꢀ
with 3 was very slow even at 25 C, although the one with 4 provided good yields at the same
temperature. With respect to enantioselectivity, the catalyst 2b a€orded the best results to give
9
2% ee and 85% ee for benzaldehyde and heptanal, respectively (entry 2). Catalyst 4 substituted
with a thiol group instead of hydroxy group of 2b gave somewhat lower enantioselectivity compared
to those obtained with 2b (entry 9). The corresponding thioacetate 3 provided low enantio-
selectivity (entry 8).
Table 1
Enantioselective addition of diethylzinc to benzaldehyde and heptanal using various chiral
ligands (2±4) as catalysta
On the other hand, to examine e€ect of temperature on enantioselectivity, we carried out the
ꢀ
same reaction using 2b as the catalyst at 25 and ^20 C. In both cases, we observed lower
enantioselectivity than those obtained at 0 C, although the reason is unclear (entries 3±4).
ꢀ
2
.3. Enantioselective addition of dialkylzinc to some other aldehydes
Based on the results in Table 1, we carried out the catalytic enantioselective addition of diethyl-
ꢀ
zinc to other aldehydes using 0.1 mol equiv. of 2b as the catalyst at 0 C. As shown in Table 2, it was
found that the catalyst was highly e€ective for the ethylation of relatively unhindered aliphatic

2
152
B. T. Cho et al. / Tetrahedron: Asymmetry 11 (2000) 2149±2157
aldehydes, such as butanal, hexanal, undecanal and 3-phenylpropanal, leading to the corre-
sponding alcohol with enantiomeric excesses in the range of 82±94% ee (entries 1±4). The reaction
for a hindered aliphatic aldehyde, 2,2-dimethylpropanal, does not occur even at room temperature,
although the same reaction for 3-methylbutanal and cyclohexanecarboxaldehyde proceeded
smoothly to give the product alcohol with high enantioselectivity (entries 5±7). In the case of the
a,b-unsaturated aldehyde, (E)-cinnamaldehyde, the reaction proceeded more slowly to produce
the desired alcohol with low enantioselectivity (entry 8). However, the catalyst a€orded high
enantioselectivities (88±91% ee) for all the aromatic aldehydes examined. In this reaction, it is
observed that the steric e€ect of the o-substituent of the aromatic ring on asymmetric induction is
not signi®cant (entries 9 vs 10; 12 vs 13). We also tested the same reaction for heterocyclic aldehydes.
In all the cases examined, the reaction proceeded much more rapidly to produce the corresponding
alcohols in good yields, although it a€orded low enantioselectivity (entries 14±16).
Table 2
Catalytic enantioselective addition of dialkylzinc to aldehydes in the presence of 10 mol% of 2b
a

B. T. Cho et al. / Tetrahedron: Asymmetry 11 (2000) 2149±2157
2153
On the other hand, the catalytic enantioselective additions using dimethylzinc and diisopropylzinc
instead of diethylzinc were compared under the same reaction conditions for benzaldehyde and
heptanal. In both cases, the reaction with diisopropylzinc proceeded much more rapidly to provide
the desired alcohols with high enantioselectivities (92% ee) compared to those obtained with
diethylzinc (entries 18 and 20). In contrast, the addition of dimethylzinc proceeded much more
slowly to give the product alcohol in low yields with low enantioselectivities, although the reaction
was carried out even with 5 mol equiv. of dimethylzinc at room temperature (entries 17 and 19).
The absolute con®gurations of all the product alcohols obtained are consistently enriched in the
R enantiomers. The stereochemical course of the enantioselective addition can be explained by
0
0
the proposed mechanism involving six-membered cyclic transition state 5, in which R in R Zn is
2
0
12
transferred to aldehydes on the re side to produce (R)-alcohols in the case of R>R (Scheme 2).
Scheme 2.
3
. Conclusions
We have established enantioselective additions of diethylzinc to aldehydes using new chiral
b-aminoalcohols, 3-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-d-altritol derivatives
±4 possessing a variety of amine substituents at the 3-position and thiol or acetylthio group at
the 4-position prepared from d-mannitol as chiral catalysts. Of the catalysts examined, 3-deoxy-
-N,N-di-n-octylamino-1,2;5,6-di-O-isopropylidene-d-altritol 2b provides the best results to give
2
3
high enantioselectivities for aromatic and relative unhindered aliphatic aldehydes. The reaction
with diisopropylzinc under the same reaction condition proceeded much more rapidly to give the
product alcohols with high enantioselectivities, whereas the case with dimethylzinc proceeded
much more slowly to give the product alcohols with low enantioselectivities.
