Highly enantioselective addition of dialkylzincs to aldehydes using dendritic chiral catalysts with flexible carbosilane backbones

Article abstract of DOI:10.1016/S0957-4166(02)00203-3

Chiral dendrimers bearing four or twelve chiral β-amino alcohols on the hyperbranched flexible carbosilane chain-ends act as efficient chiral catalysts for the enantioselective addition of dialkylzinc to aldehydes to afford enantiomerically enriched sec-alcohols with up to 93% e.e.

Full text of DOI:10.1016/S0957-4166(02)00203-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 805–808
Highly enantioselective addition of dialkylzincs to aldehydes
using dendritic chiral catalysts with flexible carbosilane
backbones
Itaru Sato, Ryo Kodaka, Kenji Hosoi and Kenso Soai*
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601,
Japan
Received 2 April 2002; accepted 25 April 2002
Abstract—Chiral dendrimers bearing four or twelve chiral b-amino alcohols on the hyperbranched flexible carbosilane chain-ends
act as efficient chiral catalysts for the enantioselective addition of dialkylzinc to aldehydes to afford enantiomerically enriched
sec-alcohols with up to 93% e.e. © 2002 Elsevier Science Ltd. All rights reserved.
Dendrimers, orderly hyperbranched macromolecules,
are defined as polymers with a particular molecular
weight and molecular architecture. Synthetic applica-
tions of functionalized dendrimers are of current inter-
est.1 All of the dendritic branches are capable of adding
chiral functionalities to their chain-ends, and the result-
ing chiral dendrimers work as dendritic chiral ligands in
asymmetric synthesis.2,3 Every chiral site at the periph-
ery would work effectively with approximately the same
effect and efficiency. It would therefore have superior
characteristics to other polymer-bound chiral ligands.4
We have recently found that those dendrimers that
possess several chiral amino alcohols on the rigidly
constructed poly(phenylethyne) framework act as effec-
tive chiral catalysts and ligands in the enantioselective
addition of dialkylzincs to aldehydes and N-
diphenylphosphinylimines, respectively.5,6 On these chi-
ral dendrimers, each catalytic site is designed to be
carbosilane skeletons are free from coordination of
organometallics; (2) interaction between chiral sites is
possible because of the flexible structure. The syntheses
of ephedrine moieties 7a, 7b and chiral dimer 1 are
shown in Scheme 1. After the amino group of (1R,2S)-
ephedrine 5 was reacted with 4-bromobenzyl bromide
4, the alcohol was protected as its tert-butyldimethyl-
silyl (TBDMS) ether to give 7a (99%) or as its
trimethylsilyl (TMS) ether to give 7b (98%). Addition of
2
mol. equiv. of lithiated 7a to the 1,6-
di(chlorodimethylsilyl)ethane, followed by cleavage of
the silyl ether using tetrabutylammonium fluoride,
resulted in chiral dimer 1. Similarly, chiral dendrimers 2
and 3 were synthesized by using tetra(chlorosilane) 8 or
dodeca(chlorosilane) 10, which were prepared accord-
ing to the procedure of van der Made and van Leeuwen
(Scheme 2).7c Treatment of tetra(chlorosilane) 8 with
4.0 mol. equiv. of lithiated 7a gave 9 in 90% yield.
Cleavage of the four silyl ether of 9 afforded the desired
dendrimer 2. The functionalization of dodeca(chlorosi-
lane) 10 with 12 ephedrine moieties was conducted by
using the TMS ether of (1R,2S)-N-(4-bromoben-
zyl)ephedrine 7b. Addition of lithiated 7b and conse-
quent cleavage of the TMS ether on silica gel produced
chiral dendrimer 3 with twelve ephedrine moieties in
located at
a
separate position and to work
independently.
Here we report the synthesis of chiral dimer 1 as well as
of dendrimers 2 and 3 (Fig. 1), bearing two, four and
twelve chiral b-amino alcohols, respectively, on the
flexible carbosilane chain-ends,7 and their effective
application to the enantioselective addition of dialkyl-
zincs to aldehydes. Rationalities of the design are: (1)
1
45% yield. The H and 13C NMR spectra and MALDI-
TOF MS analysis clearly show the structure of 3.
Enantioselective addition of dialkylzincs to aldehydes8
was examined in the presence of a catalytic amount of
* Corresponding author.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00203-3