4
. Experimental
4
.1. General
All operations with air-sensitive materials were carried out under a nitrogen atmosphere with
oven-dried glassware. Liquid materials were transferred with a double-ended needle. The reactions
were monitored by TLC using silica gel plates and the products were puri®ed by ¯ash column
chromatography on silica gel (Merck; 230±400 mesh). NMR spectra were recorded at 400 MHz
1
13
for H and 100 MHz for C using Me Si as the internal standard in CDCl . J-Values are given in
4
3

2
154
B. T. Cho et al. / Tetrahedron: Asymmetry 11 (2000) 2149±2157
hertz. Optical rotations were measured with a high resolution digital polarimeter. Melting points
were uncorrected. Enantiomeric excesses (% ees) of the product alcohols were determined by
1
3
capillary GLC analyses of their (R)-MTPA esters [a-methoxy-a-[tri¯uoromethyl]phenylacetates]
14
TM
or (^)-menthyl carbonates with a 25 m Spelcowax column or a 50 m methylsilicon column or by
capillary GLC analyses using a 20 m Chiraldex G-TA, B-PH and b-Dex 120 chiral column or by a
HPLC analysis using a 25 cm Chiralcel OD.
4
.2. Materials
Most of the organic compounds utilized in this study were commercial products of the highest
purity. They were further puri®ed by distillation when necessary. Toluene was distilled over sodium
and stored in an ampoule under nitrogen atmosphere. Diethylzinc, dimethylzinc, (R)-MTPA
chloride and (^)-menthyl carbonyl chloride were purchased from Aldrich Chemical Company.
Diisopropylzinc was prepared according to the literature procedure.15
4
.3. Preparation of 3-deoxy-3-N,N-dialkylamino-1,2;5,6-di-O-isopropylidene-d-altritols (2)
4
.3.1. General method
11
A mixture of 3-amino-3-deoxy-1,2;5,6-di-O-isopropylidene-d-altritol (5 mmol), alkyl bromide
11 mmol) or a,o-alkyl dibromide (5.5 mmol), sodium iodide (15 mmol) and anhydrous potassium
(
carbonate (15 mmol) in acetonitrile (25 ml) was heated to re¯ux for 24 h. After a usual work-up, the
products obtained was further puri®ed by ¯ash chromatography on silica gel using appropriate
eluents.
4
.3.2. 3-Deoxy-3-N,N-di-n-butylamino-1,2;5,6-di-O-isopropylidene-d-altritol 2a
Yield: 48%; R 0.52 (EtOAc:Hex=1:4); oil (found: C, 63.33; H, 10.34; N, 3.75. C H NO
20 39
^1
f
5
2
D
0
requires: C, 64.34; H, 10.52; N, 3.75%); ‰ꢀŠ =+37.65 (c 1.12, CHCl ); ꢁ
(®lm)/cm 3484,
3
max
1
2
7
2
3
1
985, 2869, 1460, 1378, 1254, 1214, 1162, 1057, 857; H NMR (400 MHz, CDCl ) ꢂ 0.91 (6H, t, J
3
.2, 2ÂCH ), 1.25±1.48 (8H, m, 4ÂCH ), 1.34 (3H, s, CH ), 1.36 (3H, s, CH ), 1.40 (6H, s,
3
2
3
3
ÂCH ), 2.58±2.65 (2H, m, N-CH ), 2.72±2.81 (3H, m, 3-H and N-CH ), 3.33 (1H, br s, OH),
3
2
2
.48 (1H, t, J 6.2, 1-H ), 3.74 (1H, t, J 7.7, 6-H ), 3.84±3.90 (1H, m, 4-H), 4.08±4.14 (3H, m, 5-H,
a
a
13
and 6-H ), 4.54±4.60 (1H, m, 2-H); C NMR (100 MHz, CDCl ) ꢂ 109.60 (CMe ), 108.78
b
3
2
(
CMe ), 76.61 (5-C), 76.26 (2-C), 71.32 (1-C), 68.51 (6-C), 67.68 (4-C), 65.49 (3-C), 53.17 (N-CH ),
2
2
3
2.28 (N-CH CH ), 27.10, 26.81, 25.94 and 25.49 [4Â(CH ) C], 20.93 (CH ), 14.52 (CH ).
2
2
3 2
2
3
4
.3.3. 3-Deoxy-3-N,N-di-n-octylamino-1,2;5,6-di-O-isopropylidene-d-altritol 2b
Yield: 46%; R 0.58 (EtOAc:Hex=1:4); oil (found: C, 69.11; H, 11.59; N, 2.64. C H NO
5
f
28 55
20
^1
requires: C, 69.23; H, 11.41; N, 2.88%); ‰ꢀŠ =+41.4 (c 1.13, CHCl ); ꢁ
(®lm)/cm 3482, 2985,
max
D
3
1
2
2
2
859, 1466, 1378, 1255, 1214, 1160, 1056, 857; H NMR (400 MHz, CDCl ) ꢂ 0.88 (6H, t, J 7.0,
3
ÂCH ), 1.26±1.48 (24H, m, 12ÂCH ), 1.34 (3H, s, CH ), 1.36 (3H, s, CH ), 1.40 (6H, s, 2ÂCH ),
3
2
3
3
3
.56±2.63 (2H, m, N-CH ), 2.71±2.80 (3H, m, 3-H and N-CH ), 3.30 (1H, br s, OH), 3.48 (1H, t,
2
2
J 6.0, 1-H ), 3.73 (1H, t, J 7.8, 6-H ), 3.84±3.89 (1H, m, 4-H), 4.09±4.14 (3H, m, 5-H, 1-H and
b
a
a
1
3
6
7
-H ), 4.53±4.59 (1H, m, 2-H); C NMR (100 MHz, CDCl ) ꢂ 109.22 (CMe ), 108.41 (CMe ),
b 3 2 2
6.23 (5-C), 75.89 (2-C), 70.93 (1-C), 68.14 (6-C), 67.31 (4-C), 65.15 (3-C), 53.05 (N-CH ), 31.86
2
(
(
N-CH CH ), 29.69, 29.63, 29.37 and 27.42 [4Â(CH ) C], 26.74, 26.45, 25.58, 25.10 and 22.67
2
2
3 2
5ÂCH ), 14.11 (CH ).
2 3

B. T. Cho et al. / Tetrahedron: Asymmetry 11 (2000) 2149±2157
2155
4
.3.4. 3-Deoxy-3-(1-pyrrolidinyl)-1,2;5,6-di-O-isopropylidene-d-altritol 2c
Yield: 42%; R 0.36 (EtOAc:Hex=1:1); oil (found: C, 61.00; H, 9.21; N, 4.71. C H NO
16 29
f
5
20
^1
requires: C, 60.93; H, 9.28; N, 4.44%); ‰ꢀŠ =+20.3 (c 1.18, CHCl ); ꢁ
(®lm)/cm 3438, 2941,
D
3
max
1
1
1
(
455, 1370, 1253, 1215, 1158, 1115, 1061, 856; H NMR (400 MHz, CDCl ) ꢂ 1.35 (3H, s, CH ),
3 3
.36 (3H, s, CH ), 1.39 (3H, s, CH ), 1.41 (3H, s, CH ), 1.64±1.75 (4H, m, 2ÂCH ), 2.91±2.95
3
3
3
2
4H, m, 2ÂN-CH ), 3.01±3.11 (2H, m, 3-H and OH), 3.47 (1H, t, J 5.6, 1-H ), 3.80 (1H, t, J 7.8,
2
a
6
-H ), 3.89±3.93 (1H, m, 4-H), 4.07±4.14 (3H, m, 5-H, 1-H and 6-H ), 4.52±4.58 (1H, m, 2-H).
a b b
1
3
C NMR (100 MHz, CDCl ) ꢂ 108.61 (CMe ), 107.65 (CMe ), 73.51 (5-C), 72.12 (4-C), 67.67 (1-
3
2
2
and 6-C), 64.32 (4-C), 62.14 (3-C), 51.27 (N-CH ), 26.68, 25.91, 25.45 and 24.81 [4Â(CH ) C],
2
3 2
2
3.29 and 22.62 (2ÂCH ).