806
I. Sato et al. / Tetrahedron: Asymmetry 13 (2002) 805–808
Figure 1.
manner to give the (R)-alcohol 12f with 93% e.e. (entry
6). The higher generation chiral dendrimer was also
found to serve as an effective chiral catalyst.9 Addition
of i-Pr2Zn to 11a using 1.7 mol% of chiral dendrimer 3
afforded alcohol 12b with 83% e.e. (entry 7). The
reaction with the recovered catalyst gave alcohol 12b
with 85% e.e. (entry 8). An increase in the amount of
catalyst 3 (5 mol%) gave 12b with a similar 86% e.e.
(entry 9). Enantioselective addition to 2-naphthalde-
hyde 11b and 1-naphthaldehyde 11c in the presence of
3 proceeded to give corresponding alcohols with 84 and
87% e.e., respectively (entries 10 and 11). Finally, enan-
tioselective addition of i-Pr2Zn to 3-phenylpropanal 11e
using chiral dendrimer 3 gave 12f with 93% e.e. (entry
13).
Scheme 1. Reagents and conditions: (i) 4 (1.0 mol. equiv.),
K2CO3, CH3CN, reflux, 87%; (ii) t-BuMe2SiCl, imidazole,
DMF, 99%; (iii) Me3SiCl, Et3N, THF, 98%; (iv) 7a (2.0 mol.
equiv.), BuLi, THF, −100°C, 65%; (v) Bu4NF, THF, rt, 83%.
In conclusion, chiral dendrimers bearing four or twelve
b-amino alcohols on the carbosilane chain-ends work
as efficient chiral catalysts for the enantioselective addi-
tion of dialkylzincs to aldehydes. Flexibility of the
skeleton of the dendritic chiral catalyst enables the high
enantioselectivity. These results constitute the guide-
lines for designing of dendritic chiral catalyst in
organometallic chemistry.
chiral dimer 1 or dendrimers 2 or 3 (Table 1). When
chiral dendrimer 2 (5 mol%) was used as the chiral
catalyst, addition of diethylzinc (Et2Zn) to benzalde-
hyde 11a gave (R)-1-phenylpropanol 12a with 82% e.e.
in 80% yield (Table 1, entry 1). Enantioselective addi-
tion of diisopropylzinc (i-Pr2Zn) was also catalyzed by
chiral dendrimer 2 to give (R)-2-methyl-1-phenyl-
propanol 12b with 82% e.e. (entry 2). 2-Naphthalde-
hyde 11b and 1-naphthaldehyde 11c were converted to
the corresponding sec-alcohols in 88 and 86% e.e.,
respectively (entries 3 and 4). Addition to 3-phenyl-
propanal 11f proceeded in a highly enantioselective
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan and by Japan
Space Forum.

I. Sato et al. / Tetrahedron: Asymmetry 13 (2002) 805–808
807
i
N
SiCl4
Si
SiMe2Cl
4
OR
Si
Si
8
4
9 (R=TBDMS)
2 (R=H)
ii
iii
N
Si
Si
SiMe2Cl
3 4
OH
10
Si
Si
Si
3
4
3
Scheme 2. Reagents and conditions: (i) 7a (4.0 mol. equiv.), BuLi, −100°C, 90% based on 8; (ii) Bu4NF, THF, 21%; (iii) 7b (24
mol. equiv.), BuLi, −100°C to rt; SiO2, CH2Cl2, two steps 45% based on 10.
Table 1. Highly enantioselective addition of dialkylzincs to aldehydes using chiral dendrimers 2, 3 or chiral dimer 1
chiral catalyst
1, 2 and 3
R1
R2
R
R22Zn
R1CHO
+
(R2=i-Pr, Et)
OH
12a (R2=Et)
toluene
11
12b-f (R2=i-Pr)
Aldehyde 11
Chiral catalyst (mol%)
(R)-Alcohol 12
Entrya
R1
R2
Yield (%)b
E.e. (%)c
1
2
3
4
5
6
Phenyl
Phenyl
11a
11a
11b
11c
11d
11e
11a
11a
11a
11b
11c
11d
11e
11a
11a
11c
2 (5.0)
2 (5.0)
2 (5.0)
2 (5.0)
2 (5.0)
2 (5.0)
3 (1.7)
3 (1.7)
3 (5.0)
3 (1.7)
3 (1.7)
3 (1.7)
3 (1.7)
1 (5.0)
1 (5.0)
1 (5.0)
Et
12a
12b
12c
12d
12e
12f
12b
12b
12b
12c
12d
12e
12f
12a
12b
12d
80
80
75
42
80
56
83
79
84
77
42
79
55
80
77
42
82
82
88
86
85
93
83
85
86
84
87
83
93
74
79
88
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
2-Naphthyl
1-Naphthyl
4-CH3OC6H4
PhCH2CH2
Phenyl
7
8d
9
Phenyl
Phenyl
10
11
12
13
14
15
16
2-Naphthyl
1-Naphthyl
4-CH3OC6H4
PhCH2CH2
Phenyl
Phenyl
1-Naphthyl
i-Pr
i-Pr
a Reactions were run in toluene for 48 h at 0°C using 2.2 molar equiv. of dialkylzinc.
b Isolated yields.
c Determined by HPLC analysis using a chiral stationary phase. For the absolute configuration, see Ref. 10.
d Recovered catalyst was used.
2. Asymmetric synthesis using chiral dendritic ligand: (a)
Seebach, D.; Marti, R. E.; Hintermann, T. Helv. Chim.
Acta 1996, 79, 1710–1740; (b) Peerlings, H. W. I.; Meijer,
E. W. Chem. Eur. J. 1997, 3, 1563–1570; (c) Ko¨llner, C.;
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Togni, A. Can. J. Chem. 2001, 79, 1762–1774; (f)
Schmitzer, A. R.; Franceshi, S.; Perez, E.; Rico-Lattes, I.;
Lattes, A.; Thion, L.; Erard, M.; Vidal, C. J. Am. Chem.
Soc. 2001, 123, 5956–5961; (g) Chung, Y.-M.; Rhee,
H.-K. Chem. Commun. 2002, 238–239.
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I. Sato et al. / Tetrahedron: Asymmetry 13 (2002) 805–808
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