2
4
.3.5. 3-Deoxy-3-(1-piperidinyl)-1,2;5,6-di-O-isopropylidene-d-altritol 2d
Yield: 48%; R 0.48 (EtOAc:Hex=1:2); oil (found: C, 61.78; H, 9.68; N, 4.24. C H NO
5
f
17 31
20
^1
requires: C, 61.98; H, 9.48; N, 4.25%); ‰ꢀŠ =+23.25 (c 1.5, CHCl ); ꢁ
(®lm)/cm 3474, 2990,
D
1
3
max
1
442, 1380, 1251, 1217, 1160, 1058, 855; H NMR (400 MHz, CDCl ) ꢂ 1.35 (3H, s, CH ), 1.37
3 3
(
3H, s, CH ), 1.39 (3H, s, CH ), 1.41 (3H, s, CH ), 1.43±1.52 (6H, m, 3ÂCH ), 2.51±2.53 (1H, m,
3
3
3
2
3
3
4
7
2
-H), 2.66±2.67 (2H, m, N-CH ), 2.89 (2H, m, N-CH ), 3.35 (1H, br s, OH), 3.54 (1H, t, J 5.7, 1-H ),
2 2 a
.75 (1H, t, J 7.8, 6-H ), 3.85±3.90 (1H, m, 4-H), 4.08±4.11 (3H, m, 5-H, 1-H and 6-H ), 4.49±
b
a
b
.55 (1H, m, 2-H); 13C NMR (100 MHz, CDCl ) ꢂ 108.31 (CMe ), 107.53 (CMe ), 75.12 (5-C),
4.34 (4-C), 69.59 (1 and 6-C), 66.87 (4-C), 66.14 (3-C), 51.97 (N-CH ), 25.81, 25.41 and
3
2
2
2
4.81[(CH ) C], 24.29 and 23.26 (CH ).
3
2
2
4
.3.6. 3-(1-Azepino)-3-deoxy-1,2;5,6-di-O-isopropylidene-d-altritol 2e
Yield: 54%; R 0.42 (EtOAc:Hex=1:2); oil (found: C, 62.76; H, 9.78; N, 4.05. C H NO
18 33
f
5
20
^1
requires: C, 62.95; H, 9.68; N, 4.08%); ‰ꢀŠ =+36.4 (c 1.11, CHCl ); ꢁ
(®lm)/cm 3483, 2990,
D
3
max
1
2
2
882, 1452, 1381, 1252, 1216, 1157, 1068, 855; H NMR (400 MHz, CDCl ) ꢂ 1.36 (6H, s,
3
ÂCH ), 1.40 (6H, s, 2ÂCH ), 1.50±1.80 (8H, m, 4ÂCH ), 2.60 (1H, t, J 8.0, 3-H), 2.73±2.79 (2H,
3
3
2
m, N-CH ), 2.99±3.02 (2H, m, N-CH ), 3.58 (1H, t, J 6.7, 1-H ), 3.73 (1H, t, J 7.9, 6-H ), 3.88
a
2
2
a
(
1H, t, J 7.7, 4-H), 4.09±4.14 (2H, m, 1- and 6-H ), 4.18±4.25 (1H, m, 5-H), 4.48±4.53 (1H, m, 2-H);
b
1
3
C NMR (100 MHz, CDCl ) ꢂ 110.22 (CMe ), 108.70 (CMe ), 75.12 (5-C), 74.0 (2-C), 70.0 (1-C),
3
2
2
6
8.49 (6-C), 68.24 (3-C), 67.42 (4-C), 66.49 (N-CH ), 65.46 (N-CH ), 26.93, 26.82 and 26.46
2 2
(CH ), 25.47, 25.40, 25.18 and 24.48 [(CH ) C].
2 3 2
4
.4. 3-Deoxy-3-N,N-di-n-octylamino-1,2;5,6-di-O-isopropylidene-d-acetylthioaltritol 3
To a mixture of 2b (2 mmol) and triethylamine (2.4 mmol) in dichloromethane (10 ml) was
ꢀ
added slowly methanesulfonyl chloride (2.4 mmol) in dichloromethane (2 ml) at ^78 C. The
ꢀ
reaction mixture was stirred for 2 h at ^78 C and then warmed up to room temperature. After
solvent was evaporated in vacuo, the residue was treated with potassium thioacetate (6 mmol) in
water (2 ml) for 18 h at room temperature. The mixture was extracted with dichloromethane
(
3Â10 ml). The extract was dried over anhydrous magnesium sulfate. After evaporation of sol-
vent, the residue was puri®ed by ¯ash column chromatography on silica gel to give the product 3;
yield: 62%; R 0.47 (EtOAc:Hex=1:9); oil (found: C, 66.21; H, 10.59; N, 2.64; S, 5.79.
f
2
0
C H NO S requires: C, 66.25; H, 10.56; N, 2.58; S, 5.90%; ‰ꢀŠ =+44.6 (c 1.13, CHCl ); ꢁ
3
0
57
5
1
D
3
max
®lm)/cm^ 2987, 2858, 1693, 1466, 1378, 1255, 1216, 1157, 1064, 860; H NMR (400 MHz,
1
(
CDCl ) ꢂ 0.88 (6H, t, J 7.0, 2ÂCH ), 1.26±1.48 (24H, m, 12ÂCH ), 1.34 (3H, s, CH ), 1.36 (3H, s,
3
3
2
3

2
156
B. T. Cho et al. / Tetrahedron: Asymmetry 11 (2000) 2149±2157
CH ), 1.40 (6H, s, 2ÂCH ), 2.56±2.63 (2H, m, N-CH ), 2.71±2.80 (3H, m, 3-H and N-CH ), 3.30
3
3
2
2
(
4
1H, br s, OH), 3.48 (1H, t, J 6.0, 1-H ), 3.73 (1H, t, J 7.8, 6-H ), 3.84±3.89 (1H, m, 4-H), 4.09±
a a
.14 (3H, m, 5-H, 1 and 6-H ), 4.53±4.59 (1H, m, 2-H); C NMR (100 MHz, CDCl ) ꢂ 194.80
b 3
13
(COCH ), 109.99 (CMe ), 108.75 (CMe ), 76.31 (2-C), 75.11 (5-C), 69.09 (6-C), 68.27 (1-C), 67.31
3 2 2
(3-C), 52.91 (N-CH ), 49.37 (4-C), 31.91 (N-CH CH ), 30.61 (COCH ), 29.75, 29.55, 29.43 and
2 2 2 3
2
7.48 [(CH ) C], 26.74, 26.46, 25.84, 25.78, 25.62 and 22.67 (CH ), 14.12 (CH ).
3 2 2 3
4
.5. 3-Deoxy-3-N,N-di-n-octylamino-1,2;5,6-di-O-isopropylidene-d-thioaltritol 4
To a suspension of lithium aluminum hydride (2 mmol) in dry ether (5 ml) was dropped a
solution of 3 (1 mmol) in dry ether (3 ml). The reaction mixture was heated to re¯ux for 18 h.
After a usual work-up, the residue was puri®ed by ¯ash column chromatography on silica gel to
ꢀ
a€ord the product 4; yield: 65%; R 0.38 (EtOAc:Hex=1:9); mp 59±60 C (found: C, 67.21; H,
f
2
D
0
1
1.19; N, 2.74; S, 6.51. C H NO S requires: C, 67.02; H, 11.05; N, 2.79; S, 6.39%); ‰ꢀŠ =+56.0
1 1
3 max
28
55
4
(c 1.01, CHCl ); ꢁ
(KBr)/cm^ 2984, 2855, 1465, 1378, 1217, 1214, 1060, 860; H NMR (400
MHz, CDCl ) ꢂ 0.88 (6H, t, J 6.6, 2ÂCH ), 1.24±1.50 (24H, m, 12ÂCH ), 1.35 (3H, s, CH ), 1.36
3
3
2
3
(3H, s, CH ), 1.40 (3H, s, CH ), 1.41 (3H, s, CH ), 2.60±2.66 (2H, m, N-CH ), 2.71±2.79 (3H, m,
H-4 and N-CH ), 3.08 (1H, dd, J 8.7 and 3.65, H-3), 3.65 (1H, t, J 7.7, 1-H ), 3.81 (1H, t, J 8.0, 6-H ),
3 3 3 2
2
a
a
13
4
.03±4.09 (1H, m, 5-H), 4.13±4.17 (2H, m, 1- and 6-H ), 4.62±4.67 (1H, m, 2-H); C NMR (100
b
MHz, CDCl ) ꢂ 109.40 (CMe ), 108.86 (CMe ), 76.21 (5-C), 76.03 (2-C), 69.21 (1-C), 68.30 (6-C),
3
2
2
6
7.94 (4-C), 61.69 (3-C), 53.41 (N-CH ), 31.88 (N-CH CH ), 29.75, 29.67, 29.45 and 27.54
2 2 2
[
(CH ) C], 26.84, 26.58, 25.79, 25.75 and 22.68 (CH ), 14.12 (CH ).
3 2 2 3
4
.6. Catalytic enantioselective addition of dialkylzinc to aldehydes
The following procedure is representative. Under a nitrogen atmosphere, a toluene solution (2 ml)
ꢀ
of diethylzinc (2 mmol) was added to 2b (0.1 mmol) in toluene (1 ml) and stirred at 0 C for 30
min. After undecanal (1 mmol) was added to this, the mixture was stirred at the same temperature
for 12 h and then diluted with ether (10 ml). The excess diethylzinc was destroyed by addition of
1N HCl and the reaction mixture was extracted with ether (3Â10 ml). The ether extract was dried
over anhydrous magnesium sulfate and concentrated in vacuo. The product alcohols was puri®ed
by ¯ash column chromatography on silica gel to give 3-tridecanol; 92% yield; R 0.43 (EtOAc:
f
Hex=1:9); oil. Enantiomeric excess of the product alcohol was measured by capillary GC analysis
of tri¯uoroacetate of the product alcohols using a Chiraldex B-PH capillary column. GLC analysis
showed a composition of 97 (R) and 3 (S) (i.e. 94% ee, R) (Table 2).
Acknowledgements
This study was supported by the Basic Science Research Institute Program (BSRI 98-015-
D00168), Korea Research Foundation, Korea.
References
1. Part 17: Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1999, 10, 1843.
2. For reviews, see: (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833 and references cited therein; (b) Noyori, R.;
Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49; (c) Modern Synthetic Methods; Sche€old, R., Ed.;

B. T. Cho et al. / Tetrahedron: Asymmetry 11 (2000) 2149±2157
2157
Springer-Verlag: Berlin, 1989; pp. 115±198; (d) Knochel, P. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; pp. 211±229.
Â
. (a) Lawrence, C. F.; Nayak, S. K.; Thijs, L.; Zwanenburg, B. Synlett 1999, 1571. (b) Reddy, K. S.; Sola, L.;
3
4
Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem. 1999, 64, 3969.
Á
. (a) Kang, J.; Kim, J. W.; Lee, J. W.; Kim, D. S.; Kim, J. I. Bull. Korean Chem. Soc. 1996, 17, 1135; (b) Anderson,
J. C.; Cubbon, R.; Harding, M.; James, D. S. Tetrahedron: Asymmetry 1998, 9, 3461; (c) Hof, R. P.; Poelert, M. A.;
Peper, N. C. M. W.; Kellog, R. M. Tetrahedron: Asymmetry 1994, 5, 31; (d) Rejnberg, E.; Hovestad, N. J.; Kleij,
A. W.; Jasterzebski, J. T. B. H.; Boersma, J.; Janssen, M. D.; Spek, A. L.; van Koten, G. Organometallics 1997, 16,
2
847; (e) Jin, M.-J.; Ahn, S.-J.; Lee, K.-S. Tetrahedron Lett. 1996, 37, 8767.
5
6
. Asami, M.; Watanabe, H.; Honda, K.; Inoue, S. Tetrahedron: Asymmetry 1998, 9, 4169.
. (a) Ding, K.; Ishii, A.; Mikami, K. Angew. Chem., Int. Ed. Engl. 1999, 38, 497. (b) Huang, W.-S.; Hu, Q.-S.; Pu, L.
J. Org. Chem. 1998, 63, 1364.
7
8
9
. Cho, B. T.; Kim, N. J. Chem. Soc., Perkin Trans. 1 1996, 2901.
. Cho, B. T.; Kim, N. Synth. Commun. 1996, 26, 855.
. Cho, B. T.; Kim, N. Synth. Commun. 1996, 26, 2273.
10. Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1998, 9, 1489.
11. (a) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655; (b) Baker, B. R.; Haines, A. H. J. Org. Chem.
1
963, 28, 442.
1
1
2. Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5237.
3. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543; MTPA=a-methoxy-a-(tri¯uoromethyl)-
phenylacetic acid.
1
1
4. Westley, J. W.; Halpern, B. J. Org. Chem. 1968, 33, 3978.
5. Rathke, M. W.; Yu, H. J. Org. Chem. 1972, 37, 1732.